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CASE REPORT FORM

COMPLETION GUIDELINES

Protocol BETH / CIRG (TRIO) 011 / NSABP B-44-I/ BO20906A Multicenter Phase III Randomized Trial of Adjuvant Therapy for Patients with HER2-Positive

Node-Positive or High Risk Node-Negative Breast Cancer Comparing Chemotherapy plus Trastuzumab with Chemotherapy plus Trastuzumab plus Bevacizumab

BETH CRF completion guidelines of 120Version 2 Final Version Date: 10 Dec 2009

GENERAL INSTRUCTIONS FOR COMPLETING of THE CASE REPORT FORM

A- General Conventions

A Case Report Form (CRF) will be completed for each patient randomized in the study.

Do not duplicate data within the CRF (e.g. an adverse event listed in the cardiac adverse events section should not be recorded in the Adverse Event Running Log either).

Do not write outside of the margins or the area specified for your answer.

These forms should be printed legibly using black ball-point pen. Corrections on the CRF are to be made by crossing out the original entry with a single line, and initialing and dating the change.A CRF must not have erasures, overwrite, or the use of correction fluid.

Every page of the CRF is identified (header) with the following:- Project number (BETH Protocol): pre-printed- Site number : number provided by CIRG or NSABP (5 characters/ digits)- Patient number : number provided at randomization

Date fields are to be completed with a DD/MMM/YYYY format (e.g. 23 FEB 2006).- If day is unknown, record the date as: UK. MMM . YYYY- If day and month are unknown, record the date as: UK . UK . YYYY- If date is completely unknown, record it as: UNKNOWN

For other data, if the information is missing or incomplete, please record as UK (Unknown), NA (Not Applicable) or ND (Not Done).

If the CRF original is lost, it should be confirmed in writing: By the investigator if the original is lost by the site via a DCF By the monitor, in all other cases (after documented effort to retrieve it). In this case, a copy of the CRF page

in the Investigator’s CRF should be made, both the investigator and the monitor should certify that the copy is identical to the one at the centre. This copy then is considered an original.

B- Description of CRF segments

Different segments are designed to record the patient and disease status at different stages of the study.

Segment Timing Purpose CRF sectionBaseline Before the start of study

treatment.- To record the condition of the

patient prior to the start of study treatment.

- B1 to B11

Chemotherapy Cycle

With each chemotherapy cycle. One cycle is defined as the interval between 2 administrations of study chemotherapy, usually every 3 weeks.

- To record the patient status during study chemotherapy treatment.

- C1 to C5


Segment Timing Purpose CRF sectionEnd of

chemotherapyEnd of chemotherapy is defined as 2-3 weeks after the last dose of study chemotherapy infusion.

- To document the reason why study chemotherapy treatment was discontinued.

- EOC

Targeted Therapy Visit

With each targeted therapy following completion of chemotherapy. One visit is defined as the interval between 2 administrations of targeted therapy, usually every 3 weeks after the end of chemotherapy to complete a total of 1 year treatment since the first dose of targeted therapy including the targeted therapy given during the chemotherapy treatment.

- This segment is used to record the patient status during targeted therapy alone (ie trastuzumab and/or bevacizumab when the patient had discontinued study chemotherapy).

- V1 to V5

End of Targeted Therapy

End of targeted therapy is defined as the last study targeted therapy infusion.

- To document the reason why study targeted therapy treatment (trastuzumab +/- bevacizumab) was discontinued.

- EOT

Adjuvant Radiotherapy

- Log to record adjuvant radiotherapy received

- To record the dates, dose and site of adjuvant radiotherapy.

- AR

Adjuvant Endocrine Therapy

- Log to record adjuvant endocrine therapy received

- To record the drugs, doses and dates of administration of adjuvant endocrine therapy.

- AET

Follow up - Every 6 months from the end of Targeted Therapy to 5 years and then every year for years 6-10.

- To record the disease status of the patient after study chemotherapy and study targeted therapy is completed.

- FU.1 to FU.3

Breast Cancer Relapse

- To document breast cancer relapse

- To record date, sites of breast cancer relapse as well as documentation of relapse.

- BCR

Second Primary Malignancy

- To document second primary malignancy

- To record date, type of second primary malignancy experienced as well as documentation of malignancy.

- SPM

Survival Follow up

- Every 6 months from the end of Targeted Therapy to 5 years and then every year for years 6-10.

- To record overall survival patient status after the patient experienced a breast cancer relapse or second primary malignancy treated with a systemic anti-cancer treatment.

- SURVIVAL

Adverse Event Running Log

- One form per adverse event

- To record adverse event (except cardiac AEs) .

- AE running log

Significant Concomitant MedicationsRunning Log

- One entry per concomitant medication

- To record significant concomitant medication received by the patient at any time during the course of the trial.

- CON MED (Running Log)


Segment Timing Purpose CRF sectionDeath Report

Form- Patient’s death - To record date and cause of

death- DEATH

Sub-Studies consent

withdrawal

- For patients who have withdrawn their consent (serum/plasma and tissue)

- To record the date of withdrawal of the Patient Informed Consent related to the serum/plasma, tissue samples

SCW_BS and SCW_TS

Serum and Plasma sample

log

- At each time point required by the protocol

- For patients who have consented to, please record the date of collection of each sample during the treatment; follow up and in case of any cardiac event according to protocol and breast recurrence

S_TP S_FUP S_CAR

P_TP P_FUP P_CAR

DNA Repository Blood sample

collection

- For the patients who have consented to the DNA sample

- To record the date of the informed consent and in case of consent withdrawal to record the date of withdrawal of the Patient Informed Consent related to DNA sample

- For patients who have consented to, please record the date of collection of the blood sample

BCS_AS

Lost to Follow up

- For the patients potentially lost to follow up

- To document in the medical records and the patients CRF the attempts performed by the site to re-establish contact with the patients potentially lost to follow up

LOST TO FOLLOW-UP

CRF pages will be 4 Part NCR, except AE running log, Concomitant Medications Running Log and Adjuvant endocrine therapy that will be 5 Part NCR.White and yellow pages are for Data Management, Pink page is for CRA, Golden page (when it exists) will be retrieved at time of analysis, upon CIRG request; Cardboard will stay at the site.

C- Use of CRF segments

All randomized patients will have at least a “baseline”, an “end of chemotherapy” and an “end of targeted therapy” segment completed.

In addition, all patients who receive at least one dose of any chemotherapy drug will have a “chemotherapy cycle” completed.

Cycles

One cycle is defined as the interval between 2 administrations of study chemotherapy, usually every 3 weeks. Each cycle will be numbered in ascending order.

The data reported on each cycle segment (except AE running log and concomitant medications running log) corresponds to the information regarding events or procedures that occurred within the same treatment cycle.


Example:

Date of study chemotherapy infusion:

Cycle 1 Cycle 2 Cycle 3 Cycle 4 …..

Date 01 JAN 01 22 JAN 01 12 FEB 01 05 MAR 01

After the first study drug infusion, the physical examination, hematology, blood chemistry and cardiac assessment, performed prior to the second study drug infusion on 22 JAN 01 should be recorded in cycle 1

End of Chemotherapy Treatment

The end of chemotherapy treatment segment is to be completed once study chemotherapy is discontinued. The visit will take place 2-3 weeks after the last administration of study chemotherapy.

Targeted Therapy Visits

A visit is defined as the interval between 2 administrations of targeted therapies (following completion of the study chemotherapy) usually every 3 weeks. Each visit will be numbered in ascending order.

The data reported in each visit segment (except AE running log and concomitant medications running log) corresponds to the information regarding events or procedures that occurred within the same treatment visit.

End of Targeted Therapy

The end of targeted therapy segment is to be completed once study targeted therapy is discontinued.

Example: A patient in TCHB regimen discontinues docetaxel after 2 cycles because of docetaxel toxicity. She gets two administrations of trastuzumab and bevacizumab alone, decides to withdraw consent to study treatment and agrees to be followed. She relapses 8 months later and gets a systemic anti-cancer treatment; she dies 3 years after relapse. The following segments will be completed: - Baseline- Cycle 1 and Cycle 2 : docetaxel, carboplatin, trastuzumab and bevacizumab- End of Chemotherapy- Visit 1 and Visit 2 : trastuzumab and bevacizumab only- End of Targeted Therapy - FUP 1 (before relapse)- FUP 2 (at the time of the relapse)- Breast Cancer Relapse- Survival FUP1, Survival FUP2 and Survival FUP3- Death Report Form

Extra Forms

These pages are provided to give details of certain findings and should be placed at the end of the appropriate segment, as needed. For these pages please tick the box indicating the applicable segment.

In general, extra forms are provided for data points where multiple entries may create the need for additional pages.


TABLE OF CONTENTSGENERAL INSTRUCTIONS FOR COMPLETING OF THE CASE REPORT FORM ..........................................................2

COVER PAGE....................................................................................................................................................................................2

BASELINE ......................................................................................................................................................................................2

B.1................................................................................................................................................................................................2PATIENT INFORMATION..........................................................................................................................................................2

B.2................................................................................................................................................................................................2BREAST CANCER SURGERY AND DIAGNOSIS........................................................................................................................2

B.3................................................................................................................................................................................................2HER2 NEU STATUS.................................................................................................................................................................2HORMONAL RECEPTOR STATUS............................................................................................................................................2

B.4................................................................................................................................................................................................2SIGNIFICANT MEDICAL HISTORY............................................................................................................................................2PHYSICAL EXAMINATION AND OTHER CLINICAL PARAMETERS.............................................................................................2

B.5................................................................................................................................................................................................2CARDIOVASCULAR HISTORY..................................................................................................................................................2LEFT VENTRICULAR EJECTION FRACTION.............................................................................................................................2ELECTROCARDIOGRAM..........................................................................................................................................................2

B6.................................................................................................................................................................................................2HEMATOLOGY.........................................................................................................................................................................2URINE PROTEIN......................................................................................................................................................................2

B.7................................................................................................................................................................................................2BLOOD CHEMISTRY................................................................................................................................................................2

B.8................................................................................................................................................................................................2BREAST IMAGING....................................................................................................................................................................2OTHER IMAGING.....................................................................................................................................................................2

B.9................................................................................................................................................................................................2OTHER CRITERIA....................................................................................................................................................................2

B.10-B.11......................................................................................................................................................................................2OTHER CRITERIA....................................................................................................................................................................2

CHEMOTHERAPY CYCLE..................................................................................................................................................................2

C.1................................................................................................................................................................................................2CHEMOTHERAPY CYCLE........................................................................................................................................................2

C1.A.............................................................................................................................................................................................2CHEMOTHERAPY CYCLE........................................................................................................................................................2

C1.B.............................................................................................................................................................................................2CHEMOTHERAPY CYCLE........................................................................................................................................................2

C.2................................................................................................................................................................................................2HEMATOLOGY.........................................................................................................................................................................2URINE PROTEIN......................................................................................................................................................................2

C.3................................................................................................................................................................................................2BLOOD CHEMISTRY................................................................................................................................................................2

C.4................................................................................................................................................................................................2PHYSICAL EXAMINATION AND OTHER CLINICAL PARAMETERS.............................................................................................2

C.5................................................................................................................................................................................................2CARDIAC TOXICITY MONITORING FORM................................................................................................................................2

E.O.C............................................................................................................................................................................................2END OF CHEMOTHERAPY REASON........................................................................................................................................2CASE REPORT FORM REVIEW................................................................................................................................................2

TARGETED THERAPY VISIT..............................................................................................................................................................2

V.1................................................................................................................................................................................................2TRASTUZUMAB/BEVACIZUMAB ADMINISTRATION..................................................................................................................2

V.2................................................................................................................................................................................................2HEMATOLOGY.........................................................................................................................................................................2URINE PROTEIN......................................................................................................................................................................2

V.3................................................................................................................................................................................................2BLOOD CHEMISTRY................................................................................................................................................................2

V.4................................................................................................................................................................................................2BREAST IMAGING....................................................................................................................................................................2


PHYSICAL EXAMINATION AND OTHER CLINICAL PARAMETERS.............................................................................................2V.5................................................................................................................................................................................................2

CARDIAC TOXICITY MONITORING FORM................................................................................................................................2E.O.T............................................................................................................................................................................................2

END OF TARGETED THERAPY................................................................................................................................................2CASE REPORT FORM REVIEW................................................................................................................................................2

AR ....................................................................................................................................................................................................2

ADJUVANT RADIOTHERAPY.........................................................................................................................................................2ADJUVANT RADIOTHERAPY REVIEW...........................................................................................................................................2

AET ..................................................................................................................................................................................................2

ADJUVANT ENDOCRINE THERAPY..............................................................................................................................................2ADJUVANT ENDOCRINE THERAPY REVIEW................................................................................................................................2

AE RUNNING LOG.............................................................................................................................................................................2

ADVERSE EVENT.........................................................................................................................................................................2

CONMED RUNNING LOG ...........................................................................................................................................................2

SIGNIFICANT CONCOMITANT MEDICATIONS...............................................................................................................................2

FOLLOW UP VISIT.............................................................................................................................................................................2

FU.1..............................................................................................................................................................................................2PHYSICAL EXAMINATION........................................................................................................................................................2CASE REPORT FORM REVIEW................................................................................................................................................2

FU.2..............................................................................................................................................................................................2BREAST IMAGING....................................................................................................................................................................2

FU.3..............................................................................................................................................................................................2CARDIAC TOXICITY MONITORING FORM................................................................................................................................2

SURVIVAL ......................................................................................................................................................................................2

SURVIVAL FOLLOW-UP................................................................................................................................................................2CASE REPORT FORM REVIEW.....................................................................................................................................................2

BCR..................................................................................................................................................................................................2

BREAST CANCER RELAPSE.........................................................................................................................................................2

SPM .................................................................................................................................................................................................2

SECOND PRIMARY MALIGNANCY................................................................................................................................................2

SERUM AND PLASMA SAMPLE LOG .....................................................................................................................................2

SCW_BS .........................................................................................................................................................................................2

SUB STUDIES CONSENT WITHDRAWAL (BLOOD)........................................................................................................................2

SCW_TS .........................................................................................................................................................................................2

SUB STUDIES CONSENT WITHDRAWAL (TISSUE)........................................................................................................................2

DEATH ............................................................................................................................................................................................2

DEATH REPORT FORM................................................................................................................................................................2

EXTRA FORMS..................................................................................................................................................................................2

1) EF1 / ANTI-TUMOR THERAPY OTHER THAN FOR BREAST CANCER RELAPSE OR SECOND PRIMARY MALIGNANCY.............22) EF2...........................................................................................................................................................................................2HEMATOLOGY.............................................................................................................................................................................2URINE PROTEIN...........................................................................................................................................................................23) EF 3 /BLOOD CHEMISTRY........................................................................................................................................................24) EF 4..........................................................................................................................................................................................2ELECTROCARDIOGRAM...............................................................................................................................................................2LEFT VENTRICULAR EJECTION FRACTION..................................................................................................................................2BLOOD PRESSURE......................................................................................................................................................................25) EF 5 / CARDIAC ADVERSE EVENTS (CHEMOTHERAPY VISIT):.................................................................................................26) EF 6 / CARDIAC ADVERSE EVENTS (TARGETED THERAPY VISIT):..........................................................................................27) EF 7 / CARDIAC ADVERSE EVENTS (FOLLOW-UP/SURVIVAL FOLLOW-UP):.............................................................................2


APPENDIX.........................................................................................................................................................................................2

APPENDIX 1.................................................................................................................................................................................2DEFINITION OF THE MOST COMMON SURGERIES......................................................................................................................2APPENDIX 2.................................................................................................................................................................................2HISTOLOGICAL TUMOR TYPE DICTIONARY.................................................................................................................................2APPENDIX 3.................................................................................................................................................................................2POST-SURGICAL HISTOPATHOLOGICAL CLASSIFICATION (PTNM)..............................................................................................2ACCORDING TO AJCC CANCER STAGING MANUAL VERSION 6.................................................................................................2APPENDIX 4.................................................................................................................................................................................2PERFORMANCE STATUS.............................................................................................................................................................2COMPLETE PHYSICAL EXAMINATION..........................................................................................................................................2APPENDIX 5.................................................................................................................................................................................2BSA CALCULATION AND CONVERTING TABLE..............................................................................................................................2


COVER PAGE

This page will not be monitored and will not be collected.

Investigator’ name: the investigator’s name be reported could be either the name of the principal investigator or the name of the sub/co-investigator, who will follow the patient.

Site number: the site number is the number attributed to the site where the patient was randomized.

Randomization number, randomization arm, for the 18 month observation period: those information are given at the time of randomization (reported on the ID-net randomization confirmation document received at the site).

BETH CRF completion guidelinesVersion 2 Final Version Date: 10 Dec 2009

BASELINE


B.1PATIENT INFORMATION

Patient Date of Birth:Enter the patient’s date of birth. Please note that date format is dd/mmm/yyyy.Patient must be at least 18 years of age to participate.

Race:Please check one category only. If other, specify in space provided.Note : if Race can not been collected, please select “other : specify : unknown”

Sex:Indicate the sex of the patient. If the patient is a male, the patient is not eligible for the study.

Ethnicity:Please check one category only.Note In case Ethnicity can not been collected, leave the corresponding box blank.

Date of signature treatment consent form:Indicate the date the treatment informed consent was dated and signed by the patient.If the patient has signed two informed consents: a first allowing her tumor material to be sent to the central laboratory for HER2 evaluation and a second for the participation in BETH study specifically, the date of informed consent to be indicated in this field must be the date the informed consent regarding the participation in BETH study was signed.

Specify if patient has agreed to participate in the sub-studies by checking the appropriate boxes.If IRB/IEC refuses the translational research component of the BETH trial, check the box “no” for each of the questions related to the informed consent.

Properly written informed consent must be obtained before any study specific related procedures are performed.

To simplify the consent process, the patients are asked to provide combined consent for the translational research on their tumor and blood (serum, plasma) samples.When patients read the main BETH trial ICF, they will have already consented to the provision of a tumor sample for central HER-2 testing

For combined consent approach, equivalent consent for provision of blood samples is established by asking patients to respond to the following statement:

1: Patient consented to have blood samples collected kept for the research times described in the protocol : YES/NO” . If the answer to this question is “no” then the responses to questions 2 to 4 only corresponds to the tumor samples. If the answer to this question is “yes”, then the responses to questions 2 to 4 correspond to both tumor and blood samples (it is not possible to only consent to research using blood samples because the site is requesting the tumor block back).

Then patients are asked to provide combined (blood and tumor) consent to three different levels of Translational Research:2 Level 1 : Patients consented to have her blood and tumor samples for Research included in the BETH

trial protocol3 Level 2: Future research, not included in the BETH protocol, related to prevention, diagnosis and

treatment of cancer4 Level 3: Future research, not included in the BETH protocol, related to prevention, diagnosis and

treatment of diseases other than cancer

The consent must be progressive, that is: Patients cannot consent to Research Level 2 if not consented to Research Level 1 Patients cannot consent to Research Level 3 if not consented to Research Level 2


B.2BREAST CANCER SURGERY AND DIAGNOSIS

Primary tumor side:Check the appropriate box indicating which breast has been diagnosed with invasive cancer: left or right

Staging:Pathological TNM:

Please refer to the AJCC Cancer Staging Manual, 6th Edition 2002 (refer to Appendix 3). - Specify the pT, pN, M stage of the patient at study entry, according to the staging at first diagnosis. If pT = pTX, pT0 or pTIS, patient is not eligible.If pN = pNX, pN2b or pN3c, patient is not eligible. Note: If pN0, must also meet at least one of the following criteria:

Pathologic tumor size > 2.0 cm; ER negative and PgR negative; Histologic and/or nuclear grade 2 (intermediate) or 3 (high); or Age < 35 years

If M = MX or M1, patient is not eligible.TNM staging must be source documented (the M staging can be evaluated by the investigator after appropriate investigations).Important Note regarding the pN staging : Need to be specific in the reporting of the staging to allow patient’s eligibility to be verified i.e do not tick pN1, pN2 or pN3 but check the sub-categories : pN1mi, pN1a, pN1b, pN1c, pN2a, pN2b, pN3a, pN3b, pN3c.

pT size (longest diameter):

Specify the pathologic size of the tumor (cm) by indicating the longest diameter of the tumor.

Additional conventions for determining the size of multifocal/multicentric lesions.

Definitions : - Multicentric = 2 separate nodules > 5 cm apart- Multifocal = 2 separate nodules < 5 cm apart

The distance of 5 cm is used because it is assumed that tumors within 5 cm have developed from the same ductal system and are therefore the “same” cancer whereas tumors > 5 cm apart have developed from different ductal systems and are therefore “different” cancers.

Of course, these are assumptions and there is a certain degree of error in this classification system.However, in both cases, the primary tumor size is the greatest diameter of the largest nodule.Example: Multifocal tumor with 2 nodules, 3.0 cm apart and nodule sizes of 1.0 cm and 1.5 cm should be recorded as a primary tumor size of 1.5 cm.

The only case when addition of measurements needs to be performed is when an excision has removed only part of a nodule. The subsequent surgery removes the remainder of that nodule. Two pathology reports are generated and the size of the two components are added together as follows to arrive at the primary tumor size: largest dimension (of one portion) + largest dimension (of the other portion)Example: Tumor in incisional biopsy : 1.5 x 1.2 x 1 cm, tumor in segmental resection : 1.5 x 1 x 0.8 cm

Largest (estimated) dimension = 1.5 + 1.5 = 3 cm

Histopathologic type:Check the appropriate box. If the box “other” is checked, specify the histopathologic type.Note: Infiltrating and Invasive are synonyms.

Histologic Grade (please refer to appendix 2):BETH CRF completion guidelines of 120Version 2 Final Version Date: 10 Dec 2009

Check the appropriate box to report the histological grade by referring to the AJCC Cancer Staging Manual, 6 th

Edition, 2002 (refer to Appendix 2).

In the case of mixed histological grades, record the highest grade (the least differentiated tumor type). Before checking the unknown box, please confirm with pathology department that histologic grade cannot be obtained.

Nuclear Grade : Check the appropriate box to report the nuclear grade.Enter grade (degree of differentiation) by referring to the AJCC Cancer Staging Manual, 6 th Edition, 2002 (refer to appendix 2). In the case of mixed nuclear grades, record the highest grade (the least differentiated grade)

Date of Most Recent Surgery:Enter the date of the most recent breast cancer surgery.Breast Cancer Surgeries:Check the appropriate box(es) for the surgery(ies) performed for breast cancer (refer to appendix 1)Report all that apply, ie breast conserving surgery and/or mastectomy and/or margins resection.Specify for the breast conserving surgery and the mastectomy, the status of the margins:

For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. (Patients with margins positive for lobular carcinoma in situ [LCIS] are eligible without additional resection).

For patients who undergo mastectomy, margins must be free of gross residual tumor. Patients with microscopic positive margins are eligible.

Patients with positive margins after first diagnosis must undergo another adequate resection with clear margins in order to be eligible for the study. The margins resection surgery should be reported in the breast cancer surgeries section and its date should be the one recorded as the date of the most recent surgery.

Date of Axillary Node Staging:Enter the most recent date of the axillary node staging assessment (either date of axillary node dissection or date of sentinel node biopsy, ie date of the procedure itself and not the date of the report).

Note : The interval between the last surgery for breast cancer (treatment or staging) and randomization must be at least 28 days but not more than 84 days.Total number of nodes removed:Enter the total number of nodes removed from all surgeries.If more than one node dissection was performed, the total number of lymph nodes resected is to be reported.

Total number of nodes positive:

Enter the total number of positive nodes from all nodal dissection procedures/surgeries.


B.3HER2 NEU STATUS

Was local testing performed?Indicate whether or not local testing was performed.If no, check the “no” box and do not complete the remainder of the section.If local testing was performed, complete the subsequent sections.

Method:Indicate the method performed locally to determine the HER2 status: In Situ Hybridization or IHC or both.

- In Situ Hybridization (ie FISH, CISH or other In Situ Hybridization method):Indicate the date the testing was performed.Results: Indicate the result of the In Situ Hybridization test: positive, negative or equivocal.

If the results are negative at the local level, the sample should not be sent to the Central Lab for duplicate testing, except if IHC is 2+ or 3+. However, with an equivocal result the sample can be sent to the Central Lab.

- IHC:Indicate the date the testing was performedResults: Indicate the results of the IHC: 0, 1+, 2+ or 3+.

If the results are 0 or 1+, at the local level, the sample should not be sent to the Central lab for duplicate testing, except if in situ hybridization is positive or equivocal.Note : if several tests have been performed and different dates are available the date of 1st positive result should be reported.

Central testingUsing the HER2 screening form completed by the central laboratory, please indicate - the date the testing was performed,(this date can be located in the fax sent by IDDI or in the ID-net screen for

each patient).- the test(s) that was(were) performed (FISH and/or IHC)- the results of the performed test(s):

- FISH:Results: Indicate the result of the FISH test: positive, negative or not assessable

- IHC:Results: Indicate the results of the IHC: 0, 1+, 2+ or 3+

If FISH results are negative or not assessable and the results of IHC were 0, 1+ or 2+ at the central level, the patient is not eligible. If : - the FISH is positive and ICH of 0, 1+/ 2+ or - the FISH is negative/not assessable and IHC 3+

then the patient is eligible.

Note : all the tests should be preferably done on the primary tumor.

HORMONAL RECEPTOR STATUS

Estrogen receptors – progesterone receptors:According to the protocol, estrogen receptor must always be assessed; progesterone must be assessed if estrogen receptor is negative. If the estrogen receptor was not assessed, the patient is not eligible.For each test (Estrogen and Progesterone), enter the date the test was performed and the result from the test positive, negative, not assessed (only one box to be ticked).

The box “Not assessed” should be ticked either if it is not possible to assess the receptor status correctly (in this case the date of the test is to be reported) or in case the test was not performed (date of test to be left blank). Per convention, if the result is borderline, the box “positive” should be ticked.BETH CRF completion guidelines of 120Version 2 Final Version Date: 10 Dec 2009

B.4SIGNIFICANT MEDICAL HISTORY

Any significant and relevant medical history?Indicate if any significant medical/surgical history and concomitant medical conditions other than those related to the breast cancer and exclude those of a cardiovascular etiology existing at study entry (Cardiovascular medical history will be recorded on page B.5).If no, check the “no” box and do not complete the remainder of the section.If yes, tick the “yes” box and complete the remainder of the section.- For each of the pre-printed conditions, indicate whether or not they constitute patient’s medical history by ticking the “yes” or the “no” box and whether they are ongoing or ceased at the time of study entry.- For the non pre-printed conditions, use a blank line and report the appropriate medical term (preferably NCI term).Note : If additional pages are required, please make a copy of the blank page and rename it as B4a, B4b, etc. (in this case all the questions corresponding to the physical examination and other clinical parameters should be answered with” no”)

Description:- Use concise medical terminology to describe any significant medical/surgical history other than breast

cancer in available space, if applicable.- Whenever possible, please list syndromes and not symptoms on this form.

Examples of significant medical history to be recorded on the “significant medical history” section:

- chronic conditions especially cardiovascular risk factors, relevant medical/surgical history Examples of non-significant medical history NOT to be recorded on the “significant medical hi story” section:

- prior exposure to birth control pills- pregnancies, caesarean-sections, abortions….- childhood diseases and surgeries (amygdalectomy, appendectomy)

Ceased/ongoing :Indicate if the condition was ongoing or ceased before the first study drug administration. If during the study there is a significant worsening of any ongoing condition listed on this from, it must be recorded as an adverse event on the AE running log. Per convention, the start date will be the date of worsening and the stop date the date the condition returned to baseline status.

Note: In case “ongoing” or “ceased” is not relevant (ex: in case of surgeries), the box “ceased” should be ticked.

PHYSICAL EXAMINATION AND OTHER CLINICAL PARAMETERS

Record the most recent evaluation prior to randomization in the study. Physical examination is required within 28 days prior to randomization.Was a physical examination performed?Indicate whether or not a physical examination was performed.If no, check the “no” box and do not complete the remainder of the section.If yes, specify the date of assessment.

Were vital signs assessed?Indicate whether or not vital signs were assessed.If no, check the “no” box and do not complete the remainder of the section.If yes, specify the date of assessment, as well as the height, weight and blood pressure value.

- Height:Enter the patient’s height in centimeters. This value should be used for dose calculation.

- Weight:


Enter the patient’s weight in kilograms. This value should be used for dose calculation.

- Blood Pressure:Record the diastolic and systolic values in mmHg.Note : please use extra forms to record BP just before cycle 1 administration in case the one recorded to randomize the patient is more than 3 days before day 1 of cycle 1Was ECOG Performance Status assessed?If no, check the “no” box and do not complete the remainder of the section.If yes, please indicate:- Date of assessment:Indicate the date ECOG performance status was assessed.- ECOG Performance Status:Indicate the ECOG Performance Status value. If the ECOG PS > 1, the patient is not eligible. ECOG value must be documented in the source documents. If the ECOG value is not documented, the

investigator has to assess it according to the source documents and the notes of the physical examination (a performance status could be retrospectively attributed and source documented).

If another scale is routinely used at the site (e.g. Karnofsky), the site can use the conversion table from the protocol (refer to Appendix 4) to convert the Karnofsky value into the ECOG value.


B.5CARDIOVASCULAR HISTORY

Is there any history of or any current cardiovascular condition?Indicate whether or not the patient had any history or current cardiovascular condition.

If no, check the “no” box and do not complete the remainder of the section.If yes, tick the “yes” box and complete the remainder of the section.

- For each of the pre-printed conditions: if they were experienced by the patient, indicate grade, ongoing or ceased and whether or not there were any medication given to treat the disease. If they were not experienced by the patient, please do not enter any information in the corresponding event.- For the non pre-printed conditions, report the appropriate term (preferably NCI term) as well as its grade, ongoing or ceased and whether or not there were any medication given to treat the disease.

Description:For Left Ventricular Systolic Dysfunction and Left Ventricular Diastolic Dysfunction, specify the NYHA Class (1-4) using Appendix B of the protocol.

Grade:Enter 1-4, when appropriate by using the NCI Toxicity Grading, otherwise use the severity code defined below:

1- mild : generally non-progressive, producing a minimal degree of tolerable discomfort2- moderate : may adversely affect normal daily activity, but is not completely incapacitating3- severe : marked intensity, may be either totally incapacitating or results in significant decrease in normal

daily activity4- life threatening : the patient was at immediate risk of death as the AE occurred. It does not include an

event that, had it occurred in a more serious form, may have caused death.

The NCI Toxicity Grading System used in BETH is NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.Note regarding the hypertension reporting:

At baseline and as per study convention, hypertension is graded according to the NCI classification even if it is well controlled at that time and even if study treatment did not yet start. This means that

- a patient not treated by an antihypertensive therapy would be reported as “hypertension grade 1”- a patient treated with antihypertensive monotherapy would be reported as “hypertension grade 2”- a patient being under anti-hypertensive treatment requiring more than one drug would be reported as

“hypertension – grade 3 – ongoing”. During the cycles/targeted therapy visits we are following at each visit all events reported as ongoing in the cardiovascular medical history and are also capturing the BP values.

Ongoing or Ceased:Indicate if the cardiac condition was ongoing or ceased at the time of the first study drug administration.

- Ongoing conditions must be reported and followed by the physician during study treatment using the “Cardiac Toxicity Monitoring Form”. This means that each ongoing cardiovascular history including controlled hypertension should be reported on C5, V5, FU3 (and if necessary EF5, EF6 and EF7) as long as the condition is not ceased.

Medication to Treat Disease:Indicate if the patient is currently receiving medication to treat this cardiac disease.If “yes” and the cardiovascular history is reported as “ongoing”, complete the concomitant medication running log.In this case, the column” Medication to Treat Disease” should be completed with code = 1


LEFT VENTRICULAR EJECTION FRACTION

To be performed within 3 months prior to randomization.

Was a LVEF performed?If no, check the “no” box and do not complete the remainder of the section. (The patient is not eligible.)If yes, please indicate:

- Date of Assessment:Enter the date of assessment of the most recent left ventricular ejection fraction at rest.

- LVEF at rest:LVEF at rest must be performed either with radionuclide angiocardiography (MUGA scan) or echocardiography. Echocardiography is the preferred method for determining the LVEF value. Indicate which method was used.If the LVEF has been assessed by both methods (radionuclide angiocardiography and echocardiography), report the results of both of them. It is strongly advised that LVEF is measured using the same method (MUGAs or echocardiographies) and that is determined at the same radiology facility and by the same team throughout the study.

-Value:Indicate the value of the LVEF at rest (%) as a numerical value which is a whole number. If the value in the source document is not a whole number, decimals reported as >5 should be rounded up and decimals reported as <5 should be rounded down.For example, a LVEF value of 54.5% will be rounded up and reported as 55%; a LVEF of 54.4% will be rounded down and reported as 54%.If the facility performing the assessment will only report the LVEF as a range, the mean (average) of the values used for the range should be calculated by the investigator and entered into patient’s medical charts so that a single numerical value can be reported. For example a range of 50- 55will have to be reported as 53 (since 52.5 is to be rounded-up).

The value of LVEF must be greater or equal than 55%, otherwise the patient is not eligible If the LVEF is greater than 70%, a review of the LVEF to confirm the accuracy or a repeated LVEF is recommended if the accuracy is uncertain. The reason is to avoid a false drop in LVEF.

ELECTROCARDIOGRAM

To be performed within 3 months prior to randomization.

Indicate if an electrocardiogram was performed.If no, check the “no” box and do not complete the remainder of the section. (The patient is not eligible.)If yes, please indicate:Date of assessment: Enter date electrocardiogram was performed and not the date of the report.


B6HEMATOLOGY

To be performed within 6 weeks prior to randomization, post surgery (please record the most recent prior to randomization).

Were lab tests performed?Indicate whether or not lab tests were performed.If no, check the “no” box and do not complete the remainder of the section. (The patient is not eligible).If yes, tick the “yes” box and complete the remainder of the section.

- Date of sample: Enter the date the hematology sample was taken rather than the date of the report.If between randomization and first infusion, additional hematology tests were performed, they should be recorded only if abnormal values were observed and should be documented using extra forms (EF2). In this case, infusion is to be given only once values are back to the normal. In case the hematology parameters were performed at different dates, report the ones corresponding to each different date in different sections.

- Value:Enter laboratory results. Do not convert. Use the same values as source documents.

- Actual Units:If the units are the same as the recommended ones, leave the actual units blank.If test units are different from the pre-printed recommended units, enter the actual unit in the appropriate column. The units recorded should therefore correspond to the units used on the source documents.

URINE PROTEIN

Urine protein should be tested within 6 weeks prior to randomization, post surgery by determination of the urine protein creatinine (UPC) ratio or by urine dipstick (please record the most recent prior to randomization).Was a Urine Protein test performed?Indicate whether or not a urine protein test was performed.If no, check the “no” box and do not complete the remainder of the section. (The patient is not eligible).If yes, tick the “yes” box and complete the remainder of the section.

- Date of sample:Enter the date the UPC or urine dipstick was done.

Method :Please indicate which method has been used (UPC ratio or urine dipstick)

- Dipstick value:Enter the result of the dipstick value (negative, trace, 1+, 2+, 3+ or 4+)If dipstick value is 2+, 3+ or 4+, a UPC ratio or a 24-hour urine collection is required.

- UPC ratio (see Appendix 7)Enter the UPC ratio.The UPC ratio is obtained by dividing the urine protein by the urine creatinine: Total urine protein (or urine albumin) ÷ urine creatinine = UPC ratioIf UPC ratio is ≥ 1.0, the patient is not eligible.Enter the result as the value with 2 decimal placesTo be completed only if dipstick method is used and value > or equal to 2 :


Was the UPC ratio performed?Indicate whether or not a UPC ratio was performed.If no, check the “no” box and do not complete the remainder of the section. If yes, tick the “yes” box and complete the remainder of the section.If UPC ratio ≥ 1, the patient is not eligibleEnter the result as the value with 2 decimal places.

Was a 24-hour urine collection performed?Indicate whether or not a 24-hour urine collection was performed.If no, check the “no” box and do not complete the remainder of the section. If yes, tick the “yes” box and complete the remainder of the section.Note that this question must be checked even if the urine protein was normal at the question above.

- Date of 24-hour urine collection:Enter the date the urine collection was started.

- Total protein: Report the total protein value in g/24 hours.If total protein ≥ 1g/24 hours, the patient is not eligible.In case the collection was incomplete do not report at all and indicate as not done.If additional urine protein evaluations were performed, they should be reported on page EF2.


B.7BLOOD CHEMISTRY

To be performed within 6 weeks prior to randomization, post surgery (please record the most recent prior to randomization).

Were lab tests performed?Indicate whether or not lab tests were performed.If no, check the “no” box and do not complete the remainder of the section. (The patient is not eligible).If yes, tick the “yes” box and complete the remainder of the section.

- Date of sample: Enter the date the blood chemistry sample was taken rather than the date of the report.If between randomization and first infusion, blood chemistry tests were performed, they should be recorded only if abnormal values were observed, and are documented by using extra forms (EF3). In this case, infusion is to be given only once values are back to the normal.In case the blood chemistry parameters were performed at different dates, report the ones corresponding to each different date separately - Value:Enter laboratory results. Do not convert. Use the same values as source documents.

Note for the creatinine clearance : Please report the measured clearance (or calculated using the Crockroft and Gault formula if not measured). The capping of clearance will not be recorded nor will the upper normal limit (UNL).

- Actual Units: If the units are the same as the recommended ones, leave the actual units blank.If test units are different from the pre-printed recommended units, enter the actual unit in the appropriate column. The units recorded should therefore correspond to the units used on the source documents.

- Upper normal limit for the institution:Enter for each test that was performed the upper normal limit for the institution (except for the upper normal limit for creatinine clearance). Unit of the upper normal limit for the institution should be the same as unit of the value.


B.8BREAST IMAGING

To be performed within 6 months prior to randomization (pre or post surgery).

Did the patient have breast imaging?Report whether or not the patient had Breast Imaging by indicating Yes or No.If no, check the “no” box and do not complete the remainder of the section. (The patient is not eligible).If yes, tick the “yes” box and complete the remainder of the section.

- Date of Assessment: Report only the date of the most recent test that was performed to check patient’s eligibility.Please report the breast imaging performed to rule-out tumor involvement in the contralateral breast-Site of Breast Imaging:The intent of this module is to exclude tumor involvement in the contralateral breast and does not apply to the site of the primary breast cancer.This means that the site of breast imaging should always be the side of the contralateral breast even if the breast imaging was bilateral (do not tick “left and right”).Example : A patient was diagnosed with a breast cancer during her annual bilateral mammogram performed on 10 Feb 2008

Tumor involvement: Left breast: positive Tumor involvement: Right breast: negative

Left Mastectomy on 24 Mar 2008.

-Type of exam:Select and Indicate the exam (only one) that was performed for assessing the breast status (mammography, MRI or other; if other, please specify the type of exam).Must be mammogram or MRI; (MRI only allowed before study entry); if another method is used, the patient is not eligible.

-Tumor involvement (applies only to the contralateral breast)Check either “yes” or “no”. If the Breast Imaging demonstrates tumor involvement “yes” in the contralateral breast, patient is not eligible.


OTHER IMAGING

Other radiological imaging must be performed within 3 months of randomization and is required in the following situations:

- Patients with AST or alkaline phosphatase ULN are eligible for inclusion in the study if liver imaging (CT, MRI, PET scan or PET-CT scan performed within 3 months prior to randomization) does not demonstrate metastatic disease and the requirements in criterion 4.2.15 are met.

- Patients with alkaline phosphatase that is ULN but 2.5 x ULN are eligible for inclusion in the study if a bone scan PET scan or PET-CT scan (performed within 3 months prior to randomization) does not demonstrate metastatic disease.

Did the patient have any other imaging performed?

Report whether or not the patient had any other imaging (other than breast imaging) by indicating Yes or No.If no, check the “no” box and do not complete the remainder of the section. If yes, tick the “yes” box and complete the remainder of the section.For each type of evaluation, please indicate:

- “Not done”: tick the box “not done” for each evaluation that was not done;- If evaluation was performed, please report the date of assessment and the tumor involvement (yes or

no)If tumor involvement is “yes”, the patient is not eligible.

If PET-scan is performed, it is considered as a Whole Body PET-scan.If a PET-CT scan is performed, please tick “other” and specify.Note : If more than one non pre-printed other imaging is performed please make a copy of the blank page and rename it as B8a; etc...


B.9OTHER CRITERIA

PAST OR CURRENT HISTORY OF NEOPLASM

Questions 1-8:Check the appropriate box “yes” or “no” for each question.If “any question n°1 to 8 is answered by “yes”, the patient is not eligible. The only exception would be for question 5 if the specified malignancy is one of the protocol accepted one (see protocol section 4.3.5). In any case, if this question 5 is answered with “yes” the specification should be indicated.

MENOPAUSAL STATUS

Please indicate whether the patient is pre or postmenopausal by checking the appropriate box.Menopausal status should be source-documented if possible or derived from the source documents using the following criteria for postmenopausal women:

Age 56 or older with no spontaneous menses for at least 12 months prior to study entry, or

Age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) AND with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard, or

A prior documented bilateral oophorectomy.Women failing to meet one of these criteria will be classified as pre-menopausal.

CHILDBEARING POTENTIAL

Date of last menses:Indicate the month and year of last menses prior to the first study drug administration.- Month is especially required when patient had her last menses within the previous year prior to randomization in order to confirm the menopausal status of the patient.

Questions 1-4:

Question 1 – Is the Patient of childbearing potential?Check the appropriate box (yes or no)

- If yes (patient is of childbearing potential), indicate the date of the negative pregnancy test (required within 14 days prior to randomization by the protocol) or tick the not done box if no pregnancy test was performed within 14 days of randomization (patient is not eligible).

Question 2 – Is the patient pregnant or lactating? To be answered in all cases whether the menopausal status is pre or postmenopausal.If yes, the patient is not eligible.

Question 3 – Is the patient using effective method of contraception? To be answered in all cases whether the menopausal status is pre or postmenopausal.If no and pre-menopausal, the patient is not eligible. If yes is checked for pre-menopausal woman, contraceptive measure must be documented in the patient chart.


Any hormonal contraception,), pills and “patch”, must be stopped before randomization, otherwise the patient is not eligible.

Question 4 – Is the patient receiving any sex hormonal therapy (e.g. birth control pills, ovarian hormone replacement therapy)?To be answered in all cases whether the menopausal status is pre or postmenopausal.If yes (ie treatment still received by the patient after randomization), the patient is not eligible.The patient is eligible if such treatments were stopped before randomization (no washout period is needed).Note : when an hormonal IUD is given and accepted (low dose), preconvention the answer should be “No”.Reminder:

According to the protocol, women of reproductive potential must agree to use an effective non-hormonal method of contraception (for example condoms, some intrauterine devices, diaphragms, vasectomized partner, or abstinence) during therapy and for at least 6 months after the last dose of bevacizumab and/or trastuzumab.


B.10-B.11OTHER CRITERIA

MEDICAL CONDITIONS

1. Has the patient had any of the following medical history?Check the appropriate box “yes” or “no” for each of the questions.If yes is ticked for any of the questions, the patient is not eligible.

2. Does the patient have any of the following active cardiac disease?Check the appropriate box “yes” or “no” for each of the questions.If yes is ticked for any of the questions, the patient is not eligible.

3. Has the patient had any of the following history of cardiac disease?Check the appropriate box “yes” or “no” for each of the questions.If yes is ticked for any of the questions, the patient is not eligible.

4. Has the patient had any psychiatric or addictive disorders or other conditions that in the opinion of the investigator would preclude the patient from meeting the study requirements?Check the appropriate box “yes” or “no”.If yes is ticked, the patient is not eligible.


CHEMOTHERAPY CYCLE


Docetaxel + Carboplatin (6 doses)

Trastuzumab (~17 doses)

Group 1A

18 weeks ~33 weeks

Docetaxel + Carboplatin (6 doses)

Trastuzumab + Bevacizumab (~17 doses)

Group 1B

18 weeks ~33 weeks

C.1CHEMOTHERAPY CYCLE

The numbering of chemotherapy cycle should start from 1.

To be completed only for the patients randomized in treatment arms 1A or 1B.

Note: For the patients randomized in the groups 2A and 2B, the header information should be completed and the page should be crossed out, dated and initialed and pages C1A and C1B should be used

One page has to be completed per chemotherapy /targeted therapy administration (corresponding to one cycle) for a maximum total number of 6 (as per protocol).

1) STUDY CHEMOTHERAPY ADMINISTRATION FOR TCH H / TCHB HB Regimen

This section should be completed to report the following chemotherapy regimen: docetaxel associated with carboplatin. Administration of trastuzumab and/or bevacizumab will be recorded in the Trastuzumab/Bevacizumab Administration section on the same page.

Docetaxel Pre-Medication Indicate if patient received docetaxel pre-medication as per the protocol by ticking the YES or NO box. Please note that the required pre-medications for docetaxel are indicated in section 8.6 of the protocol:

Dexamethasone 8 mg po BID the day before and the day of chemotherapy is recommended. At the physician’s discretion, dexamethasone may be continued on the day after chemotherapy. An equivalent dose of other corticosteroids may be substituted (dexamethasone 8 mg = methylprednisolone 40 mg = prednisone 50 mg = prednisolone 50 mg).

Administration of IV dexamethasone (dose at the investigator's discretion) as a substitute for oral dexamethasone prior to chemotherapy is at the investigator's discretion.

At the physician's discretion, other non-steroidal premedications, e.g., diphenhydramine hydrochloride 50 mg IV and H-2 blocker IV (cimetidine 300 mg, ranitidine 50 mg, or famotidine 20 mg) may be given in addition to dexamethasone.

Docetaxel pre-medications do not have to be recorded in the Concomitant Medications running log.This includes dexamethasone but also the non-steroidal premedication like cimetidine that may be given in addition to dexamethasone.Note : any other medication given with other intent such as antiemetic does need to be reported.

Administration date: Enter the date of infusion of docetaxel and carboplatin. If the chemotherapy was given on different days, please record the earliest of the two dates. BETH CRF completion guidelines of 120Version 2 Final Version Date: 10 Dec 2009

For each drug specify: Intended dose:

- Docetaxel: the dose expressed in mg/m² which is intended to be given to the patient according to the protocol (dose level according to table 11 of the protocol or dose reduced according to the guidelines related to the dose modifications) should be recorded.

- Carboplatin: the scheduled dose expressed in AUC (mg/mL/min) should be recorded according to the protocol (dose level according to table 11 of the protocol)

Total dose given: Record the actual dose administered in this cycle in mg. If the infusion of study drug was interrupted, record the total dose given (i.e. before and after interruption). In case the exact dose is not known, record the estimated one. Note that in case the total dose given is then less than planned this wouldn’t have to be reported as a reduction of the intended dose and therefore not to be reported as a dose reduction.

For Docetaxel: the dose should be calculated with the Baseline Body Surface Area and will not be recalculated for slight changes in BSA. BSA will be recalculated only if there is a 10% or greater change in body weight compared to Baseline (at the investigator’s discretion). No ideal body weight should be used for the calculated BSA.If the calculated BSA of the patient is > 2.2 m2, the dose to be given to the patient can be calculated according to a capped BSA = 2.2 m2.Rounding of drug doses is optional . If the treating physician decides to round the dose, it is recommended that the dose should be rounded to the nearest 5 mg.

For Carboplatin: the dose is calculated as total mg using a modified Calvert Formula as follows:

Total dose (mg) = (Target AUC) x (Creatinine Clearance + 25)The initial Target AUC = 6 mg/mL/min

The creatinine clearance must either be measured or estimated using the Cockroft-Gault formula as follows and the calculation of the creatinine clearance will be performed before each administration according to the most recent serum creatinine, i.e., the serum creatinine measured before each chemotherapy cycle.

Creatinine Clearance (mL/min) = = body weight (kg) x (140 – age in years) x 0.85 72 x serum creatinine (mg/dL)

Or

= body weight (kg) x (140 – age in years) x 0.85 815 x serum creatinine (mmol/L)

The creatinine clearance value may be capped at 110 mL/min, per investigator's discretion. Revised creatinine clearance value is the one to be used at each cycle according to the most recent serum creatinineRounding of drug doses is optional . If the treating physician decides to round the dose, it is recommended that the dose should be rounded to the nearest 10 mg.

If the laboratory performing creatinine testing utilizes Isotope Dilution Mass Spectrometry (IDMS)-traceable calibration methods, it is recommended that the following correction to the creatinine value be applied:Non-IDMS creatinine (mg/dL) = IDMS creatinine (mg/dL) x 1.065 + 0.067orNon-IDMS creatinine (mol/L) = IDMS creatinine (mol/L) x 1.065 + 5.92The result should then be rounded to one decimal place and used for estimation of creatinine clearance for the Cockcroft-Gault formula. (There is no change in the Calvert formula to calculate the actual carboplatin AUC dose based on GFR.) For additional information refer to: http://nkdep.nih.gov/labprofessionals/index.htm

Note : In order to make it easier for the sites, a carboplatin calculator is now available to assist the sites in calculating the carboplatin dose to be administered to the patient. Access is via www.beth-trial.org or through ID-Net website.


http://nkdep.nih.gov/labprofessionals/index.htm

Dose reduction: Indicate for each drug (docetaxel and/or carboplatin) if the dose has been reduced by ticking the “Yes” or “No” box at each cycle. Review the intended and total dose given of the drug in comparison to the previous cycle. In case of dose reduction, check the box “Yes” in the cycle the reduction occurs. The reason for dose reduction must be specified:

Adverse Event: this includes all AEs (hematological or non hematological) related or not related, cardiac or non cardiac.In case there has been an interruption due to an Adverse Event, the dose reduction box can be ticked and the corresponding AE must be reported on the AE running log or on the Cardiac Toxicity Monitoring Form.Examples: study drug related hematological abnormalities, coagulation abnormalities, fever in absence of infection with neutropenia, skin reactions, neurological adverse events….

If docetaxel or carboplatin dose was reduced due to an AE, the AE box should be ticked and the corresponding AE reported on the AE running log or on page C5 (Cardiac Toxicity Monitoring Form) with action taken “dose reduced”.

Other: If the “other” box is ticked, the reason should be specified.

Note regarding the reporting of error in calculating the doseIt should be reported only in case of dose reduction (and not in case of dose escalation) and if the actual dose given corresponds to a lower dose level as specified in the protocol (changes of dose level according to the protocol). For example, if the intended dose for docetaxel is 75 mg/m2 but by mistake the actual dose given corresponds to 60 mg/m2, dose reduction should be reported. But on the other hand if the planned dose is 75 mg/m2 but the actual dose given corresponds to 70 mg/m 2, no dose reduction should be indicated. However, the intended dose in both cases should remain 75 mg/m2.

Conventions: At cycle 1, the dose reduction will be recorded as “No”.

If the dose remains the same in the next cycles (no additional reduction), box “reduced” should be “No” in the next cycles. Please note that no dose re-escalation is allowed.

If there is a subsequent reduction, “reduced” will be noted as “yes” each time a new reduction occurs (with the reason specified).

In case of missed dose, the date to be reported as well as the intended dose are the theoretical ones and the dose to be reported is 000 mg.

Note: A reduction of the dose given due to a recalculation of the BSA does not constitute a reduction of the intended dose. No dose reduction should be recorded in such case.

Dose delay: Indicate, at each cycle if there was a delay in the administration of the chemotherapy regimen compared to the previous administration by ticking the “Yes” or “No” box. It is considered as a delay when the administration of the cycle n+1 occurs more than 21 + 3 days after the administration of cycle n (delay starts if case, the next administration occurs at D25) If there are less than 25 days between the administration of two subsequent cycles, delay should be noted as “no”.

Conventions:

At cycle 1, the dose delay will be recorded as “No” by convention.

If the “Yes” box is ticked, the reason of the delay must be specified:


1. Adverse Event: this includes all AEs (hematological or non hematological) related or not related, cardiac or non cardiac. Examples: study drug related hematological abnormalities, coagulation abnormalities, fever in absence of infection with neutropenia, skin reactions, neurological adverse events….

If the chemotherapy dose was delayed due to an AE, the AE box should be ticked and the corresponding AE reported on the AE running log or on page C5 (Cardiac Toxicity Monitoring Form) with action taken “dose delay/hold”.

2. Other: If the “other” box is ticked, the reason should be specified. Examples: Scheduling delay, holiday, administrative reason, etc.

2) TRASTUZUMAB / BEVACIZUMAB ADMINISTRATION This section should be completed to report the targeted therapy (ies) taken concomitantly with the chemotherapy.In case the targeted therapy is discontinued, nothing needs to be reported on the corresponding line but make sure the previous cycle indicated this discontinuation.

Administration date: Enter the date of infusion of trastuzumab +/- bevacizumab (for group 1A; tick the “Not Applicable” box for bevacizumab).

Intended dose: - Specify for trastuzumab +/- bevacizumab, the intended dose in mg/kg according to the protocol.- For trastuzumab: please note that the first dose is 8 mg/kg IV over 90 minutes with subsequent doses

being infused at 6 mg/kg IV over 30-60 minutes.

Total dose given: Record the actual dose administered in this cycle in mg.

Dose Delay/Hold Indicate, at each cycle if there was a delay/hold in the administration of the trastuzumab and/or bevacizumab by ticking the Yes or No box.It is considered a delay when the administration of the cycle n+1 occurs more than 21 + 3 days after the administration of cycle n (delay starts in case the next administration occurs at D25) If there are less than 25 days between the administration of two subsequent cycles, delay should be noted as “No”.It is considered as a “hold” when the administration of the target therapy will not occur at this given cycle. In this case, the date to be reported as well as the intended dose are the theoretical ones and the dose to be reported is 000 mg . Answer to question ‘Trastuzumab/Bevacizumab ongoing at the end of cycle?” should be ticked Yes(can be answered only once the cycle ends) .In case the targeted therapy has been discontinued, nothing needs to be reported on the corresponding line but make sure the previous cycle indicated this discontinuation.

Conventions: At cycle 1, record dose delay/hold as “No” by convention.

If the Yes box is ticked, the reason of the Delay/Hold must be specified:

1. Adverse Event: this includes all AEs (hematological or non hematological) related or not related, cardiac or non cardiac.

Examples: study drug related hematological abnormalities, coagulation abnormalities, fever in absence of infection with neutropenia, skin reactions, neurological adverse events….

If trastuzumab and/or bevacizumab was delayed or held due to an AE, the AE box should be ticked and the corresponding AE reported on the AE running log or on page C5 (Cardiac Toxicity Monitoring Form). If delayed, ensure AE reported has action taken “dose delay/hold”.

2. Other: If the “other” box is ticked, the reason should be specified. Examples: Investigator’s decision, patient request….


Note:If trastuzumab is held, trastuzumab should be resumed at 6 mg/kg. At the physician’s discretion, a loading dose of 8 mg/kg may be given followed by the continuation of the maintenance dose of 6 mg/kg for the remaining doses.

Rounding of drug doses is optional .If the treating physician decides to round the dose it is recommended that the dose should be rounded:

- For bevacizumab : to the nearest 25 mg- For trastuzumab : to the nearest 20 mg.

Trastuzumab/Bevacizumab ongoing at the end of the cycle?: Indicate by ticking the Yes or No box if the trastuzumab or bevacizumab was still being given at the end of the cycle.If the No box was ticked for either targeted therapy, the reason for the discontinuation should be reported on the End of Targeted Therapy (EOT) CRF page.

Note:- If trastuzumab is discontinued: bevacizumab should be discontinued- If trastuzumab is held, bevacizumab should be held.- If bevacizumab is discontinued/held, administration of trastuzumab could continue.


Docetaxel (3 doses)

Trastuzumab (3 doses)

Group 2A FEC (3 doses)

Trastuzumab (~14 doses)

9 weeks 9 weeks ~42 weeks

Docetaxel (3 doses)

Trastuzumab + Bevacizumab (3 doses)Group 2B

FEC (3 doses)

Trastuzumab + Bevacizumab (14 doses)

9 weeks 9 weeks ~ 42 weeks

C1.ACHEMOTHERAPY CYCLE

To be completed only for the patients randomized in treatment arms 2A or 2B.

Note: For the patients randomized in the groups 1A and 1B, the header information should be completed and the page should be crossed out, dated and initialed as well as page C1B.

One page has to be completed per chemotherapy administration (corresponding to one cycle) for a maximum total number of 3 (as per protocol).

1) STUDY CHEMOTHERAPY ADMINISTRATION FOR TH FEC H / THB FEC HB

This section should be completed to report chemotherapy regimen of docetaxel for the treatment arm THFECH or THBFECHB (T portion for CYCLES 1 to 3).

Note: During cycles 4 to 6 when FEC regimen is administered, please ask the site to cross out, date and initial the section related to TH/THB administrations.

Administration of trastuzumab and/or bevacizumab will be recorded in Trastuzumab/Bevacizumab Administration section on the same page.

Docetaxel Pre-Medication Indicate if patient received docetaxel pre-medication as per the protocol by ticking the YES or NO box. Please note that the required pre-medications for docetaxel are indicated in section 8.6 of the protocol:

Dexamethasone 8 mg po BID the day before and the day of chemotherapy is recommended. At the physician’s discretion, dexamethasone may be continued on the day after chemotherapy. An equivalent dose of other corticosteroids may be substituted (dexamethasone 8 mg = methylprednisolone 40 mg = prednisone 50 mg = prednisolone 50 mg).

Administration of IV dexamethasone (dose at the investigator's discretion) as a substitute for oral dexamethasone prior to chemotherapy is at the investigator's discretion.


At the physician's discretion, other non-steroidal premedications, e.g., diphenhydramine hydrochloride 50 mg IV and H-2 blocker IV (cimetidine 300 mg, ranitidine 50 mg, or famotidine 20 mg) may be given in addition to dexamethasone.

Docetaxel pre-medications do not have to be recorded in the Concomitant Medications running log. This includes dexamethasone but also the non-steroidal premedication like cimetidine that may be given in addition to dexamethasone.Note : any other medication given with other intent such as antiemetic does need to be reported.

Administration date: Enter the date of infusion of docetaxel.

Intended dose: Specify the dose expressed in mg/m² which is intended to be given to the patient according to the protocol (dose level according to table 15 of the protocol or dose reduced according to the guidelines related to the dose modifications) should be recorded.


Dosing: the dose should be calculated with the Baseline Body Surface Area and will not be recalculated for slight changes in BSA. BSA will be recalculated only if there is a 10% or greater change in body weight compared to Baseline. No ideal body weight should be used for the calculated BSA.If the calculated BSA of the patient is > 2.2 m2, the dose to be given to the patient can be calculated according to a capped BSA = 2.2 m2.Rounding of drug doses is optional If the treating physician decides to round the dose, it is recommended that the dose should be rounded to the nearest 5 mg

Dose reduction: Indicate by ticking the “Yes” or “No” box at each cycle, if docetaxel was reduced. Review the intended dose and the total dose given of the drug in comparison to the previous cycle. In case of dose reduction, check the box “Yes” in the cycle the reduction occurs. The reason for dose reduction must be specified:

1. Adverse Event : this includes all AEs (hematological or non hematological) related or not related, cardiac or non cardiac.

In case there has been an interruption due to an Adverse Event leading to a dose level reduction, the dose reduction box can be ticked and the corresponding AE must be reported on the AE running log or on the Cardiac Toxicity Monitoring Form.


If the docetaxel dose was reduced due to an AE, the AE box should be ticked and the corresponding AE reported on the AE running log or on page C5 (Cardiac Toxicity Monitoring Form) with the action taken “dose reduced”.

2. Other: If the “other” box is ticked, the reason should be specified.

Note regarding the completion of error in calculating the dose


It should be reported only in case of dose reduction (and not in case of dose escalation) and if the actual dose given corresponds to a lower dose level as specified in the protocol (changes of dose level according to the protocol). For example, if the intended dose for docetaxel is 100 mg/m2 but by mistake the actual dose given corresponds to 75 mg/m2, dose reduction should be reported. But on the other hand if the planned dose is 100 mg/m2 but the actual dose given corresponds to 95 mg/m2, no dose reduction should be indicated. However, the intended dose in both cases should remain 100 mg/m2.

Conventions: At cycle 1, the dose reduction will be recorded as No.

If the dose remains the same in the next cycles (no additional reduction), box “reduced” should be “no” in the next cycles. Please note that no dose re-escalation is allowed.

If there is a subsequent reduction, “reduced” will be noted as “yes” each time a new reduction occurs (with the reason specified).


Note: A reduction of the dose given due to a recalculation of the BSA does not constitute a reduction of the intended dose. No dose reduction should be recorded in such case.

Dose delay:

Indicate, at each cycle (except cycle 1), if there was a delay in the administration of the chemotherapy compared to the previous administration by ticking the “Yes” or “No” box. It is considered a delay when the administration of the cycle n+1 occurs more than 21 + 3 days after the administration of cycle n.If there are less than 25 days between the administration of two subsequent cycles, delay should be noted as “no”.Convention: At cycle 1, the dose delay will be recorded as “No” by convention.

If the “Yes” box is ticked, the reason of the delay must be specified:1. Adverse Event: this includes all AEs (hematological or non hematological) related or not related, cardiac or non cardiac.


If the chemotherapy was delayed due to an AE, the AE box should be ticked and the corresponding AE reported on the AE running log or on page C5 (Cardiac Toxicity Monitoring Form) with action taken “dose delay/hold”.

2. Other: If the “other” box is ticked, the reason should be specified. Examples: Scheduling delay, holiday, etc.

2) TRASTUZUMAB / BEVACIZUMAB ADMINISTRATION

This section should be completed to report the targeted therapy (ies) taken concomitantly with the chemotherapy.In case the targeted therapy is discontinued, nothing needs to be reported on the corresponding line but make sure the previous cycle indicated this discontinuation.

Administration date: Enter the date of infusion of trastuzumab +/- bevacizumab (for group 2A:, tick the “Not Applicable” box for bevacizumab).


Intended dose: - Specify for trastuzumab +/- bevacizumab, the intended dose in mg/kg according to the protocol.- For trastuzumab: please note that the first dose is 8 mg/kg IV over 90 minutes with subsequent doses

being infused at 6 mg/kg IV over 30-60 minutes.

Total dose given: Record the actual dose administered in this cycle in mg.

Dose Delay/Hold Indicate, at each cycle if there was a delay/hold in the administration of the trastuzumab and/or bevacizumab by ticking the “Yes” or “No” box.It is considered as a delay when the administration of the cycle n+1 occurs more than 21 +3 days after the administration of cycle n (delay starts in case, the next administration occurs at D25) If there are less than 25 days between the administration of two subsequent cycles, delay should be noted as “No”.It is considered as a “hold” when the administration of the target therapy will not occur at this given cycle. In this case, the date to be reported as well as the intended dose are the theoretical ones and the dose to be reported is 000 mg . Answer to question ‘Trastuzumab/Bevacizumab ongoing at the end of cycle?” should be ticked Yes (can be answered only once the cycle ends) .In case the targeted therapy is discontinued, nothing needs to be reported on the corresponding line but make sure the previous cycle indicated this discontinuation.

Conventions: At cycle 1, record dose delay/hold as “No” by convention.

If the “Yes” box is ticked, the reason of the Delay/Hold must be specified:



If trastuzumab and/or bevacizumab was delayed or held due to an AE, the AE box should be ticked and the corresponding AE reported on the AE running log or on page C5 (Cardiac Toxicity Monitoring Form) with action taken “dose delay/hold”..



Rounding of drug doses is optional If the treating physician decides to round the dose, It is recommended that the dose should be rounded :

- For bevacizumab : to the nearest 25 mg- For trastuzumab : to the nearest 20 mg.

Trastuzumab/Bevacizumab ongoing at the end of the cycle?: Indicate by ticking the Yes or No box if the trastuzumab or bevacizumab was still being given at the end of the cycle.

Note : For patient treated in group 2, during the treatment by FEC, targeted therapies are stopped and will start gain after. In this case, the question “Trastuzumab/Bevacizumab ongoing at the end of the cycle? “ should be answered by “Yes” by convention.If the No box was ticked for either targeted therapy, the reason for the discontinuation should be reported on the End of Targeted Therapy (EOT) CRF page.


Note :- If trastuzumab is discontinued: bevacizumab should be discontinued.- If trastuzumab is held, bevacizumab should be held.- If bevacizumab is discontinued/held, administration of trastuzumab could continue.


C1.BCHEMOTHERAPY CYCLE

To be completed only for the patients randomized in treatment arms 2A or 2B.One page has to be completed by FEC chemotherapy administration (corresponding to one cycle) for a maximum total number of 3 (as per protocol).

Note: For the patients randomized in the groups 1A and 1B, the header information should be completed and the page should be crossed out, dated and initialed as well as page C1A.

STUDY CHEMOTHERAPY ADMINISTRATION FOR TH FEC H/THB FEC HB

This section should be completed to report FEC administration for the treatment arm THFECH or THBFECHB (FEC portion for CYCLES 4 to 6).

Note: During cycles 1 to 3 when TH or THB are administered, please cross out, date and initial the section related to FEC administration.

No administration of trastuzumab and bevacizumab is planned during the FEC treatment.

Administration date: Enter the date of infusion of the 5FU, epirubicin and cyclophosphamide. If the chemotherapy was given on different days, please record the earliest of the dates.

Intended dose: Specify for 5FU, epirubicin and cyclophosphamide the intended dose given in mg/m2, according to the protocol (dose level according to table 17 of the protocol or dose reduced according to the guidelines related to the dose modifications) should be recorded.


Conventions: Dosing of 5-fluorouracil, epirubicin and cyclophosphamide should be calculated with the Baseline Body Surface

Area and will not be recalculated for slight changes in BSA. BSA will be recalculated only if there is a 10% or greater change in body weight compared to Baseline.

If the calculated BSA of the patient is > 2.2 m2, the dose to be given to the patient can be calculated according to a capped BSA = 2.2 m2. No ideal body weight should be used for the calculated BSA.

Rounding of drug doses is optional. If the treating physician decides to round the dose(s), the following guidelines are recommended.- for 5-Fluorouracil : the dose should be rounded to the nearest 25 mg.- for Cyclophosphamide: the dose should be rounded to the nearest 20 mg- for Epirubicin: the dose should be rounded to the nearest 2 mgDose reduction: Indicate by ticking the “Yes” or “No” box at each cycle, if either 5 FU, cyclophosphamide and/or epirubicin were reduced. Review the intended dose and the total dose given of the drug in comparison to the previous cycle.

In case of dose reduction, check the box “Yes” in the cycle the reduction occurs. The reason for dose reduction must be specified:


1.Adverse Event: this includes all AEs (hematological or non hematological) related or not related, cardiac or non cardiac.

In case there has been an interruption due to an Adverse Event leading to a dose level reduction, the dose reduction box can be ticked and the corresponding AE must be reported on the AE running log or on the Cardiac Toxicity Monitoring Form.


If the chemotherapy was reduced due to an AE, the AE box should be ticked and the corresponding AE reported on the AE running log or on page C5 (Cardiac Toxicity Monitoring Form) with action taken “dose reduced.

2. Other: If the “other” box is ticked, the reason should be specified.

Note regarding the completion of error in calculating the doseIt should be reported only in case of dose reduction (and not in case of dose escalation) and if the actual dose given corresponds to a lower dose level as specified in the protocol (changes of dose level according to the protocol). For example, if the intended dose for epirubicin is 90 mg/m2 but by mistake the actual dose given corresponds to 75 mg/m2, dose reduction should be reported. But on the other hand if the planned dose is 90 mg/m2 but the actual dose given corresponds to 85 mg/m 2, no dose reduction should be indicated. However, the intended dose in both cases should remain 90 mg/m2.

Conventions:

If the dose remains the same in the next cycles (no additional reduction), box “reduced” should be “no” in the next cycles. Please note that no dose re-escalation is allowed.

If there is a subsequent dose reduction, “reduced” will be noted as “yes” each time the reduction occurs (with the reason specified).


Note: A reduction of the dose given due to a recalculation of the BSA does not constitute a reduction of the

intended dose. No dose reduction should be recorded in such case.Dose delay Indicate, at each cycle if there was a delay in the administration of the chemotherapy regimen compared to the previous administration by ticking the “Yes “or “No” box.

It is considered a delay when the administration of the cycle n+1 occurs more than 21 +3 days after the administration of cycle n (delay starts in case the next administration occurs at D25).If there are less than 25 days between the administration of two subsequent cycles, delay should be noted as “no”.

Conventions:

If the “Yes” box is ticked, the reason of the delay must be specified:




If the chemotherapy was delayed due to an AE, the AE box should be ticked and the corresponding AE reported on the AE running log or on page C5 (Cardiac Toxicity Monitoring Form) with action taken “dose delay/hold”.

2. Other: If the “other” box is ticked, the reason should be specified. Examples: Scheduling delay, holiday, etc.


C.2HEMATOLOGY

To be performed within 3 days before each chemotherapy cycle beginning with cycle 2.

Per convention, please note that the tests that are performed prior cycle number n should be reported at cycle n-1

For instance, the evaluations performed prior to C2 should be reported within C1, even if they are performed the same day that C2D1 (but before the infusion).

Were lab tests performed?Indicate whether or not lab tests were performed.If no, check the “no” box and do not complete the remainder of the section.

If “yes, tick the “yes” box and complete the remainder of the section.

Date of sample: Enter the date the hematology sample was taken rather than the date of the report.

Record the most recent hematology sample obtained prior to the next chemotherapy infusion.

If additional hematology tests were performed, they should be recorded only if abnormal values were observed by using extra forms (EF2). In this case, infusion is to be given only once values are back to the normal. The hematological tests with the values back to normal have to be reported in the CRF as well (using EF2). In case the hematology parameters were performed at different dates, report the ones corresponding to each different date separately.

Value: Enter laboratory results. Do not convert. Use the same values as source documents.If one test was not performed, enter ND in the value field.

Actual Units: If the units are the same as the recommended ones, leave the actual units blank.If test units are different from the pre-printed recommended units, enter the actual unit in the appropriate column The units recorded should therefore correspond to the units used on the source documents. If the value of the test is reported as ND (Not done) leave the actual unit blank.

Note:In case of clinically significant abnormal hematology values: please report it on the AE running log. Clinically significant abnormal laboratory findings are those that:

are accompanied by a clinical symptom(s) or

result in a change of study therapy (e.g., dose modification, delay, or permanent discontinuation); or

result in a change in concomitant therapy (e.g., addition of, delay of, discontinuation of, or any other change in a concomitant medication, therapy, or treatment).

are “serious”.

URINE PROTEIN

Urine protein should be performed every 6 weeks for Groups 1B and 2B only.


Was a Urine Protein test performed?Indicate whether or not a urine protein test was performed.If no, check the “no” box and do not complete the remainder of the section.


Date of sample :Enter the date the UPC or the urine dipstick was done.

Method : Please indicate which method has been used (UPC ratio or urine dipstick)

- Dipstick value:Enter the result of the dipstick value (negative, trace, 1+, 2+, 3+ or 4+)

If dipstick value is 2+, 3+ or 4+, a UPC ratio or an 24-hour urine collection is required.

- UPC ratio (See Appendix 7) Enter the UPC ratio. The UPC ratio is obtained by dividing the urine protein by the urine creatinine: Total urine protein (or urine albumin) ÷ urine creatinine = UPC ratioEnter the result as the value with 2 decimal places.

To be completed only if dipstick method is used and value > or equal to 2+ : Was the UPC ratio performed?

Indicate whether or not a UPC ratio was performed.If no, check the “no” box and do not complete the remainder of the section. If yes, tick the “yes” box and complete the remainder of the section.

Was a 24-hour urine collection performed ?Indicate whether or not a 24-hour urine collection was performed.If no, check the “no” box and do not complete the remainder of the section. If “yes, tick the “yes” box and complete the remainder of the section.Note that this question must be checked even if the urine protein was normal in the question above.

Date of 24-hour urine collection :Enter the date the urine collection was started.

Total protein: Report the total protein value in g/24 hours. In case the collection was incomplete do not report at all and indicate as not done.

If additional urine protein evaluations were performed they should be reported on page EF2.

Note:In case of clinically significant abnormal urine protein value: please report it on the AE running log. Clinically significant abnormal laboratory findings are those that:




are “serious”.


C.3BLOOD CHEMISTRY

To be performed within 3 days before each chemotherapy beginning with cycle 2.Per convention, please note that the tests that are performed prior cycle number n should be reported at cycle n-1 For instance, the evaluations performed prior to C2 should be reported within C1, even if they are performed the same day that C2D1 (but before the infusion).



Date of sample: Enter the date the blood chemistry sample was taken rather than the date of the report.

Record the most recent blood chemistry sample obtained prior to the next chemotherapy infusion.

If additional blood chemistry tests were performed, they should be recorded only if abnormal values were observed by using extra forms (EF3). In this case, infusion is to be given only once values are back to the normal. The blood chemistry tests with the values back to normal have to be reported in the CRF as well (using EF3). In case the biochemistry parameters were performed at different dates, report the ones corresponding to each different date in different sections.

Test: Creatinine Clearance is only required for Groups 1A and 1B. If this is not applicable for the patient, tick the NA box located in the Value column.

Value: Enter laboratory results. Do not convert. Use the same values as in source documents.If one test was not performed, enter ND in the value field.

Note for the creatinine clearance : Please report the measured creatinine clearance (or calculated using the Crockroft and Gault formula if not measured). The capping of clearance will not be recorded nor will the UNL


Actual Units: If the units are the same as the recommended ones, leave the actual units blank.If test units are different from the pre-printed recommended units, enter the actual unit in the appropriate column. The units recorded should therefore correspond to the units used on the source documents.If the value of the test is reported as ND (Not done) or NA box is ticked, leave the actual unit blank.

Upper normal limit for the institution: For each test that was performed enter the upper normal limit for the institution (except for the creatinine clearance). Unit of the upper normal limit for the institution should be the same as the unit of the value.

Note: In case of clinically significant blood chemistry abnormality: please report it on the AE running log.Clinically significant abnormal laboratory findings are those that:




are “serious”.


C.4PHYSICAL EXAMINATION AND OTHER CLINICAL PARAMETERS

To be performed within 3 days before each chemotherapy cycle.



Was a physical examination performed?Indicate whether or not a physical examination was performed.If no, check the “no” box and leave the remainder of this section blank. If yes, specify the date of assessment. Whenever appropriate, record Clinical Adverse Events on AE Running Log and/or Cardiac Adverse Events on page C5.

Was the Weight obtained?:If no, check the “no” box and leave the remainder of this section blank.

If yes, specify the date of assessment and the patient’s weight in kilograms. This value should be used for dose calculation in case there has been a > or equal to 10% variation of the baseline weight.

Whenever appropriate, a weight loss or a weight gain should be reported in the AE running log:- for the first 300 patients in each cohort: grade 1 AEs will be recorded.

- for the remaining patients: : grades 1 and 2 AEs that require a change in treatment (i.e., a delay in treatment, a dose reduction, or discontinuation of one or more of the study therapy drugs), grade 3 and 4 AEs will be recorded.

Was ECOG Performance Status assessed?If no, check the “no” box and leave the remainder of this section blank.

If yes, specify the date of assessment and ECOG value.

ECOG Performance Status:Indicate the ECOG Performance Status value.

ECOG value must be documented in the source documents. If the ECOG value is not documented, the investigator has to assess it according to the source documents and the notes of the physical examination (a performance status could be retrospectively attributed and source documented). .


Whenever appropriate, fatigue should be reported in the AE running log:- For the first 300 patients in each cohort: grade 1 AEs will be recorded.

- For the remaining patients: grades 1 and 2 AEs that require a change in treatment (i.e., a delay in treatment, a dose reduction, or discontinuation of one or more of the study therapy drugs), grade 3 and 4 AEs will be recorded.


C.5CARDIAC TOXICITY MONITORING FORM

This page must be faxed to CIRG Data Management (FAX Number: (1) 780 702 0190) :1. Within 21 days after LVEF assessments

- Required at the protocol specified time points (see LVEF TIMING table below)- Not scheduled but done for any reason during the 5 years following randomization

2. Within 21 days of learning of any of the following cardiac events - Cardiac left ventricular dysfunction with NYHA Class III/IV symptoms- Definite cardiac death defined as death due to congestive heart failure, myocardial infarction or documented

primary arrhythmia- Probable cardiac death defined as sudden death without documented etiology- Grade 3/4 cardiac ischemia/infarction- Grade 3 systolic or diastolic dysfunction witht NYHA Class II symptoms- Grade 2 systolic dysfunction Note: If only hypertension is reported, the form does not have to be faxed. For the purpose of BETH, grade 1 decrease in LVEF will be defined as asymptomatic drop to 50-54%, LVEF values of 55-59% will not be considered gr 1 LVEF dysfunction.

LVEF TIMING

For Patients in Groups 1A and 1B(TCHH or TCHBHB)

For Patients in Groups 2A and 2B(THFECH or THBFECHB)

1 Baseline - within 3 months prior to randomization

2 2-3 weeks after cycle 3 of TCH/TCHB(before cycle 4)

2-3 weeks after the last dose of TH/THB(before FEC begins)

3 2-3 weeks after the last dose of TCH/TCHB(before targeted therapy continues)

2-3 weeks after the last dose of FEC(before targeted therapy resumes)

4 After 3 months of targeted therapy alone (H/HB) (about 7 months following randomization)5 After 6 months of targeted therapy alone (H/HB) (about 10 months following randomization)6 At 18 months following randomization7 At 36 months following randomization8 At 60 months following randomization

1) Left Ventricular Ejection Fraction

Was a LVEF performed?: Indicate if a LVEF was performed by ticking the “Yes” or “No” box. If no, check the “no” box and leave the remainder of this section blank.

If “yes”, please complete the remainder of this section:

Date of Assessment: Enter the date of assessment of the left ventricular ejection fraction at rest.

LVEF at rest: LVEF at rest must be performed either with echocardiography (preferred technique) or radionuclide angiocardiography (MUGA scan). Indicate which method was used.

If the LVEF has been assessed by both methods (radionuclide angiocardiography and echocardiography), report the results of both of them on page C.5. Use E.F.4 to record any additional results.

Value: BETH CRF completion guidelines of 120Version 2 Final Version Date: 10 Dec 2009

Indicate the value of the LVEF at rest (%) as a numerical value which is a whole number. If the value in the source document is not a whole number, decimals reported as >5 should be rounded up and decimals reported as <5 should be rounded down.For example, a LVEF value of 54.5% will be rounded up and reported as 55%; a LVEF of 54.4% will be rounded down and reported as 54%.

If the facility performing the assessment will only report the LVEF as a range, the mean (average) of the values used for the range should be calculated by the investigator and entered into patient’s medical charts so that a single numerical value can be reported. For example a range of 50-55will have to be reported as 53 (since 52.5 is to be rounded-up).



It is strongly advised that LVEF is measured using the same method (MUGAs or echocardiography) and that they are determined at the same radiology facility and by the same team as at baseline.

2) Blood PressureTo be performed within 3 days prior to each chemotherapy cycle.If additional blood pressure measurements were taken, they should be recorded only if abnormal values were observed by using extra forms (EF4).



Was Blood Pressure Taken?: Indicate if Blood Pressure was performed by ticking the “Yes” or “No” box. If no, check the “no” box and do not complete the remainder of this section.

If “yes”, please complete the remainder of this section.

Date of Assessment: Enter the date of assessment of the Blood Pressure.

Value: Record the diastolic and systolic values in mmHg.3) Cardiac Adverse Events:

Reporting of Cardiac Adverse eventsThe following table summarizes the cardiac events to be reported during the therapy:


For the first 300 pts enrolled in Groups 1A and 1B and the first 300 pts in Groups 2A and 2B

(information provided at randomization)For the remaining pts

All cardiac AEs with grade 1 must be recorded The following events must be recorded:

All cardiac AEs of special interest with grade 2

- Cardiac ischemia/infraction;

- Hypertension

- Left ventricular diastolic dysfunction

- Left ventricular systolic dysfunction

Grades 1 and 2 AEs that require a change in treatment (i.e., a delay in treatment, a dose reduction, or discontinuation of one or more of the study therapy drugs),

All cardiac AEs grade 3

Sudden death without documented etiology

Are there any Cardiac Adverse Events?

Indicate if any Cardiac Adverse Events were experienced in this cycle by ticking the Yes or No box.If no cardiac adverse events are to be reported in either this page or extra form for cycle (EF5), check the “no” box.

If yes, complete the remainder of the section as indicated below should the patient experienced cardiac adverse event pre-printed on this page. Otherwise complete the page EF5 for other cardiac adverse events as indicated in the corresponding section of this document specific for page EF5.

Description: For Left Ventricular Systolic Dysfunction and Left Ventricular Diastolic Dysfunction, specify the NYHA Class (1-4) using Appendix B of the protocol.

Grade: Report the highest grade experienced during the cycle (from the infusion reported in this cycle until just before the next infusion).Enter 1-5, when appropriate by using the NCI CTCAE v3.0, otherwise use the severity code defined below:1. mild : generally non-progressive, producing a minimal degree of tolerable discomfort2. moderate : may adversely affect normal daily activity, but is not completely incapacitating3. severe : marked intensity, may be either totally incapacitating or results in significant decrease in normal daily

activity4. life threatening : the patient was at immediate risk of death as the AE occurred. It does not include an event that,

had it occurred in a more serious form, may have caused death.5. death

The NCI Toxicity Grading System used in BETH is NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0

Serious: Enter either “yes” or “no” for each event indicating if the event was a serious adverse event as per the protocol:BETH CRF completion guidelines of 120Version 2 Final Version Date: 10 Dec 2009

A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: results in death, is life-threatening (NOTE: The term "life-threatening" in the definition of serious refers to an event in which the

patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe),

requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect

Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the outcomes listed in the definition above. These should also usually be considered serious.

Please refer to the SAE reporting completion guidelines.

If serious, make sure all information is matching the corresponding SAE report form in its last follow-up.

Start Date / End Date: - Indicate the start date or if the AE was ongoing at time of study drug infusion of the cycle, tick the “ongoing” box.If ongoing, please cross check that the AE was previously reported in the previous visit/Baseline.Ongoing conditions must be reported and followed by the physician during study treatment using the “Cardiac Toxicity Monitoring Form”.

- Indicate the stop date or if the event is still ongoing at the end of the cycle, the box “ongoing” should be ticked.

Medication to Treat Adverse Event: Indicate if the patient has received or is receiving medication to treat the cardiac adverse event.If yes, complete the concomitant medication running log.

Action taken (Study drug) (regarding study drug administration for the next cycle).Complete using one of the following codes and specify for each adverse event the action taken regarding study drug for chemotherapy, trastuzumab and bevacizumab.For patients in the TCHH or THFECH regimens, the action taken (study drug) for bevacizumab should be completed with NA.

0. None : no change in study drug was made1. Discontinued: administration of study drug was permanently discontinued (i.e. the patient was

discontinued from study) due to this clinical adverse event. Please cross check with End of Chemotherapy (EOC) page. In this case, the investigator has to select the main event(s) which led to patient’s discontinuation.

2. Dose Reduced: the total dose of study drug for the next cycle will be reduced due to clinical adverse event (not applicable for trastuzumab or bevacizumab). Please cross check with the study drug administration page(s) at the next cycle.

3. Dose Delay / Hold: change in the dosing regimen occurred prior to next cycle (i.e, a delay > 4 days of next cycle’s study drug infusion) due to cardiac adverse event. Please cross check with the study drug administration page(s) at the next cycle.

4. Dose Reduced and Dose Delay: the combination of choices 2 and 3 (not applicable for trastuzumab or bevacizumab)

Relationship to study drug: Relationship to study drug concerns the relationship of the adverse event to chemotherapy, trastuzumab and bevacizumab.Enter “No” or “Yes” for chemotherapy, trastuzumab and bevacizumab.


0. No: the clinical adverse event is definitely unrelated to the study drug (it does not follow a temporal sequence from study drug administration, may have been present prior to receiving study medication).

1. Yes: the clinical adverse event appears related to study drug with a high degree of certainty (it follows a reasonable temporal sequence from drug administration and abates upon discontinuation of the drug, cannot be reasonably explained by known characteristics of the patient’s clinical state or other modes of therapy administered to the patient).

Assigning the relationship to study drug is the PI’s or sub/co-investigator’s responsibility. This relationship must be source documented. Please note that ND is not acceptable.


E.O.CEND OF CHEMOTHERAPY REASON

As per the protocol, the End of Chemotherapy visit should take place 2 to 3 weeks after the last chemotherapy infusion.

Specify primary reason for the patient’s discontinuation of chemotherapy:

One and only one reason must be indicated:

Received maximum number of cycles as per protocol : This box must be ticked when patient has completed the required number of cycles of study chemotherapy (6 cycles for patients randomized to TCHH/TCHBHB arms and 6 cycles for patients randomized to the THFECH/THBFECHB arms.)

Breast Cancer Relapse : If the primary reason is a relapse, complete page BCR.

Second Primary Malignancy : If the primary reason is a second primary malignancy, complete page SPM.

Death : If primary reason is “death”, at least one adverse event must be marked on the AE Running Log or Cardiac Toxicity Monitoring Form with an outcome of “death”. Death Report Form and SAE Report Form must be completed.

Cardiac Adverse Event : If the primary reason is “cardiac adverse event”, the main cardiac adverse event for which treatment discontinuation was required should be reported in last cycle with Action Taken (study drug) (chemo) = “discontinued” (code 1) regardless of the relationship to study medication.

Non-Cardiac Adverse Event : If the primary reason is “non-cardiac adverse event”, the main adverse event for which treatment discontinuation was required should be reported in the adverse event running log with Action Taken (study drug) (chemo) = “discontinued” regardless of the relationship to study drug.

Consent withdrawn : This represents a patient decision and by convention does not allow for an adverse event to be noted with Action Taken (study drug)“discontinued”. Consent withdrawn is also the appropriate box to be checked if the patient decided to pursue an alternative cancer therapy prior to the documentation of relapse of the disease while on study drug. Please tick the appropriate box to indicate whether the patient still agrees to have her medical history recorded for survival status (agrees to be followed) or does not want to be followed at all. If the patient withdrew her consent but agreed to be followed, this must be clearly source documented.

Lost to follow-up : This is only acceptable if source documentation confirms that repeated attempts to contact the patient have failed (as per BETH guidelines regarding lost-to-follow-up patients). The date of last contact must be specified and the Lost to follow-up form filled-in.

Other, specify : This is the appropriate selection for example for patients who decide to discontinue the study participation for an adverse event which according to the protocol does not need the chemotherapy to be stopped. In the CRF please report the reason as : other patient decision (AE XXX grade X)


CASE REPORT FORM REVIEW

Preferably, all patients’ CRFs will be reviewed and the case report form review module signed by the site’s principal investigator after completion and corrections during the monitoring visits. However, any appropriately identified sub/co-investigator may review and sign ..

If the investigator has signed the EOC page before the monitoring visit and significant corrections are made to the preceding CRF segments during the visit, the investigator should re-sign and date the Case Report Form review before retrieval by the monitor.


TARGETED THERAPY VISIT


V.1TRASTUZUMAB/BEVACIZUMAB ADMINISTRATION

The numbering of targeted therapy visit should start from 1: the visit number should be completed using only one single box (even if the visit number is a 2 digits number).Note : see graphs related to the number of targeted therapy to be administered (pages C1 and C1A)This segment is to be used only when per protocol targeted therapy is administered alone (i.e. trastuzumab +/- bevacizumab when the patient has completed study chemotherapy).

One segment has to be completed per targeted therapy administration (corresponding to one visit) for a maximum of 1 year treatment since the beginning of the targeted therapy administration (taking into account the ones given during the chemotherapy).

TRASTUZUMAB/BEVACIZUMAB ADMINISTRATION AFTER CHEMOTHERAPY

Administration Date: For each of the targeted therapy (trastuzumab and bevacizumab if applicable) enter the date of infusion of trastuzumab +/- bevacizumab.For the patients randomized in arm TCH (group 1A) or THFEC (group 2A) or for the patients randomized in group 1B or 2B and bevacizumab stopped: tick the “Not Applicable” box for bevacizumab and leave blank the remaining fields.

Intended dose: - Specify for trastuzumab +/- bevacizumab, the intended dose in mg/kg according to the

protocol.- For trastuzumab: please note that the first dose is 8 mg/kg IV over 90 minutes with

subsequent doses being infused at 6 mg/kg IV over 30-60 minutes (unless after a treatment interruption, the investigator judges it necessary to give a new loading dose).

No dose reduction is possible for the targeted therapies.

Total dose given: - Record the actual dose administered at this visit in mg. If the infusion of study drug was

interrupted, record the date when infusion started and the total dose given (i.e. before and after interruption). In case the exact dose is not known, record the estimated one.

- If the administration has been “held”, please report 000 mg.

Dose delay/Hold: Indicate, at each visit if there was a delay/hold in the administration of the trastuzumab and/or bevacizumab by ticking the “Yes” or “No” box.It is considered as a delay when the administration of the visit n+1 occurs more than 21 + 3 days after the administration of visit n (delay starts in case the next administration occurs at D25) If there are less than 25 days between the administration of two subsequent visits, delay should be noted as “No”.It is considered as a “hold” when the administration of the target therapy will not occur at this given visit: in this case, the date to be reported as well as the intended dose are the theoretical ones and the dose to be reported is 000 mg . Answer to question ‘Trastuzumab/Bevacizumab ongoing at the end of cycle?” should be ticked Yes (can be answered only once the visit ends).


In case the targeted therapy is discontinued, nothing needs to be reported on the corresponding line but make sure the previous cycle indicated this discontinuation.Conventions:If the “Yes” box is ticked, the reason of the Delay/Hold must be specified:

1. Adverse Event: this includes all AEs (hematological or non hematological) related or not related, cardiac or not cardiac. Examples: study drug related hematological abnormalities, coagulation abnormalities, fever in absence of infection with neutropenia, skin reactions, neurological adverse events….

If the trastuzumab +/- bevacizumab was delayed or held due to an AE, the AE box should be ticked and the corresponding AE reported on the AE running log or on page V5 (Cardiac Toxicity Monitoring Form) with action taken “dose delay/hold”.



Rounding of drug doses is optional. If the treating physician decides to round the dose(s), the following guidelines are recommended - For bevacizumab to the nearest 25 mg.- For trastuzumab to the nearest 20 mg.

Trastuzumab/bevacizumab ongoing at the end of the visit? Indicate by ticking the “Yes” or “No” box if the Trastuzumab or Bevacizumab was still being given at the end of the visit.If the “No” box was ticked for either targeted therapy, the reason for the discontinuation should be reported on the End of Targeted Therapy (EOT) CRF page.

Note :- If trastuzumab is discontinued: bevacizumab should be discontinued.- If trastuzumab is held, bevacizumab should be held.- If bevacizumab is discontinued/hold, administration of trastuzumab could continue.


V.2HEMATOLOGY

To be performed every 6 weeks (every other visit).

Per convention, please note that the tests that are performed prior to targeted visit number n should be reported at visit number n-1. For instance, the evaluations performed prior to V3 should be reported within V2, even if they are performed the same day that V3D1 (but before the infusion).


If “yes”, tick the “yes” box and complete the remainder of the section.

Date of sample: Enter the date the hematology sample was taken rather than the date of the report.Record the most recent Hematology sample obtained prior to the next infusion.

If additional hematology tests were performed, they should be recorded only if abnormal values were observed by using extra forms (EF2). In this case, infusion is to be given only once values are back to the normal. The hematological tests with the values back to normal have to be reported in the CRF as well (using EF2). In case the hematological parameters were performed at different dates, report the ones corresponding to each different date in different sections.


Actual Units: If the units are the same as the recommended ones, leave the actual units blank.If test units are different from the pre-printed recommended units, enter the actual unit in the appropriate column. The units recorded should therefore correspond to the units used on the source documents. If the value of the test is reported as ND (Not done) leave the actual unit blank as well.





are “serious”


URINE PROTEIN

Urine protein should be performed every 6 weeks for Groups 1B and 2B (every other visit).



Date of sample :Enter the date the UPC or the urine dipstick was done.

Method : Please indicate which method has been used (UPC ratio or urine dipstick)



- UPC ratio (See Appendix 7) Enter the UPC ratio. The UPC ratio is obtained by dividing the urine protein by the urine creatinine: Total urine protein (or urine albumin) ÷ urine creatinine = UPC ratioEnter the result as the value with 2 decimal places.



Was a 24-hour urine collection performed ?Indicate whether or not a 24-hour urine collection was performed.If no, check the “no” box and do not complete the remainder of the section. If “yes”, tick the “yes” box and complete the remainder of the section.Note that this question must be checked even if the urine protein was normal in the question above.



If additional urine protein evaluations were performed they should be reported on page EF2.


Note:In case of clinically significant abnormal urine protein value: please report it on the AE running log. Clinically significant abnormal laboratory findings are those that:



result in a change in concomitant therapy (e.g., addition of, delay of, discontinuation of, or any other change in a concomitant medication, therapy, or treatment)

are “serious”.


V.3BLOOD CHEMISTRY


Per convention, please note that the tests that are performed prior to targeted visit number n should be reported at visit number n-1.

For instance, the evaluations performed prior to V3 should be reported within V2, even if they are performed the same day that V3D1 (but before the infusion).

Were lab tests performed?Indicate whether or not lab tests were performed.If no, check the “no” box and do not complete the remainder of the section If “yes”, tick the “yes” box and complete the remainder of the section.

Date of sample:

Enter the date the blood chemistry sample was taken rather than the date of the report.Record the most recent Blood Chemistry sample obtained prior to the next infusion.If additional blood chemistry tests were performed, they should be recorded only if abnormal values were observed by using extra forms (EF3). In this case, infusion is to be given only once values are back to the normal. The blood chemistry tests with the values back to normal have to be reported in the CRF as well (using EF3). In case the biochemistry parameters were performed at different dates, report the ones corresponding to each different date in different sections.


Actual Units: If test units are different from the pre-printed recommended units, enter the actual unit in the appropriate column. The units recorded should therefore correspond to the units used on the source documents.

Upper normal limit for the institution: Enter for each test that was performed the upper normal limit for the institution. Unit of the upper normal limit for the institution should be the same as unit of the value.

Note:In case of clinically significant blood chemistry abnormality: please report it on the AE running log.Clinically significant abnormal laboratory findings are those that:





are “serious”.


V.4BREAST IMAGING

To be performed every 12 months. First assessment will be 1 year from the most recent mammogram (or MRI) performed prior to randomization.

Did the patient have breast imaging?Report whether or not the patient had Breast Imaging by indicating Yes or No.If no, check the “no” box and do not complete the remainder of the section.Please note that this is however required by the protocol every 12 months.


Date of Assessment : Report the date of the breast imaging assessment that was performed.

Site of Breast Imaging: Tick the appropriate box (indicating on which breast the assessment was done)If bilateral mammogram is performed, the “Left and Right” box is to be checked.

Type of exam: Indicate the exam that was performed for assessing the breast status (mammography, MRI or other; if other, please specify the type of exam). Please note that the mammography is the only method allowed per the protocol after randomization.

Tumor involvement: Check either “yes” or “no”. If the Breast Imaging demonstrates tumor involvement “yes”, the BCR or SPM CRF page should be completed.

PHYSICAL EXAMINATION AND OTHER CLINICAL PARAMETERS


Was a physical examination performed?Indicate whether or not a physical examination was performed. If no, check the “no” box and answer to the next questions of the section. If yes, indicate the date of assessment. Whenever appropriate, record Clinical Adverse Events on the AE Running Log and/or on page V5:

- for the first 300 patient in each cohort: grade 1 AEs will be recorded.

- for the remaining patients : grades 1 and 2 AEs that require a change in treatment (i.e., a delay in treatment, a dose reduction, or discontinuation of one or more of the study therapy drugs), grade 3 and 4 AEs will be recorded.

Was the Weight obtained? If no, check the “no” box and answer to the next question of the section.


If yes, indicate the date of assessment and the weight value in kg. This value should be used for dose calculation in case there has been a > or equal to 10% variation of the baseline weight.Whenever appropriate, a weight loss or a weight gain should be reported in the AE running log:

- for the first 300 patients in each cohort: grade 1 AEs will be recorded.

- for the remaining patients: grades 1 and 2 AEs that require a change in treatment (i.e., a delay in treatment, or discontinuation of one or more of the study therapy drugs) grade 3 and 4 AEs will be recorded.

, Was ECOG performance status assessed?If no, check the “no” box and do not complete the remainder of the section.

If yes, specify the date of assessment and ECOG value.

ECOG Performance Status:Indicate the ECOG Performance Status value.

ECOG value must be documented in the source documents. If the ECOG value is not documented, the investigator has to assess it according to the source documents and the notes of the physical examination (a performance status could be retrospectively attributed and source documented).


Whenever appropriate, fatigue should be reported in the AE running log:- for the first 300 patients in each cohort: grade 1 AEs will be recorded.

- for the remaining patients: grades 1 and 2 AEs that require a change in treatment (i.e., a delay in treatment, or discontinuation of one or more of the study therapy drugs), grade 3 and 4 AEs will be recorded.


V.5CARDIAC TOXICITY MONITORING FORM

This page must be faxed to CIRG Data Management (FAX Number: (1) 780 702 0190):1. Within 21 days after LVEF assessments - Required at the protocol specified timepoints (see LVEF TIMING table below)- Not scheduled but done for any reason during the 5 years following randomization

2. Within 21 days of learning of any of the following cardiac events - Cardiac left ventricular dysfunction with NYHA Class III/IV symptoms- Definite cardiac death defined as death due to congestive heart failure, myocardial

infarction or documented primary arrhythmia- Probable cardiac death defined as sudden death without documented etiology- Grade 3/4 cardiac ischemia/infarction- Grade 3 systolic or diastolic dysfunction with NYHA Class II symptoms- Grade 2 systolic dysfunction -Note: If only hypertension is reported, the form does not have to be faxed.

For the purpose of BETH, grade 1 decrease in LVEF will be defined as asymptomatic drop to 50-54%, LVEF values of 55-59% will not be considered gr 1 LVEF dysfunction.

LVEF TIMING









1) Left Ventricular Ejection Fraction

Was a LVEF performed?: Indicate if a LVEF was performed by ticking the “Yes” or “No” box. If no, check the “no” box and answer to the other questions of the page.

If “yes”, tick the yes box and complete the remainder of the section.



LVEF at rest: LVEF at rest must be performed either with echocardiography (preferred technique) or radionuclide angiocardiography (MUGA scan). Indicate which method was used.

If the LVEF has been assessed by both methods (radionuclide angiocardiography and echocardiography), report the results of both of them on page V.5. Use E.F.4 to record any additional results.

Value: Indicate the value of the LVEF at rest (%) as a numerical value which is a whole number. If the value in the source document is not a whole number, decimals reported as >5 should be rounded up and decimals reported as <5 should be rounded down.For example, a LVEF value of 54.5% will be rounded up and reported as 55%; a LVEF of 54.4% will be rounded down and reported as 54%.

Per convention, please note that the tests that are performed prior to targeted visit number n should be reported at visit number n-1.

For instance, the evaluations performed prior to V5 should be reported within V4, even if they are performed the same day that V5D1 (but before the infusion).

If the facility performing the assessment will only report the LVEF as a range, the mean (average) of the values used for the range should be calculated by the investigator and entered into patient’s medical charts so that a single numerical value can be reported. For example a range of 50-55 will have to be reported as 53 (since 52.5 is to be rounded-up).

It is strongly advised that LVEF is measured using the same method (MUGA or echocardiography) and that they are determined at the same radiology facility by the same team as at baseline.

2) Blood PressureTo be performed every 3 weeks.Per convention, please note that the tests that are performed prior to targeted visit number n should be reported at visit number n-1. For instance, the evaluations performed prior to V3 should be reported within V2, even if they are performed the same day that V3D1 (but before the infusion).

If additional blood pressure measurements were taken, they should be recorded only if abnormal values were observed by using extra forms (EF4).

Was Blood Pressure Taken?: Indicate if Blood Pressure was performed by ticking the “Yes” or “No” box. If no, check the “no” box and do not complete the remainder of the Blood Pressure section.

If “yes”, please complete the remainder of this section.


Value: Record the diastolic and systolic values in mmHg.

3) Cardiac Adverse Events:BETH CRF completion guidelines of 120Version 2 Final Version Date: 10 Dec 2009

Reporting of Adverse eventsThe following table summarizes the cardiac events to be reported during the therapy

For the first 300 pts enrolled in Groups 1A and 1B and the first 300 pts in Groups 2A

and 2B(information provided at randomization)

For the next pts

All cardiac AEs with grade 1 must be recorded

The following events must be recorded:

All cardiac AEs of special interest with grade 2- Cardiac ischemia/infraction;

- Hypertension



Grades 1 and 2 AEs that require a change in treatment (i.e., a delay in treatment, or discontinuation of one or more of the study therapy drugs),



Are there any Cardiac Adverse Events?

Indicate if any Cardiac Adverse Events were experienced in this visit by ticking the Yes or No box.If no cardiac adverse events are to be reported in either this page or extra form for targeted therapy visit (EF6), check the “no” box.

If yes, complete the remainder of the section as indicated below should experienced cardiac event be pre-printed on this page. Otherwise complete the page EF6 for other cardiac adverse events as indicated in the corresponding section of this document specific for page EF6.


Grade : Report the worst grade experienced during the visit (from the infusion reported in this visit until just before the next infusion) Enter 1-5, when appropriate by using the NCI CTCAE v3.0, otherwise use the severity code defined below:

1. mild : generally non-progressive, producing a minimal degree of tolerable discomfort2. moderate : may adversely affect normal daily activity, but is not completely

incapacitating


3. severe : marked intensity, may be either totally incapacitating or results in significant decrease in normal daily activity

4. life threatening : the patient was at immediate risk of death as the AE occurred. It does not include an experience that, had it occurred in a more serious form, may have caused death.

5. death


Serious: Enter either “yes” or “no” for each event indicating if the event was a serious adverse event as per the protocol:

A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose:

results in death (NOTE: for the non-cardiac AEs, death is an outcome, not an event), is life-threatening (NOTE: The term "life-threatening" in the definition of serious refers to

an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe),





Start Date/End Date: - Indicate the start date or if the AE was ongoing at time of study drug infusion of the visit, tick the “ongoing” box. If ongoing, please cross check that the AE was previously reported in the previous visit.Ongoing conditions must be reported and followed by the physician during study treatment using the “Cardiac Toxicity Monitoring Form”.

- Indicate the stop date or if the event is still ongoing at the end of the visit, the box “ongoing” should be ticked.

Medication to Treat Disease: Indicate if the patient has received or is receiving medication to treat the cardiac disease.If yes, complete the concomitant medication running log.

Action taken (study drug) (regarding study drug administration for the next visit).Complete using one of the following codes and specify for each adverse event the action taken regarding study medication for trastuzumab and bevacizumab.


For patients in the TCHH or THFECH regimens, the action taken study drug for bevacizumab should be completed with NA.

0. None : no change in study drug was made1. Discontinued: administration of study drug was permanently

discontinued (i.e. the patient was discontinued from study) due to this clinical adverse event. Please cross check with End of Targeted Therapy (EOT) page). In this case, the investigator has to select the main event(s) which led to patient’s discontinuation.

3. Dose Delay/Hold: change in the dosing regimen occurred prior to next visit (i.e, a delay > 4 days of next cycle’s study drug infusion) due to cardiac adverse event. Please cross check with the study drug administration page(s) at the next visit.

Most likely cause: Most Likely Cause concerns the relationship of the cardiac adverse event, which can be to study chemotherapy (1), Trastuzumab (2), Bevacizumab (3), Adj. Endocrine Therapy (4), Adj. Radiotherapy (5) and other (99) cause.

For each adverse event, enter the most likely cause. If there is more than one most likely cause per adverse event, then the combination of the most likely causes must be recorded.In case of several entries, the different causes should be listed separated by a comma.Ex: for an adverse event being due to study chemotherapy and trastuzumab, record as a most likely cause “1, 2”.

Assigning the most likely cause of the adverse event is the PI’s or co-investigator’s responsibility. This relationship must be source documented. Please note that ND is not acceptable.


E.O.T.END OF TARGETED THERAPY

As per the protocol, the End of targeted therapy visit should take place 2 to 3 weeks after the last infusion of trastuzumab and/or bevacizumab.The purpose of this page is to document the reason why study targeted therapy treatment (trastuzumab and bevacizumab) was discontinued.

1) Discontinuation of Trastuzumab:

If the patient never started trastuzumab, tick the “Not applicable “box and complete the next section about the discontinuation of bevacizumab.

If the patient started trastuzumab, specify primary reason for the patient’s discontinuation of trastuzumab:

One and only one reason must be indicated: Received total duration of one year treatment : If patient received until 1 year following first dose regardless of

any missed doses.

Breast Cancer Relapse : If the primary reason is a relapse, complete page BCR

Second Primary Malignancy : If the primary reason is a second primary malignancy, complete page SPM

Death : If primary reason is “death”, at least one adverse event must be recorded either in the AE running log or in the Cardiac Monitoring Form with an outcome of “death”. Death Report Form and SAE Report Form must be completed.

Cardiac Adverse Event : If the primary reason is “cardiac adverse event”, the main cardiac event should be reported in last visit with action taken (study drug) trastuzumab = “discontinued” ( code1) regardless of the relation to study medication.

LVEF decline : If the primary reason is LVEF decline, report the corresponding LVEF assessment(s) on form(s) C5 and/or V5.

Non-Cardiac adverse event : If the primary reason is “non-cardiac adverse event”, the main adverse event for which treatment discontinuation was required should be reported in the adverse event running log with Action Taken (study drug) trastuzumab = “discontinued” regardless of the relation to study medication.

Refused to continue trastuzumab : If the patient does not wish to receive additional administrations of trastuzumab but wishes to stay on study. This represents a patient decision and by convention does not allow for an adverse event to be noted with action taken study medication “discontinued”.

Consent withdrawn : This represents a patient decision. Consent withdrawn is also the appropriate box to be checked if the patient decided to pursue an alternative cancer therapy prior to the documentation of relapse of the disease while on study drug. Please tick the appropriate box to indicate whether the patient still agrees to have her medical history recorded for survival status (agrees to be followed) or does not want to be followed at all. If the patient withdrew her consent but agreed to be followed, this must be clearly source documented.


Other, specify : This is the appropriate selection for patients who decide to discontinue the study for an adverse event which according to the protocol does not need the trastuzumab to be stopped. In the CRF please report the reason as : other patient decision (AE XXX grade X)


2) Discontinuation of bevacizumab:

If the patient never started bevacizumab, tick the “Not Applicable” box.

If the patient started bevacizumab, specify primary reason for the patient’s discontinuation of bevacizumab:

One and only one reason must be indicated: Received total duration of one year treatment : If patient received until 1 year following first dose regardless of

any missed doses.

Breast Cancer Relapse : If the primary reason is a relapse, complete page BCR

Second primary Malignancy : If the primary reason is a second primary malignancy, complete page SPM

Death : If primary reason is “death”, at least one adverse event must recorded either in the AE running log or in the Cardiac Monitoring Form with an outcome of “death”. Death Report Form and SAE Report Form must be completed.

Cardiac Adverse Event : If the primary reason is “Cardiac Adverse Event” the main cardiac event(s) should be reported in last visit with action taken (study drug) bevacizumab = “discontinued” (code 1) regardless of the relation to study medication.

LVEF decline : If the primary reason is LVEF decline, report the corresponding LVEF assessment(s) on form(s) C5 and/or V5

Non-Cardiac Adverse Event : If the primary reason is “Non-Cardiac Adverse Event ”, the main adverse event for which treatment discontinuation was required should be reported in the adverse event running log with Action Taken (study drug) with action taken (study drug) bevacizumab = “discontinued” regardless of the relation to study medication.

Refused to continue bevacizumab : If the patient does not wish to receive additional administrations of bevacizumab but wishes to stay on study. This represents a patient decision and by convention does not allow for an adverse event to be noted with action taken study medication “discontinued”.

Consent withdrawn : This represents a patient decision. Consent withdrawn is also the appropriate box to be checked if the patient decided to pursue an alternative cancer therapy prior to the documentation of relapse of the disease while on study drug. Please tick the appropriate box to indicate whether the patient still agrees to have her medical history recorded for survival status (agrees to be followed) or does not want to be followed at all. If the patient withdrew her consent but agreed to be followed, this must be clearly source documented.


Other, specify : This is the appropriate selection for patients who were randomized but never treated.

This is also the appropriate selection for patients who decide to discontinue the study participation for an adverse event which according to the protocol does not need bevacizumab to be stopped. In the CRF please report the reason as : other patient decision (AE XXX grade X)


Preferably, all patient CRFs will be reviewed and the case report form review module signed by the site’s principal investigator after completion and corrections during the monitoring visits. However, any appropriately identified sub-investigator may review and sign s.


If the investigator has signed the EOT page before the monitoring visit and significant corrections are made to the preceding CRF segments during the visit, the investigator should re-sign and date the case report form review before retrieval by the monitor.


AR

ADJUVANT RADIOTHERAPY

Did the patient receive adjuvant radiation therapy?:- If NO, specify the main reason why the patient did not receive radiation therapy : site decision (i.e was not planned by the protocol or site decided not to give adjuvant radiotherapy to the patient) patient refusal other, specify. Please specify reason in the blank space provided.

- If YES, specify the main reason why the patient did receive radiation therapy : as per protocol site decision (ie was not planned as per protocol, but site decided however to give adjuvant radiotherapy to the patient) patient request other, specify. Please specify reason in the blank space provided.

If the patient received adjuvant radiation therapy, complete the remaining portion of the section with the information regarding the sites where radiation therapy was given.

Start date of radiation: Indicate the start date of the radiation therapy. If radiation occurred on different sites and started at different dates, indicate the date the first dose of radiation was received.

End date of radiation: Indicate the end date of the radiation therapy. If radiation occurred on different sites and stopped at different dates, indicate the date the last dose of radiation was received.

Radiation location: Specify if the patient received radiation therapy on the left or right side by ticking the applicable box.

Site (Description): Indicate the different sites where the patient received adjuvant radiotherapy. Preferably, use the pre-printed terms, however, if adjuvant radiotherapy was given to a site that is not pre-printed, record it as “other” and specify the site. Irradiation of the internal mammary nodes is discouraged because of the concern of potential cardiotoxicity.

Total dose: For each site irradiated, specify the estimated total dose given in the unit cGy.

ADJUVANT RADIOTHERAPY REVIEWPreferably, all patient CRF pages will be reviewed and signed by the site’s principal investigator after completion and correction during the monitoring visits. However, any appropriately identified sub-investigator may review and sign the patient CRFs.

The investigator’s signature date should be after the date of monitoring of the CRF page. If the investigator signed page AR before the monitoring visit and significant corrections were made during the visit, the investigator should re-sign and date the AR page before retrieval by the monitor. The form should be signed even if the adjuvant radiotherapy was not administered.


AET

ADJUVANT ENDOCRINE THERAPYDid the patient receive adjuvant endocrine therapy?Specify if the patient received adjuvant endocrine therapy by ticking the “Yes” or “No” box.If “No”, please leave the rest of the page blank.If “Yes”, please complete the remaining section.

Product name: Indicate in capital letters the product name on the blank line provided. Trade name is preferred.Please use only one product per line.

Start date and end date: Enter the start and end dates of administration of each product. Please note the order of the date is day/month/year. Note: if the treatment has been stopped for few days, it is not necessary to capture it at 2 different entries with start and stop dates.

Reason for Early Discontinuation of Endocrine Therapy: Indicate the reason for the early discontinuation of the given product by ticking the applicable box:

- BCR: Breast cancer relapse (complete form BCR)- SPM: Second primary Malignancy (complete form SPM)- AE: Adverse Event(s): specify in form V5, FU3 or AE Running Log. The Most Likely Cause of the

corresponding AE is expected to be Adj. Endocrine Therapy- Other, specify the reason.

ADJUVANT ENDOCRINE THERAPY REVIEW

Preferably, all patient CRF pages will be reviewed and signed by the site’s principal investigator after completion and correction during the monitoring visits. However, any appropriately identified sub-investigator may review and sign the patient CRFs.

The investigator’s signature date should be after the date of monitoring of the CRF page. If the investigator signed page AET before the monitoring visit and significant corrections were made during the visit, the investigator should re-sign and date the AET page before retrieval by the monitor.

The form should be signed even if adjuvant endocrine therapy was not administered.


AE RUNNING LOG

ADVERSE EVENT

The purpose of this CRF page is to record NON CARDIAC adverse events occurring at any time during the course of the trial. Only one adverse event is to be recorded per page and is to be followed from beginning to resolution.They are numbered in consecutive order starting from 01

Check on the randomization confirmation form to determine whether the patient is in the category of patients for whom, until the 18-month observation period, all AEs of any grade are to be reported, or whether the patient is in the category of patients for whom, until the 18-month observation period, only AEs of special interest > grade 2 , grades 1 and 2 AEs that require a change in treatment (i.e., a delay in treatment, a dose reduction, or discontinuation of one or more of the study therapy drugs), and all AEs > grade 3 are to be reported.


and 2BFor the next pts

AE reporting until 18 months after randomization

All AEs with grade 1 must be recorded All AEs of special interest ** with grade 2 Grades 1 and 2 AEs that require a change

in treatment (i.e., a delay in treatment, a dose reduction, or discontinuation of one or more of the study therapy drugs),

All AEs grade 3

AE reporting AFTER 18 months after randomization *

All related AEs grade 3 All AEs of special interest * with grade 2

* Reporting needs to be stopped in case of systemic treatment given for documented invasive Breast Cancer recurrence or diagnosis of 2nd primary malignancy (except for the serious related Adverse Events).

** List of AEs of special interest:In this study, "AEs of Special Interest" will include the following AEs which are listed using the NCI CTCAE v3.0 terminology:

Cardiac General: refer to Cardiac Toxicity Monitoring form Dermatology/Skin: Wound complication - non-infectious (dehiscence) Gastrointestinal: Fistula, GI Perforation, GI Hemorrhage/bleeding: Hemorrhage, GI Metabolic/laboratory: Proteinuria Neurology: CNS cerebrovascular ischemia (TIA, stroke) Neuropathy – sensory Other – Reversible Posterior Leukoencephalopathy Syndrome


Pulmonary/upper respiratory: Fistula Perforation Renal/genitourinary: Fistula, GU Perforation, GU Vascular: Peripheral arterial ischemia Thrombosis/thrombus/embolism Visceral arterial ischemia

Event:Indicate the Adverse Event experienced by the patient in the space provided. All AEs must be reported by using their corresponding NCI Terms when possible. If there is no appropriate NCI Term, report the most appropriate medical term. Record syndromes, not symptoms of a syndrome.

The NCI Toxicity Grading System used in BETH is NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 In case of SAE, the event term should be the same as the one used in the last follow-up SAE report form.

Conventions:

Reporting of abnormal laboratory result: please refer to the corresponding section of the CRF completion guidelines i.e “hematology” and “blood chemistry”.

Reporting of intermittent AEs:When AEs occur intermittently between the sequential administrations of treatment (i.e. between two scheduled treatments), they should be recorded only once, and their reoccurrence should be documented by marking the intermittent field in the CRF.

Reporting of death:Death due to an AE not of cardiac origin should not be reported as an AE grade 5 “as those AE could only be graded from 1 to 4) but will be reported as an outcome. Therefore, the most probable cause of death should be identified and reported as the AE with outcome death.

Reporting of breast cancer recurrence:An invasive breast cancer recurrence or the development of ipsilateral or contralateral DCIS occurring during the treatment period or during the follow-up period is not considered an AE and should therefore NOT be recorded as an AE, but should be recorded on the Breast Cancer Recurrence form in the CRF and documented as part of the efficacy evaluation.

This would also include any AE of CTCAE grade 3 or 4 intensity, or clinically significant grade 1 or 2 hematologic or biochemical laboratory values that are considered to be consistent with a confirmed or suspected breast cancer recurrence. Symptoms of recurrent breast cancer may be reported as AEs if the symptom(s) cannot be determined as exclusively due to the recurrence of a breast malignancy, or does not fit the expected pattern of recurrence for breast cancer.

Hospitalization due solely to a breast cancer recurrence and its symptoms should not be reported as a serious adverse event.

Reporting of a second invasive primary malignancyThe development of a second invasive primary malignancy (in-situ cancers are not included) is one of the events of the primary endpoint and should, therefore, not be considered and recorded as an AE. However, second primary malignancies that satisfy the SAE definition will be reported as an SAE regardless of causality and regardless of time of occurrence.

Note that reporting of adverse events, including AEs of Special Interest and cardiac AEs, is not required following a documented invasive breast cancer recurrence or diagnosis of a second primary malignancy, if treated with


systemic anticancer therapy. However, AEs that satisfy the criteria for an SAE and are considered to be related to study therapy/procedures must be reported as an SAE with no limit of time.

Start date:In any case, report the start date of the Adverse Event regardless of the grade. Please note the order is day/month/year.

Grade (Initial Intensity):Tick the box corresponding to the initial intensity of the adverse event. Tick the box associated with 1-4, when appropriate by using the NCI Toxicity grade, otherwise use the severity code defined below:

Clinical Definition of Severity CTCAE Grade*

Mild Discomfort noticed but not resulting in the disruption of the patient’s normal daily activity 1

ModerateDiscomfort sufficient to reduce or affect daily activity; no treatment or medical intervention is indicated although this could improve the overall well-being or symptoms of the patient

2

SevereInability to work or perform normal daily activity; treatment or medical intervention is indicated in order to improve the overall well-being or symptoms; delaying the onset of treatment is not putting the survival of the patient at direct risk

3

Life-Threateningor

Disabling

An immediate threat to life or leading to a permanent mental or physical condition that prevents work or performing normal daily activities; treatment or medical intervention is required in order to maintain survival

4

Grade (Most Extreme Intensity):Tick the box (only one) corresponding to the most extreme intensity of the adverse event. When appropriate always use the NCI Toxicity Grade, otherwise use the severity code defined above. This most extreme intensity can only be indicated when the adverse event is resolved.

Serious:Indicate whether the event was serious or not. If the event was serious, complete an SAE reporting form and submit it within 1 working day:

- For all NSABP sites to NSABP Biostatistical Center Fax Number for SAE Reporting: 1 (412) 622-2113

- For all other sites to CIRG Drug Safety Fax Number for SAE Reporting: U.S. and Canada: 1 (310) 478-7085Rest of World: +33 (1) 58 10 09 05


Outcome:Tick the box (only one) that best describes the outcome of the event:

- Resolved – no sequelae: The AE is resolved and no deficiency following the patient adverse event is remaining even after the event is resolved

- Resolved – with sequelae: The AE is resolved but a deficiency remains even after the adverse event is resolved

- Unresolved at the final visit: The AE is not resolved (still ongoing) at the time the AE running log is collected. This box is to be ticked if the AE is not resolved but does not need to be followed anymore according to the protocol.

- Death (complete the Death Report Form): only to be indicated if the death is a direct outcome of this specific AE.

Date Resolved:


For the first 300 pts enrolled in Groups 1A and 1B and the first 300 pts in Groups 2A and 2 B until 18 months after randomization: For the adverse events that were resolved (with or without sequelae), please indicate the date of resolution.

Note: an AE is considered resolved when all components are resolved (for example a febrile neutropenia will be resolved when both fever and neutropenia are resolved).

For the first 300 pts enrolled in Groups 1A and 1B and the first 300 pts in Groups 2A and 2 B and for the other patients : the date resolved to be reported would be the date when the AE does not require to be reported anymore according to the protocol.Example : Patient after the first 300 patients until the 18 months after vrandomization.AE of grade 3 that became a grade 2.The “date resolved” will be the date when the AE became a grade 2 as only AE grade 3 needs to be reported.

Intermittent:Some AEs are known to occur for the most part continuously, but have brief periods of resolution. These events may start, stop, and reoccur over relatively short intervals (e.g., frequent headaches, nausea, vomiting) between treatment cycles.

When AEs occur intermittently between the sequential administration of treatment (i.e., between two scheduled treatments), such AEs should be recorded only once, and their reoccurrence should be documented by marking the intermittent field in the CRF.

Tick the box “Yes” or “No” to confirm if the AE is intermittent. If the AE is intermittent, the start date of the adverse event to be reported is the date the AE was experienced for the first time, the date resolved (if the AE resolved) is the date the AE was resolved when experienced for the last time.

Action taken (study drug): For each of the drugs received by the patient (chemotherapy, trastuzumab and bevacizumab), tick the action taken to the study drug:

- None: no action taken – no change in study drug was made- Discontinued: administration of study drug was permanently discontinued due to the clinical adverse event

If chemotherapy is ticked as discontinued, primary reason for end of chemotherapy reason on page EOC should be “non cardiac adverse event”

If trastuzumab is ticked as discontinued, primary reason for discontinuation of trastuzumab on page EOT should be “non cardiac adverse event”

If bevacizumab is ticked as discontinued, primary reason for discontinuation of bevacizumab on page EOT should be “non cardiac adverse event”

- Dose delay/hold: administration of study drug was temporarily delayed or held, due to the non cardiac adverse event. This should be reflected on the following cycle/visit administration form.

- Dose reduction: the dose of study drug for the next cycle was reduced due to the non cardiac adverse event. This is not applicable for trastuzumab and bevacizumab which cannot be reduced. This should be reflected on the following cycle/visit administration form.

Note: If the patient is not or no longer taking the relevant study medication when the adverse event starts, please tick the “none” box.

Most likely cause:Indicate the most likely cause of the adverse event More than one most likely cause per adverse event can be ticked

1. Chemotherapy 2. Trastuzumab3. Bevacizumab4. Adjuvant Endocrine Therapy5. Adjuvant Radiotherapy99 Other, for example: if the patient has received another chemotherapy after the study treatment, and if

the investigator considers that the adverse event is due to this new chemotherapy, its most likely cause should be “other”.


Criteria for assigning a drug-adverse event relationship:YES NO

Reasonable temporal association with drug administration

It does not follow a reasonable temporal sequence from administration of the drugIt may readily have been produced by the patient’s clinical state, environmental or toxic factors, or other modes of therapy administered to the subject

Known response pattern to suspected drug It does not follow a known pattern of response to the suspected drug

Disappears or decreases on cessation or reduction in dose

Reappears on rechallenge It does not reappear or worsen when the drug is re-administered

Was any significant medication administered to treat this adverse event?Tick the “Yes” or “No” box to confirm the administration of significant medication to treat the adverse event.If “Yes”, the Conmed Running Log should be completed and the “medications given to treat the AE” should be recorded with indication = code 2 “non cardiac adverse events”.Note : The AE running log should be collected once all information completed except in case of interim analysis where the golden copy should be retrieved.

Examples:

1) Example 1 : A patient is randomized after the first 300 patients. At cycle 02 (date of administration: 08 Jun 2009)She experienced grade 1 diarrhea starting on 08 Jun 09. The diarrhea becomes a grade 3 on 14 Jun 09 for which the patient was hospitalized and corrective treatment given. Diarrhea later resolved on 16 Jun 09. The next cycle (cycle03) was not delayed but the chemotherapy was reduced of one dose level.

Of note : in case most extreme grade = 2 and no dose reduction for chemotherapy, this AE does not need to be reported.


2) Example 2 :Cycle 01 was administered on 09 Feb 09. Thrombocytopenia grade 2 started on 01 Mar 09.Cycle 02 was due to 02 Mar 09 but due to the thrombocytopenia, the treatment was delayed.The patient returned on 09 Mar 2009 and her platelets were 29,000 or grade 3. Therefore the cycle was again delayed. One week later the patient was seen on 16 Mar 09 and thrombocytopenia was grade 1. The study treatment was administered on that day at a reduced dose (one dose level reduction for chemotherapy). The patient came back for the next cycle on 06 Apr 09. The patient had thrombocytopenia grade 4 and was hospitalized. Study treatment was held again.One week later (13 Apr 09), thrombocytopenia resolved and the treatment was given with a second dose reduction.


CONMED RUNNING LOG

SIGNIFICANT CONCOMITANT MEDICATIONS

Please record only:- medications given for pre-existing ongoing significant cardiovascular medical history reported on B5. - significant medications given to treat reportable adverse events (cardiac or non-cardiac).

Note: if the Adverse Event is not required to be collected (for example after the 1 st 300 patients) and is treated, there is no need to report the respective treatment on the Concomitant Medication Running Log.

- significant medications given with a prophylactic intent – do not record docetaxel premedications (This includes dexamethasone but also the non-steroidal premedication like cimetidine that may be given in addition to dexamethasone).any other medication given with other intent such as antiemetic does need to be reported.

Please do not record phytotherapy or homeopathy medications.Product name:Indicate in capital letters the product name on the blank line provided. Trade name is preferred.Please use only one product per line.

Indication for use:Enter one code for each drug entry.If the same medication is used for more than one indication (example prophylaxis and adverse event), then recordonly the main indication.Nevertheless, if it is helpful in a medical perspective, split the drug and report in two lines (curative / prophylactic).

Code “1”: Cardiac Adverse Event. Note: also applicable for ongoing pre-existing significant cardiovascular medical history

Code “2”: Non Cardiac Adverse EventCode “3”: Prophylaxis

All listed medications with code 1 or 2 must be cross-referenced with the medication question on the Cardiac Adverse Event and/or AE Running log pages (C.5, V5, FU3 and AE Running Log) or in the cardiovascular history section (B5).

Start date:Indicate the start date of the concomitant medication. End date:Indicate the stop date of the concomitant medication or tick the “ongoing” box if it was ongoing at the time of last visit.

If the patient dies and had concomitant therapies ongoing at the time of death, these should remain as ongoing at the time of death.

Note : The Conmed running log should be collected once all information completed except in case of interim analysis where the golden copy should be retrieved.


FOLLOW UP VISIT


FU.1PHYSICAL EXAMINATION

The numbering of follow up visits should start from 01.

Was a physical examination performed? To be performed every 6 months +/- 1 month from year 1 to year 5 and then every 12 months +/- 2 months from year 6 to year 10.Indicate whether or not a physical examination was performed.If no, check the “no” box. The Investigator should then sign off in the case report review section.

If yes, specify the date of assessment. Date of Assessment

Indicate the date when the physical examination was performed.If no physical exam was performed but there is still something to be reported (i.e. death, lost to follow up or other) date of assessment should be entered as NA

Are there any changes since the previous assessment? Indicate if there were any changes since the previous assessment by ticking the “Yes” or “No” box. If “Yes”, please tick the box that best describes the change. Breast Cancer Relapse : Complete page BCR

Second primary Malignancy : Complete page SPM

Death : If primary reason is “death”, Death Report Form must be reportd. The SAE Report Form must be completed if the death occurred within 30 days after the last administration with the exception if the death due to breast recurrence (not to be reported as AE according to the protocol). After this period the death will have to be reporting as SAE only if applicable.

In case it is applicable according to the protocol AE reporting rules, the corresponding one adverse event must be marked with significant consequences “death” except. Cardiac adverse event : If “cardiac adverse event”, the main cardiac event(s) should be reported on page FU3

with the most likely cause clearly identified.

Non-cardiac adverse event : If “non-cardiac adverse event”, the main adverse event(s) should be reported in the adverse event running log. In case the AE wouldn’t have to be reported anymore, the box shouldn’t be ticked.

Received any cancer therapy other than the assigned protocol therapy : Complete form EF1 (anti-tumor therapy other than for breast cancer therapy relapse or second primary malignancy).

Consent withdrawn : This represents a patient decision Consent withdrawn is also the appropriate box to be checked if the patient decided to pursue an alternative cancer therapy prior to the documentation of relapse of the disease. Please tick the appropriate box to indicate whether the patient still agrees to have her medical history recorded for survival status (agrees to be followed) or does not want to be followed at all (did not agree to be followed)

If the patient withdrew her consent but agreed to be followed:o this must be clearly source documentedo the date of annual telephone contact should be recorded as the “date of assessment” on the FU1 follow-

up visit page. Pages FU2 and FU3 of the Follow-up visit do not need to be completed and can be left blank at the site.



Other, specify : This is the appropriate selection if none of the previous possibilities correspond to the patient’s situation.


Preferably, all patient CRFs will be reviewed and signed by the site’s principal investigator after completion and corrections during the monitoring visits. However, any appropriately identified sub/co-investigator may review and sign patient CRFs.

If the investigator has signed the FU1 page before the monitoring visit and significant corrections are made to the preceding CRF segments during the visit, the investigator should re-sign and date the FU1 Cae report form review before retrieval by the monitor.


FU.2BREAST IMAGING

To be performed every 12 months (+/- 1 month from year 1 to year 5 and +/- 2 months from year 6 to year 10) . The first assessment will be 1 year from the most recent mammogram or MRI performed prior to randomization.

Did the patient have breast imaging?Report whether or not the patient had Breast Imaging by indicating “Yes” or “No”.If “no”, check the “no” box and do not complete the remainder of the section.

If “yes”, please indicate:

Date of Assessment:Report only the date of the most recent test that was performed to check patient’s current status (do not report twice the same assessment: in case the assessment was already reported in a previous visit, tick the “no” box in previous question).

Site of Breast Imaging:Tick the appropriate box (indicating on which breast the assessment was done)If bilateral mammogram is performed, the Left and Right box is to be checked.

Type of exam:Indicate the exam that was performed for assessing the breast status (mammography, MRI or other; if other, please specify the type of exam).

Please note that the mammography is the only method allowed per the protocol after randomization.

Tumor involvement:Check either “yes” or “no”.

- If the Breast Imaging demonstrates tumor involvement “yes”, complete the BCR or SPM CRF page.


FU.3CARDIAC TOXICITY MONITORING FORM

This page must be faxed to CIRG Data Management (FAX Number: (1) 780 702 0190):1. Within 21 days after LVEF assessments

- Required at the protocol specified timepoints (see LVEF TIMING table below)- Not scheduled but done for any reason during the 5 years following randomization- Not scheduled but done because the patient has signs and symptoms of CHF during years 6 to 10

following randomization

2. Within 21 days of learning of any of the following cardiac events - Cardiac left ventricular dysfunction with NYHA Class III/IV symptoms- Definite cardiac death defined as death due to congestive heart failure, myocardial infarction or documented

primary arrhythmia- Probable cardiac death defined as sudden death without documented etiology- Grade 3/4 cardiac ischemia/infarction3. Grade 3 systolic or diastolic dysfunction with NYHA Class II symptoms4. Grade 2 systolic dysfunction

Note: if only hypertension is reported, the form does not need to be faxed. For the purpose of BETH, grade 1 decrease in LVEF will be defined as asymptomatic drop to 50-54%, LVEF values of 55-59% will not be considered gr 1 LVEF dysfunction.

LVEF TIMING









Left Ventricular Ejection Fraction

Was a LVEF performed?: Indicate if a LVEF was performed by ticking the “Yes” or “No” box. If “No”, tick the no box and answer to the other questions of the page.If “yes”, tick the yes box and complete the remainder of this section.


LVEF at rest: LVEF at rest must be performed either with echocardiography or radionuclide angiocardiography (MUGA scan). Indicate which method was used.


If the LVEF has been assessed by both methods (radionuclide angiocardiography and echocardiography), report the results of both of them on page FU3, use page E.F.4 to record any additional results.


If the facility performing the assessment will only report the LVEF as a range, the mean (average) of the values used for the range should be calculated by the investigator and entered into patient’s medical charts so that a single numerical value can be reported. For example a range of 50- 55will have to be reported as 53 (since 52.5 is to be rounded-up).

It is strongly advised that LVEF is measured with the same method (MUGA or echocardiography) and that they are determined at the same radiology facility and by the same team as at baseline.

Blood PressureTo be performed at each Follow up visit.If additional blood pressure were taken, they should be recorded only if abnormal values were observed by using extra forms (EF4).

Was Blood Pressure Taken?: Indicate if Blood Pressure was performed by ticking the Yes or No box.

If yes, please complete the remainder of this section.

Date of Assessment: Enter the date of assessment.



Cardiac Adverse Events:

Reporting of Adverse eventsThe following table summarizes the cardiac events to be reported during the follow up:







- Hypertension





Are there any Cardiac Adverse Events?Indicate if any Cardiac Adverse Events were experienced during this follow up visit by ticking the Yes or No box.If no cardiac adverse events are to be reported in either this page or extra form for targeted therapy visit (EF6), check the “no” box.

If yes, complete the remainder of the section as indicated below should the experienced cardiac event be pre-printed on this page. Otherwise complete the page EF6 for other cardiac adverse events as indicated in the corresponding section of this document specific for page EF6.


Grade: Enter 1-5, when appropriate by using the NCI CTCAE v3.0, otherwise use the severity code defined below:

1. mild : generally non-progressive, producing a minimal degree of tolerable discomfort2. moderate : may adversely affect normal daily activity, but is not completely incapacitating3. severe : marked intensity, may be either totally incapacitating or results in significant decrease in

normal daily activity4. life threatening : the patient was at immediate risk of death as the AE occurred. It does not include

an event that, had it occurred in a more serious form, may have caused death.5. death


Serious:Enter either “yes” or “no” for each event indicating if the event was a serious adverse event as per the protocol:

A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: results in death (NOTE: for the non-cardiac AEs, death is an outcome, not an event),


is life-threatening (NOTE: The term "life-threatening" in the definition of serious refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe),


Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the outcomes listed in the definition above. These should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or


All serious adverse events must be reported within 24 hours. If serious, make sure all information is matching the corresponding SAE report form in its last follow-up.

Start Date/End Date:Indicate the start date and/or end date and/or if the AE was ongoing.

Medication to Treat Disease:Indicate if the patient has received or is receiving medication to treat the cardiac disease.If yes, complete the concomitant medication running log.

Most Likely Cause:Most Likely Cause concerns the relationship of the cardiac adverse event to chemotherapy, Trastuzumab, Bevacizumab, Endocrine Therapy, Radiotherapy or other cause.

Indicate the most likely cause of the adverse event More than one most likely cause per adverse event could be chosen (in case of several entries, the different causes should be listed separated by a comma):Study chemotherapy

2. Trastuzumab3. Bevacizumab4. Adjuvant Endocrine Therapy5. Adjuvant Radiotherapy99. Other

Assigning the most likely cause of the adverse event is the PI’s or co-investigator’s responsibility. This relationship must be source documented.


SURVIVAL

SURVIVAL FOLLOW-UPThe purpose of the Survival Follow up is to record overall survival and the patient status ONLY after the patient experienced a breast cancer relapse or second primary malignancy treated with a systemic anti-cancer treatment. This form should be completed every 6 months +/- 1 month from year 1 to year 5 and then every 12 months +/- 2 months from year 6 to year 10 after patient experienced a breast cancer relapse or second primary malignancy for which she received a systemic anti-cancer treatment. Note: a patient who experienced a BCR or SPM treated with non-systemic treatment should go on regular follow-up.

PATIENT STATUS :

Date of AssessmentIndicate the date of assessment and complete the section.Are there any changes since the previous assessment?Indicate if there were any changes since the previous assessment by ticking the “Yes” or “No” box. If “Yes”, please tick the box that best describes the change.Check all that apply: Breast Cancer Relapse : Complete page BCR

Second primary Malignancy : Complete page SPM

Death : Death Report Form, AE running log + SAE Report Form (if related) must be completed.

Cardiac adverse event : If “cardiac adverse event”, the main cardiac event should be reported on page EF7 with the most likely cause clearly identified. Note: if case of a related non-cardiac AE, please select “other” and report the Adverse Event description.

Consent withdrawn : This represents a patient decision and by convention does not allow for an adverse event to be noted with action taken study medication “discontinued”. Consent withdrawn is also the appropriate box to be checked if the patient decided to pursue an alternative cancer therapy prior to the documentation of relapse of the disease while on study drug. Please tick the appropriate box to indicate whether the patient still agrees to have her medical history recorded for survival status (agrees to be followed) or does not want to be followed at all (did not agree to be followed). If the patient withdrew her consent but agreed to be followed, this must be clearly source documented.


Other, specify : This is the appropriate selection if none of the previous possibilities correspond to the patient’s situation


Preferably, all patient CRFs will be reviewed and signed by the site’s principal investigator after completion and corrections during the monitoring visits. However, any appropriately identified sub/co-investigator may review and sign patient CRFs. If the investigator has signed the Survival page before the monitoring visit and significant corrections are made to the preceding CRF segments during the visit, the investigator should re-sign and date the Survival case report form review before retrieval by the monitor.


BCR

BREAST CANCER RELAPSE

The purpose of the Breast Cancer Relapse page is to record the date, sites of breast cancer relapse as well as proof of relapse. Note : the medication given to treat a BCR and/or SPM are not to be recorded in the CRFBreast cancer relapse number:If a patient experiences more than one breast cancer relapse, the relapse number should be specified on the top right corner of the CRF (e.g. enter “01” for the first relapse and “02” for the second relapse…)

Diagnosis:Check all that apply: “local”, “regional” and/or “distant”.For each type of relapse, specify the site(s) where the breast cancer relapsed and specify what exam was performed to prove the event.

Note: Whenever possible, every effort should be made to obtain the histological/pathological/cytologic proof of relapse.

In the case that the relapse occurs during follow-up, a full work-up should be done in order to determine the extent of the disease and a full follow-up visit should be completed reporting when breast cancer relapse was assessed. In the follow up or survival follow up CRF page, the question ”are they any changes since previous assessment” should be recorded as “yes”, with “breast cancer relapse” given as the reason.

Date of Assessment:Enter objective date of relapse (clinical examination, work-up assessment…).In case of a procedure, please report the date of procedure rather than the date of the report.

For local relapse, this corresponds to the date of the positive biopsy. However, if a patient also meets criteria for regional or distant metastatic disease, results of clinical exams alone will be sufficient to document local recurrences.For regional relapse, this corresponds to the date of the positive biopsy or cytology. However, if a patient meets criteria for distant metastatic disease, results of clinical exams alone will be sufficient to document regional recurrences.For distant relapse, this corresponds to the date of work-up (Chest-X-Ray, abdominal ultrasound, CT-Scan….)

Collection of relapse:

- Only the first local and regional relapses should be reported.- If the first local recurrence is non-invasive breast cancer, the first invasive breast cancer recurrence must

also be reported.- The first distant recurrence and the first central nervous system recurrence will be collected and

reported.

Note: once the patient had a breast relapse, the treatment (systemic or local) given for the BCR does not have to be reported as well as any potential adverse event. Any ongoing AE at that time will be reported as “ongoing at the final visit”.


SPM

SECOND PRIMARY MALIGNANCY

The purpose of the Second Primary Malignancy CRF is to record the diagnosis, the proof and the date of occurrence of any second primary malignancy.

Diagnosis:Indicate the location of the second primary malignancy by ticking the applicable pre-printed box.If the diagnosis is not listed, clearly indicate it in the “Other”, specify space provided.

If ipsilateral to the primary tumor and same histology, please fill-in only the breast cancer relapse form.

Exam to Prove Event:Indicate the evaluation/method used to determine the Second Primary Malignancy by ticking the applicable box. If another diagnosis was specified, please also clearly indicate the evaluation/method used in the “Other”, specify space provided.

Date of Assessment:Enter the date the pathology sample was taken and not the date the result was obtained or the date of report.

Collection of second primary malignancyAll second primary malignancies should be collected, whether or not the patient has received any systemic or non systemic treatment for breast cancer relapse or for a previous second malignancy.Note:

- SPM can meet SAE criteria and thus be reported as an SAE.- Once the patient had a diagnosis of second malignancy, the treatment (systemic or local) given for the SPM

does not have to be reported as well as any potential adverse event. Any ongoing AE at that time will be reported as “ongoing at the final visit”.


SERUM AND PLASMA SAMPLE LOG

Optional: For patients who have consented to the serum/plasma samples collection.

Time points of samples collection:Collection of serum and plasma samples during study therapy and follow up period should be performed within 72 hours prior to the actual chemotherapy cycle or dose of targeted therapy:

After randomization prior to therapy Prior to C2 Prior to C4 After end of chemotherapy prior to targeted therapy After 3 months of targeted therapy alone After 6 months of targeted therapy alone At 18 months (+/- one month) after randomization At 36 months after randomization Every 12 months beginning from year 3 through year 10 (following randomization)

In addition, collection of Serum and plasma samples are also requested within 2 weeks after any of the protocol-specified cardiac events and following diagnosis of breast cancer recurrence (before initiation of therapy). For each time point, please complete the date of sample collection.

Note: The CRF contains 3 pages for each blood (serum or plasma) collection, corresponding to the following samples collection time points:

during the treatment phase during the follow up phase in case Cardiac adverse event and in case of breast cancer relapse


SCW_BS

SUB STUDIES CONSENT WITHDRAWAL (BLOOD – Plasma, Serum)This CRF page should only be completed for patients who entered in the blood sub-studies (i.e. allowed blood samples to be collected for the purpose of the study) AND who withdrew their consent.A patient may withdraw from the serum and plasma portion of the sub-study without withdrawing from the PG protocol, and vice versa.Note regarding the informed consent withdrawal related to the DNA sample (PG protocol): This information is recorded separately on the BSC_AS page (DNA repository blood sample collection form)

Consent withdrawal status blood samples:

Please specify the date of consent withdrawal.

Consent withdrawal review-blood samples


SCW_TS

SUB STUDIES CONSENT WITHDRAWAL (TISSUE)

This CRF page should only be completed for patients who entered in the sub-studies (i.e. allowed tissue samples to be kept by the central laboratory for further testing) AND who withdrew their consent.

Consent withdrawal status tissue samples:Please specify the date of consent withdrawal.

Consent withdrawal review-tissue samples



BCS_ASDNA REPOSITORY BLOOD SAMPLE COLLECTION

Optional: For patients who have consented to the DNA sample collection (PG protocol)

Blood sample:

Indicate the date the informed consent related to the collection of the DNA sample was dated and signed by the patient as well as the date of collection of this sample.

Consent withdrawal status blood sample:

Please specify the date of consent withdrawal for the DNA blood sample.

Consent withdrawal review-blood samples

Preferably, all patient CRFs will be reviewed and signed by the site’s principal investigator after completion and corrections during the monitoring visits. However, any appropriately identified sub/co-investigator may review and sign patient CRFs


LOST TO FOLLOW UPThis log must be completed for each patient potentially lost to follow up i.e. who misses a visit planned by the protocol.

This log must be completed to summarize the different attempts for contacting the patient.

Date of Contact Attempt The investigator research team should attempt to contact patients for each visit planned by the protocol. Each contact attempt made as per the guidelines for reducing loss to follow-up should be recorded.

Comments: Please indicate the method of contact (call, letter...) and the outcome.


DEATH

DEATH REPORT FORM

Date of death:Indicate the date of death.Complete as applicable an End of chemotherapy, End of Targeted therapy, a follow-up or survival follow-up visit (if the patient had received any systemic therapy for breast cancer relapse or second primary malignancy with the box “death” marked ) at the date of death.

Primary Cause of death:Indicate the primary cause of death by ticking one (just one option is allowed) of the following reasons:

- Breast cancer relapse : a breast cancer relapse section should be completed (page BCR)

- Malignant disease, other than breast cancer : a second primary malignancy form should be completed (page SPM)

- Cardiac adverse event : If “cardiac adverse event”, the main cardiac event should be reported on page C5, V5 FU3 with grade 5 and the most likely cause clearly identified.

Note: a sudden death of unknown etiology falls into this category

- Non-cardiac adverse event : If “non-cardiac adverse event”, the main adverse event should be reported in the adverse event running log with outcome death. Note: if the adverse event is not to be reported anymore according to the AE reporting rules as per protocol, then this box should not be selected and ‘other’ would be the most appropriate box to be ticked.

- Other, specify the cause of death. This may include death due to a non-reportable adverse event (for example a non-study drug related adverse event).

Underlying cause of death (if applicable):If applicable, clearly write the underlying cause of death in the space provided.

Causal Relationship to Study Drug:Tick the appropriate “Yes” or “No” box for each question, confirming the suspected causal relationship to chemotherapy, trastuzumab and bevacizumab.

AUTOPSY

Was an autopsy performed?Indicate whether or not an autopsy was performed by ticking the Yes or No box.If yes, specify the sites of disease at autopsy (check all that apply and, if “other” is ticked, specify). If there was no evidence of the disease, tick the “No evidence of disease” box.

DEATH REPORT REVIEWThe form must be dated and signed by the investigator.

A patient’s death during study chemotherapy period (from registration to 30 days after the last study drug infusion) requires the completion of a Serious Adverse Event Form unless it is due to relapse of breast cancer. After this period, only deaths related to study therapy/procedures would need to be reported as SAE.


EXTRA FORMS

1) EF1 / ANTI-TUMOR THERAPY OTHER THAN FOR BREAST CANCER RELAPSE OR SECOND PRIMARY MALIGNANCY

This form is to be completed only to record anti-tumor therapies given for other reasons than breast cancer relapse or second primary malignancy.

Please tick the baseline box or indicate the cycle, visit or follow up number in the space provided beneath the header.

Did the patient receive systemic anti-cancer therapy?:Indicate if the patient received any systemic anti-cancer therapy (other than for breast cancer relapse or second primary malignancy) by ticking the “Yes” or “No” box. If no, check the “no” box and do not complete the remainder of the section.

If “Yes”, (ie the patient received systemic therapy) indicate: Type of therapy: Complete the section corresponding to the type of therapy received. Tick “NOT APPLICABLE”

for the therapy(ies) that was/were not given.One row must be completed per regimen of systemic therapy received.

Trade name: enter the trade name of the systemic anti-cancer therapy, one trade name per line. If the patient received a combination of chemotherapy agents as one regimen, record the names of the different drugs in the same regimen box but use one line for each of them.

Start date: Indicate the date the systemic anti-tumor therapy started or if it was ongoing at the time the CRF page was collected.

End date: Indicate the date the systemic anti-tumor therapy stopped or if it was ongoing at the time the CRF page was collected.

Did the patient receive non-systemic anti-cancer therapy?:Indicate if the patient received non-systemic anti-cancer therapy by ticking the “Yes” or “No” box.If no, check the “no” box and do not complete the remainder of the section.

If “Yes”, (ie the patient received non systemic therapy) indicate: Type of therapy: Complete the section corresponding to the type of therapy received.

Site/procedure for radiotherapy and surgery: indicate the site and or the procedure of the radiotherapy or surgery.

Start date: Indicate the date the surgery was performed or the start date of the radiotherapy.

End date : Indicate the end date of the radiotherapy or tick ongoing if the CRF page is collected prior to being completed.

2) EF2

HEMATOLOGY


Please tick the baseline box or indicate the cycle, visit or follow up number in the space provided beneath the header.



Date of sample:

Enter the date the hematology sample was taken rather than the date of the report.

If additional hematology tests were performed, they should be recorded only if abnormal values were observed. In this case, infusion is to be given only once values are back to the normal. This has to be documented by recording the normal values just prior to infusion.


Actual Units: If the units are the same as the recommended ones, leave the actual units blank. If test units are different from the pre-printed recommended units, enter the actual unit in the appropriate column. The units recorded should therefore correspond to the units used on the source documents.





are “serious”.

URINE PROTEIN



Date of sample :Enter the date the UPC or the urine dipstick was done.- Method:

Please indicate which method has been used (UPC ratio or urine dipstick)



- UPC ratio (See Appendix 7)Enter the UPC ratio. The UPC ratio is obtained by dividing the urine protein by the urine creatinine:


Total urine protein (or urine albumin) ÷ urine creatinine = UPC ratioEnter the result as the value with 2 decimal places.



Was a 24-hour urine collection performed ?Indicate whether or not a 24-hour urine collection was performed.If no, check the “no” box and do not complete the remainder of the section. If “yes”, tick the “yes” box and complete the remainder of the section.Note that this question must be checked even if the urine protein was normal in the question above.



Note:In case of clinically significant abnormal urine protein value: please report it on the AE running log Clinically significant abnormal laboratory findings are those that:


result in a change of study therapy (e.g., dose modification, delay, or permanent discontinuation); or result in a change in concomitant therapy (e.g., addition of, delay of, discontinuation of, or any other change in a

concomitant medication, therapy, or treatment).

are “serious”.


3) EF 3 /BLOOD CHEMISTRYPlease tick the baseline box or indicate the cycle, visit or follow up number in the space provided beneath the header.



Date of sample: Enter the date the blood chemistry sample was taken rather than the date of the report.If additional blood chemistry tests were performed, they should be recorded only if abnormal values were observed. In this case, infusion is to be given only once values are back to the normal. This has to be documented by recording the normal values just prior to infusion.

Test: Creatinine Clearance is only required for Groups 1A and 1B.

Value: Enter laboratory results. Do not convert. Use the same values as in source documents.If one test was not performed, enter ND in the value field.

Actual Units: If the units are the same as the recommended ones, leave the actual units blank. If test units are different from the pre-printed recommended units, enter the actual unit in the appropriate column. The units recorded should therefore correspond to the units used on the source documents.

Upper normal limit for the institution: Enter for each test that was performed the upper normal limit for the institution except for the creatinine clearance).. Unit of the upper normal limit for the institution should be the same as unit of the value.

Note:In case of clinically significant blood chemistry abnormality: please report it on the AE running log.Clinically significant abnormal laboratory findings are those that:




are “serious”.


4) EF 4Fax this page to CIRG at 1-780-702-0190 per Protocol Section 5.0

Please tick the baseline box or indicate the cycle, visit, follow up or Survival Follow up number in the space provided beneath the header.

ELECTROCARDIOGRAM

Was an additional electrocardiogram performed?Indicate if an additional electrocardiogram was performed by ticking the “Yes” or “No” box.If “no”, check the “no” box and do not complete the remainder of the section. If “yes”, tick the “yes” box and specify:

Date of assessment: Enter date electrocardiogram was performed (and not the date of the report).

LEFT VENTRICULAR EJECTION FRACTION

Was a LVEF performed? Indicate if a LVEF was performed by ticking the “Yes” or “No” box. If no, check the “no” box and do not complete the remainder of the section.If “yes”, tick the “yes” box and specify:


LVEF at rest: LVEF at rest must be performed either with echocardiography or radionuclide angiocardiography (MUGA scan). Indicate which method was used.

If the LVEF has been assessed by both methods (radionuclide angiocardiography and echocardiography), report the results of both of them.


If the facility performing the assessment will only report the LVEF as a range, the mean (average) of the values used for the range should be calculated by the investigator and entered into patient’s medical charts so that a single numerical value can be reported. For example a range of 50-55will have to be reported as 53 (since 52.5 is to be rounded-up).

It is strongly advised that LVEF is measured using the same method (MUGA or echocardiography) and that they be determined at the same radiology facility and by the same team as at baseline.

BLOOD PRESSURE. Was Blood Pressure Taken?: Indicate if Blood Pressure was performed by ticking the “Yes” or “No” box. If no, check the “no” box and do not complete the remainder of the section.If “yes”, tick the “yes” box and specify:


5) EF 5 / CARDIAC ADVERSE EVENTS (CHEMOTHERAPY VISIT):

This page must be faxed to CIRG Data Management (FAX Number: (1) 780 702 0190):

Within 21 days of learning of any of the following cardiac events- Cardiac left ventricular dysfunction with NYHA Class III/IV symptoms- Definite cardiac death defined as death due to congestive heart failure, myocardial infarction or documented

primary arrhythmia- Probable cardiac death defined as sudden death without documented etiology- Grade 3/4 cardiac ischemia/infarction- Grade 3 systolic or diastolic dysfunction with NYHA Class II symptoms- Grade 2 systolic dysfunction

Note: For the purpose of BETH, grade 1 decrease in LVEF will be defined as asymptomatic drop to 50-54%, LVEF values of 55-59% will not be considered grade 1 LVEF dysfunction.

Reporting of Adverse eventsThe following table summarizes the cardiac events to be reported during the therapy:







- Hypertension



Grades 1 and 2 AEs that require a change in treatment (i.e., a delay in treatment, a dose reduction, or discontinuation of one or more of the study therapy drugs),



Description: Please use the blank space provided to report additional cardiac adverse events experienced during the cycle that could not be reported on CRF page C.5.

Grade: Report the worst grade experienced during the cycle (from the infusion reported in this cycle until just before the next infusion) Enter 1-5, when appropriate by using the NCI Toxicity Grade, otherwise use the severity code defined below:

1 mild: generally non-progressive, producing a minimal degree of tolerable discomfort2 moderate: may adversely affect normal daily activity, but is not completely incapacitating3 severe: marked intensity, may be either totally incapacitating or results in significant decrease in normal daily activity4 life threatening: the patient was at immediate risk of death as the AE occurred. It does not include an event that, had it occurred in a more serious form, may have caused death.


5 death



A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: results in death (NOTE: for the non-cardiac AEs, death is an outcome, not an event), is life-threatening (NOTE: The term "life-threatening" in the definition of serious refers to an event in which the






Start Date or ongoing/Stop Date or ongoing: - Indicate the date of onset or if the AE was ongoing at time of study drug infusion of the cycle, tick the “ongoing” box:Ongoing conditions must be reported and followed by the physician during study treatment using the “Cardiac Toxicity Monitoring Form”.

- Indicate the end date or if the event is still ongoing at the end of the cycle, the box “ongoing” should be ticked.

Medication to Treat AE: Indicate if the patient has received or is receiving medication to treat the cardiac disease.If yes, complete the concomitant medication running log.

Action taken (Study drug) (regarding study drug administration for the next cycle).Complete using one of the following codes and specify for each adverse event the action taken regarding study medication for chemotherapy, Trastuzumab and Bevacizumab.For patients in the TCHH or THFECH regimens, the action taken study medication for Bevacizumab should be completed with 0 or NA.

1. None : no change in study drug was made2. Discontinued: administration of study drug was permanently discontinued (i.e the patient was

discontinued from study) due to clinical adverse event (cross-reference with page E.O.C). In this case, the investigator has to select the main event which led to patient’s discontinuation.

3. Dose reduced : the total dose of study drug for the next cycle will be reduced due to clinical adverse event (not applicable for Trastuzumab or Bevacizumab. Please cross check with the study drug administration page(s) at the next cycle.

4. Dose delay/Hold: change in the dosing regimen occurred prior to next cycle (i.e, a delay > 4 days of next cycle’s study drug infusion) due to cardiac adverse event. Please cross check with the study drug administration page(s) at the next cycle.

5. Dose reduced and dose delay: the combination of choices 2 and 3 (not applicable for Trastuzumab or Bevacizumab)


Relationship to study drug: Relationship to study medication concerns the relationship of the adverse event to chemotherapy, Trastuzumab and Bevacizumab.Enter “No” or “Yes” for chemotherapy, Trastuzumab and Bevacizumab

1. No: the clinical adverse event is definitely unrelated to the study drug (it does not follow a temporal sequence from study drug administration, may have been present prior to receiving study medication).

2. Yes: the clinical adverse event appears related to study drug with a high degree of certainty (it follows a reasonable temporal sequence from drug administration and abates upon discontinuation of the drug, cannot be reasonably explained by known characteristics of the patient’s clinical state or other modes of therapy administered to the patient).

Note: For patients in the TCHH or THFECH regimens, the action taken study medication for Bevacizumab should be completed with NA.

Assigning the relationship to study drug is the PI’s or co-investigator’s responsibility. This relationship must be source documented. Please note that ND is not acceptable.

6) EF 6 / CARDIAC ADVERSE EVENTS (TARGETED THERAPY VISIT):

This page must be faxed to CIRG Data Management (FAX Number: (1) 780 702 0190):

Within 21 days of learning of any of the following cardiac events- Cardiac left ventricular dysfunction with NYHA Class III/IV symptoms- Definite cardiac death defined as death due to congestive heart failure, myocardial infarction or documented

primary arrhythmia- Probable cardiac death defined as sudden death without documented etiology- Grade 3/4 cardiac ischemia/infarction- Grade 3 systolic or diastolic dysfunction with NYHA Class II symptoms- Grade 2 systolic dysfunctionBETH CRF completion guidelines of 120Version 2 Final Version Date: 10 Dec 2009

Reporting of Adverse eventsThe following table summarizes the cardiac events to be reported during the therapy:







- Hypertension



Grades 1 and 2 AEs that require a change in treatment (i.e., a delay in treatment, or discontinuation of one or more of the study therapy drugs),



Description: Please use the blank space provided to report additional cardiac adverse events experienced during the cycle that could not be reported on CRF page V.5.

Grade: Report the worst grade experienced during the visit (from the infusion reported in this visit until just before the next infusion) Enter 1-5, when appropriate by using the NCI Toxicity Grade, otherwise use the severity code defined below:

1 mild : generally non-progressive, producing a minimal degree of tolerable discomfort2 moderate : may adversely affect normal daily activity, but is not completely incapacitating3 severe : marked intensity, may be either totally incapacitating or results in significant decrease in normal daily activity4 life threatening : the patient was at immediate risk of death as the AE occurred. It does not include an event that, had it occurred in a more serious form, may have caused death.5 death





requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or


is a congenital anomaly/birth defect




Start Date or ongoing/Stop Date or ongoing: - Indicate the date of onset or if the AE was ongoing at time of study drug infusion of the visit, tick the “ongoing” box:Ongoing conditions must be reported and followed by the physician during study treatment using the “Cardiac Toxicity Monitoring Form”.

- Indicate the end date or if the event is still ongoing at the end of the visit, the box “ongoing” should be ticked.


Action taken (Study drug) (regarding study drug administration for the next visit).Complete using one of the following codes and specify for each adverse event the action taken regarding study medication for trastuzumab and bevacizumab.For patients in the TCHH or THFECH regimens, the action taken (study drug) for bevacizumab should be completed with 0 or NA.

0. None : no change in study drug was made 1. Discontinued: administration of study drug was permanently discontinued (i.e. the patient was

discontinued from study) due to clinical adverse event. Please cross check with End of Targeted Therapy (EOT) page). In this case, the investigator has to select the main event which led to patient’s discontinuation. 5. Dose Delay/Hold : change in the dosing regimen occurred prior to next visit (i.e, a delay > 4 days of next

cycle’s study drug infusion) due to cardiac adverse event. Please cross check with the study drug administration page(s) at the next visit.


For each adverse event, enter the most likely cause. If there is more than one most likely cause per adverse event, then the combination of the most likely causes must be recorded.For an adverse event being due to study chemotherapy and trastuzumab, record as a most likely cause “1,2”.

Note: For patients in the TCHH (group 1A) or THFECH (group 2A) regimens, the action taken (study drug) for bevacizumab should be completed with NA.



7) EF 7 / CARDIAC ADVERSE EVENTS (FOLLOW-UP/SURVIVAL FOLLOW-UP):

Please mark the appropriate box and indicate the number of the Follow up or Survival Follow up.This page must be faxed to CIRG Data Management (FAX Number: (1) 780 702 0190):Within 21 days of learning of any of the following cardiac events- Cardiac left ventricular dysfunction with NYHA Class III/IV symptoms- Definite cardiac death defined as death due to congestive heart failure, myocardial infarction or documented

primary arrhythmia- Probable cardiac death defined as sudden death without documented etiology- Grade 3/4 cardiac ischemia/infarction- Grade 3 systolic or diastolic dysfunction with NYHA Class II symptomsGrade 2 systolic dysfunction Reporting of Adverse eventsThe following table summarizes the cardiac events to be reported during the follow up or survival follow up:







- Hypertension



Grades 1 and 2 AEs that require a change in endocrine treatment



Description: Please use the blank space provided to report additional cardiac adverse events experienced during the cycle that could not be reported on CRF page FU3.

Grade: Report the worst grade experienced during the follow-up (from last follow-up (or last infusion if this is the 1 st

follow-up) until follow-upEnter 1-5, when appropriate by using the NCI Toxicity Grade, otherwise use the severity code defined below:

1- mild : generally non-progressive, producing a minimal degree of tolerable discomfort2- moderate : may adversely affect normal daily activity, but is not completely incapacitating3- severe : marked intensity, may be either totally incapacitating or results in significant decrease in normal

daily activity4- life threatening : the patient was at immediate risk of death as the AE occurred. It does not include an

event that, had it occurred in a more serious form, may have caused death.5- death










Start Date or ongoing/Stop Date or ongoing: - Indicate the date of onset or if the AE was ongoing at the beginning of the follow up visit, tick the “ongoing” box:Ongoing conditions must be reported and followed by the physician during study treatment using the “Cardiac Toxicity Monitoring Form”.

- Indicate the end date or if the event is still ongoing at the end of the follow up, the box “ongoing” should be ticked.



For each adverse event, enter the most likely cause). If there is more than one most likely cause per adverse event, then the combination of the most likely causes must be recorded.For an adverse event being due to study chemotherapy and trastuzumab, record as a most likely cause “1,2”.

Note: For patients in the TCHH (group 1A) or THFECH (group 2A) regimens, the action taken (study drug) for bevacizumab should be completed with NA.



APPENDIX


APPENDIX 1

DEFINITION OF THE MOST COMMON SURGERIES

The term “Mastectomy” includes the following surgeries: Modified radical mastectomy

Total mastectomy with axillary lymph node dissection and preservation of the pectoralis major muscle.

Radical mastectomyEn bloc removal of the breast and skin overlying the tumor and the pectoralis major and minor muscles, as well as complete axillary dissection.

Extended radical mastectomyEn bloc radical mastectomy plus en bloc radical excision of the internal mammary lymph node chain and vessels which involves an intrapleural resection of these structures with a portion of the sternum and adjacent ribs.

Total (simple) mastectomyRemoval of the entire breast, including the nipple areolar complex with the pectoralis major muscle fascia but without axillary lymph node dissection or removal of the pectoralis muscles.

The term “Breast conserving surgery” includes the following: Excision (tumorectomy, lumpectomy): removal of the tumor grossly without attention to margins.

Wide excision (limited resection, partial mastectomy): excision of the tumor with grossly normal, clean margins.

Quadrantectomy: en bloc excision of the tumor within a quadrant of breast tissue along with the pectoralis major muscle fascia and overlying skin.

Quadrantectomy and axillary lymph node dissection.

Sentinel Node BiopsyA sentinel node is defined as the first lymph node that drains a cancer. The status of this node would predict the status of the remaining nodes in the axillary nodal basin. In a sentinel node biopsy, only these lymph nodes are assessed initially to assess tumor involvement status. This technique offers the possibility of reliably identifying patients with axillary node involvement with a lower morbidity surgery and it allows complete axillary dissection to be limited to patients with a tumor involvement in the sentinel node.


APPENDIX 2

HISTOLOGICAL TUMOR TYPE DICTIONARY

PLEASE USE THE FOLLOWING HISTOLOGICAL TYPES:

DUCTAL- Comedocarcinoma, non infiltrating- Comedocarcinoma NOS (Not Otherwise Specified)- Inflammatory carcinoma- Infiltrating duct carcinoma invasive with predominant intraductal component

invasive, NOS- Intraductal carcinoma, non infiltrating NOS- Intraductal papilloma- Medullary carcinoma with lymphocytic infiltrate- Mucinous adenocarcinoma (= colloid)- Non infiltrating intraductal papillary adenocarcinoma- Papillary adenocarcinoma NOS- Scirrhous adenocarcinoma- Tubular adenocarcinoma

LOBULAR- Lobular carcinoma in situ- Lobular carcinoma NOS invasive with predominant in situ component

invasive

NIPPLE- Paget's disease, mammary, NOS- Paget's disease with invasive ductal carcinoma- Paget's disease with intraductal carcinoma

PLEASE DO NOT USE THE FOLLOWING TERMS :- Adenocarcinoma NOS- Adenocarcinoma in situ

HISTOPATHOLOGICAL GRADING [NUCLEAR GRADE] (G):

Record as Low: G1 - Well differentiated (score 3-5). Intermediate: G2 - Moderately differentiated (score 6-7)High: G3 - Poorly differentiated and G4 – Undifferentiated (score 8-9)Unknown: GX - Differentiation cannot be assessed

BETH CRF completion guidelines of 120Version 2 Draft Version 4Date: 07 Dec 2009

APPENDIX 3

POST-SURGICAL HISTOPATHOLOGICAL CLASSIFICATION (pTNM)

According to AJCC Cancer Staging Manual Version 6.

Primary Tumour (T):Tx Primary tumour cannot be assessedT0 No evidence of primary tumourTis Carcinoma in situ : intraductal carcinoma, lobular carcinoma in situ, or paget's disease of the nipple with no

tumourT1 Tumor 2 cm in greatest dimensionT1mic Microinvasion 0.1 cm in greatest dimensionT1a Tumor > 0.1 cm but not > 0.5 cm in greatest dimensionT1b Tumor > 0.5 cm but not > 1 cm in greatest dimensionT1c Tumor > 1 cm but not > 2 cm in greatest dimensionT2 Tumour more than 2 cm but not more than 5 cm in greatest dimensionT3 Tumour more than 5 cm in greatest dimensionT4 Tumour of any size with direct extension to chest wall or skinT4a Extension to chest wall, not including pectoralis muscleT4b Edema (including peau d'orange) or ulceration of the skin of breast or satellite skin nodules confined to

same breastT4c Both T4a and T4bT4d Inflammatory carcinoma

Lymph Node (N):NX Regional lymph nodes cannot be assessed(eg, previously removed)N0 No regional lymph node metastasisN1 Metastasis to movable ipsilateral axillary lymph node(s)N2 Metastasis to ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent ipsilateral internal

mammary nodes in the absence of clinically evident axillary lymph node metastasisN2a Metastasis to ipsilateral axillary lymph node(s) fixed to one another (matted) or to other structuresN2b Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically

evident axillary lymph node metastasisN3 Metastasis to ipsilateral infraclavicular lymph node(s), or in clinically apparent ipsilateral internal mammary

lymph node(s) and in the presence of clinically evident axillary lymph node metastasis ; or metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement

N3a Metastasis to ipsilateral infraclavicular lymph node(s)N3b Metastasis to ipsilateral internal mammary lymph node(s) and axillary lymph node(s)N3c Metastasis to ipsilateral supraclavicular lymph node(s)

Distant Metastatis (M):MX Presence of distant metastasis cannot be assessedM0 No distant metastatisM1 Distant metastatis

STAGE GROUPING

0 Tis N0 M0I T1 N0 M0BETH CRF completion guidelines of 120Version 2 Final Version Date: 10 Dec 2009

IIA T0 N1 M0T1 N1 M0T2 N0 M0

IIB T2 N1 M0T3 N0 M0

IIIA T0 N2 M0T1 N2 M0T2 N2 M0T3 N1 M0T3 N2 M0

IIIB T4 N0 M0T4 N1 M0T4 N2 M0

IIIC Any T N3 M0IV Any T Any N M1

Pathologic Classification (pN)pNx Regional lymph nodes cannot be assessed (eg, previously removed or not removed for pathological

study)pN0 No regional lymph node metastasis histologically, no additional examination for isolated tumor cellspN0(i-) No regional lymph node metastasis histologically, negative IHCpN0(i+) No regional lymph node metastasis histologically, positive IHC, no IHC cluster > 0.2 mmpN0(mol-) No regional lymph node metastasis histologically, negative molecular findings (RT-PCR)pN0(mol+) No regional lymph node metastasis histologically, positive molecular findings (RT-PCR)pN1mi Micrometastasis (> 0.2 mm, none > 2.0 mm)pN1 Metastasis in 1 to 3 axillary lymph nodes and/or in internal mammary nodes with microscopic disease

detected by sentinel lymph node dissection but not clinically apparentpN1a Metastatis in 1 to 3 axillary lymph nodespN1b Metastatis in internal mammary nodes with microscopic disease detected by sentinel lymph node

dissection but not clinically apparent pN1c Metastatis in 1 to 3 axillary lymph nodes and in internal mammary lymph nodes with microscopic disease

detected by sentinel lymph node dissection but not clinically apparent. pN2 Metastasis in 4 to 9 axillary lymph nodes, or clinically apparent internal mammary lymph nodes in the

absence of axillary lymph node metastasispN2a Metastasis in 4 to 9 axillary lymph nodes (at least one tumor deposit > 2.0 mm)pN2b Metastasis in clinically apparent internal mammary lymph nodes in the absence of axillary lymph node

metastasispN3 Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically apparent

ipsilateral internal mammary lymph nodes in the presence of 1 or more positive axillary lymph nodes; or in more than 3 axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes

pN3a Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit > 2.0 mm), or metastasis to the infraclavicular lymph nodes

pN3b Metastasis in clinically apparent ipsilateral internal mammary lymph nodes in the presence of 1 or more positive axillary lymph nodes; or in more than 3 axillary lymph nodes and in internal mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but not clinically apparent

pN3c Metastasis in ipsilateral supraclavicular lymph nodes

APPENDIX 4

PERFORMANCE STATUS

ECOG or Zubrod Scale

Karnofsky Score


0Fully active; able to carry on all pre-disease performance without restriction

90-100%

1 Restricted in physically strenuous activity but ambulatory 70-80%

2Ambulatory and capable of self-care; but unable to carry out any work activities.

50-60%

3Capable of only limited self-care; confined to bed or chair more than 50% of waking hours

30-40%

4 Completely disabled 10-20%

COMPLETE PHYSICAL EXAMINATION

ASSESSMENT SHOULD INCLUDEGeneral appearance AbdomenSkin Lymph nodes (other than satellite of cancer)Eyes Spine and extremities (skeletal)Ears, nose and throat UrogenitalHeart NeurologicalChest/breast


APPENDIX 5

BSA CALCULATION and CONVERTING TABLE

BSA calculation In the study, it is recommended to use the formula developed by DuBois and DuBois for BSA calculation.This formula is give below:

BSA in M2 = 0.007184 x (Height in cm)0.725 x (Weight in kilos)0.425

Converting table

Convertion in cm Convertion lb kg1 in = 2.54 cm 1 lb = 0.4536 kg

1cm = 0.3937 in 1 kg = 2.205 lb

In: inch

cm: centimeter

lb: pound

kg : kilogram


APPENDIX 6

hematology normal laboratory values

Test Lower Limit Upper Limit UnitsHemoglobin 12.00 15.60 g/dL

Platelets 150.00 400.00 109/L

White Blood Cells 4.00 10.00 109/L

Neutrophils 2.00 6.00 109/L

Lymphocytes 2.00 4.00 109/L

Monocytes 0.20 0.95 109/L

Eosinophils 0.04 0.60 109/L

Basophils 0.01 0.05 109/L

Atypical lymphocytes 0

The table above provides the standard normal ranges that will be used to analyze hematological parameters for the BETH Trial. The standard values have been taken from Clinical Decision Levels for Lab Tests by B.E. Statland, published by Medical Economics Books, 1987.


APPENDIX 7URINE PROTEIN/URINE CREATININE (UPC) RATIO INSTRUCTIONS

The BETH Trial requires screening for proteinuria prior to randomization and at scheduled time points during the study. Proteinuria can be assessed by the dipstick method or by calculation of the urine protein/urine creatinine (UPC) ratio. If the UPC ratio method is utilized, follow the instructions in this appendix.

A. Procedure for calculating the UPC ratio

1. The patient provides at least 4 mL of a random urine sample. (24-hour urine collection is not required.)2. The lab determines urine protein (or urine albumin) concentration. (Result should be measured in

mg/dL.)3. The lab determines urine creatinine concentration. (Result should be measured in mg/dL.)4. The coordinator (or lab) calculates the UPC ratio by dividing the urine protein (#2 above) by the urine creatinine (#3 above).

Total urine protein (or urine albumin) ÷ urine creatinine = UPC ratioExample of UPC calculation:46.5 mg/dL (urine protein) ÷ 1501.1 mg/dL (urine creatinine) = 0.0309 (UPC ratio)

5. The coordinator documents the UPC ratio to the nearest tenth or to one decimal point. Rounding the value is permitted. If the number being rounded in the hundredth position is 5 or greater, round the number up. If the number in the hundredth position is 4 or less, round the number down. In the above example, the UPC ratio of 0.0309 would be rounded down to 0.0. Other examples of rounding the UPC ratio:

0.167 is rounded up to 0.20.132 is rounded down to 0.10.941 is rounded down to 0.90.951 is rounded up to 1.0

Important reminders:Do NOT use serum protein or serum creatinine results for this calculation.Do NOT use microalbumin values to calculate the UPC ratio.

B. Using the UPC ratio for bevacizumab dose modifications and AE reporting

The UPC ratio directly correlates with the amount of protein excreted in the urine per 24 hours. A UPC of 1.0 is roughly equivalent to 1 gram of protein in a 24-hour urine collection. If the UPC ratio is < 1.0, then the amount of protein in a 24-hour urine specimen can be assumed to be < 1 gram per 24 hours.

For the purposes of the BETH Trial, proteinuria will be graded based on the UPC ratio applied to the CTCAE v3.0 criteria for grading proteinuria (measured in grams/24 hours).

Example of using the UPC ratio for AE grading: UPC ratio of 2.5 approximates 2.5 g/24 hrs = grade 2 proteinuria (> 1.0 - 3.5 g/24 hours)


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