PRIMA Investigator Meeting Wednesday, June 8, 2005 Villa Castagnola, Lugano.

PRIMAPRIMAInvestigator Investigator

MeetingMeeting

Wednesday, June 8, 2005Wednesday, June 8, 2005

Villa Castagnola, LuganoVilla Castagnola, Lugano

PRIMAPRIMAInvestigator Meeting Investigator Meeting

Agenda Agenda Welcome and IntroductionWelcome and Introduction

Gilles SallesGilles Salles Regulation and status of the trialRegulation and status of the trial

Stephanie BauluStephanie Baulu Protocol and medical issuesProtocol and medical issues

Gilles SallesGilles Salles Logistics of DataLogistics of Data

Stephanie BauluStephanie Baulu Path Review Path Review

Luc XerriLuc Xerri TMA proposal : Lyndsey GoffTMA proposal : Lyndsey Goff

DiscussionDiscussion

Regulation and StatusRegulation and Status

Validation of country’s Validation of country’s participationparticipation

Validation of center’s Validation of center’s participationparticipation

Countries StatusCountries Status

Registration StatusRegistration Status

PRIMA ORGANIZATIONPRIMA ORGANIZATION PRIMA Study will be conducted in PRIMA Study will be conducted in

accordance with :accordance with : ICH-GCP (Topic E6)ICH-GCP (Topic E6) Helsinki DeclarationHelsinki Declaration Local laws and regulatory Local laws and regulatory

requirements as new European requirements as new European directive (2001/83 and 2002/98)directive (2001/83 and 2002/98)

Countryregulation

Centeractivation

Patient registration

Case ReportForm filling

SAEs declarationand AEs

Validation of country’s Validation of country’s participation participation

Define the country coordinatorDefine the country coordinator Define all centers that will participate to the Define all centers that will participate to the

studystudy To be sent To be sent to the GELARCto the GELARC::

““Contract between GELA and National Contract between GELA and National Representative”Representative” (National Study Group or (National Study Group or Roche Affiliate)Roche Affiliate)

List of all centersList of all centers with principal with principal investigator’s name, address, phone number investigator’s name, address, phone number and E-mail and E-mail

Curriculum VitaeCurriculum Vitae (1 page) of principal (1 page) of principal investigator for each center investigator for each center

Name and address of the PathologistName and address of the Pathologist in in charge of local review if applicablecharge of local review if applicable GELARC send back all documents for local GELARC send back all documents for local

submissionsubmission

Validation of country’s Validation of country’s participationparticipation

Apply to ethics and national health authoritiesApply to ethics and national health authorities

Send Send by the Local Coordinator to the GELARCby the Local Coordinator to the GELARC:: Ethic Committee approvalEthic Committee approval Health Authorities approvalHealth Authorities approval Insurance Insurance ““Regulatory Documents Certification” signed Regulatory Documents Certification” signed

by Coordinatorby Coordinator Informed consent and information sheet in Informed consent and information sheet in

local languagelocal language Any local amendment must be approved by GELA Any local amendment must be approved by GELA

before local submissionbefore local submission

Your country is ready to start the studyYour country is ready to start the study

Validation of center’s Validation of center’s participationparticipation

GELARC will send by express-courrier to GELARC will send by express-courrier to the local coordination center (National the local coordination center (National Study Group or Roche Affiliate contact) :Study Group or Roche Affiliate contact) :

Case Report FormCase Report Form

Investigator’s Study File for all centersInvestigator’s Study File for all centers

To be completed with all regulatory To be completed with all regulatory documents required by local laws.documents required by local laws.

Initiation visits could be doneInitiation visits could be done

Countries StatusCountries Status 2929 countries participate to PRIMA study : countries participate to PRIMA study :

1212 in European Community (GELA official sponsor) in European Community (GELA official sponsor) 1717 for the rest of the world (Roche affiliates or for the rest of the world (Roche affiliates or

others)others)

4 4 countries are activated : countries are activated : Belgium, Colombia, Denmark and France.Belgium, Colombia, Denmark and France.

1919 countries have submitted and are waiting countries have submitted and are waiting for the approvals : for the approvals : Other Latin America Countries, Turkey, Thailand, Other Latin America Countries, Turkey, Thailand,

Netherlands, India, Finland, Serbia, Spain, Croatia, Netherlands, India, Finland, Serbia, Spain, Croatia, China, Australia/NZ and South Africa.China, Australia/NZ and South Africa.

66 countries are in progress for submission : countries are in progress for submission : Germany, UK, Czech Republic Germany, UK, Czech Republic and Israel, Poland and Portugaland Israel, Poland and Portugal

Impossible to add another new country !Impossible to add another new country !


Global World Recruitment - PRIMA Study

1 10 2039

6078 86

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Real Recruitment

Estimated World Recruitment


The first patient will be randomized for The first patient will be randomized for maintenance on July 2005 in Francemaintenance on July 2005 in France

Country Recruitment - PRIMA study

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Brazil

China

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PRIMA :PRIMA :Primary Rituximab and Primary Rituximab and

Maintenance Maintenance No standard first line chemotherapy in follicular No standard first line chemotherapy in follicular

lymphomalymphoma Rituximab when combined with chemotherapy Rituximab when combined with chemotherapy

(CVP, CHOP, CHVP+IFN, MCP, FCM…) does (CVP, CHOP, CHVP+IFN, MCP, FCM…) does improve CR rate end EFSimprove CR rate end EFS

Rituximab maintenance improves EFS in rituximab Rituximab maintenance improves EFS in rituximab (alone) or chemo (CVP alone) treated patients(alone) or chemo (CVP alone) treated patients

Primary objective : Primary objective : To evaluate in patients with To evaluate in patients with advanced follicular lymphoma the benefit of advanced follicular lymphoma the benefit of maintenance therapy with rituximab after maintenance therapy with rituximab after induction of response with chemotherapy plus induction of response with chemotherapy plus rituximab in comparison with no maintenance rituximab in comparison with no maintenance therapy therapy

PRIMA Study PRIMA Study FinalFinal DesignDesign

PDs/SDsoff study

MabThera Maintenance1 dose every 8 weeks

for 24 months

Observation

R CR/PR

Chairs : G Salles, R Marcus & M HeroldChairs : G Salles, R Marcus & M Herold

R-CVP x 8 or R-CHOP x 6 + 2Ror R-FCM x 6 + 2Ror R-MCP x 6 +2R

Untreated Follicular NHL

High tumor burden

PRIMAPRIMAScientific design of the Scientific design of the

studystudy The primary efficacy parameter is The primary efficacy parameter is event-event-

free survivalfree survival. Event-free survival will be . Event-free survival will be measured from the day of randomization measured from the day of randomization to the date of first documented disease to the date of first documented disease progression, death by any cause or progression, death by any cause or institution of new treatmentinstitution of new treatment. Responding . Responding patients and patients who are lost to patients and patients who are lost to follow up will be censored at their last follow up will be censored at their last tumor assessment date.tumor assessment date.

PRIMAPRIMAScientific design of the Scientific design of the

studystudy New anti-lymphoma treatment is New anti-lymphoma treatment is

defined :defined :

as the institution of as the institution of anyany radiation therapy radiation therapy (even focal) or chemotherapy or (even focal) or chemotherapy or immunotherapy, alone or in any immunotherapy, alone or in any combination of them, which is instituted for combination of them, which is instituted for lymphoma treatment.lymphoma treatment.

Any new anti-lymphoma treatment not Any new anti-lymphoma treatment not planed in the protocol will be considered planed in the protocol will be considered as an eventas an event..

PRIMAPRIMAInclusion criteriaInclusion criteria (1) (1)

Patients previously Patients previously untreateduntreated

Histologically confirmed follicular Histologically confirmed follicular lymphoma grade 1, 2 or lymphoma grade 1, 2 or 3a3a

With a path report of less than 3 With a path report of less than 3 monthsmonths


Patients with Patients with at least oneat least one of the following of the following symptomssymptoms requiring initiation of treatment:requiring initiation of treatment: Bulky disease at study entry Bulky disease at study entry

nodal or extranodal mass > 7cm in its greater diameternodal or extranodal mass > 7cm in its greater diameter B symptoms B symptoms Elevated serum LDH (above N) or Elevated serum LDH (above N) or 2-microglobulin (2-microglobulin (>> 3mg/L) 3mg/L) involvement of at least 3 nodal sites (each with a diameter involvement of at least 3 nodal sites (each with a diameter

greater than 3 cm) greater than 3 cm) symptomatic splenic enlargement symptomatic splenic enlargement compressive syndrome compressive syndrome pleural/peritoneal effusionpleural/peritoneal effusion

Of note, stage I or II Of note, stage I or II if present these criteriaif present these criteria can be can be includedincluded


Age must be Age must be >> 18 years 18 years.. Performance status Performance status << 2 on the ECOG scale 2 on the ECOG scale

(see appendix E).(see appendix E). Adequate hematological function within 28 Adequate hematological function within 28

days prior to registration (unless those days prior to registration (unless those abnormalities are related to lymphoma abnormalities are related to lymphoma extension), this includes:extension), this includes: Hemoglobin ≥ 8.0 g/dl (5.0 mmol/L)Hemoglobin ≥ 8.0 g/dl (5.0 mmol/L) Absolute neutrophil count (ANC) ≥ 1.5 109/LAbsolute neutrophil count (ANC) ≥ 1.5 109/L Platelet count ≥ 100 109/LPlatelet count ≥ 100 109/L


Women are not breast feeding, are using Women are not breast feeding, are using effective contraception, are not pregnant and effective contraception, are not pregnant and agree not to become pregnant during agree not to become pregnant during participation in the trial and during the 12 participation in the trial and during the 12 months thereafter. Men agree not to father a months thereafter. Men agree not to father a child during participation in the trial and child during participation in the trial and during the 12 months thereafter.during the 12 months thereafter.

Having previously signed a written informed Having previously signed a written informed consent form.consent form.

PRIMAPRIMAExclusion criteriaExclusion criteria (1) (1)

Transformation to high-grade Transformation to high-grade lymphoma (secondary to “low-grade” lymphoma (secondary to “low-grade” follicular lymphoma).follicular lymphoma).

Grade 3b follicular lymphomaGrade 3b follicular lymphoma.. Presence or history of CNS disease Presence or history of CNS disease

(either CNS lymphoma or (either CNS lymphoma or lymphomatous meningitis).lymphomatous meningitis).


Patients regularly taking corticosteroids Patients regularly taking corticosteroids during the last 4 weeks, unless administered during the last 4 weeks, unless administered at a dose equivalent to at a dose equivalent to << 20 mg/day 20 mg/day prednisone prednisone (over the last 4 weeks). (over the last 4 weeks).

Patients with prior or concomitant Patients with prior or concomitant malignancies except non-melanoma skin malignancies except non-melanoma skin cancer or adequately treated in situ cervical cancer or adequately treated in situ cervical cancer. cancer.

Major surgery (excluding lymph node biopsy) Major surgery (excluding lymph node biopsy) within 28 days prior to registration.within 28 days prior to registration.


Poor renal function:Poor renal function: Serum creatinine > 2.0 mg/dl (197 μmol/L),Serum creatinine > 2.0 mg/dl (197 μmol/L),

Poor hepatic function: Poor hepatic function: total bilirubin > 2.0 mg/dl (34 μmol/L) or AST (SGOT) > total bilirubin > 2.0 mg/dl (34 μmol/L) or AST (SGOT) >

3 x the upper limit of normal unless these abnormalities 3 x the upper limit of normal unless these abnormalities are related to lymphomaare related to lymphoma

Known HIV infection or active HBV or HCV Known HIV infection or active HBV or HCV infectioninfection

Serious underlying medical conditions, which Serious underlying medical conditions, which could impair the ability of the patient to could impair the ability of the patient to participate in the trial (e.g. ongoing infection, participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease). Judgment is up to active autoimmune disease). Judgment is up to the investigatorthe investigator


Life expectancy < 6 monthsLife expectancy < 6 months Known sensitivity or allergy to Known sensitivity or allergy to

murine productsmurine products Treatment within a clinical trial Treatment within a clinical trial

within 30 days prior to trial entrywithin 30 days prior to trial entry Adult patient under tutelageAdult patient under tutelage


PDs/SDsoff study


for 24 months

Observation

R CR/PR


Untreated Follicular NHL

PRIMAPRIMAInduction treatment (1)Induction treatment (1)

Induction of response with Induction of response with

8 x rituximab combined 8 x rituximab combined with 8 cycles of CVP every 21 dayswith 8 cycles of CVP every 21 days or 6 cycles of CHOP in 21-day cycles or 6 cycles of CHOP in 21-day cycles or 6 cycles of FCM in 28-day cycles or 6 cycles of FCM in 28-day cycles or 6 cycles of MCP in 28-day cycles.or 6 cycles of MCP in 28-day cycles.


After registration induction therapy has to be started within After registration induction therapy has to be started within 7 days from registration7 days from registration

The The assignment to one of the four chemotherapyassignment to one of the four chemotherapy groups (R- groups (R-CVP, R-CHOP, R-FCM and R-MCP) is CVP, R-CHOP, R-FCM and R-MCP) is on a per centre on a per centre decisiondecision. Every centre has to decide . Every centre has to decide upfrontupfront ( (before before initiation of the studyinitiation of the study) which chemotherapy schedule is ) which chemotherapy schedule is standard of care for follicular lymphoma patients in that standard of care for follicular lymphoma patients in that center and therefore center and therefore will be given to all patients of that will be given to all patients of that center throughout the studycenter throughout the study (information will be reported (information will be reported on registration form)on registration form)

In France, only R-CVP and R-CHOP will be considered as In France, only R-CVP and R-CHOP will be considered as standard. In Germany, the regimen will be allocated to each standard. In Germany, the regimen will be allocated to each patient through randomization (OSHO/GLSG procedure).patient through randomization (OSHO/GLSG procedure).


8 R-CVP / 21-day CYCLES (cycles 1 to 8)

Chemotheray regimen Dose Mode D1 D2 D3 D4 D5

Rituximab 375 mg/m2 IV

Cyclophosphamide 750 mg/m2 IV push

Vincristine 1.4 mg/m2

(2 mg max.)IV

bolus

Prednisone 40 mg/m2

dayPO

PRIMAPRIMAInduction treatment (4)Induction treatment (4) 6 R-CHOP / 21-day CYCLES (cycles 1 to 6)

Chemotheray regimen Dose Mode D1 D2 D3 D4 D5


Cyclophosphamide 750 mg/m2 IV

Doxorubicin 50 mg/m2 IV push

Vincristine 1.4 mg/m2

(2 mg max.)IV push

Prednisone 100 mg/day PO

2 Rituximab / 21-day CYCLES (cycles 7 and 8)

Rituximab 375 mg/m2 IV 1 injection 21 days (3 weeks) after cycle 6 of R-CHOP

1 injection 42 days (6 weeks) after cycle 6 of R-CHOP


6 R-FCM / 28- day cycles (cycles 1 to 6) C1 to C6

Chemotherapy regimen

Dose Mode D1 D2 D3

Rituximab 375mg/m2

IV

Cyclophosphamide 200mg/m2

IV – 4 hours infusion

Fludarabine 25 mg/m2

IV - 30 min. infusion

Mitoxantrone 6 mg/m2

IV – 30 min. infusion

2 Rituximab D15 of C1 D15 of C4



6 R-MCP / 28-day cycles (cycles 1 to 6) C1 to C6

Chemotherapy regimen Dose Mode D1 D2 D3 D4

D5


Mitoxantrone 8 mg/m2 IV – 30 min. infusion

Chlorambucil 3 x 3 mg/m2

PO

Prednisolone 25 mg/m2 PO

2 Rituximab D15 of C1 D15 of C4


PRIMAPRIMARequirements for RandomizationRequirements for Randomization

Being registered in the trial before treatment Being registered in the trial before treatment andand having filled / send the CRF having filled / send the CRF for baseline periodfor baseline period

All lesions reported in the on-study form have been re-All lesions reported in the on-study form have been re-evaluated. evaluated.

Patient must have reached a PR, CRu or CR. Patient must have reached a PR, CRu or CR. (According to appendix C).(According to appendix C).

Patient should have received all full doses of induction Patient should have received all full doses of induction treatment, excepted planned modifications.treatment, excepted planned modifications.

Exclusion :Exclusion : Patient with delayed chemotherapy courses Patient with delayed chemotherapy courses for more than 2 weeks (> 14 days).for more than 2 weeks (> 14 days).


PDs/SDsoff study


for 24 months

Observation

R CR/PR


Untreated Follicular NHLstages III–IV

PRIMAPRIMA3 years follow-up period3 years follow-up period ! !

Following assessments for response Following assessments for response evaluation should be performed, evaluation should be performed, every three every three months during the first year then every 6 months during the first year then every 6 months during two additional yearsmonths during two additional years:: Physical examinationPhysical examination Tumor lesion assessment: two dimensional Tumor lesion assessment: two dimensional

diameters of all lymph nodes, spleen and liver diameters of all lymph nodes, spleen and liver enlargementenlargement

B-symptoms and ECOG performance statusB-symptoms and ECOG performance status Every 6 monthsEvery 6 months: CT scan of the chest, : CT scan of the chest,

abdomen, and pelvisabdomen, and pelvis Every 12 monthsEvery 12 months: Quality of life : Quality of life

questionnaires FACT-G and QLQ-C30.questionnaires FACT-G and QLQ-C30.

Logistical AspectsLogistical Aspects

RegistrationRegistration

CRFs and MonitoringCRFs and Monitoring

Serious Adverse Serious Adverse EventsEvents

REGISTRATIONREGISTRATION Obtain consent of patient : the patient must sign Obtain consent of patient : the patient must sign 3 3

copiescopies of the informed consent form (1 for himself, 1 for of the informed consent form (1 for himself, 1 for the investigator and 1 for the GELA)the investigator and 1 for the GELA)

Complete and fax the registration form to the GELA Complete and fax the registration form to the GELA randomization center randomization center withwith the pathological reportthe pathological report

GELA send it back in 1 day (Monday to Friday) with GELA send it back in 1 day (Monday to Friday) with patient registration numberpatient registration number

Local coordination center and Principal Investigator of Local coordination center and Principal Investigator of each country will be informed of country inclusions by each country will be informed of country inclusions by emailemail

Case Report Form (CRF) sent by local monitor after each Case Report Form (CRF) sent by local monitor after each inclusioninclusion

Only patient initials (3 first of the surname + 2 first of Only patient initials (3 first of the surname + 2 first of the firstname) should be recorded on the formsthe firstname) should be recorded on the forms

GELA Randomization GELA Randomization CenterCenter

Registration and Randomization Registration and Randomization Forms have to be faxed to GELA Forms have to be faxed to GELA randomization center :randomization center :

St Louis Hospital – Centre HayemSt Louis Hospital – Centre Hayem

Fax : +33 1 42 49 99 72Fax : +33 1 42 49 99 72Monday to Friday - 09:00 am to Monday to Friday - 09:00 am to

05:00 pm05:00 pm(French time)(French time)

CRF and MonitoringCRF and Monitoring CRFs have to be completed CRFs have to be completed in Englishin English.. Only patient Only patient

initials should be recorded on the CRF pages.initials should be recorded on the CRF pages.

Monitoring of data reported on CRF is planned on Monitoring of data reported on CRF is planned on key parameters (underlined), twice a year key parameters (underlined), twice a year for all for all patientspatients, following an organization at your , following an organization at your convenience.convenience.

Baseline period has to be monitored before Baseline period has to be monitored before randomizationrandomization

Pages of CRF are Triplicate FormsPages of CRF are Triplicate Forms

After monitoring, please send as soon as possible After monitoring, please send as soon as possible to GELARC 2 forms (original and 1 copy) of to GELARC 2 forms (original and 1 copy) of complete partscomplete parts

Flow Chart of QueriesFlow Chart of Queries After Double data entry, Data After Double data entry, Data

management may edit queries about datasmanagement may edit queries about datas

Queries/data corrections will be sent by Queries/data corrections will be sent by email to the local coordinator for all email to the local coordinator for all centers centers

Each Investigator has to answer on the Each Investigator has to answer on the Query Form, sign and date it (print name) Query Form, sign and date it (print name) and keep a copy in the CRFand keep a copy in the CRF

Original forms must be : Original forms must be : 1/ faxed to GELARC1/ faxed to GELARC2/ sent with CRF pages after monitoring2/ sent with CRF pages after monitoring

Serious Adverse EventSerious Adverse Event Complete Complete in Englishin English the 3 pages the 3 pages Attach documents if necessaryAttach documents if necessary Signed by Signed by a physiciana physician (authorized person) (authorized person) Fax it to your local coordination center Fax it to your local coordination center Local coordination center will send it to Local coordination center will send it to

GELARCGELARC SAE Form must be monitored with the CRF SAE Form must be monitored with the CRF

and and original + 1 copyoriginal + 1 copy must be sent with CRF must be sent with CRF pagespages

GELARC will send back (by fax) SAE GELARC will send back (by fax) SAE registration number/ query about SAE to registration number/ query about SAE to local coordination center which transmit to local coordination center which transmit to centercenter

SAE Form Flow ChartSAE Form Flow Chart

Complementary information

SAE Number / Summary

CIOMS (e-mail)

Investigator

GELARCGenentech -

Hoffman La Roche PV - Basel

French Health Authorities + Ethic

Committee

Local EC + Local

Authorities

SUSAR

All Local Investigators

CIOMS – DIL (e-mail)

Complementary Information

SAEs / SUSARs According to

local law

Roche Affiliate / National

Study Group

All SAEs (fax)

All SAEs (fax)

All SAEs

Pr Gilles SALLES : Pr Gilles SALLES : [email protected]@chu-lyon.fr

Delphine GERMAIN : Delphine GERMAIN : [email protected]@chu-lyon.fr

Stéphanie BAULU : Stéphanie BAULU : [email protected]@chu-lyon.fr

http://prima.gela.orghttp://prima.gela.org

ContactsContacts

Pathology StudyPathology StudyPRIMA TRIALPRIMA TRIAL

Luc Xerri Luc Xerri

For the french GELA reviewing For the french GELA reviewing panel : N. Brousse, F. panel : N. Brousse, F. Charlotte, B. FabianiCharlotte, B. Fabiani

Aims of the Pathology Review Process Aims of the Pathology Review Process

1) to confirm the diagnosis of follicular lymphoma1) to confirm the diagnosis of follicular lymphoma

appropriate panel of antbodies (CD20, CD5, Bcl-6, appropriate panel of antbodies (CD20, CD5, Bcl-6, Bcl2) Bcl2)

To classify it according to the WHO grading (2001), To classify it according to the WHO grading (2001),

2) store a block of the tumoral sample 2) store a block of the tumoral sample

Tissue-Micro-Array of follicular lymphoma specimens Tissue-Micro-Array of follicular lymphoma specimens

To To evaluate the relevance of the expression of prognostic evaluate the relevance of the expression of prognostic

markers in the response to therapy and outcome. markers in the response to therapy and outcome.

PRIMA Investigator Meeting Wednesday, June 8, 2005 Villa Castagnola, Lugano.

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Transcript of PRIMA Investigator Meeting Wednesday, June 8, 2005 Villa Castagnola, Lugano.