ANZGOG – 0701

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NHMRC Clinical Trials Centre NHMRC Clinical Trials Centre ANZGOG AGM, 2 April 2009, Noosa NHMRC Clinical Trials Centre NHMRC Clinical Trials Centre Symptom Benefit Study Measuring the Benefit of Palliative Chemotherapy in women with platinum refractory/ resistant ovarian cancer ANZGOG – 0701

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Symptom Benefit Study Measuring the Benefit of Palliative Chemotherapy in women with platinum refractory/ resistant ovarian cancer. ANZGOG – 0701. Study Background. - PowerPoint PPT Presentation

Transcript of ANZGOG – 0701

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NHMRC Clinical Trials CentreNHMRC Clinical Trials CentreANZGOG AGM, 2 April 2009, NoosaNHMRC Clinical Trials CentreNHMRC Clinical Trials Centre

Symptom Benefit Study

Measuring the Benefit of Palliative Chemotherapy in women with platinum refractory/ resistant

ovarian cancer

ANZGOG – 0701

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NHMRC Clinical Trials CentreNHMRC Clinical Trials CentreANZGOG AGM, 2 April 2009, NoosaNHMRC Clinical Trials CentreNHMRC Clinical Trials Centre

Study Background

• The aim is to develop a method to measure the benefit of chemotherapy, which takes into account BOTH subjective and objective responses

• Document time to symptom progression as an additional endpoint as well as symptom benefit

• Better insight into patterns of care and reasons for treatment with platinum resistant or refractory ovarian cancer

• Develop a prognostic index that better defines outcomes and test in a separate group

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NHMRC Clinical Trials CentreNHMRC Clinical Trials CentreANZGOG AGM, 2 April 2009, NoosaNHMRC Clinical Trials CentreNHMRC Clinical Trials Centre

Objective

• Stage 1: To determine the symptoms and aspects of HRQL that are rated most severe, troublesome in patients and identify best instruments to use in stage 2

• Stage 2: To determine the proportion of women benefiting from palliative chemotherapy as defined by a clinically significant improvement in HRQL scores and improvement of symptoms and time to symptom progression.

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Makhija S et al. ProcASCO 2007;Abstract 5507

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NHMRC Clinical Trials CentreNHMRC Clinical Trials CentreANZGOG AGM, 2 April 2009, NoosaNHMRC Clinical Trials CentreNHMRC Clinical Trials Centre

REGISTER

Target Population

>18yrs

platinum resistant/ refractory epithelial ovarian cancer

ECOG 0-3

Able to commence treatment within 2wks of registration

Ability to complete QoL formsindependently

During Trial

Stage1• Complete QoL questionnaires at each cycle

• 20 subjects will participate in additional QoL telephone interviews

Stage2

Determine the optimal QoL forms from Stage1Longer follow-upPrognostic data collected at baseline

Data Collection

4 Treatment

cycles or

Disease progression

Proposed longer

follow-up for Stage 2

Study Schema

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NHMRC Clinical Trials CentreNHMRC Clinical Trials CentreANZGOG AGM, 2 April 2009, NoosaNHMRC Clinical Trials CentreNHMRC Clinical Trials Centre

Lung Cancer as a Model

Close parallels between platinum resistant/ refractory ovarian cancerand recurrent NSCLC and SCLC in terms of response rates and survival

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Copyright © American Society of Clinical Oncology

von Pawel, J. et al. J Clin Oncol; 17:658 1999

Fig 1. Survival in weeksTOPOTECAN VS. CAV

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Symptom improvement compared with baseline in patients with SCLC treated with i.v. topotecan or CAV

Symptom i.v. topotecan % CAV % p value

Anorexia 32 16 0.042

Chest pain 25 17 0.371

Cough 25 15 0.160

Dyspnea 28 7 0.002

Fatigue 23 9 0.032

Hemoptysis 27 33 0.706

Hoarseness 33 13 0.043

Insomnia 33 19 0.085

Interference with daily activities 27 11 0.023

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Jassem et al.

2002 [33]Osoba et al.

1985 [36]Fernandez et al.

1989 [38]Hardy et al.

1989 [39]Ellis et al.

1995 [34]Tummarello et al.

1995 [37]Cullen et al.

1988 [35]

Regimen GP BEP PVM/I MVbP MVbP PMVb MIP

Overall response (%) 41 44 42 21 32 33 56

Overall symptom improvement (%)a — — — 67 69 54 —

Symptom improvement (%)

    Anorexia — — 50 — — — 58

    Cough 44 68 45 71 66 40 70

    Dyspnea 36 31 78 65 59 66 46

    Hemoptysis 75 78 91 — — 100 92

    Malaise — 53 — — 53 62 —

    Pain — 68 47 63 60 39 77

    Weight loss — 44 89 — — 30 —

Non Small Cell Lung Cancer – Studies Gralla Oncologist 2004; 9:14-24

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LCSS in relation to standard efficacy measures- Maximum Improvementfrom baseline LCSS items- 2nd line therapy

De marinis et al JTO 3;1 2008

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LCSC in relation to standard efficacy measures

De marinis et al JTO 3;1 2008

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Lung Cancer Studies

● Confirm that Symptom Benefit is a valid and valuable endpoint

● Correlation of Symptom Benefit with Response and SD

● Instruments sensitive to detect symptom benefit● Provides complimentary efficacy data

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Current status

Fourteen sites open to recruitment

Twelve in Australia

Two in CanadaA further nine Australian sites are currently awaiting final ethics approval

Total recruitment

46

26 Australia

20 Canada

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Baseline Demographics

Symptom control/palliation + rising CA125 + radiological progression 28

Rising CA125 + radiological progression 9

Symptom control/palliation + rising CA125 6

Symptom Control + radiological evidence 1

Radiological Evidence only 1

Rising CA125 only 1

N = 46

Reason for treatment at enrolment

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Baseline Demographics cont’d

Major symptoms reported at baseline:

1. Pain

2. Fatigue

3. Abdominal Bloating

ECOG 0 = 17 (N = 45 - missing data for one patient)

1 = 26

2 = 2

3 = 0

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NHMRC Clinical Trials CentreNHMRC Clinical Trials CentreANZGOG AGM, 2 April 2009, NoosaNHMRC Clinical Trials CentreNHMRC Clinical Trials Centre

Previous lines of chemotherapy

1 x line 2 x lines 3 x lines 4 x lines 5 x lines 7 x lines

18 8 9 5 2 1

N = 43* Missing data on 3 x pts – awaiting response from sites

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Majority Platinum Resistant

Compliance

All questionnaires were completed to a very high compliance rate with few or no missing data

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Death/Disease Progression

1 x pt. has withdrawn consent

3 x pts. off study due to site error

NB. Due to centralised data entry, there is a time lag in receipt of CRFs

Cycle 2

Cycle 3

Cycle4

Deaths 4 1

Disease progression 1 6

Completed 34 22 14

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Stage 1 QoL Questionnaires

1. Symptom Representation Questionnaire

2. FACT-O (includes FOSI)

3. EORTC QLQ-C30

4. EORTC QLQ-OV28

5. Patient Data Form

6. Expected and Perceived Benefit Scale7. HAD Scale (Baseline & End of Treatment only)

8. Herth Hope Index (Baseline & End of Treatment only)

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Ovarian Symptom Benefit Study (OSBS)

Initial results and rationale for choosing the FACT-O and revising the

Patient DATA Form – Ovarian as the patient reported outcome measures (PRO)

for stage 2

Prepared by Madeleine King and Martin Stockler on behalf of the

Ovarian Symptom Benefit Study Team6 October 2009

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Background: What’s the problem?

• OSBS stage 1 uses 4 questionnaires to measure symptoms and/or quality of life:

items1. Symptom Representation Questionnaire (SRQ) 662. Pt Disease & Treatment Assessment (Pt DATA Form) 483. FACT-O (including 8 items of FOSI) 394. QLQ-C30 + Ov28 58

• The booklet was deliberately long and repetitive to corroborate findings and help determine the best subset of items for future studies

• Interviews with 10 patients indicated that they neither preferred nor disliked any particular questionnaires

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Substitutability of candidate questionnaires

• SRQ vs. Patient DATA Form– designed to measure clinically important aspects of QOL– similar layouts, 0 to 10 scales– single-item scoring (rather than multi-item or domain scoring)

• QLQ-C30/Ov28 vs. FACT-O – designed to measure quality of life (QOL) in cancer clinical trials– similar format and layout, similar response scales– multi-item domains & scoring (QLQ-C30 incl. some single

items)

• We decided to choose for OSBS stage 2– Either SRQ or Pt-DATA Form for individual symptoms – Either QLQ-C30/Ov28 or FACT-O for multi-dimensional QOL

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

‘First filter’ analysis: aims & methods

Aim Determine which 4 PRO questionnaires to retain for stage 2

Analysis1. Prevalence of each possible symptom in the

‘Top Three Most Noticed Symptoms in the last week’ (as asked by the Symptom Representation Questionnaire).

2. Summary statistics and histograms describing the frequency distributions of items and domain scores for each symptom at baseline

3. Changes from baseline in item and domain scores

Data31 patients who completed QOL questionnaires at baseline (pre-C1) AND (pre-C2 (AND/OR) pre-C3) by Jul

‘09

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Results: Top 10 Symptoms of the ‘Three Most Noticed Symptoms in the last week’

at baseline Rank Symptom

No. who nominated this symptom in her

Top 3 (n=31)

1 Fatigue 17

2 Pain - general 11

3 Abdominal bloating 10

4 Sleep disturbance 9

5 Nausea and vomiting 8

6 Appetite 7

7 Shortness of breath 6

8 Bowel disturbances (including constipation) 6

9 Pain - abdominal 5

10 Urinary problems 3

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Coverage of Top 10 symptoms by candidate questionnaires

Symptom SRQ Pt DATA FACT-O FOSI QLQ-C30 QLQ-OV28

Fatigue 2 1 1 1 3 -

Pain - general 1 1 1 1 2 -

Abdominal bloating 1 1 1 1 - 1

Sleep disturbance 1 1 1 - 1 -

Nausea and vomiting 2 2 2 2 2 -

Appetite 1 2 1 - 1 1

Shortness of breath 1 1 - - 1 -

Bowel disturbances 1 3 1 - 2 3

Pain - abdominal - 1 1 1 - 1

Urinary problems 1 1 - - - 1

# items covering Top 10 12 15 9 6 12 9

Total # items in q’aire 24 18 39 8 30 28

% 50% 83% 23% 75% 40% 32%

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Detailed example of overlap Pain - general

Q’aire Item stem Response scale Scoring

SRQ Pain 0 = did not have the symptom10 = as bad as I can imagine

Single item

Pt-DATA Pain (all or anywhere) 0 = no trouble at all10 = worst I can imagine

Single item

FACT-O I have pain 0 = Not at all 1 = A little bit 2 = Somewhat 3 = Quite a bit 4 = Very much

One of 7 items in the Physical Wellbeing scale of the FACT

One of 8 items in the FOSI

QLQ-C30 Have you had pain? 1 = Not at all 2 = A little 3 = Quite a bit 4 = Very much

These two items form the pain scale of the QLQ-C30QLQ-C30 Did pain interfere with

your daily activities?

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Results at baseline (pre-cycle 1)• For each of the top 10 symptoms:

– we compared distributions and summary statistics for similar items

– No major ceiling or floor effects– Similar distributions for similar items

• Nothing to choose between questionnaires

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Change at Cycles 2 and 3

• For each of the top 10 symptoms: – we compared distributions and summary

statistics of change scores on similar items– Mean change ~0 with large SD reflecting

improvements in some women and deteriorations in others

– Comparable results across q’aires• Nothing to choose between questionnaires

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

DecisionsRetain modified Pt DATA Form – Ovarian to measure key symptoms• Enhance coverage of the Top 10• Allow measurement of both current status and change• Modifications by developer and OSBS investigators

OSBS Recent Status Form (after each cycle) OSBS Change Form (after every 2nd cycle)

• Develop a separate Side Effects Form for net clinical benefitRetain FACT-O (including FOSI) to measure QOLFACT-O• Has fewer items: 39 (incl. 8 for FOSI) vs. 58 in the

QLQ-C30/Ov28• Provides summary scores: overall QOL, Trial Outcome Index,

FOSI• Overall QOL based on all itemsQLQ-C30• 22 sub scales• Duplication of single-item symptoms with Pt DATA Form• Global QOL based on 2 items

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Prognostic Modelvariables

No. of lines of therapy Performance status Volume of disease Sites of disease CA125 velocity LDH; Hb; Albumin; Platelets Inflammatory markers Grade; histological subtype

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Platinum Resistant Ovarian CancerPFS

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Platinum Resistant Ovarian CancerOS

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Platinum Resistant Ovarian CancerHypothetical Risk Groups

PFS

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Platinum Resistant Ovarian CancerHypothetical Risk Groups

OS

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ANZGOG AGM, Noosa 2 April 2009NHMRC Clinical Trials Centre

Discussion Points

• Comments and questions of study and design- relatively fluid at present

• Comments on circulated CRF’s

• Which groups will join stage 2 study and when ? Feasibility; Time Frame; Trials

Translations

Funding arrangements in different groups

ECRF’s and scanning of HRQOL forms