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ANZGOG – 0701

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

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ANZGOG – 0701

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  1. Symptom Benefit StudyMeasuring the Benefit of Palliative Chemotherapy in women with platinum refractory/ resistant ovarian cancer ANZGOG – 0701

  2. 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

  3. 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.

  4. Makhija S et al. Proc ASCO 2007;Abstract 5507

  5. Study Schema • 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 Stage1 • Longer follow-up • Prognostic data collected at baseline Target Population >18yrs platinum resistant/ refractory epithelial ovarian cancer ECOG 0-3 Able to commence treatment within 2wks of registration Ability to complete QoL forms independently Data Collection 4 Treatment cycles or Disease progression Proposed longer follow-up for Stage 2 REGISTER

  6. Lung Cancer as a Model Close parallels between platinum resistant/ refractory ovarian cancer and recurrent NSCLC and SCLC in terms of response rates and survival

  7. Fig 1. Survival in weeks TOPOTECAN VS. CAV von Pawel, J. et al. J Clin Oncol; 17:658 1999

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

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

  10. LCSS in relation to standard efficacy measures- Maximum Improvement from baseline LCSS items- 2nd line therapy De marinis et al JTO 3;1 2008

  11. LCSC in relation to standard efficacy measures De marinis et al JTO 3;1 2008

  12. 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

  13. Current status Fourteen sites open to recruitment Twelve in Australia Two in Canada A further nine Australian sites are currently awaiting final ethics approval Total recruitment 46 26 Australia 20 Canada

  14. Baseline Demographics Reason for treatment at enrolment N = 46

  15. 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

  16. Previous lines of chemotherapy N = 43 * Missing data on 3 x pts – awaiting response from sites

  17. Majority Platinum Resistant Compliance All questionnaires were completed to a very high compliance rate with few or no missing data

  18. 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

  19. Stage 1 QoL Questionnaires • Symptom Representation Questionnaire • FACT-O (includes FOSI) • EORTC QLQ-C30 • EORTC QLQ-OV28 • Patient Data Form • Expected and Perceived Benefit Scale • HAD Scale (Baseline & End of Treatment only) • Herth Hope Index (Baseline & End of Treatment only)

  20. 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 theOvarian Symptom Benefit Study Team 6 October 2009

  21. Background: What’s the problem? • OSBS stage 1 uses 4 questionnaires to measure symptoms and/or quality of life: items • Symptom Representation Questionnaire (SRQ) 66 • Pt Disease & Treatment Assessment (Pt DATA Form) 48 • FACT-O (including 8 items of FOSI) 39 • 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

  22. 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

  23. ‘First filter’ analysis: aims & methods Aim Determine which 4 PRO questionnaires to retain for stage 2 Analysis • Prevalence of each possible symptom in the ‘Top Three Most Noticed Symptoms in the last week’ (as asked by the Symptom Representation Questionnaire). • Summary statistics and histograms describing the frequency distributions of items and domain scores for each symptom at baseline • Changes from baseline in item and domain scores Data 31 patients who completed QOL questionnaires at baseline (pre-C1) AND (pre-C2 (AND/OR) pre-C3) by Jul ‘09

  24. Results: Top 10 Symptoms of the ‘Three Most Noticed Symptoms in the last week’at baseline

  25. Coverage of Top 10 symptoms by candidate questionnaires

  26. Detailed example of overlap Pain - general

  27. 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

  28. 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

  29. Decisions Retain 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 benefit Retain FACT-O (including FOSI) to measure QOL FACT-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 items QLQ-C30 • 22 sub scales • Duplication of single-item symptoms with Pt DATA Form • Global QOL based on 2 items

  30. 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

  31. Platinum Resistant Ovarian CancerPFS

  32. Platinum Resistant Ovarian CancerOS

  33. Platinum Resistant Ovarian CancerHypothetical Risk GroupsPFS

  34. Platinum Resistant Ovarian CancerHypothetical Risk GroupsOS

  35. 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

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