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

NHMRC Clinical Trials Centre ANZGOG AGM, 2 April 2009, Noosa NHMRC 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

NHMRC Clinical Trials Centre ANZGOG AGM, 2 April 2009, Noosa NHMRC 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.

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Makhija S et al. Proc ASCO 2007;Abstract 5507

NHMRC Clinical Trials Centre ANZGOG AGM, 2 April 2009, Noosa NHMRC Clinical Trials Centre REGISTERREGISTER 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 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 Data Collection 4 Treatment cycles or Disease progression Proposed longer follow-up for Stage 2 Study Schema

NHMRC Clinical Trials Centre ANZGOG AGM, 2 April 2009, Noosa NHMRC Clinical Trials Centre 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

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

Symptom improvement compared with baseline in patients with SCLC treated with i.v. topotecan or CAV Symptomi.v. topotecan %CAV %p value Anorexia Chest pain Cough Dyspnea Fatigue Hemoptysis Hoarseness Insomnia Interference with daily activities

Jassem et al [33] Osoba et al [36] Fernandez et al [38] Hardy et al [39] Ellis et al [34] Tummarello et al [37] Cullen et al [35] RegimenGPBEPPVM/IMVbP PMVbMIP Overall response (%) Overall symptom improvement (%) a ——— — Symptom improvement (%) Anorexia——50———58 Cough Dyspnea Hemoptysis757891——10092 Malaise—53—— 62— Pain— Weight loss—4489——30— Non Small Cell Lung Cancer – Studies Gralla Oncologist 2004; 9:14-24

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

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

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

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre 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 Australia 20 Canada

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Baseline Demographics Symptom control/palliation + rising CA125 + radiological progression28 Rising CA125 + radiological progression9 Symptom control/palliation + rising CA1256 Symptom Control + radiological evidence1 Radiological Evidence only1 Rising CA125 only1 N = 46 Reason for treatment at enrolment

ANZGOG AGM, Noosa 2 April 2009 NHMRC 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

NHMRC Clinical Trials Centre ANZGOG AGM, 2 April 2009, Noosa NHMRC Clinical Trials Centre Previous lines of chemotherapy 1 x line2 x lines3 x lines4 x lines5 x lines7 x lines N = 43 * Missing data on 3 x pts – awaiting response from sites

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Majority Platinum Resistant Compliance All questionnaires were completed to a very high compliance rate with few or no missing data

ANZGOG AGM, Noosa 2 April 2009 NHMRC 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 Cycle 4 Deaths41 Disease progression16 Completed342214

ANZGOG AGM, Noosa 2 April 2009 NHMRC 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 Scale 7.HAD Scale (Baseline & End of Treatment only) 8.Herth Hope Index (Baseline & End of Treatment only)

ANZGOG AGM, Noosa 2 April 2009 NHMRC 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 Team 6 October 2009

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Background: What’s the problem? OSBS stage 1 uses 4 questionnaires to measure symptoms and/or quality of life: items 1.Symptom Representation Questionnaire (SRQ)66 2.Pt Disease & Treatment Assessment (Pt DATA Form) 48 3.FACT-O (including 8 items of FOSI)39 4.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

ANZGOG AGM, Noosa 2 April 2009 NHMRC 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

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre ‘First filter’ analysis: aims & methods Aim D etermine which 4 PRO questionnaires to retain for stage 2 Analysis 1.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 Data 31 patients who completed QOL questionnaires at baseline (pre-C1) AND (pre-C2 (AND/OR) pre-C3) by Jul ‘09

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Results: Top 10 Symptoms of the ‘Three Most Noticed Symptoms in the last week’ at baseline RankSymptom No. who nominated this symptom in her Top 3 (n=31) 1Fatigue17 2Pain - general11 3Abdominal bloating10 4Sleep disturbance9 5Nausea and vomiting8 6Appetite7 7Shortness of breath6 8Bowel disturbances (including constipation)6 9Pain - abdominal5 10Urinary problems3

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Coverage of Top 10 symptoms by candidate questionnaires Symptom SRQPt DATAFACT-OFOSIQLQ-C30QLQ-OV28 Fatigue Pain - general Abdominal bloating Sleep disturbance Nausea and vomiting Appetite Shortness of breath Bowel disturbances Pain - abdominal Urinary problems # items covering Top Total # items in q’aire %50%83%23%75%40%32%

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Detailed example of overlap Pain - general Q’aireItem stemResponse scaleScoring SRQPain 0 = did not have the symptom 10 = as bad as I can imagine Single item Pt-DATAPain (all or anywhere) 0 = no trouble at all 10 = worst I can imagine Single item FACT-OI 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-C30Have 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-C30 QLQ-C30Did pain interfere with your daily activities?

ANZGOG AGM, Noosa 2 April 2009 NHMRC 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

ANZGOG AGM, Noosa 2 April 2009 NHMRC 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

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre 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 2 nd 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

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Prognostic Model variables No. of lines of therapy Performance status Volume of disease Sites of disease CA125 velocity LDH; Hb; Albumin; Platelets Inflammatory markers Grade; histological subtype

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Platinum Resistant Ovarian Cancer PFS

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Platinum Resistant Ovarian Cancer OS

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Platinum Resistant Ovarian Cancer Hypothetical Risk Groups PFS

ANZGOG AGM, Noosa 2 April 2009 NHMRC Clinical Trials Centre Platinum Resistant Ovarian Cancer Hypothetical Risk Groups OS

ANZGOG AGM, Noosa 2 April 2009 NHMRC 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