WG Session : Incorporation of PROs in clinical trial. Digest of the OCC plenary session Recommendations? Publication?

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1 WG Session : Incorporation of PROs in clinical trial Digest of the OCC plenary session Recommendations? Publication?

2 Plenary Presentation Incorporating Patient Reported Outcomes in GCIG Ovarian Cancer Trials Challenges and Opportunities Florence Joly MD PhD (GINECO) Michael Friedlander MD PhD (ANZGOG) 5 th Ovarian Cancer Consensus Conference The Jikei University, Tokyo, Japan November 7-9 th,

3 Checklist for PRO s in GCIG phase 3 clinical trials CONTEXT HYPOTHESES Patient population what are the aims and objectives of treatment (context specific : first line, poor/good prognosis relapse, maintenance) Are we measuring what patients consider important? Will the results impact on regulatory approval and/ clinical practice? What is the a-priori PRO hypothesis? Will PRO s support the primary trial endpoint? What are the most important PRO endpoints (according to context specific)? METHODS Have we selected the right instrument/s? Criteria for what constitutes a clinical important difference Is the study adequately powered for the PRO/QOL endpoints? Do we have a SAP in place to PRO s ( with strategy to reduce or avoid missing data? Reporting/publications : Adhere to the CONSORT-PRO extension guidelines 5 th Ovarian Cancer Consensus Conference The Jikei University, Tokyo, Japan November 7-9 th,

4 Challenges of GCIG for the future Summary of the WG discussion/actions Publication of the PROs considerations issued from the ovarian conference consensus (as a separated paper) Tools : - QoL Questionnaires : how to select relevant symptoms from the tools? - Waiting for the definitive validation of MOST - Patient preferences : Methodological issues To be addressed during Chicago SG Working group meeting - Patients reported adverse events Meeting with NCI PRO CTCAE pts reported Toxicity in Chicago, - Doctor reported side effects (grade 2, nb, evolution over time PRO s Endpoints : consensus to support co-primary endpoint in poor prognostis relapse ovarian Cancer How to deal with missing data with the EORTC QoL Gyn Group Work with Harmonization, Interaction 5 th Ovarian Cancer Consensus Conference The Jikei University, Tokyo, Japan November 7-9 th,

5 Closed studies SB study QoL Penelope

6 Symptom Benefit Study Does palliative chemotherapy improve symptoms Does palliative chemotherapy improve symptoms in women with recurrent ovarian cancer?

7 SBS Status Closed to recruitment: 31/12/2014 ANZGOG-0701 TOTAL ACCRUAL

8 Current/Planned Analyses MOST Validation - ISOQOL ESGO 2015 MOST- MCID- in progress Analysis of patient outcomes/ symptom complex- general - ASCO publication planned Prognostic Factors Prognostic Index -ASCO-publication planned Baseline HRQoL as a prognostic factor Identifying ultra-poor prognostic subset- patients who should not be treated Patient/Clinician expectations and perceived benefit Patient reported adverse effects Patient reported symptom benefit Cross cultural variations

9 Relative Efficiency: Cancer symptoms (Yes vs. No) OV1 (QLQ-OV28) 1.21 (0.90, 1.59) OCS (FACT) 2.05 (1.39, 3.26) FOSI - 8 item 0.97 (0.76, 1.28) TOI (FACT) 1.95 (1.39, 2.86) FOSI - 15 item 1.69 (1.24, 2.32) Favours alternative measure Favours MOST-OSI The University of Sydney Page 9

10 Relative Efficiency: Ascites (Yes vs. No) OV1 (QLQ-OV28) 0.84 (0.60, 1.19) OCS (FACT) 1.52 (1.01, 2.35) FOSI - 8 item 1.16 (0.84, 1.62) TOI (FACT) 1.79 (1.21, 2.76) FOSI - 15 item 1.78 (1.22, 2.60) Favours alternative measure Favours MOST-OSI The University of Sydney Page 10

11 The University of Sydney Page 11

12 Median PFS in PPS >3 and PRR groups was 5.5 months ( ) and 3.6 months ( ) The University of Sydney Page 12

13 13 Patient-reported outcome results from the AGO-OVAR 2.20/ENGOT-ov14/PENELOPE double-blind placebo-controlled randomised phase III trial evaluating chemotherapy with or without pertuzumab for platinum-resistant ovarian cancer Felix Hilpert 1, Elfriede Greimel 2, Petronella Ottevanger 3, Joern Rau 4, Domenica Lorusso 5, Judith Kroep 6, Mansoor Raza Mirza 7, Alain Zeimet 8, Nicolas Martin 9, Christian Kurzeder 10 1 AGO and Klinik für Gynäkologie und Geburtshilfe, Kiel, Germany; 2 Medical University Graz, Graz, Austria; 3 DGOG and Radboud University Medical Center, Nijmegen, The Netherlands; 4 Coordinating Center for Clinical Trials, Philipps-University of Marburg, Marburg, Germany; 5 MITO and Fondazione IRCCS National Cancer Institute, Milan, Italy; 6 DGOG and Leids Universitair Medisch Centrum, Leiden, The Netherlands; 7 NSGO and Rigshospitalet, Copenhagen, Denmark; 8 AGO-A and Medical University Innsbruck, Innsbruck, Austria; 9 F Hoffmann-La Roche, Basel, Switzerland; 10 AGO and Kliniken Essen Mitte, Essen, Germany

14 14 Figure 2. PRO instruments and assessment schedule Time (weeks) of up treatment End Follow QLQ-C30, QLQ-OV28, HADS, FOSI Three worst symptoms EORTC QLQ-C30 EORTC QLQ-OV28 HADS: Hospital Anxiety Depression Scale FOSI: Functional Assessment of Cancer Therapy (FACT)/National Comprehensive Cancer Network (NCCN) Ovarian Symptom Index Three worst symptoms questionnaire (only at baseline). The predefined primary PRO endpoint was mixed-model repeated measures (MMRM) analysis of the QLQ-OV28 abdominal/gi symptoms scale. EORTC = European Organization for Research and Treatment of Cancer; QLQ = quality of life questionnaire.

15 15 Figure 3. Compliance rates: QLQ-OV28 (primary PRO instrument) Baseline (N=156) Week 9 (N=92) Week 18 (N=49) Week 27 (N=23) Week 36 (N=14) The denominator used to calculate the percentage at baseline is all randomised patients. For all other time points, the denominator is the number of patients known to be alive, progression-free and on study treatment at the start of the time period.

16 16 Figure 4. MMRM analysis of change from baseline in the QLQ-OV28 abdominal/gi symptom scale (primary PRO endpoint) Worsening Least-squares mea ans estimate 5.2 [ 1.8 to 12.1] 3.0 [ 6.2 to 12.3] 11.4 [ 1.1 to 23.8] Profile: p= [ 18.9 to 11.4] 3.9 [ 3.3 to 11.2] Improvement No. of patients Pertuzumab + CT Placebo + CT

17 17 Table 4. Secondary PRO endpoints: MMRM analysis of change from baseline in five prespecified scales of EORTC QLQ-C30 Least-squares mean estimate (95% CI), overall profile Scale Physical functioning Emotional functioning Fatigue Nausea and vomiting Diarrhoea Pertuzumab + chemotherapy 8.1 ( 12.6 to 3.5) 4.8 ( 1.0 to 10.5) 9.4 (3.7 to 15.1) 8.6 (1.7 to 15.6) 23.9 (16.6 to 31.2) Placebo + chemotherapy 5.5 ( 10.5 to 0.5) 0.1 ( 6.2 to 6.4) 6.9 (0.5 to 13.3) 4.4 ( 3.4 to 12.2) 2.7 ( 5.7 to 11.0) Difference: pertuzumab placebo 2.6 ( 9.4 to 4.2) 4.6 ( 4.0 to 13.2) 2.5 ( 6.2 to 11.1) 4.2 ( 6.2 to 14.6) 21.2 (10.1 to 32.3) p-value

18 18 Exploratory endpoint: Worst symptoms questionnaire Approximately half of all randomised patients (N=84; 54%) completed the worst symptoms questionnaire at baseline. The symptom most commonly ranked as worst was abdominal pain (14 patients; 17%), followed by fatigue (13 patients; 15%). The symptom most commonly ranked within the three worst symptoms was fatigue (N=33; 39%), followed by trouble sleeping (N=28; 33%), bloated feeling in the abdomen/stomach (N=27; 32%) and pain (N=26; 31%).

19 Ongoing studies Elderly Expression IV AGO 19/Trust Survivors The University of Sydney Page 19

20 EWOC-1 Elderly Women Ovarian Cancer Multicenter, randomized trial of carboplatin +/- paclitaxel in vulnerable elderly patients with stage IIB-IV advanced ovarian cancer First ENGOT-GCIG international study of elderly patients in Ovarian Cancer ENGOT OV-23 Participating Groups GINECO, AGO, MITO, ANZGOG, Canada, ICORG, GOTIC, NSGO The University of Sydney Page 20

21 EWOC-1 Recruitment EWOC GINECO First Patient In 12/12/2013 MITO First Patient in 20/07/ Planned Randomized Actual randomizations 0 Dec 2013 janv-14 Feb March Apr May Jun Jul Aug Sep Oct Nov Dec janv-15 Feb March Apr May Jun Jul Aug Sep Oct Nov Dec janv-16 Feb March Apr May Jun Jul Aug Sep Oct Nov Dec The University of Sydney GCIG meeting 10/11/ Page 21

22 Sites Status Countries EWOC-1 Planned sites Open sites Active sites Inclusions Randomised Patients Germany 16 0 Italy Ireland 4 0 Sweden 2 0 Denmark 3 0 Finland 3 0 Canada 1 0 France Australia 0 Japon 0 TOTAL IDMC and TSC meetings to be scheduled in November First interim analysis when the first 66 pts have completed treatment The University of Sydney GCIG meeting 10/11/ Page 22

23 Expression IV Results of 641 patients of the NOGGO/ENGOT-ov22 survey: What are the expectations of patients with ovarian cancer to a maintenance therapy? R. Chekerov, M. Keller, R. Richter, J. Ziga, C. Marth, A. Reinthaller, F. Joly, J-M. Kurtz, P. Achimas, V. Vergote, E. van Niewenhuysen, J. Sehouli First Interim Analysis Participating countries: Austria (A-AGO), Belgium (BGOG), Italy (MITO), Romania, Slovenia, France (GINECO) and Germany (NOGGO) Current status of recrutment : 1243 pts

24 Results Participants Country : 641 Participants

25 Results Personal objective for taking maintenance therapy Shrinking of the tumor Decrease of CA-125 no deterioration of quality of life delay of tumor growth Improvement of quality of life Increase the chances of cure Percent Rezidiv Primary

26 If only PFS effects of maintenance, how long should be the time benefit? 33 months? 8.1% 4-6 months? 12.9% >6 months? 51.5%

27 AGO OVAR 19 - QoL longitudinal all Pts with suspicion for OC III- IV FRAGILE: prim. Endpoint: 10-PFS F R A G I L E S c r e e n i n g c Allocation to study/ Randomisation/Strat ification QoL every 3 months until first recurrence/progression Z1 Z2 Z3 Z4 Z5 Z6 EoT QoL TRUST every 3 months until first recurrence/progression Z1 Z2 Z3 Z4 Z5 Z6 EoT PDS QoL every 3 months until first recurrence/progression QoL Z1 Z2 Z3 Z4 Z5 Z6 EoT IDS every 3 months until first recurrence/progression Best Supportive Care QoL-BL 1. ROC QoL-BL 1. ROC QoL-BL 1. ROC every 3 months until first recurrence/progression every 3 months until frecurrence/progression every 3 months until frecurrence/progression QoL-BL 2. ROC QoL-BL 2. ROC QoL-BL 2. ROC every 3 months until recurrence/progression every 3 months until recurrence/progression QoL-BL 3. ROC QoL-BL 3. ROC QoL-BL every 3 months until recurrence/progression 3. ROC

28 study design all pts with suspected advanced ovarian cancer PROSPECTIVE COLLECTION OF VARIABLES numeric age at diagnosis BMI laboratory: albumine, creatinine Hb, leucocytes, thrombocytes CA 125 Charlson-Comorbidity-Index (age adjusted) time up and go test suspected FIGO IV y/n chest CX-ray: pleural effusions y/n ascites y/n ECOG ASA HADS-Score symptoms: abdominal symptoms y/n treatment-requiring abd. symptoms y/n dyspnea y/n treatment to the investigators decision (TRUST trial optional, NACT optional) documentation of: surgical outcome, FIGO stage, histology, complications, revision surgery, sytemic treatment, cycle number, ECOG after 6 months Follow-Up for months after 6th cycle primary end point: evaluating of factors which describe frail pts who do not benefit from standard therapy sequence surgery CTX ( progression or death within 10months after registration secondary end-points:3-months-survival, feasibility (surgery until 1st cycle 6 weeks, cycle number), residual tumor, FIGO-stage, TNM-stage, ECOG after 6 months, 6-months PFS, revision surgery

29 Secondary prevention and treatment of palmo-plantar erythema in gynecologic oncology with Mapisal - a prospective, double-blind, placebocontrolled randomised phase III study of the AGO Study GroupAGO PRO-2 Screening: Pts. with gyn cancer under PLD with PPE Grade II, and expected to receive 2 cycles 126 Pts duration: months Strata: PLD 30 vs > 30 mg/m2 Mapisal 3 x daily local + PLD Baseline: PPE recovered grade 0/I, min. 2 further cycles PLD planned R Placebo 3 x daily local + PLD No grade III/IV PPE: continiue with PLD until PD PPE III/IV : EOT No grade III/IV PPE: continue PLD until PD PPE III/IV : EOT Primary endpoint : G ¾ PPI