GCIG

1. GCIG OvCa Clinical Trials Planning Meeting Orlando May 2009

2. Efficient designs for Phase 11/111 Trials • Bad Phase 11 study design leads to missing effective treatments/misuse of resources in planning and execution of Phase III studies particularly when modest benefit aimed for.eg only 28% pos Phase III studies following Phase II • Randomised Phase II design allows for smaller patient numbers/incorporation of data from both arms into the subsequent Phase III eg GOG 182/ICON5....drop arms earlier • Size of benefit aimed for is critical to relevant design...three outcome design may reduce sample size 20-30% (but area of uncertainty)

3. Where to set the null bar? • Too low, go to Phase III too often and increases the sample size • Too high, do not go to Phase III often enough and miss a potential winner • Integrated randomised phase II/III design works well under the global null… E[N] and E[T] no larger than that of a randomized phase II study

4. What HAS changed in RECIST 1.1

5. GCIG CA125 criteria • Developed by GCIG to complement RECIST criteria • Response criteria1 • For use in phase II studies in relapsed disease • Evaluable pts must have baseline CA125 > 2 x ULN • CA125 response: 50% decrease confirmed > 28 days • Date response = date of first 50% fall • Progression Criteria2 • For use in front-line setting to complement objective PD • CA125 PD: Double of UNL (or nadir if > UNL) confirmed > 7 days • Date CA125 PD = date of first doubling • Date overall PD = earliest date of CA125 or objective PD • Exception: recent surgery or intraperitoneal procedure • Rustin GJ, et al: J Natl Cancer Inst. 2004 96:487-8 • Vergote I, et al. J Natl Cancer Inst. 2000, 92:1534-5

6. CA125 PD definition • Does including CA125 as part of PD definition add value or just complexity? • Majority of pts with elevated CA125 have imaging and are found to have objective PD i.e. would it be enough to measure CA125 routinely BUT to consider PD based on objective findings only? Main advantage: trial conduct simplified Need data from other front-line trials which used GCIG definition PD to determine if value added by this composite endpoint

7. Phase II screening trials: • CA125 RR is usually higher than objective RR: does this mean anything? • Are drugs with CA125 responses but no objective responses “active”? Have any been identified and tested in phase III? • Is CA125 RR value added in drug development? (there is no doubt CA125 is useful in clinical management but that is another question) • Are other functional/molecular imaging endpoints of value? • Is non-progression rate (CR + PR + SD) more meaningful than response rate? • Need DATA to answer all these questions!

8. Phase III trials: • Although Baden Baden endpoint recommendations are symptom benefit or OS, PFS is often used in these trials as primary endpoint. • Does PFS prolongation of 1-2 mo have any “meaning” for patients in situation of recurrent disease if NOT accompanied by either OS or symptom improvement? • Is PFS a surrogate for OS in recurrent disease?

9. CONCLUSIONS • progression-free survival will become increasingly important endpoint as treatment options in recurrent disease increase but ….. in the modern era of novel targeted therapies in ovarian cancer do not assume that the same rules apply in assessment of disease progression, and more emphasis may need to be placed on RECIST, rather than CA125 changes

10. New Imaging Modalities • PET CT • Dynamic contrast enhanced CT (DCE-CT) • Dynamic contrast enhanced MRI (DCE MRI) • Nodal imaging...esp small nodes. • Ultrasmallsuperparamagnetic iron oxide (USPIO) MRI • Diffusion weighted imaging (DWI) MRI

11. PET-CT.. 30% Impact BUT WERE THEY APPROPRIATE?

12. Dynamic Contrast Enhanced MRI As a Biomarker • Correlates with pathologic prognostic indicators Tumour grade, microvessel density, VEGF expression • Predict clinical response to therapy Anti-VEGF antibody, tyrosine kinase inhibitor • Prospectively acquired DCE MRI databases Neoadjuvant breast cancer Recurrent glioblastoma

13. 2 PET-CT in Recurrence n=53 CT alone PET-CT Sensitivity 92% 97% Specificity 60% 80% Kappa 0.29 0.63

14. New Agents • Signalling Pathway interventions….eg P13 Kinase • XL47/ Perifosine/mTOR….. • E-Cadherin disruption • AZD0530 is a highly potent and selective, orally available, once-daily Src inhibitor....enhances taxane cell kill.. • Acceptable side effect profile both as monotherapy and in combination with chemotherapy • OVERT I is the first randomised evaluation of the clinical benefit of Src inhibition in combo with CBP Anti-angiogenics • VEG TRAP in highly pretreated • Bevacizumab data...leading to toxic antiangiogenic combinations... • Bevacizumab and m-TOR inhibitors egeverolimus under investigation

16. RESPONSE TO OLAPARIB BY PLATINUM-FREE INTERVAL

17. PARP Inhibitors in Clinical Trials..Phase I/II/III

18. Clinical Impact of Genomic Characterization of Clear Cell Cancers • Remove clear cell tumors from ovarian cancer phase III trials….all genomically similar. • Create clear cell specific phase II trials. • Utilize understanding of molecular pathways of clear cell cancers from other organs to better treat ovarian cancer….eg HIF1 Pathway

19. Tumourmicroenvironment …the soil. NEJM (2003) 348: 203 Nature Med (2004) 10: 942 PNAS (2005) 102:18538

20. Potential targets.. Cytokines eg TNF- IL-6 CCL2

21. Increase in Oncology Drugs • Pharmacogenomics (PGx) • Influence of Individual Genomic Polymorphisms on Drug Response • Personalized Medicine • Identify Risk for Toxicities..rising concerns….increased patient feedback • Identify Predictive Markers of Efficacy prior to drug release egTx and CYP2D6 • Need to get blood in all Trials we do…

22. UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSINGRandomizedPHASE III TC vs DDT+C in first-line AOC patients: a JGOG Study • Randomized phase III • T 180 mg/m2 + Carbo AUC 6 d1, q 3wk • T 80 mg/m2 d1,8,15 + Carbo AUC 6 d1, q3wk • Endpoint: PFS • n: 637 pts • PFS(median follow up 29 m): • 17,1m vs 27,9m (p:0.0014) log-rank test • OS (at 2 years): • 77,7% vs 83,6% (p:0.05) • RR: similar • Toxicity: Anemia G3-4 in weekly arm more freq Isohishi S et al . ASCO 2008,Abstract-5506 (Oral)

23. UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSINGONGOING STUDIES in front-line ovarian cancer

24. GOG172 Trial Epithelial Ovarian Cancer Optimal Stages III Randomization Paclitaxel 135 mg/m2/24h IV D1 Cisplatin 75 mg/m2 IV D2 Q21, 6 Cycles Paclitaxel 135 mg/m2/24h IV D1 Cisplatin 100 mg/m2 IP D2 Paclitaxel 60 mg/m2 IP D8 Q21, 6 Cycles

25. Planned Japanese IP Trial Epithelial Ovarian Cancer Stages II-IV Excluding Clear Cell Carcinoma Randomization Paclitaxel 80 mg/m2 IV Weekly Carboplatin AUC 6 IV Q21, 6-8 Cycles Paclitaxel 80 mg/m2 IV Weekly Carboplatin AUC 6 IP Q21, 6-8 Cycles Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOL

26. Planned GOG Trial Paclitaxel 175 mg/m2 IV Carboplatin AUC 6 IV Bevacizumab Q21, 6-8 Cycles Paclitaxel 175 mg/m2 IV Carboplatin AUC 6 IP Bevacizumab Q21, 6-8 Cycles Optimal Debulked Stage III Epithelial Ovarian Cancer R A N D O M Z E Paclitaxel 135 mg/m2 IV Cisplatin 75 mg/m2 6 IP Paclitaxel 60 mg/m2 IP D8 Bevacizumab Q21, 6-8 Cycles

27. Initial Therapy of Ovarian Cancer: Controversial Areas • How can we best use targeted biologics with initial chemotherapy to improve outcome? ICON7/GOG218/Tarceva…?ICON8 • Should consolidation therapy be offered to all ovarian cancer patients? SWOG9071/GOG 178 • Should BRCA-associated cancers be treated differently…PARP Inhibitors with no BRCA mutation? • Should cost of treatment be an issue in designing clinical trials? Adding biologicals increases cost x10-20 • Should access/eligibility be broadened to reflect the “real world” Comparative effectiveness research…

28. SURGICAL TRIALS • AGO/OVAR OP3...lymphadenectomyvs no lymphadenectomy in optimal debulked cases DESKTOP 3...High AGO score...plat sensitive .....op vs no op (secondary debulk)

29. Rare Tumours • Mucinous .. ..CT VS OXALI/ CAPE +-BEV • Sex Cord...CT vs BEP ... BEVACICZUMAB Serous LMP....AZD 6244

30. But ….still many Questions !! • Impact of treatment on HRQOL • Which instruments do we use • How important is hope in decision making? • Would good palliative care achieve the same • Would palliative care be acceptable • How much time do patients spend in hospital as a result of toxicity • How many patients receive treatment within 30 days of death • Can we identify patients most likely to benefit

31. Questions Lunney, J. R. et al. JAMA 2003 von Gruenigen et al. Cancer 2008 What is the QOL of elderly ovarian cancer patients? What type of impact does their “age” have on QOL and feasibility of surgery/chemotherapy? Why is the elderly death rate so high (GOG 182, 158; ICON3)? And, what are the causes of death? What is their trajectory of decline and what happens to QOL and needs? What doses should we give? PK differences? What about >80?

32. What we Bring Novel Molecules Global Presence Advocacy Links Financial support What we Need Timeliness Concept→PA→FPV RegulatoryQuality Data Collection Cooperation with CTR Requirements Tissue for biological studies to predict response Partnering …Industry Perspective

33. Intellectual Property (cfAlberts presentation) Biomarker-Pt Segmentation CONTRACTING CoContractingntracting Data NDA sNDA Timeline(s) Stakeholder dialogue Safe harbor Common Clauses Streamlined Optimized Standardized/caBIG Surrogate Endpoints (PFS -Ind/Review-EBM) Challenges Opportunities Curt G; McClellan M, Benner JS; Niederhuber JE The Oncologist 2009 in press

34. Industry-Cooperative group relationships Group Industry sponsor sponsor Late development(organ-specific phase II, combination trials) Early development (phase I, early efficacy phase II, pivotal phase III for approval)

35. The good guys and the bad guys

36. Industry-Cooperative group relationships What rules between industry and cooperative groups ? ENGOT minimal requirement for Academic trials • What to share and how ?- one protocol - one data base (ownership, - one crf (e-crf)- monitoring , SOPs, SAEs flow- statistical analysis- IDSMB- publication policy

37. KEY ISSUES FROM HERE....

38. Trial design

39. Should each group take on a randomised Phase II and then expand to an Intergroup Stage III given the large number of new drugs? • Assessment of toxicity an important issue in such studies.

40. Response Assessment

41. CA125 PD definition • Does including CA125 as part of PD definition add value or just complexity? • Majority of pts with elevated CA125 have imaging and are found to have objective PD i.e. would it be enough to measure CA125 routinely BUT to consider PD based on objective findings only? Main advantage: trial conduct simplified Need data from other front-line trials which used GCIG definition PD to determine if value added by this composite endpoint

42. Phase III trials: • Although Baden Baden endpoint recommendations are symptom benefit or OS, PFS is often used in these trials as primary endpoint. • Does PFS prolongation of 1-2 mo have any “meaning” for patients in situation of recurrent disease if NOT accompanied by either OS or symptom improvement? • Is PFS a surrogate for OS in recurrent disease?

43. CONCLUSIONS • progression-free survival will become increasingly important endpoint as treatment options in recurrent disease increase but ….. in the modern era of novel targeted therapies in ovarian cancer do not assume that the same rules apply in assessment of disease progression, and more emphasis may need to be placed on RECIST, rather than CA125 changes

44. Imaging

45. OVCA and Radiology • What modalities should we use? Pragmatic or ideal? • Can we expect investigators to have two different standards? • What should be the minimum? USG/CT/MRI? • How do we use PET-CT?..eg response? • Do we need centralised radiological review ? • Can we build radiological databases to include translational questions? Indeed if we can, should we? • Before embarking on the 2009 randomised Stage IIb study prior to ICON 10... A 10 arm study, we need to establish what each group has available and feels is appropriate. • Liase with ACRIN

46. New Agents and Approaches

47. WHEN TO TEST NEW AGENTS AND APPROACHES?How to prioritise which pathway inhibitor to use? What is the exact mechanism in vivo...how can we identify those tumours which will respond? Will diet and exercise be as good?

48. Pharmacogenomics • All studies need to have blood collection built into the protocol. • Funding??

49. Separating the populations • Histology alone....eg clear cell,mucinous. • Are we ready to include homogenous histological groups only...eg G3 Serous....do we need arrays to identify first? • Are grade I serous tumours really like LMP tumours? • Why are we so behind breast cancer?

50. Initial therapy questions