OvCa Clinical Trials Planning Meeting Orlando May 2009 GCIG OvCa Clinical Trials Planning Meeting Orlando May 2009

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)

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

What HAS changed in RECIST 1.1 Measuring tumor burden 10 targets 5 per organ For response: 5 targets (2 per organ) Lymph node Measure long axis as for other lesions. Silent on normal size Measure short axis. Define normal size. Progression definition 20% increase in sum 20% increase and at least 5 mm absolute increase Non-measurable disease PD “must be unequivocal” Expanded definition to convey impact on overall burden of disease. Examples. Confirmation of objective response required Required when response primary endpoint—but not otherwise New lesions -- New section which includes comment on FDG PET interpretation

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

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

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!

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?

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

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

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

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

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

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 eg everolimus under investigation

Ph II, nonrandomized; pts with persistent or recurrent EOC or PPC NCT Identifier Agent(s) Study Design NCT00429793 Temsirolimus Ph II, nonrandomized; pts with persistent or recurrent EOC or PPC NCT00408655 Temsirolimus + carboplatin/paclitaxel Ph I, open label; in pts with advanced endometrial cancer, ovarian cancer NCT00523432 Temsirolimus + topotecan Ph I, open label, nonrandomized; in pts with gynecologic malignancies.. NCT00703170 Temsirolimus+ Doxil Resistant solid Malignancies NCT00703625 Temirolimus+ docetaxel Resistant solid malignancies 15

RESPONSE TO OLAPARIB BY PLATINUM-FREE INTERVAL   Total Platinum sensitive Platinum resistant Platinum refractory No. of evaluable patients 46 10 25 11 Responders by RECIST 13 (28%) 5 (50%) 8 (32%) 0 (0%) Responders by GCIG CA125 18 (39%) 8 (80%) 2 (18%) Responders by either RECIST or GCIG criteria 21 (46%) 11 (44%) SD (> 4 cycles) 9 (15%) 1 (10%) 4 (16%) 1 (9%) Median duration of response in weeks (range) 31 (10-96) 31 (16-96) 29 (10-84) 39 (27-51)

PARP Inhibitors in Clinical Trials..Phase I/II/III Agent Company Strategy Administration AG014699 Pfizer Combination* IV KU59436 AstraZeneca-Kudos Single Oral ABT-888 Abbott BSI-201 BiPar Combinations INO-1001 Inotek-Genentech MK Merck Single agent and combination GPI 21016 MGI Pharma

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

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

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

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 eg Tx and CYP2D6 Need to get blood in all Trials we do…

PFS (median follow up 29 m): OS (at 2 years): RR: similar UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING Randomized PHASE 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)

UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING ONGOING STUDIES in front-line ovarian cancer Group Study Design Tmg/m2 n Primary Objetive Secondary Objetives Status Intergroup MO22225 (OCTAVIA) Phase II T80 d1,8,15 q21 + C AUC 6 q21 + Beva 7.5q21 180 PFS ORR RR Duration OS Safety Open in June 09 MITO-7 Phase III R C AUC6+ T175 vs T60 d1,8,15, q21 C AUC 2 q 21 500 QoL PFS, Open

Epithelial Ovarian Cancer 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

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

Optimal Debulked Stage III Epithelial Ovarian Cancer 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

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…

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

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

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

Questions 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? Compared a retrospective cohort of ovarian cancer patients age >70 after opt. surgical procedure receiving IV carboplatin/paclitaxel as first line treatment Lunney, J. R. et al. JAMA 2003 von Gruenigen et al. Cancer 2008

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

Challenges Opportunities Intellectual Property (cf Alberts 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) Curt G; McClellan M, Benner JS; Niederhuber JE The Oncologist 2009 in press

Industry Group Industry-Cooperative group relationships sponsor CAELYX - Module 2 Industry-Cooperative group relationships Industry Group Late development (organ-specific phase II, combination trials) sponsor sponsor Early development (phase I, early efficacy phase II, pivotal phase III for approval)

The good guys and the bad guys

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

KEY ISSUES FROM HERE....

Trial design

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.

Response Assessment

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

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?

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

Imaging

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

New Agents and Approaches

WHEN TO TEST NEW AGENTS AND APPROACHES 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?

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

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?

Initial therapy questions

Initial Therapy of Ovarian Cancer: Controversial Areas How can we best use targeted biologics with initial chemotherapy to improve outcome? ICON7/GOG218…?ICON8 Dose dense? Should consolidation therapy be offered to all ovarian cancer patients? Does receiving consolidation therapy alter response to subsequent chemotherapy? Should BRCA-associated cancers be treated differently? Should cost of treatment be an issue in designing clinical trials? Should access/eligibility be broadened to reflect the “real world”

Questions about the use of PARP inhibitors in ovarian cancer Is there a role for PARP inhibitors in ovarian cancer patients without a BRCA mutation? Eg High grade serous… Other defects in the homologous recombination pathway…approx 40% in ovca Are platinum resistant patients likely to be PARP inhibition resistant? Platinum plus PARP inhibitors?

Future Challenges Validation of prognostic and predictive biomarkers. Larger numbers of carefully annotated specimens FFPE technologies Identification and validation of small molecule inhibitors targeting pathways Integrated biomarkers will be mandated. Molecular basis for resistance Recurrent tumor biopsies should be a requirement in all GCIG studies…ascites as a surrogate?. How do we get to the tumour micro-environment?

UNANSWERED QUESTIONS IN UPFRONT THERAPY Weekly Dosing What is the standard weekly dose? Which drugs should be administered in a weekly schedule Only Taxane? Taxane + carboplatin? How to incorporate weekly dose as i.p strategy? biologic agents combination? How best to determine the appropriate duration of weekly dose therapy?

IP Chemotherapy in Ovarian Cancer Trial Endpoints to be Answered Less Toxic Combinations Can Carboplatin replace Cisplatin? NCIC….winner Is Day 8 IP Paclitaxel required? Efficacy Assessment Is IP Carboplatin better than IV Carboplatin? Current study .. Dose Day 8 IP Paclitaxel matter or Only Day 8 Paclitaxel (IV) matter? New Approaches… Adding Bevacizumab and testing the effect of day 8 Taxane

Neoadjuvant Chemotherapy How to design trials incorporating both upfront surgery and IDS? How to add new agents...ICON8 the answer? Is there really a point in removing ‘normal’ organs? How best to schedule surgery and bevacuzimab or weekly taxane?

Neoadjuvant Chemo Can we develop a rational superiority trial incorporating neoadjuvant chemotherapy? What info can we get using neoadjuvant chemo?...eg re-biopsy. How to best determine extensive disease? What is the best way to incorporate neoadjuvant chemotherapy into advanced age and poor performance populations? What is the best timing for surgery in patients undergoing neoadjuvant chemotherapy (3 vs. 6 months)? Which patients should not undergo surgical intervention?

Quality of Life

QOL issues Do we need more instruments? Are Symptom Indices a surrogate?..’FOSI’ the answer? PROMIS of use across all GCIG trials? When in the illness do we assess QOL? 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? Does response translate into symptomatic benefit? How many patients receive treatment within 30 days of death? Can we identify patients most likely to benefit?

Questions What is the QOL of elderly ovarian cancer patients? Are there cultural differences? What type of impact does their “age” have on QOL and feasibility of surgery/chemotherapy? Should neoadjuvant chemo be the standard of care? 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? Compared a retrospective cohort of ovarian cancer patients age >70 after opt. surgical procedure receiving IV carboplatin/paclitaxel as first line treatment Lunney, J. R. et al. JAMA 2003 von Gruenigen et al. Cancer 2008

WHAT ABOUT THE PARTNERS?

Industry Issues

Communication Confidence and Transparency

Rules or guidelines with industry?