Presentation on theme: "OvCa Clinical Trials Planning Meeting Orlando May 2009"— Presentation transcript:
1OvCa Clinical Trials Planning Meeting Orlando May 2009 GCIGOvCa Clinical Trials Planning MeetingOrlando May 2009
2Efficient 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 IIRandomised 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 earlierSize of benefit aimed for is critical to relevant design...three outcome design may reduce sample size 20-30% (but area of uncertainty)
3Where to set the null bar? Too low, go to Phase III too often and increases the sample sizeToo high, do not go to Phase III often enough and miss a potential winnerIntegrated 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
4What HAS changed in RECIST 1.1 Measuring tumor burden10 targets5 per organFor response: 5 targets(2 per organ)Lymph nodeMeasure long axis as for other lesions.Silent on normal sizeMeasure short axis.Define normal size.Progression definition20% increase in sum20% increase and at least5 mm absolute increaseNon-measurable disease PD“must be unequivocal”Expanded definition to convey impact on overall burden of disease. Examples.Confirmation of objective responserequiredRequired when response primary endpoint—but not otherwiseNew lesions--New section which includes comment on FDG PET interpretation
5GCIG CA125 criteria Developed by GCIG to complement RECIST criteria Response criteria1For use in phase II studies in relapsed diseaseEvaluable pts must have baseline CA125 > 2 x ULNCA125 response: 50% decrease confirmed > 28 daysDate response = date of first 50% fallProgression Criteria2For use in front-line setting to complement objective PDCA125 PD: Double of UNL (or nadir if > UNL) confirmed > 7 daysDate CA125 PD = date of first doublingDate overall PD = earliest date of CA125 or objective PDException: recent surgery or intraperitoneal procedureRustin GJ, et al: J Natl Cancer Inst :487-8Vergote I, et al. J Natl Cancer Inst. 2000, 92:1534-5
6CA125 PD definitionDoes 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 PDi.e. would it be enough to measure CA125 routinely BUT to consider PD based on objective findings only? Main advantage: trial conduct simplifiedNeed data from other front-line trials which used GCIG definition PD to determine if value added by this composite endpoint
7Phase 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!
8Phase 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?
9CONCLUSIONSprogression-free survival will become increasingly important endpoint as treatment options in recurrent disease increasebut ….. in the modern era of novel targeted therapies in ovarian cancerdo 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
10New Imaging Modalities PET CTDynamic contrast enhanced CT (DCE-CT)Dynamic contrast enhanced MRI (DCE MRI)Nodal imaging...esp small nodes.Ultrasmall superparamagnetic iron oxide (USPIO) MRIDiffusion weighted imaging (DWI) MRI
12Dynamic Contrast Enhanced MRI As a Biomarker Correlates with pathologic prognostic indicatorsTumour grade, microvessel density, VEGF expressionPredict clinical response to therapyAnti-VEGF antibody, tyrosine kinase inhibitorProspectively acquired DCE MRI databasesNeoadjuvant breast cancerRecurrent glioblastoma
13PET-CT in Recurrence n=53 2PET-CT in Recurrence n=53CT alone PET-CTSensitivity 92% %Specificity 60% %Kappa
14New Agents Signalling Pathway interventions….eg P13 Kinase XL47/ Perifosine/mTOR…..E-Cadherin disruptionAZD0530 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 chemotherapyOVERT I is the first randomised evaluation of the clinical benefit of Src inhibition in combo with CBPAnti-angiogenicsVEG TRAP in highly pretreatedBevacizumab data...leading to toxic antiangiogenic combinations...Bevacizumab and m-TOR inhibitors eg everolimus under investigation
15Ph II, nonrandomized; pts with persistent or recurrent EOC or PPC NCT IdentifierAgent(s)Study DesignNCTTemsirolimusPh II, nonrandomized; pts with persistent or recurrent EOC or PPCNCTTemsirolimus + carboplatin/paclitaxelPh I, open label; in pts with advanced endometrial cancer, ovarian cancerNCTTemsirolimus + topotecanPh I, open label, nonrandomized; in pts with gynecologic malignancies..NCTTemsirolimus+DoxilResistant solid MalignanciesNCTTemirolimus+docetaxelResistant solid malignancies15
16RESPONSE TO OLAPARIB BY PLATINUM-FREE INTERVAL TotalPlatinum sensitivePlatinum resistantPlatinum refractoryNo. of evaluable patients46102511Responders by RECIST13 (28%)5 (50%)8 (32%)0 (0%)Responders by GCIG CA12518 (39%)8 (80%)2 (18%)Responders by either RECIST or GCIG criteria21 (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)
17PARP Inhibitors in Clinical Trials..Phase I/II/III AgentCompanyStrategyAdministrationAG014699PfizerCombination*IVKU59436AstraZeneca-KudosSingleOralABT-888AbbottBSI-201BiParCombinationsINO-1001Inotek-GenentechMKMerckSingle agent and combinationGPI 21016MGI Pharma
18Clinical 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
21Increase in Oncology Drugs Pharmacogenomics (PGx)Influence of Individual Genomic Polymorphisms on Drug ResponsePersonalized MedicineIdentify Risk for Toxicities..rising concerns….increased patient feedbackIdentify Predictive Markers of Efficacy prior to drug release eg Tx and CYP2D6Need to get blood in all Trials we do…
22PFS (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 StudyRandomized phase IIIT 180 mg/m2 + Carbo AUC 6 d1, q 3wkT 80 mg/m2 d1,8,15 + Carbo AUC 6 d1, q3wkEndpoint: PFSn: 637 ptsPFS (median follow up 29 m):17,1m vs 27,9m (p:0.0014) log-rank testOS (at 2 years):77,7% vs 83,6% (p:0.05)RR: similarToxicity: Anemia G3-4 in weekly arm more freqIsohishi S et al . ASCO 2008,Abstract-5506 (Oral)
23UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING ONGOING STUDIES in front-line ovarian cancer GroupStudy Design Tmg/m2nPrimary ObjetiveSecondary ObjetivesStatusIntergroupMO22225 (OCTAVIA)Phase IIT80 d1,8,15 q21+ C AUC 6 q21 + Beva 7.5q21180PFSORRRR DurationOSSafetyOpen in June 09MITO-7Phase III R C AUC6+ T175vsT60 d1,8,15, q21 C AUC 2 q 21500QoLPFS,Open
24Epithelial Ovarian Cancer GOG172 TrialEpithelial Ovarian CancerOptimal Stages IIIRandomizationPaclitaxel 135 mg/m2/24h IV D1Cisplatin 75 mg/m2 IV D2Q21, 6 CyclesPaclitaxel 135 mg/m2/24h IV D1Cisplatin 100 mg/m2 IP D2Paclitaxel 60 mg/m2 IP D8Q21, 6 Cycles
25Planned Japanese IP Trial Epithelial Ovarian CancerStages II-IVExcluding Clear Cell CarcinomaRandomizationPaclitaxel 80 mg/m2 IV WeeklyCarboplatin AUC 6 IVQ21, 6-8 CyclesPaclitaxel 80 mg/m2 IV WeeklyCarboplatin AUC 6 IPQ21, 6-8 CyclesPrimary Endpoint: PFSSecondary Endpoint: OS, Toxicity, QOL
27Initial Therapy of Ovarian Cancer: Controversial Areas How can we best use targeted biologics with initial chemotherapy to improve outcome? ICON7/GOG218/Tarceva…?ICON8Should consolidation therapy be offered to all ovarian cancer patients? SWOG9071/GOG 178Should 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 x10-20Should access/eligibility be broadened to reflect the “real world” Comparative effectiveness research…
28SURGICAL TRIALS AGO/OVAR OP3...lymphadenectomy vs no lymphadenectomy in optimal debulked casesDESKTOP 3...High AGO score...plat sensitive .....op vs no op (secondary debulk)
29Rare Tumours Mucinous .. ..CT VS OXALI/ CAPE +-BEV Sex Cord...CT vs BEP... BEVACICZUMABSerous LMP....AZD 6244
30But ….still many Questions !! Impact of treatment on HRQOLWhich instruments do we useHow important is hope in decision making?Would good palliative care achieve the sameWould palliative care be acceptableHow much time do patients spend in hospital as a result of toxicityHow many patients receive treatment within 30 days of deathCan we identify patients most likely to benefit
31Questions 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 treatmentLunney, J. R. et al. JAMA 2003von Gruenigen et al. Cancer 2008
32Partnering …Industry Perspective What we BringNovel MoleculesGlobal PresenceAdvocacy LinksFinancial supportWhat we NeedTimelinessConcept→PA→FPVRegulatory Quality Data CollectionCooperation withCTR RequirementsTissue for biological studies to predict response
33Challenges Opportunities Intellectual Property(cf Alberts presentation)Biomarker-Pt SegmentationCONTRACTINGCoContractingntractingDataNDAsNDATimeline(s)Stakeholder dialogueSafe harborCommon ClausesStreamlinedOptimizedStandardized/caBIGSurrogate Endpoints (PFS -Ind/Review-EBM)Curt G; McClellan M, Benner JS; Niederhuber JEThe Oncologist 2009 in press
34Industry Group Industry-Cooperative group relationships sponsor CAELYX - Module 2Industry-Cooperative group relationshipsIndustryGroupLate development (organ-specific phase II, combination trials)sponsorsponsorEarly development (phase I, early efficacy phase II, pivotal phase III for approval)
36Industry-Cooperative group relationships What rules between industry and cooperative groups ?ENGOT minimal requirement for Academic trialsWhat to share and how ? - one protocol - one data base (ownership, - one crf (e-crf) - monitoring , SOPs, SAEs flow - statistical analysis - IDSMB - publication policy
41CA125 PD definitionDoes 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 PDi.e. would it be enough to measure CA125 routinely BUT to consider PD based on objective findings only? Main advantage: trial conduct simplifiedNeed data from other front-line trials which used GCIG definition PD to determine if value added by this composite endpoint
42Phase 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?
43CONCLUSIONSprogression-free survival will become increasingly important endpoint as treatment options in recurrent disease increasebut ….. in the modern era of novel targeted therapies in ovarian cancerdo 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
45OVCA 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 A 10 arm study, we need to establish what each group has available and feels is appropriate.Liase with ACRIN
47WHEN 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?
48PharmacogenomicsAll studies need to have blood collection built into the protocol.Funding??
49Separating 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?
51Initial Therapy of Ovarian Cancer: Controversial Areas How can we best use targeted biologics with initial chemotherapy to improve outcome? ICON7/GOG218…?ICON8Dose 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”
52Questions 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 ovcaAre platinum resistant patients likely to be PARP inhibition resistant?Platinum plus PARP inhibitors?
53Future Challenges Validation of prognostic and predictive biomarkers. Larger numbers of carefully annotated specimensFFPE technologiesIdentification and validation of small molecule inhibitors targeting pathwaysIntegrated biomarkers will be mandated.Molecular basis for resistanceRecurrent tumor biopsies should be a requirement in all GCIG studies…ascites as a surrogate?.How do we get to the tumour micro-environment?
54UNANSWERED QUESTIONS IN UPFRONT THERAPY Weekly Dosing What is the standard weekly dose?Which drugs should be administered in a weekly scheduleOnly Taxane?Taxane + carboplatin?How to incorporate weekly dose asi.p strategy?biologic agents combination?How best to determine the appropriate duration of weekly dose therapy?
55IP Chemotherapy in Ovarian Cancer Trial Endpoints to be AnsweredLess Toxic CombinationsCan Carboplatin replace Cisplatin? NCIC….winnerIs Day 8 IP Paclitaxel required?Efficacy AssessmentIs 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
56Neoadjuvant 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?
57Neoadjuvant ChemoCan 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?
59QOL issuesDo 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?
60QuestionsWhat 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 treatmentLunney, J. R. et al. JAMA 2003von Gruenigen et al. Cancer 2008