Presentation on theme: "Senior Lecturer in Medical Oncology"— Presentation transcript:
1Senior Lecturer in Medical Oncology ICON8 Evaluating Weekly Chemotherapy Scheduling in the First–line Management of Ovarian CancerAwarded central funding by CRUK. As academic trial with no pharmaceutical industry involvement there is no per patient fees.Build on results of JGOG3016Extrapolation to European popn/ patients undergoing DPSAndrew ClampSenior Lecturer in Medical OncologyThe ChristieBGCS-NCRI MeetingWestminster5th July 201211
2Background Current standard-of-care 3-weekly carboplatin-paclitaxel No improvement with additional cytotoxics/ maintenance therapyIncreasing role of neoadjuvant chemotherapy with delayed primary surgeryMcGuire et al NEJM 1996; Piccart et al JNCI 2000; Ozols et al JCO 2003Vergote et al NEJM 2010
3Weekly Paclitaxel Dose density Dose intensity Acceleration of schedule to maximise exposure of tumour cells to PTX in accelerated growth phaseDose intensityAchieve higher total doseReduced toxicity (myelosuppression)Anti-angiogenic activityDose density- given dose administered over a shorter time intervalDose intensity- greater total dose of drugNorton-Simon hypothesis- chemotherapy results in rate of regression in tumour volume proportional to rate of growth for an unperturbed tumour of that sizeDose-dense manner- ensures more constant exposure of tumour cells to phase of growth when most cells in mitosis.Duration of exposure to PTX above a threshold concentration key for cytotoxic effects rather than peak concentration.
4Stage II-IV EOC/FTC/PPC n=637 JGOG 3016Stage II-IV EOC/FTC/PPC n=6371:1 randomisationCarboplatin AUC6 q3wPaclitaxel 180mg/m2 q3wPaclitaxel 80mg/m2 q1w66% stage III98% ECOG PS 0-289% primary debulking, 10% delayed debulking55% residual disease >1cm56% serous, 12% endometrioid, 11% clear cell, 5% mucinous18% stage II, 15% stage IV- allowed histologically or cytologically confirmed cancerAge >20, PS 0-3, adequate organ function.Stratified on basis of residual disease, FIGO stage, histological type (clear cell or mucinous vs other)Katsumata et al; Lancet 2009/ ASCO 2012
5JGOG3016: Updated PFS median follow-up period: 6.4 years dd-TC c-TC Katsumata et al ASCO 2012dd-TCc-TCmedian follow-up period: 6.4 yearsTreatmentnEvent, n (%)Median PFSP valueHR95%CIdd-TC312197 (63)28.2 mos.0.00370.76c-TC319229 (72)17.5 mos.5
6OS: by residual disease Median OS- all comersddTC- 312 pts 139 deaths (45%), median OS –NR 5yr OS- 58.7%cTC- 319 pts 168 deaths (53%), media nOS-62.2mo 5yr OS- 51.1%HR 0.79 p=0.039Katsumata et al ASCO 2012Median OS< 1cm, dd-TC (n=144) not reached< 1cm, c-TC (n=145) not reachedPatients surviving (%)HR 0.76 ( ), P = 0.234Median OS> 1cm, dd-TC (n=174) 51.2 mos.> 1cm, c-TC (n=168) 33.5 mos.HR 0.75 ( ), P =Interaction: P = 0.9256
7Cox model for OS Variable Univariate Multivariate HR 95% CI P 0.79 Treatment, c-TC v dd-TC0.790.0390.680.0015Disease, ovary v fallopian tube0.410.01420.5700.1218ovary v peritoneal2.17<.00011.6270.0024Stage, II v III4.913.058II v IV9.224.146Histology, serous v clear/mucinous0.830.22Residual disease, <1cm v >1 cm3.702.338Age, < 60 v > 601.61PS, 0-1 v 2-32.651.5720.0068RBC transfusion, no v yes0.001Relative dose intensity (Carboplatin) >80% v <80%1.62Relative dose intensity(Paclitaxel) >80% v <80%1.77<.0011.4240.0047
8JGOG treatment delivery and toxicity Discontinuation due to toxicity 36% vs 22%Haematological 60% vs 43%Gd 3-4 Anaemia 69% vs 44%Dose intensityCarboplatin (AUC/wk 1.54 vs 1.71)Paclitaxel (mg/m2/wk 63 vs 52)% patientsFigures for dose-dense arms first.Main reason for discontinuation –haem parameters 60% vs 43% of those discontinuing therapyNeuro 3% vs 7%Allergy 4% vs 10% ie. Higher in conventional arm!Dose reductions occurred in higher propn on dose dense arm 48% vs 35%No cycles receivedKatsumata et al; Lancet 2009
9PharmacogenomicsDelivery of carboplatin- paclitaxel associated with more toxicity in Japanese populationCompletion rate 6 cycles >85% in European trialsLung cancer dataParallel NSCLC phase III trials US/JapanCommon CT control armImproved survival outcomes in JapanGreater haematological toxicityAssociation of ethnically- distributed PG SNPs (CYP3A4*1B/ ERCC2K751Q) with survival and toxicityCarboplatin AUC6/ PTX 225mg/m2Similar disease profilesPFS- 6 vs 4moOS 14 vs 9moFebrile neut- 12% vs 2%Paclitaxel primarily eliminated through multiple hydroxylation reactions via cytochrome pathways (including CYP3A4) *1B assoc with increased activity.Du Bois study (2003)- dose reductions 11% and delays 30% vs 35% and 67% in JGOGNo data on pharmacogenomics and weekly paclitaxel.Gandara et al J Clin Oncol 2009
10Weekly carboplatin- paclitaxel reduce myelosuppressionimprove tolerabilityallow delivery of increased dose intensityincorporate dose-dense platinumLittle preclinical supporting evidenceCmax probably more important for platinum than paclitaxelUsed in several UK centres for patients of poor PS.
11Diagnosis of Stage IC-IV EOC/PPC/FTC Immediate Primary Surgery (IPS)Delayed Primary Surgery (planned)Randomise 1:1:1Randomise 1:1:1Arm 16 cyclesArm 26 cyclesArm 36 cyclesArm 13 cyclesArm 23 cyclesArm 33 cyclesCycle 3 d15 omittedArm 1 Carboplatin AUC q3w(control) Paclitaxel 175mg/m q3wDelayed Primary Surgery (DPS)Arm 2 Carboplatin AUC q3wPaclitaxel 80mg/m q1wThree-arm studyPre-specified stratification for immediate or delayed primary surgery.30-40% UK patients with IIIc/IV undergo DPS.6 possible treatment pathways.Arm 13 cyclesArm 23 cyclesArm 33 cyclesArm 3 Carboplatin AUC q1wPaclitaxel 80mg/m q1wSingle trial with a pre-specified stratification for IPS vs. DPS1111
12Three-Stage Trial Design Stage 1 - Feasibility and ToxicityFeasibility = ability to deliver 6 cycles of chemotherapy (at least 2 out of 3 planned weekly doses) for each armToxicity with special reference to neuropathy and febrile neutropeniaStage 1A – First 50 patients randomised per armStage 1B – First 50 patients undergoing DPS randomised per armStage 2 – Activity (9-month PFS rate)First 62 patients randomised per armStage 3 – EfficacyPrimary outcome measures: PFS and OSSecondary: Toxicity, quality of life and health economicsSample size required = 1485 womenStage 1- at least 37 of 50 pts in exptal arms complete protocol therapy- excludes a completion rate of <60%. Would anticipate completion rates of >80% in control arm form ICON3/5 and EORTC Also assessment of dose intensity.Toxicity- total gd3/4 toxicity in exptal arms exceeds control arms by 15% need to reassess.Stage 2- futility analysis- based on 9mo PFS after 62pts per arm completed 9mo therapy 44 alive without PD. Give 80% power to detect 9-mo PFS of <60%. Based on expected of 75%.Stage 3- final jointly powered for PFS and OS.1212
13ICON8 recruitment 38 Open sites 149 patients recruited 38 sites currently open. Number in set-upAhead of recruitment target currently- 149 in (end June), 131 expected.47 sites in set-up.5 International groups committed to participate- Korea/Mexico/Ireland close to opening. Mayo clinic/ANZGOG further behind.149 patients recruited47 additional sites in set-up5 International groups collaborating
14ICON8-time to R&D approval Median =6.1 monthsMedian = 10.0 months
16ICON 7 Best overall response 48% CT vs 67% Bev-CT 1:1 Front-line: epithelial OV, PP or FT cancerstage I or IIa (grade 3 or clear cell)stage IIb–IVN=1,528R A N D O M I S EPaclitaxel 175mg/m2Carboplatin AUC 6Bevacizumab 7.5mg/kgBest overall response48% CT vs 67% Bev-CT1:1High risk – FIGO IV or III with >1cm residual diseaseHR-0.87HR-0.64PFS- ITT populationOS- ‘high risk’Perren et al NEJM 2011
17BevacizumabCarboplatin-paclitaxel + bevacizumab is becoming a standard of care for “high-risk” ovarian cancer following publication of GOG218/ICON7 PFS and interim resultsICON7 final OS analysis expected 2013Bevacizumab is now licensed for the treatment of Stage IIIB-IV ovarian cancer in combination with carboplatin/paclitaxel in Europe and is available in England via CDF for “high-risk” diseaseNot available for collaborating groups or in Scotland/ WalesJGOG update to be presented by Prof Katsumata on SaturdayMedian PFS 28.1 mo vs 17.5 mo p=0.00375yr OS 58.6% vs 51.0% p=0.045
18Increase median PFS (mo) Increase median OS (mo) Phase III endpointsSurgical statusNo ptsPFS (HR)Increase median PFS (mo)OS (HR)Increase median OS (mo)3-weekly C +ddT vs. 3-weekly CTJGOG 3016All6310.7610.70.79NA>1cm residual3420.67NR0.7517.7Bevacizumab+3-weekly CT vs. 3-weekly CTICON715280.872.40.85 (NS)High risk4650.735.50.647.8GOG21812480.773.80.88 (NS)496
19Proposed modification Two parallel randomisationsICON8A - dose fractionationstill important in patients with optimally debulked diseaseICON8B- dose fractionation and bevacizumabTwo new ‘standards of care’ in high risk diseaseCompare ICON7 bevacizumab regimen with JGOG dose-dense paclitaxelCombination BEV and dose-dense paclitaxelTo address additional questions of interest post-GOG218/ICON7Can we achieve the same improvement in PFS by dose-fractionation rather than using BEV?Can we further improve outcomes by combining dose-fractionation and BEV- Is there an interaction?Is BEV safe and effective in patients undergoing delayed primary surgery?
20Diagnosis of Stage IC-IV EOC/PPC/FTC ICON 8AArm 26 cyclesArm 3Arm 1Randomise 1:1:1Diagnosis of Stage IC-IV EOC/PPC/FTCArm 1 Carboplatin AUC q3w(control) Paclitaxel 175mg/m q3wArm 2 Carboplatin AUC q3wPaclitaxel 80mg/m q1wArm 3 Carboplatin AUC q1wPaclitaxel 80mg/m q1wEligibility criteriaStage IC-II or III with <1cm residual after immediate primary surgeryIII with >1cm residual disease after primary surgery, IV, or primary chemotherapy with delayed primary surgery if;contraindications to bevacizumabpatient declines bevacizumabor if not able to participate in ICON8BTargetting HR0.75 with 3yr recruitment and 2yr FUfor 90% power pts80% power allows reduction in sample size to 1050
2116 cycles maintenance Bevacizumab ICON 8BDiagnosis of Stage III-IV EOC/PPC/FTC with >1cm residual disease or planned for neoadjuvant therapyArm 26 cyclesArm 3Arm 1Randomise 1:1:116 cycles maintenance BevacizumabArm 1 Carboplatin AUC q3wPaclitaxel 175mg/m q3wBevacizumab 7.5mg/kg q3wArm 2 Carboplatin AUC q3wPaclitaxel 80mg/m q1wArm 3 Carboplatin AUC q3wBevacizumab 7.5mg/kg q3wNon-inferiority comparison not feasible- requires c.2500 pts and 2100 progression events targeting a HR of 0.87Targetting HR0.75 2α=0.025 with 80% power requires 300 pts per armIn neoadjuvant setting, surgery between C3 and C4 omit BEV C3 and C4. At least 6 weeks between BEV and surgeryTo detect HR-0.75 in 2 superiority comparisons between Arm 3 and Arms 1 and 2 requires c.300 pts per arm
23Carboplatin-Paclitaxel q3w + Bevacizumab GOG218: Stge III sub-opt debulked & Stge IV post surgeryICON7: Stge IC-IV; high-risk sub-group Stge III sub-opt debulked & Stge IVGOG262: Stge III sub-opt debulked & Stge IV post surgeryICON8B: Stge III sub-opt debulked/primary chemo & Stge IVGOG218 HR 0.717( )ICON8B, GOG262ICON7 HR 0.81 ( )Carboplatin-Paclitaxel q3wCarboplatin-Paclitaxel q1w+ Bevacizumab(ICON8B)ICON8BJGOG 3016 HR 0.71 ( )ICON8AICON8B: Stge III sub-opt debulked, primary chemo & Stge IVJGOG3016: Stge II-IVICON8A: Stge IC-IVCarboplatin-Paclitaxel q1wOther trials: MITO-7, Stge IC-IV, C-Pq3w vs wCwP 60mg/m2
24Summary ICON8 remains open to recruitment and currently meeting target Bevacizumab will be incorporated if secure funding availableTRICON8 sample collection (Brenton) awaiting outcome of CTAAC review
25Feedback welcome Chief Investigators Trials Unit ICON8@ctu.mrc.ac.uk Andrew ClampJonathan LedermannTrials UnitJane Hook Trial Physician/CTU Project LeadLaura Farrelly Project ManagerMonique Tomiczek Trial ManagerCheryl Courtney Senior Data ManagerTim Brush Data ManagerSuzanne Freeman Statistician