对比贝伐珠单抗、贝伐珠单抗联合洛莫司汀、洛莫司汀治疗复发性胶质母细胞瘤患者的随机II期研究课件.ppt

Randomized phase II study of Bevacizumab versus Bevacizumab plus Lomustine versus Lomustine in patients with recurrent GlioblastomaThe BELOB trial(LWNO trial 0901),W.Taal,H.M.Oosterkamp,A.M.E.Walenkamp,L.Beerepoot,M.Hanse,J.Buter,A.Honkoop,D.Boerman,F.Y.F.de Vos,R Jansen,F.W.P.J.van den Berkmortel,D.Brandsma,R.H.Enting,J.M.Kros,J.E.Bromberg,I.van Heuvel,M.Smits,B.van der Holt,R.M.Vernhout,M.J.van den Bent,Glioblastoma,Most aggressive adult primary brain tumorMedian survival 12-14 monthsStandard of care:combined chemo-irradiation with TemozolomideAt relapse:usually limited options availableMedian survival 7-8 months2nd line chemotherapies only modestly activeNo well established salvage regimenLomustine currently considered reasonable optionBRAIN trial:evidence of activity of Bevacizumab in recurrent glioblastoma?,Bevacizumab:the BRAIN trial(FDA report),Friedman et al.JCO 2009,Response or progression,that is the question,Bevacizumab restores abnormal vascular leakinessReduces edema,enhancementReduction of enhancement not necessarily correlated to anti-tumor effectDevelopment of gliomatosis in some anti-VEGF treated patientsQuestions significance classical ORR&PFS based on T1C MR imaging,Baseline,Cycle 1,Cycle 2,Cycle 3,Pseudoresponse in anti-VEGF treated recurrent glioblastoma,T1+C,T2,Status Bevacizumabin recurrent glioblastoma,BRAIN trial led to conditional FDA approval in the USAWith confirmatory trial planned in newly diagnosed GBM(AVAGLIO)No European approval(EMA)Despite that,widespread use in EuropeMany single arm phase II trials,bination regimensNeed for well controlled studies in recurrent glioblastoma remains,Bevacizumab in recurrent glioblastoma,In the Netherlands two-arm BELOB trial initiatedBevacizumab vs Bevacizumab/Lomustine in recurrent glioblastomaPrimary endpoint PFS 6 moAfter the negative ruling of EMA amended intoThree arm randomized open label controlled phase II study,including control arm Lomustine Primary endpoint OS 9 mo,Randomized phase II study of Bevacizumab versus Bevacizumab plus Lomustine versusLomustine in patients with recurrent Glioblastoma,1st recurrenceGlioblastoma,followup,Lomustine every 6 weeks,RANDOMIZATION,Bevacizumab every 2 weeks+Lomustine every 6 weeks,Bevacizumab every 2 weeks,Stratification:age,PFS,Design contd,Major inclusion criteria:Histologically proven Glioblastoma1st recurrence after combined chemo-irradiation with TemozolomideWHO PS 0-2,age=18 yNo radiotherapy within the three months prior to the diagnosis of progressionAdequate bone marrow,liver and renal function etc,Design contd,Primary endpoint:OS at 9 monthsSecondary endpoints:median PFS,6 mo PFS,median OS,12 mo OS,response(RANO citeria)QOL(EORTC QLQ-C30/BN-20)Deterioration free survival(WHO PS decrease)Statistical design:Modified Fleming one stage(AHern)P0:35%,P1:55%,With alfa 0.10,beta 0.10:44 patients per arm(total 132 pts),Design BELOB,Treatment arms:Lomustine 110 mg/m2 every 6 weeks for 6 cycles(cap at 200 mg)Bevacizumab 10 mg/kg every 2 weeks until progressionLomustine 110 mg/m2 every 6 weeks for 6 cycles(cap at 200 mg)and 10 mg/kg Bevacizumab every 2 weeks until progressionNo safety data on the combination Bevacizumab&Lomustine availablePre-planned safety analysis after the first 10 patients in the combination arm,Safety review,First 8 patients in combination arm:in 3 patients“DLTs”observedgrade 4 platelets:2 Bevacizumab dose intensity 66%(Bevacizumab calculated dose intensity:48%and 58%)Hematological toxicity:Platelets grade 4:2 pts;grade 3:3 pts(incl plts 26)ANC grade 3:3 ptsAmendment 3:restart combination arm on 90 mg/m2 Lomustine(cap:160 mg)(Bev/Lom 90),Results,153 patients entered between Dec 11,2009 and Nov 10,20117 randomized in two-arm stage of the trial21 randomized at time of the decreased dose of Lomustine in combination arm5 considered non-eligible:148 eligible patients,Randomized:153 pts,Lomustine:47 Not eligible:1Violation inclusion criteria:1Eligible:46,Bev/Lom 110:8Eligible:8,Bevacizumab:51 Not eligible:1Violation inclusion criteria:1Eligible:50,Bev/Lom 90:47Not eligible:3Violation inclusion criteria:2Death at the time random.:1Eligible:44,Baseline characteristics,Median number of cycles:Bevacizumab:2Lomustine:1Bev/Lom 90:3,Number of cycles,reason for discontinuation,Number of cycles,Nr of cycles,Reason discontinuation,Grade 3 and 4 Adverse Events(all;related and non-related),Nadir Platelet toxicity,No excessive hematological toxicity with Bevacizumab/Lomustine 90 mg/m2 compared to Lomustine single agentNB:at Bevacizumab/Lomustine 110 mg/m2 no clinically significant adverse events,Outcome:OS 9 months,and median OS,PFS 6 months,(Between brackets:95%confidence interval),Outcome:OS 9 months,median OS and PFS 6 months,Primary endpoint,Conclusions,Combination Bevacizumab 10 mg/kg every 2 weeks and Lomustine 110 mg/m2 every 6 weeks significant hematological toxicityAt dose level Bevacizumab 10 mg/kg every 2 weeks and Lomustine 90 mg/m2 every 6 weeks toxicity well manageableDespite modest 6 mo PFS of single agent treatments,median OS in accordance with literature findings,Conclusions contd,OS 9 months in Bevacizumab/Lomustine combination arm meets prespecified criterion for phase III study:Lomustine single agent:43%(95%CI 29-57%)Bevacizumab single agent 38%(95%CI 25-51%)Bevacizumab/Lomustine 90:59%(95%CI 43-72%)Modest activity of single agent Bevacizumab in this community trial,Conclusions contd,Phase III trial comparing Bevacizumab/Lomustine to Lomustine single agent in recurrent Glioblastoma is warrantedOngoing EORTC 26101 randomized phase II study into combinations of Bevacizumab and Lomustine will be modified into a two-arm phase III addressing this question,Acknowledgements,This trial was financially supported byAn unrestricted grant from Roche NLThe Dutch Cancer SocietyDisclosuresMJ van den Bent and HM Oosterkamp have been consultants for Roche and have received honoraria,