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218TiP A phase Ib study of irinotecan, bevacizumab and biweekly TAS-102 in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplation (MODURATE)

2016; Elsevier BV; Volume: 27; Linguagem: Inglês

10.1016/s0923-7534(21)00375-6

1569-8041

Hiroya Taniguchi, Yukiya Narita, Shigenori Kadowaki, Takashi Ura, Masashi Ando, Kei Muro, Satoshi Hamauchi, Takahiro Tsushima, Tomoya Yokota, Akiko Todaka, Nozomu Machida, Akira Fukutomi, Yusuke Onozawa, Hirofumi Yasui, Keita Mori, Kentaro Yamazaki,

Lung Cancer Treatments and Mutations

Background The phase III RECOURSE trial demonstrated that TAS-102, an oral fixed-combination drug consisting of trifluridine and tipiracil hydrochloride, significantly improved overall survival compared with placebo for refractory metastatic colorectalcancer. PreclinicalstudiesshowedTAS-102additivelyenhancedthe anticancereffectofirinotecan(CPT-11),andthephaseIstudyofTAS-102 administratedondays1-5and8-12ofa28-daycyclewithafixeddosageofCPT-11 (150mg/m2)every2weeksinJapanesepatientsdemonstratedthatthemaximum tolerateddose(MTD)ofTAS-102was30mg/m2/BID.Thiscombinationtherapy showedtheexpectedantitumoractivity, althoughtherelativedoseintensityofCPT-11 was low due to hematological toxicities. Now, we conduct a phase Ib study ofbiweekly TAS-102(day1-5ofa14-dayscycle)withCPT-11andbevacizumabevery2weeks. Trial design: The study is conducted in 2 parts: a dose-escalation part (part 1) to determine the MTD and an expansion part (part 2) to further evaluate the safetyand preliminary efficacy. Eligibility criteria include histologically proven colorectal adenocarcinoma,failuretofirst-linechemotherapywithfluoropyrimidineand oxaliplatin,ageof20-75years,ECOGPSof0-1,andadequateorganfunction.The primaryendpointofpart1isincidenceofthedose-limitingtoxicity(DLT)ofTAS-102, CPT-11andbevacizumab(5mg/kg),andthatofpart2isincidenceoffebrile neutropenia(FN).DLTsincludeprolonged(>7days) grade4neutropeniaandFN. FivedoselevelsofTAS-102andCPT-11 areplannedasfollows;Level1:TAS-102 25mg/m2/BIDCPT-11 180mg/m2,Level2a:TAS-10230mg/m2/BIDCPT-11 180mg/ m2,Level3a:TAS-10235mg/m2/BIDCPT-11180mg/m2,Level2b:TAS-10230mg/ m2/BIDCPT-11150mg/m2,Level3b:TAS-10235mg/m2/BIDCPT-11150mg/m2.In part 1, patients undergoa3 + 3 design schemato evaluatethe DLT. The recommended doseisdefinedasthehighestdoselevelwherenomorethan2of6patientsexperiencea DLT during 2 cycles. Clinical trial indentification: This study is registered to the University Hospital Medical Information Network (UMIN000019828), and activated in August 2016. Legal entity responsible for the study: Shizuoka Cancer Center and Aichi Cancer Center Hospital Funding: Taiho Pharma Disclosure: H. Taniguchi, K. Muro: honoraria by Taiho Pharma. K. Yamazaki: honoraria and research funding by Taiho Pharma. All other authors have declared no conflicts ofinterest. Gastrointestinal tumours, non-colorectal