phase Ib study of irinotecan, bevacizumab and biweekly trifluridine/tipiracil in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin: Preliminary report of MODURATE study

Background Trifluridine/tipiracil (FTD/TPI) showed survival benefit as monotherapy and in combination with bevacizumab (BEV) in the late-line treatment for metastatic colorectal cancer (mCRC). Preclinical studies showed FTD/TPI additively enhanced the anticancer effect of irinotecan (IRI), and a phase Ib study of a standard schedule of FTD/TPI with biweekly IRI demonstrated the expected antitumor activity although further investigation is warranted due to high incidence of febrile neutropenia. This phase Ib study of biweekly FTD/TPI with IRI and BEV for previously treated mCRC was conducted. Methods This study consisted of 2 parts: a dose-escalation part (part 1) to determine the recommended phase II dose (RPTD) and an expansion part (part 2) to further evaluate the safety and efficacy. Key eligibility criteria included histologically confirmed colorectal adenocarcinoma, failure or intolerance to fluoropyrimidine and oxaliplatin, no prior therapy with FTD/TPI and IRI, age of 20-75 years, ECOG PS of 0–1. Pts received two-week cycles of treatment with FTD/TPI (twice daily, days 1 to 5), IRI (day1) and BEV (5mg/kg, day1). Five dose levels of FTD/TPI and IRI are planned as follows; Level 1: 25 mg/m 2 and 180 mg/m 2, Level 2a: 30 mg/m 2 and 180 mg/m 2, Level 3a: 35 mg/m 2 and 180 mg/m 2, Level 2b: 30 mg/m 2 and 150 mg/m 2, Level 3b: 35 mg/m 2 and 150 mg/m 2 . In part 1, patients underwent a 3+3 design schema to evaluate the dose limiting toxicity (DLT). The RPTD was defined as the highest dose level where no more than 2 of 6 pts experienced a DLT during 2 cycles. Results Between Oct 2016 and May 2019, 18 pts were enrolled to part 1 (3 pts in Level 1/2a/3a/2b and 6 pts in Level 3b). Pts characteristics were as follows; median age, 68 (33-74) years; male/female, 10/8; PS 0/1, 13/5; right-/left-sided tumor, 5/13; number of metastatic site 1/>1, 6/12; RAS mutant/wild, 12/6; prior history of BEV/anti-EGFR, 7/6. DLT was observed in 5 pts; grade 3 febrile neutropenia in 2 pts, grade 3 gastrointestinal perforation, grade 2 anorexia resulting >2 week delay in subsequent cycle initiation, and grade 3 ALT elevation in each 1 pt. Among 6 pts enrolled to Level 3b, 2 pts experienced DLT and the RPTD was determined Level 3b. At the data cut-off date as of Mar 14, 2019, 16 pts terminated protocol treatment, due to disease progression in 12 pts and adverse events in 4 pts, and the median cycle of treatment administrated was 7 (range, 1-42+). As preliminary efficacy analysis in part 1, partial response and stable disease was observed in 4 (22%) and 11 pts (61%), respectively. The most common grade 3/4 adverse event was neutropenia (61%), and the incidence of febrile neutropenia was 11%. No treatment-related death was observed. Conclusion The RPTD of biweekly FTD/TPI with IRI and BEV was determined to be 35 mg/m 2 of FTD/TPI, 150 mg/m 2 of IRI, and 5mg/kg of BEV. An additional 10 pts were already enrolled in the expansion part of the study at this dose and follow-up is underway. Editorial acknowledgement Fuji Pharma Valley Initiatives, Shizuoka, Japan Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan. Legal entity responsible for the study The author. Funding Taiho Pharmaceutical. Disclosure Kentaro Yamazaki has an affiliation with Grant/Research Support: Taiho Pharmaceutical; Speaker's Bureau: Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha.