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Phase II study of FOLFIRI plus ramucirumab with recurrent colorectal cancer refractory to adjuvant chemotherapy with oxaliplatin/fluoropyrimidine (RAINCLOUD)
Background
The RAISE study demonstrated the superiority of FOLFIRI plus ramucirumab (Ram) to FOLFIRI in second-line metastatic colorectal cancer (CRC) patients progressed after oxaliplatin, fluoropyrimidine with bevacizumab. But no evidence of FOLFIRI plus Ram for patients who were pretreated oxaliplatin, fluoropyrimidine without an anti-angiogenesis antibody. Therefore, we prospectively investigated the efficacy and toxicity of FOLFIRI plus Ram after CRC patients refractory to adjuvant chemotherapy with oxaliplatin plus fluoropyrimidine.
Methods
RAINCLOUD study was a multicenter single-arm phase II trial. Key eligibility criteria were as follows: histologically or cytologically confirmed colorectal cancer, confirmed recurrent colorectal cancer, refractory to fluoropyrimidine, refractory or intolerant of oxaliplatin without pretreated anti-angiogenesis therapy, had measurable or non-measurable lesion, PS=0 or 1, had adequate coagulation function, 20 years or older. FOLFIRI plus Ram were administered as follows; each 2-week cycle, patients received either 8 mg/kg ramucirumab intravenous infusion, followed by the FOLFIRI regimen (150～180 mg/m2 intravenous irinotecan concurrent with 200 mg/m2 intravenous leucovorin followed by 400 mg/m2 fluorouracil given as an intravenous bolus then 2400 mg/m2 given as a continuous infusion over 48 h). Primary endpoint of this study was progression-free survival (PFS). Secondary endpoints were overall survival (OS), overall response rate (ORR), disease control rate (DCR) and safety. The number of patients was set at 48 based on the threshold and expected median PFS values were 3.9 months and 6.9 months, respectively, with a one-sided alpha error of 0.05 and power of 0.80. This study was conducted in MCSGO (Multicenter Clinical Study Group of Osaka, Colorectal Cancer Treatment Group).
Results
A total of 48 patients were enrolled from 15 sites between September 2017 and September 2020. Patient characteristics: Median age 63.5 years (25∼77), male / female 25 / 23, ECOG PS0/1 44/4, sidedness right/left 10/38, and RAS WT/MT/UN 13/33/2. Median PFS was 6.2 months (90% CI: 5.6-8.6), so primary endpoint was met. PFS rates of 6M and 12M were 54.1% (95% CI: 41.4-70.8) and 23.8% (95% CI: 14.0-40.6), respectively. Median OS was 21.2months (95% CI: 17.4-NA). The ORR and DCR were 41.7 % and 81.3 %, respectively. The incidence of grade 3/4 adverse events over 5% were neutropenia (43.8 %), leucopenia (10.4 %), and hypertension (8.3 %). No unexpected adverse events and treatment related death were observed.
Conclusions
Our data suggested that FOLFIRI plus Ram was effective and tolerable for patients with recurrent colorectal cancer refractory to adjuvant chemotherapy with oxaliplatin plus fluoropyrimidine. The results of the pre-planned translational research will be available soon.
Clinical trial identification
Clinical trial information: UMIN000028677.
Legal entity responsible for the study
The authors.
Funding
Eli Lilly.
Disclosures
Y. Kagawa: Speaker Bureau / Expert testimony: Bayer Co., Ltd., Chugai Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Sanofi Co., Ltd., Eli Lilly Japan Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Merck Co., Ltd.. All other authors have declared no conflicts of interest.
