Protocol of the QUATTRO-II study: a multicenter randomized phase II study comparing CAPOXIRI plus bevacizumab with FOLFOXIRI plus bevacizumab as a first-line treatment in patients with metastatic colorectal cancer

Abstract

Background: First-line treatment with FOLFOXIRI plus bevacizumab (BEV) is highly effective and regarded as one of the standards-of-care for patients with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea as side effects. AXEPT, an Asian phase III study, showed that modified CAPIRI+BEV [capecitabine (CAP: 1600 mg/m2), irinotecan (IRI: 200 mg/m2), and BEV (7.5 mg/m2)] was non-inferior to FOLFIRI+BEV as a second-line therapy for mCRC patients and was associated with a lower incidence of hematologic toxicities. Thus, a reduced dose of the CAP and IRI regimen in combination with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) may be more feasible than FOLFOXIRI+BEV, without compromising efficacy.

Methods: QUATTRO-II is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses of OX and IRI will be investigated as a safety lead-in. In Step 2, patients will be randomized to the recommended dose of either CAPOXIRI+BEV or FOLFOXIRI+BEV. Induction triplet chemotherapy plus BEV treatments will be administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The primary endpoint is progression-free survival (PFS). The similarity in PFS between the two arms will be evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls between 0.80 and 1.25. Ensuring a 70% probability that the observed HR will be "0.8 < HR < 1.25" under the assumption of the true HR of 1.0, and 100 patients will be evaluated during the 3-year study period. Secondary endpoints include overall survival, overall response rate, safety, and patient reported outcome (PRO) (FACT/GOG-Ntx4).

Discussion: Considering the lower incidence of hematologic toxicities with modified CAPIRI+BEV than with FOLFIRI+BEV, CAPOXIRI+BEV may be a promising treatment option if sufficient efficacy and lower hematologic toxicities are indicated in this study. Additionally, a lower incidence of peripheral sensory neuropathy (PSN) reported following CAPEOX treatment compared to that after FOLFOX in ACHIEVE, an adjuvant phase III trial, suggest that CAPOXIRI+BEV can mitigate OX-induced PSN.

Trial registration: Clinicaltrials.gov NCT04097444 . Registered September 20, 2019, https://ichgcp.net/clinical-trials-registry/NCT04097444 / Japan Registry of Clinical Trials jRCTs041190072. Registered October 9, 2019.

Keywords: Bevacizumab; CAPOXIRI; Colorectal cancer; Dose confirmation; FOLFOXIRI; First-line treatment; Multicenter; Progression-free survival; Randomized; Safety.

Conflict of interest statement

AT receives honoraria from Chugai Pharmaceutical Co., Ltd. as well as grants from Kyowa Kirin Co., Ltd. TY receives grants from Chugai Pharmaceutical Co., Ltd. HS receives honoraria from Chugai Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. HB receives honoraria from Chugai Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. TY receives honoraria and grants from Chugai Pharmaceutical Co., Ltd. YK receives honoraria and grants from Chugai Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., and Kyowa Kirin Co., Ltd. HT receives honoraria from Chugai Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. KM receives fee for speakers’ bureau from Chugai Pharmaceutical Co., Ltd. KY receives honoraria from Chugai Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. EO receives lecture fees from Chugai Pharmaceutical Co., Ltd. MK receives honoraria from Chugai Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. KO receives honoraria from Chugai Pharmaceutical Co. HB receives research funding and fees for speakers’ bureau from Chugai Pharmaceutical Co., Ltd. All authors declared that they have no other competing interests.

Figures

Fig. 1

Graphical representation of the QUATTRO-II study design. mCRC, metastatic colorectal cancer; CAP, capecitabine; BEV, bevacizumab; OX, oxaliplatin; IRI, irinotecan; 5-FU/LV, fluorouracil and folinate; PFS, progression-free survival; ORR, overall response rate; OS, overall survival

Fig. 2

Drug dose confirmation step (Step 1). A dose confirmation part was established as Step 1 based on the doses in the AXEPT Study (CAP: 1600 mg/m2, IRI: 200 mg/m2). Steering Committee (SC) will assess dose limiting toxicity (DLT) for each dose level of OX and IRI in Cycle 1 (before the start of Cycle 2) to determine the recommended doses (RDs). After RD review by the Efficacy and Safety Assessment Committee, SC will report upon approval by the Certified Review Board. CAP, capecitabine; BEV, bevacizumab; OX, oxaliplatin; IRI, irinotecan

Fig. 3

Induction therapy of FOLFIRI+BEV and CAPOXIRI+BEV (Step 2). FOLFOXIRI+BEV (bi-weekly) will be repeated 8 cycles (max: 12 cycles). CAPOXIRI+BEV (tri-weekly) will be repeated 6 cycles (max: 8 cycles), in which OX and IRI dose levels are determined by Step 1. The use of supportive therapy during protocol induction therapy is strongly recommended. CAP, capecitabine; BEV, bevacizumab; OX, oxaliplatin; IRI, irinotecan; 5-FU/LV, fluorouracil and folinate

Fig. 4

Maintenance therapy of 5-FU/LV + BEV and CAP+BEV (Step 2). 5-FU/LV + BEV or CAP+BEV will be selected by investigators during the protocol maintenance therapy. After selecting the regimen, no change of drugs is permitted. The protocol treatment will be discontinued when the primary disease progresses or when the protocol treatment cannot be continued because of adverse events or at the patients’ request. CAP, capecitabine; BEV, bevacizumab; OX, oxaliplatin; IRI, irinotecan; 5-FU/LV, fluorouracil and folinate