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://clinicaltrials.gov/ct2/show/study/NCT04097444 / Japan Registry of 
Clinical Trials jRCTs041190072. Registered October 9, 2019.