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

BMC Cancer. 2020 Jul 23;20(1):687. doi: 10.1186/s12885-020-07186-5.

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://clinicaltrials.gov/ct2/show/study/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.

Publication types

  • Clinical Trial Protocol

MeSH terms

  • Adenocarcinoma* / drug therapy
  • Adenocarcinoma* / pathology
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols* / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Bevacizumab* / administration & dosage
  • Camptothecin* / administration & dosage
  • Camptothecin* / analogs & derivatives
  • Clinical Trials, Phase II as Topic
  • Colonic Neoplasms* / drug therapy
  • Colonic Neoplasms* / genetics
  • Colonic Neoplasms* / pathology
  • Deoxycytidine* / administration & dosage
  • Deoxycytidine* / analogs & derivatives
  • Drug Administration Schedule
  • Fluorouracil* / administration & dosage
  • Fluorouracil* / analogs & derivatives
  • Genes, ras
  • Glucuronosyltransferase / genetics
  • Humans
  • Leucovorin / administration & dosage
  • Multicenter Studies as Topic
  • Organoplatinum Compounds / administration & dosage
  • Proto-Oncogene Proteins B-raf / genetics
  • Randomized Controlled Trials as Topic
  • Rectal Neoplasms* / drug therapy
  • Rectal Neoplasms* / genetics
  • Rectal Neoplasms* / pathology

Substances

  • Bevacizumab
  • BRAF protein, human
  • Camptothecin
  • Deoxycytidine
  • Fluorouracil
  • Glucuronosyltransferase
  • Leucovorin
  • Organoplatinum Compounds
  • Proto-Oncogene Proteins B-raf
  • UGT1A1 enzyme

Supplementary concepts

  • capecitabine-irinotecan combination
  • FOLFOXIRI protocol

Associated data

  • ClinicalTrials.gov/NCT04097444