FOLFOX8 Versus mFOLFOX6 With Bevacizumab or Cetuximab for First-Line Unresectable Metastatic Colorectal Cancer (Phase II)

Official title

A Prospective, Multicenter, Randomized Controlled, Phase II Study to Evaluate the Efficacy and Safety of FOLFOX8 Versus mFOLFOX6 Combined With Bevacizumab or Cetuximab as First-Line Treatment for Unresectable Metastatic Colorectal Cancer

Overview

This is a prospective, multicenter, randomized controlled, phase II study. It is expected to enroll 229 patients and aims to evaluate the efficacy and safety of FOLFOX8 versus mFOLFOX6 combined with bevacizumab or cetuximab as first-line treatment for unresectable metastatic colorectal cancer. The primary objective is to assess progression-free survival (PFS) of the patients. Secondary objectives include assessment of objective response rate (ORR), overall survival (OS), safety, and other outcomes.

Detailed description

Levofolinic Acid For Injection is the first approved class 2.1 sodium levoleucovorin formulation in China. It contains only the active l-isomer of levoleucovorin, with an equivalent dose half that of leucovorin. As a sodium salt, it has higher solubility, is compatible with 5-FU, and allows concurrent infusion. The FOLFOX8 regimen is based on mFOLFOX6 and takes advantage of the sodium salt formulation of Levofolinic Acid For Injection by changing the traditional sequential infusion of 5-FU and calcium levoleucovorin to concurrent infusion of Levofolinic Acid For Injection and 5-FU, thereby prolonging the duration of synergistic action and enhancing overall efficacy. It is expected to further delay disease progression in patients with colorectal cancer.

This study is a prospective, multicenter, randomized controlled phase II trial. A total of 229 patients will be enrolled and randomly assigned to the experimental group (FOLFOX8) or the control group (mFOLFOX6). Targeted therapy (bevacizumab or cetuximab) will be selected based on the patient's RAS mutation status and tumor location. Treatment will be administered every two weeks. Before and after each treatment cycle, patients will undergo routine clinical examinations including blood tests. A maximum of 12 cycles will be given, and patients without disease progression will enter the maintenance phase. Tumor assessments will be performed every 8 weeks after the start of treatment (based on RECIST V1.1 criteria), and concomitant medications and adverse events will be recorded.

The primary endpoint of this study is progression-free survival (PFS). Secondary endpoints include objective response rate (ORR), overall survival (OS), safety, and the impact of the treatment regimen on infusion time.

Interventions

• Drug Oxaliplatin
  85 mg/m² intravenously over 2 hours on Day 1, every 2 weeks for up to 12 cycles. For patients without disease progression after 12 cycles, oxaliplatin is discontinued and not used in maintenance.
• Drug 5-Fluorouracil
  400 mg/m² intravenous bolus on Day 1, followed by 2400 mg/m² administered as a continuous intravenous infusion over 46-48 hours. Cycle repeats every 2 weeks for up to 12 cycles. Patients without disease progression then enter maintenance with the same 5-FU regimen every 2 weeks until disease progression or unacceptable toxicity.
• Drug Levofolinic Acid For Injection
  200 mg/m² mixed with 5-FU 2400 mg/m² as a continuous intravenous infusion over 46-48 hours on Day 1 (concurrent infusion). Cycle repeats every 2 weeks for up to 12 cycles. Patients without disease progression then enter maintenance with the same mixture every 2 weeks until disease progression or unacceptable toxicity.
• Drug Calcium Folinate
  400 mg/m² intravenously over 2 hours on Day 1, administered sequentially before 5-FU. Cycle repeats every 2 weeks for up to 12 cycles. Patients without disease progression then enter maintenance with the same dose and schedule of calcium folinate (without oxaliplatin) every 2 weeks until disease progression or unacceptable toxicity.
• Drug Bevacizumab
  5 mg/kg intravenously on Day 1 every 2 weeks, starting from Cycle 2 (after genetic testing results are available). Continue through induction and maintenance until disease progression or unacceptable toxicity.
• Drug Cetuximab (EGFR inhibitor)
  500 mg/m² intravenously over more than 2 hours on Day 1 every 2 weeks, starting from Cycle 2 (after genetic testing results are available). Continue through induction and maintenance until disease progression or unacceptable toxicity.

Primary outcome measures

• Progression-Free Survival（PFS） [Time frame: From date of randomization to disease progression or death, an average of 14 months.]

Secondary outcome measures (4)

• Objective Response Rate（ORR） [Time frame: From randomization until disease progression or death, an average of 14 months.]
• Overall Survival (OS) [Time frame: From randomization until death, an average of 30 months.]
• Impact of Treatment Regimen on Infusion Time [Time frame: Measured from cycle 1 until treatment discontinuation，an average of 14 months]
• Incidence of Adverse Events（AEs） [Time frame: From first dose of study treatment to 28 days after last dose, an average of 15 months.]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years, male or female.
• ECOG performance status 0-2.
• Histologically or cytologically confirmed unresectable metastatic colorectal cancer with no prior treatment for unresectable or metastatic disease.
• Adequate organ function: Hb ≥ 70 g/L; WBC ≥ 3.0×10⁹/L; NEUT ≥ 1.5×10⁹/L; PLT ≥ 75×10⁹/L; AST and ALT ≤ 3× ULN; sCr ≤ 2× ULN; TBIL ≤ 2× ULN.
• Expected survival > 3 months.

Exclusion criteria

• Known allergy to the study drug(s) and/or their excipients.
• Contraindications to chemotherapy.
• Patients with MSI-H or dMMR colorectal cancer.
• Patients with BRAF mutation.
• Pregnant or breastfeeding women.
• History of any second malignancy within 2 years prior to randomization, except for cured localized tumors such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the prostate, cervical carcinoma in situ, or breast carcinoma in situ, which are allowed for enrollment.
• Patients with systemic medical or psychiatric disorders that make them unsuitable for chemotherapy.
• Patients deemed unsuitable for enrollment in this study by the investigator's judgment.
• Participation in another clinical trial of an investigational drug within 4 weeks prior to randomization.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Sun Yat-sen University Cancer Center — Guangzhou

Identifiers

NCT: NCT07621497 · HL-ZY-054

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗