A Phase Ia/II, Single Arm Trial on the Efficacy of Vemurafenib in Combination With Irinotecan and Cetuximab in BRAF V600E-Mutant Metastatic Colorectal Cancer
Overview
- Phase
- Phase 1
- Intervention
- Cetuximab
- Conditions
- Colorectal Cancer Metastatic
- Sponsor
- Sun Yat-sen University
- Enrollment
- 37
- Locations
- 1
- Primary Endpoint
- Overall response rate from the date of first drug administration until the date of first documented progression or date of death, whichever came first.
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This prospective, multicenter, single arm clinical trial was designed to evaluate the efficacy and safety of Vemurafenib in combination with Irinotecan and Cetuximab in the treatment of BRAF V600E-Mutant Metastatic Colorectal Cancer.
Detailed Description
PRIMARY OBJECTIVES: To evaluate the Overall Response Rate (ORR) of v-raf murine sarcoma viral oncogene homolog B (BRAF) V600E mutant metastatic colorectal cancer patients treated with Vemurafenib in combination with Irinotecan and Cetuximab (VIC regimen). SECONDARY OBJECTIVES: To evaluate the Progression Free Survival (PFS), Overall Survival (OS), safety and toxicity of VIC regimen in the treatment of BRAF V600E mutant colon cancer. EXPLORATORY OBJECTIVES: Mechanism of primary and secondary resistance to VIC regimen in the treatment of BRAF V600E mutant colon cancer. OUTLINE: Patients receive Cetuximab and Irinotecan intravenously on day 1 and Vemurafenib orally (PO) twice daily (BID) on days 1 to 14. Courses are repeated every 2 weeks in the absence of disease progression or unacceptable toxicity.
Investigators
Yuhong Li
Clinical Professor
Sun Yat-sen University
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed diagnosis of metastatic colorectal cancer
- •Histopathological or ctDNA analysis positive for BRAF V600E mutant
- •Patients must have had at least undergone one first line treatment with FOLFOX or FOLFIRI or FOLFOXIRI±Bevacizumab before disease progression.
- •Measurable and assessable disease according to RECIST 1.1 criteria
- •Adequate hematologic function (Platelet\>90×109/L; White blood cells\>3.0×109/L; Neutrophils\>1.5×109/L; Hb\>10.0g/100ml)
- •Serum bilirubin ≤1.5 times the upper limit of normal (ULN), transaminase ≤5 times ULN
- •No ascites, normal coagulation function, albumin ≥35g/L
- •Child-Pugh class A
- •Serum creatinine is less than the upper limit of normal (ULN), or calculated creatinine clearance rate\> 50ml/min (using Cockcroft-Gault equation)
- •ECOG performance status of grade 0-2
Exclusion Criteria
- •Patients with KRAS and NRAS mutations
- •Previously received anti-EGFR monoclonal antibodies or EGFR inhibitors, BRAF inhibitors (with the exception of regorafenib)
- •Patients with known contraindications to receiving cetuximab or irinotecan at the planned dose
- •Patients with retinal vein occlusion or have current risk factors for retinal vein occlusion (for example, uncontrolled glaucoma or ocular hypertension)
- •History of acute or chronic pancreatitis
- •History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive drugs or surgery) within 12 months prior to enrollment
- •Gastrointestinal diseases that may greatly affect the absorption of Vimurafenib (for example, ulcer disease, uncontrolled vomiting, malabsorption syndrome, small bowel resection and reduced intestinal absorption)
- •Neuromuscular diseases associated with elevated CK (eg, inflammatory myopathy, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
- •Patients with any residual CTCAE ≥ Grade 2 toxicity from previous anti-tumor therapy (excluding hair loss or neuropathy of Grade 2 and above)
- •History of HIV infection
Arms & Interventions
VIC regimen
Patients will receive VIC regimen every 2 weeks: Cetuximab 500mg/m2 IV on Day 1; Irinotecan 180mg/m2 IV on Day 1 (If patient carries UGT\*28 7/7 or UGT\*6 A/A or UGT\*28 6/7 and UGT\*6 A/G variants, use Irinotecan IV 150mg/m2 instead); Vemurafenib PO BID on Days 1 to 14 (Dosage: 480mg; 720mg; 960mg, determined by the maximum tolerated dose (MTD) in Phase Ia trial).
Intervention: Cetuximab
VIC regimen
Patients will receive VIC regimen every 2 weeks: Cetuximab 500mg/m2 IV on Day 1; Irinotecan 180mg/m2 IV on Day 1 (If patient carries UGT\*28 7/7 or UGT\*6 A/A or UGT\*28 6/7 and UGT\*6 A/G variants, use Irinotecan IV 150mg/m2 instead); Vemurafenib PO BID on Days 1 to 14 (Dosage: 480mg; 720mg; 960mg, determined by the maximum tolerated dose (MTD) in Phase Ia trial).
Intervention: Irinotecan
VIC regimen
Patients will receive VIC regimen every 2 weeks: Cetuximab 500mg/m2 IV on Day 1; Irinotecan 180mg/m2 IV on Day 1 (If patient carries UGT\*28 7/7 or UGT\*6 A/A or UGT\*28 6/7 and UGT\*6 A/G variants, use Irinotecan IV 150mg/m2 instead); Vemurafenib PO BID on Days 1 to 14 (Dosage: 480mg; 720mg; 960mg, determined by the maximum tolerated dose (MTD) in Phase Ia trial).
Intervention: Vemurafenib
Outcomes
Primary Outcomes
Overall response rate from the date of first drug administration until the date of first documented progression or date of death, whichever came first.
Time Frame: up to 17 months
The proportion of patients who achieved a complete or partial response as their best overall response based on RECIST v1.1 criteria
Secondary Outcomes
- Progression free survival from the date of first drug administration until the date of first documented progression or date of death, whichever came first.(up to 17 months)
- Number of patients with adverse events and severity according to NCI CTCAE v5.0(up to 6 months)
- Overall Survival from the date of first drug administration until the date of death from any cause.(up to 17 months)