Efficacy of VIC Regimen in BRAF Mutant Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Drug: Cetuximab
* Drug: Irinotecan
* Drug: Vemurafenib


Participation Criteria
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Eligibility Criteria
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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 Life expectancy> 3 months Patients must provide a signed Informed Consent Form Patients must have good compliance till the end of this study 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 Active hepatitis B or C infection History of Gilbert syndrome Interstitial pneumonia or widespread symptomatic interstitial pulmonary fibrosis Serious uncontrollable systemic complications such as infection or diabetes Clinically serious cardiovascular diseases such as cerebrovascular accident (within 6 months prior to enrollment), myocardial infarction (within 6 months prior to enrollment), hypertension that cannot be controlled after proper medical treatment, unstable angina pectoris, congestion Heart failure (NYHA 2-4), arrhythmia requiring medication History of or showing signs of a central nervous system disease (such as primary brain tumors, epilepsy that cannot be controlled by standard treatment, any brain metastases or history of stroke) Patients must not suffer from other uncontrolled concurrent diseases, including but not limited to hypertensive crisis or hypertensive encephalopathy, active bleeding, uncontrolled infections/diseases, uncontrolled non-malignant medical diseases or use research therapies that could worsen non-malignant medical diseases or mental illnesses/social conditions No history of other malignant tumors in the past 5 years (excluding skin basal cell carcinoma and/or cervical carcinoma in situ and/or thyroid cancer after radical resection) Patients allergic to any drugs in the study Patients must not be pregnant or breastfeeding Women of reproductive potential (<2 years after the last menstruation) who have not used or refused to use effective non- hormonal contraceptive methods (intrauterine contraceptive ring, barrier contraception combined with spermicidal gel or sterilization) or Men wanting to keep their reproductive potential. Patients unable or unwilling to comply with the protocol of this clinical trial Existence of any other diseases, dysfunction caused by metastatic lesions, or suspicious diseases found during physical examination, which may indicate contraindications to the use of the drugs in this study or could bring about high risk of treatment-related complications to the patient

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VIC regimen<br>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). | Drug: Cetuximab<br>* Route of administration: Intravenous<br>* Other names: Erbitux;Drug: Irinotecan<br>* Route of administration: Intravenous<br>* Other names: Camptosar;Drug: Vemurafenib<br>* Route of administration: Oral<br>* Other names: Zelboraf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate from the date of first drug administration until the date of first documented progression or date of death, whichever came first. | The proportion of patients who achieved a complete or partial response as their best overall response based on RECIST v1.1 criteria | up to 17 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival from the date of first drug administration until the date of first documented progression or date of death, whichever came first. | The length of time during and after the treatment of the disease, that a patient lives with the disease without its aggravation | up to 17 months | 
| Overall Survival from the date of first drug administration until the date of death from any cause. | The length of time from the start of treatment that patients diagnosed are still alive | up to 17 months | 
| Number of patients with adverse events and severity according to NCI CTCAE v5.0 | Summary of the Adverse events experienced during treatment related to the drug used in this study | up to 6 months |