Tolerability and Safety of Vemurafenib, Cetuximab Combined With Camrelizumab for BRAF V600E-mutated /MSS Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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BRAF mutation exists in about 10-12% of colorectal cancer, among which BRAF V600E mutation is the most common type, which is an important biomarker for predicting the prognosis and precise treatment efficacy of metastatic colorectal cancer (mCRC). The prognosis of metastatic colorectal cancer with BRAF V600E mutation is very poor, with OS of about 6-9 months. Previous studies have shown that single anti-BRAF inhibitor are ineffective, while multi-target inhibitions of Ras-Raf -MEK pathway is a possible effective strategy for BRAF V600E-mutant mCRC. Currently, the proven effective regimens include the VIC regimen (Vemurafenib + cetuximab + Irinotecan) and BEACON regimen (Encorafenib+ cetuximab +/- Binimetinib) from the SWOGS1406 study. Furthermore, BRAF inhibitor +MEK inhibitor combined with PD-1 monoclonal antibody has been shown to be an effective strategy in BRAF V600E-mutant malignant melanoma, which promote the study of the regimens for the treatment of BRAF V600E-mutant mCRC. Increasing basic and clinical studies have shown that cetuximab has ADCC effect, induces immunogenic cell death, promotes immune cell infiltration and other immunomodulatory effects, and has a synergistic effect with PD-1 monoclonal antibody in colorectal cancer. Based on those theories, we conducted the phase I study to explore the safety and preliminary efficacy of the regimen of Vemurafenib (BRAFi) plus cetuximab (EGFRi) combined with PD-1 monoclonal antibody in BRAF V600E-mutant /MSS type mCRC.

Official Title
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A Phase I Study on Tolerance and Safety of Vemurafenib Film-coated Tablets, Cetuximab Solution for Infusion and Camrelizumab Protocol(VCC) in the After Line Therapy of BRAF V600E Mutation/MSS Metastatic Colorectal Cancer

Conditions
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BRAF V600E-mutated /MSS Metastatic Colorectal Cancer, Vemurafenib (BRAFi) Plus Cetuximab (EGFRi) Combined With PD-1 Monoclonal Antibody

Intervention / Treatment
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* Drug: Vemurafenib Oral Tablet [Zelboraf]
* Drug: Cetuximab Injection [Erbitux]
* Drug: Camrelizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥ 18 years of age Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Participants must have histologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum, with clinical confirmation of unresectable and/or metastatic disease that is measurable according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria Presence of BRAF V600E in tumor tissue determined by local assay at any time prior to screening and confirmed by central laboratory. And confirmation of MSS or pMMR status from immunohistochemistry or PCR or NGS; Prior treatment with at least one systemic treatment (chemotherapy or target therapy) for mCRC, and prior treatment did not include cetuximab Adequate organ and marrow function: ①Hemoglobin (Hb) ≥ 90 g/L；Platelets (PLT) ≥ 75 x 10^9/L；Neutrophil ≥1.5 x 10^9/L ②Total bilirubin ≤ 1.5 x upper limit of normal (ULN)；Aspartate aminotransferase (AST) ≤3 x ULN ；Alanine aminotransferase (ALT) ≤3 x ULN ③Serum creatinine ≤ 1.5 x ULN, or calculated creatinine clearance (determined as per Cockcroft-Gault) ≥ 50 mL/min at screening ④INR, APTT, and PT≤ 1.5 x ULN ⑤Serum albumin≥ 28 g/L ⑥ECG showed no evident abnormality Written informed consent Exclusion Criteria: Known hypersensitivity or contraindication to any component of cetuximab or PD-1 monoclonal antibody or macromolecular protein reagent. A history of other malignancies with a disease-free survival of less than 5 years, with the following exceptions: adequately treated basal or squamous cell skin cancer, carcinoma in-situ of the cervix, and gastrointestinal tumors treated curatively with endoscopic mucosectomy; Any active autoimmune disease or a history of autoimmune disease Use of immunosuppressive medications or glucocorticoid therapy ≤2 weeks prior to entry Uncontrolled active infection requiring antibiotics Known history of HIV infection or active hepatitis Severe complications, including any of the following: ①Massive gastrointestinal bleeding, perforation, or gastrointestinal obstruction ②Symptomatic heart disease ③Uncontrolled diabetes and hypertension ④Uncontrolled diarrhea Women who are pregnant or lactating and people who do not agree to avoid pregnancy Patients with serious psychiatric that may interfere treatment. Other conditions which are inappropriate to participate in the study confirmed by investigators.

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: Vemurafenib, Cetuximab Combined With Camrelizumab (VCC)<br>Cetuximab and Camrelizumab in the fixed dose Vemurafenib have two dose groups: 960mg qd or 960mg bid | Drug: Vemurafenib Oral Tablet [Zelboraf]<br>* Vemurafenib 960mg qd or 960mg bid (2 cohorts)<br>* Other names: Zelboraf;Drug: Cetuximab Injection [Erbitux]<br>* Cetuximab 500mg/m2 Q2W<br>* Other names: Erbitux;Drug: Camrelizumab<br>* Camrelizumab 200mg Q2W<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate tolerability and safety and identify the recommended Phase 2 dose(RP2D) |  | Subjects will be treated and observed for dose-limiting toxicity(DLT) through the end of the first cycle (Days 1-28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Object Response Rate (ORR) | Rate of patients with partial or complete response according to modified RECIST criteria. | up to 24 weeks | 
| Disease Control Rate (DCR) | the proportion of patients who had a best response rating of complete response, partial response, or stable disease according to modified RECIST | up to 24 weeks | 
| Progression Free Survival (PFS) | Progression free survival (Medium, Kaplan-Meier-estimation, ITT- population) | up to 1 year | 
| Overall Survival (OS) | Overall survival (Kaplan-Meier-estimation, ITT- population) | up to 3 year | 
| Preliminary efficacy | Evaluation of preliminary efficacyaccording to RECIST 1.1 | up to 1 year |