Efficacy and Safety of Tunlametinib Plus Vemurafenib in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This is a multicenter, randomized, open-label, 3-arm Phase 3 study

Detailed Description
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This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate Tunlamatinib plus Vemurafenib versus Investigator's choice of Chemotherapy based treatment as controls in patients with BRAFV600E mutant Metastatic Colorectal Cancer (CRC) whose disease has progressed after 1 or more prior regimens in the metastatic setting.

Official Title
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A Multicenter, Randomized, Open-label, Phase 3 Study to Evaluate the Efficacy and Safety of Tunlametinib Plus Vemurafenib in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Drug: Tunlametinib plus Vemurafenib
* Drug: Doublets Chemotherapy ± Bevacizumab or Doublets Chemotherapy ± Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria: Before study entry, written informed consent must be obtained from the patient prior to performing any study-related procedures. Male or female patients with 18 to 70 years of age at time of informed consent; Histological or cytologically confirmed metastatic CRC Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any time prior to Screening or by the central laboratory (BRAFV600 is permitted) Able to provide a sufficient amount of representative tumor specimen (primary or metastatic, archival or newly obtained) for confirmatory central laboratory testing of BRAF mutation status. Progression of disease after 1 or more prior regimens in the metastatic setting At least 1 site of radiographically measurable disease by RECIST 1.1 Eastern Cooperative Oncology Group (ECOG) Performance Status(PS) of 0 to 1; Life expectancy ≥ 3 months; Can swallow the medicine, Adequate hematologic, renal, cardiac and liver function as defined by laboratory values performed within 7 days prior to initiation of dosing: Be willing and able to complete all the study procedures and follow-up examinations. Exclusion Criteria: Exclusion Criteria: Prior treatment with any BRAF and MEK inhibitor; Known contraindication to receive the treatment of control arm (according to latest PI). Symptomatic brain metastasis or leptomeningeal disease History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization Known history of acute or chronic pancreatitis Uncontrolled GI bleeding, Dysphagia，refractory nausea, vomiting, small bowel resection or any other gastrointestinal ailment that would preclude study drug absorption. Serious cardiovascular disease , including uncontrolled congestive heart failure, uncontrolled hypertension, cardiac ischemia, myocardial infarction, and severe cardiac arrhythmia , deep vein thrombosis or pulmonary emboli or cerebrovascular events ≤ 6 months prior to starting study treatment; History or current evidence of retinal vein occlusion or current risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) Concurrent neuromuscular disorder that is associated with the potential of elevated creatine (phosphor)kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) Uncontrolled blood pressure despite medical treatment Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy Residual common terminology criteria for adverse events (CTCAE) ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy Anti-HIV(+) , Anti-TP( +); Active hepatitis B or hepatitis C infection …….

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>Tunlamatinib plus Vemurafenib | Drug: Tunlametinib plus Vemurafenib<br>* 12mg BID Tunlametinib+720mg BID Vemurafenib<br>|
| Active Comparator: Control<br>Investigators' choice | Drug: Doublets Chemotherapy ± Bevacizumab or Doublets Chemotherapy ± Cetuximab<br>* According to investigators' suggestion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | defined as the time from first dose to the earliest documented disease progression or death due to any cause | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival（OS） | defined as the time from the date of taking drugs to the date of death due to any cause | up to 12 months | 
| Overall Response Rate（ORR） | Defined as the proportion of subjects with an optimal response of CR or PR over the course of the study from enrollment to disease progression | up to 12 months | 
| Duration of Response（DOR） | Defined as the time from the first CR or PR evaluation of tumor efficacy to the first occurrence of PD or death from any cause (whichever occurs first) | up to 12 months | 
| Disease control rate (DCR) | roportion of subjects with response defined as CR, PR, and SD throughout the study from subjects first dose to disease progression or death | up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRAFV600E mutant