Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer

Study Overview
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Brief Summary
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This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.

Detailed Description
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The primary and secondary objectives of the study: PRIMARY OBJECTIVES: I. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III) SECONDARY OBJECTIVES: I. To evaluate and compare overall survival (OS) between the two treatment arms. II. To evaluate and compare the toxicity profile between the two treatment arms. III. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms. IV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms. EXPLORATORY OBJECTIVE: I. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up. ARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.

Official Title
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Randomized Trial of Consolidation Targeted Adjuvant Therapy With Encorafenib and Cetuximab Versus Usual Care for Patients With Stage II/III BRAF V600E Colon Cancer

Conditions
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Colon Adenocarcinoma, Microsatellite Stable Colon Carcinoma, Stage IIB Colon Cancer AJCC v8, Stage IIC Colon Cancer AJCC v8, Stage III Colon Cancer AJCC v8

Intervention / Treatment
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* Drug: Encorafenib
* Biological: Cetuximab
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Procedure: Magnetic Resonance Imaging
* Other: Patient Observation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRE-REGISTRATION (STEP 0) ELIGIBILITY CRITERIA: BRAF V600 mutational status may be determined either locally or by central testing. This testing is mandatory prior to registration to determine eligibility. Tissue submission should be initiated as soon after surgery as possible. For tumors evaluated at local laboratories, formalin-fixed paraffin-embedded (FFPE) tumor tissue must still be submitted for central confirmation of BRAF status REGISTRATION (STEP 1) ELIGIBILITY CRITERIA: Histologically-proven stage III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk (pT4) stage II colon adenocarcinoma. Tumors must be deemed to originate in the colon including tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve) and must have been completely resected BRAF V600E mutation MMR proficient (pMMR) or microsatellite stable (MSS) tumor Histologic documentation: adenocarcinoma Stage: III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk II (pT4) Tumor site: colon Patients must have received at least 3 months of adjuvant chemotherapy with either leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) (minimum of 5 cycles) or capecitabine and oxaliplatin (CAPOX) (minimum of 3 cycles) Adjuvant therapy must be completed at most 8 weeks prior to registration No other prior medical therapy (chemotherapy, immunotherapy, biologic, or targeted therapy) or radiation therapy for the current colon cancer is permitted Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required Age >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status: 0-2 Absolute neutrophil count (ANC) >= 1.0 x 10^9/L Platelet count >= 75 x 10^9/L Hemoglobin > 9.0 g/dL Total bilirubin =< 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN Corrected QT (QTc) Interval =< 480 msec Creatinine = calculated (calc.) creatinine clearance >= 40 mL/min Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial No medical condition such as uncontrolled infection, uncontrolled diabetes mellitus, or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient Patients with known history or current symptoms of cardiac disease or history of treatment with cardiotoxic agents in the last 12 months, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better No uncontrolled or poorly-controlled hypertension (> 180 mmHg systolic or > 130 mmHg diastolic) No history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab No currently active second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for >= 3 years Patients are not considered to have a currently active malignancy if they had a gastric or bowel carcinoid < 1 cm, ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS) of the breast without invasive cancer, or endometrial dysplasia/carcinoma in situ Patients are not considered to have a currently active malignancy if they had a sebaceous neoplasm (sebaceous adenoma, sebaceous epithelioma, sebaceous adenocarcinoma, keratoacanthoma, and squamous cell carcinoma) that was noninvasive No known medical condition causing an inability to swallow oral formulations of agents No residual Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 grade >= 2 toxicity from prior chemotherapy, with the exception of grade 2 alopecia or neuropathy Drugs that prolong the QTc interval should be avoided if possible, as encorafenib can prolong the QTc interval. Drugs that are generally accepted to have a risk of causing Torsades de Pointes should be discontinued or replaced with drugs that do not carry this risk if at all possible. Patients who receive potential QTc-prolonging medications should be monitored closely Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed during treatment on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study Chronic concomitant treatment with strong CYP3A4 inducers is not allowed during treatment on this study. Patients must discontinue the drug 14 days prior to registration on the study Exclusion Criteria: N/A

Ages Eligible for Study
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Minimum Age: 18 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: Arm I (encorafenib, cetuximab)<br>Patients receive encorafenib PO and cetuximab IV on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up. | Drug: Encorafenib<br>* Given PO<br>* Other names: LGX-818;Biological: Cetuximab<br>* Given IV<br>* Other names: Erbitux;Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: CT Scan;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: MRI;|
| Active Comparator: Arm II (patient observation)<br>Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: CT Scan;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: MRI;Other: Patient Observation<br>* Undergo observation per usual care<br>* Other names: Watchful Waiting;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circulating tumor deoxyribonucleic acid (ctDNA) clearance rate (Phase II; ctDNA positive cohort) | defined as the proportion of patients with undetectable ctDNA status at 6 months after randomization among patients with detectable ctDNA status at randomization. The ctDNA clearance rate at 6 months after randomization in experimental arm will be compared to control arm by Chi-squared test. The one-sided p-value will be reported. Due to small sample size, Cochran and Mantel-Haenszel test, stratified by stratification factors will be performed as sensitivity analysis. | At 6 months after randomization | 
| tDNA recurrence-free survival rate (ctDNA-RFS) (Phase II; ctDNA negative cohort) | Defined as the proportion of patients who remained undetectable ctDNA status, recurrence-free, and alive at 6 months after randomization among patients with undetectable ctDNA status at randomization. The ctDNA-RFS in experimental arm will be compared to control arm by Cochran and Mantel-Haenszel test, stratified by stratification factors. The one-sided p-value will be reported. | at 6 months after randomization | 
| Disease free survival (DFS) (Phase III) | Defined as the time from the date of randomization to the date of first documented recurrence or death due to all cause, whichever occurs first. Patients without events observed at the end of the study will be censored at the date of last disease evaluation which shows no evidence of disease. At each analysis (Interim #1, Interim #2, and Final), stratified Cox model will be conducted to compare DFS in the experimental arm to DFS in the control arm with stratification factors as stratum, based on all data collected at the analysis time point. | Assessed up to 6 years after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Defined as the time from the date of randomization to death due to all causes. The distributions of time-to-event endpoints will be estimated, in each arm, using the method of Kaplan-Meier and compared by a stratified Cox regression model. | Assessed up to 6 years | 
| Incidence of adverse events after randomization | The maximum grade for each type of adverse events that are possibly, probably, or definitely related to study treatments will be summarized for each patient. The frequency tables will be reviewed to determine the patterns. The overall adverse event rates for grade 4 or higher adverse events will be compared between two treatment groups using Chi-square test (or Fisher's exact test if the data in the contingency table is sparse). | up to 6 years | 
| Alternative disease free survival | Defined as the time from the date of primary tumor resection to the date of first documented recurrence or death due to all cause, whichever occurs first. The distributions of time-to-event endpoints will be estimated, in each arm, using the method of Kaplan-Meier and compared by a stratified Cox regression model. | assessed up to 6 years |