This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.
PRIMARY OBJECTIVE: I. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab. SECONDARY OBJECTIVES: I. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms. II. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab. BANKING OBJECTIVE: I. To bank tissue and blood specimens for future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
84
CTCA at Western Regional Medical Center
Goodyear, Arizona, United States
Mercy Cancer Center - Carmichael
Carmichael, California, United States
Mercy San Juan Medical Center
Carmichael, California, United States
Kaiser Permanente Dublin
Dublin, California, United States
Mercy Cancer Center - Elk Grove
Elk Grove, California, United States
Progression-free survival (PFS)
Conducted in all eligible participants according to the intent-to-treat principle using the stratified log rank test when a total of 66 PFS events have been observed. Estimated using the Kaplan-Meier method and compared using the stratified log rank test.
Time frame: From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years
Overall response rate (ORR)
Evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (confirmed and unconfirmed, complete and partial response) and compared across treatment arms via Fisher's exact test.
Time frame: Up to 3 years
Overall survival (OS)
Estimated using the Kaplan-Meier method and compared using the stratified log rank test. The distribution of OS will be estimated using the method of Kaplan-Meier and compared using the stratified log rank test.
Time frame: From date of registration to date of death due to any cause, assessed up to 3 years
Duration of response (DoR)
Estimated using the Kaplan-Meier method and compared using the stratified log rank test. The distribution of DoR will be estimated using the method of Kaplan-Meier and compared using the stratified log rank test.
Time frame: From date of first documentation of confirmed response (complete response or partial response) to date of first documentation of progression or symptomatic deterioration or death due to any cause among participants who achieve a response, up to 3 years
Immune related progression-free survival (irRC-PFS) in Arm I
The distribution of irRC-PFS in Arm 1 (nivolumab + encorafenib + cetuximab) will be estimated using the method of Kaplan-Meier.
Time frame: From date of registration to date of initial documentation of irRC-progression that has subsequently been confirmed or symptomatic deterioration, or death due to any cause, assessed up to 3 years
Incidence of adverse events
At least 25 eligible participants in each arm are sufficient to estimate the probability of a particular toxicity within ±20% (95% confidence interval), and any toxicity occurring with at least 10% probability is likely (93% chance) to be seen at least once. At least 50 eligible participants are sufficient to estimate the probability of a particular toxicity within ±14% (95% confidence interval), and any toxicity occurring with at least 5% probability is likely (92% chance) to be seen at least once.
Time frame: Up to 3 years
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Kaiser Permanente-Fremont
Fremont, California, United States
Kaiser Permanente-Fresno
Fresno, California, United States
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, United States
Kaiser Permanente-Modesto
Modesto, California, United States
Kaiser Permanente-Oakland
Oakland, California, United States
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