This phase II trial studies how well encorafenib and binimetinib work before surgery in treating patients with BRAF V600-mutated stage IIIB-D melanoma that has spread to the lymph nodes. Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This trial also studies how well 18F-FLT positron emission tomography (PET)/computed tomography (CT) works in predicting the response of melanoma to encorafenib and binimetinib. 18F-FLT is an imaging agent, sometimes called a tracer. PET and CT are types of imaging scans. Using 18F-FLT PET/CT together with encorafenib and binimetinib may provide more information on melanoma over time.
PRIMARY CLINICAL OBJECTIVE: I. To evaluate the pathologic complete response (pCR) rate of neoadjuvant treatment with encorafenib and binimetinib. SECONDARY CLINICAL OBJECTIVES: I. To determine response rate (RR) (Response Evaluation Criteria in Solid Tumors \[RECIST\]), disease-free survival (DFS) and overall survival (OS). II. To describe correlation of pCR with RR, DFS and OS. III. To assess safety and toxicity. CORRELATIVE SCIENCE OBJECTIVES: I. To evaluate CD8 positive (+) T cell infiltration and Ki-67 status in tumor or tumor bed pre, during, and post neoadjuvant treatment and the change in CD8+ tumor infiltrating lymphocyte (TIL) with neoadjuvant treatment and correlate with clinical response. II. To compare local review for pathologic response with central pathology review. III. To assess the correlation between change in fluorothymidine F-18 (18F-FLT) PET/CT uptake and change in Ki-67. IMAGING OBJECTIVES: I. To compare the change in 18F-FLT PET/CT uptake (from baseline to post-neoadjuvant therapy) among patients with and without pathologic complete response. II. To compare post-neoadjuvant 18F-FLT PET/CT uptake among patients with and without pathologic complete response. III. To estimate an optimal threshold for prediction of pathologic complete response using i) change in 18F-FLT PET/CT uptake, and ii) post-neoadjuvant 18F-FLT PET/CT uptake. IV. To assess the correlation between change in 18F-FLT PET/CT uptake and change in Ki-67. OUTLINE: NEOADJUVANT TREATMENT: Patients receive 18F-FLT intravenously (IV) and undergo a PET/CT scan approximately 60 minutes later. Within 2 weeks, patients receive encorafenib orally (PO) once daily (QD) and binimetinib PO twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive 18F-FLT IV and undergo a second PET/CT scan approximately 60 minutes later. SURGICAL RESECTION: Within 2 weeks of completing therapy with encorafenib and binimetinib, patients undergo surgery. ADJUVANT TREATMENT: Within 2-7 days after surgery, patients resume treatment with encorafenib PO QD and binimetinib PO BID on days 1-28. Treatment repeats every 28 days for up to 11 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year, then every 6 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
3
Given PO
Undergo surgery
Given PO
Given IV
Los Angeles County-USC Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, United States
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, United States
Washington University School of Medicine
St Louis, Missouri, United States
Siteman Cancer Center-South County
St Louis, Missouri, United States
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
University of Wisconsin Carbone Cancer Center
Madison, Wisconsin, United States
Pathologic Complete Response
Pathologic complete response (pCR) is defined as complete absence of viable tumor in the treated tumor bed. Partial pathologic response (pPR) is defined as less than or equal to 50% of the treated tumor bed is occupied by viable tumor cells. Pathologic non-response is defined as great than 50% of the treated tumor bed is occupied by viable tumor cells.
Time frame: Assessed at 10-12 weeks
Objective Response
Objective response is defined as either complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Complete response is defined as disappearance of all lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters and/or persistence of one or more non-target lesion(s). Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: Assessed at baseline, 8 weeks, then every 12 weeks up to 1.4 years
Disease-free Survival
Disease-free survival is defined as the time from date of surgical resection to the date of recurrence or death, whichever occurs first. Recurrence must be documented by radiologic exams and with biopsy in all cases except for brain metastases (biopsy not required). Abnormal blood studies alone (e.g., elevated transaminases or alkaline phosphatase) are not sufficient evidence of relapse. Whenever possible, histologic proof of recurrence should be obtained unless the lesion is not accessible or a biopsy would cause undue risk to the patient.
Time frame: Assessed at baseline, 8 weeks, then every 12 weeks up to 19.4 months
Overall Survival
Overall survival is defined as the time from registration to death or date last known alive, which is the censoring date for patients who are still alive.
Time frame: Assessed at every 3 months for 2 years and then every 6 months, up to 2 years 9 months
Associations Between pCR and Best Response
Association between pCR and best response will be reported.
Time frame: Assessed at baseline, 8 weeks, then every 12 weeks up to 1.4 years
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