Adjuvant Therapy Based on Pathologic Response after Neoadjuvant Encorafenib and Binimetinib for the Treatment of Stage IIIB-IV Melanoma
This early phase I trial studies the effect of adjuvant therapy based on pathologic response after neoadjuvant encorafenib and binimetinib in treating patients with stage IIIB-IV melanoma. Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 or encorafenib and binimetinib as adjuvant therapy based on pathologic response after neoadjuvant encorafenib and binimetinib may work better in treating patients with melanoma.
Inclusion Criteria
- Age >= 18 years at the time of informed consent
- Histologically confirmed diagnosis of melanoma. Any primary or unknown origin is permitted
- Melanoma must have a BRAFV600 mutation (using a Clinical Laboratory Improvement Amendments [CLIA]-validated assay), either stage III (B/C/D) or stage IV (American Joint Committee on Cancer [AJCC] 8th edition)
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Hemoglobin >= 8 g/dL
- Platelets >= 75 x 10^9/L
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN); in participants with liver metastases =< 5 x ULN
- Total bilirubin =< 1.5 x ULN and < 2 mg/dL; OR total bilirubin > 1.5 x ULN with indirect bilirubin < 1.5 x ULN
- Serum creatinine =< 2.0 x ULN
- Female participants of childbearing potential, must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test result. Female participants of childbearing potential must agree to use methods of contraception that are highly effective or acceptable. Participants must agree to not use hormonal contraceptives, as encorafenib can result in decreased concentration and loss of efficacy. Male participants must agree to use methods of contraception that are highly effective or acceptable
Exclusion Criteria
- Participants may have received prior therapy with a BRAF and/or a MEK inhibitor if it was completed at least 6 months prior to study enrollment. Patients who had prior disease progression while on BRAF/MEK inhibitor therapy are not eligible. (Progression after stopping treatment is permitted). Patients may have received prior therapy an anti-PD-1/PD-L1 or CTLA-4 inhibitor
- Participants must not have had adverse events related to encorafenib and/or binimetinib specifically, that required discontinuation of one or both drugs due to toxicity
- Participants who have had major surgery or radiotherapy =< 14 days prior to start of study treatment or who have not recovered from side effects of such procedure
- Participants must be willing to avoid consuming grapefruit, pomegranates, star fruits, Seville oranges or products containing the juice during the study while they are taking encorafenib/binimetinib
- Uncontrolled or symptomatic brain metastases or leptomeningeal carcinomatosis that are not stable, require steroids, are potentially life-threatening or have required radiation within 28 days prior to starting study drug. Patients with previously treated brain metastases may participate provided they are stable (e.g., without evidence of progression by radiographic imaging for at least 28 days before the first dose of study treatment and neurologic symptoms have returned to baseline)
- Impaired cardiovascular function as below: * Congestive heart failure requiring treatment (New York Heart Association grade >= 3); * Presence of uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia * Baseline corrected QT interval by Fridericia formula (QTcF) interval >= 500 ms
- Known history of retinal vein occlusion (RVO)
- Current use of a prohibited medication (including herbal medications, supplements, or foods), or use of a prohibited medication =< 1 week prior to the start of study treatment
- Participants with a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 90 days prior to randomization
- Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment must have an undetectable HCV viral load prior to randomization
- Pregnancy or breast feeding
Additional locations may be listed on ClinicalTrials.gov for NCT04741997.
Locations matching your search criteria
United States
Florida
Tampa
PRIMARY OBJECTIVE:
I. To estimate the rate of disease relapse and hazard rate of disease relapse after neoadjuvant therapy based on the statuses of pathologic complete response (CR) or non-pathologic complete response (pCR), and postoperative adjuvant therapy.
SECONDARY OBJECTIVES:
I. To estimate the median relapse free survival, defined as time from surgery until disease relapse.
II. To estimate the rate of pathologic CR and non-pCR during surgery.
III. To estimate the overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 after neoadjuvant therapy (for patients who have measurable disease per RECIST 1.1 criteria at start of neoadjuvant therapy).
IV. Median overall survival, defined as time from surgery to death from any cause.
V. Toxicity per Common Terminology Criteria for Adverse Events (CTCAE) version (v.)5.
TRANSLATIONAL OBJECTIVES:
I. Identify potential candidate biomarkers that correlate with pathologic CR in patients undergoing neoadjuvant BRAF-MEK inhibitor therapy.
II. Determine whether serial measurement of circulating tumor (ct) deoxyribonucleic acid (DNA) can predict pathologic response and/or identify the need for treatment alteration.
OUTLINE:
Patients receive encorafenib orally (PO) once daily (QD) and binimetinib PO twice daily (BID) on days 1-28. Cycles repeat every 28 days for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery no later than 6 weeks after the end of neoadjuvant treatment with encorafenib and binimetinib. Beginning 12 weeks after surgery, patients with pCR are then randomized to Arms 1 and 2, and patients with non-pCR are randomized to Arm 3 and 4.
ARM 1: Patients undergo surveillance.
ARM 2/3: Patients receive encorafenib PO QD and binimetinib PO BID. Cycles repeat every 28 days for 24 weeks in the absence of disease progression or unacceptable toxicity.
ARM 4: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 4 weeks for 24 weeks in the absence of disease progression or unacceptable toxicity.
Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and as clinically indicated on study. Patients undergo computed tomography (CT), magnetic resonance imaging (MRI), and blood sample collection throughout the study.
After completion of study treatment, patients are followed at 30-40 days, every 3 months for the first year, and then every 6 months for up to 5 years after date of surgery or end of treatment, whichever is earlier.
Trial PhasePhase O
Trial Typetreatment
Lead OrganizationMoffitt Cancer Center
Principal InvestigatorZeynep Eroglu
- Primary IDMCC-20641
- Secondary IDsNCI-2021-01124
- ClinicalTrials.gov IDNCT04741997