This phase II trial tests whether nivolumab in combination with cabozantinib works in patients with mucosal melanoma. 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. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It works by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps stop the spread of tumor cells. Giving nivolumab in combination with cabozantinib could prevent cancer from returning.
PRIMARY OBJECTIVE: I. To compare the efficacy of adjuvant nivolumab (480 mg every \[q\]4 weeks) versus nivolumab plus cabozantinib s-malate (cabozantinib) (40 mg daily) in patients with mucosal melanoma. SECONDARY OBJECTIVES: I. To compare overall survival between the two adjuvant therapies. II. To evaluate the adverse effects in each arm. III. To assess the correlation between PD-L1 expression in tumor cells with survival (recurrence free survival \[RFS\] and overall survival \[OS\]). IV. To evaluate the overall response rate (ORR), duration of response (DOR), progression free survival (PFS), and OS of nivolumab plus cabozantinib in patients who cannot undergo gross total resection of disease or have metastatic disease at baseline. V. Results of the primary analysis will be examined for consistency, while taking into account the stratification factors and/or covariates of baseline quality of life (QOL) and fatigue. OUTLINE: Patients whose tumor has been fully removed by surgery are randomized to Arm 1 or Arm 2. Patients whose tumor has not been fully removed by surgery or has spread are assigned to Arm 3. ARM 1: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 and cabozantinib orally (PO) once daily (QD) of each cycle. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. ARM 2: Patients receive nivolumab IV over 30 minutes on day 1 and placebo PO QD of each cycle. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. ARM 3: Patients receive nivolumab IV over 30 minutes and cabozantinib PO QD of each cycle. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiogram (ECHO) during screening and as clinically indicated throughout the trial. Patients may undergo computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)/CT at baseline, CT and MRI may be repeated every 6 months on study. Additionally, patients may undergo bone scans, as well as optional blood and tissue sample collection throughout the trial. After completion of study treatment, patients are followed up every 3 months until disease progression, and then every 6 months for up to 5 years from registration or until death.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
99
Undergo blood and tissue sample collection
Undergo bone scan
Given PO
Undergo CT
Undergo ECHO
Undergo MRI
Given IV
Given PO
Undergo PET
Sutter Auburn Faith Hospital
Auburn, California, United States
RECRUITINGAlta Bates Summit Medical Center-Herrick Campus
Berkeley, California, United States
RECRUITINGPalo Alto Medical Foundation-Fremont
Fremont, California, United States
RECRUITINGKeck Medicine of USC Koreatown
Los Angeles, California, United States
Recurrence free survival (RFS)
Will evaluate RFS of single agent adjuvant nivolumab plus placebo compared to the combination treatment of adjuvant nivolumab plus cabozantinib in patients with resected mucosal melanoma.
Time frame: Number of days from registration until either local or distant recurrence or death (due to any cause), assessed up to 5 years
Overall survival (OS)
Will be evaluated utilizing the Kaplan-Meier (KM) method and, when appropriate, cox proportional hazards models. Median OS is calculated (along with 95% Confidence intervals) using the KM method. A Cox proportional hazards model is built to compare arms 1 and 2 with respect to OS.
Time frame: Number of days from registration until death (due to any cause, assessed up to 5 years
RFS
Median RFS will be calculated (along with 95% Confidence intervals) using the KM method. A Cox proportional hazards model will also be built to compare arms 1 and 2 with respect to RFS, with and without stratifying for PD-L1 categorization. For non-resected cohort, If a patient in this group has surgery, their RFS data will be censored at the time of surgery.
Time frame: Number of days from registration until either local or distant recurrence or death (due to any cause), assessed up to 5 years
Progression free survival
Will be evaluated in multiple settings utilizing the KM method and, when appropriate, cox proportional hazards models.
Time frame: Number of days from registration until either radiographic or clinical progression or death (due to any cause), assessed up to 5 years
Objective response rate (Arm 3)
Will assess this endpoint utilizing a two-stage Simon that looks to improve from a rate of 20% to 47%.
Time frame: Up to 5 years
Duration of response (Arm 3)
A KM analysis is performed to calculate the median duration of response and 95% confidence intervals are constructed.
Time frame: Time from the first evidence of response until progression, assessed up to 5 years
Incidence of adverse events
The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events version 5.0. The frequency and percentage of grade 3+ adverse events will be summarized.
Time frame: Up to 5 years
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Los Angeles General Medical Center
Los Angeles, California, United States
RECRUITINGUSC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
RECRUITINGMemorial Medical Center
Modesto, California, United States
RECRUITINGUSC Norris Oncology/Hematology-Newport Beach
Newport Beach, California, United States
RECRUITINGPalo Alto Medical Foundation Health Care
Palo Alto, California, United States
SUSPENDEDStanford Cancer Institute Palo Alto
Palo Alto, California, United States
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