A Randomized Phase II Trial of Adjuvant Nivolumab With or Without Cabozantinib in Patients With Resected Mucosal Melanoma

  • End date
    Dec 19, 2023
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 22 October 2022


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.



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.


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 cycle in the absence of disease progression or unacceptable toxicity.

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.

Condition Anal Melanoma, Bladder Melanoma, Cervical Melanoma, Esophageal Melanoma, Gallbladder Melanoma, Mucosal Melanoma, Mucosal Melanoma of the Head and Neck, Mucosal Melanoma of the Urinary System, Oral Cavity Mucosal Melanoma, Penile Mucosal Melanoma, Rectal Melanoma, Recurrent Mucosal Melanoma, Sinonasal Mucosal Melanoma, Stage II Vulvar Cancer AJCC v8, Stage IIIC Vulvar Cancer AJCC v8, Stage IV Vulvar Cancer AJCC v8, Stage IVA Vulvar Cancer AJCC v8, Stage IVB Vulvar Cancer AJCC v8, Urethral Melanoma, Vaginal Melanoma, Vulvar Melanoma
Treatment Nivolumab, Placebo Administration, Cabozantinib S-malate
Clinical Study IdentifierNCT05111574
SponsorNational Cancer Institute (NCI)
Last Modified on22 October 2022


Yes No Not Sure

Inclusion Criteria

Histologically proven mucosal melanoma by local pathology
Central PD-L1 tumor tissue submission
Receipt of the central PD-L1 testing results available
Disease status-Resected R0 or R1 disease patients. Patients eligible for randomization have resected R0 or R1 disease (with negative margins or positive microscopic margins) that must meet one of the following 4 criteria as defined below
Regional lymph node (LN) involvement; OR
In-transit metastases/satellite primary disease; OR
Single localized, primary disease meeting one of the following site-specific
Head/neck - any primary lesion if sinonasal; pT4a or above for nasal or oral cavity, given slightly improved OS
Anorectal - any primary lesion
Vaginal/cervical - any primary, as they have 5 year OS rates of 5-25
Urinary tract - any primary urethral or bladder tumor
Vulvar- AJCC cutaneous stage IIB or higher
Esophageal/gallbladder - any primary
Locoregionally recurrent following prior resection, meeting at least one of the
above criteria
In addition, patients must have undergone cross-sectional imaging of the brain, chest, abdomen and pelvis with no evidence of distant metastatic disease
Disease status-Non-resected R2 or metastatic disease patients
Non-resected R2 or metastatic disease that is assessable and measurable radiographically or by physical examination
Prior Treatment
No prior systemic checkpoint inhibitor therapy of mucosal melanoma, including in the adjuvant setting, is allowed. Prior adjuvant chemotherapy or interferon is allowed
No other active, concurrent malignancy that requires ongoing systemic treatment or interferes with radiographic assessment of melanoma response as determined by the investigator
Any radiation must have completed 28 days prior to randomization and the patient must have adequately recovered from its effects
Surgery must have completed 28 days prior to randomization
Surgery must have completed no more than 84 days prior to randomization
Not pregnant and not nursing, because this study has 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) >= 1,500/mm^3
Platelet count >= 100,000/mm^3
Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) >= 50mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
Albumin >= 2.8 g/dL
Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis
Urine protein/creatinine =< 1
Total bilirubin =< 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
No cardiovascular disease, including
No history of acute coronary syndromes (including myocardial infarction and unstable angina), coronary artery bypass graft (CABG) coronary angioplasty, or stenting within 6 months prior to study entry
No history of current class II or higher congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
No refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg despite adequate attempts at anti-hypertensive therapy
No history of myocarditis
No history of syncope of cardiovascular etiology, uncontrolled cardiac arrhythmia, history of Mobitz II second degree or third degree heart block without a permanent pacemaker in Association (NYHA) class II to IV heart failure, or stroke/transient ischemic attack (TIA) within the past 3 months
No corrected QT interval by Fridericia's formula (QTcF) > 500 msec. Note: if initial QTcF is found to be > 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard
No underlying hematologic issues, including
Congenital bleeding diathesis
Gastrointestinal (GI) bleeding requiring intervention within the past 6 months, unless directly related to mucosal melanoma
Active hemoptysis within 42 days prior to study enrollment
Active tumor lesions with cavitations or tumor lesions which invade, encase, or abut major blood vessels. The anatomic location and characteristics of primary tumors or metastases as well as the medical history should be carefully reviewed in the selection of subjects for treatment with cabozantinib/placebo
Pulmonary emboli or deep vein thromboses (DVT) that require an active anticoagulation regimen
No known or suspected history of cytopenia (low white blood cell [WBC], hemoglobin or platelet count) of greater than 3 months duration with an unknown cause, myelodysplastic syndrome, or hematologic malignancies
No clinical, laboratory or radiographic evidence of an active bacterial, fungal, or
viral infection requiring treatment at the time of pre-registration (e.g
active symptoms of COVID-19 infection or a post-infectious symptomatic
autoimmune syndrome, serious bacterial infections requiring antibiotics)
No known or suspected gastrointestinal disorder affecting absorption of oral medications
Comorbid conditions
No active autoimmune disease or any condition requiring systemic treatment with either corticosteroids (> 10 mg daily of prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
No history of autoimmune motor neuropathy (e.g., Guillain-Barre syndrome, myasthenia gravis) or non-infectious pneumonitis
No history of severe allergic reactions to an unknown allergen or any components of the study drugs or its excipients
No history of gastrointestinal perforation or abdominal fistula
No clinically suspected central nervous system (CNS) (leptomeningeal or parenchymal) metastases. Patients with a history of CNS metastasis(s) will be allowed as long as
The metastatic site(s) were adequately treated as demonstrated by clinical and radiographic improvement, AND
The patient has recovered from the intervention (no residual adverse events > Common Terminology Criteria for Adverse Events [CTCAE] grade 1), AND
The patient has remained without occurrence of new or worsening CNS symptoms for a period of 28 days prior to enrollment
No history of seizure or any condition that may increase the patient's seizure
risk (e.g., prior cortical stroke, significant brain trauma) within 2 years
No clinically active or chronic liver disease resulting in moderate/severe hepatic impairment (Child-Pugh class B or C), ascites, coagulopathy or bleeding due to liver dysfunction
No untreated spinal cord compression or evidence of spinal metastases with a risk of impending fracture or spinal cord compression. Spinal metastases must have completed planned radiation or surgical therapy prior to registration
Concomitant medications
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed 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. Patients must discontinue the drug 14 days prior to the start of study treatment
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