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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05111574
Other study ID # NCI-2021-11794
Secondary ID NCI-2021-11794A0
Status Recruiting
Phase Phase 2
First received
Last updated
Start date August 11, 2022
Est. completion date December 19, 2024

Study information

Verified date March 2024
Source National Cancer Institute (NCI)
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


Description:

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 cycle 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 stool sample collection at baseline, and blood and tissue sample collection at baseline and on 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.


Recruitment information / eligibility

Status Recruiting
Enrollment 99
Est. completion date December 19, 2024
Est. primary completion date December 19, 2024
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - STEP 0 INCLUSION CRITERIA - Histologically proven mucosal melanoma by local pathology - Central PD-L1 tumor tissue submission - STEP 1 INCLUSION CRITERIA - 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 requirements: - Head/neck - Sinonasal (including nasopharynx): any primary lesion; Nasal or oral cavity; pT4a or above, given slightly improved OS - NOTE: Conjunctival: does not meet the qualification for eligibility - 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 - Penile - 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. Exceptions may allow for adjuvant no evidence of disease (NED) cancers undergoing hormone based therapy may be eligible pending the other eligibility criteria are met and the principal investigator (PI) affirms the hormonal agent would not change the melanoma response. - Any radiation must have completed 28 days prior to randomization and the patient must have adequately recovered from its effects. - For resectable patients only: Surgery must have completed 28 days prior to randomization. - For resectable patients only: 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 - 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 5 days prior to the start of study treatment. - Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 5 days prior to the start of study treatment.

Study Design


Intervention

Procedure:
Biospecimen Collection
Undergo blood, stool and tissue sample collection
Drug:
Cabozantinib S-malate
Given PO
Procedure:
Computed Tomography
Undergo CT
Echocardiography
Undergo ECHO
Magnetic Resonance Imaging
Undergo MRI
Biological:
Nivolumab
Given IV
Drug:
Placebo Administration
Given PO
Procedure:
Positron Emission Tomography
Undergo PET

Locations

Country Name City State
Canada Jewish General Hospital Montreal Quebec
Canada Odette Cancer Centre- Sunnybrook Health Sciences Centre Toronto Ontario
Canada University Health Network-Princess Margaret Hospital Toronto Ontario
United States Mary Greeley Medical Center Ames Iowa
United States McFarland Clinic - Ames Ames Iowa
United States Community Hospital of Anaconda Anaconda Montana
United States Sutter Auburn Faith Hospital Auburn California
United States Rush - Copley Medical Center Aurora Illinois
United States UM Sylvester Comprehensive Cancer Center at Aventura Aventura Florida
United States Memorial Sloan Kettering Basking Ridge Basking Ridge New Jersey
United States Bronson Battle Creek Battle Creek Michigan
United States Alta Bates Summit Medical Center-Herrick Campus Berkeley California
United States Billings Clinic Cancer Center Billings Montana
United States Saint Alphonsus Cancer Care Center-Boise Boise Idaho
United States McFarland Clinic - Boone Boone Iowa
United States Dana-Farber Cancer Institute Boston Massachusetts
United States Bozeman Health Deaconess Hospital Bozeman Montana
United States Minnesota Oncology - Burnsville Burnsville Minnesota
United States Saint Alphonsus Cancer Care Center-Caldwell Caldwell Idaho
United States Miami Valley Hospital South Centerville Ohio
United States Centralia Oncology Clinic Centralia Illinois
United States Northwestern University Chicago Illinois
United States Case Western Reserve University Cleveland Ohio
United States Kootenai Health - Coeur d'Alene Coeur d'Alene Idaho
United States Mercy Hospital Coon Rapids Minnesota
United States UM Sylvester Comprehensive Cancer Center at Coral Gables Coral Gables Florida
United States Carle at The Riverfront Danville Illinois
United States Dayton Physician LLC - Englewood Dayton Ohio
United States Miami Valley Hospital Dayton Ohio
United States Miami Valley Hospital North Dayton Ohio
United States Premier Blood and Cancer Center Dayton Ohio
United States Cancer Care Specialists of Illinois - Decatur Decatur Illinois
United States Decatur Memorial Hospital Decatur Illinois
United States UM Sylvester Comprehensive Cancer Center at Deerfield Beach Deerfield Beach Florida
United States HSHS Sacred Heart Hospital Eau Claire Wisconsin
United States Marshfield Medical Center-EC Cancer Center Eau Claire Wisconsin
United States Fairview Southdale Hospital Edina Minnesota
United States Carle Physician Group-Effingham Effingham Illinois
United States Crossroads Cancer Center Effingham Illinois
United States Parkland Health Center - Farmington Farmington Missouri
United States McFarland Clinic - Trinity Cancer Center Fort Dodge Iowa
United States Atrium Medical Center-Middletown Regional Hospital Franklin Ohio
United States Palo Alto Medical Foundation-Fremont Fremont California
United States Corewell Health Grand Rapids Hospitals - Butterworth Hospital Grand Rapids Michigan
United States Trinity Health Grand Rapids Hospital Grand Rapids Michigan
United States Benefis Sletten Cancer Institute Great Falls Montana
United States Saint Vincent Hospital Cancer Center at Saint Mary's Green Bay Wisconsin
United States Saint Vincent Hospital Cancer Center Green Bay Green Bay Wisconsin
United States Miami Valley Cancer Care and Infusion Greenville Ohio
United States Memorial Sloan Kettering Westchester Harrison New York
United States M D Anderson Cancer Center Houston Texas
United States McFarland Clinic - Jefferson Jefferson Iowa
United States Ascension Borgess Cancer Center Kalamazoo Michigan
United States Bronson Methodist Hospital Kalamazoo Michigan
United States West Michigan Cancer Center Kalamazoo Michigan
United States Kalispell Regional Medical Center Kalispell Montana
United States Kettering Medical Center Kettering Ohio
United States Cancer Centers of Southwest Oklahoma Research Lawton Oklahoma
United States Keck Medicine of USC Koreatown Los Angeles California
United States Los Angeles General Medical Center Los Angeles California
United States USC / Norris Comprehensive Cancer Center Los Angeles California
United States University of Wisconsin Carbone Cancer Center - University Hospital Madison Wisconsin
United States McFarland Clinic - Marshalltown Marshalltown Iowa
United States Carle Physician Group-Mattoon/Charleston Mattoon Illinois
United States University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida
United States NYU Langone Hospital - Long Island Mineola New York
United States Abbott-Northwestern Hospital Minneapolis Minnesota
United States Marshfield Clinic-Minocqua Center Minocqua Wisconsin
United States Community Medical Center Missoula Montana
United States Memorial Medical Center Modesto California
United States Trinity Health Muskegon Hospital Muskegon Michigan
United States Saint Alphonsus Cancer Care Center-Nampa Nampa Idaho
United States Laura and Isaac Perlmutter Cancer Center at NYU Langone New York New York
United States Memorial Sloan Kettering Cancer Center New York New York
United States USC Norris Oncology/Hematology-Newport Beach Newport Beach California
United States Cancer and Hematology Centers of Western Michigan - Norton Shores Norton Shores Michigan
United States Cancer Care Center of O'Fallon O'Fallon Illinois
United States Saint Vincent Hospital Cancer Center at Oconto Falls Oconto Falls Wisconsin
United States University of Oklahoma Health Sciences Center Oklahoma City Oklahoma
United States Saint Alphonsus Cancer Care Center-Ontario Ontario Oregon
United States Palo Alto Medical Foundation Health Care Palo Alto California
United States Stanford Cancer Institute Palo Alto Palo Alto California
United States Thomas Jefferson University Hospital Philadelphia Pennsylvania
United States University of Pittsburgh Cancer Institute (UPCI) Pittsburgh Pennsylvania
United States UM Sylvester Comprehensive Cancer Center at Plantation Plantation Florida
United States Kootenai Clinic Cancer Services - Post Falls Post Falls Idaho
United States Corewell Health Reed City Hospital Reed City Michigan
United States VCU Massey Cancer Center at Stony Point Richmond Virginia
United States Virginia Commonwealth University/Massey Cancer Center Richmond Virginia
United States Mayo Clinic in Rochester Rochester Minnesota
United States Sutter Roseville Medical Center Roseville California
United States Sutter Medical Center Sacramento Sacramento California
United States Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center Saint Joseph Michigan
United States Missouri Baptist Medical Center Saint Louis Missouri
United States Park Nicollet Clinic - Saint Louis Park Saint Louis Park Minnesota
United States Regions Hospital Saint Paul Minnesota
United States United Hospital Saint Paul Minnesota
United States Sainte Genevieve County Memorial Hospital Sainte Genevieve Missouri
United States California Pacific Medical Center-Pacific Campus San Francisco California
United States Kootenai Clinic Cancer Services - Sandpoint Sandpoint Idaho
United States Palo Alto Medical Foundation-Santa Cruz Santa Cruz California
United States Saint Vincent Hospital Cancer Center at Sheboygan Sheboygan Wisconsin
United States Avera Cancer Institute Sioux Falls South Dakota
United States Memorial Medical Center Springfield Illinois
United States Southern Illinois University School of Medicine Springfield Illinois
United States Springfield Clinic Springfield Illinois
United States Marshfield Medical Center-River Region at Stevens Point Stevens Point Wisconsin
United States Saint Vincent Hospital Cancer Center at Sturgeon Bay Sturgeon Bay Wisconsin
United States Missouri Baptist Sullivan Hospital Sullivan Missouri
United States Palo Alto Medical Foundation-Sunnyvale Sunnyvale California
United States BJC Outpatient Center at Sunset Hills Sunset Hills Missouri
United States Munson Medical Center Traverse City Michigan
United States Upper Valley Medical Center Troy Ohio
United States Carle Cancer Center Urbana Illinois
United States Sutter Solano Medical Center/Cancer Center Vallejo California
United States Marshfield Medical Center - Weston Weston Wisconsin
United States Asplundh Cancer Pavilion Willow Grove Pennsylvania
United States University of Michigan Health - West Wyoming Michigan
United States Rush-Copley Healthcare Center Yorkville Illinois

Sponsors (1)

Lead Sponsor Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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. Number of days from registration until either local or distant recurrence or death (due to any cause), assessed up to 5 years
Secondary 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. Number of days from registration until death (due to any cause, assessed up to 5 years
Secondary 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 PFS data will be censored at the time of surgery. Number of days from registration until either local or distant recurrence or death (due to any cause), assessed up to 5 years
Secondary Progression free survival (PFS) Will be evaluated in multiple settings utilizing the KM method and, when appropriate, cox proportional hazards models. Number of days from registration until either radiographic or clinical progression or death (due to any cause), assessed up to 5 years
Secondary Overall response rate (Arm 3) Up to 5 years
Secondary Duration of response (Arm 3) A KM analysis is performed to calculate the median duration of response and 95% confidence intervals are constructed. Time from the first evidence of response until progression, assessed up to 5 years
Secondary 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. Up to 5 years
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