Using Nivolumab Alone or With Cabozantinib to Prevent Mucosal Melanoma Return After Surgery

Mucosal Melanoma Clinical Trial

Official title:

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

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
• 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
• 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.

Related Conditions & MeSH terms

• Melanoma
• Mucosal Melanoma
• Mucosal Melanoma of the Head and Neck
• Oral Cavity Mucosal Melanoma
• Recurrent Mucosal Melanoma
• Stage II Vulvar Cancer AJCC v8
• Stage III Vulvar Cancer AJCC v8
• Stage IV Vulvar Cancer AJCC v8
• Vulvar Neoplasms

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 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 Blood and Cancer Center	Dayton	Ohio
United States	Dayton Physician LLC-Miami Valley Hospital North	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	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	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	Benefis Healthcare- 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	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 Winthrop Hospital	Mineola	New York
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Community Medical Hospital	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 Medical 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 Cancer Clinic	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	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	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