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Using Nivolumab Alone or With Cabozantinib to Prevent Mucosal Melanoma Return After Surgery
NCT05111574 · National Cancer Institute (NCI)
In plain English
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Official title
A Randomized Phase II Trial of Adjuvant Nivolumab With or Without Cabozantinib in Patients With Resected Mucosal Melanoma
About this study
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.
Eligibility criteria
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
* Report is required for randomization of resection R0 or R1 patients
* Testing must be started in Step 0 but results can be reported after registration for resection R2 patients
* 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- American Joint Committee on Cancer (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 electrocardiograms (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
Enrollment target: 101 participants
Allocation: randomized
Masking: double
Age groups: adult, older_adult
Timeline
Starts: 2022-08-11
Estimated completion: 2026-09-01
Last updated: 2026-04-13
Interventions
Procedure: Biospecimen CollectionProcedure: Bone ScanDrug: Cabozantinib S-malateProcedure: Computed TomographyProcedure: Echocardiography TestProcedure: Magnetic Resonance ImagingBiological: NivolumabDrug: Placebo AdministrationProcedure: Positron Emission Tomography
Primary outcomes
- • Recurrence free survival (RFS) (Number of days from registration until either local or distant recurrence or death (due to any cause), assessed up to 5 years)
Sponsor
National Cancer Institute (NCI) · nih
Contacts & investigators
InvestigatorAlexander N Shoushtari · principal_investigator, Alliance for Clinical Trials in Oncology
All locations (147)
Sutter Auburn Faith HospitalRecruiting
Auburn, California, United States
Alta Bates Summit Medical Center-Herrick CampusRecruiting
Berkeley, California, United States
Palo Alto Medical Foundation-FremontRecruiting
Fremont, California, United States
Keck Medicine of USC KoreatownRecruiting
Los Angeles, California, United States
Los Angeles General Medical CenterRecruiting
Los Angeles, California, United States
USC / Norris Comprehensive Cancer CenterRecruiting
Los Angeles, California, United States
Memorial Medical CenterRecruiting
Modesto, California, United States
USC Norris Oncology/Hematology-Newport BeachRecruiting
Newport Beach, California, United States
Palo Alto Medical Foundation Health CareSuspended
Palo Alto, California, United States
Stanford Cancer Institute Palo AltoRecruiting
Palo Alto, California, United States
Sutter Roseville Medical CenterRecruiting
Roseville, California, United States
Sutter Medical Center SacramentoRecruiting
Sacramento, California, United States
California Pacific Medical Center-Pacific CampusRecruiting
San Francisco, California, United States
UCSF Medical Center-Mission BayRecruiting
San Francisco, California, United States
Mills Health CenterRecruiting
San Mateo, California, United States
Palo Alto Medical Foundation-Santa CruzRecruiting
Santa Cruz, California, United States
Sutter Pacific Medical FoundationRecruiting
Santa Rosa, California, United States
Palo Alto Medical Foundation-SunnyvaleRecruiting
Sunnyvale, California, United States
Sutter Solano Medical Center/Cancer CenterRecruiting
Vallejo, California, United States
The Melanoma and Skin Cancer InstituteActive Not Recruiting
Englewood, Colorado, United States
UM Sylvester Comprehensive Cancer Center at AventuraActive Not Recruiting
Aventura, Florida, United States
UM Sylvester Comprehensive Cancer Center at Coral GablesActive Not Recruiting
Coral Gables, Florida, United States
UM Sylvester Comprehensive Cancer Center at Deerfield BeachActive Not Recruiting
Deerfield Beach, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer CenterActive Not Recruiting
Miami, Florida, United States
UM Sylvester Comprehensive Cancer Center at PlantationActive Not Recruiting
Plantation, Florida, United States
Saint Alphonsus Cancer Care Center-BoiseSuspended
Boise, Idaho, United States
Saint Alphonsus Cancer Care Center-CaldwellSuspended
Caldwell, Idaho, United States
Kootenai Health - Coeur d'AleneRecruiting
Coeur d'Alene, Idaho, United States
Saint Alphonsus Cancer Care Center-NampaSuspended
Nampa, Idaho, United States
Kootenai Clinic Cancer Services - Post FallsRecruiting
Post Falls, Idaho, United States
Kootenai Clinic Cancer Services - SandpointRecruiting
Sandpoint, Idaho, United States
Rush-Copley Medical CenterRecruiting
Aurora, Illinois, United States
Centralia Oncology ClinicRecruiting
Centralia, Illinois, United States
Northwestern UniversityRecruiting
Chicago, Illinois, United States
Carle at The RiverfrontRecruiting
Danville, Illinois, United States
Cancer Care Specialists of Illinois - DecaturRecruiting
Decatur, Illinois, United States
Decatur Memorial HospitalRecruiting
Decatur, Illinois, United States
Northwestern Medicine Cancer Center KishwaukeeRecruiting
DeKalb, Illinois, United States
Carle Physician Group-EffinghamRecruiting
Effingham, Illinois, United States
Crossroads Cancer CenterRecruiting
Effingham, Illinois, United States
Northwestern Medicine Cancer Center DelnorRecruiting
Geneva, Illinois, United States
Northwestern Medicine Glenview Outpatient CenterRecruiting
Glenview, Illinois, United States
Northwestern Medicine Grayslake Outpatient CenterRecruiting
Grayslake, Illinois, United States
Northwestern Medicine Lake Forest HospitalRecruiting
Lake Forest, Illinois, United States
Carle Physician Group-Mattoon/CharlestonRecruiting
Mattoon, Illinois, United States
Cancer Care Center of O'FallonRecruiting
O'Fallon, Illinois, United States
Northwestern Medicine Orland ParkRecruiting
Orland Park, Illinois, United States
Southern Illinois University School of MedicineRecruiting
Springfield, Illinois, United States
Springfield ClinicRecruiting
Springfield, Illinois, United States
Springfield Memorial HospitalRecruiting
Springfield, Illinois, United States
Carle Cancer CenterRecruiting
Urbana, Illinois, United States
Northwestern Medicine Cancer Center WarrenvilleRecruiting
Warrenville, Illinois, United States
Rush-Copley Healthcare CenterRecruiting
Yorkville, Illinois, United States
Mary Greeley Medical CenterRecruiting
Ames, Iowa, United States
McFarland Clinic - AmesRecruiting
Ames, Iowa, United States
UI Health Care Mission Cancer and Blood - Ankeny ClinicRecruiting
Ankeny, Iowa, United States
McFarland Clinic - BooneSuspended
Boone, Iowa, United States
UI Health Care Mission Cancer and Blood - West Des Moines ClinicRecruiting
Clive, Iowa, United States
Mercy Medical Center - Des MoinesRecruiting
Des Moines, Iowa, United States
UI Health Care Mission Cancer and Blood - Laurel ClinicRecruiting
Des Moines, Iowa, United States
McFarland Clinic - Trinity Cancer CenterRecruiting
Fort Dodge, Iowa, United States
McFarland Clinic - JeffersonSuspended
Jefferson, Iowa, United States
McFarland Clinic - MarshalltownRecruiting
Marshalltown, Iowa, United States
UI Health Care Mission Cancer and Blood - Waukee ClinicRecruiting
Waukee, Iowa, United States
Dana-Farber Cancer InstituteRecruiting
Boston, Massachusetts, United States
Bronson Battle CreekRecruiting
Battle Creek, Michigan, United States
Corewell Health Grand Rapids Hospitals - Butterworth HospitalRecruiting
Grand Rapids, Michigan, United States
Trinity Health Grand Rapids HospitalRecruiting
Grand Rapids, Michigan, United States
Bronson Methodist HospitalRecruiting
Kalamazoo, Michigan, United States
West Michigan Cancer CenterRecruiting
Kalamazoo, Michigan, United States
Beacon Kalamazoo Cancer CenterRecruiting
Kalamazoo, Michigan, United States
Trinity Health Muskegon HospitalRecruiting
Muskegon, Michigan, United States
Corewell Health Lakeland Hospitals - Niles HospitalRecruiting
Niles, Michigan, United States
Cancer and Hematology Centers of Western Michigan - Norton ShoresRecruiting
Norton Shores, Michigan, United States
Corewell Health Reed City HospitalRecruiting
Reed City, Michigan, United States
Corewell Health Lakeland Hospitals - Marie Yeager Cancer CenterRecruiting
Saint Joseph, Michigan, United States
Munson Medical CenterRecruiting
Traverse City, Michigan, United States
University of Michigan Health - WestRecruiting
Wyoming, Michigan, United States
Minnesota Oncology - BurnsvilleRecruiting
Burnsville, Minnesota, United States
Mercy HospitalRecruiting
Coon Rapids, Minnesota, United States
Fairview Southdale HospitalRecruiting
Edina, Minnesota, United States
Abbott-Northwestern HospitalRecruiting
Minneapolis, Minnesota, United States
North Memorial Medical Health CenterRecruiting
Robbinsdale, Minnesota, United States
Mayo Clinic in RochesterRecruiting
Rochester, Minnesota, United States
Park Nicollet Clinic - Saint Louis ParkRecruiting
Saint Louis Park, Minnesota, United States
Regions HospitalRecruiting
Saint Paul, Minnesota, United States
United HospitalRecruiting
Saint Paul, Minnesota, United States
Parkland Health Center - FarmingtonRecruiting
Farmington, Missouri, United States
Sainte Genevieve County Memorial HospitalRecruiting
Sainte Genevieve, Missouri, United States
Missouri Baptist Medical CenterRecruiting
St Louis, Missouri, United States
Missouri Baptist Sullivan HospitalRecruiting
Sullivan, Missouri, United States
BJC Outpatient Center at Sunset HillsRecruiting
Sunset Hills, Missouri, United States
Community Hospital of AnacondaRecruiting
Anaconda, Montana, United States
Billings Clinic Cancer CenterRecruiting
Billings, Montana, United States
Bozeman Health Deaconess HospitalRecruiting
Bozeman, Montana, United States
Benefis Sletten Cancer InstituteRecruiting
Great Falls, Montana, United States
Logan Health Medical CenterRecruiting
Kalispell, Montana, United States
Community Medical CenterRecruiting
Missoula, Montana, United States
Memorial Sloan Kettering Basking RidgeRecruiting
Basking Ridge, New Jersey, United States
Hematology Oncology Associates of CNY at CamillusRecruiting
Camillus, New York, United States
Hematology Oncology Associates of Central New York-East SyracuseRecruiting
East Syracuse, New York, United States
Memorial Sloan Kettering WestchesterRecruiting
Harrison, New York, United States
Northwell Health/Center for Advanced MedicineRecruiting
Lake Success, New York, United States
NYU Langone Hospital - Long IslandRecruiting
Mineola, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU LangoneRecruiting
New York, New York, United States
Memorial Sloan Kettering Cancer CenterRecruiting
New York, New York, United States
Miami Valley Hospital SouthRecruiting
Centerville, Ohio, United States
Good Samaritan Hospital - CincinnatiRecruiting
Cincinnati, Ohio, United States
Case Western Reserve UniversityRecruiting
Cleveland, Ohio, United States
MetroHealth Medical CenterRecruiting
Cleveland, Ohio, United States
Miami Valley HospitalRecruiting
Dayton, Ohio, United States
Premier Blood and Cancer CenterRecruiting
Dayton, Ohio, United States
Dayton Physician LLC - EnglewoodActive Not Recruiting
Dayton, Ohio, United States
Miami Valley Hospital NorthRecruiting
Dayton, Ohio, United States
Atrium Medical Center-Middletown Regional HospitalRecruiting
Franklin, Ohio, United States
Miami Valley Cancer Care and InfusionRecruiting
Greenville, Ohio, United States
Kettering Medical CenterActive Not Recruiting
Kettering, Ohio, United States
Upper Valley Medical CenterRecruiting
Troy, Ohio, United States
Cancer Centers of Southwest Oklahoma ResearchRecruiting
Lawton, Oklahoma, United States
University of Oklahoma Health Sciences CenterRecruiting
Oklahoma City, Oklahoma, United States
Saint Alphonsus Cancer Care Center-OntarioSuspended
Ontario, Oregon, United States
Thomas Jefferson University HospitalActive Not Recruiting
Philadelphia, Pennsylvania, United States
University of Pittsburgh Cancer Institute (UPCI)Recruiting
Pittsburgh, Pennsylvania, United States
Asplundh Cancer PavilionActive Not Recruiting
Willow Grove, Pennsylvania, United States
Rapid City Regional HospitalActive Not Recruiting
Rapid City, South Dakota, United States
Avera Cancer InstituteRecruiting
Sioux Falls, South Dakota, United States
M D Anderson Cancer CenterRecruiting
Houston, Texas, United States
VCU Massey Cancer Center at Stony PointRecruiting
Richmond, Virginia, United States
VCU Massey Comprehensive Cancer CenterRecruiting
Richmond, Virginia, United States
HSHS Sacred Heart HospitalSuspended
Eau Claire, Wisconsin, United States
Marshfield Medical Center-EC Cancer CenterRecruiting
Eau Claire, Wisconsin, United States
Saint Vincent Hospital Cancer Center Green BayRecruiting
Green Bay, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Saint Mary'sRecruiting
Green Bay, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - Eastpark Medical CenterRecruiting
Madison, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - University HospitalRecruiting
Madison, Wisconsin, United States
Marshfield Medical Center-MarshfieldRecruiting
Marshfield, Wisconsin, United States
Marshfield Medical Center - MinocquaRecruiting
Minocqua, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Oconto FallsRecruiting
Oconto Falls, Wisconsin, United States
Marshfield Medical Center-Rice LakeRecruiting
Rice Lake, Wisconsin, United States
Saint Vincent Hospital Cancer Center at SheboyganRecruiting
Sheboygan, Wisconsin, United States
Marshfield Medical Center-River Region at Stevens PointRecruiting
Stevens Point, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Sturgeon BayRecruiting
Sturgeon Bay, Wisconsin, United States
Marshfield Medical Center - WestonRecruiting
Weston, Wisconsin, United States
Ottawa Hospital and Cancer Center-General CampusRecruiting
Ottawa, Ontario, Canada
Odette Cancer Centre- Sunnybrook Health Sciences CentreRecruiting
Toronto, Ontario, Canada
University Health Network-Princess Margaret HospitalRecruiting
Toronto, Ontario, Canada
Jewish General HospitalRecruiting
Montreal, Quebec, Canada