Using Nivolumab Alone or With Cabozantinib to Prevent Mucosal Melanoma Return After Surgery
Purpose
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.
Conditions
- Anal Melanoma
- Bladder Melanoma
- Cervical Melanoma
- Esophageal Melanoma
- Gallbladder Melanoma
- Head and Neck Mucosal Melanoma
- Mucosal Melanoma
- Nasopharyngeal Mucosal Melanoma
- Oral Cavity Mucosal Melanoma
- Penile Mucosal Melanoma
- Rectal Melanoma
- Recurrent Mucosal Melanoma
- Sinonasal Mucosal Melanoma
- Urethral Melanoma
- Urinary System Mucosal Melanoma
- Vaginal Melanoma
- Vulvar Melanoma
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Sex
- All
- Accepts Healthy Volunteers
- No
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
- Phase
- Phase 2
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Arm 1 (nivolumab, cabozantinib) |
Patients receive nivolumab IV over 30 minutes on day 1 and cabozantinib PO QD of each cycle. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO during screening and as clinically indicated throughout the trial. Patients may undergo CT, MRI, or 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. |
|
|
Active Comparator Arm 2 (nivolumab, placebo) |
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. Patients undergo ECHO during screening and as clinically indicated throughout the trial. Patients may undergo CT, MRI, or 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. |
|
|
Experimental Arm 3 (nivolumab, cabozantinib) |
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 ECHO during screening and as clinically indicated throughout the trial. Patients may undergo CT, MRI, or 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. |
|
Recruiting Locations
Auburn, California 95602
Berkeley, California 94704
Fremont, California 94538
Los Angeles, California 90020
Site Public Contact
213-388-0908
Los Angeles, California 90033
Los Angeles, California 90033
Site Public Contact
323-865-0451
Modesto, California 95355
Newport Beach, California 92663
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323-865-0451
Palo Alto, California 94304
Roseville, California 95661
Sacramento, California 95816
San Francisco, California 94115
San Francisco, California 94158
San Mateo, California 94401
Santa Cruz, California 95065
Santa Rosa, California 95403
Sunnyvale, California 94086
Vallejo, California 94589
Coeur d'Alene, Idaho 83814
Post Falls, Idaho 83854
Sandpoint, Idaho 83864
Aurora, Illinois 60504
Centralia, Illinois 62801
Chicago, Illinois 60611
Danville, Illinois 61832
Decatur, Illinois 62526
Decatur, Illinois 62526
DeKalb, Illinois 60115
Effingham, Illinois 62401
Effingham, Illinois 62401
Geneva, Illinois 60134
Glenview, Illinois 60026
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312-695-1102
Grayslake, Illinois 60030
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312-695-1102
Lake Forest, Illinois 60045
Mattoon, Illinois 61938
O'Fallon, Illinois 62269
Orland Park, Illinois 60462
Springfield, Illinois 62702
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Springfield, Illinois 62702
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800-444-7541
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Ames, Iowa 50010
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Ames, Iowa 50010
Ankeny, Iowa 50023
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Clive, Iowa 50325
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Des Moines, Iowa 50314
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Waukee, Iowa 50263
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Boston, Massachusetts 02215
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877-442-3324
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Kalamazoo, Michigan 49007
Kalamazoo, Michigan 49009
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Burnsville, Minnesota 55337
Coon Rapids, Minnesota 55433
Edina, Minnesota 55435
Minneapolis, Minnesota 55407
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Saint Paul, Minnesota 55101
Saint Paul, Minnesota 55102
Farmington, Missouri 63640
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Sainte Genevieve, Missouri 63670
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St Louis, Missouri 63131
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Anaconda, Montana 59711
Billings, Montana 59101
Bozeman, Montana 59715
Great Falls, Montana 59405
Kalispell, Montana 59901
Missoula, Montana 59804
Basking Ridge, New Jersey 07920
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Camillus, New York 13031
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East Syracuse, New York 13057
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Harrison, New York 10604
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Lake Success, New York 11042
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Mineola, New York 11501
New York, New York 10016
New York, New York 10065
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Centerville, Ohio 45459
Cincinnati, Ohio 45220
Cleveland, Ohio 44106
Cleveland, Ohio 44109
Dayton, Ohio 45409
Dayton, Ohio 45409
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Dayton, Ohio 45415
Franklin, Ohio 45005-1066
Greenville, Ohio 45331
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Troy, Ohio 45373
Lawton, Oklahoma 73505
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Oklahoma City, Oklahoma 73104
Pittsburgh, Pennsylvania 15232
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Sioux Falls, South Dakota 57105
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Richmond, Virginia 23235
Richmond, Virginia 23298
Eau Claire, Wisconsin 54701
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Green Bay, Wisconsin 54303
Madison, Wisconsin 53718
Madison, Wisconsin 53792
Marshfield, Wisconsin 54449
Minocqua, Wisconsin 54548
Oconto Falls, Wisconsin 54154
Rice Lake, Wisconsin 54868
Sheboygan, Wisconsin 53081
Stevens Point, Wisconsin 54482
Sturgeon Bay, Wisconsin 54235-1495
Weston, Wisconsin 54476
More Details
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
Study Contact
Detailed 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 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.