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Melanoma

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Nevus

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Genital Diseases

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Female Urogenital Diseases and Pregnancy Complications

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Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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 stool sample collection at baseline, and blood and tissue sample collection at baseline and on the trial.

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 stool sample collection at baseline, and blood and tissue sample collection at baseline and on the trial.

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 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 stool sample collection at baseline, and blood and tissue sample collection at baseline and on the trial.

Undergo blood, stool and tissue sample collection

Biospecimen Collection

Cabozantinib S-malate

Computed Tomography

Echocardiography

Magnetic Resonance Imaging

Placebo Administration

Positron Emission Tomography

Site Public Contact

Ari D. Baron

Gino K. In

Sunil A. Reddy

Leonel F. Hernandez-Aya

John M. Schallenkamp

Pratima Chalasani

Bryan A. Faller

Sunandana Chandra

Joseph J. Merchant

Elizabeth I. Buchbinder

Kathleen J. Yost

Daniel M. Anderson

Robert R. McWilliams

Alexander N. Shoushtari

Maya Dimitrova

Tarek M. Sabagh

Ankit Mangla

Howard M. Gross

Adam S. Asch

Rino Seedor

Jason J. Luke

Alexander N Shoushtari

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.

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.

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

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

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

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.

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.

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.

Will be evaluated in multiple settings utilizing the KM method and, when appropriate, cox proportional hazards models.

A KM analysis is performed to calculate the median duration of response and 95% confidence intervals are constructed.

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.

National Cancer Institute (NCI)

Digestive System Diseases

Mouth and Tooth Diseases

Esophageal Neoplasms

Carcinoma

Vaginal Neoplasms

Mouth Neoplasms

Neoplasms, Glandular and Epithelial

Disease Attributes

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Mouth Diseases

Stomatognathic Diseases

Vaginal Diseases

Esophageal Cancer

Vaginal Cancer

Oral Cancer

Antibodies

Antibodies, Monoclonal

Ipilimumab

Immunoglobulins

PART I: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Within 3-6 weeks after receiving nivolumab and ipilimumab, patients undergo surgery per standard of care. Within 84 days of last surgical resection, patients may also undergo adjuvant RT, if clinically appropriate.

PART II: Patients undergo active surveillance for 1 year.

PART I: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Within 3-6 weeks after receiving nivolumab and ipilimumab, patients undergo surgery per standard of care. Within 84 days of last surgical resection, patients may also undergo adjuvant RT, if clinically appropriate.

PART II: Patients receive nivolumab IV over 30 minutes once every 2 weeks for 4 doses. Patients then continue to receive nivolumab IV over 30 minutes once every 4 weeks for up to 11 doses in the absence of disease progression or unacceptable toxicity.

Conventional Surgery

Laboratory Biomarker Analysis

Patient Observation

Radiation Therapy

Alexander Shoushtari

This randomized phase II trial studies how well nivolumab or expectant observation following ipilimumab, nivolumab, and surgery work in treating patients with high-risk mucosal melanoma that is restricted to the site of origin without evidence of spread, has spread to a local and regional area of the body, or has come back. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread. Sometimes the mucosal melanoma may not need more treatment until it progresses. In this case, observation may be sufficient. It is not known if nivolumab or expectant observation following ipilimumab, nivolumab, and surgery may be better in treating patients with mucosal melanoma.

PRIMARY OBJECTIVES:

I. Recurrence free survival (RFS) in patients with mucosal melanoma (MM) treated with neoadjuvant ipilimumab plus nivolumab and surgery followed by adjuvant nivolumab and expectant observation.

SECONDARY OBJECTIVES:

I. Pathologic complete response with neoadjuvant ipilimumab plus nivolumab. II. Distant recurrence-free survival (DRFS) with adjuvant nivolumab and expectant observation.

III. Overall survival (OS) with adjuvant nivolumab and expectant observation. IV. Safety/toxicity as measured by maximum grade adverse event in (a) the neoadjuvant setting, (b) the adjuvant nivolumab cohort after randomization, and (c) the observation cohort after randomization.

V. Rate of delayed primary surgery.

TERTIARY OBJECTIVES:

I. Demonstrate that baseline tumors harboring a higher neoepitope burden have superior median RFS than those who have a lower neoepitope burden in the arm receiving adjuvant nivolumab.

II. Demonstrate that tumors with higher CD8+ infiltration at the tumor invasive margin at surgical resection have superior median RFS than those with lower CD8+ infiltration.

III. Demonstrate that tumors harboring a "T cell inflamed" ribonucleic acid (RNA) expression signature at surgical resection following neoadjuvant nivolumab plus ipilimumab have a superior distant RFS than those harboring a "non-T cell inflamed" signature, both in the overall group and within those who receive adjuvant nivolumab.

IV. Identify recurrent genetic alterations at baseline that are associated with higher CD8+/PD1+ infiltration at baseline and following 1 dose of neoadjuvant nivolumab plus ipilimumab.

V. Tumor response rate will be estimated based on patients whose imaging are captured and submitted during the neo-adjuvant portion of the study (imaging is not required).

OUTLINE:

PART I: Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes on day 1. Within 3-6 weeks after receiving nivolumab and ipilimumab, patients undergo surgery per standard of care. Within 84 days of last surgical resection, patients may also undergo adjuvant radiation therapy (RT), if clinically appropriate.

PART II: Within 84 days of last surgical resection, patients are randomized to 1 of 2 arms.

ARM I: Patients undergo active surveillance for 1 year.

ARM II: Patients receive nivolumab IV over 30 minutes once every 2 weeks for 4 doses. Patients then continue to receive nivolumab IV over 30 minutes once every 4 weeks for up to 11 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 90 days for 2 years, every 180 days for 3 years or until disease progression, whichever is first, and every 6 months thereafter until a maximum of 5 years following registration.

Nivolumab or Expectant Observation Following Ipilimumab, Nivolumab, and Surgery in Treating Patients With High Risk Localized, Locoregionally Advanced, or Recurrent Mucosal Melanoma

A Randomized Phase II Trial of Adjuvant Nivolumab or Expectant Observation Following Neoadjuvant Ipilimumab Plus Nivolumab and Surgical Resection of High-Risk Localized, Locoregionally Advanced, or Recurrent Mucosal Melanoma

CD8+ infiltration levels will be compared to RFS times using a cox proportional hazards model.

Neoepitope burden will be compared to RFS using a cox proportional hazards model.

The rate of pathologic complete response will be estimated using and a 95% confidence interval will be calculated using properties of the binomial distribution.

Patients will be categorized by driver mutation, including BRAF, RAS family (NRAS/KRAS/HRAS), KIT, and/or NF1 alterations. The degree of CD8+ and/or PD-L1 infiltration will be compared across various categories of driver mutation using descriptive statistics. Pending further advances in genomic understanding of these tumors, alternate categories may be constructed.

Patients will be categorized has having a "T dell inflamed" RNA expression signature versus a "non-T cell inflamed" signature. These groups will be compared to each other in terms of RFS times using a cox proportional hazards model. An additional model will be constructed with randomized arm included to determine if there is an interaction between signature and arm.

RFS of patients receiving adjuvant nivolumab will be compared to patients undergoing observation. Kaplan- Meier curves will be constructed and median RFS times will be calculated for each arm.

Will be evaluated using the Kaplan- Meier method. Median times to DRFS will be calculated for each arm and a cox proportional hazards model will be constructed to determine if there is a DRFS benefit for patients in the adjuvant Nivolumab arm (compared to observation).

Maximum grade adverse events will be summarized in each of the following settings: during the neo-adjuvant phase of the trial (i.e. from registration until a patient is randomized to adjuvant nivolumab or observation), the adjuvant nivolumab arm after randomization, he observation arm after randomization.

Will be evaluated using the Kaplan- Meier method. Median OS times will be calculated for each arm and a cox proportional hazards model will be constructed to determine if there is a DRFS benefit for patients in the adjuvant Nivolumab arm (compared to observation).

Reasons for delay will be summarized and the rate of delay will be calculated along with a 95% confidence interval using the properties of the binomial distribution.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Using Nivolumab Alone or With Cabozantinib to Prevent Mucosal Melanoma Return After Surgery	NCT05111574	Anal Melanoma Bladder Melanom... Cervical Melano... Esophageal Mela... Gallbladder Mel... Mucosal Melanom... Mucosal Melanom... Mucosal Melanom... Nasopharyngeal ... Oral Cavity Muc... Penile Mucosal ... Rectal Melanoma Recurrent Mucos... Sinonasal Mucos... Stage II Vulvar... Stage III Vulva... Stage IV Vulvar... Urethral Melano... Vaginal Melanom... Vulvar Melanoma	Biospecimen Col... Cabozantinib S-... Computed Tomogr... Echocardiograph... Magnetic Resona... Nivolumab Placebo Adminis... Positron Emissi...	18 Years -	National Cancer Institute (NCI)
Nivolumab or Expectant Observation Following Ipilimumab, Nivolumab, and Surgery in Treating Patients With High Risk Localized, Locoregionally Advanced, or Recurrent Mucosal Melanoma	NCT03220009	Cervical Carcin... Esophageal Carc... Mucosal Melanom... Mucosal Melanom... Oral Cavity Muc... Recurrent Melan... Stage II Vulvar... Stage III Vulva... Stage IIIA Vulv... Stage IIIB Vulv... Stage IIIC Vulv... Stage IV Oral C... Stage IV Vulvar... Stage IVA Oral ... Stage IVB Oral ... Stage IVC Oral ... Vaginal Carcino...	Conventional Su... Ipilimumab Laboratory Biom... Nivolumab Patient Observa... Radiation Thera...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for oral cavity mucosal melanoma