Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Rare Diseases

Recurrence

Melanoma

Melanoma, Cutaneous Malignant

Skin Neoplasms

Disease Attributes

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Pembrolizumab

Antibodies

Antibodies, Monoclonal

Ipilimumab

Immunoglobulins

Interferons

Interferon-alpha

Interferon alpha-2

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Antiviral Agents

Immunologic Factors

INDUCTION THERAPY: Patients receive high-dose recombinant interferon alfa-2B intravenously (IV) over 20 minutes on days 1-5. Treatment repeats weekly for 4 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for a total of 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive high-dose recombinant interferon alfa-2B subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 12 weeks for 3 years in the absence of disease progression or unacceptable toxicity.

Patients undergo CT scan, PET scan, MRI and blood sample collection throughout the study.

Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan, MRI and blood sample collection throughout the study.

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Positron Emission Tomography

Quality-of-Life Assessment

Recombinant Interferon Alfa-2b

Sapna Patel

This randomized phase III trial studies how well pembrolizumab works compared with the current standard of care, physician/patient choice of either high-dose recombinant interferon alfa-2B or ipilimumab, in treating patients with stage III-IV melanoma that has been removed by surgery but is likely to come back or spread. High-dose recombinant interferon alfa-2B may help shrink or slow the growth of melanoma. Immunotherapy with monoclonal antibodies, such as ipilimumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether pembrolizumab is more effective than the current standard of care in treating patients with melanoma.

PRIMARY OBJECTIVES:

I. To compare overall survival (OS) of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon recombinant interferon alfa-2b (alfa-2b) or ipilimumab versus MK-3475 (pembrolizumab).

II. Among patients who are PD-L1 positive, to compare OS of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab versus MK-3475 (pembrolizumab).

III. To compare relapse-free survival (RFS) of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab to MK-3475 (pembrolizumab).

SECONDARY OBJECTIVES:

I. To estimate OS and RFS for patients who are PD-L1 negative or PD-L1 indeterminate in this population.

II. To compare OS and RFS of patients between the two arms within PD-L1 positive and negative subgroups and to look at the interaction between PD-L1 (positive versus negative) and treatment arm.

III. To assess the safety and tolerability of the regimens.

ADDITIONAL OBJECTIVES:

I. To bank tissue and whole blood in anticipation of future correlative studies in this patient population.

II. To evaluate PD-L1 expression through immunohistochemistry assay. III. To evaluate the effect of treatment-related side effects that may have an impact on the health-related domains of quality of life (QOL) using the Functional Assessment of Cancer Therapy (FACT)-Biological Response Modifiers (BRM), European Quality of Life Five Dimension Three Level Scale (EQ-5D-3L), and Functional Assessment of Chronic Illness Therapy Diarrhea (FACIT-D) between patients treated with physician/patient choice of either high-dose interferon alfa-2b or ipilimumab and MK-3475 (pembrolizumab).

IV. Pharmacokinetic (PK) and anti-drug antibody (ADA) testing will be performed on all patients receiving MK-3475 (pembrolizumab).

TRANSLATIONAL OBJECTIVES RELATED TO T-CELL RECEPTOR BETA CHAIN SEQUENCING:

I. To evaluate the association between TCR beta variable gene (TRBV) haplotype and grade 3-4 immune-related adverse events (irAEs) among stage III melanoma patients treated with adjuvant ipilimumab or pembrolizumab.

II. To describe the TRBV haplotype distribution among this cohort of patients studied.

TRANSLATIONAL MEDICINAL OBJECTIVE RELATED TO ASSOCIATION OF CIRCULATING TUMOR DNA (ctDNA) WITH RELAPSE-FREE SURVIVAL IN HIGH-RISK, RESECTED MELANOMA PATIENTS.

I. To evaluate associations between pretreatment ctDNA (present versus absent) and relapse within 2 years of randomization in a case-control analysis across treatment arms.

II. To evaluate associations between pretreatment ctDNA (present versus absent) and relapse within 2 years of randomization in a case-control analysis across treatment arms.

III. To evaluate associations between pretreatment ctDNA and relapse within 2 years of randomization in a case-control analysis within each treatment arm (after treatment arm data are unblinded to investigators).

IV. To evaluate associations between "early-on treatment" ctDNA levels and relapse within 2 years of randomization.

V. To describe ctDNA levels at end of therapy and time of relapse.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I:

INDUCTION THERAPY: Patients receive high-dose recombinant interferon alfa-2B intravenously (IV) over 20 minutes on days 1-5. Treatment repeats weekly for 4 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for a total of 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive high-dose recombinant interferon alfa-2B subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 12 weeks for 3 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo computed tomography (CT) scan, positron emission tomography (PET) scan, magnetic resonance imaging (MRI) and blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days, 6 and 12 weeks, every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.

Physician/Patient Choice of Either High-Dose Recombinant Interferon Alfa-2B or Ipilimumab, Versus Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

A Phase III Randomized Trial Comparing Physician/Patient Choice of Either High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in Patients With High Risk Resected Melanoma

From date of randomization to date of death due to any cause. Patients last known to be alive were censored at date of last contact. OS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population.

From date of randomization to date of first documentation of disease recurrence (relapse) or death due to any cause. On study disease assessments by imaging were to be performed every 12 weeks until 2 years from randomization, and then every 6 months until 5 years from randomization. Patients last known to be alive and relapse-free were censored at date of last contact. RFS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population.

From date of randomization to date of death due to any cause. Patients last known to be alive were censored at date of last contact. OS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population among those patients with PD-L1 positive tumors.

PD-L1 expression was evaluated by immunohistochemistry (IHC) assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5 (with higher numbers reflecting a higher level of PD-L1 expression); a score of 2 or higher (staining on greater than 1% of cells) was considered to indicate PD-L1 positivity.

From date of randomization to date of first documentation of disease recurrence (relapse) or death due to any cause. On study disease assessments by imaging were to be performed every 12 weeks until 2 years from randomization, and then every 6 months until 5 years from randomization. Patients last known to be alive and relapse-free were censored at date of last contact. RFS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population among those patients with PD-L1 positive tumors.

PD-L1 expression was evaluated by immunohistochemistry (IHC) assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5 (with higher numbers reflecting a higher level of PD-L1 expression); a score of 2 or higher (staining on greater than 1% of cells) was considered to indicate PD-L1 positivity.

From date of randomization to date of death due to any cause. Patients last known to be alive will be censored at date of last contact. OS estimates will be calculated using the method of Kaplan-Meier. Cox regression models will be used to estimate hazard ratios and calculate confidence intervals to compare treatment arms in the PD-L1 negative subgroup. In addition Cox regression models for OS will be used to estimate interaction terms between PD-L1 status and treatment arm.

PD-L1 expression was evaluated by immunohistochemistry (IHC) assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5 (with higher numbers reflecting a higher level of PD-L1 expression); a score of 0-1 (staining on ≤ 1% of cells) was considered to indicate PD-L1 negative status.

From date of randomization to date of first documentation of disease recurrence (relapse) or death due to any cause. On study disease assessments by imaging were to be performed every 12 weeks until 2 years from randomization, and then every 6 months until 5 years from randomization. Patients last known to be alive and relapse-free were censored at date of last contact. RFS estimates will be calculated using the method of Kaplan-Meier. Cox regression models will be used to estimate hazard ratios and calculate confidence intervals to compare treatment arms in the PD-L1 negative subgroup. In addition Cox regression models for RFS will be used to estimate interaction terms between PD-L1 status and treatment arm.

PD-L1 expression was evaluated by IHC assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5; a score of 2 or higher was considered to indicate PD-L1 positivity. a score of 0-1 was considered to indicate PD-L1 negative status.

The proportion of patients experiencing a particular adverse event (AE), as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE version 5.0 beginning April 1, 2018), for each treatment regimen using the number of patients who received at least one dose of that regimen as the denominator. AEs are AE proportions will be estimated along with a 95% confidence intervals.

National Cancer Institute (NCI)

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Vulvar Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Vulvar Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Vulvar Cancer

Nivolumab

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

Cabozantinib S-malate

Echocardiography

Placebo Administration

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Physician/Patient Choice of Either High-Dose Recombinant Interferon Alfa-2B or Ipilimumab, Versus Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery	NCT02506153	Clinical Stage ... Clinical Stage ... Metastatic Cuta... Metastatic Muco... Metastatic Non-... Non-Cutaneous M... Recurrent Cutan... Recurrent Mucos... Recurrent Non-C...	Biospecimen Col... Computed Tomogr... Ipilimumab Magnetic Resona... Pembrolizumab Positron Emissi... Quality-of-Life... Recombinant Int...	18 Years -	National Cancer Institute (NCI)
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)

Spots Global Cancer Trial Database for recurrent mucosal melanoma