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Nevus

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Genital Diseases

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Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antibodies

Antibodies, Monoclonal

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

National Cancer Institute (NCI)

Spots Global Cancer Trial Database for stage iv vulvar cancer ajcc v7