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
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Cervical Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Locations
- 1
- Primary Endpoint
- Recurrence free survival (RFS)
- Status
- Withdrawn
- Last Updated
- 7 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •STEP 1 ELIGIBILITY CRITERIA
- •Documentation of disease:
- •Histologic documentation: histologically proven mucosal melanoma by local pathology
- •Tumor tissue: tumor tissue from the primary site of disease must be available for PD-L1 testing (stratification factor)
- •Disease status
- •Tumors must have NOT been completely resected, or must be locoregionally recurrent if previously resected; tumor must be deemed potentially resectable by local surgeon
- •MM arising from the head/neck, genitourinary, or gastrointestinal tract
- •Disease meets any 1 of 4 characteristics:
- •Regional lymph node (LN) involvement; OR
- •Multifocal/satellite primary disease; OR
Exclusion Criteria
- Not provided
Outcomes
Primary Outcomes
Recurrence free survival (RFS)
Time Frame: From randomization to either adjuvant nivolumab or observation until evidence of disease recurrence, assessed up to 5 years
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.
Secondary Outcomes
- Distant recurrence-free survival (DRFS)(From randomization to either adjuvant nivolumab or observation until a distant recurrence is observed, assessed up to 5 years)
- Incidence of adverse events evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0(Up to 5 years)
- Overall survival (OS)(From randomization to either adjuvant nivolumab or observation until death due to any cause; assessed up to 5 years)
- Rate of delayed surgery(Up to 6 weeks after registration)