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
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 2
- 主要终点
- Recurrence free survival (RFS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •Single localized, primary disease meeting one of the following site-specific requirements:
- •Head/neck - any primary lesion if sinonasal; pT4a or above for nasal or oral cavity
- •Anorectal - any primary lesion
- •Conjunctiva - any primary lesion T2 or T3 stage by American Joint Committee on Cancer (AJCC)
- •Vaginal/cervical - any primary
- •Vulvar (hair bearing surface, labia majora) - AJCC cutaneous stage IIB or higher
- •Esophageal - any primary
- •Locoregionally recurrent following prior resection
- •No evidence of metastatic disease at the time of registration
- •No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for MM, unless locoregionally recurrent; if recurrent, no prior medical or radiation therapy is allowed for the latest recurrence
- •No history of the following:
- •Active known or suspected autoimmune disease
- •Human immunodeficiency virus (HIV) with CD4+ count < 300 or detectable viral load; patients with HIV, undetectable viral load, and CD4+ count >= 300 are eligible
- •Known active hepatitis B or C
- •Hepatitis B can be defined as:
- •Hepatitis B virus surface antigen (HBsAg) > 6 months
- •Serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) 20,000 IU/ml (105 copies/ml), lower values 2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B virus e antigen (HBeAg)-negative chronic hepatitis B
- •Persistent or intermittent elevation in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels
- •Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation
- •Hepatitis C can be defined as:
- •Hepatitis C antibody (AB) positive
- •Presence of hepatitis C virus (HCV) RNA
- •Known active pulmonary disease with hypoxia defined as oxygen saturation < 85% on room air
- •Not pregnant and not nursing
- •For women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- •Absolute neutrophil count (ANC) >= 1,500/mm^3
- •Platelet count >= 100,000/mm^3
- •Creatinine clearance >= 30 mL/min by Modified Diet in Renal Disease (MDRD) equation or Cockcroft-Gault
- •Total bilirubin =< 1.5 x upper limit of normal (ULN)
- •Except in case of Gilbert disease
- •AST/ALT =< 2.5 x upper limit of normal (ULN)
- •Thyroid-stimulating hormone (TSH) within normal limits (WNL)
- •Supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH if free T4 is normal and patient is clinically euthyroid, patient is eligible
- •Concomitant medications
- •No systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration (inhaled steroids for patients with underlying chronic pulmonary disease is acceptable as long as they meet other eligibility as listed above)
- •No other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study
- •STEP 2 ELIGIBILITY CRITERIA
- •Surgical resection of all gross disease
- •This assessment will be made by the local investigator based on review of the operative report, pathology results, and/or radiology reports; microscopically positive margins (e.g. R1 resection) are permitted
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排除标准
- 未提供
研究组 & 干预措施
Arm II (nivolumab, ipilimumab, surgery, nivolumab)
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.
干预措施: Ipilimumab (Biological)
Arm I (nivolumab, ipilimumab, surgery, active surveillance)
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.
干预措施: Nivolumab (Biological)
Arm I (nivolumab, ipilimumab, surgery, active surveillance)
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.
干预措施: Ipilimumab (Biological)
Arm II (nivolumab, ipilimumab, surgery, nivolumab)
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.
干预措施: Nivolumab (Biological)
Arm I (nivolumab, ipilimumab, surgery, active surveillance)
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.
干预措施: Conventional Surgery (Procedure)
Arm I (nivolumab, ipilimumab, surgery, active surveillance)
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.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (nivolumab, ipilimumab, surgery, active surveillance)
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.
干预措施: Patient Observation (Other)
Arm I (nivolumab, ipilimumab, surgery, active surveillance)
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.
干预措施: Radiation Therapy (Radiation)
Arm II (nivolumab, ipilimumab, surgery, nivolumab)
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.
干预措施: Conventional Surgery (Procedure)
Arm II (nivolumab, ipilimumab, surgery, nivolumab)
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.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (nivolumab, ipilimumab, surgery, nivolumab)
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.
干预措施: Radiation Therapy (Radiation)
结局指标
主要结局
Recurrence free survival (RFS)
时间窗: 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.
次要结局
- 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)