A Phase II Randomized Study of Nivolumab (NSC-748726) With Ipilimumab (NSC-732442) or Ipilimumab Alone in Advanced Melanoma Patients Refractory to an Anti-PD1 or Anti-PD-L1 Agent
Overview
- Phase
- Phase 2
- Intervention
- Ipilimumab
- Conditions
- Clinical Stage III Cutaneous Melanoma AJCC v8
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 94
- Locations
- 637
- Primary Endpoint
- Progression Free Survival
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This phase II trial studies how well ipilimumab with or without nivolumab work in treating patients with melanoma that is stage IV or stage III and cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Detailed Description
PRIMARY OBJECTIVE: I. To compare progression free survival (PFS) of patients with advanced melanoma refractory to an anti-PD-1 or anti-PD-L1 agent, treated with combination therapy ipilimumab plus nivolumab versus ipilimumab alone. SECONDARY OBJECTIVES: I. To estimate difference in T-cell infiltrate between on-study biopsy samples of patients who respond to combination therapy (including confirmed and unconfirmed, complete and partial response per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1, in each treatment arm). II. To evaluate the objective response rate (ORR), defined as confirmed complete or partial response per RECIST 1.1, in each treatment arm. III. To evaluate the overall survival (OS) of patients in each treatment arm. IV. To evaluate the toxicity profile of patients in each treatment arm. TRANSLATIONAL OBJECTIVES: I. To assess the marginal prognostic value of baseline T-cell density, T-cell receptor (TCR) clonality, mutational load, messenger ribonucleic acid (mRNA) and other phenotypical expression levels, and circulating tumor deoxyribonucleic acid (DNA) in terms of response. II. To assess the joint prognostic value of T-cell density, TCR clonality, and mutational load, mRNA and other phenotypical expression levels, and circulating tumor DNA in terms of response. III. To identify T-cell poor subtype(s) that are associated with response. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for 2 years and then annually for 1 year.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have pathologically confirmed melanoma that is either stage IV or unresectable stage III; patients may have primaries of cutaneous, mucosal or unknown origin; patients with uveal (ocular) primary are not eligible
- •Patients must have measurable disease per RECIST 1.1; all measurable lesions must be assessed by physical examination, computed tomography (CT) scans or magnetic resonance imaging (MRI) within 28 days prior to registration; if the only measurable disease is cutaneous or subcutaneous, lesions must be at least 10 mm in greatest dimension and able to be serially recorded using calipers and photographs; tests used to assess non-measurable disease must have been performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form
- •Patients with central nervous system (CNS) metastases must have all lesions adequately treated with stereotactic radiation therapy, craniotomy, Gamma Knife (registered trademark) therapy, or whole brain radiotherapy, with no subsequent evidence of CNS progression; patients must not have required steroids for at least 14 days prior to registration; patients with a history of central nervous system metastases must have MRI of the brain within 42 days prior to registration
- •Patients must have had prior treatment with anti-PD1 or anti-PD-L1 agents and had documented disease progression per the treating physician either while on these agents or after stopping therapy with these agents without intervening therapy; patients who received adjuvant therapy for previously resected disease with PD-1 or PD-L1 agents may also be eligible if disease recurrence occurred while still receiving the PD-1 or PD-L1 therapy and no intervening therapy was received; patients must have discontinued anti-PD-1 or anti-PD-L1 therapy at least 21 days prior to registration
- •Patients must be \>= 18 years of age
- •Patients must have Zubrod performance status of =\< 2
- •Patients must have complete history and physical examination within 28 days prior to registration
- •Absolute neutrophil count (ANC) \>= 1,500/mcL (within 28 days prior to registration)
- •Hemoglobin \>= 8 g/dL (within 28 days prior to registration)
- •Platelets \>= 100,000/mcL (within 28 days prior to registration)
Exclusion Criteria
- •Patients must not have achieved a partial or complete response to the anti-PD-1 or anti-PD-L1 agents prior to progression per the treating physician
- •Patients must not have had any systemic therapy, including anti-PD-1 or anti-PD-L1 agents, within 21 days prior to registration
- •Patients must not have had prior radiation therapy within 14 days prior to registration
- •Patients must not have had:
- •Prior treatment with ipilimumab or other CTLA-4 antagonists
- •Systemic therapy between progression on the anti-PD-1 or anti-PD-L1 agents and registration
- •Note: Systemic therapy (including BRAF-targeting agents) prior to anti-PD-1 or anti-PD-L1 therapy is allowed
- •Patients must not be planning to require any additional form of systemic anti-tumor therapy while on protocol treatment
- •Patients must not have known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection prior to registration
- •Patients must not have an active infection requiring systemic therapy at time of registration
Arms & Interventions
Arm I (ipilimumab)
Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention: Ipilimumab
Arm II (nivolumab, ipilimumab)
Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Ipilimumab
Arm II (nivolumab, ipilimumab)
Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Nivolumab
Outcomes
Primary Outcomes
Progression Free Survival
Time Frame: From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years
Progression-free survival (PFS) is defined as the time from date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Participants last known to be alive without report of progression are censored at date of last contact. Progression is defined as either 20% increase in the sum of diameters of target measurable lesions, unequivocal progression of non-measurable disease in the opinion of the treating physician, appearance of any new lesion, or death due to disease without prior documentation of progression and without symptomatic deterioration. Symptomatic deterioration is defined as global deterioration of health status requiring discontinuation of treatment without objective evidence of progression.
Secondary Outcomes
- Overall Objective Response Rate(Up to 3 years)
- Change in CD8+ Expression(Up to 3 years)
- Overall Survival(Up to 3 years)
- Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs(Duration of treatment and follow-up until death or 3 years post registration)