This randomized phase II trial studies how well nivolumab with or without ipilimumab works in treating patients with sarcoma that has spread from the primary site to other parts of the body (metastatic) or cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, 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 nivolumab works better with or without ipilimumab in treating patients with metastatic or unresectable sarcoma.
PRIMARY OBJECTIVE: I. To evaluate the confirmed response rate of single agent nivolumab and dual agent nivolumab plus ipilimumab in patients with locally advanced/unresectable or metastatic soft tissue sarcoma. SECONDARY OBJECTIVES: I. To evaluate adverse event rates (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\]4.0) within each treatment arm. II. To evaluate duration of response, clinical benefit rate, time to progression, progression-free survival, and overall survival within each treatment arm. CORRELATIVE SCIENCE OBJECTIVES: I. To potentially detect an early signal of confirmed response rate within a histologically defined patient cohort. II. To assess the potential association between programmed cell death 1 ligand 1 (PD-L1) expression (by immunohistochemistry \[IHC\]) and clinical outcome, within each treatment. III. To evaluate associations between selected biomarker measured in serial peripheral blood and with clinical efficacy, within each treatment. IV. To evaluate the association between selected biomarker measured in tumor tissue with clinical efficacy, within each treatment. V. To evaluate the association between baseline tumor mutational burden and neoantigen production with clinical efficacy within each treatment. EXPLORATORY PHASE II OBJECTIVES (CROSSOVER TREATMENT): I. To evaluate secondary endpoints within patients crossing over to dual agent nivolumab plus ipilimumab after experiencing progressive disease while receiving single agent nivolumab. II. To evaluate correlative science objectives endpoints within patients crossing over to dual agent nivolumab plus ipilimumab after experiencing progressive disease while receiving single agent nivolumab. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress after 10 weeks on single agent nivolumab may elect to cross over to Arm II. ARM II: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress by imaging during the first 12 weeks of therapy may continue treatment, at the discretion of the patient and treating investigator. After completion of study treatment, patients are followed up at 4 weeks and then every 6 months 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
164
Anchorage Associates in Radiation Medicine
Anchorage, Alaska, United States
Anchorage Radiation Therapy Center
Anchorage, Alaska, United States
Alaska Breast Care and Surgery LLC
Anchorage, Alaska, United States
Alaska Oncology and Hematology LLC
Anchorage, Alaska, United States
Alaska Regional Hospital
Anchorage, Alaska, United States
Number of Participants Who Achieved a Confirmed Response
The number of participants who achieved a confirmed response is defined as the number of patients having a best objective tumor status of complete response (CR) or partial response (PR) lasting at least 4 weeks as determined using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).
Time frame: Up to 44 months
Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Event Regardless of Attribution
The number of participants who experienced at least one grade 3 or higher adverse event (AE) regardless of attribution. AEs are graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 beginning April 1, 2018).
Time frame: Up to 4 weeks after completion of study treatment
Duration of Response
Duration of response is defined for all evaluable patients who have achieved a confirmed response as the date at which the patient's objective status is first noted to be a CR or PR to the earliest date progression (PD) is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites, PD: Any new lesion or increase by \>= 50% of previously involved sites from nadir).
Time frame: Time from first response to progression, assessed up to 3 years
6-Month Clinical Benefit Rate [Initial Cohort]
The 6-month clinical benefit rate is defined as the percentage of participants with a response or stable disease (CR, PR, or SD) at 6 months. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites, PD: Any new lesion or increase by \>= 50% of previously involved sites from nadir, SD: Not CR/PR or PD).
Time frame: At 6 months
6-Month Clinical Benefit Rate [Expansion LPS and UPS/MFH Cohorts Only]
The 6-month clinical benefit rate is defined as the percentage of participants with a response or stable disease (CR, PR, or SD) at 6 months. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites, PD: Any new lesion or increase by \>= 50% of previously involved sites from nadir, SD: Not CR/PR or PD).
Time frame: At 6 months
6-Month Clinical Benefit Rate [Expansion GIST Cohort Only]
The 6-month clinical benefit rate is defined as the percentage of participants with a response or stable disease (CR, PR, or SD) at 6 months. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites, PD: Any new lesion or increase by \>= 50% of previously involved sites from nadir, SD: Not CR/PR or PD).
Time frame: At 6 months
Progression-free Survival (PFS)
Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression (PD) is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. (PD: Any new lesion or increase by \>= 50% of previously involved sites from nadir).
Time frame: Time from randomization to first of either disease progression or death from any cause, assessed up to 3 years
Overall Survival (OS)
Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
Time frame: Time from randomization to death from any cause, assessed up to 3 years
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