Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Sarcoma That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Randomized Phase II Study of Nivolumab With or Without Ipilimumab in Patients With Metastatic or Unresectable Sarcoma

Conditions
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Locally Advanced Bone Sarcoma, Locally Advanced Dedifferentiated Liposarcoma, Locally Advanced Gastrointestinal Stromal Tumor, Locally Advanced Soft Tissue Sarcoma, Metastatic Bone Sarcoma, Metastatic Liposarcoma, Metastatic Soft Tissue Sarcoma, Metastatic Undifferentiated Pleomorphic Sarcoma, Metastatic Unresectable Sarcoma, Pleomorphic Liposarcoma, Stage III Bone Sarcoma AJCC v7, Stage III Soft Tissue Sarcoma AJCC v7, Stage IV Bone Sarcoma AJCC v7, Stage IV Soft Tissue Sarcoma AJCC v7, Stage IVA Bone Sarcoma AJCC v7, Stage IVB Bone Sarcoma AJCC v7, Unresectable Bone Sarcoma, Unresectable Dedifferentiated Liposarcoma, Unresectable Liposarcoma, Unresectable Malignant Gastrointestinal Stromal Tumor, Unresectable Soft Tissue Sarcoma

Intervention / Treatment
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* Biological: Ipilimumab
* Other: Laboratory Biomarker Analysis
* Biological: Nivolumab
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRE-REGISTRATION ELIGIBILITY CRITERIA: Patients must have a formalin-fixed, paraffin-embedded (FFPE) tumor block OR 1 representative hematoxylin and eosin (H&E) and 20 unstained sarcoma tissue slides available for submission to central pathology review; this review is mandatory prior to registration to confirm eligibility REGISTRATION ELIGIBILITY CRITERIA: Patients must have histologically confirmed bone or soft tissue sarcoma by central pathology review Patients must have histologically confirmed liposarcoma (LPS) (only dedifferentiated and pleomorphic; well differentiated not eligible), undifferentiated pleomorphic sarcoma (UPS)/malignant fibrous histiocytoma (MFH), or gastrointestinal stromal tumor (GIST) Measurable disease Locally advanced/unresectable or metastatic disease >= 1 prior systemic therapy for sarcoma, including adjuvant systemic therapy No prior therapy with ipilimumab or nivolumab, or any agent targeting programmed cell death 1 (PD-1), PD-L1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) No treatment with biologic therapy, immunotherapy, chemotherapy, investigational agent for malignancy, or radiation =< 28 days before study registration; no treatment with nitrosourea or mitomycin =< 42 days before study registration; for GIST, tyrosine kinase inhibitor can be continued for up to 3 days prior to initiation of study treatment Patients should have resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE, version 4.0, grade 1 or less No history of the following: Active known or suspected autoimmune disease Patients with human immunodeficiency virus (HIV) are eligible if the lymphocytes > 350 cluster of differentiation (CD)4+ cells and no detectable viral load Symptomatic, untreated, or uncontrolled brain metastases present Active autoimmune colitis Autoimmune panhypopituitarism Autoimmune adrenal insufficiency Known active hepatitis B or C Hepatitis B can be defined as: Hepatitis B 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 e antigen (HBeAg)-negative chronic hepatitis B Persistent or intermittent elevation in alanine aminotransferase (ALT)/alanine 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) ribonucleic acid (RNA) Known active pulmonary disease with hypoxia defined as: Oxygen saturation < 85% on room air or Oxygen saturation < 88% despite supplemental oxygen No systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of registration Not pregnant and not nursing because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects; therefore for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance > 45 mL/min using the lean body mass formula only (Modified Cockcroft and Gault; Shargel and Yu 1985) Total bilirubin =< 1.5 x upper limit of normal (ULN) in absence of Gilbert disease (total bilirubin =< 3 x ULN with Gilbert); also, if hyperbilirubinemia is clearly attributed to liver metastases total bilirubin =< 3 x ULN is permitted AST/ALT =< 3 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 RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): Measurable disease RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): Locally advanced/unresectable or metastatic disease RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): Patient MUST have had progressive disease (radiographic or clinical) while on arm 1 single agent nivolumab while registered to A091401 RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): Patients removed from any immunotherapy for reasons other than progressive disease, including arm 1 single agent nivolumab of A091401, are NOT eligible for re-registration RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): Patients must have completed a minimum of 10 weeks of single agent nivolumab on arm 1 of A091401 to be eligible for re-registration RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): Patients must have completed study drug on arm 1 of A091401 (i.e., last dose of nivolumab) =< 12 months of re-registration to crossover dual agent therapy RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): No treatment with immunotherapy =< 21 days before re-registration; no treatment with biologic therapy, chemotherapy, investigational agent for malignancy, or radiation =< 28 days before re-registration; no treatment with nitrosourea or mitomycin =< 42 days before re-registration RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): Patients should have resolution of any toxic effects of prior therapy (except fatigue and alopecia) to NCI CTCAE, version 4.0, grade 1 or less, including immune toxicity RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): No systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of re-registration RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): Not pregnant and not nursing because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects; therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to re-registration is required RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): ECOG performance status 0 or 1 RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): ANC >= 1,500/mm^3 RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): Platelet count >= 100,000/mm^3 RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): Creatinine =< 1.5 ULN OR calc. creatinine clearance > 45 mL/min (using lean body mass formula only [Modified Cockcroft and Gault; Shargel and Yu 1985]) RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): Total bilirubin =< 1.5 x ULN in absence of Gilbert disease (total bilirubin =< 3 x ULN with Gilbert); if hyperbilirubinemia is clearly attributed to liver metastases, total bilirubin =< 3 x ULN is permitted RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): AST/ALT =< 3 x ULN RE-REGISTRATION ELIGIBILITY CRITERIA (FOR PATIENTS WHO CROSSOVER FROM ARM 1 NIVOLUMAB ALONE TO DUAL AGENT NIVOLUMAB AND IPILIMUMAB UPON PROGRESSION): TSH 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (nivolumab)<br>Patients receive nivolumab 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. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm II (nivolumab, ipilimumab)<br>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. | Biological: Ipilimumab<br>* Given IV<br>* Other names: Yervoy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Up to 44 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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 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). | 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). | 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). | 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 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 from randomization to death from any cause, assessed up to 3 years |