Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Sarcoma That Cannot Be Removed by Surgery
Condition: 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
MeSH terms: Sarcoma; Gastrointestinal Stromal Tumors; Liposarcoma; Osteosarcoma; Histiocytoma, Malignant Fibrous
Intervention: Ipilimumab; Laboratory Biomarker Analysis; Nivolumab; Quality-of-Life Assessment
Intervention description: Given IV; Correlative studies; Given IV; Ancillary studies
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 164.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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