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

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ClinicalTrials.gov Identifier: NCT02500797
Recruitment Status : Suspended (Scheduled Interim Monitoring)
First Posted : July 17, 2015
Last Update Posted : December 10, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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 or cannot be removed by surgery. Monoclonal antibodies, such as nivolumab and ipilimumab, may block tumor growth in different ways by targeting certain cells. It is not yet known whether nivolumab works better with or without ipilimumab in treating patients with metastatic or unresectable sarcoma.

Condition or disease Intervention/treatment Phase
Dedifferentiated Liposarcoma Gastrointestinal Stromal Tumor Metastatic Liposarcoma Metastatic Undifferentiated Pleomorphic 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 Liposarcoma Biological: Ipilimumab Other: Laboratory Biomarker Analysis Biological: Nivolumab Other: Quality-of-Life Assessment Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 195 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase II Study of Nivolumab With or Without Ipilimumab in Patients With Metastatic or Unresectable Sarcoma
Actual Study Start Date : July 30, 2015
Estimated Primary Completion Date : January 30, 2022
Estimated Study Completion Date : January 30, 2022


Arm Intervention/treatment
Experimental: Arm I (nivolumab)
Patients receive nivolumab IV over 30 minutes once every 2 weeks. Courses 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
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Experimental: Arm II (nivolumab, ipilimumab)
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. Courses 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
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment




Primary Outcome Measures :
  1. Confirmed response rate estimated as the number of patients having a best objective tumor status of complete response (CR) or partial response (PR) lasting at least 4 weeks, divided by the number of evaluable patients [ Time Frame: Up to 6.5 years ]
    The confirmed response rate will be estimated as the number of patients having a best objective tumor status of CR or PR lasting at least 4 weeks, divided by the number of evaluable patients.


Secondary Outcome Measures :
  1. Adverse event (AE) rates 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 ]
    Categorical data analysis will be used to summarize adverse event rates in each treatment arm and as a maximum severity during treatment for each patients and AE classification.

  2. Duration of response [ Time Frame: Time from first response to progression, assessed up to 3 years ]
    Evaluated using Kaplan-Meier methodology.

  3. Clinical benefit rate [ Time Frame: Up to 3 years ]
    Evaluated by counting the number of patients with a response or stable disease (PR, CR, stable disease) and dividing by the total number of evaluable patients.

  4. Progression-free survival (PFS) [ Time Frame: Time from randomization to first of either disease progression or death from any cause, assessed up to 3 years ]
    Evaluated using Kaplan-Meier methodology.

  5. Overall survival (OS) [ Time Frame: Time from randomization to death from any cause, assessed up to 3 years ]
    Evaluated using Kaplan-Meier methodology.


Other Outcome Measures:
  1. PD-L1 expression assessed using immunohistochemistry (IHC) [ Time Frame: Up to 3 years ]
    Categorical data analysis and logistic regression will be used to evaluate the associations between PD-L1 expression (by IHC) and clinical outcome (eg, response, clinical benefit, progression-free survival, and survival). Kaplan-Meier methodology and Cox proportional hazards models will be used to evaluate time to event endpoints.

  2. Change in selected biomarkers measured in serial peripheral blood [ Time Frame: Baseline to up to 3 years ]
    Summary statistics will be used to for describing changes across time. The time course of biomarker outcomes will be investigated graphically, by summary plots or individual patient plots. If there is suggestion of meaningful trend, methods such as linear mixed models may be used to characterize the pattern of change over time. Kaplan-Meier methodology and Cox proportional hazards models will be used to evaluate time to event endpoints.

  3. Selected biomarkers measured in tumor tissue [ Time Frame: Up to week 6 ]
    Categorical data analysis and logistic regression will be used to correlated biomarkers with and clinical outcome (eg, response, clinical benefit, time to progression, progression free survival, and survival) within each study component. Kaplan-Meier methodology and Cox proportional hazards models will be used to evaluate time to event endpoints.

  4. Confirmed response in patients who crossover from single agent nivolumab to dual agent treatment following progression [ Time Frame: Up to 3 years ]
    Confirmed response will be evaluated in patients who crossover from single agent nivolumab to dual agent treatment following progression.

  5. Duration of response in patients who crossover from single agent nivolumab to dual agent treatment following progression [ Time Frame: Time from first response to progression, assessed up to 3 years ]
    Evaluated using Kaplan-Meier methodology.

  6. Progression-free survival (PFS) in patients who crossover from single agent nivolumab to dual agent treatment following progression [ Time Frame: Time from randomization to first of either disease progression or death from any cause, assessed up to 3 years ]
    Evaluated using Kaplan-Meier methodology.

  7. Overall survival (OS) in patients who crossover from single agent nivolumab to dual agent treatment following progression [ Time Frame: Time from randomization to death from any cause, assessed up to 3 years ]
    Evaluated using Kaplan-Meier methodology.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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; 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
  • 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)
  • Re-registration: measurable disease
  • Re-registration: locally advanced/unresectable or metastatic disease
  • Patient MUST have had progressive disease (radiographic or clinical) while on arm 1 single agent nivolumab while registered to A091401
  • 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
  • Patients must have completed a minimum of 10 weeks of single agent nivolumab on arm 1 of A091401 to be eligible for re-registration
  • 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
  • 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
  • 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
  • No systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of re-registration
  • Not pregnant and not nursing; therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to re-registration is required
  • ECOG performance status 0 or 1
  • Re-registration: ANC >= 1,500/mm^3
  • Re-registration: platelet count >= 100,000/mm^3
  • Re-registration: creatinine =< 1.5 ULN OR calc. creatinine clearance > 45 mL/min (using lean body mass formula only)
  • Re-registration: 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: AST/ALT =< 3 x ULN
  • Re-registration: 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02500797


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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Sandra D'Angelo Alliance for Clinical Trials in Oncology

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02500797     History of Changes
Other Study ID Numbers: NCI-2015-00260
NCI-2015-00260 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
A091401
A091401 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A091401 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
First Posted: July 17, 2015    Key Record Dates
Last Update Posted: December 10, 2018
Last Verified: September 2018

Additional relevant MeSH terms:
Sarcoma
Gastrointestinal Stromal Tumors
Liposarcoma
Osteosarcoma
Histiocytoma, Malignant Fibrous
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Connective Tissue
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Neoplasms, Adipose Tissue
Neoplasms, Bone Tissue
Histiocytoma
Neoplasms, Fibrous Tissue
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs