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Trial record 1 of 1 for:    A091401
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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 : Active, not recruiting
First Posted : July 17, 2015
Last Update Posted : February 7, 2020
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 (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.

Condition or disease Intervention/treatment Phase
Dedifferentiated Liposarcoma Gastrointestinal Stromal Tumor Locally Advanced Bone Sarcoma 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 Liposarcoma Unresectable Soft Tissue Sarcoma Biological: Ipilimumab Other: Laboratory Biomarker Analysis Biological: Nivolumab Other: Quality-of-Life Assessment Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 164 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
Actual Primary Completion Date : April 1, 2019


Arm Intervention/treatment
Experimental: Arm I (nivolumab)
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
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. 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
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. Number of participants who achieved a confirmed response [ Time Frame: Up to 44 months ]
    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).


Secondary Outcome Measures :
  1. Number of participants who experienced at least one grade 3 or higher adverse event deemed at least possibly related to study treatment [ Time Frame: Up to 4 weeks after completion of study treatment ]
    The number of participants who experienced at least one grade 3 or higher adverse event (AE) deemed at least possibly related to study treatment. AEs are graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 beginning April 1, 2018).

  2. Duration of response [ Time Frame: Time from first response to progression, assessed up to 3 years ]
    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).

  3. 6-Month clinical benefit rate [ Time Frame: At 6 months ]
    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).

  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 ]
    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).

  5. Overall survival (OS) [ Time Frame: Time from randomization to death from any cause, assessed up to 3 years ]
    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.


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 (e.g., 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 (e.g., 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. 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. 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 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

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


Locations
Show Show 651 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Sandra P D'Angelo Alliance for Clinical Trials in Oncology
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02500797    
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: February 7, 2020
Last Verified: February 2020
Additional relevant MeSH terms:
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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
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents