Clinical Trial: Nivolumab Alone or in Combination With Ipilimumab in Treating Patients With Advanced Uterine Leiomyosarcoma

Study Status: Suspended
Recruit Status: Suspended
Study Type: Interventional

Official Title: A Phase 2 Study of Nivolumab and Ipilimumab in Advanced Leiomyosarcoma of the Uterus

Brief Summary: This phase II trial studies how well nivolumab alone or in combination with ipilimumab works in treating patients with uterine cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread.

Detailed Summary:

PRIMARY OBJECTIVES:

I. To evaluate the objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of patients with advanced leiomyosarcoma of the uterus (ULMS) treated with nivolumab.

II. To evaluate the objective response rate per RECIST 1.1 of patients with advanced ULMS treated with nivolumab in combination with ipilimumab.

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of nivolumab in patients with advanced ULMS. II. To evaluate the toxicity of nivolumab in combination with ipilimumab in patients with advanced ULMS.

III. To evaluate the progression-free survival of ULMS treated with nivolumab. IV. To evaluate the progression-free survival of ULMS treated with nivolumab in combination with ipilimumab.

V. To explore the relationship between PDL1, programmed death PD1 in infiltrating lymphocytes and PD2 status in archival tumor, and pre/post treatment biopsies in a minimum of 10 patients.

TERTIARY OBJECTIVES:

I. To explore the relationship between general immune response and specific markers of immunomodulation and response to nivolumab.

II. To explore the relationship between tumor inflammatory gene signature and response to nivolumab in archival material.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

Cohort A (closed to accrual on 21-Oct-2015): Patients receive nivolumab intravenously (IV) over approximately 60 minutes once every 2 weeks for up
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

• Objective response per RECIST 1.1 among patients with advanced ULMS treated with nivolumab (Cohort A) [ Time Frame: Up to 100 days ]
  For the primary endpoint of overall response with a null hypothesis of 5% and an alternative hypothesis of 20%, 37 patients are needed in a two-stage design with 12 patients in the first stage and 25 patients in the second stage. At the first stage analysis, overall response, at least 1 response out of 12 patients will need to be observed to continue through the second stage. At the second stage, at least 4 responses out of 37 patients will need to be observed to accept the treatment. The overall power for overall response rate is 90%. The overall type I error, the chance of incorrectly reject
• Objective response per RECIST 1.1 among patients with advanced ULMS treated with nivolumab and ipilimumab (Cohort B) [ Time Frame: Up to 100 days ]
  For the primary endpoint of overall response with a null hypothesis of 5% and an alternative hypothesis of 30%, 25 patients are needed in a two-stage design with 8 patients in the first stage and 17 patients in the second stage. At the first stage analysis, overall response, at least 1 response out of 8 patients will need to be observed to continue through the second stage. At the second stage, at least 3 responses out of 25 patients will need to be observed to accept the treatment. The overall power for overall response rate is 94%. The overall type I error, the chance of incorrectly rejectin

Original Primary Outcome: Objective response per RECIST 1.1 [ Time Frame: Up to 100 days ]

Current Secondary Outcome:

• Incidence of toxicity, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Cohort A) [ Time Frame: Up to 100 days ]
  Among the first phase of 12 patients, there is at least 58% probability of observing one or more rare (7% true probability) events, and 83% probability of observing toxicities that have a true occurrence of at least 15%. Among the total cohort of 37 patients, there is at least 85% probability of observing one or more rare (5% true probability) events, and 95% probability of observing toxicities that have a true occurrence of at least 8%. With 37 treated patients, the maximum width of a 90% two-sided exact binomial confidence interval for any estimated adverse event proportion will be no wider
• Incidence of toxicity, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Cohort B) [ Time Frame: Up to 100 days ]
  Among the first phase of 8 patients, there is at least 57% probability of observing one or more rare (10% true probability) events, and 73% probability of observing one or more toxicities that have a true occurrence rate as low as 15%. Among the total cohort of 25 patients, there is at least 84% probability of observing one or more rare (7% true probability) events, and 93% probability of observing toxicities that have a true occurrence of at least 10%. With 25 treated patients, the maximum width of a 90% two-sided exact binomial confidence interval for any estimated adverse event proportion w
• PD1 in infiltrating lymphocytes [ Time Frame: Up to 100 days ]
  The relationship between PD1 in infiltrating lymphocytes and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to treatment. The power to detect the relationship of interest increases as the prevalence of the biomarker increases.
• PD2 status in archival tumor [ Time Frame: Baseline ]
  The relationship between PD2 status in archival tumor and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to treatment. The power to detect the relationship of interest increases as the prevalence of the biomarker increases.
• PDL1 status [ Time Frame: Up to 100 days ]
  The relationship between PDL1 status and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to treatment. The power to detect the relationship of interest increases as the prevalence of the biomarker increases.
• Rate of progression-free survival (Cohort A) [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed at 12 weeks ]
  A null hypothesis of 20% and an alternative hypothesis of 40% at 12 weeks will be investigated. Patients lost to follow-up or deaths within 12 weeks will be counted as failures. The overall power for overall progression-free rate at 12 weeks is 87%, using the exact binomial distribution. The operating characteristics of this design are calculated using a one-sided exact test with 10% type I error.
• Rate of progression-free survival (Cohort B) [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed at 6 months ]
  A null hypothesis of 18% and an alternative hypothesis of 40% at 6 months will be investigated. Patients lost to follow-up or deaths within 6 months will be counted as failures. The overall power for overall progression-free rate at 6 months is 85%, using the exact binomial distribution. The operating characteristics of this design are calculated using a one-sided exact test with 10% type I error.

Original Secondary Outcome:

• Incidence of toxicity, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 100 days ]
  With 37 treated patients, the maximum width of a 90% two-sided exact binomial confidence interval for any estimated adverse event proportion will be no wider than ± 14%.
• PD2 status in archival tumor [ Time Frame: Baseline ]
  The relationship between PD2 status in archival tumor and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to nivolumab. The power to detect the relationship of interest increases as the prevalence of the biomarker increases.
• PDL1 in infiltrating lymphocytes [ Time Frame: Up to 100 days ]
  The relationship between PDL1 in infiltrating lymphocytes and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to nivolumab. The power to detect the relationship of interest increases as the prevalence of the biomarker increases.
• PDL1 status [ Time Frame: Up to 100 days ]
  The relationship between PDL1 status and response to nivolumab will be explored. A Fisher's exact test will be used to assess the relationship between each biomarker and response to nivolumab. The power to detect the relationship of interest increases as the prevalence of the biomarker increases.
• Rate of progression-free survival at 6 months [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed at 6 months ]
  The overall power for overall progression-free rate at 6 months is 87%, using the exact binomial distribution.

Dates:
Date Received: April 23, 2015
Date Started: April 2015
Date Completion:
Last Updated: May 19, 2017
Last Verified: May 2017