A Phase 2 Study of Nivolumab and Ipilimumab in Advanced Leiomyosarcoma of the Uterus
Overview
- Phase
- Phase 2
- Intervention
- Laboratory Biomarker Analysis
- Conditions
- Metastatic Leiomyosarcoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 20
- Locations
- 2
- Primary Endpoint
- Objective Response Per RECIST 1.1 Among Patients With Advanced ULMS Treated With Nivolumab and Ipilimumab (Cohort B)
- Status
- Completed
- Last Updated
- last year
Overview
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 Description
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, 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 to 46 doses in the absence of disease progression or unacceptable toxicity. Cohort B: Patients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 100 days.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically or cytologically confirmed advanced leiomyosarcoma of the uterus (ULMS); advanced ULMS is defined as metastatic ULMS or unresectable primary ULMS
- •Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) with conventional techniques or as \>= 10 mm (\>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
- •Patients must have received at least one prior line of chemotherapy, for ULMS (either in the adjuvant or metastatic setting)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Life expectancy of greater than 9 months
- •Absolute neutrophil count \>= 1,500/mcL
- •Platelets \>= 100,000/mcL
- •Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (except patients with Gilbert syndrome, who can have total bilirubin \< 3.0 mg/dL)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN/ =\< 5 x ULN for subjects with liver metastases
- •Serum creatinine =\< 1.5 x ULN OR creatinine clearance (CrCl) \>= 50 mL/min (if using the Cockcroft-Gault formula)
Exclusion Criteria
- •Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (AEs) due to agents administered more than 3 weeks earlier; patients who have had prior pelvic radiation may be at increased risk for bowel perforation, and therefore may not have residual inflammatory disease of the bowel or residual bowel toxicity based on baseline imaging and clinical assessment; palliative (limited-field) radiation therapy is permitted, if all of the following criteria are met:
- •Repeat imaging demonstrates no new sites of bone metastases
- •The lesion being considered for palliative radiation is not a target lesion
- •Bowel toxicity is not expected from the target field due to increased risk of perforation
- •Patients who are receiving any other investigational agents
- •Patients are excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-ligand 2 (L2), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
- •Active brain metastasis or leptomeningeal disease; patients with known brain metastases are allowed if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 12 weeks after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab
- •History of severe hypersensitivity reaction to any monoclonal antibody
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Arms & Interventions
Cohort A (nivolumab - closed to accrual on 21-Oct-2015)
Patients receive nivolumab IV over approximately 60 minutes once every 2 weeks for up to 46 doses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Cohort A (nivolumab - closed to accrual on 21-Oct-2015)
Patients receive nivolumab IV over approximately 60 minutes once every 2 weeks for up to 46 doses in the absence of disease progression or unacceptable toxicity.
Intervention: Nivolumab
Cohort B (nivolumab and Ipilimumab)
Patients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Ipilimumab
Cohort B (nivolumab and Ipilimumab)
Patients receive nivolumab IV over approximately 60 minutes followed by a saline flush and ipilimumab IV over 90 minutes. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Outcomes
Primary Outcomes
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 rejecting the null hypothesis is 9%. The probability of stopping at the first stage under the null hypothesis is 66%. The operating characteristics of this design are calculated using the exact binomial distribution.
Objective Response Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Among Patients With Advanced Leiomyosarcoma of the Uterus (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 rejecting the null hypothesis is 9%. The probability of stopping at the first stage under the null hypothesis is 54%. The operating characteristics of this design are calculated using the exact binomial distribution.
Secondary Outcomes
- Rate of Progression-free Survival (Cohort A)(Time from start of treatment to time of progression or death, whichever occurs first, assessed at 12 weeks)
- Incidence of Toxicity, Graded Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Version 5.0 Beginning April 1, 2018) (Cohort B)(Up to 4 cycles)
- Rate of Progression-free Survival (Cohort B)(Time from start of treatment to time of progression or death, whichever occurs first, assessed at 6 months)
- PDL1 Status(Up to 100 days)
- Incidence of Toxicity, Graded Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Version 5.0 Beginning April 1, 2018) (Cohort A)(Up to 4 cycles)