Phase I Study of Ipilimumab, Nivolumab, and the Combination in Patients With Newly Diagnosed Glioblastoma
Overview
- Phase
- Phase 1
- Intervention
- Ipilimumab
- Conditions
- Gliosarcoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 32
- Locations
- 11
- Primary Endpoint
- Immune-related dose-limiting toxicities for the single-agent treatment with nivolumab
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This phase I trial studies the safety and best dose of ipilimumab, nivolumab, or both in combination with temozolomide in treating patients with newly diagnosed glioblastoma or gliosarcoma. Monoclonal antibodies, such as ipilimumab and nivolumab, may block tumor growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known which combination is a better treatment for glioblastoma or gliosarcoma.
Detailed Description
PRIMARY OBJECTIVES: I. Determine the maximum safe dose of single-agent treatment with ipilimumab, nivolumab and the combination when given with temozolomide during maintenance treatment for newly diagnosed glioblastoma. SECONDARY OBJECTIVES: I. Collect and record the side effect profiles for single-agent treatment with ipilimumab, nivolumab, and the combination when given with temozolomide during the maintenance phase for newly diagnosed glioblastoma. II. Perform pilot studies of immune cells within tumor samples, e.g. phenotyping tumor infiltrating lymphocytes (TILs) by interrogating tumor tissues from diagnostic tumor blocks. III. Report the number of patients alive at 1 and 2 years after the start of single-agent treatment with ipilimumab, nivolumab, and the combination when given with temozolomide during the maintenance phase for newly diagnosed glioblastoma. OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM I: Within 5 weeks after completion of chemoradiation, patients receive temozolomide orally (PO) on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab intravenously (IV) over 90 minutes once every 4 weeks for 4 courses and then beginning 3 months after course 4 once every 3 months for 4 courses in the absence unacceptable toxicity. ARM II: Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 60 minutes once every 2 weeks for 16 weeks and then once every 2 weeks for 48 weeks in the absence unacceptable toxicity. ARM III: Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab IV over 90 minutes once every 4 weeks for 4 courses and nivolumab IV over 60 minutes once every 2 weeks for 64 weeks in the absence unacceptable toxicity. After completion of study treatment, patients are followed up at 1 month, and then every 3 months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histopathologically proven diagnosis of glioblastoma or gliosarcoma prior to registration by pathology report
- •The tumor must be unifocal, confined to the supratentorial compartment and have undergone a gross total or near gross total resection; this will increase the likelihood that the patient will not require corticosteroids or develop pseudoprogression
- •The formalin-fixed, paraffin-embedded (FFPE) tumor tissue block must be available to be sent for retrospective central pathology review after registration
- •Patients must be registered within 35 days of completion of chemoradiation
- •History/physical examination within 7 days prior to registration
- •Patients must have undergone an evaluation by magnetic resonance imaging (MRI) within 35 days of completing radiation and must also be within 7 days prior to registration; MRI must NOT demonstrate tumor progression, but patients with imaging changes consistent with pseudo-progression, stable neurologic function and not needing corticosteroid treatment are eligible
- •Karnofsky performance status \>= 70 within 7 days prior to registration
- •Absolute neutrophil count \>= 1,500 cells/mm\^3
- •Platelet count \>= 100,000 cells/mm\^3
- •Hemoglobin (Hgb) \> 9 g/dL (can be achieved with transfusion)
Exclusion Criteria
- •Definitive clinical or radiologic evidence of progressive disease
- •Prior placement of Gliadel wafer or local brachytherapy
- •Use of an immunotherapy such as a vaccine therapy, dendritic cell vaccine or intracavitary or convectional enhanced delivery of therapy
- •Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years
- •Unstable angina within the last 6 months prior to registration
- •Transmural myocardial infarction within the last 6 months prior to registration
- •Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of \>= 2 mm using the analysis of an electrocardiogram (EKG) performed within 7 days prior to registration
- •New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to registration
- •History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months prior to registration
- •Serious and inadequately controlled cardiac arrhythmia
Arms & Interventions
Arm I (temozolomide and ipilimumab)
Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab IV over 90 minutes once every 4 weeks for 4 courses and then beginning 3 months after course 4 once every 3 months for 4 courses in the absence unacceptable toxicity.
Intervention: Ipilimumab
Arm I (temozolomide and ipilimumab)
Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab IV over 90 minutes once every 4 weeks for 4 courses and then beginning 3 months after course 4 once every 3 months for 4 courses in the absence unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Arm I (temozolomide and ipilimumab)
Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab IV over 90 minutes once every 4 weeks for 4 courses and then beginning 3 months after course 4 once every 3 months for 4 courses in the absence unacceptable toxicity.
Intervention: Temozolomide
Arm II (temozolomide and nivolumab)
Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 60 minutes once every 2 weeks for 16 weeks and then once every 2 weeks for 48 weeks in the absence unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Arm II (temozolomide and nivolumab)
Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 60 minutes once every 2 weeks for 16 weeks and then once every 2 weeks for 48 weeks in the absence unacceptable toxicity.
Intervention: Nivolumab
Arm II (temozolomide and nivolumab)
Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 60 minutes once every 2 weeks for 16 weeks and then once every 2 weeks for 48 weeks in the absence unacceptable toxicity.
Intervention: Temozolomide
Arm III (temozolomide, nivolumab, ipilimumab)
Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab IV over 90 minutes once every 4 weeks for 4 courses and nivolumab IV over 60 minutes once every 2 weeks for 64 weeks in the absence unacceptable toxicity.
Intervention: Ipilimumab
Arm III (temozolomide, nivolumab, ipilimumab)
Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab IV over 90 minutes once every 4 weeks for 4 courses and nivolumab IV over 60 minutes once every 2 weeks for 64 weeks in the absence unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Arm III (temozolomide, nivolumab, ipilimumab)
Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab IV over 90 minutes once every 4 weeks for 4 courses and nivolumab IV over 60 minutes once every 2 weeks for 64 weeks in the absence unacceptable toxicity.
Intervention: Nivolumab
Arm III (temozolomide, nivolumab, ipilimumab)
Within 5 weeks after completion of chemoradiation, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab IV over 90 minutes once every 4 weeks for 4 courses and nivolumab IV over 60 minutes once every 2 weeks for 64 weeks in the absence unacceptable toxicity.
Intervention: Temozolomide
Outcomes
Primary Outcomes
Immune-related dose-limiting toxicities for the single-agent treatment with nivolumab
Time Frame: Up to 8 weeks
The frequency and severity of toxicities will be reported.
Immune-related dose-limiting toxicities for the combination of ipilimumab and nivolumab when given with temozolomide
Time Frame: Up to 8 weeks
The frequency and severity of toxicities will be reported.
Immune-related dose-limiting toxicities for the single-agent treatment with ipilimumab
Time Frame: Up to 8 weeks
The frequency and severity of toxicities will be reported.
Secondary Outcomes
- Number of patients who are alive(2 years after the start of immunotherapy treatment)
- Incidence of adverse events, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0(Up to 1 month post-treatment)
- Biomarker analysis of immune cells within tumor samples using standard immunohistochemistry(Up to 1 month post-treatment)