A Phase I/II Study of Nivolumab Plus or Minus Ipilimumab in Combination With Multi-Fraction Stereotactic Radiosurgery for Recurrent High-Grade Radiation-Relapsed Meningioma
Overview
- Phase
- Phase 1
- Intervention
- Stereotactic Radiosurgery
- Conditions
- Grade 2 Meningioma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 38
- Locations
- 31
- Primary Endpoint
- Maximum tolerated combination of radiosurgery and nivolumab plus or minus ipilimumab (Phase I)
- Status
- Active, Not Recruiting
- Last Updated
- 19 days ago
Overview
Brief Summary
This phase I/II trial studies the side effects and best dose of nivolumab when given together with multi-fraction stereotactic radiosurgery and to see how well they work with or without ipilimumab in treating patients with grade II-III meningioma that has come back (recurrent). 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. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Giving nivolumab and multi-fraction stereotactic radiosurgery with or without ipilimumab may work better in treating patients with grade II-III meningioma.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the maximum tolerated combination and safety profile of multi-fraction radiosurgery with concurrent nivolumab plus or minus ipilimumab for recurrent radiation-relapsed high-grade meningioma. (Phase I) II. To evaluate the objective response rate (ORR), either complete response or partial response as assessed on magnetic resonance imaging (MRI) per the modified Macdonald Criteria, of multi-fraction radiosurgery with concurrent nivolumab plus or minus ipilimumab for recurrent radiation-relapsed high-grade meningioma. (Phase II) SECONDARY OBJECTIVE: I. To evaluate duration of overall response, progression-free survival (PFS) and overall survival (OS) of recurrent radiation-relapsed high-grade meningioma patients treated with the combination of multi-fraction radiosurgery and nivolumab plus or minus ipilimumab. CORRELATIVE OBJECTIVES: I. To analyze the immunophenotype changes of peripheral T-cells during the treatment with multi-fraction radiosurgery in combination with nivolumab plus or minus ipilimumab. II. To perform molecular profiling assays on pretreatment/baseline archival tumor, including, but not limited to, whole exome sequencing (WES) and messenger ribonucleic acid (RNA) sequencing (RNAseq), in order to IIa. Identify potential predictive and prognostic biomarkers (such as neoantigen signature or mutation burden) beyond any genomic alteration by which treatment may be assigned. IIb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based assessment platforms. III. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome. IV. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA analysis), and nucleic acids obtained from patients at the National Cancer Institute Early-Phase and Experimental Clinical Trials Biospecimen Bank (EET Biobank). OUTLINE: This is a phase I, dose-escalation study of nivolumab followed by a phase II study. Patients are randomized to 1 of 2 cohorts. COHORT A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. COHORT B: Patients receive nivolumab IV over 30 minutes every 2 weeks for 12 doses (6 months) and then every 4 weeks for additional 6 months. Patients also receive ipilimumab IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 6 weeks for 4 doses in the absence of disease progression or unacceptable toxicity. Patients undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo echocardiography (ECHO) as clinically indicated. After completion of study treatment, patients are followed up for 100 days.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically confirmed World Health Organization (WHO) grade II-III meningioma which has relapsed after prior radiation therapy with radiologically progressive or recurrent disease
- •Patients must have measurable disease, defined as at least 1 lesion that can be accurately measured in at least one dimension as \>= 1 cm on brain magnetic resonance imaging (MRI) but with the maximum dimension =\< 5 cm OR gross tumor volume \< 20 cm\^
- •All the relapsed disease would need to be eligible to be treated with reirradiation
- •Patients must have at least one prior surgery with available archival formalin-fixed paraffin-embedded (FFPE) tumor blocks of the initial or recurrent meningioma. If there are multiple tumor blocks from multiple surgeries, the most recent tumor block (and ideally of the relapsed tumor after initial radiation therapy) should be submitted. If a tumor block is not available, an alternative of 20-30 unstained slides may be submitted instead. Annotation regarding whether the tumor block is before or after initial radiation therapy should be provided
- •Prior initial radiation therapy may include external beam radiation or radiosurgery, or combination of both. However, the total dose of prior radiation exposure to the site of recurrent tumor (for consideration of re-irradiation) cannot be more than 70 Gy. The duration since the previous radiation exposure to the site of reirradiation need to be at least 6 months
- •Age \>= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
- •Leukocytes \>= 3,000/mcL
- •Absolute neutrophil count \>= 1,500/mcL
- •Platelets \>= 100,000/mcL
Exclusion Criteria
- •Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
- •Patients who have had radiation therapy (to the site of reirradiation) within 6 months prior to entering the study
- •Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1); however, alopecia, sensory neuropathy =\< grade 2, or other =\< grade 2 not constituting a safety risk based on the investigator's judgment are acceptable
- •Patients who are receiving any other investigational agents
- •Patients who have previous treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab and/or ipilimumab
- •History of severe hypersensitivity reaction to any monoclonal antibody
- •Current use of immunosuppressive medication (EXCEPT for the following: Intranasal, inhaled, topical steroids, or local steroid injection \[e.g. intra-articular injection\]; systemic corticosteroids at doses =\< 4 mg/day of dexamethasone or equivalent; steroids as premedication for hypersensitivity reactions \[e.g. computed tomography (CT) scan premedication\])
- •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. However, patients with human immunodeficiency virus (HIV) on stable therapy with minimal viral loads and patients with hepatitis B and hepatitis C who have received treatment with minimal viral loads will be eligible
- •Pregnant women are excluded from this study because radiation therapy is teratogenic and that the effects of nivolumab and/or ipilimumab on the developing human fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab and/or ipilimumab, breastfeeding should be discontinued if the mother is treated with nivolumab and/or ipilimumab
Arms & Interventions
Cohort B (nivolumab, ipilimumab, radiosurgery)
Patients receive nivolumab IV over 30 minutes every 2 weeks for 12 doses (6 months) and then every 4 weeks for additional 6 months. Patients also receive ipilimumab IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 6 weeks for 4 doses in the absence of disease progression or unacceptable toxicity. Patients undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo ECHO as clinically indicated.
Intervention: Stereotactic Radiosurgery
Cohort B (nivolumab, ipilimumab, radiosurgery)
Patients receive nivolumab IV over 30 minutes every 2 weeks for 12 doses (6 months) and then every 4 weeks for additional 6 months. Patients also receive ipilimumab IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 6 weeks for 4 doses in the absence of disease progression or unacceptable toxicity. Patients undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo ECHO as clinically indicated.
Intervention: Magnetic Resonance Imaging
Cohort B (nivolumab, ipilimumab, radiosurgery)
Patients receive nivolumab IV over 30 minutes every 2 weeks for 12 doses (6 months) and then every 4 weeks for additional 6 months. Patients also receive ipilimumab IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 6 weeks for 4 doses in the absence of disease progression or unacceptable toxicity. Patients undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo ECHO as clinically indicated.
Intervention: Ipilimumab
Cohort A (nivolumab, radiosurgery)
Patients receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo ECHO as clinically indicated.
Intervention: Biospecimen Collection
Cohort A (nivolumab, radiosurgery)
Patients receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo ECHO as clinically indicated.
Intervention: Echocardiography Test
Cohort A (nivolumab, radiosurgery)
Patients receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo ECHO as clinically indicated.
Intervention: Magnetic Resonance Imaging
Cohort A (nivolumab, radiosurgery)
Patients receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo ECHO as clinically indicated.
Intervention: Nivolumab
Cohort B (nivolumab, ipilimumab, radiosurgery)
Patients receive nivolumab IV over 30 minutes every 2 weeks for 12 doses (6 months) and then every 4 weeks for additional 6 months. Patients also receive ipilimumab IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 6 weeks for 4 doses in the absence of disease progression or unacceptable toxicity. Patients undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo ECHO as clinically indicated.
Intervention: Nivolumab
Cohort A (nivolumab, radiosurgery)
Patients receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo ECHO as clinically indicated.
Intervention: Stereotactic Radiosurgery
Cohort B (nivolumab, ipilimumab, radiosurgery)
Patients receive nivolumab IV over 30 minutes every 2 weeks for 12 doses (6 months) and then every 4 weeks for additional 6 months. Patients also receive ipilimumab IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 6 weeks for 4 doses in the absence of disease progression or unacceptable toxicity. Patients undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo ECHO as clinically indicated.
Intervention: Biospecimen Collection
Cohort B (nivolumab, ipilimumab, radiosurgery)
Patients receive nivolumab IV over 30 minutes every 2 weeks for 12 doses (6 months) and then every 4 weeks for additional 6 months. Patients also receive ipilimumab IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 6 weeks for 4 doses in the absence of disease progression or unacceptable toxicity. Patients undergo multi-fraction stereotactic radiosurgery on days 1, 3, and 5. Patients undergo brain MRI and blood sample collection throughout the study. Patients may also undergo ECHO as clinically indicated.
Intervention: Echocardiography Test
Outcomes
Primary Outcomes
Maximum tolerated combination of radiosurgery and nivolumab plus or minus ipilimumab (Phase I)
Time Frame: Up to 100 days
Incidence of adverse event profile (Phase I)
Time Frame: Up to 100 days
Will be evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The number and percentage of subjects experiencing each type of adverse event will be tabulated by severity, and relationship to treatment. If appropriate, confidence intervals will be used to characterize the precision of the estimate. A complete listing of adverse events will also be tabulated, and will provide details including severity, relationship to treatment, onset, duration, and outcome. Laboratory data measured on a continuous scale will be characterized by summary statistics (mean and standard deviation).
Objective radiological response (Phase II)
Time Frame: Up to 100 days
Will include either complete response or partial response as assessed on magnetic resonance imaging per the modified Macdonald Criteria. 80% confidence intervals will be calculated.
Maximum tolerated combination of radiosurgery and nivolumab plus or minus ipilimumab (Phase I)
Time Frame: Up to 100 days
Incidence of adverse event profile (Phase I)
Time Frame: Up to 100 days
Will be evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The number and percentage of subjects experiencing each type of adverse event will be tabulated by severity, and relationship to treatment. If appropriate, confidence intervals will be used to characterize the precision of the estimate. A complete listing of adverse events will also be tabulated, and will provide details including severity, relationship to treatment, onset, duration, and outcome. Laboratory data measured on a continuous scale will be characterized by summary statistics (mean and standard deviation).
Objective response rate (Phase II)
Time Frame: From the start of treatment through at least two years of follow-up
Objective radiological response (Phase II)
Time Frame: Up to 100 days
Will include either complete response or partial response as assessed on magnetic resonance imaging per the modified Macdonald Criteria. 80% confidence intervals will be calculated.
Secondary Outcomes
- Progression-free survival(From the start of treatment to 6 months and 2 years)
- Overall survival(From the start of treatment through at least two years of follow-up)
- Duration of overall response(From the start of treatment through at least two years of follow-up)