Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Recurrence

Meningioma

Disease Attributes

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Neoplasms, Vascular Tissue

Meningeal Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antibodies

Antibodies, Monoclonal

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

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.

Biospecimen Collection

Echocardiography

Magnetic Resonance Imaging

Undergo multi-fraction stereotactic radiosurgery

Stereotactic Radiosurgery

Site Public Contact

Aaron B. Simon

Douglas E. Ney

Gregory A. Azzam

Sani H. Kizilbash

David Akhavan

Lawrence R. Kleinberg

Jiayi Huang

Aya Haggiagi

Simon Khagi

Megan Mantica

Joe S. Mendez

David Schiff

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.

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) 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 magnetic resonance imaging (MRI) and blood sample collection throughout the study. Patients may also undergo echocardiogram (ECHO) as clinically indicated.

After completion of study treatment, patients are followed up for 100 days.

Nivolumab and Multi-fraction Stereotactic Radiosurgery With or Without Ipilimumab in Treating Patients With Recurrent Grade II-III Meningioma

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

Will be explored by comparing the differences in theses biomarkers between responders versus non-responders using t-test or Mann-Whitney rank-sum test as appropriate. Permutation test will be used to determine whether the observed difference is larger than might be expected by chance, while the null distribution of test statistics will be generated using 10,000 permutation samples where the response status will be randomly re-shuffled. The observed test statistics will be compared to the null distributions. For each outcome, the permuted p-value will be the fraction of permuted samples that resulted in a small statistic than the original sample.

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).

Will include either complete response or partial response as assessed on magnetic resonance imaging (MRI) per the modified Macdonald Criteria. 80% confidence intervals will be calculated.

80% confidence intervals will be assessed using Kaplan-Meier product limit methods.

Each T-cell subset will be quantified as a percentage of the overall T-cell population by normalizing to CD3+ cells. Linear mixed model for repeated measurement data will be used to assess the change over time as well as the differences between subgroups (e.g., responders vs. non-responders) for immunogenicity and other biomarkers (i.e., frequency of CD8+Ki67+PD1+ T-cells, etc.). Receiver operating characteristic (ROC) curves will also be used to assess the overall predictive ability and to explore the optimal cut-off points for baseline biomarkers to differentiate responders versus non-responders.

National Cancer Institute (NCI)

Lutetium Lu 177 dotatate

Radiopharmaceuticals

Patients receive gallium Ga 68-DOTATATE IV and undergo a PET/MRI or PET/CT before cycles 1 and 4. Patients then receive lutetium Lu 177 dotatate IV over 30-40 minutes. Treatment repeats every 8 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI on study and during follow-up, as well as blood sample collection and possible SEPCT/CT dosimetry on study.

Gallium Ga 68-DOTATATE

Lutetium Lu 177 Dotatate

Positron Emission Tomography

Questionnaire Administration

Computed Tomography

Single Photon Emission Computed Tomography

Clinical Trials Referral Office

Kenneth W. Merrell, M.D.

This phase II trial studies how well lutathera works in treating patients with meningioma that cannot be treated with surgery (inoperable) and is growing, spreading, or getting worse (progressive) after external beam radiation therapy. Lutathera is a radioactive drug administered in the vein that is designed to target and kill tumor cells. The goal of this study is to determine whether this drug is safe and effective in treating meningiomas that progress after radiation treatment. WHO Grade I and Cohort WHO II/III cohorts will be evaluated.

PRIMARY OBJECTIVES:

I. To estimate the efficacy of lutetium Lu 177 dotatate (LUTATHERA) treatment in patients with recurrent grade 1 meningioma as measured by 6-month progression-free survival (PFS) rate.

II. To estimate the efficacy of LUTATHERA treatment in patients with recurrent grade 2 or 3 meningioma as measured by 6-month PFS rate.

SECONDARY OBJECTIVES:

I. To determine the overall survival (by grade cohort) of patients with recurrent meningioma during or after treatment of LUTATHERA.

II. To determine the progression-free survival (by grade cohort) of patients with recurrent meningioma during or after treatment of LUTATHERA.

III. To determine the toxicity of LUTATHERA treatment in patients with recurrent meningioma.

CORRELATIVE RESEARCH OBJECTIVES:

I. To assess the impact of treatment on the patient's quality of life (QOL) using the Promise-10, Brief Fatigue Inventory (BFI), and Mayo Patient Survey National Comprehensive Cancer Network (NCCN)-Functional Assessment of Cancer Therapy (FACT) Brain Symptom Index Questionnaire-24 (FBrSI-24) (version 2) instruments.

II. To compare the response assessment between standard of care brain magnetic resonance imaging (MRI) and gallium Ga 68-DOTATATE (68Ga-DOTATATE) positron emission tomography (PET) imaging.

III. To determine the best objective response (Macdonald criteria) of patients with recurrent meningioma during or after treatment of LUTATHERA.

IV. To determine the duration of local control with death as a competing risk (by grade cohort) of patients with recurrent meningioma during or after treatment of LUTATHERA.

V. To perform a quantitative dosimetric analysis of radiation dose delivered with lutathera:

Va. To determine intratherapeutic dosimetry for the target meningioma; Vb. To correlate treatment response of lutathera with target dose received; Vc. To determine intratherapeutic dosimetry for kidneys and other abdominal organs.

OUTLINE:

Patients receive gallium Ga 68-DOTATATE intravenously (IV) and undergo a PET/MRI or PET/computed tomography (CT) before cycles 1 and 4. Patients then receive lutetium Lu 177 dotatate IV over 30-40 minutes. Treatment repeats every 8 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI on study and during follow-up, as well as blood sample collection and possible single photon emission computed tomography (SPECT)/CT dosimetry on study.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for up to 5 years.

Lutathera for the Treatment of Inoperable, Progressive Meningioma After External Beam Radiation Therapy

A Prospective, Phase II Study of Lutetium Lu 177 Dotatate (LUTATHERA®) in Patients With Inoperable, Progressive Meningioma After External Beam Radiation Therapy

QOL will be measured using the standard survey series for this population of patients, and QOL trajectory over time will be examined. The survey series includes Promise-10, Brief Fatigue Inventory, and Mayo Patient Survey National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy Brain Symptom Index Questionnaire-24 (version 2). The main QOL impact will be measured with differences from baseline to 6, 12 and 24 months in patient reported outcomes via the symptom scales from the above surveys. All other QOL analyses will be exploratory and may include change from baseline to all time points using t-test and generalized linear models to test for changes at each time point and non-zero slopes, respectfully. No formal comparisons will be made among the cohorts.

Will be defined as a best objective response of stable disease, partial or complete response to treatment as determined by Macdonald Criteria. The proportion of patients who have achieved local control will be summarized by cohort and 95% confidence intervals calculated according to the methods described in Clopper-Pearson. No formal comparison will be made among the cohorts.

The distribution of local control and survival without progression as a competing risk model will be constructed using Kaplan-Meier estimates. No formal comparisons will be made amongst the cohorts.

Will be determined by Macdonald Criteria. The proportion of patients in each response category will be summarized by cohort and 95% confidence intervals calculated according to the methods described in Clopper-Pearson. No formal comparison will be made among the cohorts.

The response rate determined by volumetric analysis will be estimated for each cohort with proportion of patients who achieve complete response/partial response deemed by volumetric analysis. The 90% two-sided confidence intervals will be calculated according to approach of Clopper-Pearson. No formal comparison will be made among the cohorts.

Will be defined as the number of evaluable patients not having progressive disease or death within six months of the first day of treatment divided by the total number of evaluable patients. The proportion of successes in each cohort will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper-Pearson. There will be no formal comparison of rates among the two different grade cohorts of patients.

The distribution of survival time for both cohorts will be estimated using the method of Kaplan-Meier. No formal comparison will be made among the cohorts.

The distribution of time to progression will be estimated using the method of Kaplan-Meier (Kaplan et. al 1958). No formal comparison will be made among the cohorts.

Will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nivolumab and Multi-fraction Stereotactic Radiosurgery With or Without Ipilimumab in Treating Patients With Recurrent Grade II-III Meningioma	NCT03604978	Grade 2 Meningi... Grade 3 Meningi... Recurrent Menin...	Biospecimen Col... Echocardiograph... Ipilimumab Magnetic Resona... Nivolumab Stereotactic Ra...	18 Years -	National Cancer Institute (NCI)
Lutathera for the Treatment of Inoperable, Progressive Meningioma After External Beam Radiation Therapy	NCT04082520	Grade 1 Meningi... Grade 2 Meningi... Grade 3 Meningi... Recurrent Menin... Unresectable Me...	Gallium Ga 68-D... Lutetium Lu 177... Magnetic Resona... Positron Emissi... Questionnaire A... Computed Tomogr... Biospecimen Col... Single Photon E...	18 Years -	Mayo Clinic
Lutathera for the Treatment of Inoperable, Progressive Meningioma After External Beam Radiation Therapy	NCT04082520	Grade 1 Meningi... Grade 2 Meningi... Grade 3 Meningi... Recurrent Menin... Unresectable Me...	Gallium Ga 68-D... Lutetium Lu 177... Magnetic Resona... Positron Emissi... Questionnaire A... Computed Tomogr... Biospecimen Col... Single Photon E...	18 Years -	Mayo Clinic

Spots Global Cancer Trial Database for grade 2 meningioma