Clinical Trials /

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

NCT03604978

Description:

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. It is not yet known whether giving nivolumab and multi-fraction stereotactic radiosurgery with or without ipilimumab may work better in treating patients with grade II-III meningioma.

Related Conditions:
  • Grade II Meningioma
  • Grade III Meningioma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Multi-fraction Stereotactic Radiosurgery With or Without Ipilimumab in Treating Patients With Recurrent Grade II-III Meningioma
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-01560
  • SECONDARY ID: NCI-2018-01560
  • SECONDARY ID: 201901009
  • SECONDARY ID: 10186
  • SECONDARY ID: 10186
  • SECONDARY ID: UM1CA186704
  • NCT ID: NCT03604978

Conditions

  • Grade II Meningioma
  • Grade III Meningioma
  • Recurrent Meningioma

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyCohort B (nivolumab, ipilimumab, radiosurgery)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoCohort A (nivolumab, radiosurgery)

Purpose

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. It is not yet known whether 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) 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 Experimental Therapeutics Clinical
      Trials Network (ETCTN) Biorepository.

      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.

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

Trial Arms

NameTypeDescriptionInterventions
Cohort A (nivolumab, radiosurgery)ExperimentalPatients 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.
  • Nivolumab
Cohort B (nivolumab, ipilimumab, radiosurgery)ExperimentalPatients 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.
  • Ipilimumab
  • Nivolumab

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 MRI but with the
             maximum dimension =< 5 cm OR gross tumor volume < 20 cm^3

          -  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

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN

          -  Serum creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 30
             mL/min/1.73 m^2 for patients with creatinine levels above 1.5 x institutional normal

          -  The effects of nivolumab and/or ipilimumab on the developing human fetus are unknown.
             For this reason and because radiation therapy is known to be teratogenic, women of
             childbearing potential (WOCBP) and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation. WOCBP should use an adequate method to avoid
             pregnancy for 5 months after the last dose of investigational drug. Women of
             childbearing potential must have a negative serum or urine pregnancy test (minimum
             sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within
             24 hours prior to the start of nivolumab. Women must not be breastfeeding. Men who are
             sexually active with WOCBP must use any contraceptive method with a failure rate of
             less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP
             will be instructed to adhere to contraception for a period of 7 months after the last
             dose of investigational product. Women who are not of childbearing potential (i.e.,
             who are postmenopausal or surgically sterile as well as azoospermic men) do not
             require contraception

               -  Women of childbearing potential (WOCBP) is defined as any female who has
                  experienced menarche and who has not undergone surgical sterilization
                  (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause
                  is defined clinically as 12 months of amenorrhea in a woman over 45 in the
                  absence of other biological or physiological causes. In addition, women under the
                  age of 55 must have a documented serum follicle stimulating hormone (FSH) level
                  less than 40 mIU/mL

               -  WOCBP receiving nivolumab will be instructed to adhere to contraception for a
                  period of 5 months after the last dose of investigational product. Men receiving
                  nivolumab and who are sexually active with WOCBP will be instructed to adhere to
                  contraception for a period of 7 months after the last dose of investigational
                  product. These durations have been calculated using the upper limit of the
                  half-life for nivolumab (25 days) and are based on the protocol requirement that
                  WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually
                  active with WOCBP use contraception for 5 half-lives plus 100 days

               -  Should a woman become pregnant or suspect she is pregnant while she or her
                  partner is participating in this study, she should inform her treating physician
                  immediately

          -  Ability to understand and the willingness to sign a written informed consent document
             or, if decision-making capacity is impaired, consent of a legally authorized
             representative (e.g., spouse, adult child, live-in caretaker).

        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

          -  Patients with active autoimmune disease or history of autoimmune disease that might
             recur, which may affect vital organ function or require immune suppressive treatment
             including systemic corticosteroids, should be excluded. These include but are not
             limited to patients with a history of immune related neurologic disease, multiple
             sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
             gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),
             connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,
             ulcerative colitis, hepatitis; and patients with a history of toxic epidermal
             necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
             excluded because of the risk of recurrence or exacerbation of disease. Patients with
             vitiligo, endocrine deficiencies including thyroiditis managed with replacement
             hormones including physiologic corticosteroids are eligible. Patients with rheumatoid
             arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with
             topical medication and patients with positive serology, such as antinuclear antibodies
             (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ
             involvement and potential need for systemic treatment but should otherwise be eligible

               -  Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
                  residual hypothyroidism due to autoimmune condition only requiring hormone
                  replacement, psoriasis not requiring systemic treatment, or conditions not
                  expected to recur in the absence of an external trigger (precipitating event)

          -  Prior organ transplantation including allogeneic stem cell transplantation

          -  Other severe acute or chronic medical conditions including immune colitis,
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatric
             conditions including recent (within the past year) or active suicidal ideation or
             behavior, or laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study

          -  Live vaccination within 4 weeks of the first dose of nivolumab and while on trial is
             prohibited except for administration of inactivated vaccines
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated combination of radiosurgery and nivolumab plus or minus ipilimumab (Phase I)
Time Frame:Up to 100 days
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:At 6 months
Safety Issue:
Description:80% confidence intervals will be assessed using Kaplan-Meier product limit methods.
Measure:Overall survival (OS)
Time Frame:Up to 100 days
Safety Issue:
Description:80% confidence intervals will be assessed using Kaplan-Meier product limit methods.
Measure:Changes of peripheral T-cells
Time Frame:Baseline up to 100 days
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 20, 2020