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A Study Testing the Effect of Immunotherapy (Ipilimumab and Nivolumab) in Patients With Recurrent Glioblastoma With Elevated Mutational Burden

NCT04145115

Description:

This phase II trial studies the effect of immunotherapy drugs (ipilimumab and nivolumab) in treating patients with glioblastoma that has come back (recurrent) and carries a high number of mutations. Cancer is caused by changes (mutations) to genes that control the way cells function. Tumors with high number of mutations may respond well to immunotherapy. Immunotherapy with monoclonal antibodies such as ipilimumab and nivolumab may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Giving ipilimumab and nivolumab may lower the chance of recurrent glioblastoma with high number of mutations from growing or spreading compared to usual care (surgery or chemotherapy).

Related Conditions:
  • Glioblastoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study Testing the Effect of Immunotherapy (Ipilimumab and Nivolumab) for People With Recurrent Glioblastoma With Elevated Mutational Burden
  • Official Title: A Phase II Study of Checkpoint Blockade Immunotherapy in Patients With Somatically Hypermutated Recurrent Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-07242
  • SECONDARY ID: NCI-2019-07242
  • SECONDARY ID: A071702
  • SECONDARY ID: A071702
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT04145115

Conditions

  • Glioblastoma, IDH-Mutant
  • Recurrent Glioblastoma

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab, ipilimumab)

Purpose

This phase II trial studies how well immunotherapy (ipilimumab and nivolumab) works in treating patients with glioblastoma that has come back (recurrent) and has a high mutational burden. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving ipilimumab and nivolumab may lower the chance of recurrent glioblastoma from growing or spreading compared to standard surgery or chemotherapy.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine whether the combination of ipilimumab and nivolumab increases the tumor
      response rate assessed by the Response Assessment in Neuro-Oncology Criteria (RANO) in
      patients with hypermutated recurrent glioblastoma.

      SECONDARY OBJECTIVES:

      I. Estimate the overall survival distribution, median survival, and one-year survival rate of
      patients with hypermutated, recurrent glioblastoma who are treated with ipilimumab and
      nivolumab.

      II. Estimate the progression-free survival distribution and median progression-free survival
      of patients with hypermutated, recurrent glioblastoma who are treated with ipilimumab and
      nivolumab.

      III. Determine the adverse event profile of patients with hypermutated, recurrent
      glioblastoma who are treated with ipilimumab and nivolumab.

      EXPLORATORY OBJECTIVES:

      I. Test whether PD-L1 or immunologic infiltrate in the tumor microenvironment are associated
      with objective tumor response, overall survival, progression-free survival, tumor mutational
      burden, or rates of grade 3 or higher adverse events.

      II. Test whether MGMT status, microsatellite instability (MSI) status, mutational signatures,
      or amount of tumor mutational burden (TMB) including germline analysis are associated with
      objective tumor response, overall survival, progression-free survival, or rates of grade 3 or
      higher adverse events.

      III. Evaluate associations between exome and transcriptome gene levels with objective tumor
      response, overall survival, progression-free survival, rates of grade 3 or higher adverse
      events.

      IV. Evaluate associations between the gut microbiome and objective tumor response.

      V. Response rate using immunotherapy (i)RANO.

      OUTLINE:

      Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30
      minutes on day 1. Treatment repeats every 3 weeks for 4 cycles in the absence of disease
      progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on
      day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients without disease progression are followed every
      8 weeks until disease progression, then every 3 months for up to 3 years. Patients with
      disease progression after completion of study treatment are followed every 3 months for up to
      3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab, ipilimumab)ExperimentalPatients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  PRE-REGISTRATION:

          -  Histologically confirmed glioblastoma (World Health Organization [WHO] grade IV)
             presenting at first or second recurrence including secondary glioblastoma

          -  Presence of measurable disease, as defined by a bidimensionally measurable lesion on
             magnetic resonance imaging (MRI) with a minimum diameter of 10 mm in both dimensions,
             prior to resection or biopsy of recurrent tumor

          -  Tissue available from surgical resection or biopsy of recurrent tumor =< 14 days prior
             to pre-registration, or planned surgery or biopsy of recurrent tumor =< 14 days after
             pre-registration

          -  Does not require > 4 mg dexamethasone beyond the perioperative period defined as the
             time =< 2 weeks after surgical procedure

          -  No active autoimmune disease or history of autoimmune disease

               -  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

          -  No prior treatment with checkpoint blockade therapies (anti-CTLA4, anti-PD1/PD-L1) or
             bevacizumab

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky
             performance status (KPS) >= 70

          -  Able to undergo brain MRI with contrast

          -  Absolute neutrophil count >= 1500/mm^3

          -  Platelet count >= 100,000/mm^3

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

               -  If Gilbert syndrome, then total bilirubin =< 3 x ULN

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.0 x ULN

          -  Creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the
             Cockcroft-Gault formula)

          -  REGISTRATION:

          -  Tissue obtained from biopsy or resection at first or second recurrence exhibits TMB >=
             20 on FoundationOne CDx testing
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 32 months
Safety Issue:
Description:Assessed by the Response Assessment in Neuro-Oncology Criteria (RANO). The proportion of patients who have a confirmed tumor response will be computed as the number of patients with a confirmed complete response (CR) or confirmed partial response (PR) as determined by RANO criteria divided by the number of evaluable patients, which are eligible patients who have measurable disease and completed one cycle of treatment. Will be estimated with a binomial point estimate that will be computed as the number of responses divided by the number of evaluable patients. Exact 95% binomial confidence intervals will be generated and reported.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From the time of treatment initiation until death from any cause, assessed up to 3 years
Safety Issue:
Description:Will be summarized using Kaplan-Meier (KM) estimators. Survival curves will be generated from the KM estimators. KM estimates will be determined for the median OS as well as the 12-month OS rates. Confidence intervals will be provided for the median values as well as the one-year rates.
Measure:Progression-free survival (PFS)
Time Frame:From the time of treatment initiation until disease progression as measured using RANO criteria or death, whichever occurs first, assessed up to 3 years
Safety Issue:
Description:Will be summarized using KM estimators. Survival curves will be generated from the KM estimators. KM estimates will be determined for the median PFS as well as the 12-month PFS rates. Confidence intervals will be provided for the median values as well as the one-year rates.
Measure:Incidence of adverse events (AEs)
Time Frame:Up to 3 years
Safety Issue:
Description:The AEs will be summarized by the frequency and relative frequency of the maximum grade experienced by the patients for all recorded AEs. Adverse event data will be summarized by each observed AE with the number of patients who reported the AE as well as the proportion of patients with the AE.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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