Clinical Trials /

Nivolumab for Recurrent or Progressive IDH Mutant Gliomas

NCT03557359

Description:

The objective of this study is to determine response rates (partial and complete responses) to nivolumab of recurrent or progressive IDH mutant high-grade gliomas with prior exposure to alkylating agents.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab for Recurrent or Progressive IDH Mutant Gliomas
  • Official Title: A Phase II, Open Label, Single Arm Study of Nivolumab for Recurrent or Progressive IDH Mutant Gliomas With Prior Exposure to Alkylating Agents

Clinical Trial IDs

  • ORG STUDY ID: AAAR6354
  • NCT ID: NCT03557359

Conditions

  • Gliomas

Interventions

DrugSynonymsArms
NivolumabOpdivo®Nivolumab

Purpose

The objective of this study is to determine response rates (partial and complete responses) to nivolumab of recurrent or progressive IDH mutant high-grade gliomas with prior exposure to alkylating agents.

Detailed Description

      Gliomas are the most common malignant primary brain tumor in adults. Their clinical
      presentation is heterogeneous and prognosis is dependent on both the grade of the tumor and
      the molecular subtype. Somatic mutations in Isocitrate dehydrogenase 1 (IDH1) or, less
      commonly, Isocitrate dehydrogenase 2 (IDH2) genes have emerged as an important prognostic
      factor in gliomas and are associated with longer survival.

      Regardless of initial grade, recurrence and transformation into higher grade tumors is almost
      universal. There is high unmet medical need in treating recurrent gliomas as there is
      currently no established standard of care therapy. Recent trials of IDH inhibitors in IDH
      mutant gliomas and programmed cell death protein 1 (PD-1) and PD-L1 inhibitors in recurrent
      gliomas have been disappointing. Multiple studies in other cancers have demonstrated that
      hypermutated tumors are associated with response to immunotherapeutic agents, including
      anti-CTLA4 agents in melanoma, anti-PD1 therapy in bladder cancer, and
      anti-programmed-cell-death protein 1 (anti-PD1) therapy in lung, and colorectal cancer.

      There is evidence to suggest that gliomas with somatic IDH mutations are more prone to
      develop hypermutation after exposure to alkylating agents than IDH wildtype tumors, providing
      strong scientific rationale for establishing nivolumab as a treatment option in this subgroup
      of patients.
    

Trial Arms

NameTypeDescriptionInterventions
NivolumabExperimentalNivolumab 240 mg will be given every 2 weeks for 8 cycles. Beginning with Cycle 9, nivolumab 480 mg will be given every 4 weeks for a total therapy duration of 2 years, or until progressive disease, unacceptable toxicity, or withdrawal of consent. Nivolumab will be administered as a 30-minute infusion. A finite treatment duration with immune therapies in this participant population remains an area of ongoing research; therefore the treatment duration chosen was 2 years.
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have signed and dated an approved written informed consent form in
             accordance with regulatory and institutional guidelines. This must be obtained before
             the performance of any protocol-related procedures that are not part of normal patient
             care.

          -  Participant must be willing and able to comply with scheduled visits, treatment
             schedule, laboratory tests, and other requirements of the study.

          -  Participant must be 18 years of age or older

          -  Participants with pathologically confirmed grade 3 or 4 gliomas with IDH mutation
             (confirmed by immunohistochemistry or sequencing) who have progressive tumor and have
             had previous exposure to alkylating agents.

          -  Participants must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension as ≥ 10mm x 10mm on brain MRI.

          -  Availability of baseline frozen tumor or formalin-fixed paraffin-embedded (FFPE) tumor
             block.

          -  Karnofsky Performance Score (KPS) of 60 and above

          -  Adequate bone marrow, kidney and liver function as defined below:

             i) White blood count (WBC) ≥ 3000/microliter (uL) ii) Neutrophils ≥ 1500/uL iii)
             Absolute lymphocyte count ≥ 500/uL iv) Platelets ≥ 100x103 /uL v) Hemoglobin ≥ 9.0g/dL
             vi) Serum creatinine ≤ 1.5x upper limit of normal (ULN) or calculated creatinine
             clearance (CrCl)> 50 mL/min (using the Cockcroft-Gault formula)

               1. Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in
                  mg/dL

               2. Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in
                  mg/dL vi) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤
                  3.0 x ULN vii) Total bilirubin (TBILI) ≤ 1.5 x ULN (except participants with
                  Gilbert Syndrome who must have a total bilirubin level of < 3.0xULN)

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin)
             within 24 hours prior to the start of study drug

          -  Women must not be pregnant or breastfeeding

          -  WOCBP must agree to follow instructions for method(s) of contraception for the
             duration of study treatment with nivolumab and 5 months after the last dose of study
             treatment (i.e., 30 days (duration of ovulatory cycle) plus the time required for the
             investigational drug to undergo approximately five half-lives.)

          -  Males who are sexually active with WOCBP must agree to follow instructions for
             method(s) of contraception for the duration of study treatment with nivolumab and 7
             months after the last dose of study treatment (i.e., 90 days (duration of sperm
             turnover) plus the time required for the investigational drug to undergo approximately
             five halflives.)

          -  Azoospermic males are exempt from contraceptive requirements. WOCBP who are
             continuously not heterosexually active are also exempt from contraceptive
             requirements, but still must undergo pregnancy testing.

          -  Investigators shall counsel WOCBP, and male participants who are sexually active with
             WOCBP, on the importance of pregnancy prevention and the implications of an unexpected
             pregnancy. Investigators shall advise on the use of highly effective methods of
             contraception, which have a failure rate of < 1% when used consistently and correctly.

          -  At a minimum, participants must agree to use 1 highly effective method of
             contraception

        Exclusion Criteria:

          -  Participants with an active, known, or suspected autoimmune disease.

          -  Participants with type I diabetes mellitus, hypothyroidism only requiring hormone
             replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring
             systemic treatment, or conditions not expected to recur in the absence of an external
             trigger are permitted to enroll.

          -  Participants with a condition requiring systemic treatment with either corticosteroids
             (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
             days of start of study treatment. Inhaled or topical steroids, and adrenal replacement
             steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of
             active autoimmune disease. Dose of dexamethasone ≤ 4 mg/day or equivalent is allowed
             at the study entry for brain tumor edema

          -  Participants who have received chemotherapy or experimental agents within 4 weeks
             (except for 6 weeks for nitrosoureas and 23 days for temozolomide) and radiotherapy
             within 12 weeks of the first dose of the study treatment.

          -  Prior use of PD-1, PD-L1, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
             inhibitors or exposure to other checkpoint inhibitors.

          -  Prior exposure to bevacizumab or other vascular endothelial growth factor (VEGF) or
             VEGFR inhibitors.

          -  Any positive test for hepatitis B virus or hepatitis C virus indicating acute or
             chronic infection, and/or detectable virus

          -  History of severe allergy or hypersensitivity to nivolumab components
      
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:Total treatment duration for 2 years or until PD, unacceptable toxicity, or withdrawal of consent.
Safety Issue:
Description:To evaluate the objective response rate (partial response (PR) and complete responses (CR)) to nivolumab of recurrent or progressive IDH mutant high-grade gliomas with prior exposure to alkylating agents.

Secondary Outcome Measures

Measure:Duration of Response
Time Frame:Until the first date that progressive disease is objectively documented or until study completion (36 months)
Safety Issue:
Description:The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Measure:Progression-Free Survival (PFS)
Time Frame:Until death or study completion (36 months)
Safety Issue:
Description:PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Participants discontinuing study treatment will remain on study for documentation of progression and death.
Measure:Overall Survival (OS)
Time Frame:Until death or study completion (36 months)
Safety Issue:
Description:OS is defined as the time from the first dose of nivolumab to death due to any cause. All other participants will be censored at the last date known to be alive.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Columbia University

Trial Keywords

  • Recurrent
  • Progressive
  • High Grade Glioma
  • IDH Mutant

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