Nivolumab for Recurrent or Progressive IDH Mutant Gliomas

May 5, 2022 updated by: Fabio Iwamoto, MD

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

The objective of this study is to determine response rates (partial and complete responses) to nivolumab of recurrent or progressive IDH mutant (grades 2, 3 or 4) gliomas with prior exposure to alkylating agents.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Miami, Florida, United States, 33176
        • Miami Cancer Center
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Dana Farber Cancer Institute
    • New York
      • New York, New York, United States, 10032
        • Columbia University Medical Center
      • New York, New York, United States, 10065
        • Weill Cornell Medical College

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Participants must have signed and dated an IRB/IEC 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 2, 3 or 4 gliomas with IDH mutation (confirmed by IDH R132H immunohistochemistry or IDH1/IDH2 next generation sequencing) who have progressive tumor and have had previous exposure to alkylating agents.
  • Participants must have measurable disease, defined as at least one enhancing tumor lesion that can be accurately measured in at least one dimension as ≥ 10mm x 10mm on brain MRI. See 13.2 Disease Parameters for more information regarding evaluation of measurable disease. Patients with non-enhancing measureable disease may be eligible upon discussion with and approval by the CUMC PI.
  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Nivolumab
Nivolumab 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.
Drug: Nivolumab
Nivolumab (Opdivo®) is a human monoclonal antibody (HuMAb; immunoglobulin G4 (IgG4)- S228P) that targets the PD-1 cluster of differentiation 279 (CD279) cell surface membrane receptor.
Other Names:
  • Opdivo®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Response Rate
Time Frame: Total treatment duration for 2 years or until PD, unacceptable toxicity, or withdrawal of consent.
To evaluate the objective response rate (partial response (PR) and complete responses (CR)) to nivolumab of recurrent or progressive IDH mutant low and high-grade gliomas with prior exposure to alkylating agents.
Total treatment duration for 2 years or until PD, unacceptable toxicity, or withdrawal of consent.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Duration of Response
Time Frame: Until the first date that progressive disease is objectively documented or until study completion (36 months)
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).
Until the first date that progressive disease is objectively documented or until study completion (36 months)
Progression-Free Survival (PFS)
Time Frame: Until death or study completion (36 months)

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.
Until death or study completion (36 months)
Overall Survival (OS)
Time Frame: Until death or study completion (36 months)
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.
Until death or study completion (36 months)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fabio Iwamoto, MD

Collaborators

Bristol-Myers Squibb

Investigators

  • Principal Investigator: Fabio Iwamoto, MD, Columbia University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 12, 2018

Primary Completion (ANTICIPATED)

December 1, 2022

Study Completion (ANTICIPATED)

December 1, 2022

Study Registration Dates

First Submitted

May 17, 2018

First Submitted That Met QC Criteria

June 4, 2018

First Posted (ACTUAL)

June 15, 2018

Study Record Updates

Last Update Posted (ACTUAL)

May 9, 2022

Last Update Submitted That Met QC Criteria

May 5, 2022

Last Verified

May 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AAAR6354

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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