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.
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.
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
