Inclusion Criteria:
3.1.1 Diagnosis Patients must have a histologically confirmed diagnosis of a
non-brainstem high-grade glioma (NB-HGG, WHO Grade III or IV astrocytoma,
oligodendrogliomas, oligoastrocytomas, ependymomas) that is recurrent, progressive or
refractory following radiotherapy with or without chemotherapy. Patients must be
candidates for standard of care surgical resection or biopsy.
3.1.2 Measurable Disease Patients must have measurable disease, defined as at least one
lesion that can be accurately measured in two dimensions.
3.1.3 Prior therapy Patients must have recovered from the acute treatment related
toxicities (defined as ≤ grade 2 if not defined in eligibility criteria) of all prior
chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to
entering this study.
3.1.3.1 Myelosuppressive Chemotherapy Patients must have received their last dose of
known myelosuppressive anticancer therapy greater than 21 days prior to enrollment.
3.1.3.2 Investigational/Biologic Agent Patients must have received their last dose of the
investigational or biologic agent ≥ 7 days prior to study enrollment.
- - For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur.
The duration must be discussed with and approved by the
study chair.
- - Monoclonal antibody treatment and/or agents with prolonged half-lives: At least
three half-lives must have elapsed prior to enrollment.
3.1.3.3 Radiation.Patients must have had their last fraction of:
- - Craniospinal irradiation ≥ 3 months prior to enrollment.
- - Other substantial bone marrow irradiation ≥6 weeks prior to enrollment.
- - Local palliative XRT ≥2 weeks.
3.1.3.4 Stem Cell Transplant ≥ 12 weeks since autologous bone marrow/stem cell transplant
prior to enrollment.*Patients with any history of allogeneic transplant are not eligible.3.1.4 Age Patient must be ≥ 4 but ≤ 26 years of age at the time of enrollment.
3.1.5 Performance Status Karnofsky ≥ 60% for > 16 years of age; Lansky ≥ 60% for children
≤ 16 years of age (Appendix A) Participants who are unable to walk because of neurologic
deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose
of assessing the performance score.
3.1.6 Organ and Marrow Function.Patients must have adequate organ and marrow function as defined below:
- - Absolute neutrophil count >1000 cells/μL.
- - Platelets >75,000 cells/μL(unsupported, defined as no platelet transfusion within 7
days)
- Hemoglobin ≥8g/dl (may receive transfusions)
- Total bilirubin ≤1.5 times institutional upper limit of normal (ULN)
- ALT(SGPT) <3 x institutional upper limit of normal.
- - Serum creatinine based on age/gender as noted in Table 1 Patients that do not meet
the criteria below but have a 24hour Creatinine Clearance or GFR (radioisotope or
iothalamate) ≥ 70 ml/min/1.73 m2 are eligible.
- - INR or PT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as
PT or PTT is within therapeutic range of intended use of anticoagulants.
- - aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as PT or
PTT is within therapeutic range of intended use of anticoagulants.
- - Pulmonary function - Pulse oximetry > 93% on room air and no evidence of dyspnea at
rest.
3.1.7 Ability to undergo surgical resection or biopsy Patient must be a candidate for
surgical resection or biopsy at the time of enrollment. The goal of surgical resection is
both cytoreduction and tumor debulking, or biopsy for diagnosis confirmation as part of
standard of care.
3.1.8 Stability Patients with neurological deficits should have deficits that are stable
for a minimum of 1 week prior to enrollment. A baseline detailed neurological exam should
clearly document the neurological status of the patient at the time of enrollment on the
study.
3.1.9 Corticosteroids Patients must be on a stable or decreasing dose of corticosteroids
for 7 days prior to enrollment. A maximum dexamethasone dose of 0.1 mg/kg/day is allowed
(4 mg maximum), but preferably have been discontinued (inhaled or topical use of steroids
is allowed).
3.1.10 Pregnancy Prevention The effects of nivolumab on the developing human fetus are
unknown. Women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry, for the duration of study participation, and for 5 months after completion of
nivolumab administration. 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. Men treated or enrolled on this protocol must also agree to use
adequate contraception prior to the study, for the duration of study participation, and 5
months after completion of nivolumab administration.
Female subjects of childbearing potential must not be pregnant or breast-feeding. Female
patients of childbearing potential must have a negative serum or urine pregnancy test
within 72 hours prior to receiving the first dose of study medication. If the urine test
is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
3.1.11 Consent Ability to understand and the willingness to sign a written informed
consent document. Parents/Legally authorized representatives may sign and give informed
consent on behalf of study participants.
Exclusion Criteria:
3.2.1 Patients with evidence of leptomeningeal, primary spinal cord, or multicentric
disease.
3.2.2 Patients who have not recovered to ≤ Grade 1 or baseline from adverse events due to
prior anti-cancer therapy.
3.2.3 Patients who are receiving any other investigational agents.
3.2.4 Female subjects of childbearing potential must not be pregnant or breast-feeding.
Female patients of childbearing potential must have a negative serum or urine pregnancy
test within 72 hours prior to receiving the first dose of study medication. If the urine
test is positive or cannot be confirmed as negative, a serum pregnancy test will be
required.
3.2.5 History of allergic reactions attributed to compounds of similar chemical or
biologic composition to nivolumab.
3.2.6 Prior treatment with an anti-PD-1, anti PD-L1 and anti-PD-L2, or anti-CTLA-4
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or
checkpoint pathways.
3.2.7 Patients who have had prior allogenic hematopoietic stem cell transplant.
3.2.8 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.
3.2.9 Patients with uncontrolled intercurrent illness or any other significant
condition(s) (serious infections or significant psychiatric, cardiac, pulmonary, hepatic,
or other organ dysfunction that in the opinion of the investigator would compromise the
patient's ability to tolerate protocol therapy, put them at additional risk for toxicity,
or would interfere with the study procedures or results.
3.2.10 Patients who have had live vaccines within 30 days prior to the first dose of
trial treatment.
