PNOC019: A Randomized, Double-Blinded, Pilot Trial of Neoadjuvant Checkpoint Inhibition followed by Combination Adjuvant Checkpoint Inhibition in Children and Young Adults with Recurrent or Progressive High Grade Glioma (HGG)

Protocol # :
Malignant Glioma
Recurrent Glioblastoma
Recurrent Malignant Glioma
Recurrent Grade III Glioma
Grade III Glioma
Feasibility / Pilot
Disease Sites
Brain and Nervous System
Principal Investigator
Chi, Susan, N
Site Research Nurses
Cavanaugh, Kerri, Lynn
Ezrre, Suzanne
Gouthro, Michelle, S.
Strachan, Marylynne
Strachan, Marylynne

Trial Description

This phase I trial studies the side effects of nivolumab and ipilimumab before and after
surgery in treating children and young adults with high grade glioma that has come back
(recurrent) or is increasing in scope or severity (progressive). Immunotherapy with
monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system
attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Eligibility Requirements

Inclusion Criteria:

1. Participants with recurrent or progressive high-grade gliomas (HGG) (World Health
Organization (WHO) grade III or grade IV) who are candidates for surgical tumor
debulking will be enrolled in this trial

2. All assessments are to occur within 14 days of registration except where otherwise
noted. The participant and their legal parent/guardian must be thoroughly informed
about all aspects of the study, including the study visit schedule and required
evaluations and all regulatory requirements for informed consent. The written informed
consent must be obtained from the participant and legal parent/guardian prior to

3. Have a history of previously treated histologically confirmed World Health
Organization grade III or IV HGG. Previous first line therapy with radiation and/or

4. Have evidence of recurrence or progression of disease by MRI scan

5. Participants must be adequate medical candidates for surgical resection. The intent of
surgical resection is to allow both cytoreduction and tumor debulking as part of
standard of care, and also collect a minimum of 100 mg of tumor tissue for the study
tissue endpoints

6. A primary goal of surgery must be cytoreduction, and not solely on diagnostic biopsy

7. Age: Participants must be > 6 months and < 22 years of age at time of enrollment

8. Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants
=< 16 years of age. Participants who are unable to walk because of paralysis, but who
are up in a wheelchair, will be considered ambulatory for the purpose of assessing the
performance score

9. Patients with neurological deficits should have deficits that are stable for a minimum
of 1 week prior to enrollment (on stable or tapering dosing of steroids). A baseline
detailed neurological exam should clearly document the neurologic status of the
patient at the time of enrollment on the study.

10. Prior Therapy: Participants must have fully recovered from the acute toxic effects of
all prior anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to enrollment. If after the required timeframe, the
defined eligibility criteria are met, e.g. blood count criteria, the patient is
considered to have recovered adequately

- Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive.
At least 21 days after the last dose of cytotoxic or myelosuppressive
chemotherapy (42 days if prior nitrosourea)

- An interval of at least 12 weeks from the completion of radiation therapy to
registration unless there is unequivocal histologic confirmation of tumor

- Hematopoietic growth factors: At least 14 days after the last dose of a
long-acting growth factor (e.g. pegfilgrastim) or 7 days for short acting growth
factor. 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 (AEs) are known to occur. The duration of this interval must be discussed
with the study chair.

- Had their last dose of biologic (anti-neoplastic agent) ≥7 days prior to
study registration, or beyond the time during which AEs are known to occur.

- Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
reduced platelet or absolute neutrophil count [ANC] counts): At least 7 days
after the last dose of agent

- Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)

- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
and toxicity related to prior antibody therapy must be recovered to grade =< 1

- An interval of at least 12 weeks from prior exposure to PD-1 or PD-L1 inhibitors.

- Participants must not have received prior exposure to CTLA4 inhibitors.

- Stem cell infusion (with or without total-body irradiation (TBI)):

- Autologous stem cell infusion including boost infusion: >= 42 days

11. Participants must be willing to forego cytotoxic anti-tumor therapies except
study-defined therapy while being treated on study

12. Organ Function Requirements:

- Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

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

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:

- Age: Maximum Serum Creatinine (mg/dL)

- 6 months to < 3 years: 0.6 (male and female)

- 3 to < 6 years: 0.8 (male and female)

- 6 to < 10 years: 1 (male and female)

- 10 to < 13 years: 1.2 (male and female)

- 13 to < 16 years: 1.5 (male), 1.4 (female)

- >= 16 years: 1.7 (male), 1.4 (female)

- Bilirubin (sum of conjugated and unconjugated) =< 1.5 x upper limit of normal
(ULN) for age (except participants with Gilbert syndrome who must have a total
bilirubin level of < 3.0

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN

- Serum albumin >= 2

13. Pregnancy: The effects of nivolumab and ipilimumab on the developing human fetus are
unknown. For this reason women of child-bearing potential 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 5 months after completion of
therapy. 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

14. MRI within 28 days prior to registration.

Exclusion Criteria:

1. Current or planned participation in a study of an investigational agent or using an
investigational device.

2. Has a diagnosis of immunodeficiency.

3. Has tumor primarily localized to the brainstem or spinal cord.

4. Has presence of diffuse leptomeningeal disease or or disseminated/multi-focal disease,
or extracranial disease.

5. Has received systemic immunosuppressive treatments (such as methotrexate, chloroquine,
azathioprine, etc.), aside from anti-neoplastic chemotherapy or systemic
corticosteroids within six months of registration.

6. Participants with a concurrent condition requiring systemic treatment with either
corticosteroids (> 0.25 mg/kg daily prednisone equivalent) or other immunosuppressive
medications within 14 days of start of study treatment. Inhaled or topical steroids,
and adrenal replacement steroid doses > 0.25 mg/kg daily prednisone equivalent, are
permitted in the absence of active autoimmune disease.

7. Unable to taper steroids due to ongoing mass effect; a maximum dexamethasone dose of
0.1 mg/kg/day is allowed (4mg maximum), but preferably have been discontinued (inhaled
or topical use of steroids is allowed).

8. Has a known history of active TB (Bacillus tuberculosis).

9. Has a known additional malignancy that is progressing or requires active treatment
within 3 years of registration. Exceptions include basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone
potentially curative therapy.

10. Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

11. Has known history of, or any evidence of active non-infectious pneumonitis.

12. Has an active infection requiring systemic therapy.

13. Has a known hypersensitivity to any of the study therapy products.

14. Has a known history of positive test for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).

- NOTE: Testing for HIV must be performed at sites where mandated locally

15. Any prior positive test result for hepatitis B virus or hepatitis C virus indicating
presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen)
positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-ribonucleic acid
(RNA) negative).

16. Participants who have had prior allogenic hematopoietic stem cell transplant (HSCT).

17. Any serious or uncontrolled medical disorder that, in the opinion of the investigator
may increase the risk associated with study participation or study drug
administration, impair the ability of the participant to receive protocol therapy or
interfere with interpretation of study results.