A Longitudinal Assessment of Tumor Evolution in Patients With Brain Cancer

Patients having a clinically planned surgical procedure (biopsy or cytoreduction) for a
suspected diagnosis of high grade glioma will be approached for participation in this study.
Tumor tissue obtained from surgery will be used for histological diagnosis and clinical
molecular profiling, and excess tumor tissue will be collected for potential correlative
studies. A small sample of blood and CSF for research will also be collected.

Once a diagnosis of high grade glioma is confirmed, the patient will be allocated to either
Treatment Arm 1 standard of care (radiation + chemotherapy), Treatment Arm 2 (nivolumab),
Treatment Arm 3 (nivolumab + ipilimumab), Treatment Arm 4 (nivolumab + ipilimumab +
bevacizumab), or Treatment Arm 5 (nivolumab + ipilimumab + temozolomide), or Treatment Arm 6
(nivolumab + ipilimumab + bevacizumab+ temozolomide). Treatment will be started approximately
7-42 days following surgery once the patient has recovered from surgery. Routine clinical
evaluations will be performed prior to treatment initiation and throughout treatment as
clinically indicated. Radiographic brain imaging will be performed approximately 21-42 after
treatment initiation and then routinely for medical management. Tumor response will be
assessed according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) Working
Group criteria.

Treatment may continue until the patient experiences unacceptable toxicity or clear disease
progression. The determination of whether to stop treatment due to disease progression will
be based on the investigator's evaluation of the patient's clinical and radiographic
condition, taking into consideration the interpretation of localized inflammatory responses
that can mimic radiographic features of tumor progress. Patients discontinuing treatment will
be directed by their treating physician for the next step in their medical management - such
as a clinically-indicated cytoreductive surgery, standard radiation chemotherapy if not
assigned to study arm 1, or a different treatment regimen. If another treatment is started,
clinical evaluations and response assessments will continue as clinically-indicated; blood
and CSF will be collected after the first month, then every three to six months.

Inclusion Criteria:

1. Participant has the ability to understand and the willingness to provide a signed and
dated informed consent form.

2. Participant has the willingness to comply with all study procedures and availability
for the duration of the study.

3. Participant is being evaluated for a potential, or known, diagnosis of high grade
glioma.

4. Participant is a candidate for brain surgery.

5. Participant is male or female, ≥ 18 years of age.

6. Participant has a Karnofsky Performance Status ≥ 60%:

Exclusion Criteria:

1. Participant has received prior anti-cancer treatment for high grade glioma.

2. Participant has a diagnosis of immunodeficiency or active autoimmune disease.

3. Participant is receiving chronic systemic steroid therapy in dosing exceeding 8 mg
daily of dexamethasone equivalent or any other form of immunosuppressive therapy
within 7 days prior to the first dose of study drug. Note: This is assessed after
surgery, prior to starting drug treatment.

4. Participant has received a live vaccine within 28 days prior to the first dose of
study agent. Examples of live vaccines include, but are not limited to measles, mumps,
rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), typhoid vaccine, and intranasal influenza vaccines (e.g.,
FluMist®).

5. Participant has a severe or uncontrolled medical disorder that would, in the
investigator's opinion, impair ability to receive study intervention (i.e.,
uncontrolled diabetes, chronic renal disease, chronic pulmonary disease or active,
uncontrolled infection, psychiatric illness/social situations that would limit
compliance with study requirements).

6. Participant is a female of childbearing potential who is pregnant or nursing.

7. Participant has a history of thrombotic or hemorrhagic stroke or myocardial infarction
within 6 months.

8. Participant has a history of intestinal perforations, fistula, hemorrhages, and/or
hemoptysis ≤ 6 months prior to first study treatment.

9. Participant has active gastrointestinal bleeding.

10. Participant has uncontrolled hypertension (systolic blood pressure ≥ 160 mm Hg and/or
diastolic blood pressure ≥ 90 mm Hg).