Epacadostat in Combination With Radiation Therapy and Avelumab in Patients With Recurrent Gliomas

Inclusion Criteria:

- Safety Run-In: histologically confirmed grade III (including those with 1p/19q
codeletion) or IV glioma or high risk grade II glioma who were treated with radiation
and chemotherapy previously. High risk grade II gliomas are IDH wild-type and 1p/19q
noncodeleted astrocytoma.

- Phase II: histologically confirmed WHO grade IV glioblastoma or gliosarcoma.

- GBM variants and secondary GBM are allowed for all patients.

- Disease must have recurred and patient must be a candidate for re-irradiation and
bevacizumab. Any number of recurrences are allowed.

- Prior use of bevacizumab is allowed for all safety run-in patients and for Cohort B
(n=19) phase II patients. Cohort A (n=24) patients must be bevacizumab-naïve.

- At least 18 years of age.

- Karnofsky performance status ≥ 60%

- Normal bone marrow and organ function as defined below:

- Absolute neutrophil count ≥ 1,000/mcL

- Platelets ≥ 75,000/mcL

- Hemoglobin ≥ 9.0 g/dL or > 5.6 mmol/L (transfusion is acceptable to meet this
criterion)

- Serum creatinine ≤ 1.5 x IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 by
Cockcroft-Gault for patients with creatinine levels above 1.5 x IULN

- Serum total bilirubin ≤ IULN OR conjugated bilirubin ≤ 2.0 x IULN for patients
with total bilirubin > IULN

- AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN

- INR or PT ≤ 1.5 x IULN unless subject 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 subject is receiving anticoagulant therapy as long as PT
or PTT is within therapeutic range of intended use of anticoagulants

- At least 28 days from any major surgery such as craniotomy and surgical wound is fully
healed.

- Women of childbearing potential and men must agree to use highly effective
contraception (hormonal or barrier method of birth control, abstinence) prior to study
entry and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she must inform her
treating physician immediately.

- Ability to understand and willingness to sign an IRB approved written informed consent
document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

- A history of other non-CNS malignancy ≤ 5 years previous with the exception of basal
cell or squamous cell carcinoma of the skin which were treated with local resection
only or carcinoma in situ of the cervix or other surgically cured malignancies

- Tumors in the brainsem or cerebellum (i.e., infratentorial)

- Currently receiving any other investigational agents.

- A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to epacadostat, avelumab, bevacizumab, or other agents used in
the study.

- Dexamethasone dose > 4 mg daily at the time of registration (higher dose of steroid
for symptom control is allowed during the study).

- History of intracranial abscess within 6 months prior to start of study therapy.

- Persisting toxicity related to prior therapy (CTCAE > grade 1); however, alopecia,
sensory neuropathy ≤ grade 2, or other ≤ grade 2 not constituting a safety risk based
on the investigator's judgment are acceptable

- Has active autoimmune disease or syndrome (i.e. moderate or severe rheumatoid
arthritis, moderate or severe psoriasis, multiple sclerosis, active inflammatory bowel
disease) that has required systemic treatment in the past 2 years (i.e. with use of
disease-modifying agents, corticosteroids, or immunosuppressive drugs) or who are
receiving systemic therapy for an autoimmune or inflammatory disease (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) is not considered a form of systemic
treatment. Subjects are permitted to enroll if they have vitiligo, resolved childhood
asthma/atopy, type I diabetes mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external trigger.

- Prior organ transplantation including allogeneic stem cell transplantation.

- Has a severe acute or chronic medical condition including immune colitis, inflammatory
bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatric conditions
including recent (within the past year) or active suicidal ideation or behavior, or
laboratory abnormalities that may increase the risk associated with study
participation or study treatment administration or may interfere with the
interpretation of study results and, in the judgment of the investigator, would make
the patient inappropriate for entry into this study.

- Has an active infection requiring systemic therapy.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or IDO
inhibitor.

- Receiving monoamine oxidase inhibitors (MAOIs) or drug which has significant MAOI
activity (meperidine, linezolid, methylene blue) within the 21 days before screening.

- Use of any UGT1A9 inhibitor from screening through follow-up period, including
acitretin, amitriptyline, androsterone, cyclosporine, dasatinib, diclofenac,
diflunisal, efavirenz, erlotinib, estradiol (17-beta), flutamide, gefitinib,
gemfibrozil, glycyrrhetinic acid, glycyrrhizin, imatinib, imipramine, ketoconazole,
linoleic acid supplements, mefenamic acid, mycophenolic acid, niflumic acid,
nilotinib, phenobarbital, phenylbutazone, phenytoin, probenecid, propofol, quinidine,
ritonavir, sorafenib, sulfinpyrazone, valproic acid, and verapamil.

- Any history of serotonin syndrome (SS) after receiving serotonergic drugs.

- Has a known history of HIV (HIV 1/2 antibodies).

- Has known active hepatitis B (e.g., HBsAg reactive or HBV DNA detected by quant RT
PCR) or hepatitis C (e.g. HCV RNA [qualitative] is detected).

- Uncontrolled intercurrent illness including, but not limited to, clinically
significant (i.e. active) cardiovascular disease: cerebral vascular accident/stroke (<
6 months prior to enrollment), myocardial infarction (< 60 months prior to
enrollment), congestive heart failure (≥ NYHA class II), unstable angina pectoris, or
serious cardiac arrhythmia requiring medication.

- History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's
opinion, is clinically meaningful. Screening QTc interval > 480 msec will require
investigator's evaluation on patient's eligibility. ECG may be repeated in triplicate,
and if the average QTcF is < 480 ms, the patient may participate. Subjects with left
bundle branch block are excluded.

- Presence of a gastrointestinal condition that may affect drug absorption.

- Receipt of live attenuated vaccine within 30 days before the first dose of study
treatment. Examples of live vaccines include, but are not limited to, the following:
measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin
(BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.
FluMist) are live attenuated vaccines and are not allowed.

- Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
pregnancy test prior to the start of study treatment.