Inclusion Criteria:
- Recurrent WHO grade IV glioblastoma or gliosarcoma, including molecular features of
glioblastoma.
- Other GBM variants and "secondary GBM" are allowed. IDH-mutant GBM that have relapsed
more than once may be included, as the prognosis of multiply recurrent GBM patients
may not differ based on IDH mutation status.
- Disease must have recurred and patient must be a candidate for re-irradiation and
bevacizumab. Any number of recurrences are allowed.
- Patients must have measurable disease per RANO criteria. Lesions will be considered
measurable when they are bi-dimensional with clearly defined margins of ≥5 mm in two
perpendicular diameters.
- Prior transient use of bevacizumab for cerebral edema or radiation necrosis is allowed
without a washout period. Prior bevacizumab use is permitted if used for treatment of
disease if administered more than 6 months prior to registration.
- 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 ≤ ULN or creatinine clearance ≥ 60 mL/min/1.73 m2 by
Cockcroft-Gault for patients
- Serum total bilirubin ≤ 1.5 ULN
- 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, and at least 14 days from LITT or biopsy. Prior to surgery, there must be
imaging evidence of measurable progressive disease (PD) per RANO criteria and noted
above.
- 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:
- 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.
- 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.
- 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 had an allogeneic tissue/solid organ transplant.
- Has an active infection requiring intravenous antibiotic therapy. Has a known history
of active tuberculosis (TB; bacillus tuberculosis).
- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or IDO
inhibitor.
- If a patient is enrolled to regimen B, they are prohibited from receiving monoamine
oxidase inhibitors (MAOIs) or drug which has significant MAOI activity (meperidine,
linezolid, methylene blue) within the 21 days before screening.
- If a patient is enrolled to regimen B, the 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 is prohibited.
- If a patient is enrolled to regimen B, the use of probiotics from screening through
end of treatment is prohibited.
- If a patient is enrolled to regimen B, the use of warfarin is prohibited. If
anti-coagulation is needed during the conduct of the study and non-warfarin regimens
are not feasible, the participant must discontinue study therapy.
- Chronic use of systemic antibiotics (> 14 days) unless medical monitor review and
approval.
- Due to the potential concern for epacadostat metabolite inhibition of CYP1A2, CYP2C8
and CYP2C19, OATP1B1 and OATPIB3 transporters with doses of epacadostat greater than
300 mg BID (eg 400 mg BID or 600 mg BID), the medications will be prohibited for
concomitant use.
- Any history of serotonin syndrome (SS) after receiving serotonergic drugs.
- Has uncontrolled HIV (HIV 1/2 antibodies). Well-controlled HIV is defined as CD4+
count > 300 cells, undetectable viral load, and receiving HAART/ART. Study specific
HIV testing is not required for patients who do not have any prior history of HIV.
- Has uncontrolled active hepatitis B (e.g., HBsAg reactive or HBV DNA detected by quant
RT PCR) or hepatitis C (e.g. HCsAg reactive or HCV RNA [qualitative or quantitative]
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. 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.
