Study of IDO Inhibitor and Temozolomide for Adult Patients With Primary Malignant Brain Tumors

The aim of this study is to identify the safety profile and the recommended dose for phase 2
study of the combination of indoximod (portion 1, phase 1b study). Investigators will then
evaluate the tolerability and the preliminary activity in patients with recurrent GBM in
three different situations:

- Combination of indoximod and temozolomide (bevacizumab-naive patients)

- Combination of indoximod and temozolomide with bevacizumab

- Combination of indoximod and temozolomide with stereotactic radiation. Ancillary
studies will be conducted to assess the correlation between intra-tumoral IDO
expression or serum biomarkers (immune monitoring) and treatment efficacy.

If the current study shows an acceptable safety profile and suggests preliminary evidence of
activity, this will provide the justification for subsequent randomized phase 2 studies in
refractory glioblastoma multiforme (GBM).

Inclusion Criteria:

- Histologically proven intracranial glioblastoma multiforme (WHO grade IV glioma) or
gliosarcoma. In addition, the Phase 1b cohort will include patients with progressive
WHO grade III glioma. There must be imaging confirmation (with and without gadolinium
contrast) of tumor progression or regrowth.

- Patients will be eligible if the original histology was lower grade glioma and a
subsequent diagnosis of glioblastoma or gliosarcoma is made.

- Unequivocal radiographic evidence for tumor progression by MRI. It is understood that
some patients may be resected prior to enrolling onto protocol

- Patients must have completed a course of radiation therapy and at least 2 adjuvant
cycles of temozolomide for the phase 2 component.

- Patients enrolling onto Cohort 2b who have been taken off bevacizumab must have had
at least a 28 day washout from any previous administration of bevacizumab. It is
preferred that patients who fail bevacizumab prior to trial entry remain on
bevacizumab in the trial.

- Prior temozolomide is not required for the phase 1 component; prior radiation is
required for the phase 1 arm. It is suggested (but not required) that patients be at
least 3 months post radiation to reduce the chances of pseudoprogression.

- Patients must be on a steroid dose less than or equal to 2 mg of dexamethasone daily
(or equivalent), and this dose must not have increased for at least 14 days prior to
obtaining the enrollment.

- ECOG performance status ≤1 or Karnofsky ≥70%.

- Age between 16

- Normal organ functions, which includes adequate:

Bone marrow function as defined by the following laboratory values:

- Absolute Neutrophil Count (ANC) ≥ 1.0 x 10^9/L

- Platelets ≥ 100 x 10^9/L

- Hemoglobin ≥ 9.0 g/dL

- Renal function (creatinine level within normal institutional limit, or
creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels
above institutional normal).

- Liver function (AST/ALT ≤2.5 X institutional upper limit of normal, Total
bilirubin ≤ 1.5 times ULN, INR within 1.5 times ULN (or if receiving
anticoagulant therapy an INR of ≤ 3.0 is allowed with concomitant increase in PT
or an aPTT ≤ 2.5 × control).

- Must be 28 days from the administration of any investigational agent or prior
cytotoxic therapy with the following exceptions:

o Must be 14 days from administration of non-cytotoxic agents (e.g., bevacizumab
(except COHORT 2b), interferon, tamoxifen, thalidomide, cis-retinoic acid,
tyrosine kinase inhibitor, etc.).

- Patients with prior therapy that included interstitial brachytherapy, Gliadel
wafer, or stereotactic radiosurgery must have confirmation of progressive
disease, rather than radiation necrosis, by PET scanning, Thallium scanning, MRI
spectroscopy, or surgical documentation.

- The effects of indoximod on the developing human fetus are unknown. For this
reason and because indoximod may affect maternal immune tolerance of the fetus,
sexually active women of child-bearing potential must agree to use two forms of
contraception (hormonal and barrier method of birth control or abstinence) prior
to study entry and for the duration of study participation. Use of contraception
or abstinence should continue for a minimum of 1 month after completion of the
study. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should discontinue the study drug and inform
her treating physician immediately. Also men should be discouraged from
fathering children while on treatment.

Exclusion Criteria:

- Prior invasive malignancy that is not low-grade glioma, high-grade glioma,
glioblastoma, or gliosarcoma (except non-melanomatous skin cancer or carcinoma in
situ of the cervix) unless the patient has been disease free and off therapy for that
disease for a minimum of 3 years.

- Patients on the phase 2 portion of the study may not have more than 2 prior regimens
for recurrent disease for glioblastoma/gliosarcoma. Patients on the phase 1 portion
of the study may not have had more than 3 prior regimens.

- Active systemic infection requiring treatment, including any HIV infection or
toxoplasmosis.

- Systemic corticosteroid therapy > 2 mg of dexamethasone daily (or equivalent) at
study enrollment.

- Baseline QTc interval of >470 at study entry or patients with congenital long QT
syndrome.

- Systemic corticosteroid therapy > 2 mg of dexamethasone daily (or equivalent) at
study enrollment

- Patients with significantly altered mental status that would prohibit the
understanding or rendering of informed consent and compliance with the requirements
of this protocol must have a legally authorized representative (LAR) willing to
participate and support the patient throughout the trial. Affected patients without a
LAR are excluded from participation.

- Other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that may increase the risk associated with study participation or study
drug 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.

- Active or history of autoimmune disease

- Pregnant women are excluded from this study, where pregnancy is confirmed by a
positive serum hCG laboratory test (> 5 mIU/mL); breastfeeding should be
discontinued.

- Patients with known autoimmune thyroid disease or positive anti-TPO antibodies
(anti-Thyroid Peroxidase) at time of screening.