HIF-2 Alpha Inhibitor PT2385 in Treating Patients With Recurrent Glioblastoma

PRIMARY OBJECTIVES:

I. To estimate the efficacy of HIF-2 alpha inhibitor PT2385 (PT2385) as measured by
radiographic response rate (by Response Assessment in Neuro-Oncology, RANO, criteria) in
patients with recurrent glioblastoma.

SECONDARY OBJECTIVES:

I. To estimate the efficacy of PT2385 as measured by progression free and overall survival in
patients with recurrent glioblastoma.

II. To determine the safety of oral PT2385 in patients with recurrent glioblastoma.

TERTIARY OBJECTIVES:

I. To describe the pharmacokinetic and pharmacodynamic properties of PT2385 in patients with
recurrent glioblastoma.

II. To describe baseline intratumoral hypoxia using novel, advanced magnetic resonance
(MR)-based neuroimaging sequences in patients with recurrent glioblastoma.

III. To explore genetic polymorphisms involved in the metabolism of PT2385.

OUTLINE:

Patients receive HIF-2 alpha inhibitor PT2385 orally (PO) twice daily (BID) on days 1-28.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 2 years and
every 6 months thereafter.

Inclusion Criteria:

- • Patients must have histologically confirmed glioblastoma that is progressive or
recurrent following radiation therapy and temozolomide according to the Response
Assessment in Neuro-Oncology (RANO) criteria with:

- New contrast-enhancing lesion outside of radiation field on decreasing, stable,
or increasing doses of corticosteroids

- Increase by >= 25% in the sum of the products of perpendicular diameters between
the postradiotherapy scan with the smallest tumor measurement and a scan at least
12 weeks from completion of radiation therapy (RT) + temozolomide (TMZ), on
stable or increasing doses of corticosteroids

** Note: clinical deterioration not attributable to concurrent medication or
comorbid conditions is sufficient to declare progression on current treatment but
not for entry onto a clinical trial for recurrence

- Tumor O(6)-methylguanine-DNA-methyltransferase (MGMT) methylation status
must be available; results of routinely used methods for MGMT methylation
testing (e.g. mutagenically separated polymerase chain reaction, MSPCR, or
quantitative polymerase chain reaction [PCR]) are acceptable

- Patients must have a tumor tissue form indicating availability of archived
tissue from a previous surgery for glioblastoma, completed and signed by a
pathologist

- Patients must have measurable (defined by at least 1 cm x 1 cm)
contrast-enhancing disease by magnetic resonance imaging (MRI) imaging
within 21 days of starting treatment

- Patients must be able to undergo MRI of the brain with gadolinium; patients
must be maintained on a stable or decreasing dose of corticosteroid regimen
(no increase for 5 days) prior to this baseline MRI

- Patients must be in first recurrence of glioblastoma following radiation
therapy and temozolomide

- Patients must have recovered from severe toxicity of prior therapy; the
following intervals from previous treatments are required to be eligible:

- 12 weeks from the completion of radiation

- 6 weeks from a nitrosourea chemotherapy

- 3 weeks from a non-nitrosourea chemotherapy

- 4 weeks from any investigational (not Food and Drug Administration
[FDA]-approved) agents

- 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g.,
erlotinib, hydroxychloroquine, etc.)

- Patients must have a Karnofsky performance status >= 60% (i.e. the patient
must be able to care for himself/herself with occasional help from others)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/ alanine aminotransferase (ALT) (serum glutamate pyruvate
transaminase [SGPT]) =< 4 x institutional upper limit of normal

- Creatinine =< institutional upper limit of normal OR creatinine clearance >=
60 ml/min/1.73m^2 for patients with creatinine levels above institutional
normal

- Activated partial thromboplastin time (APTT) or partial thromboplastin time
(PTT) =< 1.5 x institutional upper limit of normal

- Patients must be able to provide written informed consent

- Women of childbearing potential must have a negative serum pregnancy test
prior to study start; women of childbearing potential and men 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 through 30 days after the last dose of study drug; should a woman become
pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately; men treated or enrolled on
this protocol must also agree to use adequate contraception prior to the
study, for the duration of study participation, and through 30 days after
the last dose of study drug

- Patients must have no concurrent malignancy except curatively treated basal
or squamous cell carcinoma of the skin or carcinoma in situ of the cervix,
breast, or bladder; patients with prior malignancies must be disease-free
for >= five years

- Patients must be able to swallow tablets

Exclusion Criteria:

- • Patients receiving any other investigational agents are ineligible

- Patients must not have received prior anti-VEGF therapy including bevacizumab
(i.e. patients must be bevacizumab naive)

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to PT2385 are ineligible

- Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for
treatment on this protocol; patients may be on non-enzyme inducing anti-epileptic
drugs or not be taking any anti-epileptic drugs; patients previously treated with
EIAED may be enrolled if they have been off the EIAED for 10 days or more prior
to the first dose of PT2385

- Patients with a history of bleeding diathesis are ineligible

- Patients who have not recovered to < Common Terminology Criteria for Adverse
Events (CTCAE) grade 2 toxicities related to prior therapy are ineligible

- Patients with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart failure, clinically
significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements, are ineligible

- Pregnant women are excluded from this study; breastfeeding should be discontinued
if the mother is treated with PT2385

- Human immunodeficiency virus (HIV)-positive patients on combination
antiretroviral therapy are ineligible due to potential drug-drug interactions
with PT2385