Terameprocol in Treating Patients With Recurrent High Grade Glioma

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) of terameprocol given orally on days 1-5
every 28 days in patients with high grade glioma. (Part 1)

II. To evaluate terameprocol tumor to plasma ratios in resected high grade gliomas following
5 days of oral terameprocol administration. (Part 2)

III. To assess the maximum duration of terameprocol that can be safely administered on a
continuous basis. (Part 3)

SECONDARY OBJECTIVES:

I. Characterize the plasma pharmacokinetic (PK) of oral terameprocol.

II. Evaluate the toxicities of oral terameprocol.

III. Assess progression-free survival.

IV. Estimate overall survival.

V. Assess tumor response.

TERTIARY OBJECTIVES:

I. Assess the contribution of cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9)
genotypes on the variability of oral terameprocol pharmacokinetics.

OUTLINE: This is a dose-escalation study.

Patients receive terameprocol orally (PO) once daily (QD) on days 1-5. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, every 2 months for
2 years, and then every 6 months thereafter.

Inclusion Criteria:

- Patients must have histologically confirmed supratentorial high grade glioma (grade
III or IV glioma) that is progressive or recurrent following radiation therapy and
chemotherapy; patients with grade IV glioma must have progressed or recurred after
initial treatment with radiation and temozolomide; patients with grade III glioma must
have received at least radiation and one regimen of chemotherapy (temozolomide or
procarbazine, lomustine, vincristine [PCV] regimen)

- Patients must have measurable contrast-enhancing disease by magnetic resonance
imaging (MRI) imaging within 21 days of starting treatment; patient must be able
to undergo MRI of the brain with gadolinium

- Patients may have had treatment for an unlimited number of prior relapses

- 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.)

- 4 weeks from prior antiangiogenesis therapy (approved or investigational)
(e.g., bevacizumab, aflibercept, ramucirumab, cediranib, cabozantinib, 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)

- Patients must be 18 years of age or older

- 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]) =< 3 x institutional upper limit of normal

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

- Activated partial thromboplastin time (APTT)/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 entry; 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 oral medications

- Part 2 (surgical) patients only: patients must be undergoing surgery that is
clinically indicated as determined by their care providers; patients must be
eligible for surgical resection according to the following criteria:

- Expectation that the surgeon is able to resect at least 100 mg of tumor from
enhancing tumor and at least 100 mg from non-enhancing tumor with low risk
of inducing neurological injury

Exclusion Criteria:

- Patients receiving any other investigational agents are ineligible

- Patient must not have known sensitivity to terameprocol or any formulation excipients

- Patients with (mean of triplicate) QTc(F) >/= 450mS on screening 12-lead triplicate
electrocardiogram (ECG) are ineligible

- Patients must not be on any anticoagulation

- Patients on any moderate or strong cytochrome P450 family 2, subfamily C, polypeptide
9 (CYP2C9) inducer (e.g., carbamazepine, rifampin) or inhibitor (e.g., amiodarone,
fluconazole) are ineligible; CYP2C9 poor metabolizers will not be excluded

- Patients on narrow-therapeutic drugs that are substrates for cytochrome P450 family 1,
subfamily A, polypeptide 2 (CYP1A2), CYP2C9, cytochrome P450 family 2, subfamily C,
polypeptide 19 (CYP2C19), and cytochrome P450 family 3, subfamily A, polypeptide 4
(CYP3A4) are ineligible (e.g., alfentanil, cyclosporine, dihydroergotamine,
ergotamine, fentanyl, phenytoin, pimozide, quinidine, sirolimus, tacrolimus,
theophylline, tizanidine, warfarin)

- Patient must not have prior gastrointestinal (GI) surgery or GI disease that might
interfere with the absorption of terameprocol

- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
or active infection, symptomatic congestive heart failure, 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 terameprocol

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy