Ketoconazole Before Surgery in Treating Patients With Recurrent Glioma or Breast Cancer Brain Metastases

PRIMARY OBJECTIVES:

I. To determine if ketoconazole alters the tGLI1 activation signature (tGAS) which is
consisted of eight validated tGLI1 regulated genes (CD24, CD44, VEGF-A, VEGF-C, VEGFR2, TEM7,
OCT-4. and heparanase) in tGLI1 expressing brain biospecimens.

SECONDARY OBJECTIVES:

I. To determine if pre-treatment with ketoconazole, an inhibitor of the tGLI1 pathway in
tissue culture and animal models, reduces circulating tGLI1 associated exosomal miRNA
expression (miR1290 and miR1246) in brain tumor patients.

II. To describe the safety of ketoconazole when administered peri-operatively to patients
with primary and secondary brain tumors.

III. To measure the blood brain penetrance of ketoconazole in serum relative to enhancing
brain tissue.

EXPLORATORY OBJECTIVES:

I. To measure blood brain penetration of ketoconazole in serum relative to cerebrospinal
fluid (CSF) and serum relative to non-enhancing brain tissue (exploratory recurrent glioma
patients only).

II. To compare tGLI1 expression and pathway modulation with ketoconazole pre-treatment in
patients with recurrent gliomas relative to breast cancer brain metastases (BCBM).

III. To determine the overall survival and toxicity outcomes for patients that continue
ketoconazole after surgery, at the discretion of the treating physician.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive ketoconazole orally (PO) once daily (QD) on days 1-4 before standard
surgery in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo standard surgery.

After completion of study treatment, patients are followed up at 30 days.

Inclusion Criteria:

- Subjects must have a history of:

- Histologically confirmed primary breast cancer including primary invasive and
metastatic breast cancers with imaging findings consistent with brain metastasis.
In the event that a patient presents with an initial diagnosis of metastatic
breast cancer with imaging findings of a new brain metastases and unequivocal
imaging findings of a primary breast cancer, consideration for study enrollment
requires approval from the study chair (primary cohort) Or

- Histologically confirmed primary glioma including astrocytoma or
oligodendroglioma of any World Health Organization grade with imaging findings
consistent with recurrent or progressive disease (exploratory cohort). Patients
with ependymoma will not be included.

- Subjects must be undergoing surgical resection for clinical purposes with anticipated
resection of at least 300 mg of tissue

- Patients with any prior number of radiation (including brain radiation), chemotherapy,
or surgical interventions will be eligible for this protocol

- The effects of ketoconazole on the developing human fetus are unknown. For this
reason, women of child-bearing potential and men must agree to use adequate
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 should inform her
treating physician immediately

- Ability to understand and the willingness to sign an Institutional Review Board
(IRB)-approved informed consent document (either directly or via a legally authorized
representative)

Exclusion Criteria:

- Subjects with contraindication to ketoconazole including:

- Prior allergic reaction or intolerance of ketoconazole

- Active hepatitis (based on blood work completed during eligibility assessment)

- Corrected QT (QTc) prolongation (based on electrocardiography [EKG] obtained
during eligibility assessment or within two weeks prior to enrollment)

- Known liver cirrhosis will be excluded from enrollment

- Positive serum pregnancy test within 14 days of enrollment

- Subjects currently taking medications that are included in the contraindicated
concurrent medications section of the Food and Drug Administration (FDA) approved
indications for ketoconazole will be required to complete a seven day wash out period
prior to consideration for enrollment

- Subjects for whom collection of blood, or tissue samples is unsafe or clinically
inadvisable

- Pregnant women are excluded from this study because ketoconazole is a Class B agent
with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with ketoconazole, breastfeeding should be discontinued if the
mother is treated with ketoconazole