Gossypol in Treating Patients With Progressive or Recurrent Glioblastoma Multiforme

PRIMARY OBJECTIVES:

I. To estimate the overall survival rate associated with AT-101 in treating adult patients
with recurrent glioblastoma multiforme.

SECONDARY OBJECTIVES:

I. To assess and estimate the acute and late toxicities. II. Tumor response rate. III. To
estimate 6-month progression free survival. IV. To explore associations of the clinical
outcome (overall survival) among the changes of potential serum biomarkers, baseline tumor
protein expression and gene methylation status.

OUTLINE: This is a multicenter study.

Patients receive oral R-(-)-gossypol once daily on days 1-21. Treatment repeats every 28
days in the absence of disease progression or unacceptable toxicity.

Patients undergo tumor tissue and blood sample collection at baseline and periodically
during study for biomarker correlative studies. Archived tumor tissue samples, if available,
are analyzed for Bcl-2 family protein expression (e.g., Bcl-2, Bcl-xL, MCl-1, Bax, Bak, and
BH3 domain for BH3 members only) and MGMT gene methylation status. Blood samples are
analyzed for apoptotic protein levels (Bcl-2) by enzyme-linked immunosorbent assay.

After completion of study therapy, patients are followed every 2 months.

Inclusion Criteria:

- Patients must have histologically confirmed supratentorial glioblastoma multiforme
which is progressive or recurrent after radiation therapy ± chemotherapy; patients
with previously low grade glioma who progressed after radiotherapy ± chemotherapy and
are biopsied and found to have glioblastoma multiforme are eligible

- Patients must have tumor tissue form completed and signed by a pathologist

- Patients must have measurable contrast enhancing progressive or recurrent
glioblastoma multiforme by MRI or CT imaging (Within 14 days before starting
treatment)

- Patients must have recovered from toxicity of prior therapy; an interval of at least
3 months must have elapsed since the completion of the most recent course of
radiation therapy, while at least 3 weeks must have elapsed since the completion of a
non-nitrosourea containing chemotherapy regimen, and at least 6 weeks since the
completion of a nitrosourea containing chemotherapy regimen; NOTE: For non-cytotoxic,
FDA approved agents (i.e. celebrex, thalidomide, etc.) therapy could be started 2
weeks after discontinuing this agent provided the patient has fully recovered from
all toxicity associated with the agent; for investigational, non-cytotoxic agents a
minimum of 3 weeks must have elasped before the patient will be eligible for this
study

- 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 >= 1500/mm^3

- Platelets >= 100,000/mm^3

- Creatinine =< 1.5mg/dl

- Total Bilirubin =< 1.5mg/dl

- Transaminases =< 2.5 times above the upper limits of the institutional norm

- Patients must be able to provide written informed consent

- Women of childbearing potential must have a negative serum pregnancy test; the
effects of AT-101 on the developing human fetus at the recommended therapeutic dose
are unknown; for this reason and because Bcl-2 inhibitors have the potential to be
teratogenic, 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, and for at least one month
following the last dose of AT-101; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately

- Patients must have a Mini Mental State Exam score >= 15

Exclusion Criteria:

- Patients with serious concurrent infection or medical illness which would jeopardize
the ability of the patient to receive the treatment outlined in this protocol with
reasonable safety; (Examples of medical illnesses are [but not limited to] the
following: uncontrolled hypertension, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that
would limit compliance with study requirements)

- Patients who are pregnant or breast-feeding

- Patients who have received more than two prior treatments

- Patients who have been previously treated with gossypol, or have allergies to
gossypol

- Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or
investigational agents); concurrent steroid use is allowed

- Patients with a concurrent malignancy are ineligible unless they are patients with
curatively treated carcinoma-in-situ or basal cell carcinoma of the skin; patients
with a prior malignancy are ineligible unless they have been free of disease for >=
five years

- Patients with ≥ Grade 2 sensory neuropathy based on the NCI CTCAE

- Patients who are taking iron supplements

- Patients with any condition (e.g., gastrointestinal tract disease resulting in an
inability to take oral medication or a requirement for IV alimentation, prior
surgical procedures affecting absorption, or active peptic ulcer disease) that
impairs their ability to swallow pills are excluded

- Patients cannot be receiving cytochrome P450-inducing anticonvulsants (EIAEDs; e.g.,
phenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine)

- Patients with malabsorption syndrome, disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel are excluded;
subjects with ulcerative colitis, inflammatory bowel disease, or a partial or
complete small bowel obstruction are also excluded

- Eligibility of patients receiving any other medications or substances known to affect
or with the potential to affect the activity or pharmacokinetics of AT-101 will be
determined following review of their case by the Principal Investigator

- Patients with symptomatic hypercalcemia that is > Grade 2 (according to CTCAE)

- Requirement for routine use of hematopoietic growth factors (including granulocyte
colony stimulating factor, granulocyte macrophage colony stimulating factor, or
interleukin-11) or platelet transfusions to maintain absolute neutrophil counts or
platelets counts above the required thresholds for study entry

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with AT-101; in addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy; appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated