A Phase 2 Study of R-(-)-Gossypol (Ascenta's AT-101) in Recurrent Glioblastoma Multiforme
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