Clinical and Molecular-Metabolic Phase II Trial of Perifosine for Recurrent/Progressive Malignant Gliomas

This is a phase II study of the small molecule inhibitor perifosine (NSC 639966, D21266,
KRX-0401) in the treatment of patients with recurrent glioblastoma multiforme (GBM) and other
recurrent malignant gliomas. The goal of the phase II study is to determine efficacy as
measured by the progressionfree survival rate after 6 months of treatment. Secondary goals
include determination of molecular and metabolic effects of perifosine by tissue analysis and
PET imaging.

In addition, when cytoreductive surgery is recommended as part of the standard of care at
study entry, patients will be considered for a "surgical arm." In this case, patients will
receive perifosine for 5-10 days before surgery during which tumor will be aliquoted both for
diagnostic purposes and for molecular effects of the drug in vivo and for analysis of drug
penetration into tumor tissue.

Inclusion Criteria:

- Patients must have shown unequivocal evidence for tumor progression by MRI or CT scan.

- Patients must be on a stable or decreasing dose of corticosteroids for a minimum of 5
days before the baseline MRI and PET scans.

- Patients must have failed prior radiation therapy.

- Patients with prior therapy that included interstitial brachytherapy or stereotactic
radiosurgery (including gamma-knife or cyber-knife) must have confirmation of true
progressive disease rather than radiation necrosis based upon either PET or Thallium
scanning, and/or MR spectroscopy, and/or MR Perfusion, and/or surgical documentation
of disease.

- All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study. Patients must have signed an authorization for
the release of their protected health information.

- Age > 18 years old, and with a life expectancy > 8 weeks.

- Karnofsky Performance Status ≥ 50%

- Patients must have recovered from all acute toxicities from prior therapies. At least
28 days must have elapsed since prior radiation.

- Patients must have adequate bone marrow function

- Patients must agree to practice adequate contraception.

Exclusion Criteria:

- Patients must not be taking EIAEDs

- Patients must not have any significant medical illnesses or other history that in the
investigator's opinion cannot be adequately controlled with appropriate therapy or
would compromise the patient's ability to tolerate this therapy.

- Patients with a history of any other cancer (except non-melanoma skin cancer or
carcinoma in-situ of the cervix), unless in complete remission and off of all therapy
for that disease for a minimum of 3 years are ineligible.

- Patients must not have active infection or serious intercurrent medical illness.

- HIV-Positive patients receiving combination anti-retroviral therapy are excluded from
the study due to possible retro-viral drug interactions.

- Patients must not have any disease that will obscure toxicity or dangerously alter
drug metabolism.