A Study of XL765 (SAR245409) in Combination With Temozolomide With and Without Radiation in Adults With Malignant Gliomas
A Study of XL765 (SAR245409) in Combination With Temozolomide With and Without Radiation in Adults With Malignant Gliomas
The purpose of this study is to determine the safety and tolerability of XL765 in combination
 with Temozolomide in adults with anaplastic gliomas or glioblastoma on a stable Temozolomide
 maintenance dose. XL765 is a new chemical entity that inhibits the kinases PI3K and mTOR. In
 preclinical studies, inactivation of PI3K has been shown to inhibit growth and induce
 apoptosis (programmed cell death) in tumor cells, whereas inactivation of mTOR has been shown
 to inhibit the growth of tumor cells. Temozolomide (TMZ, Temodar®) is an orally administered
 alkylating agent with activity against malignant gliomas. It is approved by the Food and Drug
 Administration for the following indications: 1) treatment of newly diagnosed glioblastoma
 multiforme (GBM) patients when given concomitantly with radiotherapy and then as maintenance
 treatment; 2) refractory anaplastic astrocytoma (AA), ie, patients who have experienced
 disease progression on a drug regimen containing nitrosourea and procarbazine. Temozolomide
 is commonly used in the treatment of other anaplastic gliomas (AG) including oligodendroglial
 tumors and mixed gliomas.
Inclusion Criteria:

 -  Histologically confirmed intracranial Grade 3 or 4 anaplastic glioma or glioblastoma
 (astrocytic tumor, anaplastic oligodendroglioma, or oligoastrocytoma)

 -  Received prior standard radiation for a Grade 3 or 4 astrocytic tumor with a minimum
 cumulative dose of 40 Gy administered

 -  Completed at least one full cycle of temozolomide of 200 mg/m2/day administered on
 Days 1-5 of a 28-day cycle, without unacceptable toxicity or progression

 -  Karnofsky performance status of 60 or more

 -  Adequate organ and bone marrow function as defined by hematological and serum
 chemistry limits

 -  At least 18 years old.

 -  Both men and women must practice adequate contraception

 -  Informed consent

 Exclusion Criteria:

 -  Progressed while on temozolomide

 -  Evidence of acute intracranial or intratumoral hemorrhage > Grade 1

 -  Restriction of some therapies/medications within specific timeframes prior to
 enrollment and during the study including cytotoxic chemotherapy other than
 temozolomide, biologic agents, nitrosoureas or mitomycin C, small-molecule kinase
 inhibitors, non-cytotoxic hormonal agents, prior therapy with a PI3K inhibitors,
 radiation therapy, enzyme-inducing anti-convulsants, valproic acid

 -  Not recovered from the toxic effects of prior therapy

 -  Pregnant or breast feeding

 -  History of diabetes mellitus

 -  Uncontrolled intercurrent illness

 -  Congestive heart failure, unstable angina, or a myocardial infarction within 3 months
 of entering the study.

 -  HIV positive

 -  Diagnosis of another malignancy may exclude subject from study