A Study of XL765 (SAR245409) in Combination With Temozolomide With and Without Radiation in Adults With Malignant Gliomas

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
A Phase 1 Dose-Escalation Study of XL765 (SAR245409) in Combination With Temozolomide With and Without Radiation in Subjects With Malignant Gliomas

Conditions
-----------------
Mixed Gliomas, Malignant Gliomas, Glioblastoma Multiforme

Intervention / Treatment
-----------------
* Drug: XL765 (SAR245409)
* Drug: Temozolomide


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: XL765 (SAR245409)<br>* Gelatin capsules supplied in 5-mg, 10-mg, and 50-mg strengths; continuous daily dosing<br>Drug: Temozolomide<br>* Capsules supplied in 5-mg, 20-mg, 100-mg, 140-mg, 180-mg, and 250-mg strengths; dosed at 200 mg/m2/day for 5 consecutive days, repeated every 28 days<br>* Other names: Temodar®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, tolerability, and maximum tolerated dose of XL765 administered in combination with temozolomide in subjects with anaplastic gliomas or glioblastoma currently stable on a maintenance temozolomide dose |  | Assessed at each visit/periodic visits | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate plasma pharmacokinetics and pharmacodynamic effects of XL765 and temozolomide when administered in combination |  | Assessed during periodic visits | 
| To evaluate preliminary efficacy of XL765 in combination with temozolomide in adults with anaplastic gliomas or glioblastoma |  | Assessed during periodic visits | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
GBM, Anaplastic glioma