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

Sponsor

Sanofi (Industry)

Overall Status

Completed

CT.gov ID

NCT00704080

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Mixed Gliomas Malignant Gliomas Glioblastoma Multiforme	Drug: XL765 (SAR245409) Drug: Temozolomide	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

54 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Aug 1, 2008

Actual Primary Completion Date :

Feb 1, 2012

Actual Study Completion Date :

Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: XL765 (SAR245409) Gelatin capsules supplied in 5-mg, 10-mg, and 50-mg strengths; continuous daily dosing Drug: Temozolomide 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 Other Names: Temodar®

Arm

Intervention/Treatment

Experimental: 1

Drug: XL765 (SAR245409)

Gelatin capsules supplied in 5-mg, 10-mg, and 50-mg strengths; continuous daily dosing

Drug: Temozolomide

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

Other Names:

Temodar®

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number	Birmingham	Alabama	United States	35205
2	Investigational Site Number	Los Angeles	California	United States	90024
3	Investigational Site Number	Boston	Massachusetts	United States	02115
4	Investigational Site Number	New York	New York	United States	10021
5	Investigational Site Number	Rochester	New York	United States	14642
6	Investigational Site Number	Cleveland	Ohio	United States	44195