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

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

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme; Malignant Gliomas; Mixed Gliomas
• Intervention / Treatment: Drug: Temozolomide; Drug: XL765 (SAR245409)

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • Investigational Site Number
  • California
    • Los Angeles, California, United States, 90024
      • Investigational Site Number
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Investigational Site Number
  • New York
    • New York, New York, United States, 10021
      • Investigational Site Number
    • Rochester, New York, United States, 14642
      • Investigational Site Number
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Investigational Site Number

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Sanofi

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): February 1, 2012
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: June 20, 2008
• First Submitted That Met QC Criteria: June 20, 2008
• First Posted (Estimate): June 24, 2008

Study Record Updates

• Last Update Posted (Estimate): April 10, 2013
• Last Update Submitted That Met QC Criteria: April 9, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: GBM; Anaplastic glioma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: TED11441; XL765-002 (Other Identifier: (other study code))