Clinical trial NCT00704080: A Study of XL765 (SAR245409) in Combination With Temozolomide With and Without Radiation in Adults With Malignant 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Mixed Gliomas
Malignant Gliomas
Glioblastoma Multiforme
Keywords: GBM
Anaplastic glioma
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2008-06-24
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: 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
timeFrame: Assessed at each visit/periodic visits
Secondary outcomes:
measure: To evaluate plasma pharmacokinetics and pharmacodynamic effects of XL765 and temozolomide when administered in combination
timeFrame: Assessed during periodic visits
measure: To evaluate preliminary efficacy of XL765 in combination with temozolomide in adults with anaplastic gliomas or glioblastoma
timeFrame: Assessed during periodic visits
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Investigational Site Number
state: Alabama
city: Los Angeles
country: United States
facility: Investigational Site Number
state: California
city: Boston
country: United States
facility: Investigational Site Number
state: Massachusetts
city: New York
country: United States
facility: Investigational Site Number
state: New York
city: Rochester
country: United States
facility: Investigational Site Number
state: New York
city: Cleveland
country: United States
facility: Investigational Site Number
state: Ohio
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: