Enzastaurin and Temozolomide in Treating Patients With Primary Gliomas

Study Overview
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Brief Summary
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RATIONALE: Enzastaurin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving enzastaurin together with temozolomide may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of enzastaurin when given together with temozolomide in treating patients with primary gliomas.

Detailed Description
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OBJECTIVES: To assess if full doses of enzastaurin hydrochloride and temozolomide can be used in combination for the treatment of patients with primary gliomas. To determine the recommended phase II dose. OUTLINE: This is a multicenter study. Patients receive oral enzastaurin hydrochloride once or twice daily on days 1-28* and oral temozolomide once daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. NOTE: *During the first course only, patients also receive enzastaurin hydrochloride on day -1. Patients undergo blood sample collection on day 22 of course 1 and on day 5 of course 2 for pharmacokinetic studies of enzastaurin hydrochloride. After completion of study treatment, patients are followed within 30 days and then every 3 months thereafter.

Official Title
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Phase I Study of Enzastaurin and Temozolomide in Patients With Gliomas

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: enzastaurin hydrochloride
* Drug: temozolomide
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed primary supratentorial glioma WHO histologic grade 3 or 4 Patients who have undergone prior treatment for low-grade glioma that has transformed to glioblastoma (biopsy proven) allowed Amenable to standard temozolomide treatment First or second recurrent disease after prior surgery and/or radiotherapy OR newly diagnosed disease that is not amenable to radiotherapy (e.g., multifocal disease) PATIENT CHARACTERISTICS: ECOG or WHO performance status 0-2 Hemoglobin ≥ 10.0 g/dL Neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin ≤ 1.5 x upper limit of normal (ULN) Alkaline phosphatase and transaminases ≤ 2.5 x ULN Serum creatinine < 1.7 mg/dL Not pregnant or lactating Negative pregnancy test Fertile patients must use effective contraception Clinically normal cardiac function No ischemic heart disease within the past 6 months No clinically significant abnormalities or uncontrolled cardiac arrhythmia by ECG QTc interval ≤ 450 msec (males) or ≤ 470 msec (females) by baseline 12-lead ECG No history of congenital long QTc syndrome No history of stroke No other prior or concurrent malignancy within the past 5 years except cone biopsied carcinoma of the cervix or adequately treated basal or squamous cell skin carcinoma No unstable systemic diseases No active uncontrolled infections No uncontrolled hypertension No psychological, familial, sociological, or geographical condition that would preclude study participation Must be able to swallow tablets PRIOR CONCURRENT THERAPY: See Disease Characteristics No more than 1 prior chemotherapy regimen in the adjuvant setting or for first recurrence Prior temozolomide allowed provided there was no disease progression during temozolomide treatment or within 6 weeks of completing temozolomide treatment Prior surgery for primary brain tumor within the past 3 months allowed Patients who are receiving corticosteroid treatment must be on a stable or decreasing dose for at least 1 week before study entry At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) At least 14 days since prior and no concurrent enzyme-inducing antiepileptic drugs including, but not limited to, any of the following: Phenytoin Carbamazepine Phenobarbital More than 30 days since prior and no other concurrent investigational treatments No concurrent anticoagulant treatment (e.g., warfarin) Low molecular weight heparin for patients who require anticoagulant therapy after starting study treatment may be allowed No concurrent routine use of colony-stimulating factors No other concurrent anticancer agents

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: enzastaurin hydrochloride|nan|
|Drug: temozolomide|nan|
|Other: pharmacological study|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase II dose |  |  | 
| Dose-limiting toxicity |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate |  |  | 
| Progression-free survival |  |  | 
| Overall survival |  |  | 
| Pharmacokinetics of enzastaurin hydrochloride alone and in combination with temozolomide |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult brain tumor, adult mixed glioma, adult anaplastic astrocytoma, adult anaplastic oligodendroglioma, adult glioblastoma, adult anaplastic ependymoma, adult giant cell glioblastoma, adult gliosarcoma, adult pineal gland astrocytoma