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.

PURPOSE: This phase I trial is studying the side effects and best dose of enzastaurin in treating patients with recurrent gliomas.

Condition	Treatment or Intervention	Phase
adult brain tumor	Drug: enzastaurin  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: biological response modifier therapy  Procedure: enzyme inhibitor therapy  Procedure: growth factor antagonist therapy	Phase I

Further Study Details: 

OBJECTIVES:

• Determine the maximum tolerated dose of enzastaurin in patients with recurrent gliomas.
• Compare twice daily dosing of this drug with once daily dosing, in terms of systemic exposure to this drug and its metabolites, in these patients.
• Correlate, preliminarily, protein kinase C-β activity (specifically GSK3-β activation) in peripheral blood mononuclear cells with clinical outcome in patients treated with this drug.
• Determine, preliminarily, the antitumor activity of this drug in these patients.

OUTLINE: This is a dose-escalation study. Patients are stratified according to concurrent enzyme-inducing antiepileptic drug (EIAED) (e.g., phenytoin, carbamazepine, or trileptal) use (yes vs no).

• Patients receive oral enzastaurin once daily in weeks 1-3 and then twice daily in weeks 4-6 OR twice daily in weeks 1-3 and then once daily in weeks 4-6 (course 1). Beginning in course 2, patients receive oral enzastaurin twice daily in weeks 1-6. Treatment repeats every 6 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity. After 9 courses of therapy, patients may receive additional courses at the investigator''''s discretion. Cohorts of 12 patients receive escalating doses of enzastaurin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 4 of 12 patients experience dose-limiting toxicity.
• Patients receive oral enzastaurin as in stratum 1. Cohorts of 6 patients receive escalating doses of enzastaurin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

After completion of study treatment, patients are followed within 2 weeks.

PROJECTED ACCRUAL: Approximately 42 patients (approximately 24 in stratum 1 and 12 in stratum 2) will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed malignant glioma, including any of the following:
• Glioblastoma multiforme
• Anaplastic astrocytoma
• Anaplastic oligodendroglioma
• Anaplastic mixed oligoastrocytoma
• Malignant glioma not otherwise specified
• Primitive neuroectodermal tumors of the CNS
• Progressive low-grade gliomas
• Radiographically diagnosed brain stem gliomas that are refractory to standard treatment
• Recurrent disease
• Must have failed prior radiotherapy
• Unequivocal evidence of tumor progression by MRI or CT scan while on a steroid dosage that has been stable for ≥ 5 days

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• Karnofsky 60-100%

Life expectancy

• More than 8 weeks

Hematopoietic

• WBC ≥ 3,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 10 g/dL* NOTE: *Transfusion allowed

Hepatic

• SGOT ≤ 2 times upper limit of normal (ULN)
• Bilirubin ≤ 2 times ULN
• No significant hepatic disease

Renal

• Creatinine ≤ 1.5 mg/dL AND/OR
• Creatinine clearance ≥ 60 mL/min
• No significant active renal disease

Cardiovascular

• No significant active cardiac disease
• No QTc with Bazett''''s correction that is unmeasurable OR QTc ≥ 460 msec by ECG
• Patients with a QTc ≥ 460 msec by ECG allowed provided repeat ECG is performed ≥ 24 hours later and the average QTc from both ECGs is < 460 msec
• No clinically significant arrhythmia (i.e., multifocal premature ventricular contraction, bigeminy, trigeminy, ventricular tachycardia, or bradycardia) by ECG that is symptomatic or requires treatment
• No asymptomatic sustained ventricular tachycardia
• No ECG suggestive of past or present cardiac ischemia unless patient undergoes appropriate cardiac testing (i.e., echocardiogram and stress test) and the results are negative

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3-6 months after study participation
• Must be able to swallow study drug
• No significant uncontrolled medical illness that would preclude study participation
• No other active malignancy except nonmelanoma skin cancer or carcinoma in situ of the cervix
• No active infection requiring IV antibiotics
• No disease that would obscure toxicity or dangerously alter drug metabolism

PRIOR CONCURRENT THERAPY: Biologic therapy

• At least 1 week since prior interferon or thalidomide
• No concurrent immunotherapy

Chemotherapy

• At least 2 weeks since prior vincristine
• At least 6 weeks since prior nitrosoureas
• At least 3 weeks since prior procarbazine
• No concurrent standard or anticancer chemotherapy

Endocrine therapy

• See Disease Characteristics
• At least 1 week since prior tamoxifen

Radiotherapy

• See Disease Characteristics
• At least 4 weeks since prior and no concurrent radiotherapy

Surgery

• Prior surgical resection of recurrent or progressive tumor allowed provided patient has recovered
• Residual disease after prior resection of tumor is not required

Other

• Recovered from prior therapy
• At least 2 weeks since prior noncytotoxic investigational agents
• At least 4 weeks since prior cytotoxic therapy
• At least 1 week since other prior noncytotoxic agents (e.g., isotretinoin) except radiosensitizers
• At least 2 weeks since prior enzyme-inducing antiepileptic drugs (stratum 1)
• No other concurrent investigational agents

Please refer to this study by ClinicalTrials.gov identifier  NCT00112788

Study chairs or principal investigators

Howard A. Fine, MD,  Principal Investigator,  NCI - Neuro-Oncology Branch   

Study ID Numbers:  CDR0000429472; NCI-05-C-0136; NCT00108056
Record last reviewed:  May 2005
Last Updated:  June 2, 2005
Record first received:  June 2, 2005
ClinicalTrials.gov Identifier:  NCT00112788
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-06-07