A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas.
Enzastaurin, a potent inhibitor of protein kinase C-beta, inhibits angiogenesis and has direct cytotoxic activity against glioma cells in preclinical studies. Patients with recurrent high-grade gliomas were stratified by histology and use of enzyme-inducing antiepileptic drugs (EIAEDs). Patients on EIAED were treated on the phase I dose-escalation portion of the trial with evaluation of serum pharmacokinetics as the primary endpoint. Patients not on EIAED were treated on the phase II portion of the trial with radiographic response and progression-free survival (PFS) as primary objectives. Patients in phase I received enzastaurin 525-900 mg/d. Phase II patients received 500 or 525 mg/d. One hundred and eighteen patients were accrued to this trial. Therapy was well tolerated with thrombosis, thrombocytopenia, hemorrhage, and elevated alanine aminotransferase as the most commonly observed drug-associated grade 3 or higher toxicities. Patients on EIAED had serum enzastaurin exposure levels approximately 80% lower than those not on EIAED. Dose escalations up to 900 mg/d did not substantially increase serum exposure levels and a maximally tolerated dose was never reached. Twenty-one of 84 evaluable patients (25%) experienced an objective radiographic response. The 6-month PFS was 7% for patients with glioblastoma and 16% for patients with anaplastic glioma. Phosphorylation of glycogen synthase kinase-3 in peripheral blood mononuclear cells was identified as a potential biomarker of drug activity. Enzastaurin has anti-glioma activity in patients with recurrent high-grade glioma, but does not appear to have enough single-agent activity to be useful as monotherapy.
Neuro-Oncology Branch, National Cancer Institute, NIH, 9030 Old Georgetown Road, Bloch Bldg. 82, room 225, Bethesda, MD 20892, USA.
Teri N
TN
Kreisl
Svetlana
S
Kotliarova
John A
JA
Butman
Paul S
PS
Albert
Lyndon
L
Kim
Luna
L
Musib
Donald
D
Thornton
Howard A
HA
Fine
D000927:Anticonvulsants / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D007211:Indoles; C504878:enzastaurin