title: Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer.
abstract: OBJECTIVE
  This phase I study was conducted to determine the recommended dose of enzastaurin, an oral protein kinase C beta (PKCbeta) inhibitor, for phase II trials. Secondary objectives were maximum-tolerated dose (MTD), pharmacokinetics (PK), toxicity, and response.
  
  
  METHODS
  Patients at least 18 years of age with advanced cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1 lower received enzastaurin orally once daily at a starting dose of 20 mg. Dose escalation proceeded using a modified Simon design.
  
  
  RESULTS
  All 47 patients enrolled (mean age, 58 years) received at least one dose of enzastaurin, with a median of two cycles (range, one to 17 cycles). Prevalent malignancies were lung (n = 10) and head and neck cancers (n = 9). Although no MTD was identified up to 700 mg/d, 525 mg was chosen as the recommended dose, and 12 additional patients were accrued at that level. Three dose-limiting toxicities (QTc changes) occurred: one at the 700-mg dose (patient discontinued), and two in the expansion cohort at the 525-mg dose. Total analytes (enzastaurin and its metabolites) exposure increased with increasing doses up to 240 mg, and appeared to plateau at 525 and 700 mg. Grade 1 chromaturia, fatigue, and other GI toxicities were the most common, while no clinically significant grade 3/4 toxicities occurred. Two deaths, unrelated to enzastaurin, occurred. Twenty-one patients (45%) achieved stable disease (SD) for two to 16 cycles.
  
  
  CONCLUSIONS
  On the basis of plasma exposures and safety data, enzastaurin 525 mg once daily is the recommended phase II dose. Enzastaurin is well tolerated up to 700 mg/d. Evidence of early activity was seen with significant stable disease.
authors.affiliation: Division of Medical Oncology, Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Luna
authors.initials: L
authors.lastname: Musib
authors.forename: Merrill S
authors.initials: MS
authors.lastname: Kies
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.forename: Mylene
authors.initials: M
authors.lastname: Truong
authors.forename: Julie R
authors.initials: JR
authors.lastname: Brahmer
authors.forename: Patricia
authors.initials: P
authors.lastname: Cole
authors.forename: Rana
authors.initials: R
authors.lastname: Sullivan
authors.forename: Jeanne
authors.initials: J
authors.lastname: Riddle
authors.forename: Jill
authors.initials: J
authors.lastname: Schmidt
authors.forename: Nathan
authors.initials: N
authors.lastname: Enas
authors.forename: Vikram
authors.initials: V
authors.lastname: Sinha
authors.forename: Donald E
authors.initials: DE
authors.lastname: Thornton
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C504878:enzastaurin