Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer

Michael A. Carducci, Luna Musib, Merrill S. Kies, Roberto Pili, Mylene Truong, Julie R. Brahmer, Patricia Cole, Rana Sullivan, Jeanne Riddle, Jill Schmidt, Nathan Enas, Vikram Sinha, Donald E. Thornton, Roy S. Herbst

Research output: Contribution to journalArticle

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Abstract

Purpose: This phase I study was conducted to determine the recommended dose of enzastaurin, an oral protein kinase C beta (PKCβ) inhibitor, for phase II trials. Secondary objectives were maximum-tolerated dose (MTD), pharmacokinetics (PK), toxicity, and response. Patients and 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)4092-4099
Number of pages8
JournalJournal of Clinical Oncology
Volume24
Issue number25
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

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Protein Kinase C beta
Pharmacokinetics
Neoplasms
Maximum Tolerated Dose
Head and Neck Neoplasms
enzastaurin
Fatigue
Safety
Lung

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. / Carducci, Michael A.; Musib, Luna; Kies, Merrill S.; Pili, Roberto; Truong, Mylene; Brahmer, Julie R.; Cole, Patricia; Sullivan, Rana; Riddle, Jeanne; Schmidt, Jill; Enas, Nathan; Sinha, Vikram; Thornton, Donald E.; Herbst, Roy S.

In: Journal of Clinical Oncology, Vol. 24, No. 25, 01.09.2006, p. 4092-4099.

Research output: Contribution to journalArticle

Carducci, MA, Musib, L, Kies, MS, Pili, R, Truong, M, Brahmer, JR, Cole, P, Sullivan, R, Riddle, J, Schmidt, J, Enas, N, Sinha, V, Thornton, DE & Herbst, RS 2006, 'Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer', Journal of Clinical Oncology, vol. 24, no. 25, pp. 4092-4099. https://doi.org/10.1200/JCO.2005.05.3447
Carducci, Michael A. ; Musib, Luna ; Kies, Merrill S. ; Pili, Roberto ; Truong, Mylene ; Brahmer, Julie R. ; Cole, Patricia ; Sullivan, Rana ; Riddle, Jeanne ; Schmidt, Jill ; Enas, Nathan ; Sinha, Vikram ; Thornton, Donald E. ; Herbst, Roy S. / Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 25. pp. 4092-4099.
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T1 - Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer

AU - Carducci, Michael A.

AU - Musib, Luna

AU - Kies, Merrill S.

AU - Pili, Roberto

AU - Truong, Mylene

AU - Brahmer, Julie R.

AU - Cole, Patricia

AU - Sullivan, Rana

AU - Riddle, Jeanne

AU - Schmidt, Jill

AU - Enas, Nathan

AU - Sinha, Vikram

AU - Thornton, Donald E.

AU - Herbst, Roy S.

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N2 - Purpose: This phase I study was conducted to determine the recommended dose of enzastaurin, an oral protein kinase C beta (PKCβ) inhibitor, for phase II trials. Secondary objectives were maximum-tolerated dose (MTD), pharmacokinetics (PK), toxicity, and response. Patients and 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. Conclusion: 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.

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