Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C

D. J. Propper, A. C. McDonald, A. Man, P. Thavasu, F. Balkwill, J. P. Braybrooke, F. Caponigro, P. Graf, C. Dutreix, R. Blackie, S. B. Kaye, T. S. Ganesan, D. C. Talbot, A. L. Harris, C. Twelves

Research output: Contribution to journalArticlepeer-review


Purpose: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days. Patients and Methods: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles. Results: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P <.02) and monocyte (P <.01) counts in patients receiving doses ≥ 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangio-carcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was o linear relationship between PKC412 dose and area under the curve0-24 hours and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 limes the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 μmol/L. Conclusion: PKC412 con be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.

Original languageEnglish
Pages (from-to)1485-1492
Number of pages8
JournalJournal of Clinical Oncology
Issue number5
Publication statusPublished - Mar 1 2001

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


Dive into the research topics of 'Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C'. Together they form a unique fingerprint.

Cite this