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

Purpose: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor w ith 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 cycle s. Results: The most frequent treatment-related toxicities were nausea, vomiti ng, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 1 5 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; a nd six of 16 patients developed CTC grade 2 diarrhea. After 1 month of trea tment, there were significant reductions in circulating lymphocyte (P <.02) and monocyte (P <.01) counts in patients receiving doses greater than or e qual to 100 mg/d. Nevertheless, only two patients developed myelosuppressio n (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasti ng 4 months. There was a linear relationship between PKC412 dose and area u nder the curve(0-24 hours) and maximum plasma concentration with marked int erpatient variability. The estimated median elimination half-life was 1.6 d ays (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 3 6 days was detected. Steady-state PKC412 plasma levels at the top three dos e cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 mu mol/L. Conclusion: PKC412 can 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 additi onally needed to optimize the drug dose and schedule. J Clin Oncol 19:1485- 1492. (C) 2001 by American Society of Clinical Oncology.