Abstract
7-Hydroxystaurosporine (UCN-01) is a protein kinase inhibitor that inhibits several serine-threonine kinases including PKC and PDK1. Due to the preclinical synergistic effects seen with topoisomerase I inhibitors and non-overlapping toxicity, UCN-01 and irinotecan were combined in a dose-finding study designed to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics (PK) of UCN-01 and irinotecan. Patients with incurable solid malignancies received UCN-01 intravenously (IV) as a 3-h infusion on day 1 and irinotecan IV over 90 min on days 1 and 8 of a 21-day cycle. Doses of UCN-01 for subsequent cycles were half the starting dose. Dose level 1 (DL1) consisted of UCN-01 and irinotecan doses of 50 and 60 mg/m(2), respectively. Blood samples were collected in cycle 1 for UCN-01, irinotecan, and irinotecan metabolites. A total of 16 patients were enrolled on the trial at UCN-01/Irinotecan doses of 50/60 mg/m(2) (DL1; n = 1), 70/60 mg/m(2) (DL2; n = 6), 90/60 mg/m(2) (DL3; n = 4), and 70/90 mg/m(2) (DL4; n = 5). Two dose-limiting toxicities were observed each in DL3 and DL4 (2 grade 3 hypophosphatemia, 1 grade 4 hyperglycemia and grade 3 hypophosphatemia, 1 grade 4 febrile neutropenia). Fatigue, diarrhea, nausea, and anorexia were the most prevalent toxicities. No objective responses were documented, and four patients had stable disease for at least ten cycles. The long half-life (292.0 +/- 135.7 h), low clearance (0.045 +/- 0.038 l/h), and volume of distribution (14.3 +/- 5.9 l) observed for UCN-01 are consistent with prior UCN-01 data. There was a significant decrease in C(max) of APC, AUC of APC and SN-38, and AUC ratio of SN-38:irinotecan when comparing days 1 and 8 PK. APC and SN-38 exposure decreased when administered in combination with UCN-01. The MTD of the combination based on protocol criteria was defined as 70 mg/m(2) of UCN-01 on day 1 and 60 mg/m(2) of irinotecan on days 1 and 8 in a 21-day cycle.
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