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Phase I and Pharmacokinetic Study of 7-Hydroxystaurosporine and Carboplatin in Advanced Solid Tumors

Purpose: Based on preclinical data showing synergy between 7-hydroxystaurosporine (UCN-01) and platinum agents, a phase I trial of carboplatin with UCN-01 administered as a 3 h infusion in patients with advanced solid tumors was done. The primary goals of this trial were to evaluate the tolerability of this combination and the pharmacokinetics of UCN-01 when administered over 3 h and to compare the tolerability and pharmacokinetics with previously described schedules. Patients and Methods: Patients with advanced solid tumors, good performance status, normal organ function, and no potentially curative therapy were eligible for the trial. Carboplatin was escalated from an area under the curve (AUC) of 3 to an AUC of 5. UCN-01 was escalated from 50 to 90 mg/m2. Results: Twenty-three patients with advanced solid tumors (20 with prior platinum treatment) received a total of 60 cycles of therapy. Full doses of both agents (carboplatin AUC 5, UCN-01 90 mg/m2 in cycle 1, 45 mg/m2 in subsequent cycles) could be administered. The major toxicity noted was hypotension, which could be abrogated with the use of saline prehydration and posthydration. No responses were seen; however, seven patients were able to receive more than two courses of therapy. Of note, two of three patients with refractory, progressive small cell lung cancer were able to receive six cycles of therapy without evidence of progression. One patient experienced resolution of paraneoplastic syndrome of inappropriate antidiuretic hormone. The pharmacokinetic variables Cmax and t1/2 of the 3 h infusion were essentially identical to those previously observed when UCN-01 was administered over 72 h. The average t1/2 for cycle 1 was 506 ± 301 h, and the mean Cmax for all dose levels was >30 μmol/L. The mean AUC over the dosing interval for each dose level ranged from ∼6,000 to 9,000 μmol/L h. Thus, the AUC of UCN-01 after the 3 h infusion was lower than was observed after a 72 h infusion. Conclusion: The regimen of carboplatin and UCN-01 (administered as a 3 h infusion) was well tolerated. Further development of this combination, particularly in small cell lung cancer, is warranted.