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The Cyclin-Dependent Kinase Inhibitor UCN-01 Plus Cisplatin in Advanced Solid Tumors: A California Cancer Consortium Phase I Pharmacokinetic and Molecular Correlative Trial

Authors' Affiliations: ¹ University of California Davis Cancer Center, Sacramento, California and ² City of Hope Comprehensive Cancer Center, Duarte, California

Requests for reprints: Primo N. Lara, Jr., University of California Davis Cancer Center, 4501 X Street, Sacramento, CA 95817. Phone: 916-734-3771; Fax: 916-734-7946; E-mail: primo.lara{at}ucdmc.ucdavis.edu.

Background: UCN-01 (7-hydroxy-staurosporine) is a novel antineoplastic agent targeting cyclin-dependent kinases, which shows potent in vitro and in vivo activity against a broad range of tumor types. Our group has previously shown that UCN-01 potentiates the apoptotic response of agents such as cisplatin in vitro by preventing sequence-specific abrogation of G₂ arrest caused by DNA-damaging chemotherapies.

Patients and Methods: This National Cancer Institute–sponsored phase I trial was designed to determine the safety, maximum tolerated dose, and pharmacokinetics of escalating doses of cisplatin in combination with UCN-01 in patients with advanced malignant solid tumors, as well as to do molecular correlative studies on tumor specimens. Cisplatin was infused over 1 hour before UCN-01 (45 mg/m²/d) given as a 72-hour continuous infusion. Escalation of cisplatin was planned through five dose levels at 20, 30, 45, 60, and 75 mg/m².

Results: Ten patients were accrued. Accrual was halted at dose level 2 (cisplatin, 30 mg/m²) due to dose-limiting toxicities consisting of grade 5 sepsis with respiratory failure associated with grade 3 creatinine (one patient) and grade 3 atrial fibrillation (one patient). Plasma and salivary pharmacokinetics of UCN-01 were unaffected by cisplatin. Pretreatment and posttreatment tumor biopsies showed that UCN-01 was active against a key molecular target, the checkpoint kinase Chk1.

Conclusions: This phase I trial failed to achieve targeted therapeutic dose levels of cisplatin when combined with prolonged infusion UCN-01. However, because preclinical data indicate that UCN-01 potentiates response to platinum, further studies with alternative dose schedules of the combination, or with other platinum analogues, are warranted.

Key Words: CDKs and CDK inhibitors • Cellular responses to anticancer drugs • Mechanisms of Drug Action/New Molecular Targets/Therapeutics • Pharmacokinetics and pharmacodynamics • Laboratory correlates

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