This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dees, E. C. Articles by Donehower, R. C. Search for Related Content PubMed PubMed Citation Articles by Dees, E. C. Articles by Donehower, R. C.

A Phase I and Pharmacokinetic Study of Short Infusions of UCN-01 in Patients with Refractory Solid Tumors

Divisions of ¹ Medical Oncology and ² Experimental Therapeutics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland and ³ Walter Reed Army Medical Center, Washington, District of Columbia

Requests for reprints: Ross C. Donehower, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Room 187, Baltimore, MD 21231. Phone: 410-955-8838; Fax: 410-955-0125; E-mail: rdonehow{at}jhmi.edu.

Purpose: To define the maximum tolerated dose and the dose-limiting toxicity of the kinase modulator UCN-01 administered as a short (1-3 hours) infusion to patients with refractory solid tumors and to evaluate the pharmacokinetics of this novel agent.

Experimental Design: Twenty-four patients (15 men, 9 women; median age, 59 years; Eastern Cooperative Oncology Group Performance Status, 0-2) were treated with UCN-01 in this phase I study. Using an accelerated titration design, six dose levels were evaluated ranging from 3 mg/m² over 3 hours to 95 mg/m² over 1 to 3 hours administered every 28 days. Plasma, urine, and saliva samples were collected for pharmacokinetic analysis.

Results: Seventy courses were evaluable for toxicity. The most frequent adverse events were grade 1 to 2 nausea, vomiting, hyperglycemia, and hypotension. Hypotension was dose limiting at 95 mg/m² when UCN-01 was administered over 1 hour. The recommended dose of UCN-01 as a short infusion is 95 mg/m² over 3 hours for the first course and 47.5 mg/m² over 3 hours for second and subsequent courses. No objective responses were observed. Mean (SD) pharmacokinetic variable values in nine patients treated at 95 mg/m² over 3 hours were volume of distribution at steady state, 14 (5.4) L; ß half-life, 406 (151) hours; systemic clearance, 0.028 (0.017) L/h; C_max, 51 (16) µmol/L; and area under the curve, 19,732 (12,195) µmol/L h.

Conclusions: UCN-01 is well tolerated when given at doses of 95 mg/m² over 3 hours every 28 days with second and subsequent courses given at 50 % of the first course dose.

Key Words: UCN-01 • antineoplastic agent • toxicity • pharmacokinetics • kinase modulator

This article has been cited by other articles:

				H. Hamed, W. Hawkins, C. Mitchell, D. Gilfor, G. Zhang, X.-Y. Pei, Y. Dai, M. P. Hagan, J. D. Roberts, A. Yacoub, et al. Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell death in vitro and in vivo Mol. Cancer Ther., March 1, 2008; 7(3): 616 - 629. [Abstract] [Full Text] [PDF]

				Y. Dai, P. Khanna, S. Chen, X.-Y. Pei, P. Dent, and S. Grant Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation Blood, May 15, 2007; 109(10): 4415 - 4423. [Abstract] [Full Text] [PDF]

				M. J. Edelman, K. S. Bauer Jr., S. Wu, R. Smith, S. Bisacia, and J. Dancey Phase I and Pharmacokinetic Study of 7-Hydroxystaurosporine and Carboplatin in Advanced Solid Tumors Clin. Cancer Res., May 1, 2007; 13(9): 2667 - 2674. [Abstract] [Full Text] [PDF]

				R. P. Perez, L. D. Lewis, A. P. Beelen, A. J. Olszanski, N. Johnston, C. H. Rhodes, B. Beaulieu, M. S. Ernstoff, and A. Eastman Modulation of Cell Cycle Progression in Human Tumors: A Pharmacokinetic and Tumor Molecular Pharmacodynamic Study of Cisplatin Plus the Chk1 Inhibitor UCN-01 (NSC 638850) Clin. Cancer Res., December 1, 2006; 12(23): 7079 - 7085. [Abstract] [Full Text] [PDF]

				D. Sampath, J. Cortes, Z. Estrov, M. Du, Z. Shi, M. Andreeff, V. Gandhi, and W. Plunkett Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial Blood, March 15, 2006; 107(6): 2517 - 2524. [Abstract] [Full Text] [PDF]

				S. J. Hotte, A. Oza, E. W. Winquist, M. Moore, E. X. Chen, S. Brown, G. R. Pond, J. E. Dancey, and H. W. Hirte Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium study Ann. Onc., February 1, 2006; 17(2): 334 - 340. [Abstract] [Full Text] [PDF]

				E. Fuse, T. Kuwabara, A. Sparreboom, E. A. Sausville, and W. D. Figg Review of UCN-01 Development: A Lesson in the Importance of Clinical Pharmacology J. Clin. Pharmacol., April 1, 2005; 45(4): 394 - 403. [Abstract] [Full Text] [PDF]