Phase 1 study of ptk787/zk 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome

ABSTRACT PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR,

VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety,

tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute

myeloid leukemia (AML), secondary AML, poor-prognosis _de novo_ AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective

could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500–1000 mg orally b.i.d. Safety and pharmacokinetic data were collected.

Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia

were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that

steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD).

Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy.In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well

tolerated and can be given in combination with chemotherapy for patients with MDS and AML. Access through your institution Buy or subscribe This is a preview of subscription content, access

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University/The New York Presbyterian Hospital, New York, NY, USA G J Roboz, R Carlin, M W Schuster & E J Feldman * MD Anderson Cancer Center, The University of Texas, Houston, TX, USA F

J Giles & J E Cortes * Arizona Cancer Center, Tucson, AZ, USA A F List * Novartis Pharmaceuticals Corp., East Hanover, NJ, USA M Kowalski, S Bilic, E Masson & M Rosamilia * Schering

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ARTICLE CITE THIS ARTICLE Roboz, G., Giles, F., List, A. _et al._ Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid

leukemia and myelodysplastic syndrome. _Leukemia_ 20, 952–957 (2006). https://doi.org/10.1038/sj.leu.2404213 Download citation * Received: 15 November 2005 * Revised: 24 January 2006 *

Accepted: 02 February 2006 * Published: 13 April 2006 * Issue Date: 01 June 2006 * DOI: https://doi.org/10.1038/sj.leu.2404213 SHARE THIS ARTICLE Anyone you share the following link with

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content-sharing initiative KEYWORDS * myelodysplastic syndrome * VEGF