ORIGINAL ARTICLE Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome GJ Roboz 1 , FJ Giles 2 , AF List 3 , JE Cortes 2 , R Carlin 1 , M Kowalski 4 , S Bilic 4 , E Masson 4 , M Rosamilia 4 , MW Schuster 1 , D Laurent 5 and EJ Feldman 1 1 Leukemia Program, Weill Medical College of Cornell University/The New York Presbyterian Hospital, New York, NY, USA; 2 MD Anderson Cancer Center, The University of Texas, Houston, TX, USA; 3 Arizona Cancer Center, Tucson, AZ, USA; 4 Novartis Pharmaceuticals Corp., East Hanover, NJ, USA and 5 Schering AG, Berlin, Germany 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 monother- apy 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 evalu- ated 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. Leukemia (2006) 20, 952–957. doi:10.1038/sj.leu.2404213; published online 13 April 2006 Keywords: myelodysplastic syndrome; VEGF Introduction Angiogenesis plays a critical role in the growth of solid tumors by facilitating delivery of nutrients to and removal of waste products from the tumor bed. 1–3 Angiogenic molecules and neovascular response may also contribute to the pathobiology of hematologic malignancies, such as leukemia. 4–7 Vascular endo- thelial growth factor-A (VEGF-A), a member of the VEGF family of angiogenic factors (VEGF-A, VEGF-B, VEGF-C, VEGF-D), is the principal growth and survival factor for endothelial cells. Expression of VEGF-A is upregulated in tumor tissue and overexpression of VEGF-A or exogenously administered VEGF-A promotes tumor growth and metastasis. 8–10 The trophic effects of VEGFs are mediated through three receptor tyrosine kinases (RTK): VEGFR-1/Flt-1, VEGFR-2/KDR/Flk-1 and VEGFR-3/Flt-4. The VEGFR-2 is critical for transmission of cellular signals promoting proliferation and differentiation of endothelial cells, and mice deficient in VEGFR-2 have defects in vasculogenesis, angiogenesis and hematopoiesis. 11,12 Bone marrow specimens from patients with acute leukemia or myelodysplastic syn- dromes (MDSs) display increased cellular expression of VEGF-A, VEGFR-1 and VEGFR-2 by myelomonocytic precursors, asso- ciated with increased medullary neovascular density and bone marrow blast percentage. 4–6,13,14 Therefore, leukemic blasts may promote their own development via both paracrine and autocrine interactions. 15–18 This hypothesis is supported by reports that (1) increased plasma concentration of VEGF-A at diagnosis is associated with decreased complete remission (CR) and survival in patients with untreated acute myeloid leukemia (AML) and MDS and (2) bone marrow cellular expression of VEGFR-2 is restored to normal in patients with CR after chemotherapy. 7,19 Finally, in vitro neutralization of VEGF-A suppresses leukemia colony-forming capacity in MDS and AML. 16 Thus, the VEGF/VEGFR-2 signaling pathway has emerged as a rational therapeutic target for the treatment of AML and MDS. PTK787/ZK 222584 (PTK/ZK) is a potent and relatively selective inhibitor of all VEGF RTK, with slightly greater activity against VEGFR-2. This inhibitor also inhibits the platelet-derived growth factor (PDGF) receptor tyrosine kinase, c-kit protein tyrosine kinase and c-fms. 20,21 There is no known effect against other tyrosine or serine/threonine kinases and there are no cytotoxic or antiproliferative effects on cells without VEGF-R at concentrations up to 10 mM. PTK/ZK inhibits VEGF-dependent endothelial cell proliferation in vitro and in animal models and inhibits growth of subcutaneously implanted human tumor xenografts in immunodeficient nude mice, corresponding to a reduction in tumor microvessels. Also, PTK/ZK inhibits growth of primary tumors and metastases in animal models. 20,21 Acute myeloid leukemia remains a devastating disease with few substantial improvements in therapy. Cytotoxic chemother- apy with cytosine arabinoside and an anthracycline is the cornerstone of treatment, although in many patients, particularly those with poor-risk cytogenetics, advanced age or refractory disease, there is little expectation for long-term control. For patients with a short (o12 months) or absent remission after induction, chemotherapy may produce short-term responses, but survival 41 year is rare. Allogeneic stem cell transplantation can result in 20–40% long-term survival, but few patients with Received 15 November 2005; revised 24 January 2006; accepted 2 February 2006; published online 13 April 2006 Correspondence: Dr GJ Roboz, Leukemia Program, Weill Medical College of Cornell University/The New York Presbyterian Hospital, 520 East 70th Street Starr 340A, New York, NY 10021, USA. E-mail: gar2001@med.cornell.edu Leukemia (2006) 20, 952–957 & 2006 Nature Publishing Group All rights reserved 0887-6924/06 $30.00 www.nature.com/leu