Angiogenesis may play a role in the pathophysiology and progression of myelodysplastic syndromes (MDS). The oral agent PTK787/ZK222584 (PTK/ZK; Novartis and Schering AG) inhibits receptor tyrosine kinases of vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and Kit. In a phase II trial, we examined if PTK/ZK induces hematological responses and/or delays progression to acute myeloid leukemia (AML) or death in MDS. Patients (pts) previously untreated with cytotoxic agents for MDS received PTK/ZK 1,250 mg orally once daily for 28-day cycles until disease progression/unacceptable toxicity. To improve tolerability, the regimen was changed after 80 pts (cohort 1: C-I) to dose escalation: 750 mg for the first 28 d, escalated in the absence of pre-defined toxicity levels to 1,000 mg for 28 d, then 1,250 mg thereafter for cohort 2 (C-II; N=58 pts). Between 03/04 and 06/06, 138 pts were enrolled (median age, 70 yrs [range, 21–91]; 64% males) and continuous toxicity and efficacy assessments made. During the 3 months (mo) prior to study entry, 50% had received red cell and 12% received platelet transfusions. Toxicity data are available for 118/138 (85%) pts. A large proportion of toxicities occurred in the first 2 cycles, but the large majority resolved on drug discontinuation. The most common NIH Common Terminology Criteria for Adverse Events gr 2–4 non-heme toxicities at least possibly attributable to PTK/ZK were fatigue (56% in C-I; 37% in C-II), nausea (47%; 19%), vomiting (28%; 12%), dizziness (28%; 12%), ataxia (16%; 7%), anorexia (16%; 5%) and diarrhea (11%; 7%). The overall incidence of any gr 4 non-heme toxicity was 11% in C-I and 5% in C-II. We recently reported marked inter-individual variability in PTK/ZK exposure in C-I pts, but could not find an association between drug exposure and early non-heme adverse events (

Gupta P et al. J Clin Oncol 2006; 24[18S]:355s
). Of 46 deaths, 2 (1 intra-cerebral hemorrhage, 1 sudden death) were possibly related to PTK/ZK. Heme toxicity (gr 1–4) attributable to PTK/ZK was reported in all 3 lineages. Compared with C-I, pts in C-II experienced less toxicity. However, early drug discontinuation (within 3 cycles, most often because of toxicity/intolerance, transformation to AML or lack of heme improvement) was similar (C-I=46/80 pts; C-II=31/58 pts). On central pathology review, 11 pts did not have MDS and were excluded from subsequent efficacy analyses. Of 89 MDS pts whose IPSS scores were available, 33% had high-risk (score ≥1.5; Int-2/High) and 67% had low-risk (score 0–1; Low/Int-1) MDS. At 6 and 12 mo, 16 and 2 pts respectively were still on PTK/ZK. Hematological improvement (HI; IWG criteria) occurred in 9/42 (21%) pts who received ≥3 cycles of PTK/ZK, and in no pts who received <3 cycles. Responses were: erythroid in 5 pts (4 major, including transfusion independence [TI] in 3), neutrophil (minor) in 1 pt and platelet in 4 pts (3 major, including TI in 2). Eight of these 9 pts had low-risk MDS (5=RCMD); cytogenetics were normal in 7, 20q- in 1 and abnormal (pending central review) in 1 pt. No pts have achieved CR or PR as of yet. The median times to development of AML/death were 10 mo in pts with high-risk and 21 mo in pts with low risk MDS. For pts with MDS, drug intolerance appears to limit the ability to remain on PTK/ZK. A proportion of pts able to receive at least 3 cycles of PTK/ZK experience clinically meaningful improvements in blood counts.

Topics:
cancer and leukemia group b, myelodysplastic syndrome, phase 2 clinical trials, protein-tyrosine kinase inhibitor, vascular endothelial growth factor receptors, brachial plexus neuritis, toxic effect, heme, adverse event, platelet-derived growth factor

Disclosures: Dr. Ravi Vij has received research funding from Novartis for an investigator-initiated trial of PTK/ZK in myeloma.

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2006, The American Society of Hematology
2006
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