A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance)

Pankaj Gupta, Flora Mulkey, Robert P. Hasserjian, Ben L. Sanford, Ravi Vij, David D. Hurd, Olatoyosi M. Odenike, Clara D. Bloomfield, Kouros Owzar, Richard M. Stone, Richard A. Larson

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Abstract

Background: Angiogenesis is implicated in the pathophysiology and progression of myelodysplastic syndromes (MDS). Vatalanib (PTK787/ZK222584; Novartis and Schering AG) inhibits receptor tyrosine kinases of vascular endothelial growth factor, platelet derived growth factor and c-Kit. We examined whether vatalanib induces hematological responses in MDS and/or delays progression to acute myeloid leukemia (AML) or death. Methods: Two cohorts were studied. Vatalanib 1250 mg orally was given once daily (cohort 1) or 750-1250 mg once daily in an intra-patient dose escalating schedule (cohort 2) in 28-day cycles to 155 patients with MDS; 142 patients were evaluable for response and 153 for toxicity. Results: The median age was 70.5 years; 51 % had low risk (International Prognostic Scoring System {IPSS} Low/Intermediate-1) and 32 % had high risk (IPSS Intermediate-2/High) MDS. Hematological improvement was achieved in 7/142 (5 %) patients; all 7 were among the 47 patients able to remain on vatalanib for at least 3 months (hematological improvement achieved in 15 % of these 47 patients). For patients with low risk and high risk MDS, respectively, median progression-free survivals were 15 and 6 months, median times to transformation to AML were 28 and 6 months, and median overall survivals were 36 and 10 months. The most frequent non-hematological adverse events grade ≥2 were fatigue, nausea or vomiting, dizziness, anorexia, ataxia, diarrhea, and pain. Two deaths (one intra-cerebral hemorrhage and one sudden death) were possibly related to vatalanib. Conclusions: Vatalanib induces improvement in blood counts in a small proportion of MDS patients. Clinical applicability is limited by side effects.

Original languageEnglish
Pages (from-to)1311-1320
Number of pages10
JournalInvestigational New Drugs
Volume31
Issue number5
DOIs
StatePublished - Oct 1 2013

Keywords

  • (MeSH): Angiogenesis inhibitors
  • Humans
  • Myelodysplastic syndromes
  • Treatment outcome
  • Vascular endothelial growth factor

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    Gupta, P., Mulkey, F., Hasserjian, R. P., Sanford, B. L., Vij, R., Hurd, D. D., Odenike, O. M., Bloomfield, C. D., Owzar, K., Stone, R. M., & Larson, R. A. (2013). A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance). Investigational New Drugs, 31(5), 1311-1320. https://doi.org/10.1007/s10637-013-9978-z