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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)

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Summary

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.

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Acknowledgements

We thank the CALGB physicians, nurses and data coordinators, and especially the patients who participated in this study and the CALGB protocol coordinator Michael Kelly, MA.

Conflict of Interest

The authors declare that they have no conflict of interest.

Funding

The research for CALGB 10105 (Alliance) was supported, in part, by National Cancer Institute grants no. CA16450 (PG), CA33601 (FM, BLS, KO), CA32291 (RPH, RMS), CA77440 (RV), CA03927 (DDH), CA41287 (OMO, RAL), CA77658 (CDB), CA31946 to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli, M.D., Chair) and CA33601 to the Alliance Statistics and Data Center (Daniel J. Sargent, Ph.D.). Dr. Clara D. Bloomfield was supported in part by the National Cancer Institute (CA101140) and by the Coleman Leukemia Research Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

The following institutions participated in this study

Christiana Care Health Services, Inc. CCOP, Wilmington, DE, Stephen Grubbs, M.D., supported by CA45418

Dana-Farber Cancer Institute, Boston, MA, Harold J. Burstein, M.D., Ph.D., supported by CA32291

Duke University Medical Center, Durham, NC, Jeffrey Crawford, M.D., supported by CA47577

Georgetown University Medical Center, Washington, DC, Bruce Cheson, M.D., supported by CA77597

Hematology-Oncology Associates of CNY CCOP, Syracuse, NY, Jeffrey Kirshner, M.D., supported by CA45389

Illinois Oncology Research Association, Peoria, IL, John W. Kugler, M.D., supported by CA35113

Kansas City Community Clinical Oncology Program CCOP, Kansas City, MO, Rakesh Gaur, M.D.

Massachusetts General Hospital, Boston, MA, Jeffrey W. Clark, M.D., supported by CA32291

Missouri Baptist Medical Center, St. Louis, MO, Alan P. Lyss, M.D., supported by CA114558-02

Mount Sinai Medical Center, Miami, FL, Michael A. Schwartz, M.D., supported by CA45564

NorthShore University HealthSystem CCOP, Evanston, IL, David L. Grinblatt, M.D.

Northern Indiana Cancer Research Consortium CCOP, South Bend, IN, Rafat Ansari, M.D., supported by CA86726

Rhode Island Hospital, Providence, RI, William Sikov, M.D., supported by CA08025

Roswell Park Cancer Institute, Buffalo, NY, Ellis Levine, M.D., supported by CA59518

Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC, James N. Atkins, M.D., supported by CA45808

State University of New York Upstate Medical University, Syracuse, NY, Stephen L. Graziano, M.D., supported by CA21060

University of Chicago, Chicago, IL, Hedy L. Kindler, M.D., supported by CA41287

University of Texas Southwestern Medical Center, Dallas, TX, supported by CA37347

University of Iowa, Iowa City, IA, Daniel A. Vaena, M.D., supported by CA47642

University of Minnesota, Minneapolis, MN, Bruce A. Peterson, M.D., supported by CA16450

University of Missouri/Ellis Fischel Cancer Center, Columbia, MO, Karl E. Freter, M.D., supported by CA12046

University of Nebraska Medical Center, Omaha, NE, Apar Ganti, M.D., supported by CA77298

University of North Carolina at Chapel Hill, Chapel Hill, NC, Thomas C. Shea, M.D., supported by CA47559

University of Oklahoma, Oklahoma City, OK, Shubham Pant, M.D., supported by CA37447

University of Vermont, Burlington, VT, Steven M. Grunberg, M.D., supported by CA77406

Wake Forest University School of Medicine, Winston-Salem, NC, David D. Hurd, M.D., supported by CA03927

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Authors and Affiliations

  1. University of Minnesota, Minneapolis, MN, USA

    Pankaj Gupta

  2. Alliance Statistics and Data Center, Duke University Medical Center, Durham, NC, USA

    Flora Mulkey, Ben L. Sanford & Kouros Owzar

  3. Massachusetts General Hospital, Boston, MA, USA

    Robert P. Hasserjian

  4. Washington University in St. Louis, St. Louis, MO, USA

    Ravi Vij

  5. Wake Forest University, Winston-Salem, NC, USA

    David D. Hurd

  6. University of Chicago, Chicago, IL, USA

    Olatoyosi M. Odenike & Richard A. Larson

  7. The Ohio State University, Columbus, OH, USA

    Clara D. Bloomfield

  8. Dana-Farber Cancer Institute, Boston, MA, USA

    Richard M. Stone

  9. Hematology/Oncology Section 111E, Minneapolis VA Health Care System, One Veterans Drive, Minneapolis, MN, 55417, USA

    Pankaj Gupta

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Gupta, P., Mulkey, F., Hasserjian, R.P. et al. 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). Invest New Drugs 31, 1311–1320 (2013). https://doi.org/10.1007/s10637-013-9978-z

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