Original Article

A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome

  1. Azra Raza MD1,†,*,
  2. Naomi Galili PhD1,
  3. Scott E. Smith MD, PhD, FACP2,
  4. John Godwin MD, MS3,
  5. Ralph V. Boccia MD, FACP4,
  6. Han Myint MD5,
  7. Daruka Mahadevan MD6,
  8. Deborah Mulford MD7,
  9. Mark Rarick MD8,
  10. Gail L. Brown MD9,‡,*,
  11. Dale Schaar MD, PhD10,
  12. Stefan Faderl MD11,
  13. Rami S. Komrokji MD12,
  14. Alan F. List MD12,
  15. Mikkael Sekeres MD13

Article first published online: 1 SEP 2011

DOI: 10.1002/cncr.26469

Issue

Cancer

Cancer

Volume 118, Issue 8, pages 2138–2147, 15 April 2012

Additional Information

How to Cite

Raza, A., Galili, N., Smith, S. E., Godwin, J., Boccia, R. V., Myint, H., Mahadevan, D., Mulford, D., Rarick, M., Brown, G. L., Schaar, D., Faderl, S., Komrokji, R. S., List, A. F. and Sekeres, M. (2012), A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome. Cancer, 118: 2138–2147. doi: 10.1002/cncr.26469

Author Information

  1. 1

    Columbia University Medical Center, New York, New York

  2. 2

    Loyola University Chicago, Cardinal Bernardin Cancer Center, Maywood, Illinois

  3. 3

    SIU Simmons Cooper Cancer Institute, Springfield, Illinois

  4. 4

    Center for Cancer and Blood Disorders, Bethesda, Maryland

  5. 5

    University of Colorado at Denver Health Sciences Center, Aurora, Colorado

  6. 6

    Arizona Cancer Center, Tucson, Arizona

  7. 7

    University of Rochester Medical Center, Rochester, New York

  8. 8

    Kaiser Permanente Northwest Region, Portland, Oregon

  9. 9

    Telik, Inc., Palo Alto, California

  10. 10

    UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey

  11. 11

    The University of Texas MD Anderson Cancer Center, Houston, Texas

  12. 12

    H. Lee Moffitt Cancer Center and Research Institute, Orlando, Florida

  13. 13

    Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio

  1. †

    Fax: (212) 305-6891

  2. ‡

    Fax: (212) 305-6891

*Columbia University Medical Center, Milstein Hospital Bldg., 6N-435, 177 Fort Washington Avenue, New York, NY 10032

Publication History

  1. Issue published online: 6 APR 2012
  2. Article first published online: 1 SEP 2011
  3. Manuscript Accepted: 5 JUL 2011
  4. Manuscript Revised: 9 JUN 2011
  5. Manuscript Received: 19 APR 2011

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

View Full Article (HTML) Get PDF (812K)

Keywords:

  • glutathione S-transferase P1-1;
  • myelodysplastic syndrome;
  • ezatiostat HCl;
  • phase 2

Abstract

BACKGROUND:

Ezatiostat is a glutathione analog prodrug glutathione S-transferase P1-1 (GSTP1-1) inhibitor. This study evaluated 2 extended dose schedules of oral ezatiostat in 89 heavily pretreated patients with low to intermediate-1 risk myelodysplastic syndrome (MDS).

METHODS:

Patients were randomized by 1 stratification factor—baseline cytopenia (anemia only vs anemia with additional cytopenias)—to 1 of 2 extended dosing schedules. Multilineage hematologic improvement (HI) responses were assessed by International Working Group 2006 criteria.

RESULTS:

Overall, 11 of 38 (29%) red blood cell (RBC) transfusion-dependent patients had HI-Erythroid (HI-E) response. The median duration of HI-E response was 34 weeks. Multilineage responses were observed. There was 1 cytogenetic complete response in a del (5q) MDS patient. An important trend was the effect of prior therapy on response. A 40% HI-E rate (6 of 15 patients) was observed in patients who had prior lenalidomide and no prior hypomethylating agents (HMAs), with 5 of 11 (45%) patients achieving significant RBC transfusion reduction and 3 of 11 (27%) achieving transfusion independence. A 28% HI-E rate (5 of 18 patients) was observed in patients who were both lenalidomide and HMA naive, with 4 of 8 (50%) patients achieving clinically significant RBC transfusion reductions. Most common ezatiostat-related adverse events were grade 1 and 2 gastrointestinal including: nausea (45%, 17%), diarrhea (26%, 7%), and vomiting (30%, 12%).

CONCLUSIONS:

Ezatiostat is the first GSTP1-1 inhibitor shown to cause clinically significant and sustained reduction in RBC transfusions, transfusion independence, and multilineage responses in MDS patients. The tolerability and activity profile of ezatiostat may offer a new treatment option for patients with MDS. Cancer 2012. © 2011 American Cancer Society.

View Full Article (HTML) Get PDF (812K)