Research

Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra^®, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome

Azra Raza^1,11 , Naomi Galili¹ , Natalie Callander² , Leonel Ochoa² , Lawrence Piro³ , Peter Emanuel⁴ , Stephanie Williams⁵ , Howard Burris III⁶ , Stefan Faderl⁷ , Zeev Estrov⁷ , Peter Curtin⁸ , Richard A Larson⁹ , James G Keck¹⁰ , Marsha Jones¹⁰ , Lisa Meng¹⁰ and Gail L Brown¹⁰

¹  University of Massachusetts Medical Center, Worcester, MA, USA

²  University of Texas Health Science Center, San Antonio, TX, USA

³  The Angeles Clinic & Research Institute, Santa Monica, CA, USA

⁴  University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL, USA

⁵  Hematology Oncology Associates of Illinois, Chicago, IL, USA

⁶  Sarah Cannon Cancer Center, Nashville, TN, USA

⁷  MD Anderson Cancer Center, Houston, TX, USA

⁸  Oregon Health & Science University, Portland, OR, USA

⁹  University of Chicago, Chicago, IL, USA

¹⁰  Telik, Inc, Palo Alto, CA, USA

¹¹  Professor of Medicine, New York Medical College, Director, MDS Program, St Vincent's Comprehensive Cancer Center, 325 West 15th Street, New York, NY 10011, USA

author email corresponding author email

Journal of Hematology & Oncology 2009, 2:20doi:10.1186/1756-8722-2-20

Published:	13 May 2009

Abstract

Background

Ezatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m²) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m² IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle.

Results

54 patients with histologically confirmed MDS were enrolled. The most common adverse events were grade 1 or 2, respectively, chills (11%, 9%), back pain (15%, 2%), flushing (19%, 0%), nausea (15%, 0%), bone pain (6%, 6%), fatigue (0%, 13%), extremity pain (7%, 4%), dyspnea (9%, 4%), and diarrhea (7%, 4%) related to acute infusional hypersensitivity reactions. The concentration of the primary active metabolites increased proportionate to ezatiostat dosage. Trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. Hematologic Improvement-Erythroid (HI-E) was observed in 9 of 38 patients (24%), HI-Neutrophil in 11 of 26 patients (42%) and HI-Platelet in 12 of 24 patients (50%). These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements. Improvement in bone marrow maturation and cellularity was also observed.

Conclusion

Phase 2 studies of ezatiostat hydrochloride liposomes for injection in MDS are supported by the tolerability and HI responses observed. An oral formulation of ezatiostat hydrochloride tablets is also in phase 2 clinical development.

Trial Registration

Clinicaltrials.gov: NCT00035867