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.

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.

• Authors: Azra Raza, Naomi Galili, Natalie Callander, Leonel Ochoa, Lawrence Piro, Peter Emanuel, Stephanie Williams, Howard Burris 3rd, Stefan Faderl, Zeev Estrov, Peter Curtin, Richard A Larson, James G Keck, Marsha Jones, Lisa Meng, Gail L Brown
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 2 Pg. 20 (May 13 2009) ISSN: 1756-8722 [Electronic] England
• PMID: 19439093 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study)

Chemical References

• Antineoplastic Agents
• Liposomes
• Prodrugs
• gamma-Glu-S-BzCys-PhGly diethyl ester
• Glutathione
• Hydrochloric Acid

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects)
• Dose-Response Relationship, Drug
• Female
• Glutathione (administration & dosage, adverse effects, analogs & derivatives, chemistry)
• Humans
• Hydrochloric Acid (administration & dosage, chemistry)
• Injections
• Liposomes
• Male
• Middle Aged
• Myelodysplastic Syndromes (drug therapy)
• Prodrugs (administration & dosage, adverse effects)
• Young Adult