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.
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.


CONCLUSIONS
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.


BACKGROUND
Clinicaltrials.gov: NCT00035867.
Raza
Azra
A
University of Massachusetts Medical Center, Worcester, MA, USA. araza@aptiumoncology.com
Galili
Naomi
N
Callander
Natalie
N
Ochoa
Leonel
L
Piro
Lawrence
L
Emanuel
Peter
P
Williams
Stephanie
S
Burris
Howard
H
Faderl
Stefan
S
Estrov
Zeev
Z
Curtin
Peter
P
Larson
Richard A
RA
Keck
James G
JG
Jones
Marsha
M
Meng
Lisa
L
Brown
Gail L
GL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D006851:Hydrochloric Acid / Q000008:administration & dosage / Q000737:chemistry; D007267:Injections; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
D000970:Antineoplastic Agents; D008081:Liposomes; D011355:Prodrugs; C096329:gamma-Glu-S-BzCys-PhGly diethyl ester; D005978:Glutathione; D006851:Hydrochloric Acid