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/m 2 ) 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/m 2 IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle.

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

“…These results confirm the previously reported proof of concept study using intravenous administration, 8 as well as the phase 1 study of the current oral formulation using an abbreviated dosing schedule. 7 The population in this study was heavily prior treated: 77% resistant to erythropoietin, 38% resistant to lenalidomide, and 47% resistant to HMAs.…”

“…The lower dose, longer exposure time dose schedule was observed to have a longer duration of response. The median time to HI-E response was 8 weeks (range, [8][9][10][11]. A 19% HI-N response rate was observed in patients with neutropenia (4 of 21; 95% CI, 5-42) and a bilineage (HI-E and HI-N) response rate of 20% (4 of 20; 95% CI, 6-44) in patients with anemia and neutropenia.…”

“…Alternatively, ezatiostat's ability to increase reactive oxygen species (ROS) in dysplastic cells may also contribute to apoptotic death and elimination, because MDS cells may lack the reducing ability to eliminate these oxidative stresses. 6 On the basis of promising multilineage responses and good tolerability profile in low to intermediate-2 MDS patients in a phase 1 study of oral ezatiostat, 7 as well as the results of a phase 1 to 2a proof-of-concept study with the intravenous formulation, 8 this randomized multicenter phase 2 study of oral ezatiostat on extended dose schedules was conducted.…”

Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death

“…TLK199 (ezatiostat hydrochloride; Telintra, Patheon, Inc., Mississauga, Ontario, Canada) is currently being tested for the treatment of myelodysplastic syndrome (MDS), a bone marrow neoplastic disease characterized by an ineffective production or dysplasia of myeloid blood cells and a risk of transformation into acute myeloid leukemia (AML). 55,56 GSTP1-1 is polymorphic. In humans, the GSTP1 gene has been mapped to chromosome 11q13, and four allelic variants have been described: GSTP1*A (wild-type Ile 105, Ala 114), GSTP1*B (Val 105, Ala 114), GSTP1*C (Val 105, Val 114), and GSTP1*D (Ile 105, Val 114).…”

Therapy of Acute Myeloid Leukemia

“…Ezatiostat hydrochloride: is a glutathione S-transferase P1-1 inhibitor, evaluated in myelodysplastic syndrome. In a phase I/II study 47 , trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements.…”