Hematologic Improvement Following Treatment with TLK199 (Telintra™), a Novel Glutathione Analog Inhibitor of GST P1-1, in Myelodysplastic Syndrome (MDS): Interim Results of a Dose-Ranging Phase 2a Study.

Introduction: TLK199 is a novel glutathione analog inhibitor of the enzyme GST P1-1. Exposure of cells to TLK199 results in the activation of the MAP kinase signaling pathway leading to JNK and ERK2 activation. TLK199 treatment induces hematopoietic progenitor cell growth, maturation and differentiation. TLK199 has demonstrated in vitro myelostimulant activity in human bone marrow cultures and accelerated neutrophil recovery in the chemotherapy induced neutropenia rodent model.

Methods: The objectives of this ongoing multicenter study in MDS are to determine the safety, efficacy and phamacokinetics. Blood levels of TLK199 and metabolites are measured by LC-MS-MS. TLK199 is administered as an i.v. infusion over 60 minutes daily x 5 days every two weeks in the dose ranging stage, and at 600 mg/m² x 5 days every 3 weeks in Phase 2a for up to 8 cycles or until lack of response, blast count progression, or unacceptable toxicity.

Results: At interim analysis, twenty-five patients (pts) with MDS (13 RA, 1 RARS, 7 RAEB, 3 RAEB-t and 1 CMML), median age 73 years (range 22-89), received 98+ cycles (500+ treatments) with a median of 3 cycles per pt (range 1–8). Seventeen pts (70%) were transfusion-dependent for red blood cells and 8 (30%) for platelets prior to enrollment. Pts failed a median of 1 prior therapy (range 0–4) including: erythropoietin (13), G-CSF (3), thalidomide (4), IL-11 (3), azacitidine (3), and other therapies (7). Five dose levels were studied from 50–600 mg/m². No dose-limiting toxicities were observed and 600 mg/m² was chosen for Phase 2a based on clinical and biologic activity. Twenty pts were evaluable for efficacy, 9 (45%) experienced improvement in one or more blood cell lineages. Six pts (30%) showed Hematologic Improvement by MDS IWG response criteria. Four of 6 experienced improvement in all 3 blood cell lineages and two pts in 2 blood cell lineages. A decrease in the marrow blast count was observed in 1 pt with RAEB. The longest duration of therapy was 8 cycles. Clinical responses were accompanied by clinical symptom improvement with decrease in transfusion requirements or transfusion independence. Bone marrow examination showed improvements in maturation, differentiation, M/E ratios, and decreased dysplastic morphology. Most common adverse events were mild (grade 1 – 2): flushing (6), rigors (4), nausea (3), headache (3), vomiting (2), pain in extremity (3), back pain (2). Grade 4 back pain occurred in one pt.

Conclusions: TLK199 is well tolerated. Nine pts (45%) experienced improvement in one or more blood lineages and six (30%) showed Hematologic Improvement by MDS IWG response criteria. Enrollment in Phase 2a continues. These data support further clinical development of TLK199 in myelodysplastic syndrome as well as in other hematologic disorders characterized by cytopenias.