Phase 1 Dose Escalation Study of TLK199 Tablets (Telintra), a Novel Glutathione Analog, in Myelodysplastic Syndrome.

Introduction: Glutathione S-transferase (GST) P1-1 binds to and inhibits Jun kinase (JNK), a key regulator of cellular proliferation, differentiation and apoptosis. TLK199, a glutathione analog, binds selectively to GSTP1-1 fostering dissociation from JNK, kinase activation and the promotion of growth and maturation of hematopoietic progenitors in preclinical models, while promoting apoptosis in human leukemia cell lines. The intravenous study with liposomal TLK199 resulted in hematologic improvement (HI) in MDS patients (pts); this trial utilizes an oral formulation of TLK199 in MDS pts.

Methods: The objectives of this study were to determine the safety and pharmacokinetics (PK) of TLK199 Tablets given b.i.d. at total daily doses ranging from 200 mg to 6000 mg for the first 7 days of each 3-week cycle. The design was a standard 3 by 3 (3 pts per dose level) dose escalation. Patients were treated until MDS progression or unacceptable toxicity up to a maximum of 8 cycles. Six pts underwent fed-fast PK analysis to determine the effect of food absorption. The PK was evaluated over the dose range for TLK199, and metabolites TLK236, TLK235, and TLK117.

Results: 44 MDS pts (32 M/12 F), (9 RA, 11 RARS, 3 RAEB/RAEB-1, 1 RAEB-II, 7 RCMD, 2 RCMD-Rs, 2 CMML, 5 MDS-U, 4 Unknown); IPSS risk-low 14 (32%), INT-1 27 (61%), and INT-2 3 (7%); median age 72 years (range 53–84), received total 206 cycles, median 4.5 (range 1–9) cycles/pt. Ten pts (23%) completed the intended 8 cycles of therapy. Two pts had dose reductions and 4 pts had dose delays (2 due to adverse event (AE) and 2 for scheduling difficulty) at single cycle. Twenty-seven pts (61%) were red cell transfusion (tx) dependent and 5 pts (11%) were platelet tx dependent. Sixteen pts (36%) had abnormal karyotypes. Most common treatment-related AEs were non-hematologic: There were no Grade 3 or 4 toxicities; Grade 2 toxicities were diarrhea and nausea in 2 pts each (5%). Grade 1 toxicities were nausea (43%), diarrhea (25%), vomiting (18%), abdominal pain (7%) and constipation (7%). Three pts (7%) experienced pill-induced dysphagia and reflux esophagitis. Two pts (5%) had Grade 4 neutropenia and 1 pt had febrile neutropenia. There were no DLTs reported. The plasma concentration of the primary active metabolite, TLK236, increases with TLK199 Tablets dose with a mean t_1/2 = 2.5 h (range 1.5–4); C_max = 4.5 uM (range 0.4–6.3). There was no difference seen in the fed vs. fasted patients. By IWG criteria, 15 individual cell line HI responses were observed at the various dose levels of 1000–6000 mg/day with 9 HI responses at dose levels 4000–6000 mg/day. These HI responses were characterized as 1 HI-E major and 4 HI-E minor, 1 HI-N major and 2 HI - N minor, 1 HI-P major and 6 HI-P minor. One bilineage response was reported at 5000 mg/day and 2 trilineage responses at 6000 mg/day. These responses were accompanied by clinical symptoms improvement.

Conclusions: TLK199 Tablets are well tolerated and HI responses in all three cell lines were observed with oral TLK199 short-course schedule. These data support the Phase 2 development of extended schedules of oral TLK199 in MDS.