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

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, 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

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.

Figures

Figure 1
Figure 1
Ezatiostat HCl Liposomes for Injection (TLK199) Mechanism of Action. 1. Esterase action on the diester prodrug, ezatiostat liberates the active moiety, the tripeptide diacid; 2. Binding of diacid to GST P1-1 leads to release of JNK; 3. JNK phosphorylated c-JUN; 4. Phosphorylated C-Jun translocates to the nucleus and participates in transcription of growth and differentiation genes; 5. Trilineage growth and differentiation results.
Figure 2
Figure 2
Ezatiostat HCl Liposomes for Injection (TLK199) Pharmacokinetics. Formation of metabolites is assumed to be unidirectional. Ezatiostat undergoes de-esterification to both TLK235 and TLK236; however, because the quantity of TLK235 measured in this study is consistently less than the level of quantification, this pathway is ignored (dashed lines). TLK236 undergoes further de-esterification to TLK117. Each of ezatiostat and TLK236 can be eliminated via more than one pathway. However, this study provides no insight into the fraction of each entity eliminated by each pathway.

References

    1. Kouides PA, Bennett JM. Morphology and classification of myelodysplastic syndromes. Hematol Oncol Clin North Am. 1992;6:485–499.
    1. Weisdorf DJ, Oken MM, Johnson GJ, Rydell RE. Chronic myelodysplastic syndrome: Short survival with or without evolution to acute leukaemia. Br J Haematol. 1983;55:691–700. doi: 10.1111/j.1365-2141.1983.tb02852.x.
    1. Mufti GJ, Galton DAG. Myelodysplastic Syndromes: Natural History and Features of Prognostic Importance. In: Griffin JD, editor. Clinics in Haematology. London, UK: W.B. Saunders Company; 1986. pp. 953–971.
    1. Bennett JM. Classification of the Myelodysplastic Syndromes. In: Griffin JD, editor. Clinics in Haematology. London, UK: W. B. Saunders Company; 1986. pp. 909–923.
    1. Morgan AS, Stanboli A, Sanderson PE. TER199 Increases Bone Marrow (BM) CFU-GM and Peripheral Platelet and Neutrophil Counts in Myelosuppressed Rodents. Proceedings of the Annual Meeting of the American Society of Hematology; December 6–10, 1996; Orlando, Florida Abstract #3263. p. 134b.
    1. Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, et al. Regulation of JNK signaling by GSTp. EMBO J. 1999;18:1321–1334. doi: 10.1093/emboj/18.5.1321.
    1. Meng F, Broxmeyer HE, Toavs D, Cristobal C, Morgan A, Gomez R, et al. TLK199: A Novel, Small Molecule Myelostimulant. Proceedings of the American Association for Cancer Research; March 24–28, 2001; New Orleans, Louisiana Abstract #1144. p. 214.
    1. Emanuel PD, Wang Z, Cai D, Stofega MR, Keck JG, Estrov Z, et al. TLK199 (Telintra™), a Novel Glutathione Analog Inhibitor of GST P1-1, Causes Proliferation and Maturation of Bone Marrow Precursor Cells and Correlates with Clinical Improvement in Myelodysplastic Syndrome (MDS) Patients in a Phase 2a Study. Proceedings of the Annual Meeting of the American Society of Hematology; December 4–7, 2004; San Diego, California Abstract #2372. p. 652a.
    1. NCI Common Toxicity Criteria. Common Toxicity Criteria (CTC) 1–35. 4-30-1999. CTEP. Cancer Therapy Evaluation Program, Common Terminology Criteria Version 2.0. DCTD, NCI, NIH, DHHS. 1998.
    1. Henderson CJ, Smith AG, Ure J, Brown K, Bacon EJ, Wolf CR. Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases. Proc Natl Acad Sci USA. 1998;95:5275–5280. doi: 10.1073/pnas.95.9.5275.
    1. Ruscoe JE, Rosario LA, Wang T, Gate L, Arifoglu P, Wolf CR, et al. Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GSTp) influences cell proliferation pathways. J Pharmacol Exp Ther. 2001;298:339–345.
    1. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96:3671–3674.
    1. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–425. doi: 10.1182/blood-2005-10-4149.

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