Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS)

Journal of Hematology & Oncology

Ruben A Mesa²  Guillermo Garcia-Manero¹  Mikkael A Sekeres⁷  Ralph Boccia⁶  Roger M Lyons⁸  David P Steensma⁴  Gail L Brown⁵  Scott E Smith⁹  Deborah Mulford³  Naomi Galili^1,10  Azra Raza^1,10 

[1] Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Mayo Clinic, Scottsdale, AZ, USA;University of Rochester, Rochester, NY, USA;Dana-Farber Cancer Institute, Boston, MA, USA;Telik, Inc., Palo Alto, CA, USA;Center for Cancer & Blood Disorders, Bethesda, MD, USA;Hematologic Oncology & Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA;Cancer Care Centers South Texas/US Oncology, San Antonio, TX, USA;Cardinal Bernardin Cancer Center, Loyola University Chicago Medical Center, Maywood, IL, USA;Columbia University Medical Center, New York, NY, USA

关键词: Non-deletion (5q);    Phase 1;    Lenalidomide;    Ezatiostat;    MDS;   

Others  :  822500
DOI  :  10.1186/1756-8722-5-18

 received in 2012-01-31, accepted in 2012-04-03,  发布年份 2012

【 摘 要 】

Background

Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells.

Results

Ezatiostat was administered to 19 patients with non-deletion(5q) myelodysplastic syndrome (MDS) at one of two doses (2000 mg or 2500 mg/day) in combination with 10 mg of lenalidomide on days 1–21 of a 28-day cycle. No unexpected toxicities occurred and the incidence and severity of adverse events (AEs) were consistent with that expected for each drug alone. The most common non-hematologic AEs related to ezatiostat in combination with lenalidomide were mostly grade 1 and 2 fatigue, anorexia, nausea, diarrhea, and vomiting; hematologic AEs due to lenalidomide were thrombocytopenia, neutropenia, and anemia. One of 4 evaluable patients (25%) in the 2500/10 mg dose group experienced an erythroid hematologic improvement (HI-E) response by 2006 MDS International Working Group (IWG) criteria. Four of 10 evaluable patients (40%) in the 2000 mg/10 mg dose group experienced an HI-E response. Three of 7 (43%) red blood cell (RBC) transfusion-dependent patients became RBC transfusion independent, including one patient for whom prior lenalidomide monotherapy was ineffective. Three of 5 (60%) thrombocytopenic patients had an HI-platelet (HI-P) response. Bilineage HI-E and HI-P responses occurred in 3 of 5 (60%), 1 of 3 with HI-E and HI-N (33%), and 1 of 3 with HI-N and HI-P (33%). One of 3 patients (33%) with pancytopenia experienced a complete trilineage response. All multilineage responses were observed in the 2000/10 mg doses recommended for future studies.

Conclusions

The tolerability and activity profile of ezatiostat co-administered with lenalidomide supports the further development of ezatiostat in combination with lenalidomide in MDS and also encourages studies of this combination in other hematologic malignancies where lenalidomide is active.

Trial registration

Clinicaltrials.gov: NCT01062152

【 授权许可】

   
2012 Raza et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Steensma DP, Tefferi A: The myelodysplastic syndrome(s): a perspective and review highlighting current controversies. Leuk Res 2003, 27:95-120.
• [2]Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997, 89:2079-2088.
• [3]Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ, Dreisbach L, Schiffer CA, Stone RM, Greenberg PL, Curtin PT, Klimek VM, Shammo JM, Thomas D, Knight RD, Schmidt M, Wride K, Zeldis JB, List AF: Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1-risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2008, 111:86-93.
• [4]Laborde E: Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death. Cell Death Differ 2010, 17:1373-1380.
• [5]Ali-Osman F, Okamura T, Turley R, Barker A, Keck JG, Laborde E, Cai D, Macsata R: Novel Ezatiostat Analogues Disrupt Binding of GSTP1 to All Three Major MAP Kinases (JNK, ERK and p38) and Exhibit Context-Dependent Antitumor Activity [abstract]. In Proceedings of the AACR-NCI-EORTC International Conference. , San Francisco; November 12–16, 2011. Abstract # B229
• [6]Stofega M, Hsu SC, Chew J, Keck JG Brown G, Raza A, Cai D: Induction of apoptosis by TLK199 in human leukemia cells [abstract]. In Proceedings of the Annual Meeting of the American Association for Cancer Research. , San Diego; April 12–16, 2008. Abstract #2270
• [7]Raza A, Raza A, Galili N, Smith SE, Godwin J, Boccia RV, Myint H, Mahadevan D, Mulford D, Rarick M, Allison MA, Melnyk OG, Meng L, Jones M, Brown GL, Young S, Sekeres MA: A Phase 2 Randomized Multicenter Study of 2 Extended Dosing Schedules of Oral Ezatiostat in Low to Intermediate-1 Risk Myelodysplastic Syndrome. Cancer 2011.
• [8]List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R, for the Myelodysplastic Syndrome-003 Study Investigators: Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion. New Eng J Med 2008, 355:1456-1465.
• [9]Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Lowenberg B, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL: Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 2000, 96:3671-3674.
• [10]Bernasconi P: Molecular pathways in myelodysplastic syndromes and acute myeloid leukemia: relationships and distinctions-a review. Br J Haematol 2009, 142:695-708.
• [11]Mrozek K, Heerema N, Bloomfield C: Cytogenetics in acute leukemia. Blood Rev 2004, 18:115-136.
• [12]Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H: Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006, 108:419-425.
• [13]NCI Common Terminology Criteria for Adverse Events. Common Terminology Criteria for Adverse Events (CTCAE): 1–71. 3-31-2003. CTEP. Cancer Therapy Evaluation Program, Common Terminology Criteria Version 3.0. DCTD, NCI, NIH, DHHS, ; 2006.
• [14]Raza A, Galili N, Smith S, Godwin J, Lancet J, Melchert M, Jones M, Keck JG, Meng L, Brown GL, List A: Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome. Blood 2009, 113:6533-6540.
• [15]Quddus F, Clima J, Seedham H, Sajjad G, Galili N, Raza A: Oral Ezatiostat HCl (TLK199) and Myelodysplastic syndrome: A case report of sustained hematologic response following an abbreviated exposure. J Hem Onc 2010. BioMed Central Full Text
• [16]Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, te Boekhorst P, Sanz G, del Cañizo C, Guerci-Bresler A, Nilsson L, Platzbecker U, Lübbert M, Quesnel B, Cazzola M, Ganser A, Bowen D, Schlegelberger B, Aul C, Knight R, Francis J, Fu T, Hellström-Lindberg E: A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5Q. Blood 2011, 118:3765-3776.
• [17]Galili N, Tamayo P, Botvinnik OB, Mesirov JP, Zikria J, Brown G, Raza A: Gene Expression Studies May Identify Lower Risk Myelodysplastic Syndrome Patients Likely to Respond to Therapy with Ezatiostat Hydrochloride (TLK199) [abstract]. In Proceedings of the American Society of Hematology. , San Diego; December 10–13, 2011. Abstract #2779