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)

Raza Azra, Galili Naomi, Mulford Deborah, Smith, Brown, Steensma, Lyons, Boccia Ralph, Sekeres, Garcia-Manero Guillermo, Mesa

Description

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

Sujets

• MDS
• Lenalidomide
• Phase 1

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 8
• Langue: English

Extrait

Raza et al. Journal of Hematology & Oncology 2012, 5:18
http://www.jhoonline.org/content/5/1/18 JOURNAL OF HEMATOLOGY
& ONCOLOGY
RESEARCH Open Access
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)
1* 1 2 3 4 5 6Azra Raza , Naomi Galili , Deborah Mulford , Scott E Smith , Gail L Brown , David P Steensma , Roger M Lyons ,
7 8 9 10Ralph Boccia , Mikkael A Sekeres , Guillermo Garcia-Manero and Ruben A Mesa
Abstract
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 lena is active.
Trial registration: Clinicaltrials.gov: NCT01062152
Keywords: MDS, Ezatiostat, Lenalidomide, Phase 1, Non-deletion (5q)
* Correspondence: [e-mail]
1Columbia University Medical Center, New York, NY, USA
Full list of author information is available at the end of the article
© 2012 Raza et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.Raza et al. Journal of Hematology & Oncology 2012, 5:18 Page 2 of 8
http://www.jhoonline.org/content/5/1/18
Background event (AE); however, these were mainly restricted to grades
Myelodysplastic syndromes (MDS) represent a diverse 1 and 2, confirming the results of the prior studies. The
group ofacquired hematopoieticstem cell disorderscharac- transfusion independence rate was higher (40%) in the sub-
terized by ineffective hematopoiesis and a variable risk of set of patients previously treated with lenalidomide (and no
transformation to acute myeloid leukemia (AML) [1]. Prog- prior hypomethylating agents), suggesting a potential role
nostically, MDS has been divided into two main groups for combining the two drugs. Finally, since ezatiostat does
according to whether there is a higher or lower risk of not have a myelosuppressive effect, it may act as a cytopro-
developing leukemia [2]. At diagnosis, two-thirds of MDS tective agent when used with lenalidomide, which is known
patients present with lower-risk disease. A select group of to be significantly myelotoxic. The doses selected for this
lower-risk patients with clonally restricted deletion of the combination therapy study were selected based on the
long arm of chromosome 5 (del[5q]) and transfusion- results from the phase 2 single-agent ezatiostat study. [7]
dependent anemia respond to lenalidomide, but lenalido- The lenalidomide dose selected is based upon the approved
mide is less effective in the majority of patients with MDS dose of lenalidomide for the treatment of MDS. [8] The
who lack del(5q) [3]. While the hypomethylating drugs aza- current phase 1 study was therefore conducted to determine
citidine and decitabine are approved by the Food and Drug the safety and efficacy of ezatiostat in combination with
Administration (FDA) for treatment of patients with a lenalidomide in IPSS Low and Intermediate-1 risk MDS
broad range of MDS subtypes, the benefit of these agents patients.
for lower-risk patients is not clearly established. Other ther-
Materials and methods
apies that have been studied for treatment of MDS include
This study was conducted in accordance with the Inter-
hematopoietic growth factors, immunosuppressive therapy,
national Conference on Harmonization and Good Clin-
various biologic response modifiers, and traditional cyto-
ical Practice standards. Institutional review board
toxic chemotherapies; however, there remains a major need
approval was obtained from all participating institutions.
for new treatment options.
All patients provided written informed consent before
Ezatiostat hydrochloride (Telintra), a glutathione-analog
study participation.
reversible inhibitor of the enzyme glutathione S-transferase
P1-1 (GSTP1-1), is being developed for the treatment of Patient population
cytopenias associated with International Prognostic Scoring Eligible patients were 18 years or older, with histologically
System (IPSS) Low or Intermediate-1 risk MDS. Ezatiostat confirmed diagnoses of non-del(5q) MDS, Low or Inter-
facilitates dissociation of GSTP1-1 from jun-N-terminal mediate-1 IPSS risk group, and Eastern Cooperative Oncol-
kinase (JNK), leading to activation of JNK and the subse- ogy Group performance status (ECOG PS) of 0 or 1. The
quent promotion of growth and maturation of normal mul- following World Health Organization (WHO) classification
tilineage hematopoietic progenitors, while promoting MDS subtypes were included: refractory anemia (RA),
apoptosis in human leukemia blasts [4,5]. Recent reports refractory nemia with excess blasts type I (RAEB-I), refrac-
have shown that GSTP1-1 may be an important mediator tory anemia with ring sideroblasts (RARS), refractory
of signaling in hematopoieticcells[4].Inaddition,theabil- cytopenia with multilineage dysplasia (RCMD), refractory
ity of ezatiostat to activate the caspase-dependent apoptotic with dysplasia with ringed sidero-
pathway may inhibit the emergence of malignant clones, blasts (RCMD-RS), MDS-unclassified (MDS-U), and MDS/
while ezatiostat's ability to increase reactive oxygen species myeloproliferative neoplasm-unclassified (MDS/MPN-U)
in dysplastic cells may contribute to apoptosis in dysplastic without leukocytosis. Patients were required to have ad-
cells [6]. These mechanistic features provide an attractive equate hepatic and renal function. Inclusion criteria allowed
profile for modulating the biology in MDS. multilineage cytopenias with assessment of response by
Recently, a randomized multicenter phase 2 study of eza- International Working Group (IWG) 2006 criteria [9],
tiostat was conducted in 89 heavily pretreated patients with <10% marrow blasts, and ineligibility or unwillingness to
IPSS Low or Intermediate-1 risk MDS on two extended undergo allogeneic stem cell transplantation. Patients were
dose schedules. In dose schedule 1, patientsreceived ezatio- excluded for prior allogeneic bone marrow transplantation,
stat at 1500 mg orally (PO) twice daily (b.i.d.) for 2 weeks a history of IPSS higher-risk MDS or of AML [10,11], prolif-
followed by a 1-week rest period in a 3-week treatment erative chronic myelomonocytic leukemia, use of oral corti-
cycle and in dose schedule 2, patients received ezatiostat at costeroids at a dose exceeding 10 mg daily, history of
1000 mg PO b.i.d. for 3 weeks followed by a 1-week rest hepatitis B/C or human immunodeficiency virus, or an ac-
period in a 4-week treatment cycle. Multilineage tive infection requiring intravenous antibiotics. Patientswere
hematologic responses were seen and 29% of RBC-transfu- not allowed to receive hematopoietic growth factors while
sion-dependent patients experienced an erythroid response. on study, and a 4-week washout period for growth factors
Ezatiostat had a very favorable tolerability profile, with and all prior MDS treatments was required before study
gastrointestinal side effects being the predominant adverse enrollment.Raza et al. Journal of Hematology & Oncology 2012, 5:18 Page 3 of 8
http://www.jhoonline.org/content/5/1/18
Study design Dose modifications
This was a multicenter phase 1 dose-ranging study Patients who experienced a treatment-related non-
evaluating ezatiostat in combination with lenalidomide hematologic AE grade 3 or higher had treatment delayed
in patients with non-del(5q) IPSS Low or Intermediate-1 for up to 3 week