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
Journal of Hematology & Oncology
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 3 10
Naomi Galili 3
Natalie Callander 1
Leonel Ochoa 1
Lawrence Piro 0
Peter Emanuel 7
Stephanie Williams 6
Howard Burris III 5
Stefan Faderl 4
Zeev Estrov 4
Peter Curtin 9
Richard A Larson 8
James G Keck 2
Marsha Jones 2
Lisa Meng 2
Gail L Brown 2
0 The Angeles Clinic & Research Institute , Santa Monica, CA , USA
1 University of Texas Health Science Center , San Antonio, TX , USA
2 Telik, Inc , Palo Alto, CA , USA
3 University of Massachusetts Medical Center , Worcester, MA , USA
4 MD Anderson Cancer Center , Houston, TX , USA
5 Sarah Cannon Cancer Center , Nashville, TN , USA
6 Hematology Oncology Associates of Illinois , Chicago, IL , USA
7 University of Alabama at Birmingham Comprehensive Cancer Center , Birmingham, AL , USA
8 University of Chicago , Chicago, IL , USA
9 Oregon Health & Science University , Portland, OR , USA
10 Professor of Medicine, New York Medical College, Director, MDS Program, St Vincent's Comprehensive Cancer Center , 325 West 15th Street, New York, NY 10011 , USA
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 ImprovementErythroid (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
Myelodysplastic syndrome (MDS) is a heterogeneous
group of clonal hematopoietic stem cell disorders
characterized by dysplasia in one or more granulocytic,
erythroid and megakaryocytic lineages, leading to ineffective
blood cell production and a variable risk of transforming
to acute myeloid leukemia (AML) [1-4]. The treatment
options available to patients with MDS are largely based
on the patient's age and their prognosis as determined by
the International Prognostic Scoring System (IPSS) .
For patients in the low to intermediate-1 IPSS risk
categories, the goal of treatment is to improve ineffective
hematopoiesis while providing the appropriate supportive care.
In the higher risk patients, the goal is to extend survival
and delay transformation to AML.
Currently, there are 3 U.S. Food and Drug Administration
(FDA) approved treatments for MDS; however, the need
for new targeted therapies with novel mechanisms of
action, such as induction of differentiation and apoptosis
continue to exist. Ezatiostat hydrochloride liposomes for
injection (TLK199), a novel glutathione analog, is
currently being developed for the potential treatment of
cytopenias associated with MDS or chemotherapy, and
potentially for the treatment of MDS that has transformed
to AML. Ezatiostat is a synthetic tripeptide analog of
glutathione that has been shown to stimulate the
proliferation of myeloid precursors . Ezatiostat is metabolized
to TLK117. TLK117 selectively binds to and inhibits
glutathione S-transferase P1-1 (GST P1-1), an enzyme that is
overexpressed in many human cancers. Glutathione
Stransferase P1-1 is known to bind to and inhibit
Jun-Nterminal kinase (JNK), a key regulator of cellular
Bone Marrow Stem Cell 2 2
EFzigatuioresta1t HCl Liposomes for Injection (TLK199) Mechanism of Action
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.
Grow th and
ation, differentiation and apoptosis (Figure 1) .
TLK117 facilitates dissociation of GST P1-1 from JNK,
leading to activation of JNK and the subsequent
promotion of growth and maturation of hematopoietic
progenitors in preclinical models (Figure 1), while promoting
apoptosis in human leukemia cell lines. Ezatiostat has
been shown to stimulate the multilineage differentiation
of blasts to mature monocytes, granulocytes and
erythrocytes with the potential to overcome the block in
differentiation (ineffective myelopoiesis) that is characteristic of
MDS [5,7,8]. Mice lacking the gene for GST P1-1, due to
gene deletion, when compared to wild type mice,
consistently demonstrate higher than normal neutrophil levels,
in addition to a significant increase in the growth rate of
their embryonal derived fibroblast cells . These results
are consistent with the reports that GST P1-1 is a negative
regulator of cellular growth and differentiation exerting its
effect by binding to JNK . These findings provide the
rationale and scientific support for evaluation of
ezatiostat in patients with MDS.
Pre-clinical data have shown that ezatiostat was well
tolerated at single and repeated doses (up to 1920 mg/m2/
day and 3200 mg/m2/day) in rats and dogs, respectively,
with no observed dose-limiting toxicity (DLT). This
firsttime-in-human phase 1-2a study of the intravenous (IV)
formulation was designed on the basis of safety
demonstrated in multi-dose toxicology studies and efficacy
reported in animal model studies. The goal of this study
was to determine the maximum tolerated dose (MTD) or
optimal biologic dose (OBD) [as defined as the maximum
therapeutic dose which may occur at doses well below the
MTD], the pharmacokinetics, safety profile and the
preliminary evidence of hematologic improvement (HI) in
MDS patients. The results of a phase 1-2a multicenter,
multiple dose-escalation, 2 dose schedules study are
Materials and methods
This study was conducted in accordance with
International Conference on Harmonization and Good Clinical
Practice standards. Institutional Review Board (IRB)
approval was obtained from all participating institutions.
(Note: authors Azra Raza and Naomi Galili moved to St.
Vincent's Comprehensive Cancer Center, New York, NY,
USA; Natalie Callander moved to University of Wisconsin
Medical Center, Madison, WI; Leonel Ochoa-Bayona
moved to Moffitt Cancer Center, Tampa, FL, USA, and
Peter Curtin moved to University of California, San
Diego, La Jolla, CA, USA; however, these institutions did
not participate in this study.) All patients provided written
informed consent prior to study participation.
Patients, age 18 years with histologically confirmed
diagnosis of primary MDS with an Eastern Cooperative
Oncology Group (ECOG) performance status of 0 to 2,
were enrolled. Patients were required to have adequate
hepatic and renal function. No prior treatment with
hematopoietic growth factors within 7 days of study entry
and ineligibility for allogeneic bone marrow
transplantation (BMT) were other inclusion criteria. Patients with a
history of allergy to eggs, leptomeningeal metastases or
leukemic meningitis; chemotherapy, radiotherapy or
immunotherapy within 2 weeks of study entry; use of oral
corticosteroids (except for the treatment of new adrenal
failure or hormones for non-MDS related conditions),
and known history of hepatitis B or C, human
immunodeficiency virus (HIV) infection, or an active infection
requiring antibiotics were excluded.
This phase 1-2a multicenter, open-label,
multidose-escalation study of ezatiostat hydrochloride liposomes for
injection (Telintra, TLK199) was conducted in patients
with all French-American-British (FAB) classification
types of MDS. The phase 1 objectives of the study were to
evaluate the safety, define the MTD or OBD, and to
evaluate the pharmacokinetics of the IV liposomal formulation.
In phase 1, ezatiostat was administered at a starting dose
of 50 mg/m2 followed by subsequent dose-escalation to
levels of 100, 200, 400 and 600 mg/m2 administered daily
at a constant rate infusion over 60 minutes on days 1 to 5
of a 14-day treatment cycle. There are no animal models
for MDS. The phase 1 dose schedule of ezatiostat
administered daily 5 every 2 weeks was based on the preclinical
animal model of chemotherapy-induced neutropenia. A
minimum of 3 patients were treated at each dose level. At
least 2 patients must have completed 5 days of treatment
and 9 days of follow-up prior to subsequent patients
being enrolled at the next higher dose level. Patients who
did not experience a drug-related toxicity were allowed to
escalate to the next dose level after at least 1
ezatiostatnave patient safely completed the next higher dose level.
If no more than none of 3 or 1 of 6 patients experienced a
DLT, 3 subsequent patients were enrolled at the next
higher dose level. Dose-escalation continued until 2 or
more patients in a cohort experienced a treatment-related
DLT. A hematologic DLT was defined as a grade 4
hematologic toxicity complicated by infection, severe
hemorrhage or marrow aplasia persisting greater than 4 weeks. A
non-hematologic DLT was defined as any
treatmentrelated grade 3 or 4 non-hematologic toxicity occurring
during the first treatment cycle.
The MTD was defined as the highest dose at which none
of 3 or 1 of 6 patients experienced a DLT or 1 full dose
level below the level where a DLT was observed. If
biologic activity based on the HI rate was observed prior to
the MTD being established, the OBD would be selected
for phase 2a evaluation. Patients were allowed to continue
treatment until the patient experienced a lack of MDS
response [defined as lack of hematologic improvement
response after receiving 2 cycles of therapy] or
The objectives for the phase 2a study were to evaluate
safety, determine the optimal dose schedule, and
determine the objective hematologic improvement response
rate by MDS International Working Group (IWG) (2000)
response criteria. Patients were enrolled sequentially to
the 2 dose schedules that were evaluated: ezatiostat
administered IV at 600 mg/m2 daily on days 1 to 5 or days
1 to 3 of a 21-day treatment cycle. In phase 2a, the 2 dose
schedules were selected to test whether clinical benefit
could be obtained in MDS patients on a more convenient
IV dose schedule(s) to ensure the regimen could be given
as an outpatient. Patients were allowed to continue
treatment until MDS progression or unacceptable toxicities. In
both phases of the study, adverse events (AEs) were
graded in accordance with the National Cancer
InstituteCommon Toxicity Criteria, version 2.0 (NCI-CTC, v2.0)
Drug formulation and administration
Ezatiostat hydrochloride liposomes for injection is
formulated as a sterile, white lyophilized powder and was
reconstituted with 0.9% Sodium Chloride for Injection, USP
(United States Pharmacopeia) and diluted in 5% Dextrose
Injection, USP prior to IV administration. Each vial
contains 103 mg of active substance (ezatiostat hydrochloride
liposomes for injection); the reconstituted product
contains 10 g/ml of ezatiostat.
The filtered infusion solution was administered at a
constant infusion rate over 60 minutes. Prior to receiving the
first infusion, patients were premedicated with
dexamethasone, antihistamines and an H2 blocker. If no acute
allergic reaction occurred after the first infusion, patients
received subsequent infusions without premedication, at
the investigator's discretion.
Baseline and follow-up assessments
All patients underwent a screening evaluation including a
complete medical history, physical examination with vital
signs, assessment of ECOG performance status,
electrocardiogram (ECG) and chest X-ray. Pretreatment laboratory
evaluation included complete blood count (CBC) with
differential, reticulocyte count, coagulation profile, serum
chemistry profile, urinalysis and pregnancy test (for
female patients of child-bearing potential only).
Within 72 hours of day 1 of each subsequent treatment
cycle, laboratory tests (CBC with differential and
chemistry profile), a physical examination including vital signs,
an assessment of ECOG performance status,
documentation of concomitant medication(s) used, and an
assessment of AEs were performed and documented. On days 1,
2 and 5 of the first treatment cycle, blood samples for
pharmacokinetic assay of ezatiostat blood levels were
obtained at specified time intervals. Concentrations of
ezatiostat and the active metabolites, TLK236 and
TLK117, were determined in whole blood by an LC-MS
assay. On day 1 in the first treatment cycle, urine samples
were also collected at pre-dose and within 24 hours
following the infusion.
Complete blood count with differential were repeated
daily on days 1 to 5 and day 8 of the first treatment cycle
and on days 1, 5 and 8 of subsequent cycles. Hematologic
improvement response assessment by IWG (2000) criteria
was performed during every other treatment cycle and at
the end of study treatment. A formal validated quality of
life instrument was not utilized in this phase 1-2a study;
however, an informal questionnaire was administered at
baseline and on day 1 of each treatment cycle to assess key
MDS clinical symptoms.
In phase 2, on day 1 in the first treatment cycle, patients
underwent a physical examination including vital signs
and an assessment of ECOG performance status,
laboratory assessments (CBC with differential, reticulocyte
count, chemistry profile and urinalysis), documentation
of concomitant medication(s) used and assessment of
AEs. Vital signs and assessment of AEs were performed on
days 1 to 5 (dose schedule 1) or days 1 to 3 (dose schedule
2) of each subsequent treatment cycle. Hematologic
improvement response assessment by IWG (2000) was
performed every other treatment cycle and at the end of
Patients who experienced any non-hematologic adverse
event of grade 3 or higher had treatment delayed by up to
a maximum of 3 weeks until recovery to grade 1 or
baseline and continued treatment at a dose reduced by 20%.
Patients who experienced uncomplicated drug-related
grade 4 neutropenia, febrile neutropenia (except
uncomplicated febrile neutropenia unassociated with grade 3 or
4 infections) and grade 4 thrombocytopenia had
treatment reduced by 20% for all subsequent treatments.
For any patient who did not meet the minimum
retreatment criteria on day 15 of a treatment cycle in phase 1 or
on day 22 in phase 2a, administration of the subsequent
treatment cycle was delayed and the toxicity was
re-evaluated. If recovery did not occur after a delay of 21 days,
treatment was discontinued and the patient was followed
until resolution of the AE.
Hematologic improvement response assessment was
performed every other treatment cycle and was based on the
standardized criteria for assessing MDS response as
proposed by the IWG (2000) for MDS [12,13]. In addition, in
phase 2a, bone marrow assessments were reviewed at 4
months for the natural history assessment per IWG
Patients with HI in the erythroid (E), neutrophil (N) and
platelet (P) cell lines were summarized by each individual
cell lineage as HI-E, HI-N and HI-P, respectively, based on
the number of cytopenic peripheral blood cell lineages at
baseline. The primary analysis was conducted under IWG
Ezatiostat hydrochloride liposomes for injection
Plasma and urinary concentrations of ezatiostat and its
metabolites (TLK235, TLK236 and TLK117) were
analyzed by an LC-MS assay. Limit of quantification (LOQ)
was 10 g/ml for all 3 entities. Figure 2 shows the
proposed pharmacokinetic model of ezatiostat using
non-linear mixed-effects modeling by NONMEM.
Demographic and baseline MDS disease characteristics of
all treated patients were summarized descriptively. The
sample size and the total number of doses administered
per cycle per patient were summarized overall and for
each dose level of ezatiostat administered IV at 50, 100,
200, 400 and 600 mg/m2.
The incidence of treatment-related AEs and clinically
significant abnormal changes in laboratory results were
summarized by the NCI-CTC v2.0 grades.
Pharmacokinetic data were analyzed with plasma
concentration-time profiles constructed for each patient treated
in phase 1. Summary statistics were generated for each
individual and for each treatment group.
The HI, HI-E, HI-N, and HI-P response rates by IWG
(2000) criteria, were calculated overall and by
demographics and MDS disease characteristics among
efficacyevaluable patients who received at least 2 cycles of
ezatiostat. Blood transfusion requirements and clinical
symptom improvements were also summarized.
Patient demographic characteristics
Fifty-four patients (35 males and 19 females) with
histologically confirmed MDS were enrolled in the study and
treated at 10 centers in the United States between May 13,
2002, and September 27, 2005 (Table 1). Fifty-six percent
of patients had an ECOG performance status of 1 and
65% were male. Ages ranged from 22 to 90 years (median
age was 70 years).
The patients treated in this study exhibited a range of FAB
subtype classifications that was typical for the disease
spectrum of MDS. Thirty (56%) patients had refractory
anemia (RA), 9 (17%) had refractory anemia with ringed
sideroblasts (RARS), 9 (17%) refractory anemia with
excess blasts (RAEB); 3 (6%) with refractory anemia with
excess blasts in transformation (RAEB-t); 1 (2%) chronic
myelomonocytic leukemia (CMML), and 2 (4%) were
unknown. There were no patients with secondary MDS on
Twenty-seven (50%) patients had an abnormal karyotype.
Trilineage cytopenia was present in 20 patients, bilineage
cytopenia was present in 16 patients, and unilineage
cytopenia was present in 18 patients.
The median number of prior therapies received by
patients enrolled in this study was 1 (range 09) with 29
(54%) having received epoetin, 8 (15%) growth factors
such as G-CSF or 1 (2%) GM-CSF, 4 (7%) lenalidomide or
thalidomide, 2 (4%) azacitidine, 5 (9%) steroids, 3 (6%)
other chemotherapies (e.g., amifostine, interleukin-11,
premaine, investigational drug, Winrho), and 2 (4%)
vitamins. At baseline, 41 (76%) patients were red blood cell
(RBC) transfusion-dependent by the IWG (2000) criteria.
Ezatiostat hydrochloride liposomes for injection study
In phase 1, five dose levels ranging from 50 to 600 mg/m2
were evaluated (Table 2). The median number of cycles
received per patient was 4 (range 18).
Dose reductions due to AEs were infrequent as only 2
patients required a dose reduction (1 each at the 50 mg/
m2 and 600 mg/m2 dose levels). A total of 13 patients had
dose delays (2 occurring at the 50 mg/m2 dose level, 3 at
100 mg/m2, 1 at 200 mg/m2, 4 at 400 mg/m2 and 3 at the
600 mg/m2 dose level). The dose of ezatiostat was
Abbreviations: RA, refractory anemia; RARS, refractory anemia with
ringed sideroblasts; RAEB, refractory anemia with excess blasts;
RAEB-t, refractory anemia with excess blasts in transformation;
CMML, chronic myelomonocytic leukemia; IPSS, International
Prognostic Scoring System; r-EPO, recombinant epoetin; G-CSF,
granulocyte colony-stimulating factor; GM-CSF, granulocyte
macrophage colony stimulating factor; HCT, hematocrit; Hgb,
Doase Cohort (mg/m2)
# of Patients
Total # Cycles Administered
Median # of Cycles per Patient (Range)
Treatment (600 mg/m2)
# of Patients
Total # Cycles Administered
Median # of Cycles per Patient (Range)
increased from 100 mg/m2 to 200 mg/m2 in the third
treatment cycle in 1 patient, and increased from 200 mg/
m2 to 400 mg/m2 in the fourth treatment cycle in another
In phase 2a, 10 patients were treated on dose schedule 1
and 18 patients on dose schedule 2. The median number
of treatment cycles received per patient was 8 (range 4
17) on dose schedule 1 and 4 (range 119) on dose
schedule 2 for a median of 7 (range 119) cycles per patient in
phase 2a. A total of 1345 doses were administered (Table
Ezatiostat-related hematologic adverse events were
uncommon with 1 patient each (2% each) for grade 4
anemia, grade 3 anemia, grade 3 leukopenia, grade 2
leukocytosis, and grade 2 thrombocytopenia (Table 3).
The most common ezatiostat related non-hematologic
AEs of all grades experienced by 10% of the patients (n
= 54) were: chills (20%), drug hypersensitivity (19%),
back pain (19%), flushing (19%), nausea (17%), bone
pain (15%), fatigue (13%), pain in extremity (13%),
dyspnea (13%), and diarrhea (11%) (Table 3). These events
were mostly grade 1 to grade 2 and were related to acute
infusion hypersensitivity reactions due to the liposomal
formulation, a known side effect of liposomal drugs.
Hypersensitivity reactions to the liposomal formulation
of ezatiostat, in some cases, were ameliorated or
prevented by use of a slower infusion rate for ezatiostat and
the prophylactic administration of low-dose
dexamethasone, antihistamines, and an H2 blocker. No DLTs were
In phase 1, across all dose levels, a total of 39 serious
adverse events (SAEs) were reported in 14 (54%) patients;
30 SAEs were unrelated to ezatiostat and 9 were ezatiostat
treatment-related (anemia [n = 1], myocardial ischemia [n
= 1], drug hypersensitivity [n = 3], cellulitis [n = 1], bone
pain [n = 2], and pulmonary hemorrhage [n = 1]). In
phase 2a, a total of 14 SAEs were reported in 10 patients
(36%) in both dose schedules combined. Three events
were ezatiostat treatment-related (anaphylactic reaction
[n = 1] and drug hypersensitivity [n = 2]).
In phase 1, treatment with ezatiostat was discontinued
due to AEs in 6 patients: 2 (33%) patients at the 50 mg/
m2 dose level, 2 (27%) patients at the 400 mg/m2 dose
level and 2 (27%) patients at the 600 mg/m2 dose level.
Four (15%) of the discontinuations were considered to be
related to ezatiostat; 2 patients at the 50 mg/m2 dose level,
1 patient at the 400 mg/m2 dose level, and 1 patient at the
600 mg/m2 dose level. In phase 2a, 2 patients (20%) on
dose schedule 1 and 6 patients (33%) on dose schedule 2
were discontinued due to an AE.
No treatment-related deaths were reported in this study.
Of the 12 deaths reported as unrelated to study treatment
in phase 1, five were related to MDS and 6 were due to
other causes. In phase 2a, no deaths were reported in the
cohort on dose schedule 2; however, 2 deaths were
reported in the cohort on dose schedule 1. These deaths
were neither treatment-related nor due to MDS. Overall
treatment-emergent adverse events for the study are
shown in Table 4.
The pharmacokinetic model for ezatiostat and its
metabolites (Figure 2) was derived from the concentrations of
ezatiostat and its metabolites in blood of patients
administered intravenous ezatiostat. Ezatiostat undergoes
deesterification to both TLK235 and TLK236. TLK235 and
TLK236 undergo further de-esterification to TLK117.
Pharmacokinetic parameters were estimated and derived
for TLK199, TLK236 and TLK117. The ezatiostat
elimination half life is 0.20 hours, an AUC/dose of 0.008 hours/
L and a distribution half-life of 0.03 hours. The active
metabolite TLK236 has a half-life of 2.65 hours, with an
AUC/dose of 0.341 hours/L; the metabolite TLK117 has a
half-life of 0.240.60 hours with an AUC/dose of 0.0116
hours/L. The data presented fit well with the proposed
pharmacokinetic model. This pharmacokinetic
population model will be further tested with ongoing patient
data collection and future studies which will further refine
the proposed model of pharmacokinetic parameters of
ezatiostat and its metabolites, TLK236 and TLK177.
Twelve (28%) patients had clinically significant
improvement in at least 1 or more cell lineages in efficacy
evaluable patients. The longest duration of therapy was 17 cycles
on dose schedule 1 and 19 cycles in dose schedule 2
(Table 2). Clinically significant improvement was
observed across all MDS FAB subtypes and in all blood
cell lineages, including trilineage response in 4 of 16
patients (25%) with 3-cell line cytopenia, bilineage
response in 1 of 13 patients (8%) with 2-cell line
cytopenia, and unilineage response in 7 of 14 patients (50%)
with single-cell line cytopenia meeting the MDS objective
response criteria for HI (Table 5). Nine of 38 (24%)
patients with low hematocrit/hemoglobin (anemia) had
HI-E, 11 of 26 (42%) patients with WBC/ANC cytopenia
had HI-N, and 12 of 24 (50%) patients with platelet
cytopenia had HI-P. Patients experienced decreased RBC and
platelet transfusion requirements, and in some cases
leading to transfusion independence.
Urinary Tract Infection
Abdominal Pain Upper
Infusion Site Bruising
Infusion Site Reaction
Infusion Site Erythema
Infusion Site Pain
Upper Respiratory Tract Infection
This phase 1-2a study was the first clinical study of
ezatiostat hydrochloride liposomes for injection in patients
with all FAB classification types of MDS.
In phase 1, patients with MDS were administered
ezatiostat at doses up to 600 mg/m2 IV daily for 5 days. Adverse
events were generally mild to moderate in grade, with
relatively few serious events reported. No DLTs were
observed; therefore, the MTD was not obtained. The
optimal biologic dose was determined to be 600 mg/m2 and
was administered on 2 schedules during phase 2a: 600
mg/m2 IV on days 1 to 5 or on days 1 to 3 of a 21-day
treatment cycle. Both dose schedules were well tolerated and
hematologic improvement responses were observed on
Hematologic improvement, including bilineage or
trilineage responses, by IWG (2000) criteria was observed across
all FAB subtypes of MDS, IPSS risk and in normal and
abnormal karyotypes. Hematologic improvement was
observed in patients who had failed or progressed
following a range of prior therapies and supportive care
regimens. Reduction of transfusion requirements or
transfusion independence was reported in some cases.
Improvements in bone marrow maturation and
cellularity were also observed.
In conclusion, further clinical investigation of ezatiostat
treatment in patients with MDS is supported by the
tolerability and hematologic improvement responses in all 3
cell lineages seen with intravenous ezatiostat, including
independence or reduction of RBC and platelet
Hematologic Improvement Response Rate (IWG 2000)
Number of Patients
Transfusion Requirements and Clinical Symptoms Improvement (IWG 2000)
Phase 1: Comparison of Decreased Transfusion Requirements and Clinical Symptoms Improvement
All Dose Levels Combined
sion requirements. An oral formulation of ezatiostat is
being evaluated in phase 2 studies in MDS.
Azra Raza has received honoraria from Celgene
Corporation to serve on their speakers bureau. Peter Emanuel has
been paid by Novartis in consultant/advisory board
capacity. Stephanie Williams has received honoraria from
Celgene Corporation and Millennium Pharmaceuticals to
serve on their speakers bureau. Peter Curtin has received
honoraria from MGI Pharma and Celgene Corporation to
serve on their speakers bureau. Naomi Galili, Natalie
Callander, Leonel Ochoa, Lawrence Piro, Howard Burris III,
Stefan Faderl, Zeev Estrov, and Richard A. Larson declare
that they have no competing interests.
James Keck, Marsha Jones, Lisa Meng and Gail L. Brown
are employed by Telik, Inc.
AR, MJ, and GB designed the research protocol; AR, NG,
NC, LO, LP, PE, SW, HB, SF, ZE, PC, RAL were involved in
treating patients and collecting data; LM conducted the
statistical analysis; AR, NG, MJ, JK and GB wrote the paper
with contributions from the other authors. All authors
read and approved the final manuscript.
Statement of prior presentation: Presented in abstract form: Raza A, Callander
N, Ochoa L, et al. Hematologic Improvement (HI) by TLK199 (Telintra),
a Novel Glutathione Analog, in Myelodysplastic Syndrome: Phase 2 Study
Results. Proceedings from the Annual Meeting of the American Society of
Hematology; December 2005; Atlanta, Georgia. Abstract #2520.
Presented in abstract form: Callander N, Ochoa-Bayona JL, Piro L, et al.
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.
Proceedings from the Annual Meeting of the American Society of Hematology;
December 47, 2004; San Diego, California, Abstract #1428.
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