Sorry the link didn't work ..here is the text..yup, Peter it was heartening to learn she is still alive..
Multi-institutional phase 2 study of TLK286
(TELCYTA, a glutathione S-transferase
P1-1 activated glutathione analog prodrug)
in patients with platinum and paclitaxel refractory
or resistant ovarian cancer
J.J. KAVANAGH*, D.M. GERSHENSON*, H. CHOI*, L. LEWIS*, K. PATELy, G.L. BROWNy,
A. GARCIA§ & D.R. SPRIGGSz
*The M.D. Anderson Cancer Center, University of Texas, Houston, Texas; §University of Southern California (USC),
Los Angeles, California; zMemorial Sloan-Kettering Cancer Center, New York, New York; yTelik, Inc., Palo Alto,
California
Address correspondence and reprint requests to: Gail L. Brown,
MD, Telik, Inc., 3165 Porter Drive, Palo Alto, CA 94304, USA.
Email: gbrown@telik.com
Glutathione S-transferases (GSTs) are a group of cytosolic
enzymes that catalyze the conjugation of electrophilic
xenobiotics with glutathione, an abundant
intracellular reducing tripeptide(1). GSTs are frequently
overexpressed in neoplastic tissues, with the GST P1-1
isoform most commonly elevated, including ovarian(2)
cancer and others(3–5). Furthermore, GST P1-1 expression
has been shown to be negatively correlated with
prognosis in ovarian cancer(6).
TLK286 is a glutathione analog prodrug that was
rationally designed to exploit the increased activity
of GST P1-1 that is present in many types of human
cancers and leukemias(7,8). TLK286 is metabolized by
GST P1-1, releasing a reactive tetrakis (chloroethyl)
phosphorodiamidate fragment and a glutathione analog
vinyl sulfone(7,8). Following activation, a series of
molecular events occur that causes the activation of the
stress response pathway, ultimately resulting in the
induction of cellular apoptosis. Specifically, human
cancer cells exposed to TLK286 demonstrate substantial
activation of mitogen-activated protein (MAP)
kinase MKK4, p38 kinase, jun-N-terminal kinase, and
caspase 3 prior to deoxyribonucleic acid fragmentation
and the loss of membrane asymmetry(9). The proapoptotic
and antitumor activity of TLK286 has been
confirmed in vitro against a variety of human cancer
cell lines, including ovarian cancer cells (OVCAR 3)(10)
and in vivo in a broad range of murine tumor models,
including those that have elevated levels of GST P1-1
and increased cancer drug resistance(11,12). No crossresistance
has been observed with nonclassical alkylators
including cisplatin or carboplatin as well as classical
alkylators and paclitaxel(13).
The two phase 1 studies of TLK286 showed antitumor
activity in a variety of solid tumors, as well as
excellent tolerability consistent with the targeted
mechanism of activation(14,15). In the first phase 1
study, the maximum tolerated dose was 1280 mg/m2
given every 3 weeks(14). At the 1280 mg/m2 dose
level, the principal study drug–related dose-limiting
toxicities were hematuria with dysuria that resolved
within 48 h without specific treatment. The toxicities
were transient, non–life threatening, and without
sequelae. In the second phase 1 study, TLK286 was
administered every week(15). In this study, safety and
efficacy were equivalent to the one that used TLK286
every 3 weeks. Based on these results, the recommended
phase 2 dose was chosen as 1000 mg/m2 and
the every 3 weeks schedule was chosen for patient
convenience.
Effective treatment options are very limited in patients
with platinum and paclitaxel refractory or resistant
ovarian cancer and represent a significant unmet
medical need. Since GST P1-1 is overexpressed in
ovarian cancer, we investigated the effect of single
agent TLK286 treatment in this patient population.
The low toxicity profile of TLK286 is suited to this
patient profile, since patients with chemotherapyresistant
ovarian cancer have been heavily pretreated
with platinum, taxanes, and additional salvage agents
and often show residual cumulative toxicities further
limiting their treatment options. We report here the
safety and efficacy results of this phase 2 study with
TLK286 in platinum and paclitaxel refractory or resistant
ovarian cancer.
Materials and methods
Patient selection
Study design
This phase 2, multicenter, open-label, single-arm study
of TLK286 in platinum refractory or resistant advanced
epithelial ovarian carcinoma enrolled 36
patients. The protocol was approved by institutional
review boards, and all patients gave written informed
consent prior to study-specific procedures.
Eligibility criteria
Women, 18 years and older, with histologically or cytologically
proven epithelial ovarian carcinoma refractory
or resistant to platinum- and taxane-based
therapy were assessed for eligibility. Patients were considered
to be platinum refractory if their disease
progressed or failed to respond during initial platinum-
based chemotherapy. Patients were considered
platinum resistant if their disease recurred within
6 months of completion of platinum-based chemotherapy
or recurred after 6 months of completion of
therapy and failed subsequent reinduction with platinum-
based chemotherapy. At least one prior chemotherapy
regimen was required, and up to three prior
chemotherapy regimens were allowed. All platinum containing
regimens were counted as one. Patients
were required to have measurable disease defined
as unidimensional measurable lesion(s) by Response
Evaluation Criteria in Solid Tumors (RECIST)(16) criteria
with documented progression within 3 months
before enrollment. Pleural effusions, ascites, osseous
metastases, CA125 blood levels, and lesions located
in previously irradiated areas were not considered
measurable disease.
Additional eligibility requirements included Eastern
Cooperative Oncology Group (ECOG) performance
status 1; absolute neutrophil count (1500/mm3),
platelets 100,000/mm3, hemoglobin 9.0 g/dL; total
bilirubin ,2.5 mg/dL, aspartate amino transferase
(AST) and alanine amino transferase (ALT) 3.0 times
the upper limits of normal, creatinine 1.5 mg/dL or
a calculated creatinine clearance of 60 mL/min, and
a disease-free period of more than 5 years from prior
malignancies. Patients with known history of central
nervous system metastases were allowed if the disease
was neurologically stable with absence of active disease
by brain computerized tomography (CT) or magnetic
resonance imaging (MRI) and if the patient did
not require oral or intravenous steroids or anticonvulsants.
Patients were reported to have adequate
bone marrow reserves.
Patients were excluded if they were pregnant or
breast-feeding, had a life expectancy of less than 12
weeks, carcinomatous meningitis or hydrocephalus,
uncontrolled infection, gross hematuria, or received
whole pelvis radiation therapy. Exclusion criteria included
any chemotherapy, radiotherapy, radiopharmaceuticals,
immunotherapy, major surgery, or failure
to recover from surgery within 4 weeks prior to study
entry. Additionally, no concurrent investigational or
antineoplastic agents were permitted during the study.
Treatment plan
Patients received TLK286 administered at 1000 mg/m2
every 3 weeks. A cycle was defined as treatment every
3 weeks. TLK286 was supplied by Telik, Inc. (Palo
Alto, CA) as a sterile, lyophilized drug product.
TLK286 was administered as a 30-min intravenous
infusion through a peripheral vein.
Duration of therapy and dose modifications
Patients received TLK286 until disease progression,
unacceptable toxicity, or the patient or investigator
requested discontinuation. If a complete response (CR)
occurred, the patient continued to receive treatment
with TLK286 for a minimum of two cycles beyond the
confirmation of CR.
Treatment with TLK286 was discontinued if the
patient was unable to tolerate TLK286 despite dose
modification, developed concurrent illness, or underwent
changes in medical condition rendering her
unacceptable for further treatment. Treatment with
TLK286 was also discontinued if any patient required
radiation therapy other than local radiation for pain or
a solitary brain metastasis.
In the event of certain hematologic and nonhematologic
toxicities, dose modifications were required.
Toxicities were graded according to the National Cancer
Institute Common Toxicity Criteria version 2.0. For
hematologic toxicity, TLK286 treatment was withheld
until recovery of absolute neutrophil count (ANC) to
1500/mm3 and platelet count 100,000/mm3. For an
ANC nadir 1000/mm3 or platelets ,50,000/mm3,
TLK286 treatment was resumed with a 20% dose
reduction. Nonhematologic toxicity of grade 3 considered
possibly related to TLK286 required a 20%
dose reduction and a delay in subsequent TLK286
treatment until the toxicity recovered to grade 2 or
pre-TLK286 baseline. The exception was for grade 3
hepatic toxicities (grade 3 ALT, alkaline phosphatase,
or total bilirubin values); those toxicities required
a 20% dose reduction and a delay in subsequent
TLK286 treatment until recovered to grade 1 or pre-
TLK286 baseline. Renal or bladder toxicity grade 2
required a TLK286 dose reduction of 20% and a delay
in subsequent therapy until all symptoms resolved to
grade 1 or to pre-TLK286 baseline levels.
Routine or prophylactic use of filgastrim or sargramostim
was not allowed during the first cycle of
TLK286 administration. However, growth factor support
was permitted to treat a neutropenic event or as
prophylaxis in a patient who experienced a neutropenic
event during a previous cycle.
Pretreatment and follow-up studies
All patients underwent a screening evaluation including
complete medical history, physical examination,
and 12-lead electrocardiogram. Radiographic imaging
studies (spiral/helical CT or MRI scans) were required
to assess measurable disease. CA125 blood levels were
determined within 3 weeks of treatment initiation.
Pretreatment laboratory evaluation included complete
blood count with differential and platelet count, calculated
creatinine clearance, serum chemistry profile,
urinalysis, and pregnancy test. Prior to each treatment,
laboratory and physical assessments were conducted,
use of concomitant medications was documented, and
toxicities were assessed.
Assessment of response and safety
Radiologic evaluation of objective tumor response
using RECIST was performed at baseline and every
6 weeks or until documentation of disease progression.
Measurement of palpable or visible tumor
lesions, if present, was obtained at screening, cycle 1
day 1, and every 6 weeks, thereafter. CA125 tumor
marker measurement was obtained at baseline and
within 72 h prior to dosing at each cycle. Radiologic
TLK286 (TELCYTA) in platinum refractory or resistant ovarian cancer 595
# 2005 IGCS, International Journal of Gynecological Cancer 15, 593–600
studies including spiral/helical CT or MRI scans were
repeated between 4 and 6 weeks after the first documentation
of objective tumor response to confirm the
tumor response. Patients with stable disease (SD), CR,
or partial response (PR) continued on TLK286 study
treatment and underwent repeat tumor assessment at
6-week intervals until progressive disease (PD) was
documented or until alternate cancer therapy was
initiated.
In order to be evaluable for response, a patient must
have received at least one cycle of treatment and must
have completed one follow-up tumor assessment for
response. RECIST was used to determine best overall
response. A CR was defined as complete disappearance
of all measurable (target) and nonmeasurable
(nontarget) disease, no new lesions, and no diseaserelated
symptoms. In addition, CR by RECIST
required the normalization of the CA125 tumor antigen
blood levels. A PR was defined as at least a 30%
decrease in the sum of the longest diameters (LDs) of
measurable target lesions, using the baseline sum of
the LDs of the measurable lesions as reference. PD
was defined as at least a 20% increase in the sum of
the LDs of target lesions, compared to the smallest
sum of the LDs (nadir) recorded since baseline, or the
appearance of new lesions. SD was defined as neither
sufficient tumor reduction to qualify for PR nor suffi-
cient increase to qualify for PD.
Safety analyses were performed on all patients who
received any amount of TLK286.
Statistical analysis
A total of 35 evaluable patients with platinum refractory
or resistant advanced epithelial ovarian cancer
were to be treated following the Fleming two-stage
design(17).
A total of 34 patients with platinum refractory or
resistant advanced epithelial ovarian cancer were evaluable
for tumor response. Two patients were not evaluable
due to not completing one follow-up spiral/helical
CT or MRI scan required for tumor assessment. All 36
patients were included in the overall intent-to-treat
Kaplan–Meier survival analysis.
Results
Patient demographics
Thirty-six patients were enrolled, and demographic
and disease characteristics of the patients are summarized
in Table 1. For the majority of patients (81%), the
primary site at diagnosis was the ovary, with peritoneum
(17%) and fallopian tube (3%) being less frequent.
All patients had metastatic disease at one or
more sites, with 73% having disease at two or more
sites. The most common sites of metastatic disease
were the peritoneum (92%), lymph nodes (28%), liver
(19%), and lung (8%). Bulky disease, a poor prognostic
variable, was present in 10 (28%) patients and ascites
was present in six (17%) patients.
Patients had received a median of three prior
chemotherapy regimens. Twenty-three patients (64%)
were platinum refractory, 13 patients (36%) were platinum
resistant, and 36 patients (100%) failed paclitaxel.
Eighty-six percent of the patients had failed additional
salvage chemotherapies, including: liposomal doxil.
Thirty-six patients received a total of 133 cycles of
TLK286. The mean cumulative dose was 3607 mg/m2,
median cumulative dose was 2000 mg/m2, and the
range was 1000–12,987 mg/m2. The full dose of
TLK286 was maintained for 95% of cycles, and 99% of
the specified dose was delivered. Dose reductions due
to toxicity were infrequent. Delayed doses were
reported on eight occasions (6%), interrupted doses on
one (.019%), dose reductions on four (3%), and granulocyte
colony stimulating factor (G-CSF) support on
five (3.7%) occasions.
Safety
All treated patients were assessable for toxicity. There
were no treatment-related deaths, and no patient was
removed from study treatment due to an adverse
event considered to be related to TLK286 administration.
TLK286 treatment was generally well tolerated,
without evidence of dose-limiting or cumulative toxicity.
Grade 3 toxicities were infrequent.
TLK286-related hematologic toxicity
TLK286 treatment–related hematologic toxicities in
this study were mostly mild or moderate (grade 1 or
2). One patient experienced a grade 4 neutropenia.
This patient had a prior history of blood-transfusion
dependence and growth factor support while on frontline
platinum-based chemotherapy. This condition
was thought to be due to an underlying autoimmune
bone marrow disorder present for several years before
study entry. This patient continued to receive six
cycles of TLK286 using filgastrim support and
achieved a PR as best response. She tolerated TLK286
well until her disease progressed.
There was no clinically significant myelosuppression
or thrombocytopenia reported in this heavily pretreated
population that would be expected to have
had limited bone marrow reserves.
TLK286-related nonhematologic toxicity
TLK286 treatment-related nonhematologic toxicities in
this study were generally mild or moderate (grade
1 or 2). The most frequent nonhematologic toxicities
were nausea, fatigue, vomiting, urinary frequency,
and dysuria. Nausea and vomiting were mild and
well controlled with standard antiemetics(14).
Patients with microscopic hematuria due to their
underlying cancer or comorbid disease such as renal
stones and tumor invasion of the bladder did not
experience an exacerbation of their baseline microscopic
hematuria when treated with TLK286. Interestingly,
one patient with hematuria was cystoscoped
and shown to have ovarian cancer invading the bladder
wall as the source of her hematuria. This patient
continued treatment with TLK286, and following a
significant reduction in her bladder mucosal tumor
had resolution of tumor-related ulceration and experienced
resolution of hematuria.
Grade 3 hematuria occurred in one patient (3%),
grade 3 dysuria in two patients (6%), and grade 3 urinary
frequency in one patient (3%) in the setting of pelvic
masses and extensive pelvic disease. These patients
were easily managed by ensuring adequate hydration
and a 20% dose reduction on subsequent treatments.
Both patients continued on treatment without subsequent
urinary symptoms. This toxicity was noncumulative.
Patients receiving TLK286 should be monitored by
urinalysis as clinically indicated and encouraged to
maintain adequate hydration prior to and following
TLK286 administration. Re-treatment with a 20% dose
modification, with adequate oral and/or intravenous
hydration at the time of TLK286 treatment, eliminated
recurrence of this toxicity.
Tumor response and survival analysis
Thirty-four patients (94%) were evaluable for objective
tumor response by RECIST, shown in Table 2. Patients
were considered evaluable for tumor response if they
had received at least one cycle of TLK286 and one
follow-up tumor assessment. One patient (3%) had
a CR, four patients (12%) had PRs for an overall
response rate of 15% (95% CI: 5–31), and 12 patients
(35%) had SDs, for an overall disease stabilization rate
(DSR ¼ CR 1 PRs 1 SDs) of 50%. Objective responses
occurred regardless of platinum responsiveness (3 of
22 or 14% refractory, 2 of 12 or 17% resistant) and as
third-line salvage therapy or greater (3 of 20 or 15%).
The median duration of SD was 157 days (range
78–316 days).
Profiles of patients with objective responses are
summarized in Table 3. Responders were seen in all
subgroups and at all participating centers. Objective
responses were accompanied by clinical symptom
improvement, decrease in CA125 levels, and ECOG
performance status was maintained or improved for
patients receiving repeated cycles of TLK286. Bulky
disease, a poor prognostic factor, was present in all the
responders.
One patient who presented with platinum and paclitaxel
refractory disease achieved a durable CR. This
patient had stage IV ovarian cancer and was treated
by inadequate debulking surgery followed by carboplatin
and paclitaxel. She progressed during her sixth
cycle, exhibiting measurable bulky (5 cm) disease in
liver and spleen (target lesions), ascites, and diffuse
abdominal metastases that were nonmeasurable, and
a rising CA125 level of 36. After two cycles (6 weeks)
of TLK286, the patient had a robust PR, and after completing
six cycles of TLK286, the patient experienced
a confirmed CR. The patient continues in complete
remission for more than 3 years and off all therapy for
more than 2.5 years.
The overall median survival, based on Kaplan–
Meier analysis, was 423 days and the estimated proportion
patients surviving at 12 months was 60% and
at 18 months was 40%.
Discussion
The effective treatment of recurrent platinum refractory
or resistant ovarian carcinoma is limited due to
chemotherapy-resistant disease, large tumor burden,
poor nutritional status, and chronic residual toxicities
from prior treatments. Furthermore, several studies
have demonstrated that response rates decline in patients
with shorter platinum-free intervals(18). In addition
to platinum-free intervals, other factors affecting
response rates include: number of prior regimens, toxicity
from prior therapy, previous use of growth factors
and/or transfusions, performance status, volume
of disease, number of disease sites, ascites, and presence
of bulky disease and symptoms of gastrointestinal
dysfunction. Since the likelihood of response to
treatment for recurrent disease decreases after each
relapse, while toxicities tend to increase, the aim of
palliative treatment in relapsed advanced ovarian cancer
should be to prolong survival and progression-free
survival while minimizing drug induced toxicity.
Maintenance or improvement in quality of life becomes
an important goal in the treatment of these
patients.
The recognition of the persistent sensitivity of many
ovarian cancers to platinum agents at the time of
documented disease recurrence has led to the recommendation
that reiterative treatment with platinumand
taxane-based regimens is the current treatment
paradigm for these patients(19). All patients eventually
become resistant to both platinum and taxane agents.
In this situation, the opportunity for major objective
responses to subsequent treatment is poor and it is dif-
ficult to impact the natural history course of the disease.
The patients are expected to have a median
survival of less than 6 months, with one third of
patients expected to survive less than 4 months(20).
This efficacy of TLK286 is reported in a patient population
with many unfavorable prognostic factors. All
patients were heavily pretreated, they received a
median of three prior chemotherapy regimens, with
36% of patients receiving TLK286 as third-line or
greater therapy. All patients were refractory or resistant
to platinum and taxanes. In addition, 86% of patients
had failed additional salvage chemotherapies with a
variety of standard and experimental agents including
liposomal doxorubicin, topotecan, gemcitabine, and
docetaxel. The best response to prior platinum-based
therapy was less favorable than expected in the general
ovarian cancer population. In addition, one third of the
patients had bulky disease, with 73% having two or
more measurable metastatic sites. Given the heavily
pretreated nature of these patients combined with
other poor prognostic factors of bulky disease, ascites,
and large number of metastatic sites, the activity seen
is clinically significant.
Similarly, the high disease stabilization rate (50%)
observed in this study is unusual in this population.
A disease stabilization rate of 17% in refractory or
resistant patients has been reported for topotecan(21).
Although the trial was single arm and nonrandomized,
the long median survival of 423 days and
1 year survival of 60% and 18 month survival of 40%
observed in this intent-to-treat population compares
favorably to reports in the evidence-based literature(
20,22). The significance of 15% objective response
rate and 50% disease stabilization rate reported with
TLK286 in this study is reinforced by the survival data.
The proportion of patients at high risk for hematologic
toxicities was overrepresented in this trial.
Advanced age, renal impairment, prior radiation therapy,
and extensive pretreatment increase the risk of
hematologic abnormalities. TLK286 was well tolerated
in this difficult-to-treat patient group, with no clinically
significant hematologic toxicities reported.
TLK286 has a profile that is suited for the development
of a new agent for the treatment of ovarian
cancer. It has a novel mechanism of action, good tolerability
linked to intracellular activation and non–crossresistance
to platinum- and taxane-based therapies
both in the laboratory and clinic setting(10). Recent reports(
10,23) of significant preclinical synergy seen with
TLK286 with carboplatin, docetaxel, and doxorubicin
formed the basis of recent clinical studies using
TLK286 for the first time in combination with these
agents(24–26). Significant synergy was seen in a phase 2
trial with TLK286 in combination with carboplatin
in platinum resistant or refractory ovarian cancer
patients(24). Similar synergy was reported in a second
trial with liposomal doxorubicin and TLK286 in combination
therapy of patients with platinum refractory or
resistant ovarian cancer(25). Further investigations of
these combinations in ovarian cancer patients are
planned.
The objective response rate seen in this trial is con-
firmatory that TLK286 is an active agent in platinum
refractory or resistant ovarian cancer and compares
favorably to the objective response rates observed
with other agents in second-line therapy, such as topotecan
and liposomal doxorubicin(22). Based on the
encouraging results from this and ongoing phase 2
studies of TLK286, a phase 3 randomized registration
trial in platinum refractory or resistant ovarian cancer
has been initiated, with the objective of improving
overall survival and progression-free survival over
what is now achievable with approved agents.
Acknowledgments
Support for this project was provided by Telik, Inc.,
Palo Alto, CA.
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Accepted for publication February 24, 2005
600 J.J. Kavanagh et al.
# 2005 IGCS, International Journal of Gynecological Cancer 15, 593–600 |
