AXOTERE® (docetaxel) Injection Concentrate should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
The incidence of treatment-related mortality associated with TAXOTERE therapy is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive TAXOTERE as a single agent at a dose of 100 mg/m2.
TAXOTERE should generally not be given to patients with bilirubin > upper limit of normal (ULN), or to patients with SGOT and/or SGPT >1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase > 1.5 x ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin, SGOT or SGPT, and alkaline phosphatase values should be obtained prior to each cycle of TAXOTERE therapy and reviewed by the treating physician.
TAXOTERE therapy should not be given to patients with neutrophil counts of < 1500 cells/mm3. In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving TAXOTERE.
Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received the recommended 3-day dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the TAXOTERE infusion and administration of appropriate therapy. TAXOTERE must not be given to patients who have a history of severe hypersensitivity reactions to TAXOTERE or to other drugs formulated with polysorbate 80.
Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day dexamethasone premedication regimen. It was characterized by one or more of the following events: poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites).
|
Drug Warning Insert |
,4,7ß,10ß,13
-hexahydroxytax-11-en-9-one
4-acetate 2-benzoate, trihydrate. Docetaxel has the
following structural formula:
Docetaxel is a white to almost-white powder with an empirical formula of C43H53NO14• 3H2O, and a molecular weight of 861.9. It is highly lipophilic and practically insoluble in water. TAXOTERE (docetaxel) Injection Concentrate is a clear yellow to brownish-yellow viscous solution. TAXOTERE is sterile, non-pyrogenic, and is available in single-dose vials containing 20 mg (0.5 mL) or 80 mg (2 mL) docetaxel (anhydrous). Each mL contains 40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80. TAXOTERE Injection Concentrate requires dilution prior to use. A sterile, non-pyrogenic, single-dose diluent is supplied for that purpose. The diluent for TAXOTERE contains 13% ethanol in water for injection, and is supplied in vials.
CLINICAL PHARMACOLOGY
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use.
HUMAN PHARMACOKINETICS
The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20-115 mg/m2 in phase I studies. The area under the curve (AUC) was dose proportional following doses of 70-115 mg/m2 with infusion times of 1 to 2 hours. Docetaxel's pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the
,
ß, and 
phases
of 4 min, 36 min, and 11.1 hr, respectively. The
initial rapid decline represents distribution to the
peripheral compartments and the late (terminal)
phase is due, in part, to a relatively slow efflux
of docetaxel from the peripheral compartment. Mean
values for total body clearance and steady state
volume of distribution were 21
L/h/m2
and 113 L, respectively. Mean total body clearance for
Japanese patients dosed at the range of 10-90
mg/m2
was similar to that of European/American populations
dosed at 100 mg/m2,
suggesting no significant difference in the elimination
of docetaxel in the two populations.
A study of
14C-docetaxel
was conducted in three cancer patients. Docetaxel was
eliminated in both the urine and feces following
oxidative metabolism of the tert-butyl ester group, but
fecal excretion was the main elimination route. Within 7
days, urinary and fecal excretion accounted for
approximately 6% and 75% of the administered
radioactivity, respectively. About 80% of the
radioactivity recovered in feces is excreted during the
first 48 hours as 1 major and 3 minor metabolites with
very small amounts (less than 8%) of unchanged drug.
A
population pharmacokinetic analysis was carried out after
TAXOTERE treatment of 535 patients dosed at 100
mg/m2.
Pharmacokinetic parameters estimated by this analysis
were very close to those estimated from phase I studies.
The pharmacokinetics of docetaxel were not influenced by
age or gender and docetaxel total body clearance was not
modified by pretreatment with dexamethasone. In patients
with clinical chemistry data suggestive of mild to
moderate liver function impairment (SGOT and/or SGPT
>1.5 times the upper limit of normal [ULN] concomitant
with alkaline phosphatase >2.5 times ULN), total body
clearance was lowered by an average of 27%, resulting in
a 38% increase in systemic exposure (AUC). This average,
however, includes a substantial range and there is, at
present, no measurement that would allow recommendation
for dose adjustment in such patients. Patients with
combined abnormalities of transaminase and alkaline
phosphatase should, in general, not be treated with
TAXOTERE.
Clearance of docetaxel in combination therapy
with cisplatin was similar to that previously observed
following monotherapy with docetaxel. The pharmacokinetic
profile of cisplatin in combination therapy with
docetaxel was similar to that observed with cisplatin
alone.
The combined administration of docetaxel,
cisplatin and fluorouracil in 12 patients with solid
tumors had no influence on the pharmacokinetics of each
individual drug.
A population pharmacokinetic analysis
of plasma data from 40 patients with hormone-refractory
metastatic prostate cancer indicated that docetaxel
systemic clearance in combination with prednisone is
similar to that observed following administration of
docetaxel alone.
A study was conducted in 30 patients
with advanced breast cancer to determine the potential
for drug-drug-interactions between docetaxel (75
mg/m2),
doxorubicin (50 mg/m2),
and cyclophosphamide (500 mg/m2)
when administered in combination. The coadministration of
docetaxel had no effect on the pharmacokinetics of
doxorubicin and cyclophosphamide when the three drugs
were given in combination compared to coadministration of
doxorubicin and cyclophosphamide only. In addition,
doxorubicin and cyclophosphamide had no effect on
docetaxel plasma clearance when the three drugs were
given in combination compared to historical data for
docetaxel monotherapy.
In vitro studies showed that
docetaxel is about 94% protein bound, mainly to
1-acid
glycoprotein, albumin, and lipoproteins. In three cancer
patients, the in vitro binding to plasma proteins was
found to be approximately 97%. Dexamethasone does not
affect the protein binding of docetaxel.
In vitro drug
interaction studies revealed that docetaxel is
metabolized by the CYP3A4 isoenzyme, and its metabolism
can be inhibited by CYP3A4 inhibitors, such as
ketoconazole, erythromycin, troleandomycin, and
nifedipine. Based on in vitro findings, it is likely that
CYP3A4 inhibitors and/or substrates may lead to
substantial increases in docetaxel blood concentrations.
No clinical studies have been performed to evaluate this
finding .CLINICAL STUDIES
Breast Cancer The efficacy and safety of TAXOTERE have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens). Randomized Trials In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with TAXOTERE (100 mg/m2 every 3 weeks) or the combination of mitomycin (12 mg/m2 every 6 weeks) and vinblastine (6 mg/m2 every 3 weeks). 203 patients were randomized to TAXOTERE and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the TAXOTERE arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results (See Table 1).
Table 1 - Efficacy of TAXOTERE in the Treatment of Breast
Cancer
Patients
Previously Treated with an Anthracycline-Containing
Regimen
(Intent-to-Treat
Analysis)
(n=203)
Vinblastine (n=189)
p=0.01 Log Rank
|
Efficacy Parameter |
Docetaxel |
Mitomycin/ | p-value | |||
|
Median Survival |
11.4 months |
8.7 months | ||||
|
Risk Ratio*, Mortality (Docetaxel: Control) 95% CI (Risk Ratio) |
0.73
0.58-0.93 |
Median Time to Progression |
4.3 months |
2.5 months | p=0.01 Log Rank | |
|
Risk Ratio*, Progression (Docetaxel: Control) 95% CI (Risk Ratio) |
0.75
0.61-0.94 |
Overall Response Rate Complete Response Rate |
28.1% 3.4% |
9.5% 1.6% | p<0.0001 Chi Square | |
*For the risk ratio, a value less than 1.00 favors
docetaxel.
In a second randomized trial, patients
previously treated with an alkylating-containing regimen
were assigned to treatment with TAXOTERE (100
mg/m2)
or doxorubicin (75 mg/m2)
every 3 weeks. 161 patients were randomized to TAXOTERE
and 165 patients to doxorubicin. Approximately one-half
of patients had received prior chemotherapy for
metastatic disease, and one-half entered the study
following relapse after adjuvant therapy. Three-quarters
of patients had measurable, visceral metastases. The
primary endpoint was time to progression. The study
results are summarized below (See Table
2).
Table 2 - Efficacy of TAXOTERE in the Treatment of Breast
Cancer Patients
Previously
Treated with an Alkylating-Containing
Regimen
(Intent-to-Treat
Analysis)
(n=161)
(n=165)
|
Efficacy Parameter |
Docetaxel |
Doxorubicin | p-value | |||
|
Median Survival |
14.7 months |
14.3 months | p=0.39 Log Rank | |||
|
Risk Ratio*, Mortality (Docetaxel: Control) 95% CI (Risk Ratio) |
0.89
0.68-1.16 |
Median Time to Progression |
6.5 months |
5.3 months | p=0.45 Log Rank | |
|
Risk Ratio*, Progression (Docetaxel: Control) 95% CI (Risk Ratio) |
0.93
0.71-1.16 |
Overall Response Rate Complete Response Rate |
45.3% 6.8% |
29.7% 4.2% | p=0.004 Chi Square | |
*For the risk ratio, a value less than 1.00 favors
docetaxel.
In
another multicenter open-label, randomized trial
(TAX313), in the treatment of patients with advanced
breast cancer who progressed or relapsed after one prior
chemotherapy regimen, 527 patients were randomized to
receive TAXOTERE monotherapy 60 mg/m2
(n=151), 75 mg/m2
(n=188) or 100 mg/m2
(n=188). In this trial, 94% of patients had metastatic
disease and 79% had received prior anthracycline therapy.
Response rate was the primary endpoint. Response rates
increased with TAXOTERE dose: 19.9% for the 60
mg/m2
group compared to 22.3% for the 75
mg/m2
and 29.8% for the 100 mg/m2
group; pair-wise comparison between the 60
mg/m2
and 100 mg/m2
groups was statistically significant, (p=0.037).
Single
Arm Studies
TAXOTERE at a dose of 100
mg/m2
was studied in six single arm studies involving a total
of 309 patients with metastatic breast cancer in whom
previous chemotherapy had failed. Among these, 190
patients had anthracycline-resistant breast cancer,
defined as progression during an anthracycline-containing
chemotherapy regimen for metastatic disease, or relapse
during an anthracycline-containing adjuvant regimen. In
anthracycline-resistant patients, the overall response
rate was 37.9% (72/190; 95% C.I.: 31.0-44.8) and the
complete response rate was 2.1%.
TAXOTERE was also
studied in three single arm Japanese studies at a dose of
60 mg/m2,
in 174 patients who had received prior chemotherapy for
locally advanced or metastatic breast cancer. Among 26
patients whose best response to an anthracycline had been
progression, the response rate was 34.6% (95% C.I.:
17.2-55.7), similar to the response rate in single arm
studies of 100 mg/m2.
Adjuvant
Treatment of Breast Cancer
A multicenter, open-label,
randomized trial (TAX316) evaluated the efficacy and
safety of TAXOTERE for the adjuvant treatment of patients
with axillary-node-positive breast cancer and no evidence
of distant metastatic disease. After stratification
according to the number of positive lymph nodes (1-3,
4+), 1491 patients were randomized to receive either
TAXOTERE 75 mg/m2
administered 1-hour after doxorubicin 50
mg/m2
and cyclophosphamide 500 mg/m2
(TAC arm), or doxorubicin 50 mg/m2
followed by fluorouracil 500 mg/m2
and cyclosphosphamide 500 mg/m2
(FAC arm). Both regimens were administered every 3 weeks
for 6 cycles. TAXOTERE was administered as a 1-hour
infusion; all other drugs were given as IV bolus on day
1. In both arms, after the last cycle of chemotherapy,
patients with positive estrogen and/or progesterone
receptors received tamoxifen 20 mg daily for up to 5
years. Adjuvant radiation therapy was prescribed
according to guidelines in place at participating
institutions and was given to 69% of patients who
received TAC and 72% of patients who received FAC.
Results from a second interim analysis (median
follow-up 55 months) are as follows: In study TAX 316,
the docetaxel-containing combination regimen TAC showed
significantly longer disease-free survival (DFS) than FAC
(hazard ratio=0.74; 2-sided 95% CI=0.60, 0.92, stratified
log rank p=0.0047). The primary endpoint, disease-free
survival, included local and distant recurrences,
contralateral breast cancer and deaths from any cause.
The overall reduction in risk of relapse was 25.7% for
TAC-treated patients. (See Figure 1).
At the time of
this interim analysis, based on 219 deaths, overall
survival was longer for TAC than FAC (hazard ratio=0.69,
2-sided 95% CI=0.53, 0.90). (See Figure 2). There will be
further analysis at the time survival data
mature.
Figure 1 - TAX 316 Disease Free Survival K-M
curve
Figure 2 - TAX 316 Overall Survival K-M
Curve
The following table describes the results of subgroup
analyses for DFS and OS (See Table 3).
Table 3 - Subset Analyses-Adjuvant Breast Cancer
Study
744
467
277
0.74
0.64
0.84
(0.60, 0.92)
(0.47, 0.87)
(0.63, 1.12)
0.69
0.45
0.93
(0.53, 0.90)
(0.29, 0.70)
(0.66, 1.32)
566 178
0.76 0.68
(0.59, 0.98) (0.48, 0.97)
0.69 0.66
(0.48, 0.99) (0.44, 0.98)
|
|
Disease Free Survival |
Overall Survival |
Patient subset | Number of patients | Hazard ratio* | 95% CI | Hazard ratio* | 95% CI | |||
|
No. of positive nodes Overall 1-3 4+ |
|
|
|
|
|
||||||
|
Receptor status Positive Negative |
|
|
|
|
|
||||||
*a hazard ratio of less than 1 indicates that TAC is
associated with a longer disease free survival or overall
survival compared to FAC.
Non-Small
Cell Lung Cancer (NSCLC)
The efficacy and safety of
TAXOTERE has been evaluated in patients with
unresectable, locally advanced or metastatic non-small
cell lung cancer whose disease has failed prior
platinum-based chemotherapy or in patients who are
chemotherapy-naïve.
Monotherapy with TAXOTERE for NSCLC
Previously Treated with Platinum-Based Chemotherapy
Two
randomized, controlled trials established that a TAXOTERE
dose of 75 mg/m2
was tolerable and yielded a favorable outcome in patients
previously treated with platinum-based chemotherapy (see
below). TAXOTERE at a dose of 100 mg/m2,
however, was associated with unacceptable hematologic
toxicity, infections, and treatment-related mortality and
this dose should not be used.
One trial (TAX317), randomized patients with locally
advanced or metastatic non-small cell lung cancer, a
history of prior platinum-based chemotherapy, no history
of taxane exposure, and an ECOG performance status
<</u>2
to TAXOTERE or best supportive care. The primary endpoint
of the study was survival. Patients were initially
randomized to TAXOTERE 100 mg/m2
or best supportive care, but early toxic deaths at this
dose led to a dose reduction to TAXOTERE 75
mg/m2.
A total of 104 patients were randomized in this amended
study to either TAXOTERE 75 mg/m2
or best supportive care.
In a second randomized trial
(TAX320), 373 patients with locally advanced or
metastatic non-small cell lung cancer, a history of prior
platinum-based chemotherapy, and an ECOG performance
status
<</u>2
were randomized to TAXOTERE 75 mg/m2,
TAXOTERE 100 mg/m2
and a treatment in which the investigator chose either
vinorelbine 30 mg/m2
days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2
g/m2
days 1-3 repeated every 3 weeks. Forty percent of the
patients in this study had a history of prior paclitaxel
exposure. The primary endpoint was survival in both
trials. The efficacy data for the TAXOTERE 75
mg/m2
arm and the comparator arms are summarized in Table 4 and
Figures 3 and 4 showing the survival curves for the two
studies.
Table 4 - Efficacy of TAXOTERE in the Treatment of
Non-Small Cell Lung Cancer
Patients
Previously Treated with a Platinum-Based Chemotherapy
Regimen
(Intent-to-Treat
Analysis)
Supportive Care/75 n=49
75 mg/m2 n=125
(V/I) n=123
††, Mortality (Docetaxel: Control) 95% CI (Risk Ratio)
† (24, 50)
† (22, 39)
|
|
TAX317 |
TAX320 |
Docetaxel | Best | Docetaxel | Control | ||||||||
|
Overall Survival Log-rank Test |
p=0.01 |
p=0.13 |
Risk Ratio |
0.56
(0.35, 0.88) |
0.82
(0.63, 1.06) |
Median Survival 95% CI |
7.5 months* (5.5, 12.8) |
4.6 months (3.7, 6.1) | 5.7 months (5.1, 7.1) | 5.6 months (4.4, 7.9) | ||||
|
% 1-year Survival 95% CI |
37%* |
12% (2, 23) | 30%** | 20% (13, 27) | ||||||||||
|
Time to Progression 95% CI |
12.3 weeks* (9.0, 18.3) |
7.0 weeks (6.0, 9.3) | 8.3 weeks (7.0, 11.7) | 7.6 weeks (6.7, 10.1) | ||||||||||
|
Response Rate 95% CI |
5.5% (1.1, 15.1) |
Not Applicable | 5.7% (2.3, 11.3) | 0.8% (0.0, 4.5) | ||||||||||
|
* p |
Only one of the two trials (TAX317) showed a clear effect
on survival, the primary endpoint; that trial also showed
an increased rate of survival to one year. In the second
study (TAX320) the rate of survival at one year favored
TAXOTERE 75 mg/m2.
Figure 3 - TAX317 Survival K-M Curves - TAXOTERE 75
mg/m2
vs.
Best Supportive Care
Figure 4 - TAX320 Survival K-M Curves - TAXOTERE 75
mg/m2
vs.
Vinorelbine or Ifosfamide Control
Patients
treated with TAXOTERE at a dose of 75
mg/m2
experienced no deterioration in performance status and
body weight relative to the comparator arms used in these
trials.
Combination Therapy with TAXOTERE for
Chemotherapy-Naïve NSCLC
In a randomized controlled
trial (TAX326), 1218 patients with unresectable stage
IIIB or IV NSCLC and no prior chemotherapy were
randomized to receive one of three treatments:
TAXOTERE
75 mg/m2
as a 1 hour infusion immediately followed by cisplatin 75
mg/m2
over 30-60 minutes every 3 weeks; vinorelbine 25
mg/m2
administered over 6-10 minutes on days 1, 8, 15, 22
followed by cisplatin 100 mg/m2
administered on day 1 of cycles repeated every 4 weeks;
or a combination of TAXOTERE and carboplatin.
The
primary efficacy endpoint was overall survival. Treatment
with TAXOTERE+cisplatin did not result in a statistically
significantly superior survival compared to
vinorelbine+cisplatin (see table below). The 95%
confidence interval of the hazard ratio (adjusted for
interim analysis and multiple comparisons) shows that the
addition of TAXOTERE to cisplatin results in an outcome
ranging from a 6% inferior to a 26% superior survival
compared to the addition of vinorelbine to cisplatin. The
results of a further statistical analysis showed that at
least (the lower bound of the 95% confidence interval)
62% of the known survival effect of vinorelbine when
added to cisplatin (about a 2-month increase in median
survival; Wozniak et al. JCO, 1998) was maintained. The
efficacy data for the TAXOTERE+cisplatin arm and the
comparator arm are summarized in Table
5.
Table 5 - Survival Analysis of TAXOTERE in Combination
Therapy for Chemotherapy-Naïve NSCLC
a
b
c
|
Comparison |
Taxotere+Cisplatin n=408 |
Vinorelbine+Cisplatin n=405 | ||||||
|
Kaplan-Meier Estimate of Median Survival |
10.9 months |
10.0 months | ||||||
|
p-value |
0.122 |
Estimated Hazard Ratio |
0.88 |
Adjusted 95% CI |
(0.74, 1.06) |
|||
|
a |
From the superiority test (stratified log rank) comparing TAXOTERE+cisplatin to vinorelbine+cisplatin |
| b | Hazard ratio of TAXOTERE+cisplatin vs. vinorelbine+cisplatin. A hazard ratio of less than 1 indicates that TAXOTERE+cisplatin is associated with a longer survival. |
| c | Adjusted for interim analysis and multiple comparisons. |
The second comparison in the study, vinorelbine+cisplatin versus TAXOTERE+carboplatin, did not demonstrate superior survival associated with the TAXOTERE arm (Kaplan-Meier estimate of median survival was 9.1 months for TAXOTERE+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the TAXOTERE+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between TAXOTERE+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 6).
Table 6 - Response and TTP Analysis of TAXOTERE in
Combination Therapy for Chemotherapy-Naïve
NSCLC
a
b (95% CI)a
|
Endpoint |
TAXOTERE+Cisplatin |
Vinorelbine+Cisplatin | p-value |
|
Objective Response Rate (95% CI) |
31.6% (26.5%, 36.8%) |
24.4% (19.8%, 29.2%) | Not Significant |
|
Median Time to Progression |
21.4 weeks (19.3, 24.6) |
22.1 weeks (18.1, 25.6) | Not Significant |
|
a |
Adjusted for multiple comparisons. |
| b | Kaplan-Meier estimates. |
2 every 3 weeks for 10 cycles.
2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
2 every 3 weeks for 10 cycles.
| •
|
TAXOTERE 75 mg/m |
| •
|
TAXOTERE 30 mg/m |
| •
|
Mitoxantrone 12 mg/m |
Table 7 - Efficacy of TAXOTERE in the Treatment of
Patients with Androgen Independent (Hormone Refractory)
Metastatic Prostate Cancer (Intent-to-Treat
Analysis)
every 3 weeks
335 18.9 (17.0-21.2) 0.761 (0.619-0.936) 0.0094
|
|
TAXOTERE |
Mitoxantrone |
|
Number of patients Median survival (months) 95% CI Hazard ratio 95% CI p-value* |
|
337 16.5 (14.4-18.6) -- -- -- |
*Stratified log rank test. Threshold for statistical
significance = 0.0175 because of 3
arms.
Figure 5 - TAX327 Survival K-M Curves
Gastric Adenocarcinoma
A multicenter, open-label,
randomized trial was conducted to evaluate the safety and
efficacy of TAXOTERE for the treatment of patients with
advanced gastric adenocarcinoma, including adenocarcinoma
of the gastroesophageal junction, who had not received
prior chemotherapy for advanced disease. A total of 445
patients with KPS>70 were treated with either TAXOTERE
(T) (75 mg/m2
on day 1) in combination with cisplatin (C) (75
mg/m2
on day 1) and fluorouracil (F) (750
mg/m2
per day for 5 days) or cisplatin (100
mg/m2
on day 1) and fluorouracil (1000 mg/m2
per day for 5 days). The length of a treatment cycle was
3 weeks for the TCF arm and 4 weeks for the CF arm. The
demographic characteristics were balanced between the two
treatment arms. The median age was 55 years, 71% were
male, 71% were Caucasian, 24% were 65 years of age or
older, 19% had a prior curative surgery and 12% had
palliative surgery. The median number of cycles
administered per patient was 6 (with a range of 1-16) for
the TCF arm compared to 4 (with a range of 1-12) for the
CF arm. Time to progression (TTP) was the primary
endpoint and was defined as time from randomization to
disease progression or death from any cause within 12
weeks of the last evaluable tumor assessment or within 12
weeks of the first infusion of study drugs for patients
with no evaluable tumor assessment after randomization.
The hazard ratio (HR) for TTP was 1.47 (CF/TCF, 95% CI:
1.19-1.83) with a significantly longer TTP (p=0.0004) in
the TCF arm. Approximately 75% of patients had died at
the time of this analysis. Overall survival was
significantly longer (p=0.0201) in the TCF arm with a HR
of 1.29 (95% CI: 1.04-1.61). Efficacy results are
summarized in Table 8 and Figures 6 and
7.
Table
8 - Efficacy of TAXOTERE in the treatment of patients
with gastric adenocarcinoma
n=221
n=224
† (95%CI) *p-value
† (95%CI) *p-value
| Endpoint |
TCF |
CF |
|
Median TTP (months) (95%CI) Hazard ratio |
5.6 (4.86-5.91) |
3.7 (3.45-4.47) |
|
1.47
(1.19-1.83)
0.0004 |
||
|
Median survival (months) (95%CI) Hazard ratio |
9.2 (8.38-10.58) |
8.6 (7.16-9.46) |
|
1.29
(1.04-1.61)
0.0201 |
||
|
Overall Response Rate (CR+PR) (%)
|
36.7 |
25.4 |
|
0.0106 |
||
|
* |
Unstratified logrank test |
| † | For the hazard ratio (CF/TCF), values greater than 1.00 favor the TAXOTERE arm. |
Figure 6 - Gastric Cancer Study (TAX325) Time to
Progression K-M Curve
Figure 7 - Gastric Cancer Study (TAX325) Survival K-M
Curve
Head
and Neck Cancer
The safety and efficacy of TAXOTERE
in the induction treatment of patients with squamous
cell carcinoma of the head and neck (SCCHN) was
evaluated in a multicenter, open-label, randomized
trial (TAX323). In this study, 358 patients with
inoperable locally advanced SCCHN, and WHO
performance status 0 or 1, received either TAXOTERE
75 mg/m2
followed by cisplatin