A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Taxotere Pharmacology, Pharmacokinetics, Studies, Metabolism - Docetaxel
Taxotere Pharmacology, Pharmacokinetics, Studies, Metabolism - Docetaxel
CLINICAL PHARMACOLOGY
Docetaxel is an antineoplastic agent that acts by disrupting
the micro-tubular 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 micro-tubule bundles without normal function
and to the stabilization of microtubules, which results in the inhibition of
mitosis in cells. Docetaxel’s 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. cokinetic profile is consistent
with a three-compartment pharmacoki-netic model, with half-lives for the a,
b, and g 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
oxida-tive 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. 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 cyclophos-phamide
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
a1-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 (see PRECAUTIONS).
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), primarily at a dose of 100 mg/m2 given as a 1-hour infusion
every 3 weeks, but with some experience at 60 mg/m2, in two large
randomized trials and a number of smaller single arm studies.
Randomized Trials: In one randomized trial, patients
with a history of prior treatment with an anthracycline-containing regimen were
assigned to treatment with TAXOTERE 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
metas-tases. The primary endpoint was time to progression. The following table
summarizes the study results:
|
Efficacy of TAXOTERE in the Treatment of Breast Cancer
Patients Previously Treated with an Anthracycline-Containing Regimen (Intent-to-Treat
Analysis)
|
|
Efficacy Parameter
|
Docetaxel(n=203)
|
Mitomycin/ Vinblastine (n=189)
|
p-value
|
|
Median Survival
|
11.4 months
|
8.7 months
|
p=0.01 Log Rank
|
|
Risk Ratio*, Mortality
|
0.73
|
|
(Docetaxel: Control)
|
|
95% CI (Risk Ratio)
|
0.58-0.93
|
|
|
Median Time to Progression
|
4.3 months
|
2.5 months
|
p=0.01
Log Rank
|
|
Risk Ratio*, Progression
|
0.75
|
|
(Docetaxel: Control)
|
|
95% CI (Risk Ratio)
|
0.61-0.94
|
|
Overall Response Rate
|
28.1%
|
9.5%
|
p<0.0001
|
|
Complete Response Rate
|
3.4%
|
1.6%
|
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 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:
|
Efficacy of TAXOTERE in the Treatment of Breast Cancer
Patients Previously Treated with an Alkylating-Containing Regimen (Intent-to-Treat
Analysis)
|
|
Efficacy Parameter
|
Docetaxel
|
Doxorubicin
|
p-value
|
| |
(n=161)
|
(n=165)
|
p=0.39 Log Rank
|
|
Median Survival
|
14.7 months
|
14.3 months
|
|
Risk Ratio*, Mortality
|
0.89
|
|
(Docetaxel: Control)
|
|
95% CI (Risk Ratio)
|
0.68-1.16
|
|
|
Median Time to Progression
|
6.5 months
|
5.3 months
|
p=0.45 Log Rank
|
|
Risk Ratio*, Progression
|
0.93
|
|
(Docetaxel: Control)
|
|
95% CI (Risk Ratio)
|
0.71-1.16
|
|
Overall Response Rate
|
45.3%
|
29.7%
|
p=0.004
|
|
Complete Response Rate
|
6.8%
|
4.2%
|
Chi Square
|
|
*For the risk ratio, a value less than 1.00 favors docetaxel.
|
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.
Hematologic and Other Toxicity: Relation to dose and
baseline liver chemistry abnormalities. Hematologic and other toxicity
is increased at higher doses and in patients with elevated baseline liver function
tests (LFTs). In the following tables, adverse drug reactions are compared for
three populations: 730 patients with normal LFTs given TAXOTERE at 100 mg/m2
in the randomized and single arm studies of metastatic breast cancer after
failure of previous chemotherapy; 18 patients in these studies who had abnormal
baseline LFTs (defined as SGOT and/or SGPT > 1.5 times ULN concurrent with
alkaline phosphatase > 2.5 times ULN); and 174 patients in Japanese studies
given TAXOTERE at 60 mg/m2 who had normal LFTs.
|
Hematologic Adverse Events in Breast Cancer Patients Previously
Treated with Chemotherapy Treated at TAXOTERE 100 mg/m2 with
Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal
Liver Function Tests
|
| |
TAXOTERE
|
TAXOTERE
|
| |
100 mg/m2
|
60 mg/m2
|
| |
Normal
|
Elevated
|
Normal
|
| |
LFTs*
|
LFTs**
|
LFTs*
|
|
Adverse Event
|
n=730
|
n=18
|
n=174
|
| |
%
|
%
|
%
|
|
Neutropenia
|
|
|
|
|
Any <2000 cells/mm3
|
98.4
|
100
|
95.4
|
|
Grade 4 <500 cells/mm3
|
84.4
|
93.8
|
74.9
|
|
Thrombocytopenia
|
|
|
|
|
Any <100,000 cells/mm3
|
10.8
|
44.4
|
14.4
|
|
Grade 4 <20,000 cells/mm3
|
0.6
|
16.7
|
1.1
|
|
Anemia <11 g/dL
|
94.6
|
94.4
|
64.9
|
|
Infection***
|
|
|
|
|
Any
|
22.5
|
38.9
|
1.1
|
|
Grade 3 and 4
|
7.1
|
33.3
|
0
|
|
Febrile Neutropenia****
|
|
|
|
|
By Patient
|
11.8
|
33.3
|
0
|
|
By Course
|
2.4
|
8.6
|
0
|
|
Septic Death
|
1.5
|
5.6
|
1.1
|
|
Non-Septic Death
|
1.1
|
11.1
|
0
|
|
*Normal Baseline LFTs: Transaminases < 1.5
times ULN or alkaline phosphatase < 2.5 times ULN or isolated
elevations of transaminases or alkaline phosphatase up to 5 times ULN
|
|
**Elevated Baseline LFTs: SGOT and/or SGPT >1.5
times ULN concurrent with alkaline phosphatase >2.5 times ULN
|
|
***Incidence of infection requiring hospitalization and/or
intravenous antibiotics was 8.5% (n=62) among the 730 patients with normal
LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46
patients had grade 4 neutropenia.
|
|
****Febrile Neutropenia: For 100 mg/m2, ANC
grade 4 and fever > 38°C 2, ANC grade 3/4 and fever >
38.1° c
|
|
Non-Hematologic Adverse Events in Breast Cancer Patients
Previously Treated with Chemotherapy Treated at TAXOTERE 100 mg/m2
with Normal or Elevated Liver Function Tests or 60 mg/m2 with
Normal Liver Function Tests
|
| |
TAXOTERE
|
TAXOTERE
|
| |
100 mg/m2
|
60 mg/m2
|
| |
Normal
|
Elevated
|
Normal
|
| |
LFTs*
|
LFTs**
|
LFTs*
|
|
Adverse Event
|
n=730
|
n=18
|
n=174
|
| |
%
|
%
|
%
|
|
Acute Hypersensitivity Reaction Regardless of Premedication
|
|
Any
|
13.0
|
5.6
|
0.6
|
|
Severe
|
1.2
|
0
|
0
|
|
Fluid Retention*** Regardless of Premedication
|
|
Any
|
56.2
|
61.1
|
12.6
|
|
Severe
|
7.9
|
16.7
|
0
|
|
Neurosensory
|
|
Any
|
56.8
|
50
|
19.5
|
|
Severe
|
5.8
|
0
|
0
|
|
Myalgia
|
22.7
|
33.3
|
3.4
|
|
Cutaneous
|
|
Any
|
44.8
|
61.1
|
30.5
|
|
Severe
|
4.8
|
16.7
|
0
|
|
Asthenia
|
|
Any
|
65.2
|
44.4
|
65.5
|
|
Severe
|
16.6
|
22.2
|
0
|
|
Diarrhea
|
|
Any
|
42.2
|
27.8
|
NA
|
|
Severe
|
6.3
|
11.1
|
|
|
Stomatitis
|
|
Any
|
53.3
|
66.7
|
19.0
|
|
Severe
|
7.8
|
38.9
|
0.6
|
|
*Normal Baseline LFTs: Transaminases < 1.5
times ULN or alkaline phosphatase < 2.5 times ULN or isolated
elevations of transaminases or alkaline phosphatase up to 5 times ULN
|
|
**Elevated Baseline Liver Function: SGOT and/or SGPT
>1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN
|
|
***Fluid Retention includes (by COSTART): edema (peripheral,
localized, generalized, lymphedema, pulmonary edema, and edema otherwise
not specified) and effusion (pleural, pericardial, and ascites); no premedication
given with the 60 mg/m2 dose
|
|
NA = not available
|
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.
|
Subset Analyses-Adjuvant Breast Cancer Study
|
| |
Disease Free Survival
|
Overall Survival
|
|
Patient subset
|
Number of patients
|
Hazard ratio*
|
95% CI
|
Hazard ratio*
|
95% CI
|
|
No. of positive nodes
|
|
Overall
|
744
|
0.74
|
(0.60, 0.92)
|
0.69
|
(0.53, 0.90)
|
|
1-3
|
467
|
0.64
|
(0.47, 0.87)
|
0.45
|
(0.29, 0.70)
|
|
4+
|
277
|
0.84
|
(0.63, 1.12)
|
0.93
|
(0.66, 1.32)
|
|
Receptor status
|
|
Positive
|
566
|
0.76
|
(0.59, 0.98)
|
0.69
|
(0.48, 0.99)
|
|
Negative
|
178
|
0.68
|
(0.48, 0.97)
|
0.66
|
(0.44, 0.98)
|
|
*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 (see BOXED WARNING, WARNINGS,
and DOSAGE AND ADMINISTRATION sections).
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
<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 75mg/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 <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 the table below and in figures 3 and 4
showing the survival curves for the two studies.
|
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)
|
| |
TAX317
|
TAX320
|
|
Docetaxel 75 mg/m2 n=55
|
Best SupportiveCare/75 n=49
|
Docetaxel 75 mg/m2 n=125
|
Control (V/I) n=123
|
|
Overall Survival Log-rank Test
|
p=0.01
|
p=0.13
|
|
Risk Ratio ††, Mortality
|
0.56
|
0.82
|
|
(Docetaxel: Control)
|
|
95% CI (Risk Ratio)
|
(0.35, 0.88)
|
(0.63, 1.06)
|
|
Median Survival
95% CI
|
7.5
|
4.6
|
5.7
|
5.6
|
|
months*
|
months
|
months
|
months
|
|
(5.5, 12.8)
|
(3.7, 6.1)
|
(5.1, 7.1)
|
(4.4, 7.9)
|
|
% 1-year Survival
|
37%*†
|
12%
|
30%*†
|
20%
|
|
95% CI
|
(24, 50)
|
(2, 23)
|
(22, 39)
|
(13, 27)
|
|
Time to
|
12.3
|
7.0
|
8.3
|
7.6
|
|
Progression
|
weeks*
|
weeks
|
weeks
|
weeks
|
|
95% CI
|
(9.0, 18.3)
|
(6.0, 9.3)
|
(7.0, 11.7)
|
(6.7, 10.1)
|
|
Response Rate
|
5.5%
|
Not Applicable
|
5.7%
|
0.8%
|
|
95% CI
|
(1.1, 15.1)
|
|
(2.3, 11.3)
|
(0.0, 4.5)
|
|
* p<0.05; †uncorrected
for multiple comparisons; ††a value less than 1.00
favors docetaxel.
|
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 the table below.
|
Survival Analysis of TAXOTERE in Combination Therapy for
Chemotherapy-Naïve NSCLC
|
|
Comparison
|
Taxotere+Cisplatin
|
Vinorelbine+Cisplatin
|
| |
n=408
|
n=405
|
|
Kaplan-Meier Estimate of Median Survival
|
10.9 months
|
10.0 months
|
|
p-valuea
|
0.122
|
|
Estimated Hazard Ratiob
|
0.88
|
|
Adjusted 95% CIc
|
(0.74, 1.06)
|
|
aFrom the superiority test (stratified log
rank) comparing TAXOTERE+cisplatin to vinorelbine+cisplatin
|
|
bHazard ratio of TAXOTERE+cisplatin vs. vinorelbine+cisplatin.
A hazard ratio of less than 1 indicates that TAXOTERE+cisplatin is associated
with a longer survival.
|
|
cAdjusted 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 below).
|
Response and TTP Analysis of TAXOTERE in Combination Therapy
for Chemotherapy-Naïve NSCLC
|
|
Endpoint
|
TAXOTERE+Cisplatin
|
Vinorelbine+Cisplatin
|
p-value
|
|
Objective
|
31.6%
|
24.4%
|
Not Significant
|
|
Response Rate
|
|
|
|
|
(95% CI)a
|
(26.5%, 36.8%)
|
(19.8%, 29.2%)
|
|
|
Median Time to Progressionb
|
21.4 weeks
|
22.1 weeks
|
Not Significant
|
|
(95% CI)a
|
(19.3, 24.6)
|
(18.1, 25.6)
|
|
|
aAdjusted for multiple comparisons.
|
|
bKaplan-Meier estimates.
|
Prostate Cancer
The safety and efficacy of TAXOTERE in combination with prednisone
in patients with androgen independent (hormone refractory) metastatic prostate
cancer were evaluated in a randomized multicenter active control trial. A total
of 1006 patients with Karnofsky Performance Status (KPS) >60 were
randomized to the following treatment groups:
• 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.
All 3 regimens were administered in combination with prednisone
5 mg twice daily, continuously.
In the TAXOTERE every three week arm, a statistically significant
overall survival advantage was demonstrated compared to mitoxantrone. In the
TAXOTERE weekly arm, no overall survival advantage was demonstrated compared
to the mitoxantrone control arm. Efficacy results for the TAXOTERE every 3 week
arm versus the control arm are summarized in the following table and figure
5:
|
Efficacy of TAXOTERE in the Treatment of Patients with
Androgen Independent (Hormone Refractory) Metastatic Prostate Cancer (Intent-to-Treat
Analysis)
|
| |
TAXOTERE
|
Mitoxantrone
|
| |
every 3 weeks
|
every 3 weeks
|
|
Number of patients
|
335
|
337
|
|
Median survival (months)
|
18.9
|
16.5
|
|
95% CI
|
(17.0-21.2)
|
(14.4-18.6)
|
|
Hazard ratio
|
0.761
|
--
|
|
95% CI
|
(0.619-0.936)
|
--
|
|
p-value*
|
0.0094
|
--
|
|
*Stratified log rank test. Threshold for statistical
significance = 0.0175 because of 3 arms.
|
Figure 5 - TAX327 Survival K-M Curves
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