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Taxotere (Docetaxel) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N- tert -butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-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

Mechanism of Action

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 α, β, and γ 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 α1-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 Drug Interactions (7) ].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of docetaxel.

Docetaxel has been shown to be clastogenic in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60th to 1/15th the recommended human dose on a mg/m2 basis). Docetaxel did not induce mutagenicity in the Ames test or the CHO/HGPRT gene mutation assays. Docetaxel produced no impairment of fertility in rats when administered in multiple IV doses of up to 0.3 mg/kg (about 1/50th the recommended human dose on a mg/m2 basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at IV doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3rd and 1/15th the recommended humandose on a mg/m2 basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

CLINICAL STUDIES

14.1Breast 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 13).

Table 13 - Efficacy of TAXOTERE in the Treatment of Breast Cancer Patients Previously Treated with an Anthracycline-Containing Regimen (Intent-to-Treat Analysis)
Efficacy ParameterDocetaxel
(n=203)
Mitomycin/Vinblastine
(n=189)
p-value
Median Survival11.4 months8.7 months
Risk Ratio 1, Mortality
(Docetaxel: Control)
0.73p=0.01
Log Rank
 
95% CI (Risk Ratio)0.58–0.93
Median Time to Progression 4.3 months2.5 months
Risk Ratio, Progression
(Docetaxel: Control)
0.75p=0.01
Log Rank
 
95% CI (Risk Ratio)0.61–0.94
Overall Response Rate28.1%9.5%p<0.0001
Complete Response Rate3.4%1.6%Chi Square

1 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 14).

Table 14 - Efficacy of TAXOTERE in the Treatment of Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen (Intent-to-Treat Analysis)
Efficacy ParameterDocetaxel
(n=161)
Doxorubicin
(n=165)
p-value
Median Survival14.7 months14.3 months
Risk Ratio 1, Mortality
(Docetaxel: Control)
0.89p=0.39
Log Rank
 
95% CI (Risk Ratio)0.68–1.16
Median Time to Progression 6.5 months5.3 months
Risk Ratio, Progression
(Docetaxel: Control)
0.93p=0.45
Log Rank
 
95% CI (Risk Ratio)0.71–1.16
Overall Response Rate45.3%29.7%p=0.004
Complete Response Rate6.8%4.2%Chi Square

1 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.

14.2Adjuvant 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 TAX316, 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 - TAX316 Disease Free Survival K-M curve

Figure 2 - TAX316 Overall Survival K-M Curve

The following table describes the results of subgroup analyses for DFS and OS (See Table 15).

Table 15 - Subset Analyses-Adjuvant Breast Cancer Study
Disease Free SurvivalOverall Survival
Patient subsetNumber of patientsHazard ratio 1 95% CIHazard ratio 95% CI
No. of positive nodes
Overall7440.74(0.60, 0.92)0.69(0.53, 0.90)
1–34670.64(0.47, 0.87)0.45(0.29, 0.70)
4+2770.84(0.63, 1.12)0.93(0.66, 1.32)
Receptor status
Positive5660.76(0.59, 0.98)0.69(0.48, 0.99)
Negative1780.68(0.48, 0.97)0.66(0.44, 0.98)

1 a hazard ratio of less than 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC.

14.3Non-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 Precautions, Dosage Adjustment During Treatment].

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 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 ≤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 16 and Figures 3 and 4 showing the survival curves for the two studies.

Table 16 - 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)
TAX317TAX320
Docetaxel
75 mg/m2
n=55
Best Supportive Care/75
n=49
Docetaxel
75 mg/m2
n=125
Control (V/I)
n=123
Overall Survival
Log-rank Testp=0.01p=0.13
Risk Ratio 1, Mortality
(Docetaxel: Control)0.560.82
95% CI (Risk Ratio)(0.35, 0.88)(0.63, 1.06)
Median Survival7.5 months 2 4.6 months5.7 months5.6 months
95% CI(5.5, 12.8)(3.7, 6.1)(5.1, 7.1)(4.4, 7.9)
% 1-year Survival37% 3 12%30% 20%
95% CI(24, 50)(2, 23)(22, 39)(13, 27)
Time to Progression12.3 weeks 7.0 weeks8.3 weeks7.6 weeks
95% CI(9.0, 18.3)(6.0, 9.3)(7.0, 11.7)(6.7, 10.1)
Response Rate5.5%Not Applicable5.7%0.8%
95% CI(1.1, 15.1)(2.3, 11.3)(0.0, 4.5)

1 a value less than 1.00 favors docetaxel.
2 p≤0.05.
3 uncorrected for multiple comparisons.


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 17.

Table 17 - Survival Analysis of TAXOTERE in Combination Therapy for Chemotherapy-Naïve NSCLC
ComparisonTaxotere+Cisplatin
n=408
Vinorelbine+Cisplatin
n=405
Kaplan-Meier Estimate of Median Survival10.9 months10.0 months
p-value 1 0.122
Estimated Hazard Ratio 2 0.88
Adjusted 95% CI 3 (0.74, 1.06)

1 From the superiority test (stratified log rank) comparing TAXOTERE+cisplatin to vinorelbine+cisplatin
2 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.
3 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 18).

Table 18 - Response and TTP Analysis of TAXOTERE in Combination Therapy for Chemotherapy-Naïve NSCLC
EndpointTAXOTERE+CisplatinVinorelbine+Cisplatinp-value
Objective Response Rate31.6%24.4%Not Significant
(95% CI) 1 (26.5%, 36.8%)(19.8%, 29.2%)
Median Time to Progression 2 21.4 weeks
(19.3, 24.6)
22.1 weeks
(18.1, 25.6)
Not Significant
(95% CI)

1 Adjusted for multiple comparisons.
2 Kaplan-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:

  • TAXOTERE 75 mg/m2 every 3 weeks for 10 cycles.
  • TAXOTERE 30 mg/m2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
  • Mitoxantrone 12 mg/m2 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 Table 19 and Figure 5.

Table 19 - Efficacy of TAXOTERE in the Treatment of Patients with Androgen Independent (Hormone Refractory) Metastatic Prostate Cancer (Intent-to-Treat Analysis)
TAXOTERE every 3 weeksMitoxantrone every 3 weeks
Number of patients335337
Median survival (months)18.916.5
95% CI(17.0–21.2)(14.4–18.6)
Hazard ratio0.761--
95% CI(0.619–0.936)--
p-value 1 0.0094--

1 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 20 and Figures 6 and 7.

Table 20 - Efficacy of TAXOTERE in the treatment of patients with gastric adenocarcinoma
EndpointTCF
n=221
CF
n=224
Median TTP (months)5.63.7
(95%CI)(4.86–5.91)(3.45–4.47)
Hazard ratio 1 0.68
(95%CI)(0.55–0.84)
2 p-value0.0004
Median survival (months)9.28.6
(95%CI)(8.38–10.58)(7.16–9.46)
Hazard ratio 0.77
(95%CI)(0.62–0.96)
p-value0.0201
Overall Response Rate (CR+PR) (%)36.725.4
p-value0.0106

1 For the hazard ratio (TCF/CF), values less than 1.00 favor the TAXOTERE arm.
2 Unstratified log-rank test

Subgroup analyses were consistent with the overall results across age, gender and race.

Figure 6 - Gastric Cancer Study (TAX325) Time to Progression K-M Curve

Figure 7 - Gastric Cancer Study (TAX325) Survival K-M Curve

14.6Head and Neck Cancer

  • Induction chemotherapy followed by radiotherapy (TAX323)

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, were randomized to one of two treatment arms. Patients on the TAXOTERE arm received TAXOTERE (T) 75 mg/m2 followed by cisplatin (P) 75 mg/m2 on Day 1, followed by fluorouracil (F) 750 mg/m2 per day as a continuous infusion on Days 1–5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 on Day 1, followed by fluorouracil (F) 1000 mg/m2/day as a continuous infusion on Days 1–5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy–2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively). Surgical resection was allowed following chemotherapy, before or after radiotherapy.

The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p=0.0077 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months respectively). Efficacy results are presented in Table 21 and Figures 8 and 9.

Table 21 - Efficacy of TAXOTERE in the induction treatment of patients with inoperable locally advanced SCCHN (Intent-to-Treat Analysis)
ENDPOINTTAXOTERE+
Cisplatin+
Fluorouracil
n=177
Cisplatin+
Fluorouracil
n=181
A Hazard ratio of less than 1 favors TAXOTERE+Cisplatin+Fluorouracil
Median progression free survival (months)
(95%CI)
11.4
(10.1–14.0)
8.3
(7.4–9.1)
Adjusted Hazard ratio
(95%CI)
Stratified log-rank test based on primary tumor sitep-value
0.71
(0.56–0.91)
0.0077
Median survival (months)
(95%CI)
18.6
(15.7–24.0)
14.2
(11.5–18.7)
Hazard ratio
(95%CI)
Stratified log-rank test, not adjusted for multiple comparisonsp-value
0.71
(0.56–0.90)
0.0055
Best overall response (CR + PR) to
chemotherapy (%)
(95%CI)
67.8
(60.4–74.6)
53.6
(46.0–61.0)
1 p-value0.006
Best overall response (CR + PR) to study
treatment [chemotherapy +/- radiotherapy] (%)
(95%CI)
72.3
(65.1–78.8)
58.6
(51.0–65.8)
p-value0.006

1 Chi square test, not adjusted for multiple comparisons


Figure 8 - TAX323 Progression-Free Survival K-M Curve

Figure 9 - TAX323 Overall Survival K-M Curve

  • Induction chemotherapy followed by chemoradiotherapy (TAX324)

The safety and efficacy of TAXOTERE in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the TAXOTERE arm received TAXOTERE (T) 75 mg/m2 by IV infusion on day 1 followed by cisplatin (P) 100 mg/m2 administered as a 30-minute to three-hour IV infusion, followed by the continuous IV infusion of fluorouracil (F) 1000 mg/m2/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m2 as a 30-minute to three-hour IV infusion on day 1 followed by the continuous IV infusion of fluorouracil (F) 1000 mg/m2/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles.

All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour IV infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70–72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT.

The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0.0058) with the TAXOTERE-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR)=0.70, 95% confidence interval (CI)= 0.54 – 0.90]. Overall survival results are presented in Table 22 and Figure 10.

Table 22 - Efficacy of TAXOTERE in the induction treatment of patients with locally advanced SCCHN (Intent-to-Treat Analysis)
ENDPOINTTAXOTERE+
Cisplatin+ Fluorouracil
n=255
Cisplatin+
Fluorouracil
n=246
A Hazard ratio of less than 1 favors TAXOTERE+cisplatin+fluorouracil
NE - not estimable
Median overall survival (months)
(95% CI)
70.6
(49.0–NE)
30.1
(20.9–51.5)
Hazard ratio:
(95% CI)
un-adjusted log-rank test p-value
0.70
(0.54–0.90)
0.0058

Figure 10 - TAX324 Overall Survival K-M Curve

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