Docetaxel (Page 10 of 11)

14.4 Castration-Resistant Prostate Cancer

The safety and efficacy of docetaxel in combination with prednisone in patients with metastatic castration-resistant 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:

  • Docetaxel 75 mg/m 2 every 3 weeks for 10 cycles.
  • Docetaxel 30 mg/m 2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
  • Mitoxantrone 12 mg/m 2 every 3 weeks for 10 cycles.

All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously.

In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 18 and Figure 5.

Table 18: Efficacy of Docetaxel in the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (Intent-to-Treat Analysis)
Docetaxel+Prednisone every 3 weeks Mitoxantrone+Prednisone every 3 weeks

*Stratified log-rank test. Threshold for statistical significance = 0.0175 because of 3 arms.

Number of patients Median survival (months) 95% CI Hazard ratio 95% CI p-value* 335 18.9 (17.0-21.2) 0.761 (0.619-0.936) 0.0094 337 16.5 (14.4-18.6) — — —

Figure 5: TAX327 Survival K-M Curves

Figure 5
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14.5 Gastric Adenocarcinoma

A multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of docetaxel 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 docetaxel (T) (75 mg/m 2 on day 1) in combination with cisplatin (C) (75 mg/m 2 on day 1) and fluorouracil (F) (750 mg/m 2 per day for 5 days) or cisplatin (100 mg/m 2 on day 1) and fluorouracil (1000 mg/m 2 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 19 and Figure 6 and Figure 7.

Table 19: Efficacy of Docetaxel in the Treatment of Patients with Gastric Adenocarcinoma
Endpoint TCF n=221 CF n=224

*Unstratified log-rank test

For the hazard ratio (TCF/CF), values less than 1.00 favor the docetaxel arm.

Median TTP (months) (95% CI) Hazard ratio† (95% CI) *p-value 5.6 (4.86-5.91) 3.7 (3.45-4.47)
0.68 (0.55-0.84) 0.0004
Median survival (months) (95% CI) Hazard ratio (95% CI) *p-value 9.2 (8.38-10.58) 8.6 (7.16-9.46)
0.77 (0.62-0.96) 0.0201
Overall Response Rate (CR+PR) (%)36.725.4
p-value0.0106

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 6
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Figure 7: Gastric Cancer Study (TAX325) Survival K-M Curve

Figure 7
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14.6 Head and Neck Cancer

Induction Chemotherapy Followed by Radiotherapy (TAX323)

The safety and efficacy of docetaxel 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 docetaxel arm received docetaxel (T) 75 mg/m 2 followed by cisplatin (P) 75 mg/m 2 on Day 1, followed by fluorouracil (F) 750 mg/m 2 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/m 2 on Day 1, followed by fluorouracil (F) 1000 mg/m 2 /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 20 and Figure 8 and Figure 9.

Table 20: Efficacy of Docetaxel in the Induction Treatment of Patients with Inoperable Locally Advanced SCCHN (Intent-to-Treat Analysis)
ENDPOINT Docetaxel+ Cisplatin+Fluorouracil n=177 Cisplatin+Fluorouracil n=181

A Hazard ratio of less than 1 favors docetaxel+cisplatin+fluorouracil

* Stratified log-rank test based on primary tumor site

** Stratified log-rank test, not adjusted for multiple comparisons

*** Chi square test, not adjusted for multiple comparisons

Median progression free survival (months) (95% CI) 11.4 (10.1-14.0) 8.3 (7.4-9.1)
Adjusted Hazard ratio (95% CI) *p-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) **p-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)
***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

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

Figure 8
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Figure 9:TAX323 Overall Survival K-M Curve

Figure 9
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Induction Chemotherapy Followed by Chemoradiotherapy (TAX324)

The safety and efficacy of docetaxel 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 docetaxel arm received docetaxel (T) 75 mg/m 2 by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m 2 administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m 2 /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/m 2 as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m 2 /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 intravenous 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 docetaxel-containing regimen compared to PF (median OS: 70.6 vs 30.1 months respectively, hazard ratio [HR]=0.70, 95% confidence interval [CI]= 0.54 – 0.90). Overall survival results are presented in Table 21 and Figure 10.

Table 21: Efficacy of Docetaxel in the Induction Treatment of Patients with Locally Advanced SCCHN (Intent-to-Treat Analysis)
ENDPOINT Docetaxel+ Cisplatin+Fluorouracil n=255 Cisplatin+ Fluorouracil n=246

A Hazard ratio of less than 1 favors docetaxel+cisplatin+fluorouracil

* unadjusted log-rank test

NE — not estimable

Median overall survival (months) (95% CI) 70.6 (49.0- NE) 30.1 (20.9-51.5)
Hazard ratio: (95% CI) *p-value 0.70 (0.54-0.90) 0.0058

Figure 10: TAX324 Overall Survival K-M Curve

Figure 10
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