DOCETAXEL (Page 15 of 20)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with docetaxel have not been performed.

Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K 1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60 th to 1/15 th the recommended human dose on a mg/m 2 basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays.

Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50 th the recommended human dose on a mg/m 2 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 intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3 rd and 1/15 th the recommended human dose on a mg/m 2 basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

14 CLINICAL STUDIES

14.1 Locally Advanced or Metastatic Breast Cancer

The efficacy and safety of docetaxel 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 docetaxel (100 mg/m 2 every 3 weeks) or the combination of mitomycin (12 mg/m 2 every 6 weeks) and vinblastine (6 mg/m 2 every 3 weeks). Two hundred three patients were randomized to docetaxel and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel 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 12.)

Table 12: Efficacy of Docetaxel 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
*
For the risk ratio, a value less than 1.00 favors docetaxel.
Median Survival 11.4 months 8.7 months
Risk Ratio *, Mortality (Docetaxel: Control) 0.73 p=0.01 Log Rank
95% CI (Risk Ratio) 0.58-0.93
Median Time to Progression 4.3 months 2.5 months
Risk Ratio *, Progression (Docetaxel: Control) 0.75 p=0.01 Log Rank
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

In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m 2) or doxorubicin (75 mg/m 2) every 3 weeks. One hundred sixty-one patients were randomized to docetaxel 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 13.)

Table 13: Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen (Intent-to-Treat Analysis)
Efficacy Parameter Docetaxel (n=161) Doxorubicin (n=165) p-value
*
For the risk ratio, a value less than 1.00 favors docetaxel.
Median Survival 14.7 months 14.3 months
Risk Ratio *, Mortality (Docetaxel: Control) 0.89 p=0.39 Log Rank
95% CI (Risk Ratio) 0.68-1.16
Median Time to Progression 6.5 months 5.3 months
Risk Ratio *, Progression (Docetaxel: Control) 0.93 p=0.45 Log Rank
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

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 docetaxel monotherapy 60 mg/m 2 (n=151), 75 mg/m 2 (n=188) or 100 mg/m 2 (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 docetaxel dose: 19.9% for the 60 mg/m 2 group compared to 22.3% for the 75 mg/m 2 and 29.8% for the 100 mg/m 2 group; pair-wise comparison between the 60 mg/m 2 and 100 mg/m 2 groups was statistically significant (p=0.037).

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