DOCEFREZ (Page 6 of 8)

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-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 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 1/50th 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 intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3rd and 1/15th the recommended human dose on a mg/m2 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 TrialsIn one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (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). 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 8).

Table 8- Efficacy of Docetaxel in the Treatment of Breast Cancer Patients Previously Treated with an Anthracycline-Containing Regimen (Intent-to-Treat Analysis)
*
For the risk ratio, a value less than 1.00 favors docetaxel.
Efficacy Parameter Docetaxel (n=203) Mitomycin/ Vinblastine (n=189) p-value
Median Survival 11.4 months 8.7 months p=0.01Log Rank
Risk Ratio *, Mortality (Docetaxel: Control) 95% CI (Risk Ratio) 0.730.58-0.93
Median Time to Progression 4.3 months 2.5 months p=0.01Log Rank
Risk Ratio *, Progression (Docetaxel: Control)95% CI (Risk Ratio) 0.750.61-0.94
Overall Response RateComplete Response Rate 28.1%3.4% 9.5%1.6% p<0.0001Chi Square

In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m2) or doxorubicin (75 mg/m2) 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 9).

Table 9- 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 p=0.39Log Rank
Risk Ratio *, Mortality (Docetaxel: Control)95% CI (Risk Ratio) 0.890.68-1.16
Median Time to Progression 6.5 months 5.3 months p=0.45Log Rank
Risk Ratio *, Progression (Docetaxel: Control)95% CI (Risk Ratio) 0.930.71-1.16
Overall Response RateComplete Response Rate 45.3%6.8% 29.7%4.2% p=0.004Chi 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/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 docetaxel 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
Docetaxel 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% to 44.8%) and the complete response rate was 2.1%.Docetaxel 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% to 55.7%), similar to the response rate in single arm studies of 100 mg/m2.

14.3 Non-Small Cell Lung Cancer (NSCLC)

The efficacy and safety of docetaxel 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 Docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy

Two randomized, controlled trials established that a docetaxel dose of 75 mg/m2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel 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, Dosage and Administration (2.7), Warnings and Precautions (5.3)].

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 docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m2. A total of 104 patients were randomized in this amended study to either docetaxel 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 docetaxel 75 mg/m2 , docetaxel 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 docetaxel 75 mg/m2 arm and the comparator arms are summarized in Table 10 and Figures 1 and 2 showing the survival curves for the two studies.

Table 10 — Efficacy of Docetaxel in the Treatment of Non-Small Cell Lung Cancer Patients Previously Treated with a Platinum-Based Chemotherapy Regimen (Intent-to-Treat Analysis)
*
Vinorelbine/Ifosfamide
a value less than 1.00 favors docetaxel
uncorrected for multiple comparisons
§
p≤0.05
TAX317 TAX320
Docetaxel 75 mg/m2 n=55 Best Supportive Care n=49 Docetaxel 75 mg/m2 n=125 Control (V/I *)n=123
Overall Survival Log-rank Testp=0.01p=0.13
Risk Ratio , Mortality (Docetaxel: Control)95% CI (Risk Ratio)0.56(0.35, 0.88)0.82(0.63, 1.06)
Median Survival95% CI7.5 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 Survival95% CI37%§(24, 50)12%(2.0, 23)30%§(22, 39)20%(13, 27)
Time to Progression95% CI12.3 weeks §(9.0, 18.3)7 weeks(6.0, 9.3)8.3 weeks(7.0, 11.7)7.6 weeks(6.7, 10.1)
Response Rate95% CI5.5%(1.1, 15.1)Not Applicable5.7%(2.3, 11.3)0.8%(0.0, 4.5)

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 docetaxel 75 mg/m2.
Figure 1 — TAX317 Survival K-M Curves — Docetaxel 75 mg/m2 vs. Best Supportive Care

docetaxel-fig1
(click image for full-size original)

Figure 2 — TAX320 Survival K-M Curves – Docetaxel 75 mg/m2 vs. Vinorelbine or Ifosfamide Control
docetaxel-fig2
(click image for full-size original)
Patients treated with docetaxel 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 Docetaxel 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: docetaxel 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m2 over 30 to 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 docetaxel and carboplatin.

The primary efficacy endpoint was overall survival. Treatment with docetaxel+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 docetaxel 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 docetaxel+cisplatin arm and the comparator arm are summarized in Table 11.

Table 11 — Survival Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naïve NSCLC
*
From the superiority test (stratified log rank) comparing docetaxel+cisplatin to vinorelbine+cisplatin
Hazard ratio of docetaxel+cisplatin vs. vinorelbine+cisplatin. A hazard ratio of less than 1 indicates that docetaxel+cisplatin is associated with a longer survival.
Adjusted for interim analysis and multiple comparisons.
ComparisonDocetaxel+Cisplatin n=408Vinorelbine+Cisplatin n=405
Kaplan-Meier Estimate of Median Survival10.9 months10 months
p-value *0.122
Estimated Hazard Ratio 0.88
Adjusted 95% CI (0.74, 1.06)

The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months for docetaxel+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the docetaxel+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 docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 12).

Table 12 — Response and TTP Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naïve NSCLC
*
Adjusted for multiple comparisons.
Kaplan-Meier estimates.
Endpoint Docetaxel+CisplatinVinorelbine+Cisplatinp-value
Objective Response Rate (95% CI)*31.6%(26.5%, 36.8%)24.4%(19.8%, 29.2%)Not Significant
Median Time to Progression (95% CI)*21.4 weeks(19.3, 24.6)22.1 weeks(18.1, 25.6)Not Significant

docetaxel-fig1docetaxel-fig2

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