Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic Properties
Pharmaco-therapeutic group: Taxanes, ATC Code: L01CD 02
Preclinical data: Docetaxel is an antineoplastic agent which acts by promoting the assembly of tubulin into stable microtubules and inhibits their disassembly which leads to a marked decrease of free tubulin.
The binding of docetaxel to microtubules does not alter the number of protofilaments.
Docetaxel has been shown in vitro to disrupt the microtubular network in cells which is essential for vital mitotic and interphase cellular functions. Docetaxel was found to be cytotoxic in vitro against various 
murine and human tumour cell lines and against freshly excised human tumour cells in clonogenic assays.
Docetaxel achieves high intracellular concentrations with a long cell residence time. In addition, docetaxel was found to be active on some but not all cell lines over expressing the p-glycoprotein which is encoded by the multidrug resistance gene. In vivo, docetaxel is schedule independent and has a broad spectrum of experimental antitumour activity against advanced murine and human grafted tumours.


Clinical data:
Breast cancer
Docetaxel in combination with doxorubicin and cyclophosphamide: adjuvant therapy Patients with operable node-positive breast cancer (TAX 316): Data from a multicenter open label randomized study support the use of docetaxel or the adjuvant treatment of patients with operable node- positive breast cancer and KPS ≥ 80%, between 18 and 70 years of age. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either docetaxel 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 cyclophosphamide 500 mg/m2 (FAC arm). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other drugs were given as IV bolus on day one. G-CSF was administered as secondary prophylaxis to patients who experienced complicated neutropenia (febrile neutropenia, prolonged neutropenia, or infection). Patients on the TAC arm received antibiotic prophylaxis with ciprofloxacin 500 mg orally b.i.d. for 10 days starting on day 5 of each cycle, or equivalent. 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. Two interim analyses and one final analysis were performed. The first interim analysis was planned 3 years after the date when half of study enrollment was done. The second interim analysis was done after 400 DFS events had been recorded overall, which led to a median follow-up of 55 months. The final analysis was performed when all patients had reached their 10-year follow-up visit (unless they had a DFS event or were lost to follow-up before). Disease-free survival (DFS) was the primary efficacy endpoint and Overall survival (OS) was the secondary efficacy endpoint.
A final analysis was performed with an actual median follow up of 96 months. Significantly longer disease free survival for the TAC arm compared to the FAC arm was demonstrated. Incidence of relapses at 10 years was reduced in patients receiving TAC compared to those who received FAC (39% versus 45%, respectively) i.e., an absolute risk reduction by 6% (p=0.0043). Overall survival at 10 years was also significantly increased with TAC compared to FAC (76% versus 69%, respectively) i.e. an absolute reduction of the risk of death by 7% (p=0.002). As the benefit observed in patient with 4+ nodes was not statistically significant on DFS and OS, the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully demonstrated at the final analysis. Overall, the study results demonstrate a positive benefit risk ratio for TAC compared to FAC.
TAC-treated patient subsets according to prospectively defined major prognostic factors were analyzed:

Disease-Free Survival               Overall Survival
Patient subset      Number of      Hazard 95% CI         p=            Hazard 95% CI            p= patients       ratio*                              ratio*
No. of positive nodes
Overall             745            0.80        0.68-0.93    0.0043     0.74        0.61-0.90    0.0020 1-3                 467            0.72        0.58-0.91    0.0047     0.62        0.46-0.82    0.0008 4+                  278            0.87        0.70-1.09    0.2290     0.87        0.67-1.12    0.2746
*a hazard ratio of less than 1 indicates that TAC is associated with a longer disease-free survival and overall survival compared to FAC

Patients with operable node-negative breast cancer eligible to receive chemotherapy (GEICAM 9805): Data from a multicenter open label randomized trial support the use of docetaxel for the adjuvant treatment of patients with operable node-negative breast cancer eligible to receive chemotherapy. 1060 patients were randomized to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (539 patients in TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2 (521 patients in FAC arm), as adjuvant treatment of operable node-negative breast cancer patients with high risk of relapse according to 1998 St. Gallen criteria (tumour size >2 cm and/or negative ER and PR and/or high histological/nuclear 
grade (grade 2 to 3) and /or age <35 years). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other medicinal products were given intravenously on day 1 every three weeks. Primary prophylactic G-CSF was made mandatory in TAC arm after 230 patients were randomized. The incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF prophylaxis (see section 4.8). In both arms, after the last cycle of chemotherapy, patients with ER+ and/or PgR+ tumours received tamoxifen 20 mg once a day for up to 5 years. Adjuvant radiation therapy was administered according to guidelines in place at participating institutions and was given to 57.3% of patients who received TAC and 51.2% of patients who received FAC.
One primary analysis and one updated analysis were performed. The primary analysis was done when all patients had a follow-up of greater than 5 years (median follow-up time of 77 months). The updated analysis was performed when all patients had reached their 10-year (median follow up time of 10 years and 5 months) follow-up visit (unless they had a DFS event or were lost to follow-up previously).
Disease-free survival (DFS) was the primary efficacy endpoint and Overall survival (OS) was the secondary efficacy endpoint.
At the median follow-up time of 77 months, significantly longer DFS for the TAC arm compared to the FAC arm was demonstrated. TAC-treated patients had a 32% reduction in the risk of relapse compared to those treated with FAC [hazard ratio = 0.68, 95% CI (0.49- 0.93), p = 0.01]. At the median follow up time of 10 years and 5 months, TAC-treated patients had a 16.5% reduction in the risk of relapse compared to those treated with FAC [hazard ratio = 0.84, 95% CI (0.65-1.08), p = 0.1646]. DFS data were not statistically significant but were still associated with a positive trend in favor of TAC.
At the median follow-up time of 77 months OS was longer in the TAC arm with TAC-treated patients having a 24% reduction in the risk of death compared to FAC [hazard ratio = 0.76, 95% CI (0.46-1.26), p = 0.29]. However, the distribution of OS was not significantly different between the 2 groups.
At the median follow up time of 10 years and 5 months, TAC-treated patients had a 9% reduction in the risk of death compared to FAC-treated patients [hazard ratio = 0.91, 95% CI (0.63-1.32)]. The survival rate was 93.7% in the TAC arm and 91.4% in the FAC arm, at the 8-year follow-up timepoint, and 91.3% in the TAC arm and 89% in the FAC arm, at the 10- year follow-up timepoint.
The positive benefit risk ratio for TAC compared to FAC remained unchanged.
TAC-treated patient subsets according to prospectively defined major prognostic factors were analyzed in the primary analysis (median follow-up time of 77 months) (see table below): 
Subset Analyses-Adjuvant Therapy in Patients with Node-negative Breast Cancer Study (primary analysis for Intent-to-Treat population)
Number of                 Disease Free Survival
Patient subset            patients in        Hazard ratio*             95% CI TAC group
Overall                  539                  0.68                0.49-0.93 Age category 1
<50 years                            260                  0.67                0.43-1.05 ≥50 years                            279                  0.67                0.43-1.05 Age category 2
<35 years                             42                  0.31                0.11-0.89 ≥35 years                            497                  0.73                0.52-1.01 Hormonal receptor Status
Negative                             195                   0.7                0.45-1.1 Positive                             344                  0.62                0.4-0.97 Tumour size
≤ 2 cm                               285                  0.69                0.43-1.1 >2 cm                                254                  0.68                0.45-1.04 Histological grade
Grade1 (includes grade                64                  0.79                0.24-2.6 not assessed)                        216                  0.77                0.46-1.3 Grade 2                              259                  0.59                0.39-0.9 Grade 3


Menopausal status
Pre-Menopausal                         285                   0.64                  0.40-1 Post-Menopausal                        254                   0.72                 0.47-1.12 *a hazard ratio (TAC/FAC) of less than 1 indicates that TAC is associated with a longer disease free survival compared to FAC.

Exploratory subgroup analyses for disease-free survival for patients who meet the 2009 St.
Gallen chemotherapy criteria – (ITT population) were performed and presented here below TAC                 FAC             Hazard ratio     p- value
(TAC/FAC)
Subgroups                  (n=539)            (n=521)             (95% CI) 
Meeting relative indication for chemotherapya
No                18/214 (8.4%)     26/227 (11.5%)           0.796 (0.434 -       0.4593 1.459)
Yes                48/325 (14.8%) 69/294 (23.5%)           0.606 (0.42 - 0.877)    0.0072 
TAC = docetaxel, doxorubicin and cyclophosphamide. FAC = 5-fluorouracil, doxorubicin and cyclophosphamide
CI = confidence interval; ER = estrogen receptor. PR = progesterone receptor.
a
ER/PR-negative or Grade 3 or tumor size >5 cm

The estimated hazard ratio was using Cox proportional hazard model with treatment group as the factor.

Docetaxel as single agent: Two randomised phase III comparative studies, involving a total of 326 alkylating or 392 anthracycline failure metastatic breast cancer patients, have been performed with docetaxel at the recommended dose and regimen of 100 mg/m² every 3 weeks.
In alkylating-failure patients, docetaxel was compared to doxorubicin (75 mg/m² every 3 weeks). Without affecting overall survival time (docetaxel 15 months vs. doxorubicin 14 months, p=0.38) or time to progression (docetaxel 27 weeks vs. doxorubicin 23 weeks, p=0.54), docetaxel increased response rate (52% vs. 37%, p=0.01) and shortened time to response (12 weeks vs. 23 weeks, p=0.007). Three docetaxel patients (2%) discontinued the treatment due to fluid retention, whereas 15 doxorubicin patients (9%) discontinued due to cardiac toxicity (three cases of fatal congestive heart failure). In anthracycline- failure patients, docetaxel was compared to the combination of Mitomycin C and Vinblastine (12 mg/m² every 6 weeks and 6 mg/m² every 3 weeks). Docetaxel increased response rate (33% vs. 12%, p<0.0001), prolonged time to progression (19 weeks vs. 11 weeks, p=0.0004) and prolonged overall survival (11 months vs. 9 months, p=0.01).
During these two phase III studies, the safety profile of docetaxel was consistent with the safety profile observed in phase II studies (see section 4.8).
An open-label, multicenter, randomized phase III study was conducted to compare docetaxel monotherapy and paclitaxel in the treatment of advanced breast cancer in patients whose previous therapy should have included an anthracycline. A total of 449 patients were randomized to receive either docetaxel monotherapy 100 mg/m² as a 1 hour infusion or paclitaxel 175 mg/m² as a 3 hour infusion. Both regimens were administered every 3 weeks. Without affecting the primary endpoint, overall response rate (32% vs 25%, p=0.10), docetaxel prolonged median time to progression (24.6 weeks vs 15.6 weeks; p<0.01) and median survival (15.3 months vs 12.7 months; p=0.03). More grade 3/4 adverse events were observed for docetaxel monotherapy (55.4%) compared to paclitaxel (23.0%).

Docetaxel in combination with doxorubicin: One large randomized phase III study, involving 429 previously untreated patients with metastatic disease, was performed with doxorubicin (50 mg/m²) in combination with docetaxel (75 mg/m²) (AT arm) versus doxorubicin (60 mg/m²) in combination with cyclophosphamide (600 mg/m²) (AC arm). Both regimens were administered on day 1 every 3 weeks.
• Time to progression (TTP) was significantly longer in the AT arm versus AC arm, p=0.0138. The median TTP was 37.3 weeks (95%CI: 33.4 - 42.1) in AT arm and 31.9 weeks (95%CI: 27.4 - 36.0) in AC arm.

• Overall response rate (ORR) was significantly higher in the AT arm versus AC arm, p=0.009. The ORR was 59.3% (95%CI: 52.8 - 65.9) in AT arm versus 46.5% (95%CI : 39.8 - 53.2) in AC arm.
In this trial, AT arm showed a higher incidence of severe neutropenia (90% versus 68.6%), febrile neutropenia (33.3% versus 10%), infection (8% versus 2.4%), diarrhoea (7.5% versus 1.4%), asthenia (8.5% versus 2.4%), and pain (2.8% versus 0%) than AC arm. On the other hand, AC arm showed a higher incidence of severe anaemia (15.8% versus 8.5%) than AT arm, and, in addition, a higher incidence of severe cardiac toxicity: congestive heart failure (3.8% versus 2.8%), absolute LVEF decrease ≥ 20% (13.1 % versus 6.1%), absolute LVEF decrease ≥ 30% (6.2% versus 1.1%). Toxic deaths occurred in 1 patient in the AT arm (congestive heart failure) and in 4 patients in the AC arm (1 due to septic shock and 3 due to congestive heart failure). In both arms, quality of life measured by the EORTC questionnaire was comparable and stable during treatment and follow-up.

Docetaxel in combination with trastuzumab: Docetaxel in combination with trastuzumab was studied for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2, and who previously had not received chemotherapy for metastatic disease. One hundred eighty six patients were randomized to receive docetaxel (100 mg/m2) with or without trastuzumab; 60% of patients received prior anthracycline-based adjuvant chemotherapy. Docetaxel plus trastuzumab was efficacious in patients whether or not they had received prior adjuvant anthracyclines. The main test method used to determine HER2 positivity in this pivotal trial was immunohistochemistry (IHC). A minority of patients were tested using fluorescence in-situ hybridization (FISH). In this trial, 87% of patients had disease that was IHC 3+, and 95% of patients entered had disease that was IHC 3+ and/or FISH positive. Efficacy results are summarized in the following table:

Parameter                            Docetaxel plus trastuzumab1         Docetaxel1 n=92                                n=94
Response rate (95% CI)              61% (50-71)                         34% (25-45) Median Duration of response         11.4 (9.2-15.0)                     5.1 (4.4-6.2) (months) (95% CI)
Median TTP (months)                  10.6 (7.6-12.9)                   5.7 (5.0-6.5) (95% CI)
Median Survival (months)             30.52 (26.8-ne)                   22.12 (17.6-28.9) (95% CI)
TTP=time to progression; “ne” indicates that it could not be estimated or it was not yet reached.
1
Full analysis set (intent-to-treat)
2
Estimated median survival

Docetaxel in combination with capecitabine: Data from one multicentre, randomised, controlled phase III clinical trial supported the use of docetaxel in combination with capecitabine for treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this trial, 255 patients were randomised to treatment with docetaxel (75 mg/m2 as a 1 hour intravenous infusion every 3 weeks) and capecitabine (1250 mg/m2 twice daily for 2 weeks followed by 1-week rest period). 256 patients were randomised to treatment with docetaxel alone (100 mg/ m2 as a 1 hour intravenous infusion every 3 weeks). Survival was superior in the docetaxel +capecitabine combination arm (p=0.0126). Median survival was 442 days (docetaxel + capecitabine) vs.
352 days (docetaxel alone). The overall objective response rates in the all- randomised population (investigator assessment) were 41.6% (docetaxel + capecitabine) vs. 29.7% (docetaxel alone); p = 0.0058.
Time to progressive disease was superior in the docetaxel + capecitabine combination arm (p<0.0001).
The median time to progression was 186 days (docetaxel + capecitabine) vs.128 days (docetaxel alone).

Doxorubicin and Cyclophosphamide followed by docetaxel in combination with Trastuzumab (AC- TH), or docetaxel in combination with Trastuzumab and Carboplatin (TCH) The efficacy and safety of docetaxel in combination with trastuzumab was studied for the adjuvant treatment of patients with operable breast cancer whose tumours overexpress HER2 (with node-positive and high risk node-negative). A total of 3,222 women were randomised in the study, and 3,174 were treated with either: AC-T, AC-TH, or TCH.

- AC-T (control arm): Doxorubicin 60 mg/m2 IV in combination with cyclophosphamide 600 mg/m2 IV on an every 3 week basis for 4 cycles, followed by docetaxel 100 mg/m2 as a 1- hour IV infusion on an every 3 week basis for 4 cycles;
- AC-TH: Doxorubicin 60 mg/m2 IV in combination with cyclophosphamide 600 mg/m2 IV on an every 3 week basis for 4 cycles. Three weeks after the last cycle of AC, trastuzumab 4 mg/kg loading dose by IV infusion over 90 minutes on day 1 of cycle 5 was administered, followed by trastuzumab 2 mg/kg by IV infusion over 30-minutes weekly starting day 8 of cycle 5; and docetaxel 100 mg/m2 administered by IV infusion over 1-hour on day 2 of cycle 5, then on day 1 on an every 3 week basis for all subsequent cycles (total 4 cycles of docetaxel). Beginning three weeks after the last cycle of chemotherapy, trastuzumab 6 mg/kg by IV infusion over 30 minutes was given every 3 weeks (for 1 year from the date of first administration);
- TCH: Trastuzumab 4 mg/kg loading dose by IV infusion over 90 minutes on day 1 of cycle 1 only, followed by trastuzumab 2 mg/kg by IV infusion over 30 minutes weekly starting on day 8 until three weeks after the last cycle of chemotherapy. Docetaxel 75 mg/m2 was administered on day 2 of cycle 1, then on day 1 of all subsequent cycles by IV infusion over 1-hour followed by carboplatin (AUC 6 mg/mL/min) as a 30-60 minute IV infusion, for a total of six cycles of docetaxel and carboplatin.
Beginning three weeks after the last cycle of chemotherapy, trastuzumab 6 mg/kg by IV infusion over 30 minutes was given every 3 weeks (for 1-year from the date of first administration).
The patients and disease characteristics at baseline were well balanced between the 3 treatment arms.
Disease Free Survival (DFS) was the primary endpoint, and Overall Survival (OS) was the secondary endpoint.
Results of the second interim analysis, performed with a median follow-up of 36 months, demonstrated that docetaxel and trastuzumab given concurrently as part of either an anthracycline-based (AC-TH) or nonanthracycline- based (TCH) adjuvant treatment regimens, for patients with HER2-positive operable breast cancer, statistically prolonged both DFS and OS compared with the control arm (AC-T). The relative reduction in the risk of relapse was 39 % (p < 0.0001) and 33% (p = 0.0003) for the AC-TH and TCH arms, respectively, compared with the AC-T arm. The relative reduction in the risk of death was 42% (p = 0.0024) and 34% (p = 0.0182) for the AC-TH and TCH arms, respectively, compared with the
AC-T arm. There was no statistically significant difference between the two trastuzumab-containing arms AC-TH and TCH for DFS and OS. Efficacy results are summarised in the following table: Doxorubicin and cyclophosphamide followed by docetaxel in combination with trastuzumab, or docetaxel in combination with trastuzumab, and carboplatin (Intent-to-Treat Population) Disease Free Survival (DFS)                  Overall Survival (OS)

AC-T           AC-TH          TCH            AC-T           AC-TH          TCH n=1073         n=1074         n=1075         n=1073         n=1074         n=1075 
Stratified analysis
Hazard ratioa         NA             0.61           0.67           NA             0.58           0.66 95% CI                NA             (0.49-0.77)    (0.54-0.83)    NA             (0.40-0.83)    (0.47-0.93) p-valueb              NA             < 0.0001       0.0003         NA             0.0024         0.0182 Percent event         80.9%          86.7%          85.5%          93.0%          95.5%          95.2% free at 3 years       (78.3-83.5%)   (84.4-89.0%)   (83.2-87.9%)   (91.2-94.8%)   (94.0-96.9%)   (93.7-96.6%) (95% CI)
Absolute benefitc                    5.8%           4.6%                          2.5%           2.2% AC-T=doxorubicin plus cyclophosphamide, followed by docetaxel; AC-TH=doxorubicin plus cyclophosphamide, followed by docetaxel in combination with trastuzumab; TCH= docetaxel in combination with trastuzumab and carboplatin.
CI=confidence interval; NA=not applicable.
a
=Relative to AC-T. Estimated using Cox regression stratified by number of nodes and hormonal receptor status.
b
=Stratified log-rank p-value.
c
=Absolute benefit in percent event free compared with AC-T.
There were 29% of patients with high risk node-negative disease included in the study. The benefit observed for the overall population was irrespective of the nodal status.
Disease Free Survival (Intent-to-Treat Population) according to Nodal Status High risk node-negative patients               Node-positive patients 
AC-T              AC-TH          TCH            AC-T           AC-TH          TCH n=                n = 306        n = 307        n=             n = 768        n = 768 309                                             764
Stratified analysis
Hazard ratioa       NA              0.36           0.52           NA             0.67           0.70 95% CI              NA              (0.19-0.68)    (0.30-0.92)    NA             (0.53-0.85)    (0.56-0.89) b p-value             NA              0.0010         0.0209         NA             0.0008         0.0029 Percent event       88.0%           94.8%          93.0%          78.1%          83.6%          82.6% free at 3 years     (84.1- 91.9%)   (91.9-97.8%)   (89.9-96.2%)   (74.9-81.3%)   (80.7-86.5%)   (79.6-85.6%) (95% CI)
Absolute benefitc                   6.8%           5.1%                          5.5%           4.6% AC-T=doxorubicin plus cyclophosphamide, followed by docetaxel; AC-TH=doxorubicin plus cyclophosphamide, followed by TAXOTERE in combination with trastuzumab; TCH= docetaxel in combination with trastuzumab and carboplatin.
CI=confidence interval; NA=not applicable.
a
=Relative to AC-T. Estimated using Cox regression stratified by number of nodes and hormonal receptor status.
b
=Stratified log-rank p-value.
c
=Absolute benefit in percent event free compared with AC-T.

Non-Small Cell Lung Cancer
Patients previously treated with chemotherapy with or without radiotherapy: In a phase III study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks) and overall survival were significantly longer for docetaxel at 75 mg/m² compared to Best Supportive Care. The 1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%). There was less use of morphinic analgesic (p<0.01), non-morphinic analgesics (p<0.01), other disease related medications (p=0.06) and radiotherapy (p<0.01) in patients treated with docetaxel at 75 mg/m² compared to those with BSC.
The overall response rate was 6.8% in the evaluable patients, and the median duration of response was 26.1 weeks.

Docetaxel in combination with platinum agents in chemotherapy-naïve patients: In a Phase III trial, 1218 patients with unresectable stage IIIB or IV NSCLC, with KPS of 70% or greater, and who did not receive previous chemotherapy for this condition, were randomised to either docetaxel (T) 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/ m2 over 30-60 minutes every 3 weeks, docetaxel 75 mg/ m2 as a 1 hour infusion in combination with carboplatin (AUC 6 mg/ml•min) over 30-60 minutes every 3 weeks, or vinorelbine (V) 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. Survival data, median time to progression and response rates for two arms of the study are illustrated in the following table:
TCis VCis         Statistical Analysis n=408 N=404
Overall Survival (Primary end-point):
Median Survival (months)           11.3    10.1      Hazard Ratio: 1.122 [97.2% CI: 0.937; 1.342]* 1-year Survival (%)                46      41        Treatment difference: 5.4% [95% CI: -1.1; 12.0]  2-year Survival (%)                21      14        Treatment difference: 6.2% [95% CI: 0.2; 12.3]
Median Time to Progression         22.0    23.0      Hazard Ratio: 1.032 [95% CI: 0.876; 1.216] (weeks):
Overall response rate (%):         31.6    24.5      Treatment difference: 7.1% [95% CI: 0.7; 13.5] *: Corrected for multiple comparisons and adjusted for stratification factors (stage of disease and region of treatment), based on evaluable patient population.
Secondary end-points included change of pain, global rating of quality of life by EuroQoL- 5D, Lung Cancer Symptom Scale, and changes in Karnofsky performance status. Results on these end-points were supportive of the primary end-points results.
For docetaxel/carboplatin combination, neither equivalent nor non-inferior efficacy could be proven compared to the reference treatment combination VCis.

Prostate Cancer
The safety and efficacy of docetaxel in combination with prednisone or prednisolone in patients with hormone refractory metastatic prostate cancer were evaluated in a randomized multicentre Phase III trial.
A total of 1006 patients with KPS ≥ 60 were randomized to the following treatment groups:
• docetaxel 75 mg/m2 every 3 weeks for 10 cycles.
• docetaxel 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 or prednisolone 5 mg twice daily, continuously.
Patients who received docetaxel every three weeks demonstrated significantly longer overall survival compared to those treated with mitoxantrone. The increase in survival seen in the docetaxel weekly arm was not statistically significant compared to the mitoxantrone control arm. Efficacy endpoints for the docetaxel arms versus the control arm are summarized in the following table: Endpoint                       Docetaxel every 3 Docetaxel every week           Mitoxantrone weeks                                     every 3 weeks
Number of patients                     335                  334                      337 Median survival (months)               18.9                 17.4                     16.5 95% CI                             (17.0-21.2)          (15.7-19.0)              (14.4-18.6) Hazard ratio                          0.761                0.912                      -- 95% CI                            (0.619-0.936)        (0.747-1.113)                  -- p-value† *                            0.0094               0.3624                     -- 
Number of patients                     291                  282                      300 PSA** response rate (%)                45.4                 47.9                     31.7 95% CI                             (39.5-51.3)          (41.9-53.9)              (26.4-37.3) p-value*                              0.0005              < 0.0001                     -- Number of patients                     153                  154                      157 Pain response rate (%)                 34.6                 31.2                     21.7 95% CI                             (27.1-42.7)          (24.0-39.1)              (15.5-28.9) p-value*                              0.0107               0.0798                      -- Number of patients                     141                  134                      137 Tumour response rate (%)               12.1                  8.2                      6.6 95% CI                              (7.2-18.6)           (4.2-14.2)               (3.0-12.1) p-value*                              0.1112               0.5853                      -- †Stratified log rank test
*Threshold for statistical significance=0.0175
**PSA: Prostate-Specific Antigen

Given the fact that docetaxel every week presented a slightly better safety profile than docetaxel every 3 weeks, it is possible that certain patients may benefit from docetaxel every week.
No statistical differences were observed between treatment groups for Global Quality of Life.

Ovarian Cancer
Supportive clinical data: Docetaxel was studied in five phase II clinical trials in patients who were diagnosed with advanced epithelial ovarian cancer and who failed a previous treatment with cisplatin and/or to carboplatin. These patients (n=281) received docetaxel 100mg/m² every three weeks as a one- hour infusion.
• Overall response rate was 26.7% with a 5.7% complete response rate.
• The median survival ranged from 11.2 to 11.9 months.

• The adverse reaction profile from these 281 patients is similar to larger populations studied for metastatic breast cancer (see Adverse Reactions section).

Gastric Adenocarcinoma
A multicentre, open-label, randomized trial, was conducted to evaluate the safety and efficacy of docetaxel for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for metastatic disease. A total of 445 patients with KPS>70 were treated with either docetaxel (T) (75 mg/m2 on day 1) in combination with cisplatin (C) (75 mg/m2 on day 1) and 5-fluorouracil (F) (750 mg/m2 per day for 5 days) or cisplatin (100 mg/m2 on day 1) and 5- fluorouracil (1,000 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 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. The risk reduction of progression was 32.1% and was associated with a significantly longer TTP (p=0.0004) in favour of the TCF arm. Overall survival was also significantly longer (p=0.0201) in favour of the TCF arm with         a risk reduction of mortality of 22.7%. Efficacy results are summarized in the following table: 
Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma Endpoint                                                 TCF N=221             CF N=224 Median TTP (months) (95%CI)                              5.6 (4.86-5.91)      3.7 (3.45-4.47) Hazard ratio (95%CI)                                             1.473 (1.189-1.825) p-value *                                                               0.0004 Median survival (months) (95%CI)                               9.2                  8.6 (8.38-10.58)          (7.16-9.46)
2-year estimate (%)                                            18.4                 8.8
Hazard ratio (95%CI)                                                    1.293 (1.041-1.606) p-value *                                                               0.0201 Overall Response Rate (CR+PR) (%)                              36.7                 25.4 p-value                                                                 0.0106 Progressive Disease as Best Overall Response (%)               16.7                 25.9 *Unstratified log rank test

Subgroup analyses across age, gender and race consistently favoured the TCF arm compared to the CF arm.
A survival update analysis conducted with a median follow-up time of 41.6 months no longer showed a statistically significant difference although always in favour of the TCF regimen and showed that the benefit of TCF over CF is clearly observed between 18 and 30 months of follow up.
Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement in favour of the TCF arm. Patients treated with TCF had a longer time to 5% definitive deterioration of global health status on the QLQ-C30 questionnaire (p=0.0121) and a longer time to definitive worsening of Karnofsky performance status (p=0.0088) compared to patients treated with CF.

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 phase III, multicentre, open- label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, received either docetaxel 75 mg/m2 followed by cisplatin 75 mg/m2 followed by 5- fluorouracil 750 mg/m2 per day as a continuous infusion for 5 days (TPF) or cisplatin 100 mg/m2 followed by 5-fluorouracil 1,000 mg/m2(PF) per day for 5 days. These regimens were administered every three weeks for 4 cycles in case at least a minor response (≥ 25% reduction in bidimensionally measured tumour size) was observed after 2 cycles. 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 for 7 weeks. Locoregional therapy with radiation was delivered either 
with a conventional fraction (1.8 Gy - 2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy), or accelerated/hyperfractionated regimens of radiation therapy (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week). A total of 70 Gy was recommended for accelerated regimens and 74 Gy for hyperfractionated schemes. Surgical resection was allowed following chemotherapy, before or after radiotherapy. Patients on the TPF arm received antibiotic prophylaxis with ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or equivalent. The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p = 0.0042 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median overall survival was also significantly longer in favour of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.5 months respectively) with a 28% risk reduction of mortality, p= 0.0128. Efficacy results are presented in the table below:

Efficacy of docetaxel in the induction treatment of patients with inoperable locally advanced SCCHN (Intent-to-Treat Analysis)
Endpoint                                         Docetaxel+Cis+5-          Cis+5-FU n=181 FU n=177
Median progression free survival (months)         11.4 (10.1-14.0)            8.3 (7.4-9.1) (95%CI)
Adjusted Hazard ratio (95%CI)                                  0.70 (0.55-0.89) *p-value                                                            0.0042 Median survival (months) (95%CI)                  18.6 (15.7-24.0)          14.5 (11.6-18.7) Hazard ratio (95%CI)                                           0.72 (0.56-0.93) **p-value                                                           0.0128 Best overall response to chemotherapy (%)         67.8 (60.4-74.6)          53.6 (46.0-61.0) (95%CI)
***p-value                                                          0.006 Best overall response to study treatment          72.3 (65.1-78.8)          58.6 (51.0-65.8) [chemotherapy +/- radiotherapy] (%)
(95%CI)
***p-value                                                          0.006 Median duration of response to                         n=128                     n=106 chemotherapy ± radiotherapy (months)              15.7 (13.4-24.6)          11.7 (10.2-17.4) (95%CI)
Hazard ratio (95%CI)                                           0.72 (0.52-0.99) **p-value                                                           0.0457 A Hazard ratio of less than 1 favors docetaxel + cisplatin + 5-FU
*Cox model (adjustment for Primary tumor site, T and N clinical stages and PSWHO) **Logrank test
*** Chi-square test

Quality of life parameters
Patients treated with TPF experienced significantly less deterioration of their Global health score compared to those treated with PF (p = 0.01, using the EORTC QLQ-C30 scale).

Clinical benefit parameters
The performance status scale, for head and neck (PSS-HN) subscales designed to measure understandability of speech, ability to eat in public, and normalcy of diet, was significantly in favour of TPF as compared to PF.
Median time to first deterioration of WHO performance status was significantly longer in the TPF arm compared to PF. Pain intensity score improved during treatment in both groups indicating adequate pain management.
• Induction chemotherapy followed by chemoradiotherapy (TAX324) The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a randomized, multicenter 
open-label, phase III, 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 arms. The study population comprised patients with technically unresectable disease, patients with low probability of surgical cure and patients aiming at organ preservation. The efficacy and safety evaluation solely addressed survival endpoints and the success of organ preservation was not formally addressed. Patients on the docetaxel arm received docetaxel (T) 75 mg/m² by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m² administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of 5-fluorouracil (F) 1,000 mg/m²/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease were to receive chemoradiotherapy (CRT) as per protocol (TPF/CRT).
Patients on the comparator arm received cisplatin (P) 100 mg/m² as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of 5- fluorouracil (F) 1,000 mg/m²/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease were to receive CRT as per protocol (PF/CRT).
Patients in both treatment arms were to receive 7 weeks of CRT following induction chemotherapy with a minimum interval of 3 weeks and no later than 8 weeks after start of the last cycle (day 22 to day 56 of 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. All patients on the docetaxel-containing arm of the study received prophylactic antibiotics. The primary efficacy endpoint in this study, overall survival (OS) was significantly longer (log-rank test, p = 0.0058) with the docetaxel-containing regimen compared to PF (median OS: 70.6 versus 30.1 months respectively), with a 30% risk reduction in mortality compared to PF (hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54-0.90) with an overall median follow up time of 41.9 months. The secondary endpoint, PFS, demonstrated a 29% risk reduction of progression or death and a 22 month improvement in median PFS (35.5 months for TPF and 13.1 for PF).
This was also statistically significant with an HR of 0.71; 95% CI 0.56-0.90; log-rank test p = 0.004. Efficacy results are presented in the table below:

Efficacy of docetaxel in the induction treatment of patients with locally advanced SCCHN (Intent-to-Treat Analysis)
Endpoint                                      Docetaxel + Cis + 5-FU          Cis + 5-FU n = 255                   n = 246
Median overall survival (months) (95% CI)         70.6  (49.0-NA)           30.1 (20.9-51.5) Hazard ratio: (95% CI)                                         0.70 (0.54-0.90) *p-value                                                           0.0058 Median PFS (months) (95% CI)                      35.5 (19.3-NA)           13.1 (10.6 - 20.2) Hazard ratio: (95% CI)                                        0.71 (0.56 - 0.90) **p-value                                                           0.004 Best overall response (CR + PR) to                71.8 (65.8-77.2)          64.2 (57.9-70.2) chemotherapy (%) (95% CI)
***p-value                                                          0.070 Best overall response (CR + PR) to study          76.5 (70.8-81.5)          71.5 (65.5-77.1) treatment [chemotherapy +/- chemoradiotherapy] (%) (95%CI)
***p-value                                                          0.209 A Hazard ratio of less than 1 favors docetaxel + cisplatin + fluorouracil *un-adjusted log-rank test
**un-adjusted log-rank test, not adjusted for multiple comparisons
***Chi square test, not adjusted for multiple comparisons
NA-not applicable

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with docetaxel in all subsets of the paediatric population in breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma and head and neck cancer, not including type II and III less differentiated nasopharyngeal carcinoma (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2 Pharmacokinetic Properties

Absorption: The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20-115 mg/m2 in Phase I studies. The kinetic profile of docetaxel is dose independent and 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 h, respectively. The late phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment.

Distribution: Following the administration of a 100 mg/m2 dose given as a one-hour infusion a mean peak plasma level of 3.7 μg/ml was obtained with a corresponding AUC of 4.6 h.μg/ml. Mean values for total body clearance and steady-state volume of distribution were 21 l/h/m2 and 113 l, respectively. Inter individual variation in total body clearance was approximately 50%. Docetaxel is more than 95% bound to plasma proteins.

Elimination: A study of 14C-docetaxel has been conducted in three cancer patients. Docetaxel was eliminated in both the urine and faeces following cytochrome P450-mediated oxidative metabolism of the tert-butyl ester group, within seven days, the urinary and faecal excretion accounted for about 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in faeces is excreted during the first 48 hours as one major inactive metabolite and 3 minor inactive metabolites and very low amounts of unchanged drug.

Special population
Age and gender: A population pharmacokinetic analysis has been performed with docetaxel in 577 patients. Pharmacokinetic parameters estimated by the model were very close to those estimated from Phase I studies. The pharmacokinetics of docetaxel were not altered by the age or sex of the patient.
Hepatic impairment: In a small number of patients (n=23) with clinical chemistry data suggestive of mild to moderate liver function impairment (ALT, AST ≥1.5 times the ULN associated with alkaline phosphatase ≥2.5 times the ULN), total clearance was lowered by 27% on average (see section 4.2).
Fluid retention: Docetaxel clearance was not modified in patients with mild to moderate fluid retention and there are no data available in patients with severe fluid retention.

Combination therapy
Doxorubicin: When used in combination, docetaxel does not influence the clearance of doxorubicin and the plasma levels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their co-administration.
Capecitabine: Phase I study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel (Cmax and AUC) and no effect by docetaxel on the pharmacokinetics of a relevant capecitabine metabolite 5’-DFUR.
Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to that observed following monotherapy. The pharmacokinetic profile of cisplatin administered shortly after Docetaxel infusion is similar to that observed with cisplatin alone.
Cisplatin and 5-fluorouracil: The combined administration of docetaxel, cisplatin and 5- fluorouracil in 12 patients with solid tumours had no influence on the pharmacokinetics of each individual drug.
Prednisone and dexamethasone: The effect of prednisone on the pharmacokinetics of docetaxel administered with standard dexamethasone premedication has been studied in 42 patients.
Prednisone: No effect of prednisone on the pharmacokinetics of docetaxel was observed.