Paclitaxel (Page 2 of 15)

CLINICAL STUDIES

Ovarian Carcinoma

First-Line Data

The safety and efficacy of paclitaxel followed by cisplatin in patients with advanced ovarian cancer and no prior chemotherapy were evaluated in 2, Phase 3 multicenter, randomized, controlled trials. In an Intergroup study led by the European Organization for Research and Treatment of Cancer involving the Scandinavian Group NOCOVA, the National Cancer Institute of Canada, and the Scottish Group, 680 patients with Stage IIB-C, III, or IV disease (optimally or non-optimally debulked) received either paclitaxel 175 mg/m2 infused over 3 hours followed by cisplatin 75 mg/m2 (Tc) or cyclophosphamide 750 mg/m2 followed by cisplatin 75 mg/m2 (Cc) for a median of 6 courses. Although the protocol allowed further therapy, only 15% received both drugs for 9 or more courses. In a study conducted by the Gynecological Oncology Group (GOG), 410 patients with Stage III or IV disease (>1 cm residual disease after staging laparotomy or distant metastases) received either paclitaxel 135 mg/m2 infused over 24 hours followed by cisplatin 75 mg/m2 or cyclophosphamide 750 mg/m2 followed by cisplatin 75 mg/m2 for 6 courses.

In both studies, patients treated with paclitaxel in combination with cisplatin had significantly higher response rate, longer time to progression, and longer survival time compared with standard therapy. These differences were also significant for the subset of patients in the Intergroup study with non-optimally debulked disease, although the study was not fully powered for subset analyses (Tables 2A and 2B). Kaplan-Meier survival curves for each study are shown in Figures 1 and 2.

Table 2A. Efficacy in the Phase 3 First-Line Ovarian Carcinoma Studies

a Paclitaxel dose in mg/m2 /infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.

b Among patients with measurable disease only.

c Unstratified for the Intergroup Study, Stratified for Study GOG-111.

Intergroup (non-optimally debulked subset) GOG-111
T175/3 a c75 (n=218) C750 a c75 (n=227) T135/24 a c75 (n=196) C750 a c75 (n=214)
• Clinical Response b (n=153)(n=153)(n=113)(n=127)
— rate (percent) 58 43 62 48
— p-valuec 0.016 0.04
• Time to Progression
— median (months)13.2 9.9 16.6 13.0
— p-valuec 0.00600.0008
— hazard ratio (HR)c 0.760.70
— 95% CIc 0.62-0.92 0.56-0.86
• Survival
— median (months) 29.5 21.9 35.5 24.2
— p-valuec 0.0057 0.0002
— hazard ratio (HR)c 73 0.64
— 95% CIc 0.58-0.91 0.50-0.81
Table 2B. Efficacy in the Phase 3 First-Line Ovarian Carcinoma Intergroup Study

a Paclitaxel dose in mg/m2 /infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.

b Among patients with measurable disease only.

c Unstratified.

T175/3 a c75 (n=342) C750 a c75 (n=338)
• Clinical Response b (n=162) (n=161)
— rate (percent) 59 45
— p-valuec 0.014
• Time to Progression
— median (months) 15.3 11.5
— p-valuec 0.0005
— hazard ratio (HR)c 0.74
— 95% CIc 0.63–0.88
• Survival
— median (months) 35.6 25.9
— p-valuec 0.0016
— hazard ratio (HR)c 0.73
— 95% CIc 0.60–0.89

Figure 1. Survival: Cc Versus Tc (Intergroup)

Figure 1
(click image for full-size original)

Figure 2. Survival: Cc Versus Tc (GOG-111)

Figure 2
(click image for full-size original)

The adverse event profile for patients receiving paclitaxel in combination with cisplatin in these studies was qualitatively consistent with that seen for the pooled analysis of data from 812 patients treated with single-agent paclitaxel in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line ovarian carcinoma studies are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 11) and narrative form.

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