Data from five Phase 1 & 2 clinical studies (189 patients), a multicenter randomized Phase 3 study (407 patients), as well as an interim analysis of data from more than 300 patients enrolled in a treatment referral center program were used in support of the use of paclitaxel in patients who have failed initial or subsequent chemotherapy for metastatic carcinoma of the ovary. Two of the Phase 2 studies (92 patients) utilized an initial dose of 135 to 170 mg/m2 in most patients (>90%) administered over 24 hours by continuous infusion. Response rates in these two studies were 22% (95% CI: 11% to 37%) and 30% (95% CI: 18% to 46%) with a total of 6 complete and 18 partial responses in 92 patients. The median duration of overall response in these two studies measured from the first day of treatment was 7.2 months (range: 3.5 to 15.8 months) and 7.5 months (range: 5.3 to 17.4 months), respectively. The median survival was 8.1 months (range: 0.2 to 36.7 months) and 15.9 months (range: 1.8 to 34.5+ months).
The Phase 3 study had a bifactorial design and compared the efficacy and safety of paclitaxel, administered at two different doses (135 or 175 mg/m2 and schedules (3- or 24-hour infusion). The overall response rate for the 407 patients was 16.2% (95% CI: 12.8% to 20.2%), with 6 complete and 60 partial responses. Duration of response, measured from the first day of treatment was 8.3 months (range: 3.2 to 21.6 months). Median time to progression was 3.7 months (range: 0.1+ to 25.1+ months). Median survival was 11.5 months (range: 0.2 to 26.3+ months).
Response rates, median survival, and median time to progression for the 4 arms are given in the following table.
|175/3 (n=96)||175/24 (n=106)||135/3 (n=99)||135/24 (n=106)|
|— rate (percent)||14.6||21.7||15.2||13.2|
|— 95% Confidence Interval||(8.5-23.6)||(14.5-31.0)||(9.0-24.1)||(7.7-21.5)|
|• Time to Progression|
|— median (months)||4.4||4.2||3.4||2.8|
|— 95% Confidence Interval||(3.0-5.6)||(3.5-5.1)||(2.8-4.2)||(1.9-4.0)|
|— median (months)||11.5||11.8||13.1||10.7|
|— 95% Confidence Interval||(8.4-14.4)||(8.9-14.6)||(9.1-14.6)||(8.1-13.6)|
Analyses were performed as planned by the bifactorial study design described in the protocol, by comparing the two doses (135 or 175 mg/m2) irrespective of the schedule (3 or 24 hours) and the two schedules irrespective of dose. Patients receiving the 175 mg/m2 dose had a response rate similar to that for those receiving the 135 mg/m2 dose: 18% vs. 14% (p=0.28). No difference in response rate was detected when comparing the 3-hour with the 24-hour infusion: 15% vs. 17% (p=0.50). Patients receiving the 175 mg/m2 dose of paclitaxel had a longer time to progression than those receiving the 135 mg/m2 dose: median 4.2 vs. 3.1 months (p=0.03). The median time to progression for patients receiving the 3-hour vs. the 24-hour infusion was 4.0 months vs. 3.7 months, respectively. Median survival was 11.6 months in patients receiving the 175 mg/m2 dose of paclitaxel and 11.0 months in patients receiving the 135 mg/m2 dose (p=0.92). Median survival was 11.7 months for patients receiving the 3-hour infusion of paclitaxel and 11.2 months for patients receiving the 24-hour infusion (p=0.91). These statistical analyses should be viewed with caution because of the multiple comparisons made.
Paclitaxel remained active in patients who had developed resistance to platinum-containing therapy (defined as tumor progression while on, or tumor relapse within 6 months from completion of, a platinum-containing regimen) with response rates of 14% in the Phase 3 study and 31% in the Phase 1 & 2 clinical studies.
The adverse event profile in this Phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the Phase 3 second-line ovarian carcinoma study are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 12) and narrative form.
The results of this randomized study support the use of Paclitaxel Injection, USP at doses of 135 to 175 mg/m2 , administered by a 3-hour intravenous infusion. The same doses administered by 24-hour infusion were more toxic. However, the study had insufficient power to determine whether a particular dose and schedule produced superior efficacy.
A Phase 3 Intergroup study (Cancer and Leukemia Group B [CALGB], Eastern Cooperative Oncology Group [ECOG], North Central Cancer Treatment Group [NCCTG], and Southwest Oncology Group [SWOG]) randomized 3170 patients with node-positive breast carcinoma to adjuvant therapy with paclitaxel or to no further chemotherapy following 4 courses of doxorubicin and cyclophosphamide (AC). This multicenter trial was conducted in women with histologically positive lymph nodes following either a mastectomy or segmental mastectomy and nodal dissections. The 3 x 2 factorial study was designed to assess the efficacy and safety of 3 different dose levels of doxorubicin (A) and to evaluate the effect of the addition of paclitaxel administered following the completion of AC therapy. After stratification for the number of positive lymph nodes (1 to 3, 4 to 9, or 10+), patients were randomized to receive cyclophosphamide at a dose of 600 mg/m2 and doxorubicin at doses of either 60 mg/m2 (on day 1), 75 mg/m2 (in 2 divided doses on days 1 and 2), or 90 mg/m2 (in 2 divided doses on days 1 and 2 with prophylactic G-CSF support and ciprofloxacin) every 3 weeks for 4 courses and either paclitaxel 175 mg/m2 as a 3-hour infusion every 3 weeks for 4 additional courses or no additional chemotherapy. Patients whose tumors were positive were to receive subsequent tamoxifen treatment (20 mg daily for 5 years); patients who received segmental mastectomies prior to study were to receive breast irradiation after recovery from treatment-related toxicities.
At the time of the current analysis, median follow-up was 30.1 months. Of the 2066 patients who were hormone receptor positive, 93% received tamoxifen. The primary analyses of disease-free survival and overall survival used multivariate Cox models, which included paclitaxel administration, doxorubicin dose, number of positive lymph nodes, tumor size, menopausal status, and estrogen receptor status as factors. Based on the model for disease-free survival, patients receiving AC followed by paclitaxel had a 22% reduction in the risk of disease recurrence compared to patients randomized to AC alone (Hazard Ratio [HR]=0.78, 95% CI, 0.67 to 0.91, p=0.0022). They also had a 26% reduction in the risk of death (HR=0.74, 95% CI, 0.60 to 0.92, p=0.0065). For disease-free survival and overall survival, p-values were not adjusted for interim analyses. Kaplan-Meier curves are shown in Figures 3 and 4. Increasing the dose of doxorubicin higher than 60 mg/m2 had no effect on either disease-free survival or overall survival.
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