Capecitabine (Page 10 of 12)

14.3 Breast Cancer

Capecitabine has been evaluated in clinical trials in combination with docetaxel (Taxotere® *) and as monotherapy.
In Combination With Docetaxel
The dose of capecitabine used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of capecitabine (14 days of treatment, followed by a 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m2 administered in 3-­week cycles of docetaxel in combination with 1250 mg/m2 twice daily for 14 days of capecitabine administered in 3-week cycles. The approved dose of 100 mg/m2 of docetaxel administered in 3-week cycles was the control arm of the phase 3 study.Capecitabine in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive capecitabine 1250 mg/m2 twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16.

Table 16 Baseline Demographics and Clinical Characteristics Capecitabine and Docetaxel Combination vs Docetaxel in Breast Cancer Trial
Capecitabine + Docetaxel (n=255)Docetaxel (n=256)
*
Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione
Age (median, years) 5251
Karnofsky PS (median) 9090
Site of Disease
Lymph nodes 121 (47%)125 (49%)
Liver 116 (45%)122 (48%)
Bone 107 (42%)119 (46%)
Lung 95 (37%)99 (39%)
Skin 73 (29%)73 (29%)
Prior Chemotherapy
Anthracycline *255 (100%)256 (100%)
5-FU 196 (77%)189 (74%)
Paclitaxel 25 (10%)22 (9%)
Resistance to an Anthracycline
No resistance 19 (7%)19 (7%)
Progression on anthracycline therapy 65 (26%)73 (29%)
Stable disease after 4 cycles of anthracycline therapy 41 (16%)40 (16%)
Relapsed within 2 years of completion of anthracycline-adjuvant therapy 78 (31%)74 (29%)
Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose 51 (20%)50 (20%)
No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease
0 89 (35%)80 (31%)
1 123 (48%)135 (53%)
2 43 (17%)39 (15%)
3 0 (0%)2 (1%)

Capecitabine in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17 , Figure 4 , and Figure 5.

Table 17 Efficacy of Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy Efficacy Parameter
*
The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm.
NA = Not Applicable
Combination Therapy Monotherapy p-value Hazard Ratio
Time to Disease Progression Median Days 95% C.I. 186(165 to 198)128(105 to 136)0.00010.643
Overall Survival Median Days 95% C.I. 442(375 to 497)352(298 to 387)0.01260.775
Response Rate *32%22%0.009NA

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MonotherapyThe antitumor activity of capecitabine as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the U.S. and Canada. A total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint was tumor response rate in patients with measurable disease, with response defined as a ≥50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month. Capecitabine was administered at a dose of 1255 mg/m2 twice daily for 2 weeks followed by a 1­-week rest period and given as 3-week cycles. The baseline demographics and clinical characteristics for all patients (n=162) and those with measurable disease (n=135) are shown in Table 18. Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen.

Table 18 Baseline Demographics and Clinical Characteristics Single-Arm Breast Cancer Trial
*
Lung, pleura, liver, peritoneum
Includes 2 patients treated with an anthracenedione.
Patients With Measurable Disease (n=135) All Patients (n=162)
Age (median, years) 5556
Karnofsky PS 9090
No. Disease Sites
1 to 2 43 (32%)60 (37%)
3 to 4 63 (46%)69 (43%)
>5 29 (22%)34 (21%)
Dominant Site of Disease
Visceral *101 (75%)110 (68%)
Soft Tissue 30 (22%)35 (22%)
Bone 4 (3%)17 (10%)
Prior Chemotherapy
Paclitaxel 135 (100%)162 (100%)
Anthracycline 122 (90%)147 (91%)
5-FU 110 (81%)133 (82%)
Resistance to Paclitaxel 103 (76%)124 (77%)
Resistance to an Anthracycline 55 (41%)67 (41%)
Resistance to both Paclitaxel and an Anthracycline 43 (32%)51 (31%)

Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.

Table 19 Response Rates in Doubly-Resistant Patients Single-Arm Breast Cancer Trial
*
Includes 2 patients treated with an anthracenedione
From date of first response
Resistance to Both Paclitaxel and an Anthracycline (n=43)
CR0
PR *11
CR + PR *11
Response Rate *(95% C.I.)25.6%(13.5, 41.2)
Duration of Response,*Median in days (Range)154 (63 to 233)

For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. The objective response rate in this population was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 18). The median time to progression was 90 days and the median survival was 306 days.

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