Capecitabine (Page 12 of 14)

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)

Age (median, years)

52

51

Karnofsky PS (median)

90

90

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

Anthracycline1

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%)

1 Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione

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

Combination Therapy

Monotherapy

p-value

Hazard Ratio

Time to Disease Progression

Median Days

186

128

0.0001

0.643

95% C.I.

(165 to 198)

(105 to 136)

Overall Survival

Median Days

442

352

0.0126

0.775

95% C.I.

(375 to 497)

(298 to 387)

Response Rate1

32%

22%

0.009

NA2

1 The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm.

2 NA = Not Applicable

Figure 4 Kaplan-Meier Estimates for Time to Disease Progression Capecitabine and Docetaxel vs Docetaxel

Figure 4
(click image for full-size original)

Figure 5 Kaplan-Meier Estimates of Survival Capecitabine and Docetaxel vs Docetaxel

Figure 5
(click image for full-size original)

Monotherapy

The 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

Patients With Measurable Disease (n=135)

All Patients (n=162)

Age (median, years)

55

56

Karnofsky PS

90

90

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

Visceral1

101 (75%)

110 (68%)

Soft Tissue

30 (22%)

35 (22%)

Bone

4 (3%)

17 (10%)

Prior Chemotherapy

Paclitaxel

135 (100%)

162 (100%)

Anthracycline2

122 (90%)

147 (91%)

5-FU

110 (81%)

133 (82%)

Resistance to Paclitaxel

103 (76%)

124 (77%)

Resistance to an Anthracycline2

55 (41%)

67 (41%)

Resistance to both Paclitaxel and an Anthracycline2

43 (32%)

51 (31%)

1 Lung, pleura, liver, peritoneum

2 Includes 2 patients treated with an anthracenedione

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

Resistance to Both Paclitaxel and an Anthracycline(n=43)

CR

0

PR1

11

CR + PR1

11

Response Rate1

25.6%

(95% C.I.)

(13.5, 41.2)

Duration of Response,1

Median in days2

154

(Range)

(63 to 233)

1 Includes 2 patients treated with an anthracenedione

2 From date of first response

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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