The recommended dose of capecitabine was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m2 /day in two divided doses, n=39), intermittent therapy with capecitabine (2510 mg/m2 /day in two divided doses, n=34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m2 /day in two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting. There was no apparent advantage in response rate to adding leucovorin to capecitabine; however, toxicity was increased. Capecitabine, 1250 mg/m2 twice daily for 14 days followed by a 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied.
Data from two open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of capecitabine in the first-line treatment of patients with metastatic colorectal carcinoma. The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study 1 was conducted in the US, Canada, Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with capecitabine at a dose of 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5, every 28 days).
In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed. Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm. Survival was assessed based on a non-inferiority analysis.
The baseline demographics for capecitabine and 5-FU/LV patients are shown in Table 13.
|Study 1||Study 2|
|Age (median, years)||64||63||64||64|
|Male (%)||181 (60)||197 (65)||172 (57)||173 (57)|
|Female (%)||121 (40)||106 (35)||129 (43)||128 (43)|
|Karnofsky PS (median)||90||90||90||90|
|Colon (%)||222 (74)||232 (77)||199 (66)||196 (65)|
|Rectum (%)||79 (26)||70 (23)||101 (34)||105 (35)|
|Prior radiation therapy (%)||52 (17)||62 (21)||42 (14)||42 (14)|
|Prior adjuvant 5-FU (%)||84 (28)||110 (36)||56 (19)||41 (14)|
The efficacy endpoints for the two phase 3 trials are shown in Table 14 and Table 15.
|Capecitabine (n=302)||5-FU/LV (n=303)|
|Overall Response Rate (%, 95% C.I.)||21 (16-26)||11 (8-15)|
|Time to Progression (Median, days, 95% C.I.)||128 (120-136)||131 (105-153)|
|Hazard Ratio (capecitabine /5-FU/LV)95% C.I. for Hazard Ratio||0.99 (0.84-1.17)|
|Survival (Median, days, 95% C.I.)||380 (321-434)||407 (366-446)|
|Hazard Ratio (capecitabine /5-FU/LV)95% C.I. for Hazard Ratio||1.00 (0.84-1.18)|
|Capecitabine (n=301)||5-FU/LV (n=301)|
|Overall Response Rate (%, 95% C.I.)||21 (16-26)||14 (10-18)|
|Time to Progression (Median, days, 95% C.I.)||137 (128-165)||131 (102-156)|
|Hazard Ratio (capecitabine /5-FU/LV)95% C.I. for Hazard Ratio||0.97 (0.82-1.14)|
|Survival (Median, days, 95% C.I.)||404 (367-452)||369 (338-430)|
|Hazard Ratio (capecitabine /5-FU/LV)95% C.I. for Hazard Ratio||0.92 (0.78-1.09)|
Figure 3 Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies 1 and 2)
Capecitabine was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of capecitabine and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that capecitabine has a clinically meaningful survival effect, statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by capecitabine. The estimate of the survival effect of 5-FU/LV was derived from a meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies 1 and 2. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between 5-FU/LV and capecitabine, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out. It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study 2 and 10% for Study 1. The pooled result is consistent with a retention of at least 50% of the effect of 5-FU/LV. It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs capecitabine difference. These results do not exclude the possibility of true equivalence of capecitabine to 5-FU/LV (see Table 14 , Table 15 , and Figure 3).
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.
1 Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione
|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%)|
|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
|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.
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
|Efficacy Parameter||CombinationTherapy||Monotherapy||p-value||Hazard Ratio|
|Time to Disease Progression Median Days 95% C.I.||186(165-198)||128(105-136)||0.0001||0.643|
|Overall Survival Median Days 95% C.I.||442(375-497)||352(298-387)||0.0126||0.775|
Figure 4 Kaplan-Meier Estimates for Time to Disease Progression Capecitabine and Docetaxel vs Docetaxel
Figure 5 Kaplan-Meier Estimates of Survival Capecitabine and Docetaxel vs Docetaxel
The antitumor activity of capecitabine as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US 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.
1 Lung, pleura, liver, peritoneum
2 Includes 2 patients treated with an anthracenedione
|Patients With MeasurableDisease (n=135)||All Patients (n=162)|
|Age (median, years)||55||56|
|No. Disease Sites|
|1-2||43 (32%)||60 (37%)|
|3-4||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%)|
|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%)|
Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.
1 Includes 2 patients treated with an anthracenedione
2 From date of first response
|Resistance to Both Paclitaxel and an Anthracycline (n=43)|
|CR + PR1||11|
|Response Rate1 (95% C.I.)||25.6%(13.5, 41.2)|
|Duration of Response,1 Median in days2 (Range)||154(63-233)|
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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