Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.
In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m2 /day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.
A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes’ C colon cancer (X-ACT) provided data concerning the use of capecitabine for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving capecitabine to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with capecitabine 1250 mg/m2 orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks) or IV bolus 5-FU 425 mg/m2 and 20 mg/m2 IV leucovorin on days 1 to 5, given as 4-week cycles for a total of 6 cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes’ stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5×109 /L, platelets ≥ 100×109 /L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of randomization.
The baseline demographics for capecitabine and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.
|Capecitabine (n=1004)||5-FU/LV (n=983)|
|Age (median, years) Range||62(25-80)||63(22-82)|
|Gender Male (n, %) Female (n, %)||542 (54)461 (46)||532 (54)451 (46)|
|ECOG PS 0 (n, %) 1 (n, %)||849 (85)152 (15)||830 (85)147 (15)|
|Staging – Primary Tumor PT1 (n, %) PT2 (n, %) PT3 (n, %) PT4 (n, %) Other (n, %)||12 (1)90 (9)763 (76)138 (14)1 (0.1)||6 (0.6)92 (9)746 (76)139 (14)0 (0)|
|Staging – Lymph Node pN1 (n, %) pN2 (n, %) Other (n, %)||695 (69)305 (30)4 (0.4)||694 (71)288 (29)1 (0.1)|
All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m2 orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline [see Dosage and Administration (2.4)]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for capecitabine included dose reductions, cycle delays and treatment interruptions (see Table 11).
|Capecitabine N = 995||5-FU/LV N = 974|
|Median relative dose intensity (%)||93||92|
|Patients completing full course of treatment (%)||83||87|
|Patients with treatment interruption (%)||15||5|
|Patients with cycle delay (%)||46||29|
|Patients with dose reduction (%)||42||44|
|Patients with treatment interruption, cycle delay, or dose reduction (%)||57||52|
The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for capecitabine compared to 5-FU/LV was 0.88 (95% C.I. 0.77 – 1.01) (see Table 12 and Figure 1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, capecitabine was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for capecitabine compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 – 1.01). The 5-year overall survival rates were 71.4% for capecitabine and 68.4% for 5-FU/LV (see Figure 2).
a Approximately 93.4% had 5-year DFS information
b Based on Kaplan-Meier estimates
c Test of superiority of capecitabine vs 5-FU/LV (Wald chi-square test)
|All Randomized Population||Capecitabine (n=1004)||5-FU/LV (n=983)|
|Median follow-up (months)||83||83|
|5-year Disease-free Survival Rates (%)b||59.1||54.6|
|Hazard Ratio (capecitabine /5-FU/LV) (95% C.I. for Hazard Ratio) p-valuec||0.88 (0.77 -1.01) p = 0.068|
Figure 1 Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population)a
a Capecitabine has been demonstrated to be non-inferior to 5-FU/LV.
Figure 2 Kaplan-Meier Estimates of Overall Survival (All Randomized Population)
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).
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