Capecitabine 150mg (Page 9 of 13)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

14 CLINICAL STUDIES

14.1 Adjuvant Colon Cancer

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.

Table 10 Baseline Demographics
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).

Table 11 Summary of Dose Modifications in X-ACT Study
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).

Table 12 Efficacy of Capecitabine vs 5-FU/LV in Adjuvant Treatment of Colon Cancera

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

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a Capecitabine has been demonstrated to be non-inferior to 5-FU/LV.

Figure 2 Kaplan-Meier Estimates of Overall Survival (All Randomized Population)

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