Epirubicin Hydrochloride (Page 7 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Conventional long-term animal studies to evaluate the carcinogenic potential of epirubicin have not been conducted, but intravenous administration of a single 3.6 mg/kg epirubicin dose to female rats (about 0.2 times the maximum recommended human dose on a body surface area basis) approximately doubled the incidence of mammary tumors (primarily fibroadenomas) observed at 1 year. Administration of 0.5 mg/kg epirubicin intravenously to rats (about 0.025 times the maximum recommended human dose on a body surface area basis) every 3 weeks for ten doses increased the incidence of subcutaneous fibromas in males over an 18-month observation period. In addition, subcutaneous administration of 0.75 or 1.0 mg/kg/day (about 0.015 times the maximum recommended human dose on a body surface area basis) to newborn rats for 4 days on both the first and tenth day after birth for a total of eight doses increased the incidence of animals with tumors compared to controls during a 24-month observation period.

Epirubicin was mutagenic in vitro to bacteria (Ames test) either in the presence or absence of metabolic activation and to mammalian cells (HGPRT assay in V79 Chinese hamster lung fibroblasts) in the absence but not in the presence of metabolic activation. Epirubicin was clastogenic in vitro (chromosome aberrations in human lymphocytes) both in the presence and absence of metabolic activation and was also clastogenic in vivo (chromosome aberration in mouse bone marrow).

In fertility studies in rats, males were given epirubicin daily for 9 weeks and mated with females that were given epirubicin daily for 2 weeks prior to mating and through Day 7 of gestation. When 0.3 mg/kg/day (about 0.015 times the maximum recommended human single dose on a body surface area basis) was administered to both sexes, no pregnancies resulted. No effects on mating behavior or fertility were observed at 0.1 mg/kg/day, but male rats had atrophy of the testes and epididymis, and reduced spermatogenesis. The 0.1 mg/kg/day dose also caused embryolethality. An increased incidence of fetal growth retardation was observed in these studies at 0.03 mg/kg/day (about 0.0015 times the maximum recommended human single dose on a body surface area basis). Multiple daily doses of epirubicin to rabbits and dogs also caused atrophy of male reproductive organs. Single 20.5 and 12 mg/kg doses of intravenous epirubicin caused testicular atrophy in mice and rats, respectively (both approximately 0.5 times the maximum recommended human dose on a body surface area basis). A single dose of 16.7 mg/kg epirubicin caused uterine atrophy in rats.

14 CLINICAL STUDIES

14.1 Adjuvant Treatment of Breast Cancer

Two randomized, open-label, multicenter studies evaluated the use of epirubicin hydrochloride injection 100 to 120 mg/m2 in combination with cyclophosphamide and fluorouracil for the adjuvant treatment of patients with axillary-node positive breast cancer and no evidence of distant metastatic disease (Stage II or III). Study MA-5 evaluated 120 mg/m2 of epirubicin hydrochloride injection per course in combination with cyclophosphamide and fluorouracil (CEF-120 regimen). This study randomized premenopausal and perimenopausal women with one or more positive lymph nodes to an epirubicin hydrochloride injection-containing CEF-120 regimen or to a CMF regimen. Study GFEA-05 evaluated the use of 100 mg/m2 of epirubicin hydrochloride injection per course in combination with fluorouracil and cyclophosphamide (FEC-100). This study randomized pre- and postmenopausal women to the FEC-100 regimen or to a lower-dose FEC-50 regimen. In the GFEA-05 study, eligible patients were either required to have greater than or equal to 4 nodes involved with tumor or, if only 1 to 3 nodes were positive, to have negative estrogen- and progesterone-receptors and a histologic tumor grade of 2 or 3. A total of 1281 women participated in these studies. Patients with T4 tumors were not eligible for either study. Table 5 shows the treatment regimens that the patients received. Relapse-free survival was defined as time to occurrence of a local, regional, or distant recurrence, or disease-related death. Patients with contralateral breast cancer, second primary malignancy, or death from causes other than breast cancer were censored at the time of the last visit prior to these events.

Table 5. Treatment Regimens Used in Phase 3 Studies of Patients with Early Breast Cancer
Treatment Groups Agent Regimen
a In women who underwent lumpectomy, breast irradiation was to be administered after completion of study chemotherapy.
b Patients also received prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole or fluoroquinolone for the duration of their chemotherapy.
c All women were to receive breast irradiation after the completion of chemotherapy.
MA-5a CEF-120 (total, 6 cycles)b N=356 Cyclophosphamide 75 mg/m2 PO, d 1 to 14, q 28 days
N=716 Epirubicin Hydrochloride Injection 60 mg/m2 IV, d 1 & 8, q 28 days
CMF (total, 6 cycles) N=360 Fluorouracil 500 mg/m2 IV, d 1 & 8, q 28 days
Cyclophosphamide 100 mg/m2 PO, d 1 to 14, q 28 days
Methotrexate 40 mg/m2 IV, d 1 & 8, q 28 days
Fluorouracil 600 mg/m2 IV, d 1 & 8, q 28 days
GFEA-05c FEC-100 (total, 6 cycles) Fluorouracil 500 mg/m2 IV, d 1, q 21 days
N=565 N=276 Epirubicin Hydrochloride Injection 100 mg/m2 IV, d 1, q 21 days
Cyclophosphamide 500 mg/m2 IV, d 1, q 21 days
FEC-50 (total, 6 cycles) Fluorouracil 500 mg/m2 IV, d 1, q 21 days
N=289 Epirubicin Hydrochloride Injection 50 mg/m2 IV, d 1, q 21 days
Tamoxifen 30 mg daily x Cyclophosphamide 500 mg/m2 IV, d 1, q 21 days
3 years, postmenopausal
women, any receptor status

In the MA-5 trial, the median age of the study population was 45 years. Approximately 60% of patients had 1 to 3 involved nodes and approximately 40% had greater than or equal to 4 nodes involved with tumor. In the GFEA-05 study, the median age was 51 years and approximately half of the patients were postmenopausal. About 17% of the study population had 1 to 3 positive nodes and 80% of patients had greater than or equal to 4 involved lymph nodes. Demographic and tumor characteristics were well-balanced between treatment arms in each study.

Relapse-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier methods in the intent-to-treat (ITT) patient populations in each study. Results were initially analyzed after up to 5 years of follow-up and these results are presented in the text below and in Table 6. Results after up to 10 years of follow-up are presented in Table 6. In Study MA-5, epirubicin hydrochloride injection-containing combination therapy (CEF-120) showed significantly longer RFS than CMF (5-year estimates were 62% versus 53%, stratified logrank for the overall RFS p=0.013). The estimated reduction in the risk of relapse was 24% at 5 years. The OS was also greater for the epirubicin hydrochloride injection-containing CEF-120 regimen than for the CMF regimen (5-year estimate 77% versus 70%; stratified logrank for overall survival p=0.043; non-stratified logrank p=0.13). The estimated reduction in the risk of death was 29% at 5 years.

In Study GFEA-05, patients treated with the higher-dose epirubicin hydrochloride injection regimen (FEC-100) had a significantly longer 5-year RFS (estimated 65% versus 52%, logrank for the overall RFS p=0.007) and OS (estimated 76% versus 65%, logrank for the overall survival p=0.007) than patients given the lower dose regimen (FEC-50). The estimated reduction in risk of relapse was 32% at 5 years. The estimated reduction in the risk of death was 31% at 5 years. Results of follow-up up to 10 years (median follow-up = 8.8 years and 8.3 years, respectively, for Study MA-5 and Study GFEA-05) are presented in Table 6.

Although the trials were not powered for subgroup analyses, in the MA-5 study, improvements in favor of CEF-120 vs. CMF were observed, in RFS and OS both in patients with 1-3 node positive and in those with greater than or equal to 4 node positive tumor involvement. In the GFEA-05 study, improvements in RFS and OS were observed in both pre- and postmenopausal women treated with FEC-100 compared to FEC-50.

Table 6. Efficacy Results from Phase 3 Studies of Patients with Early Breast Cancer*
MA-5 Study GFEA-05 Study
CEF-120 CMF FEC-100 FEC-50
N=356 N=360 N=276 N=289
*Based on Kaplan-Meier estimates
**Patients in MA-5 were stratified by nodal status (1 to 3, 4 to 10, and greater than 10 positive nodes), type of initial surgery (lumpectomy versus mastectomy), and by hormone receptor status (ER or PR positive (greater than or equal to10 fmol), both negative (less than 10 fmol), or unknown status). Patients in GFEA-05 were stratified by nodal status (1 to 3, 4 to 10, and greater than 10 positive nodes).
Hazard ratio: CMF:CEF-120 in MA-5, FEC-50:FEC-100 in GFEA-05
RFS at 5 yrs (%) 62 53 65 52
Hazard ratio 0.76 0.68
2-sided 95% CI (0.60, 0.96) (0.52, 0.89)
Logrank Test (p = 0.013) (p = 0.007)
stratified**
OS at 5 yrs (%) 77 70 76 65
Hazard ratio 0.71 0.69
2-sided 95% CI (0.52, 0.98) (0.51, 0.92)
Logrank Test (p = 0.043) (p = 0.007)
stratified** (unstratified p = 0.13)
RFS at 10 yrs (%) 51 44 49 43
Hazard ratio 0.78 0.78
2-sided 95% CI (0.63, 0.95) (0.62, 0.99)
Logrank Test (p = 0.017) (p = 0.040)
stratified** (unstratified p = 0.023) (unstratified p = 0.09)
OS at 10 yrs (%) 61 57 56 50
Hazard ratio 0.82 0.75
2-sided 95% CI (0.65, 1.04) (0.58, 0.96)
Logrank Test (p = 0.100) (p = 0.023)
stratified** (unstratified p = 0.18) (unstratified p = 0.039)

The Kaplan-Meier curves for RFS and OS from Study MA-5 are shown in Figures 3 and 4 and those for Study GFEA-05 are shown in Figures 5 and 6.

Figure 3. Relapse-Free Survival in Study MA-5

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Figure 4. Overall Survival in Study MA-5

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Figure 5. Relapse-Free Survival in Study GFEA-05

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Figure 6. Overall Survival in Study GFEA-05

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See Table 6 for statistics on 5 and 10 year analyses.

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