LETROZOLE (Page 8 of 12)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma AUC0 12h r levels in mice at 60 mg/kg/day were 55 times higher than the AUC0 24 h r level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC0 -2 4h r levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose. The benign ovarian stromal tumors observed in mice and rats were considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone resulting from the decrease in circulating estrogen.

Letrozole Tablets was not mutagenic in in v itro tests (Ames and E.coli bacterial tests) but was observed to be a potential clastogen in in v itro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in v i v o (micronucleus test in rats).

Studies to investigate the effect of letrozole on fertility have not been conducted; however, repeated dosing caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (about one, 0.4 and 0.4 the daily maximum recommended human dose on a mg/m2 basis, respectively). Oral administration of Letrozole Tablet to female rats starting 2 weeks before mating until pregnancy day 6 resulted in decreases in the incidence of successful mating and pregnancy at equal to or greater than 0.03 mg/kg/day (approximately 0.1 times the recommended human dose on a mg/m2 basis). An increase in pre-implantation loss was observed at doses equal to or greater than 0.003 mg/kg/day (approximately 0.01 times the recommended human dose on a mg/m2 basis).

Letrozole administered to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage, resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis at exposures less than exposure anticipated at the clinical dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures.

13.2 Animal Toxicology and/or Pharmacology

ReproductiveToxicology:Reproduction studies in rats at letrozole doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that letrozole is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, increased postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic in rats. A 0.03 mg/kg dose (about 1/10 the daily maximum recommended human dose on a mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion.

Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily maximum recommended human dose on a mg/m2 basis, respectively). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.

14 CLINICAL STUDIES

Figure 1 Disease-Free Survival (Median follow-up 73 months, ITT Approach)Figure 2 Kaplan-Meier Estimates of Time to Progression (Tamoxifen Study)Figure 3 Survival by Randomized Treatment ArmFigure 4 Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study)Figure 5 Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study)

14.1 Updated Adjuvant Treatment of Early Breast Cancer

In a multicenter study enrolling over 8,000 postmenopausal women with resected, receptor-positive early
breast cancer, one of the following treatments was randomized in a double-blind manner:
Option 1:
A. tamoxifen for 5 years
B. Letrozole Tablets, USP for 5 years
C. tamoxifen for 2 years followed by Letrozole Tablets ,USP for 3 years
D. Letrozole Tablets, USP for 2 years followed by tamoxifen for 3 years
Option 2:
A. tamoxifen for 5 yearsB. Letrozole Tablets USP, for 5 years

The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether Letrozole Tablets for 5 years was superior to tamoxifen for 5 years (Primary Core Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 5. The primary endpoint of this trial was disease-free survival (DFS) (i.e., interval between randomization and earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast cancer, or death from any cause). The secondary endpoints were overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, time to breast cancer recurrence (TBR) and time to distant metastasis (TDM).

The Primary Core Analysis (PCA) included all patients and all follow-up in the monotherapy arms in both randomization options, but follow-up in the two sequential treatments arms was truncated 30 days after switching treatments. The PCA was conducted at a median treatment duration of 24 months and a median follow-up of 26 months. Letrozole Tablets was superior to tamoxifen in all endpoints except overall survival and contralateral breast cancer [e.g., DFS: hazard ratio, HR 0.79; 95% CI (0.68, 0.92); P =0.002; SDFS: HR 0.83; 95% CI (0.70, 0.97); TDM: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06).

In 2005, based on recommendations by the independent Data Monitoring Committee, the tamoxifen arms were unblinded and patients were allowed to complete initial adjuvant therapy with Letrozole Tablets (if they had received tamoxifen for at least 2 years) or to start extended adjuvant treatment with Letrozole Tablets (if they had received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients crossed to Letrozole Tablets or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to Letrozole Tablets to complete initial adjuvant therapy and most of these crossed in years 3 to 4. All of these patients were in Option 1. A total of 184 patients started extended adjuvant therapy with Letrozole Tablets (172 patients) or with another aromatase inhibitor (12 patients). To explore the impact of this selective crossover, results from analyses censoring follow-up at the date of the selective crossover (in the tamoxifen arm) are presented for the Monotherapy Arms Analysis (MAA).

The PCA allowed the results of Letrozole Tablets for 5 years compared with tamoxifen for 5 years to be reported in 2005 after a median follow-up of only 26 months. The design of the PCA is not optimal to evaluate the effect of Letrozole Tablets after a longer time (because follow-up was truncated in two arms at around 25 months). The Monotherapy Arms Analysis (ignoring the two sequential treatment arms) provided follow-up equally as long in each treatment and did not over-emphasize early recurrences as the PCA did. The MAA thus provides the clinically appropriate updated efficacy results in answer to the first primary question, despite the confounding of the tamoxifen reference arm by the selective crossover to Letrozole Tablets. The updated results for the MAA are summarized in Table 6. Median follow-up for this analysis is 73 months.

The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary analysis for the Sequential Treatments Analysis (STA) was from switch (or equivalent time-point in monotherapy arms) + 30 days (STA-S) with a twsided test applied to each pair-wise comparison at the 2.5% level. Additional analyses were conducted from randomization (STA-R) but these comparisons (added in light of changing medical practice) were under-powered for efficacy.

Table 5: Adjuvant Study — Patient and Disease Characteristics (ITT Population)
Primary Core Analysis (PCA) Monotherapy Arms Analysis (MAA)
Characteristic Letrozole tablets N=4003 n (%) tamoxifen N=4007 n (%) letrozole tablets USP N=2463 n (%) tamoxifen N=2459 n (%)
Age (median, years) 61 61 61 61
Age range (years) 38-89 39-90 38-88 39-90
Hormone receptor status (%)
ER+ and/or PgR+ 99.7 99.7 99.7 99.7
Both unknown 0.3 0.3 0.3 0.3
Nodal status (%)
Node negative 52 52 50 52
Node positive 41 41 43 41
Nodal status unknown 7 7 7 7
Prior adjuvant chemotherapy (%) 24 24 24 24
Table 6: Updated Adjuvant Study –Monoherapy Arms Analysis (Median Follow-up 73 Months)
Letrozole Tablets USP N=2463 T amoxifen N=2459 Hazard ratio
Events (%) 5-year rate Events (%) 5-year R ate (95% CI) P
Disease-freesurvival1 ITT 445 (18.1) 87.4 500 (20.3) 84.7 0.87 (0.76, 0.99) 0.033
Censor 445 87.4 483 84.2 0.84 (0.73, 0.95)
0 positive nodes ITT 165 92.2 189 90.3 0.88 (0.72, 1.09)
1-3 positive nodes ITT 151 85.6 163 83.0 0.85 (0.68, 1.06)
>=4 positive nodes ITT 123 71.2 142 62.6 0.81 (0.64, 1.03)
Adjuvant chemotherapy ITT 119 86.4 150 80.6 0.77 (0.60, 0.98)
No chemotherapy ITT 326 87.8 350 86.1 0.91 (0.78, 1.06)
Systemic DFS2 ITT 401 88.5 446 86.6 0.88 (0.77, 1.01)
Time to distant metastasis3 ITT 257 92.4 298 90.1 0.85 (0.72, 1.00)
Adjuvantchemotherapy ITT 84 109 0.75 (0.56, 1.00)
No chemotherapy ITT 173 189 0.90 (0.73, 1.11)
Distant DFS4 ITT 385 89.0 432 87.1 0.87 (0.76, 1.00)
Contralateral breast cancer ITT 34 99.2 44 98.6 0.76 (0.49, 1.19)
Overall survival ITT 303 91.8 343 90.9 0.87 (0.75, 1.02)
Censor 303 91.8 338 90.1 0.82 (0.70, 0.96)
0 positive nodes ITT 107 95.2 121 94.8 0.90 (0.69, 1.16)
1-3 positive nodes ITT 99 90.8 114 90.6 0.81 (0.62, 1.06)
>=4 positive nodes ITT 92 80.2 104 73.6 0.86 (0.65, 1.14)
Adjuvant chemotherapy ITT 76 91.5 96 88.4 0.79 (0.58, 1.06)
No chemotherapy ITT 227 91.9 247 91.8 0.91 (0.76, 1.08)

Definition of:
1 Disease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event
2 Systemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event
3 Time to distant metastasis: Interval from randomization to distant metastasis
4 Distant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause
ITT analysis ignores selective crossover in tamoxifen arms
Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed toLetrozole Tablets or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005

Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis

Figure 1 Disease-Free Survival (Median follow-up 73 months, ITT Approach)
(click image for full-size original)

Figure 1 Disease-Free Survival (Median follow-up 73 months, ITT Approach)

DFS events defined as loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death from any cause (i.e., definition excludes second non-breast primary cancers).

The medians of overall survival for both arms were not reached for the Monotherapy Arms Analysis (MAA). There was no statistically significant difference in overall survival. The hazard ratio for survival in the Letrozole Tablets arm compared to the tamoxifen arm was 0.87, with 95% CI (0.75, 1.02) (see Table 6).

There were no significant differences in DFS, OS, SDFS, and Distant DFS from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g., [Tamoxifen 2 years followed by] Letrozole Tablets 3 years versus tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [Letrozole Tablets 2 years followed by] tamoxifen 3 years versus Letrozole Tablets beyond 2 years, DFS HR 0.93; 97.5% CI 0.71, 1.22).

There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential Treatments Analyses.

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