Electronic Document Room Biostat Reviewer Doses, Survival FDA Electronic Document Room Biostat Reviewer Doses, Survival Tumor incidence Carcinogenicity study Study report – pdf (SEND?) Tumor data – xpt (SEND?) 13 week toxicity study Human PK study Study report – pdf (SDTM?) Sponsor Pharm/Tox Reviewer Tumor incidence with statistical significance Doses, Survival AUCs (animal and human) Result – labeling statement “The NOAEL for tumors in mice was 30 mg/kg or 15 times the exposure in humans at the maximum recommended human dose.” Clin Pharm Reviewer Human Drug Conc.

FDA Biostat-generated table NOAEL FDA Biostat-generated table Organ Tumor type Sex Quantity Control Low 10 mg/kg Mid 30 mg/kg High 100 mg/kg Mammary gland Adenocarcinoma F p-value of pairwise and trend tests <0.0001 .1407 .0632 Poly-3 adjusted incidence rate 51% 62% 66% 91% Observed number of cases 28 34 35 60 .

TK parameters from tox study report Male Female Analyte Dose (mg/kg) Cmax (ng/mL) AUC (ng∙h/mL) Parent 10 3782 21895 3656 24000 30 10729 54005 6759 61500 100 23265 295346 11350 183867 AUC at NOAEL PK parameter from Clin Pharm Review Human AUC at maximum recommended human dose = 4150 ng∙h/mL Animal to human AUC ratio at NOAEL = 61500 ng∙h/mL  4150 ng∙h/mL= 14.82 ≈ 15