mbination with trastuzumab.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Trastuzumab products have not been tested for carcinogenic potential.No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterialand human peripheral blood lymphocyte mutagenicity assays at concentrations of up to 5000 mcg/mL. In an invivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observedfollowing bolus intravenous doses of up to 118 mg/kg of trastuzumab.
A fertility study was conducted in female cynomolgus monkeys at doses up to 25 times the weeklyrecommended human dose of 2 mg/kg of trastuzumab and has revealed no evidence of impaired fertility, asmeasured by menstrual cycle duration and female sex hormone levels.
14 CLINICAL STUDIES
14.1 Adjuvant Breast Cancer
The safety and efficacy of trastuzumab in women receiving adjuvant chemotherapy for HER2 overexpressingbreast cancer were eva luated in an integrated analysis of two randomized, open-label, clinical trials (Studies 1and 2) with a total of 4063 women at the protocol-specified final overall survival analysis, a third randomized,
open-label, clinical trial (Study 3) with a total of 3386 women at definitive Disease-Free Survival analysis forone-year trastuzumab treatment versus observation, and a fourth randomized, open-label clinical trial with atotal of 3222 patients (Study 4).
Studies 1 and 2
In Studies 1 and 2, breast tumor specimens were required to show HER2 overexpression (3+ by IHC) or geneamplification (by FISH). HER2 testing was verified by a central laboratory prior to randomization (Study 2) orwas required to be performed at a reference laboratory (Study 1). Patients with a history of active cardiac
disease based on symptoms, abnormal electrocardiographic, radiologic, or left ventricular ejection fraction findings or uncontrolled hypertension (diastolic > 100 mm Hg or systolic > 200 mm Hg) were not eligible.
Patients were randomized (1:1) to receive doxorubicin and cyclophosphamide followed by paclitaxel(AC→paclitaxel) alone or paclitaxel plus trastuzumab (AC→paclitaxel + trastuzumab). In both trials, patientsreceived four 21-day cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2
. Paclitaxel was
administered either weekly (80 mg/m2
) or every 3 weeks (175 mg/m2
) for a total of 12 weeks in Study 1;
paclitaxel was administered only by the weekly schedule in Study 2. Trastuzumab was administered at 4 mg/kgon the day of initiation of paclitaxel and then at a dose of 2 mg/kg weekly for a total of 52 weeks.
Trastuzumabtreatment was permanently discontinued in patients who developed congestive heart failure, orpersistent/recurrent LVEF decline [see Dosage and Administration (2.3)]. Radiation therapy, if administered,was initiated after the completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonaltherapy. The primary endpoint of the combined efficacy analysis was Disease-Free Survival (DFS), defined asthe time from randomization to recurrence, occurrence of contralateral breast cancer, other second primarycancer, or death. The secondary endpoint was overall survival (OS).
A total of 3752 patients were included in the joint efficacy analysis of the primary endpoint of DFS following amedian follow-up of 2.0 years in the AC→paclitaxel + trastuzumab arm. The pre-plan |
