icin: Concentrations of paclitaxel and doxorubicin and their major metabolites (i.e.,6-α hydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively) were not altered in the presenceof trastuzumab when used as combination therapy in clinical trials. Trastuzumab concentrations were notaltered as part of this combination therapy.
Docetaxel and carboplatin: When trastuzumab was administered in combination with docetaxel orcarboplatin, neither the plasma concentrations of docetaxel or carboplatin nor the plasma concentrations oftrastuzumab were altered.
Cisplatin and capecitabine: In a drug interaction substudy conducted in patients in Study 7, thepharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered incombination 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 Amesbacterial and human peripheral blood lymphocyte mutagenicity assays, at concentrations of up to5000 mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bonemarrow cells was observed following 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,as measured 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 HER2overexpressing breast cancer were eva luated in an integrated analysis of two randomized, open-label,clinical trials (Studies 1 and 2) with a total of 4063 women at the protocol-specified final overall survivalanalysis, a third randomized, open-label, clinical trial (Study 3) with a total of 3386 women at definitiveDisease-Free Survival analysis for one-year trastuzumab treatment versus observation, and a fourthrandomized, open-label clinical trial with a total 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) orgene amplification (by FISH). HER2 testing was verified by a central laboratory prior to randomization(Study 2) or was required to be performed at a reference laboratory (Study 1). Patients with a history ofactive cardiac disease based on symptoms, abnormal electrocardiographic, radiologic, or left ventricularejection 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 wasadministered at 4 mg/kg on the day of initiation of paclitaxel and then at a dose of 2 mg/kg weekly for a total of 52 weeks. Trastuzumab treatment was pe |
