A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE)

This 2-arm, randomized, open-label study will evaluate the efficacy and safety of trastuzumab emtansine versus trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer who have residual tumor present in the breast or axillary lymph nodes following preoperative therapy. Eligible patients will be randomized to receive either trastuzumab emtansine 3.6 mg/kg or trastuzumab 6 mg/kg intravenously every 3 weeks for 14 cycles. Radiotherapy and/or hormone therapy will be given in addition if indicated.


Eligibility Criteria:
Inclusion Criteria:

* Adult patient, \>/= 18 years of age
* HER2-positive breast cancer
* Histologically confirmed invasive breast carcinoma
* Clinical stage T1-4/N0-3/M0 at presentation (patients with T1a/bN0 tumors will not be eligible)
* Completion of preoperative systemic chemotherapy and HER2-directed treatment consisting of at least 6 cycles of chemotherapy with a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of taxane-based therapy
* Adequate excision: surgical removal of all clinically evident disease in the breast and lymph nodes as specified in protocol
* Pathological evidence of residual invasive carcinoma in the breast or axillary lymph nodes following completion of preoperative therapy
* An interval of no more than 12 weeks between the date of surgery and the date of randomization
* Known hormone-receptor status
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Adequate hematologic, renal and liver function
* Screening Left ventricular ejection fraction (LVEF) \>/= 50% on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no decrease in LVEF by more than 15% absolute points from the pre-chemotherapy LVEF. Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be \>/= 55% after completion of neoadjuvant chemotherapy.
* For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 7 months after the last dose of study drug
* Documentation of hepatitis B virus and hepatitis C virus serology is required

Exclusion Criteria:

* Stage IV (metastatic) breast cancer
* History of any prior (ipsi- or contralateral breast cancer except lobular carcinoma in situ
* Evidence of clinically evident gross residual or recurrent disease following preoperative therapy and surgery
* Progressive disease during preoperative systemic therapy
* Treatment with any anti-cancer investigational drug within 28 days prior to commencing study treatment
* History of other malignancy within the last 5 years except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other non-breast malignancies with a similar outcome to those mentioned above
* Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons
* Current NCI CTCAE (Version 4.0) Grade \>/= 2 peripheral neuropathy
* History of exposure to the following cumulative doses of anthracyclines: Doxorubicin \> 240 mg/m2; Epirubicin or Liposomal Doxorubicin-Hydrochloride (Myocet®) \> 480 mg/m2; For other anthracyclines, exposure equivalent to doxorubicin \> 240 mg/m2
* Cardiopulmonary dysfunction as defined by protocol
* Prior treatment with trastuzumab emtansine
* Current severe, uncontrolled systemic disease
* Pregnant or lactating women
* Any known active liver disease, e.g. due to HBV, HCV, autoimmune hepatic disorders, or sclerosing cholangitis
* Concurrent serious uncontrolled infections requiring treatment or known infection with HIV
* History of intolerance, including Grade 3 to 4 infusion reaction or hypersensitivity to trastuzumab or murine proteins or any components of the product