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)
Condition: Breast Cancer
MeSH terms: Breast Neoplasms; Neoplasm, Residual
Intervention: trastuzumab; trastuzumab emtansine
Intervention description: 6 mg/kg intravenously every 3 weeks, 14 cycles; 3.6 mg/kg intravenously every 3 weeks, 14 cycles
Intervention MeSH terms: Trastuzumab; Ado-Trastuzumab Emtansine; Maytansine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1487.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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