Title A Randomized, Multicenter, Open-Label Phase III Study To Evaluate The Efficacy And Safety Of Trastuzumab Emtansine Versus Trastuzumab As Adjuvant Therapy For Patients With Her2-Positive Primary Breast Cancer Who Have Residual Tumor Present Pathologically In The Breast Or Axillary Lymph Nodes Following Preoperative Therapy


CC 061310C

Hospital Fairview, Hillcrest, Main Campus

Phase Phase 3

Disease Breast

Drug Trastuzumab, Trastuzumab Emtansine



  • To compare invasive disease-free survival (IDFS, Section 3.4.1) in patients with residual invasive breast cancer after treatment with preoperative chemotherapy and HER2-directed therapy including trastuzumab followed by surgery between the 2 treatment arms
  • To compare IDFS including second non-breast cancers, DFS, OS, and distant recurrence-free interval (DRFI) between the 2 treatment arms
  • To compare cardiac safety and overall safety between the 2 treatment arms according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0
  • To compare PROs between the 2 treatment arms using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30) questionnaire and Quality of Life Questionnaire - Breast Cancer (QLQ-BR23) module
  • To characterize the PK of trastuzumab emtansine (including total trastuzumab and DM1) in trastuzumab emtansine treated patients
  • To characterize the PK of trastuzumab in trastuzumab-treated patients and permit an intra-study comparison of trastuzumab exposure in the 2 treatment arms
  • To investigate exposure�effect (efficacy and safety) relationships in this patient population
  • To assess correlations between biomarker status and efficacy and/or safety
  • To assess the incidence of anti-therapeutic antibodies (ATAs) and the effect of ATAs on PK, safety, and efficacy
Inclusion Criteria

Inclusion Criteria

Disease-Specific Inclusion Criteria
  1. HER2-positive breast cancer

    HER2-positive status will be based on pretreatment biopsy material and defined as an immunohistochemistry (IHC) (Appendix 6) score of 3+ and/or positive by in situ hybridization (ISH) (Appendix 7) prospectively confirmed by a central laboratory prior to study enrollment. ISH positivity is defined as a ratio of ≥ 2.0 for the number of HER2 gene copies to the number of signals for chromosome 17 copies. Formalin-fixed paraffin-embedded tumor tissue block or a partial block must be available for central evaluation of HER2 expression. If sites are unable to send a tissue block due to local regulations, at least 8 unstained slides should be sent for HER2 testing, and in addition up to 5 slides for exploratory biomarker research. A central laboratory will perform both IHC and ISH assays; however, only one positive result is required for eligibility. In the event that sufficient material from the pretreatment biopsy is not available for submission, central HER2 determination for eligibility may be performed on residual tumor tissue from the time of definitive surgery.

    Patients with synchronous bilateral invasive disease are eligible provided both lesions are HER2-positive.

  2. Histologically confirmed invasive breast carcinoma
  3. Clinical stage at presentation: T1-4, N0-3, M0 (Note: Patients with T1a/bN0 tumors will not be eligible)
  4. Completion of preoperative systemic chemotherapy and HER2-directed treatment. Systemic therapy must consist of at least 6 cycles of chemotherapy, with a total duration at least 16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of taxane-based chemotherapy. Patients may have received an anthracycline as part of preoperative therapy in addition to taxane chemotherapy.

    Patients receiving dose-dense chemotherapy regimens are eligible, provided at least 8 weeks of taxane-based therapy and at least 8 weeks of trastuzumab have been given.

    Patients may have received more than one HER2-directed therapy. Note: HER2-directed therapy alone periods will not satisfy the requirement for cycles of preoperative systemic chemotherapy.

    All systemic chemotherapy should be completed preoperatively.

  5. Adequate excision: surgical removal of all clinically evident disease in the breast and lymph nodes as follows:

    Breast surgery: total mastectomy with no gross residual disease at the margin of resection, or breast-conserving surgery with histologically negative margins of excision

    For patients who undergo breast-conserving surgery, the margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. Patients with margins positive for lobular carcinoma in situ (LCIS) are eligible without additional resection.

    Lymph node surgery:

    In case of positive results from a fine-needle aspiration, core biopsy, or sentinel node biopsy performed prior to preoperative therapy, additional surgical evaluation of the axilla following preoperative therapy is required.

    If only micrometastases are present in sentinel nodes preoperatively (i.e., if the greatest diameter of the nodal metastasis in a sentinel node is 0.2 mm or less), no additional surgical evaluation of the axilla is required.

    If sentinel node biopsy performed before preoperative therapy was negative, no additional surgery evaluation of the axilla is required after preoperative therapy.

    If the only sentinel node identified by isotope scan is in the internal mammary chain, surgical evaluation of the axilla is recommended.

    If sentinel node biopsy performed after preoperative therapy is positive, additional surgical evaluation of the axilla is recommended.

    If sentinel node evaluation after preoperativetherapy is negative, no further additional surgical evaluation of the axilla is required.

    Axillary dissection without sentinel node evaluation is permitted after preoperative therapy.

  6. Pathologic evidence of residual invasive carcinoma in the breast or axillary lymph nodes following completion of preoperative therapy. If invasive disease is present in both breasts, residual invasive carcinoma must be present in at least 1 breast or axillary lymph node postoperatively.
  7. An interval of no more than 12 weeks between the date of primary surgery and the date of randomization
  8. Known hormone receptor status

    Hormone receptor-positive status can be determined by either known positive ER or known positive PgR status; hormone receptor-negative status must be determined by both known negative ER and known negative PgR.

General Inclusion Criteria
  1. Signed written informed consent approved by the study site's Institutional Review Board (IRB)/Ethical Committee (EC)
  2. Age ≥ 18 years
  3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  4. Life expectancy ≥6 months
  5. Adequate organ function during screening, defined as:
    • Absolute neutrophil count ≥ 1200 cells/mm3
    • Platelet count ≥ 100000 cells/mm3
    • Hemoglobin ≥ 9.0 g/dL; patients may receive red blood cell transfusions to obtain this level
    • Serum creatinine < 1.5 x upper limit of normal (ULN)
    • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
    • Serum AST and ALT ≤ 1.5 x ULN
    • Serum total bilirubin (TBILI) ≤ 1.0 x ULN (within normal limits), except for patients with Gilbert�s syndrome, for whom direct bilirubin should be within the normal range
    • Serum alkaline phosphatase (ALK) ≤ 1.5 x ULN
    • Screening LVEF ≥ 50% on ECHO or MUGA and no decrease in LVEF by more than 15% absolute points from the pre-chemotherapy LVEF (pre-chemotherapy LVEF must be documented in the CRF)
      • LVEF assessment may be repeated once up to 3 weeks following the initial screening assessment to assess eligibility
  6. Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of nonhormonal contraception or 2 effective forms of nonhormonal contraception by the patient and/or partner and to continue its use for the duration of study treatment and for 6 months after the last dose of study treatment
    • Acceptable forms of effective contraception should include 2 of the following:
      1. Placement of non-hormonal intrauterine device (IUD)
      2. Condom with spermicidal foam/gel/film/cream/suppository
      3. Diaphragm or cervical/vault caps with spermicidal foam/film/cream/suppository
    • The above contraception is not a requirement in the case of any of the following:
      1. The male patient, or male partner of a female patient, is surgically sterilized.
      2. The female patient is > 45 years of age and is postmenopausal (has not menstruated for at least 12 consecutive months)
      3. The patient truly abstains from sexual activity and when this is the preferred and usual lifestyle of the patient.
    • Contraception use should continue for the duration of the study treatment and for at least 6 months after the last dose of study treatment. Periodic abstinence (e.g., calendar ovulation, symptothermal, and post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    • Male patients whose partners are pregnant must use condoms or truly refrain from sexual activity for the duration of the pregnancy.
  7. Negative serum pregnancy test for premenopausal women including women who have had a tubal ligation and for women less than 12 months after the onset of menopause
  8. Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is required: this includes HB surface antigen (HBsAg) and/or total HB core antibody (anti-HBc) in addition to HCV antibody testing. The most recent serologic testing must have occurred within 3 months prior to initiation of neoadjuvant therapy. If such testing has not been done, it must be performed during screening.
Exclusion Criteria

Exclusion Criteria

Disease-Related Exclusion Criteria
  1. Stage IV (metastatic) breast cancer
  2. History of any prior (ipsi- or contralateral) breast cancer except lobular CIS
  3. Evidence of clinically evident gross residual or recurrent disease following preoperative therapy and surgery
  4. An overall response of PD according to the investigator at the conclusion of preoperative systemic therapy
  5. Treatment with any anti-cancer investigational drug within 28 days prior to commencing study treatment
  6. History of other malignancy within the last 5 years except for appropriately treated CIS of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other non-breast malignancies with an outcome similar to those mentioned above
  7. Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons (e.g., connective tissue disorder or prior ipsilateral breast radiation)
  8. Current NCI CTCAE (Version 4.0) Grade ≥ 2 peripheral neuropathy
  9. History of exposure to the following cumulative doses of anthracyclines:
    • Doxorubicin > 240 mg/m2
    • Epirubicin > 480 mg/m2
    • For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m2
  10. Cardiopulmonary dysfunction as defined by any of the following:

    History of NCI CTCAE (Version 4.0) Grade ≥ 3 symptomatic CHF or NYHA criteria Class ≥ II

    Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease

    • High-risk uncontrolled arrhythmias: i.e., atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)

    Significant symptoms (Grade ≥ 2) relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia while or since receiving preoperative therapy.

    History of a decrease in LVEF to < 40% with prior trastuzumab treatment (e.g., during preoperative therapy)

    Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg)

    Evidence of transmural infarction on ECG

    Requirement for continuous oxygen therapy

  11. Prior treatment with trastuzumab emtansine
General Exclusion Criteria
  1. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound-healing disorders; ulcers)
  2. For female patients, current pregnancy and/or lactation
  3. Major surgical procedure unrelated to breast cancer or significant traumatic injury within approximately 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
  4. Any known active liver disease, for example, disease due to HBV, HCV, autoimmune hepatic disorders, or sclerosing cholangitis. Patients who have positive HBV or HCV serologies without known active disease must meet the eligibility criteria for ALT, AST, TBILI, INR, aPTT, and alkaline phosphatase (ALK) on at least two consecutive occasions, separated by at least 1 week, within the 30 day screening period.
  5. Concurrent, serious, uncontrolled infections or known infection with HIV
  6. History of intolerance, including Grade 3 to 4 infusion reaction or hypersensitivity to trastuzumab or murine proteins or any components of the product
  7. Active, unresolved infections at screening requiring treatment
  8. Assessment by the investigator as being unable or unwilling to comply with the requirements of the protocol