ABCSG 32 Details

Multicentre, randomized phase-II-study of neoadjuvant trastuzumab plus docetaxel with and without bevacizumab and trastuzumab plus non-pegylated liposome-encapsulated doxorubicin (NPLD) with and without bevacizumab

Start:

2011

Contact ABCSG-Trial office

E-mail: info@abcsg.at
Phone: +43 1 408 92 30
Fax: +43 1 409 09 90

Design

ABCSG-32 Design
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Primary objectives:

  • To evaluate the cardiac toxicity of the combination trastuzumab and docetaxel with bevacizumab and trastuzumab, docetaxel, and NPLD plus/minus bevacizumab in comparison to the standard therapy, trastuzumab and docetaxel using a composite endpoint appearing between day 1 of cycle 1 and day 28 after the day of final surgery.

Secondary objectives:

Assessments of:

  • Pathological complete response (ypCR), defined as absence of invasive tumor at final surgery;
  • Total pathological complete response (ytpCR), defined as absence of invasive tumor and tumor cells in the breast and the axillar lymphnodes (ypT0 or yDCIS and ypN=0)
  • Overall clinical response rate (cORR), defined as the percentage of patients with either a complete clinical response (cCR) or a partial clinical response (cPR) but no ypCR.
  • Safety of the combination trastuzumab and docetaxel with bevacizumab and trastuzumab, docetaxel, and NPLD plus/minus bevacizumab

Inclusion criteria:

  1. Female or male, age ≥ 18 years
  2. Pathologically confirmed invasive primary breast adenocarcinoma (except inflammatory breast cancer, T4d) scheduled for taxan containing neoadjuvant systemic treatment with or without palpable lymph nodes
  3. Documented HER2 protein overexpression as determined by immunohistochemistry (IHC) 3+ or by demonstrated HER2/c-erbB2 gene amplification according to fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) of the primary tumor by a local laboratory
  4. LVEF ≥ 55% measured by echocardiography (biplane Simpson´s method) or multiple gated nuclear angiography (MUGA) within 4 weeks before randomization
  5. ECOG Performance Status ≤ 1
  6. Able and willing to comply with scheduled visits, treatmentplans, laboratory tests, and other study procedures
  7. Written Informed Consent, indicating that the patient has been informed of all the pertinent aspects of the trial prior to randomization

Exclusion criteria:

Current Treatment

  1. Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine
  2. Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone equivalent) excluding inhaled steroids
  3. Chronic daily treatment with aspirin and aspirin analogs (>325 mg/day) or clopidogrel (> 75 mg/day)
  4. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of the study treatment
  5. Current or recent (within 30 days prior to randomization) treatment with another investigational drug or participation in another investigational study

Laboratory

  1. Inadequate bone marrow function: absolute neutrophil count (ANC) < 1.5 x 109/L, platelet count < 100 x 109/L or hemoglobin (Hb) < 9 g/dL
  2. Inadequate liver function: serum (total) bilirubin > upper limit of normal (ULN), aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN, AST or ALT > 1.5 x ULN concurrent with serum alkaline phosphatase > 2.5 ULN
  3. Inadequate renal function: Serum creatinine > 177 μmol/L or 2.0 mg/dL. If urine dipstick for proteinuria is ≥ 2+ at baseline, the patient must undergo 24-hour urine collection and demonstrate ≤ 1 g of protein/24 hr
  4. Patients not receiving anticoagulant medication who have activated partial thromboplastin time (aPTT) > 1.5 x ULN within 7 days prior to Day1 of the cycle 1

    Note: Patients receiving full dose oral or parenteral anticoagulants may be included as long as anticoagulant dosing has been stable for at least 2 weeks prior to randomization and the appropriate coagulation monitoring tests are within therapeutic limits as follows:

    • Patients on heparin treatment must have a baseline aPTT between 1.5 – 2.5 x ULN or equivalent to the patient’s value before starting heparin treatment
    • Patients on low molecular weight heparins (LMWH) should receive daily dose of 1.5 – 2 mg/kg of enoxaparin or appropriate doses of the correspondent anticoagulant, according to the package insert
    • Patients on coumarin derivatives should have an International normalized ratio (INR) between 2.0 and 3.0 assessed at baseline in two consecutive measurements 1-4 days apart prior to DAY1/cycle1

Concomitant Conditions

  1. Other malignancy within the last 5 years before randomization except for curatively treated carcinoma insitu of the cervix or non-melanomatous skin cancer
  2. Evidence of distant metastasis judged clinically and at least by chest-X-ray, liver-sonography and bone scan. If there is any clinical suspicion of brain metastasis, a computerized tomography (CT) scan or magnetic resonance imaging (MRI) of the brain must be conducted within 4 weeks prior to randomization
  3. Serious concurrent disease which could affect compliance with the protocol or interpretation of results, including, but not limited to:
    • Active infection requiring IV antibiotics
    • Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg)
    • Clinically significant history of cardiovascular disease as indicated by: cerebrovascular accident or stroke; myocardial infarction; unstable angina; New York Heart Association (NYHA) (see Appendix 2) Grade II or greater congestive heart failure (CHF); cardiac arrhythmia requiring medication; clinically significant valvular heart disease
    • Dyspnea at rest necessitating supportive oxygen therapy or with significant pleural effusions
    • Poorly controlled diabetes mellitus
    • History or evidence upon physical/neurological examination of CNS disease unrelated to cancer (e.g.
    • uncontrolled seizures) unless adequately treated with standard medical therapy
    • History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding
    • History of abdominal fistula, GI perforation, or intraabdominal abscess within 6 months of randomization
    • Serious non-healing wound, peptic ulcer, or bone fracture
    • Clinically significant malabsorption syndrome, ulcerative colitis, disease affecting GI function, resection of the stomach or small bowel, or inability to take oral medication
    • Uncorrected hypokalemia or hypomagnesemia
    • Organ allografts requiring immunosuppressive therapy
  4. Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect patient compliance with study routines, or place the patient at high risk from treatment related complications
  5. Known hypersensitivity to any of the study drugs or excipients
  6. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies

Other

  1. Pregnant, lactating females or women of childbearing potential without a negative pregnancy test – urine or serum, within 7 days prior to DAY1/cycle1, irrespective of the method of contraception used, including tubal ligation
  2. Fertile males or females of childbearing potential (<12 month since last menstruation) unwilling or unable to use effective non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly, or surgical sterilization)
  3. Patients not accessible for treatment or follow-up