ABCSG 39/Aphinity Details

A randomized, multicenter, double-blind, placebo-controlled comparison of chemotherapy plus trastuzumab plus placebo vs. chemotherapy plus trastuzumab plus pertuzumab as adjuvant therapy in patients with operable HER2-positive primary breast cancer

Start:


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

Design

1 Injektion enthält entweder 60 mg Denosumab oder Placebo

ABCSG-39 Design
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Primary objectives:

To compare invasive disease-free survival (IDFS) in patients with HER2-positive breast cancer randomized to chemotherapy plus one year of trastuzumab plus placebo or chemotherapy plus one year of trastuzumab plus pertuzumab.

Secondary objectives:

To compare invasive disease-free survival including second non-breast cancers, disease-free survival (DFS), overall survival (OS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), cardiac safety, overall safety and health-related quality of life (HRQL) in the two treatment arms.

Inclusion criteria:

  1. Age ≥ 18 years
  2. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
  3. Non-metastatic operable primary invasive carcinoma of the breast that is:
    1. Histologically confirmed;
    2. Adequately excised:

      Patients must have undergone either a total mastectomy or breast conserving surgery

      For patients who undergo conservative surgery, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (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 reexcision (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. For patients who undergo mastectomy, margins must be free of gross residual tumor. Patients with microscopic positive margins are eligible (see radiation therapy requirements).

    3. pTNM staging:

      Pathological classification of regional lymph nodes: micrometastases (tumor deposits >0.2 mm) are considered pN1, but isolated tumor cells (ITC) are considered pN0.

      For patients with node-positive disease (pN ≥1), any tumor size except T0. Node-negative patients are NOT allowable under Protocol B.

      Below applies to Protocol A ONLY:

      For patients with node-negative disease (pN0) (Protocol A ONLY): Tumor size must be > 1.0 cm OR

      For tumor size between > 0.5 cm and ≤ 1.0 cm, at least one of the following features must be present: histologic/nuclear grade 3 OR negative for ER and PgR OR age < 35 years. Enrollment of patients with node negative tumors ≤ 1.0 cm will be limited to <10% of the total number of randomized patients.

      For multifocal (the presence of two or more tumor foci within a single quadrant of the breast) or multicentric disease (the presence of two or more tumor foci within different quadrants of the same breast), the size of the largest invasive tumor is to be used to determine T stage.

      Patients with synchronous bilateral invasive disease are eligible so long as both lesions are HER2-positive.

  4. Known hormone receptor status (estrogen receptor [ER] and progesterone receptor [PgR])
  5. The interval between definitive surgery for breast cancer and the first dose of chemotherapy must be no more than 8 weeks (56 days). All procedures, including randomization, must occur during this period. The first cycle of chemotherapy must be administered within 7 days of randomization or on Day 56, whichever occurs first
  6. Baseline LVEF ≥55% measured by echocardiography (preferred) or MUGA scan
  7. HER2-positive breast cancer confirmed by a central laboratory and defined as:

    IHC 3+ in >10% immunoreactive cells OR c-erbB2 gene amplification by in situ hybridization [ISH] (ratio of c-erbB2 gene signals to centromere 17 signals ≥2). Availability of formalin-fixed paraffin-embedded (FFPE) tissue block with at least 5-mm invasive tumor and, wherever possible, a minor component of non-neoplastic breast tissue for central confirmation of HER2 eligibility, hormone receptor status and biomarker evaluation is mandatory (a minimum of 4 and up to 7 × 1-mm cores will be taken for translational research and the block returned to the site)

  8. Completion of all necessary baseline laboratory and radiologic investigations prior to randomization
  9. Women of childbearing potential and male participants with partners of childbearing potential must agree to use a “highly-effective”, non-hormonal form of contraception or two “effective” forms of non-hormonal contraception by the patient and/or partner. Contraception must continue for the duration of study treatment and for at least 6 months after the last dose of study treatme
  10. Signed informed consent

Exclusion Criteria:

  1. History of any prior (ipsi- and/or contralateral) invasive breast carcinoma
  2. History of non-breast malignancies within the 5 years prior to study entry*, except for the following: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin (*malignancies occurring more than 5 years prior to study entry are permitted if curatively treated with surgery alone)
  3. Any “clinical” T4 tumor as defined by TNM, including inflammatory breast cancer
  4. Any node-negative tumor
  5. Any previous systemic chemotherapy (e.g., neoadjuvant or adjuvant) for cancer OR radiation therapy for cancer:
    • Patient with a past history of DCIS and/or LCIS are not allowed to enter the study if they have received any form of systemic therapy for its treatment; OR radiation therapy to the ipsilateral breast where invasive cancer subsequently develops
    • Patients who had their DCIS/LCIS treated with surgery only are allowed to enter the study
    • High risk patients who have received chemoprevention drugs in the past are not allowed to enter the study
  6. Prior use of anti-HER2 therapy (e.g., lapatinib, neratinib or other tyrosine kinase inhibitors [TKIs]) for any reason or other prior biologic or immunotherapy for cancer
  7. Concurrent anti-cancer treatment in another investigational trial, including hormone therapy, bisphosphonate therapy and immunotherapy
  8. Serious cardiac illness or medical conditions including but not confined to:
    • History of documented heart failure or systolic dysfunction (LVEF <50%)
    • 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)
    • Angina pectoris requiring anti-anginal medication
    • Clinically significant valvular heart disease
    • Evidence of transmural infarction on ECG
    • Poorly controlled hypertension (e.g., systolic >180 mm Hg or diastolic >100 mm Hg)
  9. Other concurrent serious diseases that may interfere with planned treatment including severe pulmonary conditions/illness (e.g., infections or poorly controlled diabetes)
  10. Any of the following abnormal laboratory tests immediately prior to randomization:
    • Serum total bilirubin >1.5 upper limit of normal (ULN); in cases of known Gilberts syndrome a total
    • bilirubin of 2 × ULN is permitted
    • Alanine amino transferase (ALAT) and/or aspartate amino transferase (ASAT) >1.25 × ULN
    • Alkaline phosphatase (ALP) >2.5 × ULN
    • Serum creatinine >1.5 × ULN
    • Total white blood cell count (WBC) 2,500 / mm3 (<2.5 × 109/L)
    • Absolute neutrophil count (ANC) <1,500 / mm3 (<1.5 × 109/L)
    • Platelets < 100,000 / mm3 (< 100 × 109/L)
  11. Pregnant, lactating or women of childbearing potential without a negative pregnancy test (serum), within 7 days prior to randomization, irrespective of the method of contraception used
  12. Women of childbearing potential or less than one year after menopause (unless surgically sterile) who are unable or unwilling to use the contraceptive measures required by this protocol during and 6 months after the last dose of study medication
  13. Sensitivity to any of the study medications or any of the ingredients or excipients of these medications, including sensitivity to benzyl alcohol