ABCSG 31/ALTTO Details

A randomized, multi-center, open-label, phase-III-study of adjuvant lapatinib, trastuzumab, their sequence and their combination in patients with HER2/ErbB2-positive primary breast cancer.

Start:
01/2010
Screening-Stopp:
06/2010

Contact ABCSG-Trial office

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

Design

ABCSG-31 Design
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Primary objectives:

  • To compare disease-free survival (DFS) in patients with HER2 overexpressing and/or amplified breast cancer randomised to trastuzumab for one year versus lapatinib for one year versus weekly trastuzumab (12 or 18 weeks, according to assigned design) followed by a six-week washout period followed by lapatinib (28 or 34 weeks, according to assigned design) versus trastuzumab in combination with lapatinib for one year.

Secondary objectives:

  • To compare overall survival (OS) in patients randomised to trastuzumab for one year versus lapatinib for one year versus weekly trastuzumab (12 or 18 weeks, according to assigned design) followed by a six-week washout period followed by lapatinib (28 or 34 weeks, according to assigned design) versus trastuzumab in combination with lapatinib for one year.
  • To compare time to recurrence (TTR), ignoring second primary cancers (including contra lateral breast cancers and non-breast second malignancies) and counting deaths without recurrence as censoring events.
  • To compare time to distant recurrence (TTDR), from time to randomisation to first distant breast cancer recurrence, ignoring loco regional recurrence and second primary cancers (including contra lateral breast cancers and non-breast second malignancies) and counting deaths without recurrence as censoring events.
  • To evaluate the safety and tolerability of all four treatment groups.
  • To compare the cumulative incidence of brain metastases as the first site of breast cancer recurrence among the treatment groups.
  • To conduct all analyses separately for cohorts defined by the presence or absence of cMyc gene amplification;
  • To conduct all analyses separately for cohorts defined by the expression levels of PTEN;
  • To conduct all analyses separately for cohorts defined by the presence or absence of p95HER2 domain.

Inclusion criteria:

  1. Age ≥18 years
  2. Eastern Cooperative Oncology Group (ECOG) performance status ≤1;
  3. Non-metastatic operable primary invasive adenocarcinoma of the breast fulfilling the following:
    1. Histologically confirmed;
    2. Adequately excised (exceptions: patients who have ‘non-resectable’ deep margin invasion are eligible provided they have had or will receive radiotherapy encompassing the region concerned; patients with histologically documented infiltration of the skin (pT4) are eligible provided they have undergone or will receive radiotherapy encompassing the tumour bed);
    3. Axilla dissected; sentinel node sampling is allowed, provided that axillary dissection follows confirmation of a positive sentinel node; sentinel node sampling alone is NOT acceptable after neoadjuvant chemotherapy (in patients receiving neoadjuvant chemotherapy lymph node status will be considered unknown, regardless of the results of post-chemotherapy axillary dissection);
    4. Axillary node positive patient OR node negative patient with a tumour greater than or equal to 1.0 cm in greatest diameter. For clarification, isolated tumour cells (ITC) are considered pN0 and micrometastases are considered pN1.
  4. Known hormone receptor status (ER/PgR or ER alone);
  5. For Designs 1 and 2: Patient must have received at least four cycles of an approved anthracycline based (neo-) adjuvant chemotherapy regimen or listed as anexception.

    For Design 1: Randomisation must be performed no longer than 12 weeks from Day 1 of the last chemotherapy cycle after obtaining a post-chemotherapy LVEF ≥50. Study treatment must start no more than 14 days after randomisation

    For Design 2: Randomisation must be performed no longer than 6 weeks from Day 1 of the last anthracycline-containing chemotherapy cycle after obtaining a post-anthracycline chemotherapy LVEF ≥50. Study treatment must start no more than 14 days after randomisation and must be concurrent with taxanes

    For Design 2B: Randomisation must be performed no longer than 8 weeks from definitive surgery. Non-anthracycline platinum containing regimen (docetaxel and carboplatin) and study treatment must start concomitantly and no more than 14 days after randomisation

  6. Baseline LVEF ≥50% measured by echocardiography or MUGA scan: For Design 1 and Design 2 – after completion of all anthracycline-based (neo-) adjuvant chemotherapy and prior to the targeted therapy(ies); for Design 2B – prior to targeted therapy(ies) and chemotherapy (docetaxel and carboplatin)
  7. Over expression and/or amplification of HER2 in the invasive component of the primary tumour (in case of neoadjuvant treatment, tissue sample used for HER2 testing should be collected before neoadjuvant treatment starts), according to one of the following definitions [Wolff, 2007] and confirmed by central laboratory prior to randomisation:
    • 3+ over expression by IHC (>30% of invasive tumour cells);
    • 2+ or 3+ (in 30% or less neoplastic cells) over expression by IHC AND in situ hybridization (FISH/CISH) test demonstrating HER2 gene amplification;
    • HER2 gene amplification by FISH/CISH (>6 HER2 gene copies per nucleus, or a FISH ratio [HER2 gene copies to chromosome 17 signals] of >2.2.)
    • Patients with a negative or equivocal overall result (FISH test ratio of ≤2.2, ≤6.0 HER2 gene copies per nucleus) and staining scores of 0,1+, 2+ or 3+ (in 30% or less neoplastic cells) by IHC are not eligible for participation in the trial
    • Equivocal local results may be submitted for a final determination by the central laboratory
  8. Completion of all necessary baseline laboratory and radiological investigations
  9. Signed written informed consent (approved by an Independent Ethics Committee (IEC) and obtained prior to any study specific screening procedures)

Exclusion criteria:

Patients meeting any ONE of the following criteria are not eligible for this study:

  1. History of any prior (ipsi- and/or contralateral) invasive breast carcinoma
  2. Past (less than 10 years) or current history of malignant neoplasms, except for curatively treated 1) basal and squamous cell carcinoma of the skin or 2) carcinoma in situ of the cervix

    NOTE: Patients with a prior malignancy diagnosed greater than 10 years in the past who have been curatively treated with surgery ONLY, WITHOUT radiation therapy or systemic therapy (chemotherapy or endocrine) are eligible for the study.

    Patients with any prior diagnosis of invasive breast cancer or melanoma, at any time, are excluded from this study.

  3. Any clinically staged T4 tumour, including inflammatory breast cancer
  4. Bilateral tumours
  5. This exclusion criterion has been removed as of protocol amendment 1

    NOTE: multifocal/multicentric tumours are permitted:

    • If the patient is node-negative: one of the lesions must be equal or greater than 1.0 cm (sum of the lesion diameters is not acceptable) AND must have positive HER2 status centrally-confirmed;
    • If patient is node-positive: lesion size does not matter BUT one of the lesions must have HER2 positivity centrally-confirmed. If several lesions are found to be HER2 positive locally, the largest lesion should be considered for central review.
  6. Maximum cumulative dose of doxorubicin >360mg/m2 or maximum cumulative dose of epirubicin >720mg/m2 or any prior anthracyclines unrelated to the present breast cancer
  7. (Neo-) or adjuvant chemotherapy using peripheral stem cell or bone marrow stem cell support
  8. Any prior mediastinal irradiation except internal mammary node irradiation for the present breast cancer
  9. Patients with positive or suspicious internal mammary nodes identified by sentinel node technique, which have not been irradiated or will not be irradiated, or patients with supraclavicular lymph node involvement (confirmed by fine needle aspirate or biopsy)
  10. Prior use of anti-HER 2 therapy for any reason or other prior biologic or immunotherapy for breast cancer
  11. Concurrent anti-cancer treatment, except hormonal therapy or radiotherapy for the present breast cancer
  12. Concurrent anti-cancer treatment in another investigational trial with hormone therapy or immunotherapy unless approved by the Executive Committee
  13. Serious cardiac illness or medical conditions including but not confined to:
    • History of documented congestive heart failure (CHF) or systolic dysfunction (LVEF <50%);
    • High-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade AV-block, supraventricular arrhythmias which are not adequately rate-controlled)
    • Angina pectoris requiring antianginal medication
    • Clinically significant valvular heart disease
    • Evidence of transmural infarction on ECG
    • Poorly controlled hypertension (e.g. systolic >180mm Hg or diastolic >100mm Hg)
  14. Other concurrent serious diseases that may interfere with planned treatment including severe pulmonary conditions/illness
  15. Any of the following abnormal laboratory tests immediately prior to randomisation:
    • serum total bilirubin >1.5 x upper limit of normal (ULN). In the case of known Gilbert’s syndrome, a higher serum total bilirubin (
    • alanine amino transferase (ALAT) or aspartate amino transferase (ASAT) >2.5 x ULN
    • alkaline phosphatase (ALP) >2.5 x ULN
    • serum creatinine >2.0 x ULN
    • total white blood cell count (WBC)
    • absolute neutrophil count
    • platelets
  16. Unresolved or unstable serious adverse events from prior adjuvant chemotherapy or radiotherapy
  17. Malabsorption syndrome, any disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, or persons unable to swallow oral medication. Subjects with ulcerative colitis are also excluded
  18. Pregnant, lactating or women of childbearing potential without a negative pregnancy test – urine or serum, within 7 days prior to randomization, irrespective of the method of contraception used, including tubal ligation
  19. Women of childbearing potential and male participants with partners of childbearing potential, including women whose last menstrual period was
  20. Concomitant use of CYP3A4 inhibitors or inducers.