Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study
Condition: Neoplasms, Breast
MeSH terms: Breast Neoplasms
Intervention: Lapatinib; Trastuzumab; Paclitaxel
Intervention description: Small molecule receptor tyrosine kinase inhibitor; Therapeutic Monoclonal Antibody; antimicrotubule agent
Intervention MeSH terms: Paclitaxel; Trastuzumab; Lapatinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Masking: None (Open Label)
Enrollment: 455.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Lapatinib; ErbB2+; Early Breast Cancer; Neoadjuvant; breast carcinoma; breast cancer; breast lump; HER2 positive metastatic breast cancer; breast cancer positive for human epidermal growth factor receptor 2 (HER2) HER2 positive metastatic breast cancer; breast cancer progression; estrogen-receptor (ER) positive(+) breast cancer; Paget's disease

Summary:

      This is a randomised, open label multicenter Phase III study comparing the efficacy of
      neoadjuvant lapatinib plus paclitaxel, versus trastuzumab plus paclitaxel, versus concomitant
      lapatinib and trastuzumab plus paclitaxel given as neoadjuvant treatment in HER2/ErbB2
      over-expressing and/or amplified primary breast cancer.

      Patients will be randomised to receive either: lapatinib 1500 mg daily, trastuzumab 4 mg/kg
      intravenous (IV) load followed by 2 mg/kg IV weekly, or lapatinib 1000 mg daily with
      trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for a total of 6 weeks. After this
      biological window, patients on monotherapy arms will continue on the same targeted therapy
      plus weekly paclitaxel 80 mg/m^2 for a further 12 weeks, up to definitive surgery. In the
      combination arm, patients will receive lapatinib 750 mg daily in combination with trastuzumab
      2 mg/kg IV plus weekly paclitaxel 80mg/m^2 IV for a further 12 weeks, up to definitive
      surgery. After surgery, patients will receive three courses of adjuvant chemotherapy with
      5-Fluorouracil Epirubicin Cyclophosphamide (FEC) followed by the same targeted therapy as in
      the biological window of the neoadjuvant setting for a further 34 weeks (in the combination
      arm, lapatinib dose will be 1000 mg daily in combination with trastuzumab). The planned total
      duration of the anti-HER2 therapy one year.

      Primary objective is to evaluate and compare the rate of pathological complete response (pCR)
      at the time of surgery in patients with HER2/ErbB2 overexpressing or amplified operable
      breast cancer randomised to lapatinib followed by lapatinib plus paclitaxel versus
      trastuzumab followed by trastuzumab plus paclitaxel versus lapatinib in combination with
      trastuzumab followed by lapatinib, trastuzumab plus paclitaxel.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Female gender;

          -  Age ≥18 years;

          -  Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1

          -  Histologically confirmed invasive breast cancer:

          -  Primary tumour greater than 2 cm diameter, measured by clinical examination and
             mammography or echography,

          -  Any N,

          -  No evidence of metastasis (M0) (isolated supraclavicular node involvement allowed);

          -  Over expression and/or amplification of HER2 in the invasive component of the primary
             tumour [Wolff et al 2006] and confirmed by a certified laboratory prior to
             randomisation

          -  Known hormone receptor status.

          -  Haematopoietic status:

          -  Absolute neutrophil count ≥ 1,5 x 10^9/L,

          -  Platelet count ≥ 100 x 10^9/L,

          -  Hemoglobin at least 9 g/dl,

          -  Hepatic status:

          -  Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN). In the case of known
             Gilbert's syndrome, a higher serum total bilirubin (< 2 x ULN) is allowed,

          -  Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times ULN,

          -  Alkaline phosphatase ≤ 2.5 times ULN,

          -  Renal status:

          -  Creatinine ≤ 2.0 mg/dL,

          -  Cardiovascular:

          -  Baseline left ventricular ejection fraction (LVEF) ³ 50% measured by echocardiography
             (ECHO) or Multiple Gate Acquisition (MUGA) scan,

          -  Negative serum pregnancy test, within 2-weeks (preferably 7 days) prior to
             randomization (For women of childbearing potential)

          -  Fertile patients must use effective contraception (barrier method - condoms, diaphragm
             - also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable,
             or implant hormonal contraceptives are not allowed)

          -  Signed informed consent form (ICF)

          -  Patient accepts to make available tumour samples for submission to central laboratory
             to conduct translational studies as part of this protocol

        Exclusion Criteria:

          -  Received any prior treatment for primary invasive breast cancer;

          -  Previous (less than 10 years) or current history of malignant neoplasms, except for
             curatively treated:

          -  Basal and squamous cell carcinoma of the skin;

          -  Carcinoma in situ of the cervix.

          -  Patients with a prior malignancy diagnosed more than 10 years prior to randomisation
             may enter the study. Patients must have been curatively treated with surgery alone.
             Radiation therapy or systemic therapy (chemotherapy or endocrine) are NOT permitted.
             Prior diagnoses of breast cancer or melanoma are excluded.

          -  Diagnosis of inflammatory breast cancer;

          -  Bilateral cancer;

          -  This criterion has been deleted from the protocol Version 1. Patients with multi-focal
             cancer are no longer excluded.

          -  Known history of uncontrolled or symptomatic angina, clinically significant
             arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled
             hypertension (≥180/110), unstable diabetes mellitus, dyspnoea at rest, or chronic
             therapy with oxygen;

          -  Concurrent disease or condition that would make the subject inappropriate for study
             participation or any serious medical disorder that would interfere with the subject's
             safety;

          -  Unresolved or unstable, serious adverse events from prior administration of another
             investigational drug;

          -  Active or uncontrolled infection;

          -  Dementia, altered mental status, or any psychiatric condition that would prevent the
             understanding or rendering of ICF;

          -  Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
             resection of the stomach or small bowel. Subjects with ulcerative colitis are also
             excluded;

          -  Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy,
             biologic therapy other than the trial therapies);

          -  Concurrent treatment with an investigational agent or participation in another
             therapeutic clinical trial;

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to trastuzumab or lapatinib or their excipients;

          -  Pregnant or lactating women;

          -  Concomitant use of CYP3A4 inhibitors or inducers