Chemotherapy and Lapatinib or Trastuzumab in Treating Women With HER2/Neu-Positive Metastatic Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: trastuzumab; docetaxel; lapatinib ditosylate; paclitaxel
Intervention description: IV q weekly (loading dose 4mg/kg; subsequent doses 2mg/kg) or IV q 3 weekly (loading dose 8mg/kg, subsequent doses 6mg/kg).; 75mg/m2 IV q 3 weekly, day 1 of a 3 week cycle for 8 cycles plus G-CSF (when given together with lapatinib).; 1250 mg po daily (while given with taxane). 1500mg PO daily (when given alone after taxane completion).; 80mg/m2 IV q weekly days 1, 8 and 15 of a 4-week cycle for 6 cycles.
Intervention MeSH terms: Paclitaxel; Docetaxel; Trastuzumab; Lapatinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 652.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: recurrent breast cancer; HER2-positive breast cancer; stage IV breast cancer

Summary:

      RATIONALE: HER2/neu is a receptor (protein) which is found in unusually high amounts in
      approximately 1 in 5 cancer patients. Scientific evidence suggests that having high amounts
      of the HER2/neu receptor is important for breast cancer to grow and spread. Women with
      previously untreated metastatic breast cancer (breast cancer that has spread to other organs)
      and with high levels of the HER2/neu receptor receive as their usual treatment chemotherapy
      with one of the approved chemotherapy drugs paclitaxel or docetaxel (called "taxanes")
      together with another approved drug called "trastuzumab". Chemotherapy drugs, such as
      paclitaxel and docetaxel, work either by killing tumour cells or by stopping them from
      dividing. Trastuzumab is an antibody that is given through a vein in the arm and it works by
      specifically "targeting" the HER2/neu i.e. it attaches to it and "turns it off". Although
      some of the patients who receive this taxane plus trastuzumab treatment feel better for some
      months, the cancer usually starts to grow again. Lapatinib is a new drug. Like trastuzumab,
      it also works by specifically "targeting" the HER2/neu receptor, but it does so in a
      different way. Lapatinib is not an antibody. It is a pill that is taken daily by mouth.
      Because lapatinib works in a different way than trastuzumab, it may be worse, as good as or
      better than trastuzumab in keeping metastatic HER/neu positive cancer from growing. However,
      this is not known.

      Purpose: This randomized Phase III trial is comparing chemotherapy (a taxane) given together
      with lapatinib with chemotherapy (a taxane) given together with trastuzumab in women with
      HER2/neu positive breast cancer.
    

Eligibility criteria:

        DISEASE CHARACTERISTICS:

          -  Histologically confirmed adenocarcinoma of the breast

          -  Metastatic (stage IV) disease at primary diagnosis or at relapse after curative intent
             therapy

          -  Local or central laboratory confirmedHER2/neu* overexpressing and/or amplified disease
             in the invasive component of the primary or metastatic lesion as defined by the
             following:

               -  3+ overexpression (in > 30% of invasive tumor cells) by immunohistochemistry
                  (IHC)

               -  2+ or 3+ overexpression (in ≤ 30% of invasive tumor cells) by IHC AND
                  demonstrates HER2/neu gene amplification by fluorescence in situ hybridization
                  (FISH) or chromogenic in situ hybridization (CISH)

               -  HER2/neu gene amplification by FISH/CISH (> 6 HER2/neu gene copies per nucleus,
                  or a FISH/CISH ratio [HER2 gene copies to chromosome 17 signals] of ≥ 2.2) NOTE:
                  *Patients with a negative or equivocal overall result (FISH/CISH ratio of < 2.2,
                  ≤ 6.0 HER2/neu gene copies per nucleus, or staining scores of 0, 1+, 2+, or 3+
                  [in ≤ 30% of neoplastic cells] by IHC) are not eligible

          -  Formalin-fixed paraffin-embedded tumor specimen available

          -  No CNS metastases (including leptomeningeal involvement)

          -  Hormone receptor status not specified

        PATIENT CHARACTERISTICS:

          -  Menopausal status not specified

          -  ECOG performance status 0-2

          -  Life expectancy > 6 months

          -  Absolute granulocyte count > 1,500/mm³

          -  Platelet count > 75,000/mm³

          -  Hemoglobin > 10 g/dL

          -  Serum creatinine ≤ 2.0 times upper limit of normal (ULN)

          -  Total bilirubin ≤ 1.5 times ULN (< 3 times ULN for patients with Gilbert's disease)

          -  AST and/or ALT ≤ 2.5 times ULN (< 5 times ULN for patients planning to receive
             paclitaxel-based therapy)

          -  LVEF ≥ 50% by MUGA or ECHO

          -  Not pregnant or nursing

          -  Negative pregnancy test

          -  Fertile patients must use effective contraception

          -  Must be accessible for study treatment and follow-up

          -  No history of other malignancies, except adequately treated ductal carcinoma in situ
             or lobular carcinoma in situ, adequately treated nonmelanoma skin cancer, curatively
             treated carcinoma in situ of the cervix, or other curatively treated solid tumor
             (non-breast) with no evidence of disease for ≥ 5 years

          -  No serious cardiac illness or condition including, but not limited to, any of the
             following:

               -  History of documented congestive heart failure

               -  Systolic dysfunction (LVEF < 50%)

               -  High-risk uncontrolled arrhythmias (i.e., ventricular tachycardia, high-grade
                  atrioventricular block, or supraventricular arrhythmias that are not adequately
                  rate-controlled)

               -  Unstable angina pectoris requiring anti-anginal medication

               -  Clinically significant valvular heart disease

               -  Evidence of transmural infarction on ECG

               -  Inadequately controlled hypertension (i.e., systolic blood pressure [BP] > 180 mm
                  Hg or diastolic BP > 100 mm Hg)

               -  New York Heart Association class III-IV functional status

          -  No serious illness or medical condition that would not allow the patient to be managed
             according to the protocol including, but not limited to, any of the following:

               -  History of significant neurologic or psychiatric disorder that would impair the
                  ability to obtain informed consent or limit compliance with study requirements

               -  Active uncontrolled infection

               -  Serious or nonhealing wound, ulcer, or bone fracture

          -  No peripheral neuropathy ≥ grade 2

          -  No gastrointestinal (GI) tract disease resulting in an inability to take oral
             medication including, but not limited to, any of the following:

               -  Malabsorption syndrome

               -  Requirement for IV alimentation

               -  Uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative
                  colitis)

          -  No history of allergic or hypersensitivity reactions to any study drug or their
             excipients or to compounds with similar chemical composition to any of the study drugs

               -  Prior allergic reactions to taxanes are allowed provided they were adequately
                  treated and, according to the treating physician, would not prohibit further
                  treatment with taxanes

        PRIOR CONCURRENT THERAPY:

          -  Recovered from all prior therapy

          -  No prior chemotherapy, immunotherapy, biological therapy, or anti-HER2/neu-targeted
             therapy for recurrent or metastatic breast cancer

          -  At least 12 months since prior chemotherapeutic agents, including taxanes, in the
             neoadjuvant or adjuvant setting

          -  At least 12 months since prior anti-HER2/neu-targeted therapy in the neoadjuvant or
             adjuvant setting

          -  Prior treatment with endocrine therapy in the neoadjuvant, adjuvant, or metastatic
             setting allowed

          -  At least 2 weeks since prior radiotherapy in the adjuvant or metastatic setting

               -  Prior radiotherapy to a solitary metastatic lesion allowed provided there is
                  documented disease progression after completion of radiotherapy

          -  More than 30 days (or 5 half-lives) since prior investigational drugs

          -  At least 7 days since prior and no concurrent CYP3A4 inhibitors (6 months for
             amiodarone)

          -  At least 14 days since prior and no concurrent CYP3A4 inducers

          -  No prior surgical procedures affecting absorption (e.g., resection of stomach or small
             bowel)

          -  No concurrent palliative radiotherapy

          -  No other concurrent anticancer treatment

          -  No other concurrent investigational drugs for breast cancer