A Randomized Open-Label, Phase II Study of Lapatinib-capecitabine or Lapatinib-vinorelbine or Lapatinib/Gemcitabine in Subjects With Her2/Neu Amplified Metastatic Breast Cancer Patients Progression After Taxanes Treatment
1. Signed informed consent must be obtained according to local ethical committee
2. Subjects must be older than 18 years old.
3. Histologically confirmed invasive adenocarcinoma of the breast which is stage IIIb,
stage IIIc with T4 lesion, or stage IV disease [according to AJCC 6th edition]
4. Documented progression after taxane based treatment for ErbB2 positive patients for
1st line metastatic breast cancer or documented progression after taxane based
regimens as adjuvant or neo-adjuvant therapy. Patients may have had a maximum of one
prior treatment with a chemotherapy regimen for metastatic disease.
5. Patients must have at least 1 measurable lesion defined by RECIST as follows:
- X-ray, physical exam > 20 mm.
- Conventional CT scan > 20 mm.
- Spiral CT scan > 10 mm.
- Measurable lesions must be outside a previous radiotherapy field if they are the
sole site of disease.
6. Local laboratory confirmed HER2/neu over expressing and/or amplified disease in the
invasive component of the primary or metastatic lesion as defined by at least one of
the following based local results:
- 3+ overexpression by IHC (> 30% of invasive tumour cells).
- 2+ or 3+ (in 30% or < % of neoplastic cells) over expression by IHC AND in situ
hybridization (FISH/CISH) test demonstrating HER2 gene amplification.
- HER2 gene amplification by FISH or CISH. (> 6 HER2 gene copies per nucleus, or a
FISH ratio (HER2 gene copies to chromosome 17 signals) of > than 2.2.
7. Prior therapy must have included a taxane regimen. Patients must have received
- Prior adjuvant treatments with taxanes-containing chemotherapy regimens
providing that at least 6 months has elapsed from the last dose of adjuvant or
neoadjuvant chemotherapy and all treatment related adverse events are < grade 1
at the time of randomization; OR
- Prior treatment with taxane based chemotherapeutic regimens for first line
metastatic breast cancer or prior taxane based neoadjuvant regimens for locally
advanced disease providing that at least 4 weeks has elapsed since the last dose
of therapy for metastatic disease and all treatment related adverse events are
< grade 1 at the time of randomization.
8. In regions where trastuzumab is available with no barriers to access, patients must
have also received prior trastuzumab alone or in combination with chemotherapy in
order to be eligible as follows:
- Prior treatment with Trastuzumab includes only first line metastatic setting; OR
- Prior trastuzumab treatment in neoadjuvant / adjuvant setting provided that at
least 6 months has elapsed from last dose of adjuvant / neoadjuvant
Trastuzumab , and all treatment related adverse events are < grade 1 at the time
9. Prior treatment with anthracyclines in the adjuvant or first line metastatic setting
are permitted provided that therapy has been discontinued before randomization, and
all treatment related adverse events are < grade 1 at the time of randomization.
10. Prior treatment with endocrine therapy in the adjuvant or metastatic setting are
permitted provided that therapy has been discontinued before randomization, and all
treatment related adverse events are < grade 1 at the time of randomization.
11. Prior treatments with radiation therapy for palliative management of metastatic
disease , to a limited area (e.g., palliative treatment for painful disease) other
than the sole site of measurable and assessable disease is allowed however, subjects
must have completed treatment at least 4 weeks of the last dose of radiotherapy
prior to starting study drugs, and must have recovered from all treatment-related
toxicities prior to Day 1.
11. Life expectancy of at least 6 months.
12. ECOG PS 0-2.
13. Patients must have normal organ and marrow function measured within 14 days prior to
randomization as defined below:
- System Laboratory Values
- Absolute neutrophil count (ANC) > 1.5 X 109/L
- Hemoglobin1 > 9 g/dL
- Platelets > 100 X 109/L
- Albumin > 2.5 gr /dl
- Total bilirubin > 1.5 X upper limit of normal (ULN)
- AST and ALT > 2.5 X ULN
- Serum Creatinine > 1.5 mg/dL o 132.6 micromol/L
- Or, if serum creatinine > 1.5 mg/dL, Calculated creatinine clearance > 50 mL/min
- Patients may not have had a transfusion within 7 days of screening assessment
14. CT head/MRI within 4 weeks prior to randomization.
15. Women of childbearing potential (WOCBP) must have a negative urine or serum
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days
prior to registration.
16. Patients must have at least 1 measurable disease according to Response Evaluation
Criteria in Solid Tumors (RECIST, Therasse, 2000). Measurable lesions may be in the
field of prior adjuvant irradiation. However, there must be at least a 4 week period
between the last radiation treatment and the baseline scan documenting disease
status. Documented progression of the irradiated lesion is also required for the
lesion to be considered measurable.
17. Subjects must have a cardiac ejection fraction within the institutional range of
normal as measured by ECHO (echocardiogram) or alternatively by MUGA (Multigated
Acquisition) scan. Cardiac ejection fraction > 50% and within the institutional range
of normal as demonstrated by echocardiogram or alternatively by MUGA scan within 4
weeks of randomization Subjects with known uncontrolled or symptomatic angina,
arrhythmias, or congestive heart failure are NOT eligible;
18. Subjects must complete all screening assessments as outlined in the protocol.
1. Pregnant or lactating women.
2. Prior therapy with other anti Erbb1 or antiErbB2 targeted agent rather than
Trastuzumab only limited to 1st line treatment of metastatic disease OR as
3. Prior exposure to gemcitabine , vinorelbine and capecitabine for 1st line treatment
of recurrent-metastatic disease OR as adjuvant / neoadjuvant therapy.
4. Treatment in the 14 days prior to randomization with anti-cancer therapy (tumor
embolization, chemotherapy , immunotherapy, biological therapy, or hormonal therapy)
or treatment with mitomycin within 6 weeks prior to randomization. Such treatment may
not be resumed or begun after study entry. Note: Patients receiving bisphosphonate
therapy prior to randomization may continue for the duration of study participation,
however bisphosphonates should not be initiated following study entry.
Prophylactic use of bisphosphonates in subjects without bone disease is not
permitted, except for the treatment of osteoporosis.
5. Active CNS metastases.
6. Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, serious non-healing wound/ulcer/bone fracture,
or psychiatric illness/social situations that would limit compliance with study
7. Patients with GI tract disease resulting in an inability to take oral medication,
malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures
affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative
8. Have current active hepatic or biliary disease(with exception of patients with
Gilbert syndrome, asymptomatic gallstones, liver metastases or stable chronic liver
disease per investigator assessment)
9. History of other malignancy. Subjects who have been disease-free for 5 years, or
subjects with a history of completely resected non-melanoma skin cancer or
successfully treated in situ carcinoma are eligible.
10. Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent.
11. Concurrent treatment with an investigational agent or participation in another
12. Used an investigational drug within 30 days or 3 half-lives, whichever is longer,
preceding the first dose of therapy.
13. History of immediate or delayed hypersensitivity or idiosyncrasy to drugs chemically
parented to Lapatinib or navelbine or capecitabine or gemcitabine and its