An Open-Label, Single-Arm, Multi-Centre, Phase II Study of Oral Lapatinib in Combination With Paclitaxel as First-Line Treatment for ErbB2-Amplified Metastatic Breast Cancer Patients
A subject will be eligible for inclusion in this study only if all of the following
- Signed informed consent.
- Only females ≥18 years of age will be recruited:
- Non-child-bearing potential (i.e., women with functioning ovaries who have a
current documented tubal ligation or hysterectomy, or women who are
- Child-bearing potential (i.e., women with functioning ovaries and no documented
impairment of oviductal or uterine function that would cause sterility). This
category includes women with oligomenorrhoea (severe), women who are
perimenopausal and young women who have begun to menstruate. These subjects must
provide a negative serum pregnancy test at Screening and agree to one of the
- Complete abstinence from intercourse from 2 weeks prior to administration of the
first dose of study medication until 28 days after the final dose of study
- Consistent and correct use of one of the following acceptable methods of birth
- Male partner who is sterile prior to the female subject's entry into the study
and is the sole sexual partner for that female subject.
- Implants of levonorgestrel.
- Injectable progestogen.
- Any intrauterine device (IUD) with a documented failure rate of less than 1% per
- Oral contraceptives (either combined or progestogen only).
- Barrier methods, including diaphragm or condom with a spermicide.
- Subjects must have histologically confirmed invasive breast cancer with stage
• Where the disease is restricted to a solitary lesion, the neoplastic nature of the
lesion should be confirmed by cytology or histology.
- Subjects whose disease is ER+ and/or PR+ or unknown status will only be included in
the study if they meet the following criteria:
- They have symptomatic visceral disease that requires chemotherapy (e.g.,
patients with liver or lung metastases).
- The disease is considered by the Investigator to be progressing rapidly or
- Subjects who have received endocrine therapy and who are no longer benefiting
from this therapy.
- Documented amplification of ErbB2 defined by FISH in primary or metastatic tumor
tissue. Results of FISH testing at local laboratories are acceptable, however, tissue
sample must still be sent to Central laboratory where results will be repeated but
not used for eligibility criterion.
- If a taxane had been administered in the neoadjuvant or adjuvant setting, progression
must have occurred ≥12 months after completion of this treatment.
- Measurable lesion(s) according to RECIST (Response Evaluation Criteria in Solid
Tumors) criteria [Stephens, 2004; Therasse, 2000].
- Radiotherapy prior to initiation of study medication is allowed to a limited area
(e.g., palliative treatment for painful bone metastases), if it is not the sole site
of disease. Subject must have completed radiation treatment and recovered from all
acute radiation treatment-related toxicities, in particular bone marrow suppression.
- Bisphosphonate therapy for bone metastases is allowed however; treatment must be
initiated prior to the first dose of study medication. Prophylactic use of
bisphosphonates in subjects without bone disease, except for the treatment of
osteoporosis, is not permitted.
- Subjects with stable central nervous system (CNS) metastases (stable for at least 3
months) as confirmed by computerized tomography (CT)/magnetic resonance imaging
(MRI)) or leptomeningeal involvement are eligible only if they are not taking oral
steroids or enzyme-inducing anticonvulsants.
- Subjects must have a cardiac ejection fraction within institutional range of normal
as measured by echocardiogram (or multigated acquisition (MUGA) scan if an
echocardiogram cannot be performed or is inconclusive). Subjects with known history
of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure are
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 - 1.
- Considered by the Investigator to have a life expectancy of at least 3 months.
- Able to swallow and retain oral medication.
- Subjects must have new or archived tumor tissue available for analysis.
- Subjects must complete all screening assessments as outlined in the protocol.
- Subject must have adequate organ function as defined in Table 1.
Table 1 Baseline Laboratory Values for Adequate Organ Function SYSTEM LABORATORY VALUES
Absolute neutrophil count ≥1.5 × 10^9/L Haemoglobin ≥9 g/dL Platelets ≥100 × 10^9/L
Albumin ≥2.5 g/dL Serum bilirubin
- 1.25 x ULN AST and ALT ≤3 × ULN without liver metastases
- 5 × ULN with documented liver metastases
Serum Creatinine1 ≤2.0 mg/dL
- OR - Calculate Creatinine Clearance1 ≥40 mL/min
1. Calculated by the Cockcroft and Gault Method. ALT = alanine aminotransferase;
AST = aspartate aminotransferase
A subject will not be eligible for inclusion in this study if any of the
following criteria apply:
- Pregnant or lactating females.
- Received prior chemotherapy, hormonal therapy, immunotherapy, biologic therapy for
- Prior therapy with ErbB1 and/or ErbB2 inhibitors.
- Concurrent anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy,
biologic therapy, hormonal therapy) while taking study medication.
- Unresolved or unstable, serious toxicity from prior administration of another
investigational drug and/or of prior cancer treatment.
- Peripheral neuropathy of grade 2 or greater.
- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel. Subjects with ulcerative colitis are also
- History of other malignancy. However, 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.
- Concurrent disease or condition that would make the subject inappropriate for study
participation, or any serious medical disorder that would interfere with the
- Active or uncontrolled infection.
- Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent.
- Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart
- Concurrent treatment with an investigational agent or participation in another
clinical trial involving investigational agents.
- Used an investigational drug within 30 days or five half-lives, whichever is longer,
preceding the first dose of investigational treatment.
- The subject has a known immediate or delayed hypersensitivity reaction or
idiosyncrasy to drugs chemically related to lapatinib or excipients and those related
to paclitaxel or excipients.