An Open-label, Multicenter, Phase I/II Dose Escalation Study of Oral GW572016 in Combination With Docetaxel (Taxotere) Plus Trastuzumab (Herceptin) in Subjects Previously Untreated for ErbB2-overexpressing Metastatic Breast Cancer
- Subjects must be 18 years of age.
Criteria for female subjects:
- Non-child-bearing potential (i.e., women with functioning ovaries who have a current
documented tubal ligation or hysterectomy, or women who are post- menopausal);
- 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 have a negative
serum pregnancy test at screening and agree to one of the following:
- 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 year; oral contraceptives (either combined or progestogen only);
or barrier methods, including diaphragm or condom with a spermicide.
- Subjects must have an ECOG Performance Status of 0 to 1.
- Subjects must have histologically- or cytologically-confirmed invasive breast cancer
with Stage IV disease.
- Subjects must have measurable lesion(s) according to RECIST criteria for phase II,
however for phase I subjects evaluable disease will be allowed (including patients
with bone lesion only disease).
- Prior to enrolment in the Phase I part of the study, subjects must have documentation
of ErbB2 over-expression via IHC3+ or FISH+ testing. Prior to enrolment in the Phase
II part of the study, subjects must have ErbB2 over-expression confirmed by a central
- Subjects with stable CNS metastases or leptomeningeal involvement are eligible only
if they are not taking oral steroids or enzyme-inducing anticonvulsants. Subjects
with CNS only disease will not be allowed.
- Subjects that received prior radiotherapy must have completed radiotherapy treatment
at least 4 weeks before enrolment and recovered from all treatment-related
- Subjects must have new or archived tumour tissue available prior to study entry to
evaluate levels of relevant biomarkers.
- Subjects must have a cardiac ejection fraction within the institutional range of
normal as measured by Multigated Acquisition (MUGA) scan or echocardiogram (ECHO).
- Subjects must have adequate haematological, hepatic, and renal function. Haemoglobin
≥9gm/dL Absolute granulocyte count ≥1500/mm³ (1.5 x 10^9/L) Platelets ≥75,000/mm³ (75
x 10^9/L) Total bilirubin ≤1.5mg/dL Both ALT and AST ≤1.5 times the upper limit of
the normal range (ULN) and alkaline phosphatase ≤2.5 times the ULN (See Taxotere Data
Sheet) Serum creatinine ≤ 2.0mg/dL or calculated creatinine clearance (CrCl)
≥40mL/min according to the formula of Cockcroft and Gault
- Subjects who received a taxane as part of adjuvant or neoadjuvant therapy are
eligible if they had progression of their disease more than 6 months after completion
- Subjects who received prior ErbB inhibitors in the adjuvant setting will be allowed,
but a disease-free interval of at least 6 months must be demonstrated after the end
- Subject has peripheral neuropathy of grade 2 or higher;
- Subject has had prior systemic therapy (except one line of hormonal therapy) for
metastatic disease. Also, any subjects with prior chemotherapy in the adjuvant or
neoadjuvant setting with anthracycline or anthracenedione-containing regimens with
cumulative doses of ≥360mg/m² of doxorubicin, ≥720mg/m² of epirubicin, or ≥72mg/m² of
- Subjects with prior systemic investigational drugs within the past 30 days or topical
investigational drugs within the past 7 days;
- Subjects with uncontrolled or symptomatic angina, arrhythmias, or congestive heart
- Subjects with a known immediate or delayed hypersensitivity or untoward reaction to
docetaxel, trastuzumab, or other related compounds, or to drugs chemically related to
lapatinib. These include other anilinoquinazolines, such as gefitinib (Iressa),
erlotinib (Tarceva), or other chemically-related compounds.
- Subjects taking any prohibited medications
- Subject neither affiliated with, nor beneficiary of a social security category (For