A Phase II, Open-Label, Randomized, Multicenter Trial of GW786034 (Pazopanib) in Combination With Lapatinib (GW572016) Compared to Lapatinib Alone as First Line Therapy in Subjects With Advanced or Metastatic Breast Cancer With ErbB2 Fluorescence In Situ Hybridization (FISH) Positive Tumors
- A subject will be eligible for inclusion in this study only if all of the following
- Women ≥ 18 years of age with a life expectancy of ≥ 12 weeks.
- Note: National Institute of Neurological and Communicative Disorders and Stroke
(NINCDS) and Alzheimer's Disease and Related Disorders Association (ADRDA).)
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
- Histologically confirmed invasive breast cancer with incurable stage IIIb, stage IIIc
with T4 lesion, or stage IV disease at primary diagnosis or at relapse after
- No prior chemotherapy, immunotherapy, biologic therapy or anti-ErbB1/ErbB2 therapy
for metastatic or recurrent disease (other than neoadjuvant or adjuvant therapy).
Prior hormonal therapy (e.g., tamoxifen, raloxifen or an aromatase inhibitor) for
advanced or metastatic disease is permitted provided at least 2 weeks have elapsed
between the completion of the prior therapy and start of study drugs.
- Note: Subjects must have documented progressive disease (PD) or be intolerant to
hormonal therapy. This must be documented in the source documentation.
- Prior neoadjuvant therapy and/or adjuvant therapy is permitted.
- (a) Subjects who have received both neoadjuvant and adjuvant therapies must have at
least 6 months between completion of the chemotherapy-component of adjuvant therapy
and start of study drug(s)
- (b) Subjects who have received only adjuvant therapy must have at least 6 months
between completion of the chemotherapy-component of adjuvant therapy and start of
- (c) Subjects who have received only neoadjuvant therapy must have at least 6 months
between completion of neoadjuvant therapy and start of study drug(s)
- (d) Subjects who have received trastuzumab or hormonal agents as all or part of
adjuvant therapy are eligible provided: (1) 2 weeks have elapsed since last dose (2)
6 months have elapsed between the start of trastuzumab or hormonal therapy and start
of study drugs.
- Radiotherapy prior to initiation of randomized therapy 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 prior to starting study drugs, and must have recovered from all
treatment-related toxicities prior to starting pazopanib and/or lapatinib.
- Documented amplification of ErbB2 by Fluorescence In Situ Hybridization (FISH) in
either the primary or metastatic tumor tissue. Archived tumor tissue must be provided
for ErbB2 FISH testing by the central laboratory, which will be used to determine
- Note: Subjects that have documented ErbB2 amplification based on prior FISH testing
or documented ErbB2 overexpression based on prior immunohistochemistry (IHC) with a
value of 3+ are eligible, however, archived tumor tissue must be provided for
confirmation by the central laboratory. If the results from prior testing are not
confirmed by the central laboratory, then the subject can continue to receive study
drug(s) at the discretion of the investigator, but will be excluded from the
- Archived tumor tissue (paraffin-embedded) must be available to correlate tumor
response with intra-tumoral genetic changes as well as expression levels of relevant
biomarkers. Results of biomarkers will not be used to determine subject eligibility
for the study.
- Ability to swallow and retain oral medication.
- Disease must be measurable according to Response Evaluation Criteria in Solid Tumors
- Subjects must have chosen treatment with lapatinib and/or pazopanib as initial
treatment over other initial treatments (such as cytotoxic chemotherapy regimens or
trastuzumab as a single agent) for locally advanced or metastatic disease.
- Adequate organ function as defined below:
- System (Laboratory Values)
- Hematologic:Absolute neutrophil count (ANC) (≥1.5 X 109/L) Platelets (≥100 X 109/L)
- Hepatic:Albumin(≥2.5 g/dL)Serum bilirubin(≤1.5 X upper limit of normal (ULN) unless
due to Gilbert's syndrome) aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) (≤2.0 X ULN)
- Renal:Calculated creatinine clearance1 (≥50 mL/min) Urine Protein2
- (Negative, trace or +1 by dipstick urinalysis or <1.0 gram determined by 24 hour
urine protein analysis).
- A patient should first be screened with dipstick urinalysis. If urine protein by
dipstick analysis is≥2+, then a 24-hour urine protein must be assessed and 24 hour
urine protein must be <1 g protein to be eligible.
- Cardiac ejection fraction within the institutional range of normal as measured by
echocardiogram. Multigated acquisition (MUGA) scans will be accepted in cases where
an echocardiogram cannot be performed or is inconclusive or where MUGA scans are the
accepted standard. Subjects with known history of uncontrolled or symptomatic
angina, arrhythmias, or congestive heart failure are not eligible.
- A female is eligible to enter and participate in this study if she is of:
- Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
including any female who has had:
- A hysterectomy
- A bilateral oophorectomy (ovariectomy)
- A bilateral tubal ligation
- Is post-menopausal (total cessation of menses for ≥1 year)
- Childbearing potential, has a negative serum pregnancy test within 2 weeks of the
first dose of study medication, and agrees to use adequate contraception during study
participation and for a minimum of 2 menstrual cycles after the last dose of study
medication. GSK acceptable contraceptive methods, when used consistently and in
accordance with both the product label and the instructions of the physician, are as
- An intrauterine device with a documented failure rate of less than 1% per year.
- Vasectomized partner who is sterile prior to the female subject's entry and is the
sole sexual partner for that female.
- Complete abstinence from sexual intercourse for 14 days before exposure to
investigation product, through the clinical trial, and for at least 2 menstrual
cycles after the last dose of investigational product.
- Double-barrier contraception (condom with spermicidal jelly, foam suppository, or
film; diaphragm with spermicide; or male condom and diaphragm with spermicide).
- Oral contraceptives are not reliable due to the potential drug-drug interactions.
- Subjects must complete all screening assessments as outlined in the protocol.
- Subjects must provide written informed consent prior to performance of any
study-specific procedures or assessments and are willing to comply with treatment and
- A subject will not be eligible for inclusion in this study if any of the following
- Subjects with bilateral breast cancer or bone metastases as the only disease site.
- Patients with high disease burden defined as >30% replacement of hepatic parenchyma
with metastases, symptomatic pulmonary metastases (e.g., clinically significant
dyspnea, cough, or chest pain attributable to pulmonary metastases), or >3 visceral
organs with tumor involvement.
- 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.
- Sarcoma histology.
- Concurrent disease or condition that would make the subject inappropriate for study
participation including (1) any unresolved or unstable, serious toxicity from prior
administration of another investigational drug, (2) any serious medical disorder that
would interfere with the subject's safety, obtaining informed consent or compliance
to the study.
- History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis, except for individuals who have previously treated CNS
metastases, are asymptomatic, and have had no requirement for steroids or antiseizure
medication for ³ 2 months prior to study enrollment. Routine screening with CNS
imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is
required only if clinically indicated or if the subject has a history of CNS
- Malabsorption Syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel.
- Active peptic ulcer disease, inflammatory bowel disease, or other gastrointestinal
condition increasing the risk of perforation; history of abdominal fistula,
gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to
- Presence of uncontrolled infection.
- Concurrent cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy,
biologic therapy, hormonal therapy, and tumor embolization).
- Concurrent treatment with an investigational agent or participation in another
- Use of an investigational anti-cancer drug within 30 days or 5 half-lives, whichever
is longer, preceding the first dose of pazopanib and/or lapatinib.
- Prior use of an investigational or licensed drug that targets either vascular
endothelial growth factor (VEGF) or VEGF receptors, or ErbB2 (except for trastuzumab
when used in the neo-adjuvant/adjuvant setting).
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to pazopanib or lapatinib.
- Has taken/is taking prohibited medications, Lapatinib-related, orPazopanib-related.
- Corrected QT interval (QTc) prolongation defined as QTc interval > 480 msecs.
- History of any one of the following cardiac conditions within the past 6 months:
- Cardiac angioplasty or stenting
- Myocardial infarction
- Unstable angina
- History of cerebrovascular accident within the past 6 months.
- Poorly controlled hypertension (systolic blood pressure (SBP) of ≥140mmHg, or
diastolic blood pressure (DBP) of ≥90mmHg).
- Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior
to study entry. The blood pressure (BP) must be re-assessed on two occasions that are
separated by a minimum of 24 hours. The mean SBP/DBP values from both BP assessments
must be < 140/90mmHg in order for a subject to be eligible for the study.
- Presence of any non-healing wound, fracture, or ulcer, or the presence of symptomatic
peripheral vascular disease.
- Evidence of bleeding diathesis or coagulopathy.
- Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks
prior to beginning therapy, or anticipation of the need for a major surgical
procedure during the course of the study; minor surgical procedures such as fine
needle aspiration or core biopsy within 1 week prior to beginning therapy are also
- Pregnant or lactating female.
- Has Class III or IV heart failure as defined by the New York Heart Association (NYHA)
functional classification system.
- History of untreated deep venous thrombosis (DVT) within the past 6 months (e.g. calf