Phase I Study to Assess the Optimal Dose for Pazopanib in Combination With Capecitabine in Patients With HER2-negative, Metastatic Breast Cancer (PazoX)
- Written informed consent for all study procedures according to local regulatory
requirements prior to beginning specific protocol procedures.
- Complete baseline documentation must be submitted via the web-based data collection
system MedCODES to the GBG Forschungs GmbH.
- Diagnosis of advanced or metastatic HER2-negative breast cancer. HER2-negative is
defined as HercepTest IHC 0-2+ or FISH negative (ratio < 2.2).
- At least one prior endocrine or one non-capecitabine-containing chemotherapy
treatment for metastatic/advanced disease.
- Documented progression of either a measurable, or a non-measurable lesion according
to the RECIST criteria, or a new lesion.
- Complete radiological and clinical tumor assessment within 4 weeks prior to
registration performed as clinically indicated.
- Age => 18 years.
- Karnofsky Performance Status index => 60%.
- Laboratory requirements: Absolute neutrophil count (ANC) => 1.5 x 109/L, Platelets =>
100 x 109/L, Hemoglobin => 9 g/dL (=> 5.6 mmol/L), Prothrombin time (PT) or
international normalised ratio (INR) =< 1.2x UNL (upper normal limit), Partial
thromboplastin time (PTT) =< 1.2x UNL, Total bilirubin < 1.5x UNL, ASAT (SGOT) and
ALAT (SGPT) =< 2.5x UNL (concomitant elevations in serum bilirubin and ASAT/ALAT
above 1.0x UNL are not permitted), The calculated creatinine clearance should be =>
50 mL/min), Urine Protein to Creatinine Ratio (UPC) < 1 (if UPC => 1, then 24-hour
urine protein must be < 1 g).
- Normal cardiac function confirmed by ECG; corrected QT interval (QTc) < 480 msec
using Bazett's formula.
- A female either of:Non-childbearing potential i.e., physiologically incapable of
becoming pregnant because of history of hysterectomy, bilateral oophorectomy
(ovariectomy), bilateral tubal ligation or postmenopausal status.
Childbearing potential with a negative serum pregnancy test within 2 weeks prior to
registration, preferably as close to the first dose as possible, and agrees to use
adequate contraception. Acceptable contraceptive methods, when used consistently and in
accordance with both the product label and the instructions of the physician, are as
follow: An intrauterine device with a documented failure rate of less than 1% per year,
Vasectomised 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 investigational product, through the dosing period, and for at least 21
days 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).
- Female subjects who are lactating should discontinue nursing prior to the first dose
of study drug and should refrain from nursing throughout the treatment period and for
14 days following the last dose of study drug.
- Known or suspected hypersensitivity reaction to the investigational compounds or
- Last metastatic treatment with capecitabine, 5-FU, bevacizumab, sunitinib, sorafenib,
or other antibodies or tyrosine kinase inhibitors with anti-angiogenic activity.
Investigational therapies within 14 days or five half-lives of the drug (whichever is
longer) prior to first dose of pazopanib.
- Any ongoing toxicity from prior anti-cancer therapy that is grade >1 and/or that is
progressing in severity, except alopecia.
- Surgery or tumor embolisation within 28 days prior to the first dose of pazopanib. At
least 4 weeks since radiotherapy, with full recovery. The measurable disease must be
completely outside the radiated field or there must be pathological proof of
- Concurrent immuno-biological or hormonal therapy for cancer.
- 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
anti-seizure medication for 6 months prior to first dose of study drug.
- Life expectancy less than 3 months.
- History of thyroid autoimmune disease or thyroid disorders with thyroid values out of
- Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding including, but not limited to: Active peptic ulcer disease,
Known intraluminal metastatic lesion/s with risk of bleeding, Inflammatory bowel
disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal
conditions with increased risk of perforation, History of abdominal fistula,
gastrointestinal perforation, or intra abdominal abscess within 28 days prior to
beginning study treatment.
- Severe liver dysfunction
- Grade 3 or 4 diarrhea.
- Clinically significant gastrointestinal abnormalities that may affect absorption of
investigational product including, but not limited to: Malabsorption syndrome, Major
resection of the stomach or small bowel.
- Presence of uncontrolled infection.
- History of any one or more of the following cardiovascular conditions within the past
6 months: Cardiac angioplasty or stenting, Myocardial infarction, Unstable angina,
Coronary artery bypass graft surgery, Symptomatic peripheral vascular disease, Class
III or IV congestive heart failure, as defined by the New York Heart Association
(NYHA), Poorly controlled hypertension (defined as systolic blood pressure [SBP] of ≥
160 mmHg or diastolic blood pressure [DBP] of ≥ 90 mmHg).
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
BP must be re-assessed on two occasions that are separated by a minimum of 1 hour; on each
of these occasions, the mean (of 3 readings) SBP/DBP values from each BP assessment must
be < 160/95 mmHg in order for a subject to be eligible for the study (see Section 9.6.1
for details on BP control and re-assessment prior to study enrollment).
- History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6
months. Note: Subjects with recent DVT who have been treated with therapeutic
anti-coagulating agents for at least 6 weeks are eligible.
- Evidence of active bleeding or bleeding diathesis including, but not limited to:
Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
placement not considered to be major), Known endobronchial lesions and/or lesions
infiltrating major pulmonary vessels, Hemoptysis prior to 6 weeks of first dose of
study drug, Blood transfusion within 7 days of study entry.
- Any serious and/or unstable pre-existing medical, psychiatric, or other condition
that could interfere with subject's safety, provision of informed consent, or
compliance to study procedures.