Pazopanib in Combination With Capecitabine in Patients With Metastatic Breast Cancer
Condition: Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Pazopanib plus capecitabine
Intervention description: Patients will receive pazopanib tablets once daily at a dose according to the allocated dose level:
dose level I: 400 mg
dose level II: 600 mg
dose level III: 800 mg
In addition patients receive capecitabine at the same oral dose for all dose levels with 1600 mg/m2 on days 1 to 14 every 3 weeks.
Treatment will be given until disease progression or unacceptable toxicity of the study drug, or withdrawal of consent of the patient.
Six patients will be recruited in each dose level. If less than 2 out of 6 patients experience a DLT within the first 2 cycles (weeks 1 to 6), the next dose level is started. Once the MTD is established, additional 6 patients will be included into this dose level to further characterise the safety of the dose regimen.
If it is reported, that two patients had a DLT, all patients are informed about it and the dose level immediately reduced by one dose level.
Intervention MeSH terms: Capecitabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: German Breast Group; GBG Forschungs GmbH; GBG; GBG 62; PazoX; Breast Cancer; Metastatic Breast Cancer; Pazopanib; Abraxane; Capecitabine; Xeloda

Summary:

      Angiogenesis is essential for the growth of large tumor. A number of anti-angiogenic agents
      are currently under development. Bevacizumab, a humanised monoclonal antibody to vascular
      endothelial growth factor (VEGF), has been shown to improve disease free survival in first
      line metastatic breast cancer when associated with chemotherapy 1. Results of a randomised
      phase II trial combining sorafenib, a tyrosine kinase inhibitor targeting multiple tyrosine
      kinases including VEGFR1, VEGFR2, VEGFR3, with capecitabine have recently been reported 2.
      Compared to capecitabine plus placebo, progression-free survival in the capecitabine +
      sorafenib arm was significantly increased from 4.1 months to 6.4 months. Toxicities were also
      increased, with an incidence rate of grade 3/4 hand foot syndrome of 45% in the capecitabine
      + sorafenib arm compared to 13% in the capecitabine + placebo arm. The increased toxicity
      will most likely limit the clinical use of this regimen.

      Pazopanib is a potent, multi-targeted TKI of VEGFR-1, -2, -3, PDGFR-α and -β and c-kit and
      has recently been approved for the treatment of renal cell cancer in the U.S. In the EU, a
      positive opinion has been issued by the European Medicines Agency.

      A phase II study of GW786034 (pazopanib) in patients with recurrent or metastatic invasive
      breast carcinoma included 19 patients after a maximum of 2 lines of chemotherapy for advanced
      disease 3. Pazopanib 800 mg daily was given continuously.

      A clinically significant rate of stable disease (58%) was detected with a median TTP of 5.3
      months (95% CI: 1.8 - 9.0 months). Four patients treated with pazopanib had SD for ≥ 6
      months, for a clinical benefit rate (CBR), defined as rate of SD for ≥ 6 months or CR or PR,
      of 5/19 (26%), which is at least comparable to sunitinib and bevacizumab (CBR 16% and 17%,
      respectively).

      The pivotal study of full dose (800 mg) daily pazopanib in renal cell cancer reported hand
      foot syndrome of all grades in only 6% of patients 4. The optimally tolerated regimen (OTR)
      of pazopanib was determined when administered in combination with capecitabine and
      oxaliplatin in patients with advanced CRC 5. In patients who received capecitabine (850 mg
      twice daily) plus 800 mg once daily pazopanib combined with oxaliplatin, the incidence of
      hand foot syndrome of all grades was 24%.

      The present study will investigate the combination of pazopanib and capecitabine in advanced
      or metastatic breast cancer with the aim to develop a new treatment option with increased
      efficacy and tolerability.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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.

        Exclusion Criteria:

          -  Known or suspected hypersensitivity reaction to the investigational compounds or
             incorporated substances.

          -  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
             progressive disease.

          -  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
             standard range

          -  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
        study entry.

        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.