Phase I Study to Assess the Optimal Dose for Pazopanib in Combination With Capecitabine in Patients With HER2-negative, Metastatic Breast Cancer (PazoX)
Overview
- Phase
- Phase 1
- Intervention
- Pazopanib plus capecitabine
- Conditions
- Metastatic Breast Cancer
- Sponsor
- German Breast Group
- Enrollment
- 9
- Locations
- 1
- Primary Endpoint
- Maximum Tolerable Dose (MTD) of Pazopanib
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief 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.
Detailed Description
Primary Objective: To assess the maximum tolerated dose (MTD) of pazopanib in combination with capecitabine as treatment for metastatic HER2-negative breast cancer. Secondary Objective: 1. To determine the dose-limiting toxicity (DLT). 2. To determine the compliance and toxicity of the combination. 3. To determine the objective response rate (ORR) and clinical benefit rate (CBR) in patients with measurable disease. 4. To determine the duration of response. 5. To determine the progression-free survival (PFS). 6. To determine the predictive value for response of serum markers such as VEGF.
Investigators
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.
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
Arms & Interventions
pazopanib plus capecitabine
Intervention: Pazopanib plus capecitabine
Outcomes
Primary Outcomes
Maximum Tolerable Dose (MTD) of Pazopanib
Time Frame: 3 years
The maximum tolerated dose (MTD) is defined as the highest dose level with DLT in no more than 1 out of 6 patients. A maximal tolerated dose (MTD) could not be established.
Secondary Outcomes
- Dose-limiting Toxicity (DLT)(3 years)
- Clinical Benefit Rate (CBR)(3 years)
- Hematological Toxicity of the Combination of Pazopanib and Capecitabine(3 years)
- Objective Response Rate (ORR)(3 years)
- Other Toxicity of the Combination of Pazopanib and Capecitabine(3 years)