Pazopanib in Combination With Capecitabine in Patients With Metastatic Breast Cancer (PazoX)
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.
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Phase I Study to Assess the Optimal Dose for Pazopanib in Combination With Capecitabine in Patients With HER2-negative, Metastatic Breast Cancer (PazoX)|
- 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.
- Dose-limiting Toxicity (DLT) [ Time Frame: 3 years ]
- Hematological Toxicity of the Combination of Pazopanib and Capecitabine [ Time Frame: 3 years ]
- Other Toxicity of the Combination of Pazopanib and Capecitabine [ Time Frame: 3 years ]
- Objective Response Rate (ORR) [ Time Frame: 3 years ]To determine the objective response rate (ORR) in patients with measurable disease. ORR consists of complete response and partial response according to the RECIST criteria. Complete Response refers to the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to less than 10 mm. Partial Response refers to an at least 30 percent decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
- Clinical Benefit Rate (CBR) [ Time Frame: 3 years ]To determine the clinical benefit rate (CBR) in patients with measurable disease. CBR consists of complete response , partial response, and stable disease lasting greater than 24 weeks. All patients are included when determining this rate. 2 patients were on study treatment for a long time.Hence the outcome rate of 25 percent ( 2 from 8 patients)
|Study Start Date:||October 2010|
|Study Completion Date:||May 2014|
|Primary Completion Date:||December 2011 (Final data collection date for primary outcome measure)|
|Experimental: pazopanib plus capecitabine||
Drug: Pazopanib plus capecitabine
Patients will receive pazopanib tablets once daily at a dose according to the allocated dose level:
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.
To assess the maximum tolerated dose (MTD) of pazopanib in combination with capecitabine as treatment for metastatic HER2-negative breast cancer.
- To determine the dose-limiting toxicity (DLT).
- To determine the compliance and toxicity of the combination.
- To determine the objective response rate (ORR) and clinical benefit rate (CBR) in patients with measurable disease.
- To determine the duration of response.
- To determine the progression-free survival (PFS).
- To determine the predictive value for response of serum markers such as VEGF.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01498458
|GBG Forschungs GmbH|
|Neu-Isenburg, Germany, 63263|