Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Capecitabine

Paclitaxel

Albumin-Bound Paclitaxel

Antimetabolites

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.

Pazopanib plus capecitabine

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.

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.

Pazopanib in Combination With Capecitabine in Patients With Metastatic Breast Cancer

Phase I Study to Assess the Optimal Dose for Pazopanib in Combination With Capecitabine in Patients With HER2-negative, Metastatic Breast Cancer (PazoX)

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.

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.

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)

German Breast Group

There was only one arm in this study as this was a dose escalation study.

Pazopanib Plus Capecitabine

premenopausal

Postmenopausal

Age, Customized

Sex: Female, Male

ECOG 0

ECOG 1

ECOG Status refers to the Eastern Cooperative Oncology Group scale . These scales and criteria are used by doctors and researchers to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis...Grade 0 Fully active

* Grade 1 restricted in physically strenuous activity
* Grade 2 Ambulatory and capable of all selfcare
* Grade 3 Capable of only limited selfcare
* Grade 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
* Grade 5 Dead

ECOG

T status describes the size of the original (primary) tumor and whether it has invaded nearby tissue,,,T1 - The tumour is 2 centimetres (cm) across or less...T2 - The tumour is more than 2 centimetres, but no more than 5 centimetres across...T3 - The tumour is bigger than 5 centimetres across...T4 refers to inflamatory breast cancer....Tis means DCIS(ductal carcinoma in situ...The tumors are all breast cancer tumors as the study has to do with breast cancer.

T status

N status is a categorisation of the number of lymph nodes..N0 - No cancer cells found in any nearby nodes...N1 is when 1 to 3 lymph nodes are found.....N2 is when 4 to 9 lymph nodes are found....N2 is when greater than 9 lymph nodes are found

N Status

Grading is a measure of the cell appearance in tumors and other neoplasms in pathology...Grade 1 Well differentiated (Low grade)...

Grade 2 Moderately differentiated (Intermediate grade)... Grade 3 poorly differentiated (High grade)

Grading

ERneg/PRneg

ERneg/PRpos

ERpos/PRneg

ERpos/PRpos

Hormone Receptor Status

Her2 Negative

Her2 Positive

HER2 Status

Dr. Andreas Schneeweiss

A maximal tolerated dose (MTD) could not be established. The study was stopped after 8 patients.

Maximum Tolerable Dose (MTD) of Pazopanib

The following DLTs resulted in permanent discontinuation of the study therapy: hypertension, (DLT 1), mucositis CTC grade 3, hand-foot-syndrome CTC grade 3, increase of liver enzymes (GOT,- and GPT) CTC grade 2 (DLT 2), and increase of liver enzymes (GOT-, GPT) CTC grade 3 (DLT 3).

Spots Global Cancer Trial Database for pazopanib plus capecitabine