Pazopanib in Combination With Capecitabine in Patients With Metastatic Breast Cancer

NCT01498458 | Completed Phase 1 Results DMC

• 2 other identifiers: GBG 622010-019510-25
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Breast Cancer

Keywords

German Breast Group; GBG Forschungs GmbH; GBG; GBG 62; PazoX; Breast Cancer; Metastatic Breast Cancer; Pazopanib; Abraxane; Capecitabine; Xeloda

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerable Dose (MTD) of Pazopanib

  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.

  3 years

Secondary Outcomes (5)

• Dose-limiting Toxicity (DLT)

  3 years

• Hematological Toxicity of the Combination of Pazopanib and Capecitabine

  3 years

• Other Toxicity of the Combination of Pazopanib and Capecitabine

  3 years

• Objective Response Rate (ORR)

  3 years

• Clinical Benefit Rate (CBR)

  3 years

Study Arms (1)

pazopanib plus capecitabine

EXPERIMENTAL

Drug: Pazopanib plus capecitabine

Interventions

Pazopanib plus capecitabine DRUG

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

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GBG Forschungs GmbH: lead

Study Sites (1)

GBG Forschungs GmbH

Neu-Isenburg, 63263, Germany

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

pazopanib; Capecitabine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Dr. Andreas Schneeweiss
• Organization: University Hospital Heidelberg

andreas.schneeweiss@med.uni-heidelberg.de

+49 (0)6221 56 36051

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2011
• First Posted: December 23, 2011
• Study Start: October 1, 2010
• Primary Completion: December 1, 2011
• Study Completion: May 1, 2014
• Last Updated: June 10, 2022
• Results First Posted: September 18, 2014

Record last verified: 2014-09

Locations

DE (1)