Reduction of Plasma Free VEGF-A Using Low-dose Bevacizumab in Hemodialysis Patients

Study Overview
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Brief Summary
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The primary purpose of this pilot study is to assess the pharmacokinetic profile of low-dose bevacizumab and its effectiveness in reducing plasma free VEGF-A levels safely in hemodialysis patients. This information will be used to plan a phase 1 clinical trial evaluating bevacizumab's role in hemodialysis vascular access failure.

Detailed Description
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It has been found that hemodialysis arteriovenous fistula failure is partly mediated through a VEGF pathway. The administration of bevacizumab (a VEGF-A monoclonal antibody) in arteriovenous fistula (AVF) murine models at a dose of 5mg/kg (a standard chemotherapeutic dose) has shown a significant reduction in stenosis formation and an overall improvement in vascular remolding. However, previous pharmacokinetic human studies have shown that bevacizumab administered at a low dose of 1.25mg intravitreally (ocular neovascularization patients) is sufficient enough to suppress circulating VEGF-A levels up to 30 days post administration. A chart review on 14 hemodialysis patients receiving an arteriovenous access and intravitreal bevacizumab has demonstrated a significant improvement in patency (HR: 0.45, p-value: 0.037) when compared to controls. Prior to a phase 1 trial, it is essential to determine if intravenous administration of bevacizumab demonstrates the same pharmacokinetics and bio-response profile as intravitreal administration, and to determine the optimal dose and frequency. This phase 0 study will be conducted in 10 existing hemodialysis patients at a dose of 1.25mg with a potential dose escalation to 2.5mg if optimal results are not seen. The findings from this study can have a substantial clinical impact not only in ESRD patients but also in patients receiving other vascular or endovascular procedures.

Official Title
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A Phase 0 Study to Evaluate the Pharmacokinetics of Low-dose Bevacizumab and Its Efficacy on Reducing Plasma Free Vascular Endothelial Growth Factor-A (VEGF-A) in Hemodialysis Patients

Conditions
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End Stage Renal Disease, Hemodialysis Vascular Access Failure

Intervention / Treatment
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* Drug: 1.25mg bevacizumab
* Drug: 2.50mg bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients between 18 and 85 years old, inclusive Patients with end stage renal disease (ESRD) who are currently undergoing hemodialysis treatment through an upper extremity fistula Hemoglobin ≥8g/dL and platelet count ≥100,000/mm3 prior to Day 1 Adequate liver function, defined as serum bilirubin ≤1.5 mg/dL; gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine transaminase (ALT), and alkaline phosphatase ≤2x upper limit of normal or international normalized ratio (INR) ≤ 1.5 prior to Day 0 or INR ≤ 2 if on anticoagulant therapy. Ability to communicate meaningfully with investigative staff, competence to give written informed consent, and ability to comply with entire study procedures If female and of childbearing years, must have a negative serum pregnancy test at the screening visit (Visit 1). Both female patients of childbearing potential and male patients with childbearing potential partners must be willing to use contraception from the time of screening to completion of the study Life expectancy of at least 1 year Exclusion Criteria Known sensitivity to bevacizumab or prior treatment with any medication known to target VEGF Current use of medications that are known to interact with the safety and efficacy of bevacizumab (most commonly: Antineoplastics (Anthracyclines), Belimumab, Bisphosphonate Derivatives, Clozapine, Dipyrone, Irinotecan, Sorafenib, and Sutent) History or evidence of severe cardiac disease (NYHA Functional Class III or IV), myocardial infarction within six months of study entry (Day 1), ventricular tachyarrhythmias requiring continuing treatment, or unstable angina Significant uncontrolled hypertension (systolic blood pressure above 160 mm Hg and/or diastolic blood pressure above 100 mm Hg); Stroke within six (6) months of study entry (Day 1) Treatment with any investigational drug/ device within 60 days prior to study entry (Day1) Treatment with vitamin K-antagonists or direct thrombin inhibitors with an INR ≥2 All patients (including both female patients of childbearing potential and male patients with childbearing potential partners) who do not use a highly effective method of birth control (failure rate less than 1% per year when used consistently and correctly), e.g. implants, injectables, combined oral contraceptives in combination with a barrier method, some intrauterine contraceptive devices, sexual abstinence, or a vasectomized partner Malignancy or treatment for malignancy within the previous 6 months Immunodeficiency including AIDS / HIV or Active autoimmune disease Documented hypercoagulable state or history of 2 or more deep vein thromboses (DVTs) or other spontaneous intravascular thrombotic events Bleeding diathesis or Anemia with a hematocrit level of less than 30% A prothrombin time or a partial thromboplastin time more than 1.2 times the upper limit of normal, or absolute platelet counts below the lower limit of normal; an absolute neutrophil count below 1,500/mm3 Active local or systemic infection (WBC > 15,000/mm3) Gastrointestinal ulcer or bleeding, or wound dehiscence Scheduled elective surgery within 2 months of start date Known serious allergy to aspirin or penicillin Any other condition which in the judgment of the investigator would preclude adequate evaluation of the safety and efficacy of bevacizumab Employees of the sponsor or patients who are employees or relatives of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1 - Low dose administration<br>Ten hemodialysis patients will receive IV infusion treatment with 1.25mg bevacizumab and undergo serial blood draws on Days 0, 1, 3, 6, 10, 15, 22, and 29 during dialysis sessions. ELISA will be performed to evaluate drug serum concentration and corresponding plasma free VEGF-A levels (pg/ml). The safety and pharmacokinetic/dynamic (PK/PD) data will be analysed and ≥50% VEGF-A suppression retained from baseline by Day 15 will be considered successful. If target outcomes are met in stage 1, the study will be terminated, otherwise the study will progress to stage 2. | Drug: 1.25mg bevacizumab<br>* Bevacizumab is a monoclonal antibody against VEGF-A. 1.25mg in 50ml 0.9% Sodium Chloride will be administered once as an intravenous infusion over 30 minutes.<br>* Other names: Avastin;|
| Experimental: Stage 2 - Dose escalation<br>If outcomes are not met in stage 1, Ten additional hemodialysis patients will receive IV infusion treatment with 2.50mg bevacizumab treatment. They will undergo serial blood draws on Days 0, 1, 3, 6, 10, 15, 22, and 29 during dialysis sessions. ELISA will be performed to evaluate drug serum concentration and corresponding plasma free VEGF-A levels (pg/ml). The safety and PK/PD data will be analysed and ≥50% VEGF-A suppression retained from baseline by Day 15 will be considered successful. If target outcome is not met, the study will be terminated. | Drug: 2.50mg bevacizumab<br>* Bevacizumab is a monoclonal antibody against VEGF-A. 2.50mg in 50ml 0.9% Sodium Chloride will be administered once as an intravenous infusion over 30 minutes.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum concentration of bevacizumab (nM) | Obtained through serial blood draws and measured through ELISA. | baseline, 4 weeks | 
| Change in plasma free VEGF-A levels (pg/ml) | Obtained through serial blood draws and measured through ELISA. ≥50% suppression from baseline retained by Day 15 will be considered successful. | baseline, 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Profile/ Adverse Events (NCI-CTCAE v. 4.0) monitoring | Monitoring of drug infusion reactions and adverse event development on subsequent follow-up visits at dialysis centers. Monitoring will include but will not be limited to allergic reactions or anaphylaxis, development of hypertension, excessive bleeding or thromboembolic events | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arteriovenous Fistula, Arteriovenous Graft, Bevacizumab, Hemodialysis, VEGF, Avastin