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

July 6, 2020 updated by: Sanjay Misra, M.D., Mayo Clinic

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

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Phase

  • Early Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: OTHER
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: SINGLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Stage 1 - Low dose administration
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
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.
Other Names:
  • Avastin
Experimental: Stage 2 - Dose escalation
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
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.
Other Names:
  • Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Serum concentration of bevacizumab (nM)
Time Frame: baseline, 4 weeks
Obtained through serial blood draws and measured through ELISA.
baseline, 4 weeks
Change in plasma free VEGF-A levels (pg/ml)
Time Frame: baseline, 4 weeks
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
Time Frame: 4 weeks
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mayo Clinic

Investigators

  • Principal Investigator: Sanjay Misra, MD, Mayo Clinic

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

August 1, 2019

Primary Completion (Anticipated)

August 1, 2020

Study Completion (Anticipated)

November 1, 2021

Study Registration Dates

First Submitted

February 25, 2016

First Submitted That Met QC Criteria

February 29, 2016

First Posted (Estimate)

March 1, 2016

Study Record Updates

Last Update Posted (Actual)

July 8, 2020

Last Update Submitted That Met QC Criteria

July 6, 2020

Last Verified

July 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 15-007414

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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