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

Early Phase 1

Withdrawn

• Conditions: End Stage Renal Disease; Hemodialysis Vascular Access Failure
• Interventions: Drug: 1.25mg bevacizumab; Drug: 2.50mg bevacizumab

• Registration Number: NCT02695641
• Lead Sponsor: Mayo Clinic

Brief Summary

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

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 Timeline

• Study First Submitted: 2016-02-25
• Study First Submitted QC: 2016-02-29
• Study First Posted: 2016-03-01
• Study Start: 2019-08-01
• Status Verified: 2020-07
• Last Update Submitted: 2020-07-06
• Last Update Posted: 2020-07-08
• Primary Completion: 2020-08
• Study Completion: 2021-11

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Stage 1 - Low dose administration	1.25mg bevacizumab	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.
Stage 2 - Dose escalation	2.50mg bevacizumab	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Safety Profile/ Adverse Events (NCI-CTCAE v. 4.0) monitoring	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