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

NCT02695641 | Withdrawn Early Phase 1 FDA Drug

• 1 other identifier: 15-007414
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

End Stage Renal Disease; Hemodialysis Vascular Access Failure

Keywords

Arteriovenous Fistula; Arteriovenous Graft; Bevacizumab; Hemodialysis; VEGF; Avastin

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• Safety Profile/ Adverse Events (NCI-CTCAE v. 4.0) monitoring

  4 weeks

Study Arms (2)

Stage 1 - Low dose administration

EXPERIMENTAL

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

Stage 2 - Dose escalation

EXPERIMENTAL

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

Interventions

1.25mg bevacizumab DRUG

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.

Also known as: Avastin

Stage 1 - Low dose administration

2.50mg bevacizumab DRUG

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.

Also known as: Avastin

Stage 2 - Dose escalation

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Mayo Clinic: lead

Related Publications (7)

• Yang B, Janardhanan R, Vohra P, Greene EL, Bhattacharya S, Withers S, Roy B, Nieves Torres EC, Mandrekar J, Leof EB, Mukhopadhyay D, Misra S. Adventitial transduction of lentivirus-shRNA-VEGF-A in arteriovenous fistula reduces venous stenosis formation. Kidney Int. 2014 Feb;85(2):289-306. doi: 10.1038/ki.2013.290. Epub 2013 Aug 7.

  PMID: 23924957 BACKGROUND

• Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, Couvillion S, Nasir MA, Rabena MD, Le K, Maia M, Visich JE. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol. 2014 Dec;98(12):1636-41. doi: 10.1136/bjophthalmol-2014-305252. Epub 2014 Jul 7.

  PMID: 25001321 BACKGROUND

• Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, Pyles EA, Yancopoulos GD, Stahl N, Wiegand SJ. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012 Jun;15(2):171-85. doi: 10.1007/s10456-011-9249-6.

  PMID: 22302382 BACKGROUND

• Matsuyama K, Ogata N, Matsuoka M, Wada M, Takahashi K, Nishimura T. Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before and after intravitreal injection of bevacizumab. Br J Ophthalmol. 2010 Sep;94(9):1215-8. doi: 10.1136/bjo.2008.156810. Epub 2010 Jun 10.

  PMID: 20538658 BACKGROUND

• Wang D, Choi KS, Lee SJ. Serum concentration of vascular endothelial growth factor after bilateral intravitreal injection of bevacizumab. Korean J Ophthalmol. 2014 Feb;28(1):32-8. doi: 10.3341/kjo.2014.28.1.32. Epub 2014 Jan 21.

  PMID: 24505199 BACKGROUND

• Zehetner C, Kirchmair R, Huber S, Kralinger MT, Kieselbach GF. Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema. Br J Ophthalmol. 2013 Apr;97(4):454-9. doi: 10.1136/bjophthalmol-2012-302451. Epub 2013 Feb 5.

  PMID: 23385630 BACKGROUND

• Garnier-Viougeat N, Rixe O, Paintaud G, Ternant D, Degenne D, Mouawad R, Deray G, Izzedine H. Pharmacokinetics of bevacizumab in haemodialysis. Nephrol Dial Transplant. 2007 Mar;22(3):975. doi: 10.1093/ndt/gfl664. Epub 2006 Nov 8. No abstract available.

  PMID: 17093010 BACKGROUND

Related Links

• Mayo Clinic Clinical Trials

MeSH Terms

Conditions

Kidney Failure, Chronic; Arteriovenous Fistula

Interventions

Bevacizumab

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Arteriovenous Malformations; Vascular Malformations; Cardiovascular Abnormalities; Cardiovascular Diseases; Vascular Fistula; Vascular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Fistula; Pathological Conditions, Anatomical

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Sanjay Misra, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, Professor, Department of Radiology

Study Record Dates

• First Submitted: February 25, 2016
• First Posted: March 1, 2016
• Study Start: August 1, 2019
• Primary Completion: August 1, 2020
• Study Completion: November 1, 2021
• Last Updated: July 8, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share