Pilot Study Using Avastin and Gleevec to Treat the Progression of Intraluminal Pulmonary Vein Stenosis (PVS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2012 by Children's Hospital Boston
Sponsor:
Information provided by (Responsible Party):
Kathy Jenkins, Children's Hospital, Boston
ClinicalTrials.gov Identifier:
NCT00891527
First received: April 30, 2009
Last updated: August 10, 2012
Last verified: August 2012
  Purpose

The purpose of this study is to determine whether biologic agents Avastin and Gleevec are effective in treating the progression of multivessel intraluminal pulmonary vein stenosis in children.


Condition Intervention Phase
Pulmonary Veno Occlusive Disease
Drug: Bevacizumab (Avastin) and Imatinib Mesylate (Gleevec)
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Adjunct Targeted Biologic Inhibition in Children With Multivessel Intraluminal Pulmonary Vein Stenosis

Resource links provided by NLM:


Further study details as provided by Children's Hospital Boston:

Primary Outcome Measures:
  • Response will be measured by CT angiography or by cardiac angiography if available. Other cardiac assessment techniques will be performed as necessary to confirm findings. [ Time Frame: at baseline, at 24, 48 and 72 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Physical assessment and interim history will be performed to assess for the occurrence of adverse events. Laboratory studies will be drawn and reviewed by the oncology team. Results of these laboratory tests will guide dosing of the medication. [ Time Frame: Every four or two weeks depending on whether patients are started on Gleevec only or on both Gleevec and Avastin ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 20
Study Start Date: October 2008
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Avastin and Gleevec Drug: Bevacizumab (Avastin) and Imatinib Mesylate (Gleevec)

Imatinib Mesylate Orange to grayish orange, opaque, 100mg capsules dissolved in 50-100mls of mineral water or apple juice. Given at 340mg/m2 once daily, preferably with a meal.

Bevacizumab Clear to slightly opalescent liquid. Given at 10mg/kg once every 2 weeks IV. The calculated dose should be placed in an IV bag and diluted with 0.9% sodium chloride to obtain a final volume of 25-100mls. The vials contain no antibacterial preservatives. Once diluted, must be administered within 8 hrs. Initially administered over 90 mins. If no adverse reactions occur, 2nd dose administered over 60 mins. If still no adverse reactions, subsequent doses administered over 30 mins. If infusion-related adverse reactions occur, further infusions administered over the shortest period that was well tolerated.

Other Names:
  • Bevacizumab (rhuMAb VEGF, Avastin), NSC 704865
  • Imatinib Mesylate (Gleevec, STI571), NSC 716051, IND 61,135

Detailed Description:

Intraluminal pulmonary vein stenosis is rare but life threatening disease that affects both infants and children. It can be isolated to a single pulmonary vein, but most often occurs in multiple vessels simultaneously. It can occur as a complicating feature of complex congenital heart disease, but can also occur in isolation in infants with otherwise normal hearts. Response to conventional surgical or transcatheter-based therapies is usually short-lived. Typically within 3 to 4 weeks the obstruction recurs. Repeat surgical attempts provide only temporary relief and eventually all of these infants die without lung transplantation.

While the cause of this disease is unknown the mechanism of progressive obstruction has recently been determined through biopsy and autopsy reviews to result from neo-proliferative cells identified as myofibroblasts which have cell markers VEGF and PDGF. Chemotherapeutic agents Avastin and Gleevec have shown to inhibit myo-proliferation through these markers. The overall objective of this protocol is to conduct a pilot study using the biologic agents Avastin and Gleevec to treat progression of intraluminal pulmonary vein stenosis (PVS). From this pilot group of 10 patients we will attempt to provide an enhanced characterization of the progressive primary disease process, as well as its secondary manifestations. Results will be analyzed descriptively; data gathered from this pilot study will be used to inform further study examining safety and efficacy outcomes.

The study objectives will be accomplished by achievement of the following Specific Aims:

  1. To describe the feasibility of administration of Gleevec® with or without Avastin® to treat the progression of intraluminal PVS in patients with multivessel disease. Patients with PVS in conjunction with congenital heart disease (CHD) will receive Gleevec® alone, with Avastin® added if significant progression occurs; patients with primary PVS and PVS in conjunction with lung disease will be treated with both drugs simultaneously.
  2. To characterize the time to progression and the proportion of patients who survive 48 weeks after enrollment.
  3. To describe the toxicity associated with administration of Gleevec® with or without Avastin® during a 48 week course of treatment among patients with multivessel PVS.

Response to therapy will be described by summarizing severity of obstruction, lobar involvement, lung involvement, left atrial wall involvement and mediastinal involvement and will be measured by CT angiography at baseline,24,48 and 72 weeks or by cardiac angiography if available. Other cardiac assessment techniques will be performed as necessary to confirm findings. Patients will be assessed by the oncology team regularly. At this time Lab studies will be drawn and reviewed & a physical assessment and interim history will be performed to assess for the occurrence of adverse events.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Eligibility Criteria: (Both groups)

  • Evidence of intraluminal pulmonary vein stenosis in > 1 vessel
  • Evidence of myofibroblast neo-proliferation, if biopsies were obtained
  • Acceptable organ function includes:

Creatinine < 1.5 x normal for age. Bilirubin < 1.5 x normal for age. ALT < or = 5x normal ANC > or = 1,500/mm3, Hemoglobin > or = 10g/dl, Platelets > or = 100,000/mm3.

Group A Eligibility Criteria: (begin treatment with Gleevec® only)

  • Significant concomitant congenital heart defect
  • Disease severity for each vessel Category 5 or lower or Category 6 or 7 in no more than 1 vessel

Group B Eligibility Criteria: (begin treatment with Gleevec® and Avastin®)

  • Primary PVS (i.e. without concomitant congenital heart defect or lung disease)
  • Significant concomitant lung disease
  • Patients with PVS and underlying CHD who have category 6 or 7 disease in at least 2 of their pulmonary veins even after surgical or cath-based interventions.
  • Accepted organ function includes:

Urine protein < 1

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00891527

Contacts
Contact: Kathy J Jenkins, MD, MPH (617)355-7275 Kathy.Jenkins@cardio.chboston.org
Contact: Mark W Kieran, MD, PhD (617) 632-4907 Mark_Kieran@dfci.harvard.edu

Locations
United States, Massachusetts
Children's Hospital Boston Recruiting
Boston, Massachusetts, United States, 02115
Contact: Kathy J Jenkins, MD, MPH    617-355-7275    Kathy.Jenkins@cardio.chboston.org   
Contact: Mark W Kieran, MD, PhD    (617) 632-4907    Mark_Kieran@dfci.harvard.edu   
Sub-Investigator: James Lock, MD         
Sub-Investigator: Laureen Sena, MD         
Sub-Investigator: Kimberlee Gauvreau, ScD         
Sub-Investigator: Steven Colan, MD         
Sub-Investigator: Antonio Perez-Atayde, MD         
Sub-Investigator: Thomas Kulik, MD         
Sub-Investigator: Frederick Grant, MD         
Sub-Investigator: Ted Treves, MD         
Principal Investigator: Kathy J Jenkins, MD, MPH         
Sub-Investigator: Mark W Kieran, MD, PhD         
Sponsors and Collaborators
Kathy Jenkins
Investigators
Principal Investigator: Kathy J Jenkins, MD, MPH Children's Hospital Boston, MA
  More Information

Publications:

Responsible Party: Kathy Jenkins, Kathy J. Jenkins, MD, MPH, Children's Hospital, Boston
ClinicalTrials.gov Identifier: NCT00891527     History of Changes
Other Study ID Numbers: 07060249
Study First Received: April 30, 2009
Last Updated: August 10, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Children's Hospital Boston:
Pulmonary Vein Stenosis,
Avastin and Gleevec,
Targeting VEGF and PDGF

Additional relevant MeSH terms:
Pulmonary Veno-Occlusive Disease
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Cardiovascular Diseases
Bevacizumab
Imatinib
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 22, 2014