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

June 6, 2019 updated by: Kathy Jenkins, Boston Children's Hospital

Adjunct Targeted Biologic Inhibition in Children With Multivessel Intraluminal Pulmonary Vein Stenosis

The objective of this study is to conduct a pilot study using biologic agents Avastin and Gleevec to treat progression of multivessel intraluminal pulmonary vein stenosis in children.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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. Initial study was limited to 10 patients, but was later expanded to 50 enrolled patients.

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.

Patients will be treated with Gleevec® with or without Avastin® for a period of 48 weeks, and will be followed until 72 weeks. Clinical status will be assessed by serial lab testing, monthly echocardiography and lung scans, and baseline and q24 week CT angiography or angiography. Obstruction of individual pulmonary veins will be assessed using a standard score, and patients will be classified as stabilized, recurred or progressed based on changes in the individual vein scores.

Study Type

Interventional

Enrollment (Actual)

50

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Boston Childrens Hospital

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

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

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: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Avastin and/or Gleevec
Patients were all treated with Gleevec (imatinib mesylate) and those without congenital heart disease and those who progressed were also treated with Avastin (bevacizumab).
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Number of Patients With Survival at 48 Weeks
Time Frame: 48 weeks
48 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Patients With Disease Progression at 48 Weeks
Time Frame: 48 weeks
Patients will be classified as having disease progression if at least 2 pulmonary veins have significantly worsened at 48 weeks. This determination is based on the study defined Pulmonary Vein Status Scale, which categorizes pulmonary veins on a scale from "1- None: No narrowing of the luminal contour," to "7- Distal atretic: Complete obliteration of the luminal contour extending >5mm within the vessel segment."
48 weeks
Number of Patients With Disease Stabilization at 48 Weeks
Time Frame: 48 weeks
48 weeks

Collaborators and Investigators

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

Sponsor

Boston Children's Hospital

Investigators

  • Principal Investigator: Kathy J Jenkins, MD, MPH, Boston Children's Hospital

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

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 (Actual)

October 1, 2008

Primary Completion (Actual)

December 1, 2015

Study Completion (Actual)

December 1, 2015

Study Registration Dates

First Submitted

April 30, 2009

First Submitted That Met QC Criteria

April 30, 2009

First Posted (Estimate)

May 1, 2009

Study Record Updates

Last Update Posted (Actual)

June 19, 2019

Last Update Submitted That Met QC Criteria

June 6, 2019

Last Verified

June 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 07060249

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

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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