Pulmonary Veno Occlusive Disease
Conditions
Keywords
Pulmonary Vein Stenosis,, Avastin and Gleevec,, Targeting VEGF and PDGF
Brief summary
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.
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.
Interventions
DRUGBevacizumab (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.
Sponsors
Boston Children's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Patients With Survival at 48 Weeks | 48 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Disease Progression at 48 Weeks | 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. |
| Number of Patients With Disease Stabilization at 48 Weeks | 48 weeks | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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). | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Avastin and/or Gleevec | — |
|---|---|---|
| Age, Customized >/= 12 months | 13 Participants | — |
| Age, Customized <3 months | 3 Participants | — |
| Age, Customized 3 to <6 months | 15 Participants | — |
| Age, Customized 6 to <12 months | 17 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 21 Participants | — |
| Sex: Female, Male Male | 27 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 11 / 48 |
| other Total, other adverse events | 48 / 48 |
| serious Total, serious adverse events | 10 / 48 |
Outcome results
Primary
Number of Patients With Survival at 48 Weeks
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avastin and/or Gleevec | Number of Patients With Survival at 48 Weeks | 42 Participants |
Secondary
Number of Patients With Disease Progression at 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.
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avastin and/or Gleevec | Number of Patients With Disease Progression at 48 Weeks | 5 Participants |
Secondary
Number of Patients With Disease Stabilization at 48 Weeks
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avastin and/or Gleevec | Number of Patients With Disease Stabilization at 48 Weeks | 15 Participants |