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

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.

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