Clinical trial NCT00891527: Pilot Study Using Avastin and Gleevec to Treat the Progression of Intraluminal Pulmonary Vein Stenosis
Official title: Adjunct Targeted Biologic Inhibition in Children With Multivessel Intraluminal Pulmonary Vein Stenosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Pulmonary Veno Occlusive Disease
Keywords: Pulmonary Vein Stenosis,
Avastin and Gleevec,
Targeting VEGF and PDGF
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
First posted: 2009-05-01
Enrollment: 50
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Number of Patients With Survival at 48 Weeks
timeFrame: 48 weeks
Secondary outcomes:
measure: Number of Patients With Disease Progression at 48 Weeks
timeFrame: 48 weeks
measure: Number of Patients With Disease Stabilization at 48 Weeks
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston Childrens Hospital
state: Massachusetts
Study officials:
affiliation: Boston Children's Hospital
name: Kathy J Jenkins, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bini RM, Cleveland DC, Ceballos R, Bargeron LM Jr, Pacifico AD, Kirklin JW. Congenital pulmonary vein stenosis. Am J Cardiol. 1984 Aug 1;54(3):369-75. doi: 10.1016/0002-9149(84)90199-1.
citation: Webber SA, de Souza E, Patterson MW. Pulsed wave and color Doppler findings in congenital pulmonary vein stenosis. Pediatr Cardiol. 1992 Apr;13(2):112-5. doi: 10.1007/BF00798218.
citation: Adey CK, Soto B, Shin MS. Congenital pulmonary vein stenosis: a radiographic study. Radiology. 1986 Oct;161(1):113-7. doi: 10.1148/radiology.161.1.3763853.
citation: Mendelsohn AM, Bove EL, Lupinetti FM, Crowley DC, Lloyd TR, Fedderly RT, Beekman RH 3rd. Intraoperative and percutaneous stenting of congenital pulmonary artery and vein stenosis. Circulation. 1993 Nov;88(5 Pt 2):II210-7.
citation: Driscoll DJ, Hesslein PS, Mullins CE. Congenital stenosis of individual pulmonary veins: clinical spectrum and unsuccessful treatment by transvenous balloon dilation. Am J Cardiol. 1982 May;49(7):1767-72. doi: 10.1016/0002-9149(82)90257-0.
citation: Bahl VK, Chandra S, Mishra S. Congenital stenosis of isolated pulmonary vein: role of retrograde pulmonary vein catheterization. Int J Cardiol. 1997 Jun 27;60(1):103-5. doi: 10.1016/s0167-5273(97)02972-0.
citation: Mendeloff EN, Spray TL, Huddleston CB, Bridges ND, Canter CB, Mallory GB Jr. Lung transplantation for congenital pulmonary vein stenosis. Ann Thorac Surg. 1995 Oct;60(4):903-6; discussion 907. doi: 10.1016/0003-4975(95)00543-t.
citation: Martinez-Climent J, Cavalle T, Ferris Tortajada J. Non-malignant tumors that can mimic cancer during the neonatal period. Eur J Pediatr Surg. 1995 Jun;5(3):156-9. doi: 10.1055/s-2008-1066193.
citation: Herman TE, Siegel MJ. Special imaging casebook. Infantile myofibromatosis: solitary and multifocal varieties. J Perinatol. 1995 May-Jun;15(3):250-2. No abstract available.
citation: Davies RS, Carty H, Pierro A. Infantile myofibromatosis--a review. Br J Radiol. 1994 Jul;67(799):619-23. doi: 10.1259/0007-1285-67-799-619.
citation: Hutchinson L, Sismanis A, Ward J, Price L. Infantile myofibromatosis of the temporal bone: a case report. Am J Otol. 1991 Jan;12(1):64-6.
citation: Goldberg NS, Bauer BS, Kraus H, Crussi FG, Esterly NB. Infantile myofibromatosis: a review of clinicopathology with perspectives on new treatment choices. Pediatr Dermatol. 1988 Feb;5(1):37-46. doi: 10.1111/j.1525-1470.1988.tb00882.x.
citation: Duffy MT, Harris M, Hornblass A. Infantile myofibromatosis of orbital bone. A case report with computed tomography, magnetic resonance imaging, and histologic findings. Ophthalmology. 1997 Sep;104(9):1471-4. doi: 10.1016/s0161-6420(97)30114-6.
citation: Coffin CM, Neilson KA, Ingels S, Frank-Gerszberg R, Dehner LP. Congenital generalized myofibromatosis: a disseminated angiocentric myofibromatosis. Pediatr Pathol Lab Med. 1995 Jul-Aug;15(4):571-87. doi: 10.3109/15513819509026993.
citation: Hasegawa M, Kida S, Yamashima T, Yamashita J, Takakuwa S. Multicentric infantile myofibromatosis in the cranium: case report. Neurosurgery. 1995 Jun;36(6):1200-3. doi: 10.1227/00006123-199506000-00023.
citation: Coffin CM, Dehner LP. Fibroblastic-myofibroblastic tumors in children and adolescents: a clinicopathologic study of 108 examples in 103 patients. Pediatr Pathol. 1991 Jul-Aug;11(4):569-88. doi: 10.3109/15513819109064791.
citation: Stenzel P, Fitterer S. Gastrointestinal multicentric infantile myofibromatosis: characteristic histology on rectal biopsy. Am J Gastroenterol. 1989 Sep;84(9):1115-9.
citation: Weyl Ben Arush M, Meller I, Moses M, Klausner J, Isakov J, Kuten A, el Hassid R. Multifocal desmoid tumor in childhood: report of two cases and review of the literature. Pediatr Hematol Oncol. 1998 Jan-Feb;15(1):55-61. doi: 10.3109/08880019809009508.
citation: Riedlinger WF, Juraszek AL, Jenkins KJ, Nugent AW, Balasubramanian S, Calicchio ML, Kieran MW, Collins T. Pulmonary vein stenosis: expression of receptor tyrosine kinases by lesional cells. Cardiovasc Pathol. 2006 Mar-Apr;15(2):91-9. doi: 10.1016/j.carpath.2005.11.006.
citation: Sadr IM, Tan PE, Kieran MW, Jenkins KJ. Mechanism of pulmonary vein stenosis in infants with normally connected veins. Am J Cardiol. 2000 Sep 1;86(5):577-9, A10. doi: 10.1016/s0002-9149(00)01022-5.