Safety Study of Gleevec® in Children With Pulmonary Hypertension

Idiopathic pulmonary artery hypertension (IPAH) is a rare but progressive disease in
children and adults with a very high mortality from right heart failure. Platelet derived
growth factor (PDGF) has been implicated in the pulmonary artery remodeling and vascular
proliferation that is a pathologic hallmark of IPAH. Animal and clinical data support the
hypothesis that activation of the PDGF receptor is critical in the development of IPAH, and
inhibition of the PDGF signaling pathways may be a potential therapeutic target. Gleevec is
a tyrosine kinase inhibitor developed for treatment of certain cancers and inhibits the PDGF
receptor. Animal and preliminary clinical data suggest that Gleevec can reverse vascular
remodeling and improve right heart failure. A small clinical trial for adults with IPAH is
ongoing in Europe, but there are no trials in children where the disease has a worse
prognosis. This project is a phase II, single dose pilot study to generate the hypothesis
that activation of the PDGF receptor is critical in the development of IPAH, and inhibition
of the PDGF signaling pathways is a potential therapeutic target. Five patients between the
ages of 8 yr to 18 yr with severe IPAH will be recruited nationally, for a 6 month trial of
Imatinib. The Specific Aim of this study is to collect preliminary data on the safety and
efficacy of Gleevec in children with IPAH. Results from this study are needed to develop a
larger, multi-center trial to determine the efficacy and therapeutic impact of Gleevec in
children with IPAH. The long term goal of this work is to develop novel therapeutic
strategies for treatment of IPAH in children. This translational study of the inhibition of
the PDGF receptor in children with IPAH could provide insights into the etiology of IPAH and
have a major impact on the development of new treatment strategies for both children and
adults with pulmonary artery hypertension from multiple origins.

Inclusion Criteria:

1. Male and female patients between the ages of 8 -18 years of age.

2. Diagnosis of idiopathic (or primary) pulmonary arterial hypertension according to the
Venice Classification system (2003).54, 55

3. Functional classification of WHO class III - IV.

4. Pulmonary vascular resistance (PVR) >300 dynes / sec / cm5.

5. IPAH medications stable for at least 3 mo prior to baseline visit.

6. Female patients of child bearing potential who are sexually active must have negative
pregnancy test within 7 days prior to initiation of study drug and use a
double-barrier local contraception, i.e., intra-uterine device plus condom, or
spermicidal gel plus condom up to the Study Completion visit.

7. Able to communicate well with the investigator, to understand and comply with the
requirements of the study. Able to verbalize understanding and sign the written
informed assent.

8. Parents, or legal guardians, must be able to communicate well with the investigator,
to understand and comply with the requirements of the study. They must verbalize
understanding and sign the written informed consent statement.

Exclusion Criteria:

1. Pre-existing lung disease including parasitic diseases affecting lungs, bronchial
asthma, congenital abnormalities of the lungs, thorax and diaphragm.

2. Congenital heart disease, left ventricular failure, or left-sided obstructive lesion
(pulmonary venous hypertension with pulmonary capillary wedge pressure > 12 mmHg)
detected at right heart catheterization.

3. Chronic thromboembolic pulmonary hypertension, congenital or acquired deficiencies of
blood coagulation, deficient thrombocyte function, thrombocytopenia < 40,000/μl, or
Sickle Cell anemia.

4. Pregnancy, breast feeding, or lack of safe contraception (hormonal contraception,
IUD, bilateral tubal ligation, hysterectomy) in premenopausal women.

5. Hepatic insufficiency with transaminase levels >4-fold the upper limit of normal, or
a bilirubin > 2-fold the upper limit of normal.

6. Renal insufficiency (serum creatinine > 200 μmol/l).

7. History of clinically significant drug allergy or history of atopic allergy (asthma,
urticaria, eczematous dermatitis). A known hypersensitivity to the study drug, or
drugs similar to the study drug.

8. Previous therapeutic radiation of lungs or mediastinum.

9. Participation in any treatment studies within 3 months prior to dosing, or longer if
required by local regulations, and for any other limitation of participation based on
local regulations.

10. History of immunodeficiency diseases, including a positive HIV (ELISA and Western
blot) test result, or a positive Hepatitis B surface antigen (HBsAg), or positive
Hepatitis C test result.

11. Any surgical or medical condition which might significantly alter the absorption,
distribution, metabolism or excretion of drugs, such as a history of inflammatory
bowel syndrome, gastritis, ulcers, gastrointestinal or rectal bleeding, or a history
of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or
bowel resection.