Pazopanib for the Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia

An Open-label, Non-randomized Study of the Efficacy of Pazopanib for the Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)

Investigators will test the value of very low dose Pazopanib administered to patients with hereditary hemorrhagic telangiectasia for the reduction in the severity of nose bleeds in those with frequent and long duration bleeding episodes.

Based on frequency and nose bleed duration, a non-randomized, single arm, open label study of 30 hereditary hemorrhagic telangiectasia patients will be treated with very low dose Pazopanib [25mg-similar] for between 16 and 24 weeks.. The primary endpoint is a reduction in bleeding duration of 50% or more, along with multiple secondary related endpoints, including bleed frequency, blood counts and quality of life; as compared to 6-12 weeks of baseline characteristics. If after the first 8 weeks of therapy benefit is suboptimal, dose advance to 50mg-similar daily can be considered.

Inclusion Criteria:

• a definite diagnosis of hereditary hemorrhagic telangiectasia defined as having at least 3 of the following criteria:

  • Spontaneous and recurrent epistaxis.

  • Multiple telangiectasias at characteristic sites: lips, oral cavity, fingers, nose.

  • Visceral lesions: GI telangiectasia, pulmonary, hepatic, cerebral or spinal AVMs.

  • A first degree relative with hereditary hemorrhagic telangiectasia according to these criteria.

  • OR a gene sequencing diagnosis of hereditary hemorrhagic telangiectasia

    2. Epistaxis due to hereditary hemorrhagic telangiectasia at least 2x per week, for a cumulative duration of at least 25 minutes per week

    3. Epistaxis is clinically stable during the 12 weeks prior to screening in the clinical judgment of the investigator (i.e. no major changes in frequency or duration of epistaxis).

    4. Participant agrees not to undergo cautery of nasal telangiectasias or take any experimental therapies for hereditary hemorrhagic telangiectasia other than the study drug while participating in the study.

    5. Male or female [non-child bearing potential]

Exclusion Criteria:

1. Participant has known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib that in the opinion of the investigator contradicts their participation.
2. Currently has untreated cerebral arterio-venous malformations (AVMs), cerebral arteriovenous fistulae, or cerebral cavernous malformations (CCMs) (Note: MRI scan does not need to be repeated at screening if AVMs, arterio-venous fistulas and CCMs were absent on a scan at age ≥18 years).
3. Currently has perfused pulmonary AVMs with feeding artery diameter >3mm.
4. Known significant bleeding sources other than nasal or gastrointestinal.
5. Systemic use of a vascular endothelial growth factor inhibitor in the past 3 months or previous enrollment in this study.
6. Active and recent onset of clinically significant diarrhea.
7. Current or recent (in the last 5 years) malignancies (except non-melanoma skin cancers)
8. Participant has had major surgery (e.g. surgical ligation of an AVM) or trauma within 28 days or had minor surgical procedures (e.g. central venous access line removal) within 7 days prior to dosing, the latter representing a recent wound, fracture or ulcer
9. Participant has a planned surgery during the period to include active treatment and 6 weeks of follow up.
10. Participant has clinically significant gastrointestinal abnormalities (other than hereditary hemorrhagic telangiectasia related vascular lesions)
11. Participant during the 6 months prior to first dose of study drug has a history of cerebrovascular accident (including transient ischemic attacks), pulmonary embolism, untreated deep vein thrombosis (DVT), myocardial infarction, or any other thrombotic event.
12. QTc ≥450 msec, based on averaged QTc values of triplicate ECGs obtained over a brief recording period [The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread. The same QT correction formula must be used for each individual participant to determine eligibility for and withdrawal from the study.]
13. Hgb <6 g/dL.
14. Platelets < 100x109/L.
15. International normalized ratio (INR) >1.2x upper limit of normal and activated partial thromboplastin time (aPTT)>1.2x upper limit of normal.
16. Alanine Transaminase >2x upper limit of normal.
17. Bilirubin >1.5x upper limit of normal (isolated bilirubin >1.5x upper limit of normal is acceptable if bilirubin is fractionated and direct bilirubin <35%).
18. Participant has poorly controlled hypertension [defined as systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg. Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry [between screen and baseline]. At Screening, blood pressure must be assessed three times and the mean SBP/DBP must be <140/90 mmHg in order for a participant to be eligible for the study.]
19. Substantive renal disease (eGFR <30 mL/min/1.73m2calculated using the Cockcroft-Gault formula)
20. Echo derived left ventricular ejection fraction <30%.
21. Thyroid stimulating hormone > upper limit of normal.
22. Urine protein to creatinine ratio >0.3.
23. Neutrophil count <1500/mm3.