Effects of Pazopanib on Hereditary Hemorrhagic Telangiectasia Related Epistaxis and Anemia (Paz)

Part B

Inclusion Criteria (all of the following are necessary):

• A definite or probable diagnosis of hereditary hemorrhagic telangiectasia (HHT):

1. Definite clinical HHT 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 orspinal AVMs.
• A first degree relative with HHT according to these criteria.

2. OR a definite diagnosis of HHT based on a pathogenic genetic mutation for HHT.

3. OR probable HHT based on having 2 of the above criteria with high clinicalsuspicion of HHT.

• Stable IV iron use and/or blood transfusions stable for 12 weeks prior to testproduct initiation.

• Must agree not to undergo cautery of nasal telangiectasias or to start new therapiesfor HHT while on study.

• Women of childbearing potential must agree to abstinence or to use an acceptabledouble method contraception until 4 weeks after drug termination. Pregnancy testingwill be done throughout the trial.

• Men are mandated to use condoms.

• Capable of giving signed informed consent.

• Able and willing to return for outpatient visits at the protocol specifiedintervals.

• Able and willing to complete blood pressure monitoring at home.

• Able and willing to complete daily patient reported outcome measurements at home.

• Must meet all of the inclusion criteria for either:

Severe Anemia Cohort:

i. Anemia mainly due to HHT (in the judgment of the PI) with average Hgb <10 g/dL regardless of gender (average of at least three measures during screening and run in).

ii. Epistaxis averaging at least 5 min/week over the six-week baseline and is generally stable in the clinical judgement of the investigator.

Severe Epistaxis Cohort:

i. Anemia mainly due to HHT (in the judgment of the PI) with Hgb <12 g/dL in women or <13 g/dL in men (average of at least three measures during screening and run in).

ii. Epistaxis averaging at least 20 min/week over the six-week baseline and is generally stable in the clinical judgement of the investigator.

Part B

Exclusion Criteria:

• Participant has known immediate or delayed hypersensitivity reaction or idiosyncrasyto drugs chemically related to pazopanib that in the opinion of the investigatorcontradicts their participation.

• Currently has incompletely treated cerebral arterio-venous malformations (AVMs) orcerebral arteriovenous fistulas (AVFs) that are symptomatic or have high-riskfeatures detected on either MRI/MRA or digital subtraction angiography. High-riskfeatures include: microhemorrhage seen on MRI; feeding artery aneurysm, nidusaneurysm or venous outflow stenosis seen on MRA, CTA, or catheter angiography.Non-shunting vascular brain lesions such as capillary vascular malformations,telangiectasias, and cavernous malformations are not an exclusion criterion. (Note:MRI scan does not need to be repeated at screening if AVMs and AVFs were absent on ascan at age ≥18 years).

• Currently has perfused pulmonary AVMs with feeding artery diameter ≥ 3mm.

• Known significant bleeding sources other than nasal or gastrointestinal.

• Systemic use of a potent VEGF inhibitor (e.g., direct inhibitors of VEGF-receptorsignaling such as sunitinib) in the 4 weeks prior to enrollment. Systemic use ofbevacizumab in the 6 weeks prior to enrollment due to its longer half-life.

• Active and recent onset of clinically significant diarrhea.

• Current or recent (in the last 5 years) malignancies (except non-melanoma skincancers)

• Participant has had major surgery (e.g. surgical ligation of an AVM) or traumawithin 28 days or had minor surgical procedures (e.g. central venous access lineremoval) within 7 days prior to dosing, the latter representing a recent wound,fracture or ulcer

• Participant has a planned surgery during periods of active treatment and 6 weeks offollow up; case by case evaluation if PI desires inclusion with medical monitoragreement.

• Participant has clinically significant gastrointestinal abnormalities (other thanhereditary hemorrhagic telangiectasia related vascular lesions).

• Participant during the 6 months prior to first dose of study drug has a history ofcerebrovascular accident (including transient ischemic attacks), pulmonary embolism,untreated deep vein thrombosis (DVT), myocardial infarction, or any other thromboticevent.

• Presence of intrinsic heart disease as evidenced by any of the following: Echoderived left ventricular ejection fraction < 45%; Unstable obstructive CAD; historyof MI, CABG, or PCI in the last 6 months; Infiltrative and/or restrictivecardiomyopathies; Significant pericardial disease; or clinical heart failure withmore than moderate mitral valve or aortic valve disease. In the absence of clinicalheart failure, EKG abnormalities, or known cardiac functional disease (e.g., MI orcardiomyopathy), a previous echo during adulthood is adequate. If there is historyfor coronary disease or cardiomyopathy, an echo in the past 5 years will be adequatefor screening. If the patient has current clinical heart failure, a recent cardiacevent in last 5 yrs, or a cardiac event since the most recent echo, an echo in thepast 6 months will be necessary for screening. Clinical heart failure due to liverAVM or anemia, and not associated with the above findings (with an EF >=45%) will beeligible for enrollment.

• Unable or unwilling to discontinue use of prohibited medications list in Section 6.5.2 for at least 14 days or 5 half-lives of a drug (whichever is longer) prior tothe randomization and for the duration of the study.

• The participant has participated in a clinical trial and has received aninvestigational product within the following time period prior to the start ofrandomization: 4 weeks, 4 half-lives or the duration of the biological effect of theinvestigational product (whichever is longer).

• QT corrected interval >450 msec for men or >460 msec for women, based on averaged QTcorrected interval values of triplicate ECGs obtained over a brief recording period.

• History of familial prolonged QT.

• Any concomitant medication which is known to prolong QT.

• Average baseline hemoglobin <6 g/dL.

• Platelets < 75x10^9 /L.

• International normalized ratio (INR) > 1.5x ULN or activated partial thromboplastintime (aPTT) > 1.5x ULN (unless due to known concurrent medications, e.g. warfarin).

• Alanine Transaminase (ALT) >2 x upper limit of normal.

• Bilirubin >1.5x upper limit of normal (isolated bilirubin >1.5x upper limit ofnormal is acceptable if bilirubin is fractionated and direct bilirubin < 35%).

• Participant has poorly controlled hypertension [defined as systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg]. If BP is poorlycontrolled at screen visit, initiation or adjustment of antihypertensivemedication(s) is permitted during the run-in period prior to randomization. Prior torandomization, blood pressure must be assessed three times and the mean SBP/DBP mustbe < 140/90 mmHg in order for a patient to be randomized.

• Substantive renal disease (eGFR <30 mL/min/1.73m2calculated using theCockcroft-Gault formula)

• Echo derived left ventricular ejection fraction < 45%.

• Thyroid stimulating hormone (TSH) > 1.5 x upper limit of normal.

• Urine protein to creatinine ratio > 0.4.

• Neutrophil count <1000 /mm^3.

Part C Eligibility

All patients who completed Part B will be eligible for Part C unless significant safety concerns have been raised.

Participants must be able and willing to sign the Extension ICF.

Neither the Study Doctor or the participant will be informed of which drug (active or placebo) received during Part B.