Bevacizumab In Hereditary Hemorrhagic Telangiectasia
Bevacizumab In Hereditary Hemorrhagic Telangiectasia
This research study is studying to see whether bevacizumab may treat chronic bleeding and
 iron deficiency anemia in Hereditary Hemorrhagic Telangiectasia (HHT).

 Hereditary Hemorrhagic Telangiectasia (HHT) is a disorder that causes abnormal blood vessel
 formation. In HHT, there is a mutation in the TGF-β pathway, which results in an increase of
 vascular endothelial growth factor (VEGF) levels. An increase in VEGF levels can result in
 poorly formed blood vessels that have a higher rate of bleeding than normal blood vessels.
 Bevacizumab is designed to block VEGF activity. It is believed that targeting increased VEGF
 levels may be able to treat HHT.

 This research study involves the following study drug:

 - Bevacizumab
In this research study, the investigators are studying the study drug, bevacizumab.
 Researchers would like to see whether bevacizumab effectively treats Hereditary Hemorrhagic
 Telangiectasia (HHT) and what side effects occur.

 - The research study procedures include: screening for eligibility, pretreatment period,
 study treatment, end-of-study visit, and follow-up visit.

 -  Participants will be observed for 12 weeks and then receive study treatment for 24 weeks
 and will be followed for 30 days after ending study treatment.

 -  This research study involves the following study drug: Bevacizumab

 -  It is expected that about 20 people will take part in this research study.

 This research study is a Phase II clinical trial. Phase II clinical trials test the safety
 and effectiveness of an investigational drug to learn whether the drug works in treating
 Hereditary Hemorrhagic Telangiectasia (HHT). "Investigational" means that the drug is being
 studied.

 The U.S. Food and Drug Administration (FDA) has not approved bevacizumab for Hereditary
 Hemorrhagic Telangiectasia (HHT), but it has been approved for other uses.
Inclusion Criteria

 -  All laboratory test criteria for study inclusion may be obtained at any point in the
 30-day screening period.

 -  A clinical diagnosis of "possible/suspected" or "definite" hereditary hemorrhagic
 telangiectasia, as defined by presence of 2 or more of the Curacao criteria
 (spontaneous and recurrent epistaxis, telangiectasias at characteristic sites,
 visceral arteriovenous malformations (AVMs), first degree relative with HHT).

 -  Age ≥18 years. Because no dosing or adverse event data are currently available on the
 use of bevacizumab for HHT in participants <18 years of age, children are excluded
 from this study, but will be eligible for future pediatric trials.

 -  Red blood cell transfusion and/or iron infusion dependence, as defined by a
 hematologic support score (HSS) of ≥3 in the 3 months prior to consent. HSS is
 calculated by dividing the total milligrams of elemental iron infused by 250 and
 adding to this the number of red cell units transfused.

 -  ECOG performance status ≤2 (see Appendix B).

 -  Participants must have adequate organ and marrow function as defined below:

 -  leukocytes ≥2,500/mcL

 -  absolute neutrophil count ≥1,500/mcL

 -  platelets ≥75,000/mcL

 -  AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN*

 -  creatinine ≤ 2.5 mg/dL OR

 -  glomerular filtration rate (GFR) ≥45 mL/min/1.73 m2

 -  Except AST and/or ALT elevation related to HHT-associated hemolytic anemia or liver
 AVMs, in the opinion of the investigator. Bilirubin thresholds are not included as
 mild chronic hyperbilirubinemia is common in HHT, likely related to subclinical
 hemolysis in AVMs. Patients with clinically advanced liver disease should be excluded
 from participation per 3.2.16.

 -  The effects of bevacizumab on the developing human fetus are unknown. For this reason
 and because anti-angiogenic agents are known to be teratogenic, women of child-bearing
 potential and men must agree to use adequate contraception (hormonal or barrier method
 of birth control; abstinence) prior to study entry and for the duration of study
 participation. Women should additionally use adequate contraception for the 6 months
 after discontinuation of bevacizumab. Should a woman become pregnant or suspect she is
 pregnant while she or her partner is participating in this study, she should inform
 her treating physician immediately. Men treated or enrolled on this protocol must also
 agree to use adequate contraception prior to the study, for the duration of study
 participation, and 4 months after completion of bevacizumab administration.

 -  Ability to understand and the willingness to sign a written informed consent document

 -  Exclusion Criteria Exclusion Criteria Exclusion Criteria

 Exclusion Criteria

 -  Participants who have received intranasal or systemic bevacizumab, systemic
 ramucirumab, or systemic ziv-aflibercept in the 6 weeks prior to consent.

 -  Participants who have received oral anti-angiogenic agents, including pazopanib,
 axitinib, sorafenib, thalidomide, lenalidomide, or pomalidomide in the 6 weeks prior
 to consent.

 -  Participants receiving oral tranexamic acid, epsilon-aminocaproic acid, or doxycycline
 unless they are on a stable dose for at least 2 weeks prior to consent to be continued
 at that same dose over the entire duration of the study.

 -  Participants receiving erythropoiesis-stimulating agents unless they are on a stable
 dose for at least 4 weeks prior to consent to be continued at that same dose over the
 entire duration of the study.

 -  Participants receiving oral iron preparations must discontinue these preparations
 within 2 weeks prior to the initiation of the study. Multivitamins or other
 pharmaceuticals containing iron are allowed if the daily dose of elemental iron does
 not exceed 25 mg per day.

 -  Participants receiving systemic estrogen or testosterone preparations unless they are
 on a stable dose for at least 4 weeks prior to consent to be continued over the entire
 duration of the study. Use of non-prescription testosterone preparations (e.g. illicit
 anabolic steroids) in the 4 weeks prior to consent is exclusionary.

 -  Participants who are receiving any other investigational agents.

 -  History of allergic reactions to bevacizumab.

 -  Participants with uncontrolled intercurrent illness, in the opinion of the
 investigator.

 -  Participants with psychiatric illness/social situations that would limit compliance
 with study requirements, in the opinion of the investigator.

 -  Pregnant women are excluded from this study because bevacizumab is an anti-angiogenic
 agent with the potential for teratogenic or abortifacient effects. Because there is an
 unknown but potential risk for adverse events in nursing infants secondary to
 treatment of the mother with bevacizumab, breastfeeding should be discontinued if the
 mother is treated with bevacizumab. Pregnancy status will be assessed with a serum
 B-HCG pregnancy test (see Section 10 for timing). Women who are menopausal or
 perimenopausal will have follicle-stimulating hormone levels drawn to confirm
 menopausal status.

 -  Known diagnosis of a hypoproliferative anemia (e.g. myelodysplastic syndrome).
 Nonimmune hemolytic anemia associated with HHT is not exclusionary.

 -  Significant proteinuria, as defined by a urine protein of >2.0 grams per day (on
 24-hour urine protein collection or spot urine protein:creatinine ratio). 24-hour
 urine protein collection or spot urine protein:creatinine ratio is necessary during
 screening to quantify urine protein only in patients with screening urine
 dipstick/urinalysis demonstrates 3+ protein or higher.

 -  Poorly-controlled hypertension, as defined by a systolic blood pressure >160 mm Hg or
 diastolic blood pressure >100 mm Hg refractory to medical management.

 -  Serious or non-healing wound, ulcer or bone fracture.

 -  Unwillingness to receive red blood cell transfusions and/or intravenous iron infusions
 according to the hematologic support protocol (HSP) while on study (see Section 5.8).

 -  Any other medical condition or factor that, in the opinion of the investigator, is
 likely to interfere with completion of the study.