bevacizumab in hereditary hemorrhagic telangiectasia

Conditions: Hereditary Hemorrhagic Telangiectasia

Summary: 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 33 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.

Eligibility criteria:
inclusion criteria * 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 ≥2,000/mcl * absolute neutrophil count ≥1,000/mcl * platelets ≥50,000/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. * 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 * 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 or epsilon-aminocaproic acid 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 prior to the initiation of the study (day 1). 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. 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. * recent hemoptysis, defined as hemoptysis of greater than or equal to one-half teaspoon of blood in the month prior to enrollment. * unwillingness to receive red blood cell transfusions and/or intravenous iron infusions according to the hematologic support protocol (hsp) while on study. * participants who have surgery planned within 6 months of trial enrollment, or those who have undergone surgery within 1 month of trial enrollment. * participants who have received therapeutic endoscopy for gastrointestinal bleeding or nasal surgery for epistaxis within 1 month of trial enrollment. * participants who have a history of major thrombophilia, including multiple prior venous and/or arterial thromboembolic events, that in the opinion of the investigator would put them at excessive thrombotic risk. * any other medical condition or factor that, in the opinion of the investigator, is likely to interfere with completion of the study.

Keywords: hereditary hemorrhagic telangiectasia