Bevacizumab for Hereditary Hemorrhagic Telangiectasia

Overseen By Hanny Al-Samkari, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Hanny Al-Samkari, MD

Must not be taking: Bevacizumab, Ramucirumab, Anti-angiogenics, others

Disqualifiers: Pregnancy, Hypertension, Thrombophilia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 11

33 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires participants to stop taking oral iron preparations before starting the study. However, multivitamins or other products with up to 25 mg of elemental iron per day are allowed. If you are on oral tranexamic acid, epsilon-aminocaproic acid, erythropoiesis-stimulating agents, or systemic estrogen or testosterone, you must be on a stable dose for a specified period before joining the study and continue at that dose during the study.

What data supports the effectiveness of the drug Bevacizumab (Avastin) for treating hereditary hemorrhagic telangiectasia?

Research shows that Bevacizumab has been used to treat severe forms of hereditary hemorrhagic telangiectasia (HHT), including reducing nosebleeds and managing severe liver issues and heart problems related to HHT. Although there are no large-scale trials, smaller studies and surveys suggest it can be effective for these symptoms. ^{1 2 3 4 5}

Is bevacizumab generally safe for humans?

Bevacizumab, also known as Avastin, is generally considered safe for humans, with common side effects including high blood pressure, protein in urine, and bleeding. Serious side effects like wound healing issues, blood clots, and gastrointestinal perforations are less common and usually manageable. ^{6 7 8 9 10}

How is the drug Bevacizumab unique for treating hereditary hemorrhagic telangiectasia?

Bevacizumab is unique for treating hereditary hemorrhagic telangiectasia because it targets and reduces the levels of vascular endothelial growth factor (VEGF), which is often elevated in this condition, helping to control abnormal blood vessel growth. Unlike other treatments, it is administered as an intranasal submucosal injection, and its dosage must be carefully managed to avoid toxicity. ^{11 12 13 14 15}

What is the purpose of this trial?

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

Research Team

Hanny Al-Samkari, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for adults over 18 with Hereditary Hemorrhagic Telangiectasia (HHT), experiencing chronic bleeding and iron deficiency anemia. Participants must meet at least two Curacao criteria, require blood transfusions or iron infusions, and have stable organ/marrow function. Women of childbearing age and men must agree to use contraception.

Inclusion Criteria

I have needed blood transfusions or iron infusions regularly in the last 3 months.

My organs and bone marrow are working well.

Agreement to use adequate contraception for women of child-bearing potential and men

Exclusion Criteria

I have coughed up blood recently.

Psychiatric illness/social situations that would limit compliance with study requirements

My high blood pressure is not well-managed.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pretreatment

Hematologic support including iron transfusions and red cell transfusions as determined by study doctor

12 weeks

Regular visits for transfusions

Induction Treatment

Bevacizumab administered once every 2 weeks via intravenous infusion

12 weeks

6 visits (in-person)

Maintenance Treatment

Bevacizumab administered once every 4 weeks via intravenous infusion

12 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Bevacizumab

Trial Overview The study tests Bevacizumab's effectiveness in treating HHT-related chronic bleeding and anemia by inhibiting VEGF activity, which is believed to reduce the formation of fragile blood vessels that lead to excessive bleeding in HHT patients.

Participant Groups

Group I: Bevacizumab Experimental Treatment 1 Intervention

* The research study procedures include: screening for eligibility, pretreatment period, study treatment, end-of-study visit, and follow-up visit. Each period consists of 12 weeks, for a total of 36 weeks. * Pretreatment Period:Hematologic Support: iron transfusions and red cell transfusions as determined by study doctor. * Induction Period (first 3 months of bevacizumab treatment): * Hematologic Support: iron transfusions and red cell transfusions as determined by study doctor. * Bevacizumab: once every 2 weeks via intravenous infusion for up to 12 weeks. * Maintenance Period (second 3 months of bevacizumab treatment): * Hematologic Support: Iron transfusions and red cell transfusions as determined by study doctor. * Bevacizumab: once every 4 weeks via intravenous infusion for up to 12 weeks.

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

Hanny Al-Samkari, MD

Lead Sponsor

Trials

2

Recruited

90+

Findings from Research

A survey of 31 international HHT Centers of Excellence found that systemic bevacizumab is commonly used for treating high-output cardiac failure (HOCF) in hereditary hemorrhagic telangiectasia (HHT), with 55% of centers reporting significant improvements in cardiac function and symptoms for most patients.

The treatment is considered safe, with 75% of centers reporting adverse event rates below 10%, and discontinuation due to side effects or ineffectiveness being rare, although there is considerable variability in maintenance treatment practices among centers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic bevacizumab for high-output cardiac failure in hereditary hemorrhagic telangiectasia: an international survey of HHT centers. Al-Samkari, H., Albitar, HA., Olitsky, SE., et al.[2020]

In a double-blind, placebo-controlled trial involving 15 adults with hereditary hemorrhagic telangiectasia (HHT), bevacizumab showed a 27% reduction in average daily epistaxis severity compared to only a 3% reduction in the placebo group, indicating a potential benefit.

Although the results did not reach statistical significance (p = .57), the trend suggests that bevacizumab may be effective in reducing nosebleeds in HHT patients, supporting its further investigation as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal submucosal bevacizumab for epistaxis in hereditary hemorrhagic telangiectasia: a double-blind, randomized, placebo-controlled trial. Riss, D., Burian, M., Wolf, A., et al.[2022]

In a retrospective study of 46 patients with severe hereditary hemorrhagic telangiectasia (HHT), intravenous bevacizumab showed clinical improvement in 74% of cases, with effects lasting an average of 6 months.

While bevacizumab appears to be beneficial, there are significant safety concerns, including wound healing complications that led to amputations and instances of arthritis and hypertension, highlighting the need for careful monitoring and further randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intra-venous bevacizumab in hereditary hemorrhagic telangiectasia (HHT): A retrospective study of 46 patients. Guilhem, A., Fargeton, AE., Simon, AC., et al.[2018]

In a study of 20 patients with Hereditary Hemorrhagic Telangiectasia (HHT), bevacizumab significantly improved hemoglobin levels in those with refractory anemia, with median hemoglobin rising from 8.1 g/dl to 10.9 g/dl after treatment, and reducing the need for blood transfusions.

Bevacizumab also showed potential as a bridge therapy for patients with high output cardiac failure, with some patients achieving complete or partial hemodynamic responses, and no serious adverse events were reported during the treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab for treating Hereditary Hemorrhagic Telangiectasia patients with severe hepatic involvement or refractory anemia. Vázquez, C., Gonzalez, ML., Ferraris, A., et al.[2020]

Intranasal bevacizumab injections were found to be an effective treatment for moderate to severe epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT), with 36.3% of patients maintaining a positive response by the end of the study.

The treatment showed variable duration of effectiveness, with some patients experiencing diminishing returns over time, and while no local adverse effects were noted, one patient did develop osteonecrosis in both knees during the treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term experience with intranasal bevacizumab therapy. Steineger, J., Osnes, T., Heimdal, K., et al.[2019]

Bevacizumab (Avastin) effectively targets VEGF to inhibit tumor angiogenesis, showing a safety profile that includes mostly mild to moderate side effects such as hypertension and proteinuria, which are manageable in clinical settings.

The side effects associated with bevacizumab, including rare but serious events like gastrointestinal perforation and arterial thrombosis, do not typically exacerbate the toxicity of standard chemotherapy, making it a suitable adjunct treatment for metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing patients treated with bevacizumab combination therapy. Gordon, MS., Cunningham, D.[2015]

A comprehensive analysis of 96,477 adverse event reports related to bevacizumab revealed 2,847 cases of hemorrhage, highlighting significant safety concerns associated with its use in treating advanced malignant tumors.

The study identified 37 specific hemorrhagic signals linked to bevacizumab, particularly affecting the vascular, gastrointestinal, and nervous systems, with colorectal, lung, and breast cancers being the most commonly associated malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pharmacovigilance study of adverse event profiles and haemorrhagic safety of bevacizumab based on the FAERS database. Tang, L., Ding, C., Li, H., et al.[2023]

In a study involving 10,555 patients with metastatic colorectal cancer, the use of bevacizumab was associated with a significant increase in the risk of hemorrhage, with an overall incidence of 5.8%.

The risk of hemorrhage was found to be dose-dependent, with higher doses (5 mg/kg/week) leading to a greater risk (RR of 4.67) compared to lower doses (2.5 mg/kg/week, RR of 1.73), and the first 6 months of treatment were identified as a critical period for these adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased risk of hemorrhage in metastatic colorectal cancer patients treated with bevacizumab: An updated meta-analysis of 12 randomized controlled trials. Zhu, X., Tian, X., Yu, C., et al.[2022]

Bevacizumab (Avastin) has been shown to improve progression-free and overall survival in patients with various advanced cancers, including colorectal, lung, renal, breast, and ovarian cancers, based on phase III trials and real-world studies.

The safety profile of bevacizumab is well established, with manageable adverse effects such as hypertension and proteinuria, making it a valuable treatment option for patients with advanced cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab: a review of its use in advanced cancer. Keating, GM.[2022]

Bevacizumab, when combined with chemotherapy, significantly improves clinical outcomes and delays disease progression in patients with advanced non-squamous non-small-cell lung cancer (NSCLC), as demonstrated in pivotal phase III trials involving large patient populations.

The safety profile of bevacizumab is well-characterized, with manageable adverse events such as hypertension and bleeding, and the overall incidence of serious side effects is similar to that of placebo, indicating it can be safely administered in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging safety data for bevacizumab in advanced non-small-cell lung cancer. Hirsh, V.[2015]

In a study of 10 patients with Type 2 idiopathic macular telangiectasia, treatment with intravitreal bevacizumab did not lead to improvements in visual acuity or retinal thickness in those with the nonproliferative form of the disease.

However, in patients with proliferative macular telangiectasia, bevacizumab treatment resulted in a decrease in central macular thickness and an improvement in visual acuity, along with the resolution of subretinal neovascularization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal bevacizumab for treatment of proliferative and nonproliferative type 2 idiopathic macular telangiectasia. Roller, AB., Folk, JC., Patel, NM., et al.[2022]

In a study of 39 eyes from 36 patients, intravitreous bevacizumab (Avastin) treatment for choroidal neovascularization (CNV) from non-age-related macular degeneration causes led to significant visual acuity improvement, with median vision improving from 20/60 at baseline to 20/30 after 3 months.

The treatment was effective across various underlying conditions, showing that patients with different causes of CNV experienced similar benefits, although the visual improvement slightly decreased by the last follow-up compared to the 3-month mark.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab treatment for subfoveal choroidal neovascularization from causes other than age-related macular degeneration. Chang, LK., Spaide, RF., Brue, C., et al.[2022]

Intravitreal bevacizumab injections in a 51-year-old female patient with type 2 idiopathic macular telangiectasia led to noticeable visual improvement, especially in reading, after two treatments over a 12-week period.

The treatment resulted in a reduction of hyperfluorescent areas on angiography and improved retinal sensitivity, suggesting that VEGF plays a significant role in the pathophysiology of type 2 IMT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term effects of intravitreal bevacizumab in type ii idiopathic macular telangiectasia. Charbel Issa, P., Scholl, HP., Holz, FG.[2014]

In an in vitro study of endothelial cells from hereditary hemorrhagic telangiectasia (HHT) patients, bevacizumab showed an initial decrease in cell proliferation, but lower concentrations (up to 4 mg/ml) allowed for recovery within 72 hours.

Higher concentrations of bevacizumab (10 mg/ml) continuously reduced VEGF expression and cell proliferation, indicating that for clinical use, the concentration should not exceed 4 mg/ml to minimize toxicity risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An in vitro study on the effect of bevacizumab on endothelial cell proliferation and VEGF concentration level in patients with hereditary hemorrhagic telangiectasia. Sadick, H., Schäfer, E., Weiss, C., et al.[2022]

Intravitreal bevacizumab (Avastin) was administered to six patients with subretinal neovascularization (SRNV) due to type 2A idiopathic juxtafoveal telangiectasia, showing significant improvement in best-corrected visual acuity (BCVA) after an average follow-up of 4.2 months, with 83% of eyes improving by two or more lines.

The treatment was found to be safe, with no significant complications reported, and it also resulted in a notable reduction in central foveal thickness, indicating effective management of the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal bevacizumab (Avastin) for subretinal neovascularization secondary to type 2A idiopathic juxtafoveal telangiectasia. Mandal, S., Venkatesh, P., Abbas, Z., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Systemic bevacizumab for high-output cardiac failure in hereditary hemorrhagic telangiectasia: an international survey of HHT centers. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Intranasal submucosal bevacizumab for epistaxis in hereditary hemorrhagic telangiectasia: a double-blind, randomized, placebo-controlled trial. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Intra-venous bevacizumab in hereditary hemorrhagic telangiectasia (HHT): A retrospective study of 46 patients. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Bevacizumab for treating Hereditary Hemorrhagic Telangiectasia patients with severe hepatic involvement or refractory anemia. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Long-term experience with intranasal bevacizumab therapy. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Managing patients treated with bevacizumab combination therapy. [2015]

7. England pubmed.ncbi.nlm.nih.gov

A pharmacovigilance study of adverse event profiles and haemorrhagic safety of bevacizumab based on the FAERS database. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Increased risk of hemorrhage in metastatic colorectal cancer patients treated with bevacizumab: An updated meta-analysis of 12 randomized controlled trials. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Bevacizumab: a review of its use in advanced cancer. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Emerging safety data for bevacizumab in advanced non-small-cell lung cancer. [2015]

11. United States pubmed.ncbi.nlm.nih.gov

Intravitreal bevacizumab for treatment of proliferative and nonproliferative type 2 idiopathic macular telangiectasia. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Bevacizumab treatment for subfoveal choroidal neovascularization from causes other than age-related macular degeneration. [2022]

13. United States pubmed.ncbi.nlm.nih.gov

Short-term effects of intravitreal bevacizumab in type ii idiopathic macular telangiectasia. [2014]

14. Greece pubmed.ncbi.nlm.nih.gov

An in vitro study on the effect of bevacizumab on endothelial cell proliferation and VEGF concentration level in patients with hereditary hemorrhagic telangiectasia. [2022]

15. Germany pubmed.ncbi.nlm.nih.gov

Intravitreal bevacizumab (Avastin) for subretinal neovascularization secondary to type 2A idiopathic juxtafoveal telangiectasia. [2018]