Pazopanib for Hereditary Hemorrhagic Telangiectasia

(Paz Trial)

Recruiting at 12 trial locations

Overseen By Cassi Friday, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Cure HHT

Must not be taking: VEGF inhibitors, Bevacizumab

Disqualifiers: Cerebral AVMs, Pulmonary AVMs, Recent malignancies, Heart disease, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

70 Participants Needed

Trial Summary

What is the purpose of this trial?

During the Efficacy Study (Part B), the investigators will study whether Pazopanib, taken daily for 24 weeks, will reduce the severity of nose bleeds in patients with hereditary hemorrhagic telangiectasia (HHT). Patients will either be provided active drug or a placebo \[sugar - inactive pill\], and be tested for nose bleed severity throughout the trial, including particularly nose bleed duration. Investigators will also test for blood loss, as well as for safety. This study is funded by the US Department of Defense USAMRAA and FDA/OOPD.

Will I have to stop taking my current medications?

The trial requires participants to stop using certain medications that are on a prohibited list for at least 14 days or 5 half-lives of the drug (whichever is longer) before starting the study and for the duration of the study. However, the specific medications on this list are not detailed in the provided information.

Do I need to stop my current medications for the trial?

The trial requires participants to stop using certain medications that are on a prohibited list at least 14 days before starting the study and for the duration of the study. However, the specific medications on this list are not detailed in the provided information.

What data supports the effectiveness of the drug pazopanib for hereditary hemorrhagic telangiectasia?

Research shows that pazopanib can help reduce severe bleeding and improve hemoglobin levels in patients with hereditary hemorrhagic telangiectasia (HHT). In studies, patients treated with pazopanib achieved transfusion independence and showed significant improvements in bleeding symptoms and quality of life. ^{1 2 3 4 5}

What data supports the effectiveness of the drug pazopanib for hereditary hemorrhagic telangiectasia?

Research shows that pazopanib can help patients with hereditary hemorrhagic telangiectasia (HHT) by reducing severe bleeding and improving hemoglobin levels, which means less need for blood transfusions. In studies, patients experienced significant improvements in bleeding symptoms and quality of life, even at lower doses than those used for cancer treatment. ^{1 2 3 4 5}

Is pazopanib generally safe for humans?

Pazopanib has been studied for various conditions, and while it can cause some side effects, such as elevated liver function tests, it has not shown serious adverse effects in studies for hereditary hemorrhagic telangiectasia. It is generally considered safe at lower doses than those used for cancer treatment. ^{1 2 4 6 7}

Is pazopanib generally safe for humans?

Pazopanib has been studied for various conditions, and while it can cause some side effects, such as elevated liver function tests, it has not shown serious adverse effects in studies for hereditary hemorrhagic telangiectasia. It is generally considered safe at lower doses than those used for cancer treatment. ^{1 2 4 6 7}

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

Pazopanib is unique because it is an oral drug that targets VEGF receptors to reduce bleeding in hereditary hemorrhagic telangiectasia, and it has shown effectiveness even in patients who did not respond to other treatments like bevacizumab. It is used at a lower dose than for cancer treatment, making it potentially safer for long-term use in this condition. ^{1 2 3 4 6}

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

Pazopanib is unique because it is an oral drug that targets VEGF receptors to reduce bleeding in hereditary hemorrhagic telangiectasia, and it has shown effectiveness even in patients who did not respond to other treatments like bevacizumab. It is used at a lower dose than for cancer treatment, minimizing serious side effects. ^{1 2 3 4 6}

Research Team

James R Gossage, MD

Principal Investigator

Augusta University

Eligibility Criteria

This trial is for individuals with hereditary hemorrhagic telangiectasia (HHT) who experience severe nosebleeds and anemia. Participants must be able to monitor their blood pressure at home, not start new HHT therapies during the study, and women of childbearing age must use effective contraception. People with certain medical conditions or on prohibited medications cannot join.

Inclusion Criteria

Women of childbearing potential must agree to abstinence or to use an acceptable double method contraception until 4 weeks after drug termination with pregnancy testing throughout the trial

I have been diagnosed with hereditary hemorrhagic telangiectasia.

I agree not to have nasal vein treatments or start new HHT therapies while in the study.

Exclusion Criteria

I have lung blood vessel malformations larger than 3mm.

Inability or unwillingness to discontinue prohibited medications

I have recently started experiencing severe diarrhea.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part B

Participants receive either 150 mg Pazopanib or placebo daily for 24 weeks to assess effects on nose bleed severity and anemia

24 weeks

Visits every 3 weeks for dosing intervals

Extension Study Part C

Participants who complete Part B may continue with active drug for an additional 24 weeks to further assess effects on nose bleeds and safety

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Pazopanib
• Placebo oral capsule

Trial Overview The trial tests if Pazopanib can reduce nosebleed severity in HHT patients over a 24-week period compared to a placebo. It also monitors blood loss and safety. Patients will take the drug daily and have regular check-ups to assess the impact on their condition.

Participant Groups

Group I: Part C Pazopanib - 150 mg Experimental Treatment 1 Intervention

Pazopanib 150 mg oral daily dosing (six 25 mg Pazopanib capsules).

Group II: Part B (Severe Anemia) Pazopanib - 150 mg Active Control 1 Intervention

150 mg pazopanib oral capsules (six 25 mg placebo capsules daily).

Group III: Part B (Severe Epistaxis) Pazopanib - 150 mg Active Control 1 Intervention

Pazopanib 150 mg oral daily dosing (six 25 mg Pazopanib capsules).

Group IV: Part B (Severe Anemia) Placebo Placebo Group 1 Intervention

Placebo oral capsules (six 25 mg placebo capsules daily).

Group V: Part B (Severe Epistaxis) Placebo Placebo Group 1 Intervention

Placebo oral capsules (six 25 mg placebo capsules daily).

Pazopanib is already approved in United States, European Union, China for the following indications:

Approved in United States as Votrient for:

• Advanced renal cell carcinoma (kidney cancer)
• Soft tissue sarcoma

Approved in European Union as Votrient for:

• Advanced renal cell carcinoma (kidney cancer)
• Soft tissue sarcoma

Approved in China as pazopanib for:

• Metastatic renal cell carcinoma (mRCC)

Who Is Running the Clinical Trial?

Cure HHT

Lead Sponsor

Trials

4

Recruited

10,400+

Food and Drug Administration (FDA)

Collaborator

Trials

184

Recruited

1,553,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

In a study of 13 patients with hereditary hemorrhagic telangiectasia (HHT) treated with pazopanib for a median of 22 months, all patients achieved transfusion independence, indicating the drug's effectiveness in managing severe bleeding associated with HHT.

Pazopanib significantly improved hemoglobin levels and reduced epistaxis severity, with a 93% reduction in RBC transfusions and a 92% decrease in iron infusions during the first 3 months of treatment, while being well-tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib for severe bleeding and transfusion-dependent anemia in hereditary hemorrhagic telangiectasia. Parambil, JG., Gossage, JR., McCrae, KR., et al.[2022]

In a proof-of-concept study involving seven patients with hereditary hemorrhagic telangiectasia (HHT), pazopanib at a low dose of 50 mg daily led to significant reductions in epistaxis duration and improvements in hemoglobin levels, indicating its potential efficacy for treating HHT-related bleeding.

The study reported no serious adverse events, with only one severe adverse event leading to withdrawal, suggesting that pazopanib can be safely administered at lower doses than typically used for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia. Faughnan, ME., Gossage, JR., Chakinala, MM., et al.[2022]

A patient with hereditary hemorrhagic telangiectasia (HHT) experienced severe nosebleeds that did not respond to multiple treatments, including six cycles of bevacizumab, but showed dramatic improvement after starting pazopanib, a drug that targets VEGF receptor-2 signaling.

After beginning pazopanib at a dose of 100 mg, the patient not only saw significant reductions in epistaxis but also normalized hemoglobin and iron levels, eliminating the need for iron infusions and blood transfusions for 12 months, suggesting pazopanib's potential efficacy in treating HHT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib effective for bevacizumab-unresponsive epistaxis in hereditary hemorrhagic telangiectasia. Parambil, JG., Woodard, TD., Koc, ON.[2021]

In a study using a mouse model of hereditary hemorrhagic telangiectasia (HHT), the antiangiogenic drugs sorafenib and a pazopanib analog significantly improved anemia and reduced gastrointestinal bleeding, while erlotinib worsened anemia.

The findings suggest that oral antiangiogenic tyrosine-kinase inhibitors are more effective for treating gastrointestinal bleeding in HHT patients than for preventing the development of skin arteriovenous malformations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia. Kim, YH., Kim, MJ., Choe, SW., et al.[2023]

Antiangiogenic therapies, such as intravenous bevacizumab, oral pazopanib, and oral thalidomide, have shown to be effective and safe in managing bleeding associated with hereditary hemorrhagic telangiectasia (HHT), providing durable hemostasis and improving patients' quality of life.

Despite the promising results, there is a lack of comprehensive guidelines for the clinical use of these therapies in HHT, highlighting the need for further research and expert guidance to optimize treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Antiangiogenic Therapies for Bleeding in Hereditary Hemorrhagic Telangiectasia: A Practical, Evidence-Based Guide for Clinicians. Al-Samkari, H.[2022]

Pazopanib significantly improves progression-free survival in patients with chemotherapy-failing nonadipocytic soft tissue sarcomas, increasing it from 1.6 months to 4.6 months based on Phase II and Phase III clinical trials.

The safety profile of pazopanib is manageable, allowing for high dose intensity over time, making it a viable option as part of the standard care for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib, a new therapy for metastatic soft tissue sarcoma. Verweij, J., Sleijfer, S.[2021]

Pazopanib, a multikinase inhibitor, was approved by the US FDA in October 2009 for treating advanced renal cell carcinoma, highlighting its significance in cancer therapy.

The drug targets vascular endothelial growth factor receptors, which play a crucial role in tumor growth and blood vessel formation, making it an effective option for managing this type of kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib. Bukowski, RM., Yasothan, U., Kirkpatrick, P.[2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Pazopanib for severe bleeding and transfusion-dependent anemia in hereditary hemorrhagic telangiectasia. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia. [2022]

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

Pazopanib effective for bevacizumab-unresponsive epistaxis in hereditary hemorrhagic telangiectasia. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia. [2023]

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

Systemic Antiangiogenic Therapies for Bleeding in Hereditary Hemorrhagic Telangiectasia: A Practical, Evidence-Based Guide for Clinicians. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Pazopanib, a new therapy for metastatic soft tissue sarcoma. [2021]

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

Pazopanib. [2021]