Tivozanib for Biliary Tract Cancer

Overseen By Jonathan M Hernandez, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anti-arrhythmics, Encephalopathy meds

Disqualifiers: Second primary malignancy, Cardiovascular disease, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

Duration: Until disease progression or unacceptable toxicity

31 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Cholangiocarcinoma (CCA) is an aggressive cancer of the bile ducts. People with CCA have few treatment options and poor survival. Researchers want to see if a new drug can stop or slow CCA growth. Objective: To find the safest and most effective dose of tivozanib to treat CCA and learn its overall response rate. Eligibility: Adults ages 18 and older with CCA not removable with surgery and have been treated with at least one type of chemotherapy. Design: Participants will be screened with the following: * Medical history * Physical exam * Assessment of their ability to do daily activities * Medicine review * Blood tests, including thyroid function tests * Urine tests * Electrocardiogram, to check heart function * Pregnancy test, if needed * Tumor biopsy, if needed * Computed tomography scans * Magnetic resonance imaging, if needed Some screening tests may be repeated during the study. Participants will be asked to enroll in protocol #13C0176. This will allow any remaining tumor or blood samples to be used in future research. Participants will take tivozanib by mouth, once a day for 21 days per cycle or every other day per cycle. Each cycle is 28 days. They can take the drug until they have bad side effects, their CCA gets worse, or if they become pregnant. They will record their blood pressure twice daily at home. They will also keep a medication diary of each dose of tivozanib they take and any side effects. Participants will have study visits before starting each new cycle and every 8 weeks. They will also have a follow-up visit 30 days after treatment ends at NIH, or if they are unable to come to NIH by phone, videocall, or other NIH-approved platform. Then they will be contacted 6 and 12 months later, and then once a year. ...

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

The trial does not specify if you need to stop taking your current medications, but you cannot have had chemotherapy, small molecule, or radiation therapy within 2 weeks before starting the study drug. It's best to discuss your current medications with the trial team to ensure they don't interfere with the study.

How does the drug Tivozanib differ from other treatments for biliary tract cancer?

Tivozanib is unique because it is a targeted therapy that inhibits specific pathways involved in cancer growth, such as the vascular endothelial growth factor receptor (VEGFR), which is different from traditional chemotherapy that affects all rapidly dividing cells. This approach may offer a more personalized treatment option for patients with biliary tract cancer, especially those who do not respond to standard chemotherapy. ^{1 2 3 4 5}

Research Team

Jonathan M Hernandez, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with inoperable biliary tract cancer (BTC), including cholangiocarcinoma or gallbladder cancer, who have already tried at least one chemotherapy. They must be able to perform daily activities to a certain extent and have adequate organ function. Women of childbearing potential must test negative for pregnancy and agree to use contraception.

Inclusion Criteria

- Creatinine clearance > 30

- AST(SGOT)/ALT(SGPT) <= 5 X institutional ULN

I am 18 years old or older.

Exclusion Criteria

I have multiple bile duct blockages and need more than one stent or external drainage.

My blood pressure is controlled and hasn't required medication changes for at least 14 days.

I am not pregnant or breastfeeding.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive tivozanib orally once a day for 21 days per 28-day cycle, with dose adjustments as needed

Until disease progression or unacceptable toxicity

Visits before each new cycle and every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

1 visit (in-person or virtual) 30 days post-treatment, then contact at 6 and 12 months, and annually

Treatment Details

Interventions

• Tivozanib

Trial Overview The trial is testing the safety and effectiveness of Tivozanib, an oral medication taken once daily for three weeks per cycle, with each cycle lasting four weeks. The goal is to determine the best dose that can manage BTC without causing severe side effects.

Participant Groups

Group I: 2/ Phase II Experimental Treatment 1 Intervention

Tivozanib at the RP2D established in Phase I

Group II: 1/ Phase I Experimental Treatment 1 Intervention

Tivozanib, P.O. daily at 0.89 mg (given on Days 1-21 of every 28-day cycle) with intra-patient escalation to 1.34 mg daily (given on Days 1-21 of every 28-day cycle) and possible dose de-escalation to 0.89 mg every other day (without interruption for a 28-day cycle) if needed to determine RP2D

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

Approved in United States as Fotivda for:

• Renal cell carcinoma

Approved in European Union as Fotivda for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Gemcitabine plus platinum chemotherapy is the standard first-line treatment for advanced biliary tract cancers (BTC), while the FOLFOX regimen is the only validated second-line therapy, showing only modest survival benefits over best supportive care.

Recent advancements in genomic analyses have revealed the molecular diversity of BTC, paving the way for personalized targeted therapies, particularly focusing on fibroblast growth factor receptor and isocitrate dehydrogenase gene alterations, as well as combination immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continuum of care for advanced biliary tract cancers. Vienot, A., Neuzillet, C.[2021]

Biliary tract cancers, including cholangiocarcinomas and gallbladder cancers, are on the rise and typically have a poor prognosis, with palliative chemotherapy being the main treatment for advanced cases.

Targeted therapies, such as pemigatinib for FGFR2 gene fusions and ivosidenib for IDH1 mutations, have shown promising results in improving patient outcomes, leading to FDA approvals and encouraging response rates in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and emerging therapies for advanced biliary tract cancers. Kam, AE., Masood, A., Shroff, RT.[2022]

In a phase II study involving 77 patients with unresectable biliary tract cancers, the combination of atezolizumab (anti-PD-L1) and cobimetinib (MEK inhibitor) significantly improved progression-free survival (PFS) to a median of 3.65 months compared to 1.87 months for atezolizumab alone.

Despite the improved PFS, the overall response rates were low in both treatment groups, indicating that biliary tract cancers may be resistant to immune therapies, and combination therapy was associated with increased side effects such as rash and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. Yarchoan, M., Cope, L., Ruggieri, AN., et al.[2023]

Targeted therapies for biliary tract cancer (BTC) are becoming important for patients who do not respond to first-line treatments, focusing on specific oncogenes like FGFR2, IDH, BRAF, and HER-2.

The genetic diversity in advanced BTCs includes common mutations found in other solid tumors, such as RET and TRK fusions, which may open up new treatment options and highlight the need for personalized medicine approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precision Oncology Targets in Biliary Tract Cancer. Farha, N., Dima, D., Ullah, F., et al.[2023]

Targeted therapies for unresectable biliary tract carcinomas (BTCs) are being actively researched, with 67 ongoing clinical trials focusing on various molecular alterations, including 15 trials specifically investigating fibroblast growth factor receptor (FGFR) inhibitors.

The review highlights a shift towards biomarker-based patient selection in BTC management, indicating that ongoing trials may lead to new treatment options tailored to specific molecular subcategories of BTCs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step? Aimar, G., Paratore, C., Zichi, C., et al.[2023]

References

1. France pubmed.ncbi.nlm.nih.gov

Continuum of care for advanced biliary tract cancers. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Current and emerging therapies for advanced biliary tract cancers. [2022]

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

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Precision Oncology Targets in Biliary Tract Cancer. [2023]

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

A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step? [2023]