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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called tivozanib (Fotivda) to determine if it can safely and effectively slow or stop the growth of cholangiocarcinoma, a challenging cancer in the bile ducts. Researchers aim to find the optimal dose and assess the cancer's response to this treatment. Suitable participants have bile duct cancer that cannot be surgically removed and have already undergone chemotherapy. Participants will take tivozanib in cycles and attend regular check-ups to monitor progress and side effects. As a Phase 1, Phase 2 trial, this research seeks to understand how the treatment works in people and measure its effectiveness in an initial group, offering participants a chance to contribute to groundbreaking cancer research.

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.

Is there any evidence suggesting that tivozanib is likely to be safe for humans?

Research has shown that tivozanib offers potential benefits in treating various cancers and may be well-tolerated. For instance, one study found that tivozanib caused fewer side effects compared to some other treatments for patients with advanced liver cancer. This finding suggests that the drug might also be safe for individuals with biliary tract cancer.

Another study found that a dose of 1.34 mg of tivozanib led to a greater reduction in tumor size and was easier for patients to tolerate. These results suggest that the drug could be safe at certain doses. However, since this trial is in its early stages, the safety of tivozanib for biliary tract cancer remains under investigation.

In early testing phases, researchers focus on understanding side effects and safety. The trial will closely monitor participants for any negative effects. Those with concerns about joining should consult their healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Tivozanib is unique because it targets the VEGF receptor, which plays a crucial role in blood vessel growth that tumors need to survive. Unlike traditional chemotherapy used for biliary tract cancer, which attacks fast-growing cells indiscriminately, tivozanib offers a more targeted approach, potentially reducing some side effects. Researchers are excited because this specificity could mean better outcomes and improved quality of life for patients, especially if tivozanib proves effective at a lower, more tolerable dosage.

What evidence suggests that tivozanib might be an effective treatment for biliary tract cancer?

Studies have shown that tivozanib can effectively treat cholangiocarcinoma (CCA), a cancer in the bile ducts. Research indicates that it blocks certain proteins that aid cancer cell growth and spread. In this trial, participants will receive tivozanib to further evaluate its effectiveness. Early data suggests that patients treated with tivozanib have experienced a slowdown in cancer progression. The drug targets the blood vessels feeding the tumor, potentially shrinking the cancer or stopping its growth. While more studies are needed, these initial findings are promising for people with CCA. ^{1 6 7 8 9}

Who Is on the Research Team?

Jonathan M Hernandez, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 have confirmed biliary tract cancer and can provide a tissue sample.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04645160

Evaluating Efficacy of Tivozanib (AV-951) in Biliary Tract ... Cytoplasmic accumulation of the nuclear export protein exportin 7, XPO7, portends poor outcomes for patients with biliary tract cancer. Using pre-clinical ...

2. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04645160/

Clinical Trial: NCT04645160 Measure: Evaluate overall survival (OS) in patients with cholangiocarcinoma treated with tivozanib ; Time Frame: baseline, every 8 weeks post- ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/tivozanib?pn=1

Clinical Trials Using Tivozanib - NCI NCI supports clinical trials that test new and more effective ways to treat cancer ... Evaluating Efficacy of Tivozanib (AV-951) in Biliary Tract Cancers. Status ...

4. withpower.com withpower.com/trial/phase-2-bile-duct-neoplasms-9-2021-68dba

Tivozanib for Biliary Tract Cancer 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 ...

5. app.trialscreen.org app.trialscreen.org/trials/phase-1-2-cholangiocarcinoma-evaluating-safety-efficacy-tivozanib-av-951-trial-nct04645160

Evaluating Efficacy of Tivozanib (AV-951) in Biliary Tract ... Benefits: Participation in this study may provide access to a new investigational drug that could potentially help treat cholangiocarcinoma, a type of cancer ...

6. onclive.com onclive.com/view/dr-mcgregor-on-the-rationale-of-analyzing-the-efficacy-and-safety-exposure-response-of-tivozanib-in-rcc

Dr McGregor on the Rationale of Analyzing the Efficacy ... Furthermore, the data suggested that tivozanib at 1.34 mg also provided a greater decrease in tumor size and may be more tolerable. The optimal ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7729327/

Tivozanib in advanced inoperable hepatocellular carcinoma In a phase 3 trial, tivozanib therapy led to significantly superior progression-free survival (PFS), objective response rate (ORR), and safety profiles in ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2021/212904Orig1s000MultidisciplineR.pdf

212904Orig1s000 - accessdata.fda.gov The safety profile of tivozanib was further supported by review of safety data from an additional 835 patients in other cinical trials who ...

9. trial.medpath.com trial.medpath.com/clinical-trial/59adca6566ea6d7e/nct04645160-phase-ii-tivozanib-biliary-tract-cancers

Evaluating Efficacy of Tivozanib (AV-951) in Biliary Tract ... Objectives: Determine the overall response rate (RECIST) of tivozanib in participants with biliary tract cancer (BTC) who were previously treated with first- ...