Evaluating Efficacy of Tivozanib (AV-951) in Biliary Tract Cancers

Cholangiocarcinoma Clinical Trial

Official title: Phase II Study Evaluating Efficacy of Tivozanib (AV-951) in Biliary Tract Cancers

Status Recruiting

Clinical Trial Summary

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.

Clinical Trial Description

Background:

Biliary Tract Cancers (BTC) (cholangiocarcinoma (CCA) and gallbladder cancer (GBC)) are aggressive malignancies that remain a clinical challenge with limited treatment options and poor survival. Combination chemotherapy with gemcitabine and cisplatin is the most validated first-line treatment, but the response rate approaches only 22% and median progression free survival is 8 months.

Cytoplasmic accumulation of the nuclear export protein exportin 7, XPO7, portends poor outcomes for patients with biliary tract cancer. Using pre-clinical models, we established XPO7 as an oncogenic driver in CCA cells and determined that this biology is driven by the interaction between XPO7 and a hitherto incompletely studied kinase, Ste-20 like kinase (SLK).

XPO7 binds to and promotes cytoplasmic localization and stabilization of SLK, which in turn activates oncogenic signaling. Targeting SLK expression via short hairpin RNA abrogates tumor formation in 3D culture and mice models, establishing SLK as a novel

target in biliary tract cancer.

The pan-vascular endothelial growth factor receptor (VEGFR) inhibitor tivozanib demonstrated activity against SLK in our in vitro screen, which we later confirmed with x-ray crystallography. Tivozanib abrogated growth of CCA tumorspheres, resulting in substantial tumor regression using murine xenograft models and patient-derived xenografts. Additionally, we evaluated tivozanib in our ex vivo tumor platform using a liver metastasis from a patient with XPO7-expressing biliary tract cancer and documented tumor cell apoptosis.

As reliable, molecular-targeted regimens either for first- or second-line therapy for the majority of patients with biliary tract cancer have remained elusive, these results support evaluation of tivozanib as a treatment option for patients with biliary tract cancer.

Objectives:

Determine the overall response rate (RECIST) of tivozanib in patients with biliary tract cancer (BTC) who were previously treated with first-line therapy.

Eligibility:

Patients with histologically or cytologically confirmed biliary tract cancer (BTC) not amenable to resection

Previous treatment with 1st line chemotherapy

Age >= 18 years of age

ECOG performance status of <=2

Preserved hepatic function

Adequate organ and marrow function

Design:

Open-label, single-center, non-randomized Phase II study

Trial is a Simon minimax two-stage Phase II trial design to determine efficacy.

Treatment is in cycles of 28 days, 3 weeks on, 1 week off (with possible dose de-escalation if needed). Treatment evaluations for efficacy will be every 2 months (8 weeks).

Accrual ceiling will be set at 24 patients ;

Related Conditions & MeSH terms

• Bile Duct Neoplasm
• Bile Duct Neoplasms
• Biliary Tract Malignancy
• Biliary Tract Neoplasms
• Cholangiocarcinoma

• NCT number: NCT04645160
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Kathleen M Smith, R.N.
• Phone: (240) 858-3531
• Email: kathleen.smith3@nih.gov
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 4, 2022
• Completion date: December 31, 2027