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

NCT04645160 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 21000621-C-0006
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Cholangiocarcinoma; Bile Duct Neoplasm; Biliary Tract Malignancy

Keywords

CCA; FOTIVDA; pan-vascular endothelial growth factor receptor (VEGFR) inhibitor; XPO7; Ste-20 like kinase (SLK)

Outcome Measures

Primary Outcomes (2)

• Phase II: Determine the overall response rate by RECIST of tivozanib in patients with cholangiocarcinoma who were previously treated with first-line therapy.

  Patients will be re-evaluated for response every 8 weeks after start of treatment. The Phase II clinical response rate (CR+PR) will be determined and reported along with a 95% confidence interval.

  baseline, every 8 weeks post-treatment

• Phase I: Determine safety and establish the recommended Phase II dose (RP2D) of tivozanib in patients with cholangiocarcinoma who were previously treated with first-line chemotherapy.

  List of adverse event frequency and grade. Patient DLTs will be counted and reported to determine the safety and tolerability of tivozanib and to establish the recommended Phase II dose (RP2D) using a standard 3+3 design.

  Every 8 weeks (Phase I only)

Secondary Outcomes (2)

• Evaluate overall survival (OS) in patients with cholangiocarcinoma treated with tivozanib

  baseline, every 8 weeks post-treatment

• Evaluate disease control response (DCR- complete response [CR] plus partial response [PR] plus stable disease [SD]) in patients with cholangiocarcinoma treated with tivozanib

  baseline, every 8 weeks post-treatment

Study Arms (2)

1/ Phase I

EXPERIMENTAL

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

Drug: Tivozanib

2/ Phase II

EXPERIMENTAL

Tivozanib at the RP2D established in Phase I

Drug: Tivozanib

Interventions

Tivozanib DRUG

Oral tivozanib taken daily for Days 1-21 continuously (of each 28-day cycle) followed with 7 days off medication (except for patients in DL-1, with dosing every other day of the 28-day cycle). Phase I: The starting dose (DL1) is 0.89 mg taken once a day continuously for Days 1-21 with 1 week off medication (except for those patients assigned to DL-1, where tivozanib should be taken every other day, around 48 hours apart in 28-day cycle). Patients may escalate to 1.34 mg taken once a day (DL2) continuously for Days 1-21 with 1 week off medication for their second cycle if there are no dose-limiting toxicities. Phase II: Tivozanib dose level will be at the recommended Phase II dose (RP2D) established in Phase I.

1/ Phase I; 2/ Phase II

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants with histologically or cytologically confirmed biliary tract cancer (BTC) (cholangiocarcinoma or gallbladder cancer). Archival tumor sample may be used but if archival tissue is not available or is not adequate, tissue biopsy will be required.
• Participants must have disease that is not amenable to resection.
• Participants must have had prior treatment with 1st line chemotherapy.
• Disease must be measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1.
• Age \>=18 years.
• NOTE: Because no dosing or adverse event data are currently available on the use of tivozanib in participants \< 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
• ECOG performance status \<= 2
• Adequate organ and marrow function as defined below:
• Hemoglobin \>= 8.0 g/dL
• Absolute Neutrophil Count \>= 1,000/mcL
• Platelets \>= 75,000/mcL
• Total Bilirubin \<= 2.5 X institutional upper limit of normal (ULN)
• AST(SGOT)/ALT(SGPT) \<= 5 X institutional ULN
• Creatinine Clearance \> 30
• Serum Albumin (g/L) \> 28

You may not qualify if:

• Chemotherapy, small molecule or radiation therapy within 2 weeks prior to administration of first dose of study drug.
• Prior treatment with Tivozanib.
• History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (e.g., no lactulose, rifaximin, etc. if used for purposes of hepatic encephalopathy).
• Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug.
• Previous malignant disease other than the target malignancy within the last 3 years with the exception of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, chronic lymphocytic leukemia, or thyroid carcinoma.
• Current active second primary malignancy, other than skin carcinoma (basal or squamous cell carcinoma), chronic lymphocytic leukemia not requiring active treatment, or differentiated thyroid carcinoma.
• History of allergic reactions or known or suspected hypersensitivity attributed to compounds of similar chemical or biologic composition to tivozanib.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy (see exceptions below), or psychiatric illness/social situations that would limit compliance with study requirements
• Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable and on suppressive therapy, if indicated. For participants with HBV infection who are currently on treatment, they are eligible if they have an undetectable HBV viral load.
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Significant cardiovascular disease, including: Active clinically symptomatic left ventricular failure, uncontrolled hypertension, myocardial infarction, severe angina, or unstable angina within 3 months prior to administration of first dose of study drug, history of serious ventricular arrhythmia, cardiac arrhythmias requiring anti-arrhythmic medications.
• Significant hematologic, gastrointestinal, thromboembolic, vascular, bleeding, or coagulation disorders.
• GI Bleeding (e.g., esophageal varices or ulcer bleeding) within 3 months. (Note: For participants with a history of GI bleeding for more than 12 months or assessed as high risk for esophageal variceal by the Investigator, adequate endoscopic therapy according to institutional standards is required.)
• Complex biliary obstruction requiring bile duct stents at more than one level of the biliary tree or external biliary drainage.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Cholangiocarcinoma; Bile Duct Neoplasms; Hereditary Sensory and Autonomic Neuropathies

Interventions

tivozanib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Biliary Tract Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Study Officials

• Jonathan M Hernandez, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kathleen M Smith, R.N.

CONTACT

(240) 858-3531; kathleen.smith3@nih.gov

Jonathan M Hernandez, M.D.

CONTACT

(240) 760-6072; jonathan.hernandez@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2020
• First Posted: November 27, 2020
• Study Start: March 4, 2022
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029
• Last Updated: May 7, 2026

Record last verified: 2026-03-26

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

Locations

US (1)