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Evaluating Safety and Efficacy of Tivozanib (AV-951) in Cholangiocarcinoma

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ClinicalTrials.gov Identifier: NCT04645160
Recruitment Status : Not yet recruiting
First Posted : November 27, 2020
Last Update Posted : March 2, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

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.


Condition or disease Intervention/treatment Phase
Cholangiocarcinoma Bile Duct Neoplasm Biliary Tract Malignancy Drug: Tivozanib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study Evaluating Safety and Efficacy of Tivozanib (AV-951) in Cholangiocarcinoma
Estimated Study Start Date : March 5, 2021
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1/ Phase I
Tivozanib, P.O. daily at 1.0 mg (given on Days 1-21 of every 28-day cycle) with intra-patient escalation to 1.5 mg daily (given on Days 1-21 of every 28-day cycle) and possible dose de-escalation to 1.0 mg every other day (without interruption for a 28-day cycle) if needed to determine RP2D
Drug: Tivozanib
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 1 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 1.5 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.

Experimental: 2/ Phase II
Tivozanib at the RP2D established in Phase I
Drug: Tivozanib
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 1 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 1.5 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.




Primary Outcome Measures :
  1. Phase II: Determine the overall response rate by RECIST of tivozanib in patients with cholangiocarcinoma who were previously treated with first-line therapy. [ Time Frame: baseline, every 8 weeks post-treatment ]
    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.

  2. 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. [ Time Frame: Every 8 weeks (Phase I only) ]
    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.


Secondary Outcome Measures :
  1. Evaluate overall survival (OS) in patients with cholangiocarcinoma treated with tivozanib [ Time Frame: baseline, every 8 weeks post-treatment ]
    CT or MRI will be used for response criteria. PFS and OS will be determined using Kaplan-Meier estimates.

  2. Evaluate disease control response (DCR- complete response [CR] plus partial response [PR] plus stable disease [SD]) in patients with cholangiocarcinoma treated with tivozanib [ Time Frame: baseline, every 8 weeks post-treatment ]
    CT or MRI will be used for response criteria. DCR (CR plus PR plus SD) will be determined and reported along with 95% confidence intervals. Wherever possible, duration of DCR will be reported.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Patients with histologically or cytologically confirmed cholangiocarcinoma by the NCI Laboratory of Pathology. Archival tumor sample may be used but if archival tissue is not available or is not adequate, tissue biopsy will be required.
    2. Patients must have cholangiocarcinoma that is not amenable to resection.
    3. Patients must have had prior treatment with 1st line chemotherapy.
    4. Disease must be measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1.
    5. Age >=18 years.

      NOTE: Because no dosing or adverse event data are currently available on the use of tivozanib in subjects < 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.

    6. ECOG performance status <= 1
    7. If the patient has liver disease; Child Pugh Class A.
    8. Adequate organ and marrow function as defined below:

      • Hemoglobin >= 9.0 g/dL
      • Absolute neutrophil count >= 1,000/mcL
      • Platelets >= 75,000/mcL
      • Total bilirubin <= 2 X institutional upper limit of normal (ULN)
      • AST(SGOT)/ALT(SGPT) <= 5 X institutional ULN
      • Creatinine clearance >= 60 mL/min/1.73 m^2 calculated by calculated using eGRF in the clinical lab
      • Serum Albumin (g/L) > 35
      • Alkaline phosphatase** <= 2.5 x ULN

        **unless bony metastases present

      • INR < 1.7
    9. Negative serum or urine pregnancy test at screening for women of childbearing potential (WOCBP).

      NOTE: WOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal. WOCBP must have a negative pregnancy test (HCG blood or urine) during screening.

    10. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 1 month after completion of treatment.
    11. Ability of subject to understand and the willingness to sign a written informed consent document.
    12. Ability and willingness to co-enroll on the tissue collection protocol 13C0176, "Tumor, Normal Tissue and Specimens from Patients Undergoing Evaluation or Surgical Resection of Solid Tumors".

EXCLUSION CRITERIA:

  1. Chemotherapy, small molecule or radiation therapy within 3 weeks prior to administration of first dose of study drug.
  2. Prior treatment with Tivozanib.
  3. Any history of elevations of both total serum bilirubin > 2X ULN AND AST and/or ALT > 3X ULN, unless related to common bile duct obstruction and treated adequately with a stent.
  4. 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).
  5. Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug.
  6. Patients with 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 or thyroid carcinoma.
  7. Current active second primary malignancy, other than skin carcinoma (basal or squamous cell carcinoma) or differentiated thyroid carcinoma.
  8. History of allergic reactions or known or suspected hypersensitivity attributed to compounds of similar chemical or biologic composition to tivozanib.
  9. Patients with 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 patients on effective anti- retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
    • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable and on suppressive therapy, if indicated.
    • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
  10. Significant cardiovascular disease, including: Active clinically symptomatic left ventricular failure, uncontrolled hypertension, myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of first dose of study drug, history of serious ventricular arrhythmia, cardiac arrhythmias requiring anti-arrhythmic medications.
  11. Uncontrolled hypertension, i.e., blood pressure (BP) of >= 180/95; patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) and meet all other inclusion criteria.
  12. Significant hematologic, gastrointestinal, thromboembolic, vascular, bleeding, or coagulation disorders.
  13. GI Bleeding (e.g., esophageal varices or ulcer bleeding) within 12 months. (Note: For patients 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.)
  14. Clinically meaningful ascites defined as ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose. Subjects on stable doses of diuretics for ascites for >= 2 months are eligible.
  15. Main portal vein thrombosis (Vp4) as documented on imaging. (VP4 is defined as portal vein thrombosis in the main trunk of the portal vein or a portal vein branch contralateral to the primarily involved lobe (or both).)
  16. Complex biliary obstruction requiring bile duct stents at more than one level of the biliary tree or external biliary drainage.
  17. Recurrent episodes of cholangitis (>1) in the preceding 3 months prior to enrollment.
  18. Therapeutic anti-coagulation or anti-platelet therapy with the exception of low molecular weight heparin or aspirin.
  19. Pregnant or lactating women. Pregnant women are excluded from this study because based on findings in animals and its mechanism of action, tivozanib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of tivozanib to pregnant rats caused adverse developmental outcomes including embryo- fetal mortality. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with tivozanib, breastfeeding should be discontinued if the mother is treated with tivozanib. These potential risks may also apply to other agents used in this study.
  20. Treatment with systemic hormonal therapy within 3 weeks prior to start of protocol therapy, with the exception of:

    • Hormonal therapy for appetite stimulation or contraception
    • Nasal, ophthalmic, inhaled and topical steroid preparations
    • Oral replacement therapy for adrenal insufficiency
    • Low-dose maintenance steroid therapy (equivalent of prednisone 10 mg/day) for other conditions
    • Hormone replacement therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04645160


Contacts
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Contact: Cathleen E Hannah (240) 409-8860 cathleen.hannah@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jonathan M Hernandez, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04645160    
Other Study ID Numbers: 210006
21-C-0006
First Posted: November 27, 2020    Key Record Dates
Last Update Posted: March 2, 2021
Last Verified: January 25, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
CCA
FOTIVDA
pan-vascular endothelial growth factor receptor (VEGFR) inhibitor
XPO7
Ste-20 like kinase (SLK)
Additional relevant MeSH terms:
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Cholangiocarcinoma
Bile Duct Neoplasms
Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Biliary Tract Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases