Phase I/II Study Evaluating Safety and Efficacy of Tivozanib (AV-951) in Cholangiocarcinoma

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Brief Title

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

Official Title

Phase I/II Study Evaluating Safety and Efficacy of Tivozanib (AV-951) in Cholangiocarcinoma

Brief Summary


      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.


      To find the safest and most effective dose of tivozanib to treat CCA and learn its overall
      response rate.


      Adults ages 18 and older with CCA not removable with surgery and have been treated with at
      least one type of chemotherapy.


      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.

Detailed Description


      Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy that remains 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 cholangiocarcinoma. 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

      XPO7 binds to and promotes cytoplasmic localization and stabilization of SLK, which in turn
      activates oncogenic AKT signaling. Targeting SLK expression via short hairpin RNA abrogates
      tumor formation in 3D culture and mice models, and leads to robust inhibition of AKT Ser 473
      phosphorylation, establishing SLK as a novel, bona fide target in cholangiocarcinoma.

      The pan-vascular endothelial growth factor receptor (VEGFR) inhibitor tivozanib, which also
      demonstrated activity against SLK in our in vitro screen, reduced AKT phosphorylation and
      abrogated growth of CCA tumorspheres and in a murine xenograft model. Additionally, we
      evaluated tivozanib in our ex vivo tumor platform using a liver metastasis from a patient
      with XPO7-expressing cholangiocarcinoma and documented effective tumor cell degeneration and

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


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

      Phase II: To determine the overall response rate (RECIST) of tivozanib in patients with
      cholangiocarcinoma who were previously treated with first-line therapy.


      Patients with histologically or cytologically confirmed cholangiocarcinoma not amenable to

      Previous treatment with 1st line chemotherapy

      Age >= 18 years of age

      ECOG performance status of <=1

      Preserved hepatic function

      Adequate organ and marrow function

      Life expectancy >= 3 months


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

      Trial will begin with enrollment in a Phase I two dose-level, intra-patient dose escalation
      and possible dose de-escalation phase to determine safety and RP2D, followed by 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 (except for patients in DL-1, with
      every other day dosing). Treatment evaluations for efficacy will be every 2 months (8 weeks).

      Accrual ceiling will be set at 30 patients

Study Phase

Phase 1/Phase 2

Study Type


Primary Outcome

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

Secondary Outcome

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





Study Arms / Comparison Groups

 1/ Phase I
Description:  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


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

March 4, 2022

Completion Date

December 31, 2027

Primary Completion Date

December 31, 2026

Eligibility 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

              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".


          1. Chemotherapy, small molecule or radiation therapy within 2 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 or ALT > 3X
             ULN, unless related to common bile duct obstruction and treated adequately with a

          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 >= 150/90 mmHg; patients who
             have a history of hypertension controlled by medication must be on a stable dose of
             antihypertensive therapy such that there has been no increase in hypertensive
             medications or dosage (for at least 30 days) 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




18 Years - N/A

Accepts Healthy Volunteers



Jonathan M Hernandez, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Cancer Institute (NCI)

Study Sponsor

Jonathan M Hernandez, M.D., Principal Investigator, National Cancer Institute (NCI)

Verification Date

November 7, 2022