Clinical Trials /

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

NCT04645160

Description:

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.

Related Conditions:
  • Cholangiocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I/II Study 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

Clinical Trial IDs

  • ORG STUDY ID: 210006
  • SECONDARY ID: 21-C-0006
  • NCT ID: NCT04645160

Conditions

  • Cholangiocarcinoma
  • Bile Duct Neoplasm
  • Biliary Tract Malignancy

Interventions

DrugSynonymsArms
Tivozanib1/ Phase I

Purpose

Background: 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 (SLK). 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 death. 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. Objectives: 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. Eligibility: Patients with histologically or cytologically confirmed cholangiocarcinoma not amenable to resection 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 Design: 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

Detailed Description

      Background:

      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
      (SLK).

      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
      death.

      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.

      Objectives:

      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.

      Eligibility:

      Patients with histologically or cytologically confirmed cholangiocarcinoma not amenable to
      resection

      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

      Design:

      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
    

Trial Arms

NameTypeDescriptionInterventions
1/ Phase IExperimentalTivozanib, 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
  • Tivozanib
2/ Phase IIExperimentalTivozanib at the RP2D established in Phase I
  • Tivozanib

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

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

Last Updated

November 30, 2020