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

  • STATUS
    Recruiting
  • End date
    Dec 31, 2025
  • participants needed
    30
  • sponsor
    National Cancer Institute (NCI)
Updated on 23 September 2022
cancer
neutrophil count

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.

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

Details
Condition Cholangiocarcinoma, Bile Duct Neoplasm, Biliary Tract Malignancy
Treatment Tivozanib
Clinical Study IdentifierNCT04645160
SponsorNational Cancer Institute (NCI)
Last Modified on23 September 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

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
Patients must have cholangiocarcinoma that is not amenable to resection
Patients 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 subjects < 18 years of age, children are excluded from
this study, but may be eligible for future pediatric trials
ECOG performance status <= 1
If the patient has liver disease; Child Pugh Class A
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
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
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
Ability of subject to understand and the willingness to sign a written informed consent document
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

Chemotherapy, small molecule or radiation therapy within 2 weeks prior to administration of first dose of study drug
Prior treatment with Tivozanib
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 stent
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
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
Current active second primary malignancy, other than skin carcinoma (basal or squamous cell carcinoma) or differentiated thyroid carcinoma
History of allergic reactions or known or suspected hypersensitivity attributed to compounds of similar chemical or biologic composition to tivozanib
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 antiretroviral 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
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
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
Significant hematologic, gastrointestinal, thromboembolic, vascular, bleeding, or coagulation disorders
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.)
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
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).)
Complex biliary obstruction requiring bile duct stents at more than one level of the biliary tree or external biliary drainage
Recurrent episodes of cholangitis (>1) in the preceding 3 months prior to enrollment
Therapeutic anti-coagulation or anti-platelet therapy with the exception of low molecular weight heparin or aspirin
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 embryofetal 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
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
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