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
- 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 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
