Recruitment

Recruitment Status
Not yet recruiting
Estimated Enrollment
Same as current

Summary

Conditions
  • Bile Duct Neoplasm
  • Biliary Tract Malignancy
  • Cholangiocarcinoma
Type
Interventional
Phase
Phase 1Phase 2
Design
Allocation: Non-RandomizedIntervention Model: Sequential AssignmentMasking: None (Open Label)Primary Purpose: Treatment

Participation Requirements

Age
Between 18 years and 125 years
Gender
Both males and females

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...

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

Tracking Information

NCT #
NCT04645160
Collaborators
Not Provided
Investigators
Principal Investigator: Jonathan M Hernandez, M.D. National Cancer Institute (NCI)