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A phase II study of multiple kinase inhibitor, TT-00420, in advanced, refractory cholangiocarcinoma
Background
Fibroblast growth factor (FGFR) alterations occur in 10-15% adult patients with advanced cholangiocarcinoma (CCA). Pemigatinib and Infigratinib, the first generation FGFR1-3 kinase inhibitors approved for the treatment of the advanced CCA with FGFR2 gene fusions or other rearrangements, are associated with a median progression-free survival of about 6 months after progression on first-line chemotherapy and acquired resistance is common. A novel spectrum-selective multi-kinase inhibitor, TT-00420, has shown clinical responses in multiple CCA patients bearing the gate-keeper mutations acquired from previous FGFR inhibitor treatment(s) in prior phase I study (NCT03654547). TT-00420, inhibits receptor tyrosine kinases (FGFRs and VEGFRs), aurora kinases A/B and janus kinases (JAK), targets cell proliferation, angiogenesis, and immune-oncology pathways, and effectively inhibits the tumor growth in the CCA PDX models bearing the FGFR2 gate-keeper mutations.
Trial design
TT420C1206 is an open-label, multicenter, phase II study of TT-00420 monotherapy, orally administered once daily in the 28-day cycle, in the adult patients with advanced/metastatic and surgically unresectable CCA exhausting standard treatment options. Per baseline FGFR alteration status, patients will be enrolled into four cohorts, which consist of patients bearing FGFR2 fusion(s) who progressed on previous FGFR2 inhibitor(s) (A1 cohort) or patients who responded to previous FGFR2 inhibitor(s) (A2 cohort), patients bearing other FGFR alteration(s) (B cohort), or patients without detectable FGFR alteration (C cohort). Eligible patients, ≥18 years old, must have measurable target lesion(s) at baseline and ECOG status of 0 or 1. Primary endpoint-overall response rate (ORR), along with other efficacy endpoints, will be evaluated. Safety, PK parameters, and biomarker profile, will be evaluated and reviewed jointly with the efficacy outcomes. In each cohort, Fleming’s two-stage design is adopted to guide the enrollment from Stage I to Stage II. Adverse events (AEs) will be grade per CTCAE version 5.0 and response will be assessed per RECIST version 1.1 criteria. Approximately a total of 80 patients will be enrolled and treated in the study. Study enrollment in all four cohorts is currently ongoing.
Clinical trial identification
NCT04919642.
Legal entity responsible for the study
The authors.
Funding
TransThera Sciences (Nanjing), Inc.
Disclosures
M. Javle: Honoraria (self): QED Therapeutics, Inc., AstraZeneca/MedImmune, EMD Serono/Merck, TransThera Biosciences; Advisory / Consultancy: QED Therapeutics, Inc., Oncosil, Incyte, Mundipharma EDO GmbH, AstraZeneca, Merck, EMD Serono, Derazantinib; Research grant / Funding (institution): Transthera, Novartis, Eli Lilly. D. Li: Advisory / Consultancy: Merck, Genentech, Exelixis; Speaker Bureau / Expert testimony: Eisai, Exelixis, Ipsen; Research grant / Funding (institution): AstraZeneca, Brooklyn Immunotherapeutics. P. Peng: Full / Part-time employment: TransThera Sciences . W. Levin: Advisory / Consultancy: WJ Levin Consulting; Full / Part-time employment: WJ Levin Consulting. H. Wang: Full / Part-time employment: TransThera Sciences (Nanjing), Ltd., TransThera Sciences (Nanjing), Ltd., TransThera Sciences (Nanjing), Ltd.. C. Sun: Full / Part-time employment: TransThera Biosciences. Q. Ru: Advisory / Consultancy: ABM Therapeutics, Cellular Biomedicine Group; Travel / Accommodation / Expenses: TransThera Sciences; Shareholder / Stockholder / Stock options: TransThera Sciences. F. Wu: Leadership role: TransThera Sciences; Shareholder / Stockholder / Stock options: TransThera Sciences. All other authors have declared no conflicts of interest.
