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John Bridgewater

Publications and source records attributed to John Bridgewater.

4 recordsLinked to original sources
PubMed2026

Futibatinib after non-covalent FGFR inhibitors in FGFR2-rearranged intrahepatic cholangiocarcinoma: clinical activity and resistance patterns.

PURPOSE: The optimal sequencing of non-covalent and covalent FGFR inhibitors in FGFR2-rearranged intrahepatic cholangiocarcinoma (iCCA) remains undefined. Futibatinib, an irreversible FGFR1-4 inhibitor, may retain activity in the setting of acquired resistance to non-covalent FGFR inhibitors, but data on the patterns of acquired alterations are limited. METHODS: We conducted a retrospective multicenter study across three European centers including patients with advanced FGFR2-rearranged iCCA treated with futibatinib after progression on non-covalent FGFR inhibitors. Clinical outcomes and safety were evaluated. Available genomic profiling at progression was analyzed to characterize resistance mechanisms and their association with outcomes. RESULTS: Sixteen patients were included. Median progression-free survival (mPFS) with prior non-covalent FGFR inhibitors was 10.2 months (95% CI 7.0-15.5), with an objective response rate (ORR) of 60.0%. Among patients with post-progression genomic profiling (n = 11), all harbored FGFR2 resistance mutations, with polyclonal alterations (≥2) in 45.5%. A higher burden of FGFR2 mutations and the presence of co-alterations were associated with shorter mPFS on non-covalent inhibitors. Futibatinib was administered at a median of fourth-line therapy. ORR was 31.3% and disease control rate was 50.0%. Median PFS and overall survival were 4.5 months (95% CI 2.0-9.1) and 9.9 months (95% CI 5.7-not reached), respectively. Notably, outcomes with futibatinib were independent of the number of acquired FGFR2 resistance mutations, and the adverse impact of co-alterations appeared attenuated. Safety was consistent with the known profile. CONCLUSIONS: Futibatinib demonstrates clinically meaningful activity after progression on non-covalent FGFR inhibitors, supporting its use in FGFR2-rearranged iCCA, including in the post-non-covalent inhibitor setting. The distinct resistance patterns provide a biological rationale for the continued efficacy of covalent FGFR inhibition. Prospective studies incorporating longitudinal molecular profiling are needed to optimize treatment sequencing.

Drug resistance↗
PubMed2004

Efficient retroviral vector targeting of carcinoembryonic antigen-positive tumors.

Many gene therapy approaches require specific, efficient gene delivery to cells in vivo. To target colorectal tumors we fused a single-chain variable fragment (scFv) directed against carcinoembryonic antigen (CEA) to the amphotropic murine leukemia virus envelope. A proline-rich hinge and matrix metalloprotease (MMP) cleavage site linked the two proteins. Following attachment to CEA, MMP cleavage of the envelope at the cell surface removed the scFv and proline-rich hinge, allowing transduction. This allowed selective targeting of CEA-positive cells in vivo after injection of producer cells at the site of the tumor, with up to 10% of cells within a CEA-positive tumor xenograft becoming transduced. Intraperitoneal injection of amphotropic producer cells resulted in transduction of cells in spleen, liver, and kidney, which was not detected when CEA-targeted producer cells were used. These results demonstrate the feasibility of using targeted retroviral vectors for in vivo gene delivery to tumors. Furthermore, the lack of transduction of host cells eliminates the risk of insertional mutagenesis leading to transformation of host hematopoietic cells.

Animals↗
PubMed2003

Pharmacokinetics of capecitabine (Xeloda) in Japanese and Caucasian patients with breast cancer.

BACKGROUND: Capecitabine (Xeloda) is a novel, oral fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumor tissue via a three-step enzymatic cascade. PURPOSE: The objective of this study was to compare the pharmacokinetics of capecitabine and its metabolites in Japanese and Caucasian cancer patients. METHODS: The study included 20 Japanese and 24 Caucasian patients with breast cancer. All patients received oral capecitabine 825 mg/m(2) twice daily for 14 days, except for study day 1 when only the morning dose was administered. On study days 1 and 14, blood and urine samples were collected after administration of the first dose and at steady state for the evaluation of the pharmacokinetics of capecitabine and its metabolites. The primary pharmacokinetic parameter was AUC(0-infinity ) of 5'-deoxy-5-fluorouridine (5'-DFUR) on day 14. The pharmacokinetic parameters in Japanese and Caucasian patients were compared using an ANOVA with calculation of the 90% confidence interval (CI) for the ratio of the geometric means. RESULTS: Statistical analysis showed equivalence in the AUC of 5'-DFUR on day 14 with a ratio of 1.01 (90% CI 0.85-1.21). Similarly, no relevant influence of race on the pharmacokinetics of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), or 5-FU was observed. Systemic exposure to alpha-fluoro-beta-alanine (FBAL) was higher in Caucasian than in Japanese patients. On study day 14, both the AUC and the maximum plasma concentration (C(max)) of FBAL were increased by 47% and 33% in Caucasian patients and Japanese patients, respectively. CONCLUSIONS: No clinically relevant differences in the pharmacokinetics of capecitabine and its key metabolites 5'-DFUR, 5'-DFCR, and 5-FU were found between Japanese and Caucasian patients. Plasma concentrations of FBAL were higher in Caucasian than in Japanese patients but this difference is not clinically relevant as FBAL has no antiproliferative activity and systemic exposure to FBAL does not correlate with the tolerability of capecitabine.

Adult↗