Merestinib monotherapy or in combination for japanese patients with advanced and/or metastatic cancer: A phase 1 study

Abstract

This phase 1, multi‐center, nonrandomized, open‐label, dose‐escalation study consisted of Part A wherein merestinib 80 or 120 mg (40‐mg tablets) was administered orally QD during a 28‐day cycle to patients diagnosed with solid tumors and Part B wherein merestinib 80 mg (40‐mg tablets) was administered orally QD, and cisplatin 25 mg/m2 + gemcitabine 1000 mg/m2 administered IV on Day 1 and Day 8 of a 21‐day cycle (for a maximum of eight cycles) to patients diagnosed with biliary tract carcinoma (BTC). Nineteen patients were screened and 18 patients were (Part A, n = 10; Part B, n = 8) enrolled in the trial and received treatment. All patients in Parts A and B were from Japan and were within an age range of 43–73 years, with an ECOG PS of 0.1. No dose‐limiting toxicity or deaths were experienced in the study. Dose‐limiting toxicity equivalent toxicity of Grade 4 platelet count decreased (n = 1) and was observed in Part B. In Part A, treatment‐related Grade ≥3 TEAEs were reported in one patient (PT: ALT increased and AST increased), while in Part B, five patients reported treatment‐related Grade ≥3 TEAEs with four of the five patients reporting an event of neutrophil count decreased. No complete response was reported in either Part. One patient in Part B reported partial response while four patients in each part reported stable disease. Merestinib monotherapy was concluded to be tolerable in Japanese patients, and its combination with cisplatin and gemcitabine is a tolerable regimen for Japanese patients with BTC. Trial registration: NCT03027284 (http://ClinicalTrials.gov) registered on 23 January 2017.

Prognostic and Predictive Molecular Markers in Cholangiocarcinoma

“…The following supporting information can be downloaded at , Table S1 : Overview of current and ongoing clinical trials for therapies targeting IDH1/2 in CCA, Table S2 : Overview of current and ongoing clinical trials for therapies targeting KRAS in CCA, Table S3 : Overview of current and ongoing clinical trials for therapies targeting FGFR in CCA, Table S4 : Overview of current and ongoing clinical trials for therapies targeting EGFR and VEGF in CCA, Table S5 : Overview of current and ongoing clinical trials for targeted therapies including multikinase inhibitors in CCA, Table S6 : Overview of current and ongoing clinical trials for therapies targeting the MET, notch, and chromatin remodeling pathways in CCA, Table S7 : Overview of current and ongoing clinical trials for immunotherapies in CCA. References [ 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 ] are cited in the supplementary materials.…”

BMS794833 inhibits macrophage efferocytosis by directly binding to MERTK and inhibiting its activity

“…At 1 nM, it inhibits FLT3 by 86.8%, ALK by 76.1%, LTK by 81.8%, AXL by 54.3%, and MERTK by 21.5%, which indicates a relatively weak inhibitory effect on MERTK 37 . Merestinib has passed phase I clinical trials and is now in phase II clinical trials for the treatment of advanced or metastatic biliary tract cancer 38 . Its primary target is MET, but it also inhibits MST1R, FLT3, AXL, PDGFRA, ROS1, TEK, DDR1/2, and MKNK-1/2 16 .…”

Gallbladder Cancer: Current Multimodality Treatment Concepts and Future Directions

“…At the moment, several therapeutic agents including small molecules targeting MET receptors (e.g., crizotinib, tivantinib, savolitinib, tepotinib, cabozantinib, and foretinib), MET receptor monoclonal antibodies (e.g., onartuzumab), and antibodies against its ligand HGF (e.g., ficlatuzumab and rilotumumab) are available and showed promising results in other C-MET-mutated solid cancers [ 127 ]. In a phase I clinical trial, a therapy regimen containing the C-met inhibitor merestinib and gemcitabine/cisplatin was evaluated in 19 patients, including eight BTC patients who showed a tolerable toxicity and safety [ 158 ].…”