Jordi Rodon1, Sophie Postel-Vinay2, Antoine Hollebecque2, Paolo Nuciforo3, Analia Azaro4, Valérie Cattan5, Lucie Marfai5, Isabelle Sudey5, Karl Brendel6, Audrey Delmas6, Stéphanie Malasse7, Jean-Charles Soria2. 1. Medical Oncology, Vall D'Hebron University Hospital and Vall D'Hebron Institut D'Oncologia, Barcelona, Spain. Electronic address: jrodon@vhio.net. 2. Drug Development Department DITEP, Institut Gustave Roussy, 94805, Villejuif, France; Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Orsay, 91405, France. 3. Molecular Oncology Laboratory, Vall D'Hebron University Hospital Institut D'Oncologia, Barcelona, Spain. 4. Medical Oncology, Vall D'Hebron University Hospital and Vall D'Hebron Institut D'Oncologia, Barcelona, Spain. 5. Oncology R&D Unit, Institut de Recherches Internationales Servier, 92284, Suresnes, France. 6. Division of Clinical Pharmacokinetics and Pharmacometrics, Institut de Recherches Internationales Servier, 92284, Suresnes, France. 7. Division of Biostatistics, Institut de Recherches Internationales Servier, 92284, Suresnes, France.
Abstract
BACKGROUND AND OBJECTIVES: S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. MATERIALS AND METHODS: Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD. Pharmacokinetic (PK) parameters were assessed and pharmacodynamic end-points were evaluated in pre- and post-treatment tumour biopsies. Preliminary anti-tumour activity was evaluated as per the Response Evaluation Criteria In Solid Tumours 1.1 criteria. RESULTS: A total of 103 patients were treated: 79 in the dose-escalation and 24 in the expansion. Doses from 15 to 900 mg were evaluated. Dose-limiting toxicities were reported in 9 patients and occurred at 30, 760 and 900 mg in the qd arm and at 180, 225 and 285 mg in the bid arm. The RD was defined at 600 mg qd. Adverse events (AEs) occurred with similar frequency in both regimens at an equivalent total daily dose. Overall, 83 patients (81.4%) had drug-related AEs, the majority (93%) of which were grade I-II (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) and only 3% led to drug discontinuation. Intratumoural PK analysis at the RD suggested hitting of MET, AXL and FGFR. CONCLUSION: S49076 demonstrated a tolerable safety profile with limited single-agent activity. PK/pharmacodynamic readouts of S49076 are encouraging for further investigation of S49076 in combination therapies. TRIAL REGISTRATION NUMBER: ISRCTN00759419.
BACKGROUND AND OBJECTIVES: S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. MATERIALS AND METHODS:Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD. Pharmacokinetic (PK) parameters were assessed and pharmacodynamic end-points were evaluated in pre- and post-treatment tumour biopsies. Preliminary anti-tumour activity was evaluated as per the Response Evaluation Criteria In Solid Tumours 1.1 criteria. RESULTS: A total of 103 patients were treated: 79 in the dose-escalation and 24 in the expansion. Doses from 15 to 900 mg were evaluated. Dose-limiting toxicities were reported in 9 patients and occurred at 30, 760 and 900 mg in the qd arm and at 180, 225 and 285 mg in the bid arm. The RD was defined at 600 mg qd. Adverse events (AEs) occurred with similar frequency in both regimens at an equivalent total daily dose. Overall, 83 patients (81.4%) had drug-related AEs, the majority (93%) of which were grade I-II (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) and only 3% led to drug discontinuation. Intratumoural PK analysis at the RD suggested hitting of MET, AXL and FGFR. CONCLUSION: S49076 demonstrated a tolerable safety profile with limited single-agent activity. PK/pharmacodynamic readouts of S49076 are encouraging for further investigation of S49076 in combination therapies. TRIAL REGISTRATION NUMBER: ISRCTN00759419.
Authors: Evgenii Skurikhin; Olga Pershina; Mariia Zhukova; Darius Widera; Natalia Ermakova; Edgar Pan; Angelina Pakhomova; Sergey Morozov; Aslan Kubatiev; Alexander Dygai Journal: Front Cell Dev Biol Date: 2021-12-03