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Invest New Drugs ; 36(5): 886-894, 2018 10.
Article in English | MEDLINE | ID: mdl-29766337

ABSTRACT

Background The MET tyrosine kinase and its ligand, hepatocyte growth factor (HGF) also known as scatter factor, are associated with tumourigenesis and metastasis by promotion of scattering, proliferation, angiogenesis, motility and invasion. ASLAN-002 is a potent inhibitor of MET as well as related kinases. A phase I dose escalation study was conducted to determine the safety and pharmacokinetics of ASLAN-002 in patients with advanced cancer. Methods Patients with advanced or metastatic solid tumours, who had progressed on standard therapy or for whom standard therapy was not known, were administered ASLAN-002 orally. The starting dose was 100 mg once daily (QD) with subsequent cohorts to receive doses of 200 mg QD, 300 mg QD, 450 mg QD, 600 mg QD, 300 mg twice daily (BID), 450 mg BID, and 600 mg BID. Results Forty patients were included across 7 dose cohorts. Cohort 8 (600 mg BID) was not opened due to the lack of appreciable pharmacokinetic (PK) differences between 300 mg BID and 450 mg BID and higher incidences of grade 3 or 4 adverse events (AE) in Cohort 7 (450 mg BID). Fifteen patients (37.5%) experienced a grade 3 or 4 AE. The most commonly reported AEs were nausea (55%), fatigue (47.5%) and constipation (30%). One dose limiting toxicity (DLT) of atrial fibrillation was observed with 450 mg BID. Conclusions ASLAN-002 is well tolerated at 300 mg BID and is the recommended dose for future phase II studies (RP2D). Clinical Trials Registry Number: NCT01721148 .


Subject(s)
Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Administration, Oral , Adult , Aged , Aged, 80 and over , Atrial Fibrillation/drug therapy , Atrial Fibrillation/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Fatigue/chemically induced , Fatigue/metabolism , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Nausea/chemically induced , Nausea/metabolism , Neoplasms/metabolism
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