First-in-human, open-label dose-escalation and dose-expansion study of the safety, pharmacokinetics, and antitumor effects of an oral ALK inhibitor ASP3026 in patients with advanced solid tumors

• Published in: Journal of hematology and oncology Vol. 9; no. 22; pp. 23 - 9
• Main Authors: Li, Tianhong, LoRusso, Patricia, Maitland, Michael L, Ou, Sai-Hong Ignatius, Bahceci, Erkut, Ball, Howard A, Park, Jung Wook, Yuen, Geoffrey, Tolcher, Anthony
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 10.03.2016; BioMed Central; BMC
• Subjects: Administration, Oral; Adult; Aged; ALK inhibitor; Anaplastic Lymphoma Kinase; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Area Under Curve; ASP3026; Biological markers; Care and treatment; Complications and side effects; Crizotinib; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm - drug effects; Fatigue - chemically induced; Female; Health aspects; Humans; Male; Metabolic Clearance Rate; Middle Aged; Nausea - chemically induced; Neoplasms; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - metabolism; Pharmacokinetics; Phase I; Protein Kinase Inhibitors - therapeutic use; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Sulfones - administration & dosage; Sulfones - adverse effects; Sulfones - pharmacokinetics; Treatment Outcome; Triazines - administration & dosage; Triazines - adverse effects; Triazines - pharmacokinetics; Tumors; Vomiting - chemically induced; Young Adult; ASP3026; Phase I; ALK inhibitor; Pharmacokinetics; Neoplasms
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-016-0254-5

ASP3026 is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has potent in vitro activity against crizotinib-resistant ALK-positive tumors. This open-label, multicenter, first-in-human phase I study ( NCT01284192 ) assessed the safety, pharmacokinetic profile, and antitumor activity of ASP3026. Advanced solid tumor patients received oral ASP3026 in 3 + 3 dose-escalation cohorts at doses of 25-800 mg once daily in 28-day cycles. The endpoints were to identify the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the pharmacokinetic profile of ASP3026. A phase Ib expansion cohort enrolled patients with metastatic, crizotinib-resistant ALK-positive solid tumors at the RP2D, and response was evaluated by RECIST 1.1. The dose-escalation cohort enrolled 33 patients, including three crizotinib-resistant, ALK-positive patients, and the dose-expansion cohort enrolled another 13 crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC) patients. ASP3026 demonstrated both linear pharmacokinetics and dose-proportional exposure for area under the plasma concentration-time curve and maximum concentration observed with a median terminal half-life of 35 h, supporting the daily dosing. Grade 3 rash and elevated transaminase concentrations were dose-limiting toxicities observed at 800 mg; hence, 525 mg daily was the MTD and RP2D. The most common treatment-related adverse events were nausea (38%), fatigue (35%), and vomiting (35 %). Among the 16 patients with crizotinib-resistant ALK-positive tumors (15 NSCLC, 1 neuroblastoma), eight patients achieved partial response (overall response rate 50%; 95% confidence interval 25-75%) and seven patients (44%) achieved stable disease. ASP3026 was well tolerated and had therapeutic activity in patients with crizotinib-resistant ALK-positive advanced tumors. ClinTrials.gov: NCT01284192.