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

Tianhong Li, Patricia LoRusso, Michael L Maitland, Sai-Hong Ignatius Ou, Erkut Bahceci, Howard A Ball, Jung Wook Park, Geoffrey Yuen, Anthony Tolcher, Tianhong Li, Patricia LoRusso, Michael L Maitland, Sai-Hong Ignatius Ou, Erkut Bahceci, Howard A Ball, Jung Wook Park, Geoffrey Yuen, Anthony Tolcher

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: ASP3026 was well tolerated and had therapeutic activity in patients with crizotinib-resistant ALK-positive advanced tumors.

Trial registration: ClinTrials.gov: NCT01284192.

Keywords: ALK inhibitor; ASP3026; Neoplasms; Pharmacokinetics; Phase I.

Figures

Fig. 1
Fig. 1
Mean plasma concentration of ASP3026, cycle 1, day 1. a Semi-log plot. b Linear plot. For patient numbers at each dose, refer to Tables 3 and 4
Fig. 2
Fig. 2
Best tumor response for target lesions in patients treated with ASP3026 in the dose-expansion cohort. Each bar represents one patient. The dotted line at 30 % indicates partial response. Maximum tumor response for the sum of target lesions is shown. The graph shows 12 patients with evaluable primary tumor diameter changes (one patient was non-evaluable, and for three stable disease patients, the overall response was not based on target lesion)

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