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|Ref Type||Journal Article|
|Authors||Li T, LoRusso P, Maitland ML, Ou SH, Bahceci E, Ball HA, Park JW, Yuen G, Tolcher A|
|Title||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.|
|Journal||Journal of hematology & oncology|
|Date||2016 Mar 10|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
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|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ALK rearrange||Advanced Solid Tumor||sensitive||ASP3026||Phase I||Actionable||In a Phase I trial, ASP3026 treatment resulted in a partial response in 50% (8/16) and stable disease in 44% (7/16) of patients with an advanced solid tumor harboring an ALK rearrangement or ALK F1174L (PMID: 26966027; NCT01284192).||26966027|