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A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors.
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2014
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OncologyMedicineMetronomic TherapyPathologyAdvanced Solid TumorsImmune Checkpoint InhibitorAccelerated Titration DesignNovel Alk InhibitorAnti-cancer AgentCancer TreatmentNsclc PatientsAlk Fusion-positive NsclcPharmacologyRadiation OncologyCancer ResearchLung CancerMolecular Oncology
8030^ Background: X-396 is a novel, potent anaplastic lymphoma kinase (ALK) small molecule TKI with significant anti-tumor activity in both ALK TKI naive and crizotinib resistant models of ALK fusion-positive NSCLC. Methods: In this multicenter phase I study, patients with advanced solid tumors were enrolled and given X-396 on a continuous 28-day schedule. This was an accelerated titration design with the dose starting at 25 mg once daily. At the first DLT cohorts were expanded to the classic 3+3 design up to 250 mg daily. All pts were assessed for adverse events (AEs) using CTCAE version 4.0, response to therapy was assessed using RECIST 1.1, and pharmacokinetics (PK) were measured. Results: As of the January 23, 2014 cutoff, 30 patients enrolled (21 NSCLC patients, 13 ALK+ - 3 crizotinib naïve and 10 crizotinib resistant), 4 H&N, 2 SCLC, 2 colorectal,1 breast). Median age 58, 12 ECOG PS 0 and 18 PS 1. The most common drug related AEs include rash (36%, G1-G3), fatigue (30%, G1-G2), nausea (27%, G1), vomiting (27%, G1) and edema (20%, G1-G2). Grade3/4 treatment related AEs were rash (2patients), edema (1patient). X-396 exhibited linear PK at doses 25 – 250mg. At 200mg QD, the t1/2 is ~23 hours, and the trough level (~300nM) is sufficient to inhibit most crizotinib resistant mutations in vitro. To date, 18 patients are evaluable for response; SD is 28% and PR 28%. Among 8 evaluable ALK+ NSCLC cases, responses occurred in crizotinib naïve and crizotinib treated patients. In the 6 ALK+ patients treated at doses ≥ 200 mg SD is 17% and PR 83%; 2 PRs were observed in patients treated with prior crizotinib. CNS responses have been observed in 2 patients, 1 crizotinib naïve and 1 crizotinib resistant. The median duration of treatment in evaluable ALK+ patients is 20+ weeks with the longest being 58+ weeks. Conclusions: X-396 is generally well tolerated at doses up to 250 mg daily and induces responses in both crizotinib naïve and crizotinib resistant ALK+ NSCLC patients. Enrollment is ongoing. Clinical trial information: NCT01625234.