A Phase Ii Single-Arm Study Of Ldk378 In Patients With Alk-Activated (Alk Plus ) Non-Small Cell Lung Cancer (Nsclc) Previously Treated With Chemotherapy And Crizotinib (Crz).

TPS8119 Background: NSCLC harboring anaplastic lymphoma kinase (ALK) gene rearrangements (2–8% of cases) are sensitive to CRZ, the only approved ALK inhibitor, but invariably develop resistance. There are currently no standard ALK-targeted treatments for CRZ-resistant ALK+ NSCLC. LDK378 is a novel, oral ALK inhibitor with 20-fold greater potency than CRZ in enzymatic assays. In an ongoing phase I trial, LDK378 has demonstrated substantial clinical activity in patients (pts) with ALK+ NSCLC whose disease has failed CRZ. At a dose ≥400 mg (45 pts), the overall response rate (ORR) was 80%, with 47% confirmed responses (data cutoff August 31, 2012). Nausea, vomiting, diarrhea and fatigue were the main toxicities. The recommended phase II dose is 750 mg daily. Methods: This phase II multicenter, open label, single-arm study (CLDK378A2201) is designed to evaluate the efficacy and safety of oral LDK378 750 mg once-daily in pts with ALK+ (by FDA-approved FISH test) advanced NSCLC. Pts must have received cytotoxic chemotherapy (1–3 lines, including 1 platinum doublet) and progressed on CRZ as the last therapy prior to study entry. Pts with ECOG PS 0–2 and stable CNS metastases are eligible. LDK378 may be continued beyond RECIST-defined PD if there is evidence of clinical benefit. The primary objective is to assess the antitumor activity of LDK378 in terms of ORR by investigator assessment (using RECIST v1.1). Secondary/exploratory objectives include evaluating response endpoints (duration of response, time to response and ORR by independent radiological review), PFS, OS, safety, PK, and impact on patient-reported outcomes. The primary analysis will occur when all pts have completed 6 cycles or discontinued treatment earlier. The study design (137 pts) provides 90% power to test a null hypothesis of ORR ≤25% vs. a target ORR of ≥38%: if ≥45 responses are observed (estimated ORR 33%), the null hypothesis will be rejected at a one-sided significance level of 0.025. The study is recruiting in 67 sites from 14 countries across Europe, Asia and North America. As of February 5, 2013, 7 pts have been enrolled. ClinicalTrials.gov identifier NCT01685060. Clinical trial information: NCT01685060.