Recommendations in a New Drug Application Review for Dose Optimization to Potentially Improve Gastrointestinal Tolerability of a Tyrosine Kinase Inhibitor.

2574 Background: On April 29 2014, the U.S. FDA approved ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. At the approved dosing regimen of ceritinib 750 mg once daily taken on an empty stomach, diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients with dose modification in 38% of patients. Anecdotal reports from patients and investigators suggest that gastrointestinal (GI) tolerability may improve when ceritinib is taken with food; however, administration of ceritinib with food increases exposure and may also increase the occurrence of non-GI related toxicities. Methods: Data were obtained from the multicenter, single-arm registration trial in 255 patients with ALK-positive tumors who received ceritinib 750 mg daily under fasted conditions and from a food effect study in healthy subjects. Exposure-response relationships for safety endpoints were evaluated by logistic regression analyses and Kaplan-Meier analyses using average exposure quartiles. Results: Compared to fasting conditions, a high-fat meal and a low fat meal increased ceritinib AUCinf by more than 50%. Higher systemic exposure appeared to be associated with more frequent and earlier safety events including overall Grade 3-4 adverse reactions (ARs), and individual ARs such as ≥ Grade 3 AST/ALT elevation and ≥ Grade 2 hyperglycemia. Higher systemic exposure also appeared to be associated with earlier and more frequent dose reductions or interruptions. A pharmacokinetic / pharmacodynamic analysis showed concentration-dependent QTc interval prolongation. Conclusions: The analyses along with the observed safety data led to an FDA requirement to conduct a postmarketing clinical trial to evaluate a lower dose of ceritinib taken with a meal (providing similar systemic exposure to that of the 750 mg dose taken under a fasted state) that potentially improves GI tolerability.