title: Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer or Other Tumors.
abstract: BACKGROUND
  Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK inhibitors, but resistance develops. This study assessed the maximum-tolerated dose, safety, pharmacokinetics (PK), and antitumor activity of ceritinib, a novel ALK inhibitor (ALKi), in Japanese patients with ALK-rearranged malignancies.
  
  
  METHODS
  This phase I, multicenter, open-label study (NCT01634763) enrolled adult patients with ALK-rearranged (by fluorescence in situ hybridization and/or immunohistochemistry) locally advanced/metastatic malignancy that had progressed despite standard therapy. The study comprised two parts: dose escalation and dose expansion. Ceritinib (single-dose) was administered orally in the 3-day PK run-in period, then once daily, in 21-day cycles. Adaptive dose escalations were guided by a Bayesian model.
  
  
  RESULTS
  Twenty patients (80% with ALKi treatment history [ALKi-pretreated]; 19 NSCLC; one inflammatory myofibroblastic tumor) received ceritinib 300 to 750 mg (19 during dose escalation, one in dose expansion). Two dose-limiting toxicities occurred: grade 3 lipase increase (600 mg); grade 3 drug-induced liver injury (750 mg). The most common adverse events were gastrointestinal (nausea: 95%; diarrhea, vomiting: 75%). Ceritinib PK profile was dose proportional across 300 to 750 mg dosages; steady state was reached by day 15. Overall response rate was 55% (11 of 20 patients). Among patients with NSCLC, partial response was observed in two of four ALKi-naive patients, five of nine crizotinib-pretreated patients, two of four alectinib-pretreated patients, and one of two crizotinib and alectinib/ASP3026 pretreated patients. The ASP3026-pretreated inflammatory myofibroblastic tumor patient achieved partial response.
  
  
  CONCLUSIONS
  Ceritinib maximum-tolerated dose was 750 mg once daily in Japanese patients. Antitumor activity was observed irrespective of prior ALKi treatment history. Dose expansion, examining the activity of ceritinib in alectinib-resistant patients, is ongoing.
authors.affiliation: *The Cancer Institute Hospital of JFCR, Tokyo, Japan; †Shizuoka Cancer Center, Shizuoka, Japan; ‡National Kyushu Cancer Center, Fukuoka, Japan; §Novartis Pharma K.K., Tokyo, Japan; ¶Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and ‖Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishio
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Murakami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Horiike
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hirai
authors.forename: Naoko
authors.initials: N
authors.lastname: Suenaga
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tajima
authors.forename: Kota
authors.initials: K
authors.lastname: Tokushige
authors.forename: Masami
authors.initials: M
authors.lastname: Ishii
authors.forename: Anthony
authors.initials: A
authors.lastname: Boral
authors.forename: Matthew
authors.initials: M
authors.lastname: Robson
authors.forename: Takashi
authors.initials: T
authors.lastname: Seto
mesh_terms: D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D021322:Antifreeze Proteins, Type I; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D044466:Asian People; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D021322:Antifreeze Proteins, Type I; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013450:Sulfones; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib