title: Protocol Design for the Bench to Bed Trial in Alectinib-Refractory Non-Small-Cell Lung Cancer Patients Harboring the EML4-ALK Fusion Gene (ALRIGHT/OLCSG1405).
abstract: Based on our preclinical study results, which showed that the activation of the hepatocyte growth factor/MET pathway is a potential mechanism of acquired resistance to alectinib, we launched the ALRIGHT (OLCSG1405 [alectinib-refractory non-small-cell lung cancer patients harboring the EML4-ALK fusion gene]), a phase II trial of the anaplastic lymphoma kinase (ALK)/MET inhibitor crizotinib in patients with non-small-cell lung cancer refractory to alectinib and harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. Patients with ALK-rearranged tumors who have developed disease progression during alectinib treatment will receive crizotinib monotherapy until disease progression or the occurrence of unacceptable toxicity. The primary endpoint is set as the objective response rate, assuming that a response in 50% of eligible patients will indicate potential usefulness and that 15% would be the lower limit of interest (1-sided α of 0.05, β of 0.20). The estimated accrual number of patients is 9. The secondary endpoints include progression-free survival, overall survival, adverse events, and patient-reported outcomes. We will also take tissue samples before crizotinib monotherapy to conduct an exploratory analysis of ALK and hepatocyte growth factor/MET expression levels and gene alterations (eg, mutations, amplifications, and translocations). We will obtain information regarding whether crizotinib, which targets not only ALK, but also MET, can truly produce efficacy with acceptable safety profiles in ALK+non-small-cell lung cancer even in the alectinib-refractory setting.
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Hideko
authors.initials: H
authors.lastname: Isozaki
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan. Electronic address: khotta@okayama-u.ac.jp.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Hotta
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Eiki
authors.initials: E
authors.lastname: Ichihara
authors.affiliation: Department of General Internal Medicine 4, Kawasaki Medical School Hospital, Okayama, Japan.
authors.forename: Nagio
authors.initials: N
authors.lastname: Takigawa
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Kadoaki
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ninomiya
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Ninomiya
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Oda
authors.affiliation: Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan.
authors.forename: Hiroshige
authors.initials: H
authors.lastname: Yoshioka
authors.affiliation: Department of Respiratory Medicine, KKR Takamatsu Hospital, Takamatsu, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Department of Thoracic Surgery, Shimonoseki City Hospital, Shimonoseki, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Internal Medicine, Fukuyama City Hospital, Fukuyama, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takata
authors.affiliation: Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Shibayama
authors.affiliation: Department of Respiratory Medicine, National Hospital Organization Iwakuni Medical Center, Iwakuni, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kuyama
authors.affiliation: Department of Respiratory Medicine, Japanese Red Cross Kobe Hospital, Kobe, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama City, Japan.
authors.forename: Daijiro
authors.initials: D
authors.lastname: Harada
authors.affiliation: Department of Respiratory Medicine, Chugoku Central Hospital, Fukuyama, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Harita
authors.affiliation: Department of Clinical Pharmaceutics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sendo
authors.affiliation: Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D002227:Carbazoles / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005500:Follow-Up Studies; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D011379:Prognosis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D015996:Survival Rate; D012107:Research Design
chemical_list: C582670:alectinib; D014408:Biomarkers, Tumor; D002227:Carbazoles; D000077547:Crizotinib; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines
keywords: ALK inhibitor; Crizotinib; EML4-ALK; Lung carcinoma; MET