title: A phase I trial of an oral subtype-selective histone deacetylase inhibitor, chidamide, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer.
abstract: OBJECTIVE
  This phase I study was to evaluate safety, maximum tolerated dose, pharmacokinetics and preliminary antitumor activity of chidamide, a novel subtype-selective histone deacetylase (HDAC) inhibitor, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Ten patients received oral chidamide 20, 25, or 30 mg twice per week continuously with paclitaxel (175 mg/m(2)) and carboplatin [area under the curve (AUC) 5 mg/mL/min] administered in a 3-week cycle. Patients with response and stable disease after four cycles maintained chidamide monotherapy until disease progression or unacceptable toxicity. Blood samples were collected for pharmacokinetic analysis after the first single oral of chidamide and first combination treatment in cycle 1 from all patients.
  
  
  RESULTS
  Two dose-limiting toxicities were recorded in the 30 mg cohort, including thrombocytopenia and prolonged neutropenia in the first cycle. Grade 3/4 neutropenia in any cycle was observed in all patients, but was not associated with significant complications. Other grade 3/4 hematologic toxicities included thrombocytopenia and leucopenia. No significant changes were observed in pharmacokinetic parameters for both chidamide and paclitaxel. One patient in the 20 mg cohort had confirmed partial response (PR). Two out of 5 patients with brain metastases had intracranial complete remission after 4-cycle treatment.
  
  
  CONCLUSIONS
  Chidamide combined with paclitaxel and carboplatin was generally tolerated without unanticipated toxicities or clinically relevant pharmacokinetic interactions. The recommended dose for chidamide in this combination was established at 20 mg, and a phase II trial is ongoing with this regimen in patients with advanced NSCLC.
authors.affiliation: Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Xingsheng
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Han
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Transfusion Medicine, Beijing 100850, China.
authors.forename: Guifang
authors.initials: G
authors.lastname: Dou
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Transfusion Medicine, Beijing 100850, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Yuankai
authors.initials: Y
authors.lastname: Shi
keywords: Chidamide; HDAC inhibitor; non-small cell lung cancer; paclitaxel and carboplatin; phase I