title: A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer.
abstract: BACKGROUND
  Bcl-2 family genes are frequently amplified in small cell lung cancer (SCLC). A phase I trial was conducted to evaluate the safety of obatoclax, a Bcl-2 family inhibitor, given in combination with standard chemotherapy.
  
  
  METHODS
  Eligible patients (3-6 per cohort) had extensive-stage SCLC, measurable disease, ≤ 1 before therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients were treated with escalating doses of obatoclax, either as a 3- or 24-h infusion, on days 1-3 of a 21-day cycle, in combination with carboplatin (area under the curve 5, day 1 only) and etoposide (100 mg m(-2), days 1-3). The primary endpoint was to determine the maximum tolerated dose of obatoclax.
  
  
  RESULTS
  Twenty-five patients (56% male; median age 66 years) were enrolled in three dose cohorts for each schedule. Maximum tolerated dose was established with the 3-h infusion at 30 mg per day and was not reached with the 24-h infusion. Compared with the 24-h cohorts, the 3-h cohorts had higher incidence of central nervous system (CNS) adverse events (AEs); dose-limiting toxicities were somnolence, euphoria, and disorientation. These CNS AEs were transient, resolving shortly after the end of infusion, and without sequelae. The response rate was 81% in the 3-h and 44% in the 24-h infusion cohorts.
  
  
  CONCLUSIONS
  Although associated with a higher incidence of transient CNS AEs than the 24-h infusion, 3-h obatoclax infusion combined with carboplatin-etoposide was generally well tolerated at doses of 30 mg per day. Though patient numbers were small, there was a suggestion of improved efficacy in the 3-h infusion group. Obatoclax 30 mg infused intravenously over 3 h on 3 consecutive days will be utilised in future SCLC studies.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Thoracic Oncology Program, 12902 Magnolia Drive, Tampa, FL 33612, USA. Alberto.Chiappori@moffitt.org
authors.forename: A A
authors.initials: AA
authors.lastname: Chiappori
authors.forename: M T
authors.initials: MT
authors.lastname: Schreeder
authors.forename: M M
authors.initials: MM
authors.lastname: Moezi
authors.forename: J J
authors.initials: JJ
authors.lastname: Stephenson
authors.forename: J
authors.initials: J
authors.lastname: Blakely
authors.forename: R
authors.initials: R
authors.lastname: Salgia
authors.forename: Q S
authors.initials: QS
authors.lastname: Chu
authors.forename: H J
authors.initials: HJ
authors.lastname: Ross
authors.forename: D S
authors.initials: DS
authors.lastname: Subramaniam
authors.forename: J
authors.initials: J
authors.lastname: Schnyder
authors.forename: M S
authors.initials: MS
authors.lastname: Berger
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects; D002490:Central Nervous System / Q000187:drug effects; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D007211:Indoles; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology
chemical_list: D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D005047:Etoposide; D016190:Carboplatin; C520962:obatoclax