title: Obatoclax mesylate, a pan-bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer.
abstract: BACKGROUND
  The proapoptotic small-molecule pan-Bcl-2 inhibitor obatoclax mesylate (GX15-070) may enhance the cytotoxicity of chemotherapy in relapsed/refractory non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Obatoclax was administered with docetaxel in patients with relapsed or refractory NSCLC- docetaxel as a 1-hour infusion on day 1 and obatoclax as a 24-hour infusion on days 1 and 2-every 3 weeks for up to eight cycles. Four dose levels were evaluated in phase 1 (level 1: docetaxel 55 mg/m × 1 and obatoclax 30 mg × 2; levels 2-4: docetaxel 75 mg/m and obatoclax 30 mg, 45 mg, or 60 mg × 2) to identify dose-limiting toxicity and a phase 2 dose. In phase 2, response and tolerability were evaluated.
  
  
  RESULTS
  Eighteen patients were included in phase 1. Two dose-limiting toxicities occurred during cycle 1: one febrile neutropenia each at dose levels 3 and 4. Maximum tolerated dose was not reached; 32 patients (including 3 from phase 1) were treated in phase 2 with docetaxel 75 mg/m and obatoclax 60 mg (median 2 cycles). Three patients (11%) had partial responses in phase 2; two demonstrated stable disease lasting 12 weeks or more. Median duration of response was 4.8 months. Overall, median progression-free survival was 1.4 months. Neutropenia (31%), febrile neutropenia (16%), and dyspnea (19%) were the most common grade 3/4 adverse events observed.
  
  
  CONCLUSIONS
  Combined obatoclax mesylate plus docetaxel is tolerable in patients with NSCLC, but response was minimal and neutropenia was a common adverse event.
authors.affiliation: *H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida; †Arlington Cancer Center, Arlington, Texas; ‡Mayo Clinic Arizona, Scottsdale, Arizona; §Georgetown University Hospital, Washington, District of Columbia; ‖University of Maryland, Greenebaum Cancer Center, Baltimore, Maryland; ¶Tower Cancer Research Foundation, Beverly Hills, California; #MedStar Research Institute, Hyattsville, Maryland; and **formerly Gemin X Pharmaceuticals, an indirect wholly owned subsidiary of Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiappori
authors.forename: Charles
authors.initials: C
authors.lastname: Williams
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.forename: John W
authors.initials: JW
authors.lastname: Adams
authors.forename: Shakun
authors.initials: S
authors.lastname: Malik
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Edelman
authors.forename: Peter
authors.initials: P
authors.lastname: Rosen
authors.forename: David A
authors.initials: DA
authors.lastname: Van Echo
authors.forename: Mark S
authors.initials: MS
authors.lastname: Berger
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D000077143:Docetaxel; D006801:Humans; D007211:Indoles; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D007211:Indoles; D011758:Pyrroles; D043823:Taxoids; D000077143:Docetaxel; C520962:obatoclax