title: A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies.
abstract: OBJECTIVE
  To establish the safety, maximum tolerated dose (MTD), recommended phase II dose, and preliminary antitumor activity of obatoclax mesylate (GX15-070MS), a Bcl-2 antagonist, in combination with topotecan in patients with solid tumor malignancies.
  
  
  METHODS
  Patients with solid tumor malignancies for whom topotecan was an appropriate treatment were administered obatoclax mesylate and topotecan on a 3-week cycle in a pre-defined, standard 3 + 3 dose escalation scheme. The starting dose for obatoclax mesylate was 14 mg/m(2) by 3-h intravenous (IV) infusion. Topotecan 1.25 mg/m(2) was given concurrently as an IV infusion on days 1-5 of each cycle.
  
  
  RESULTS
  Fourteen patients received 40 cycles of obatoclax mesylate at the following doses: 14 mg/m(2) on day 1, 14 mg/m(2) on days 1 and 3, and 20 mg/m(2) on day 1. The most common toxicities related to obatoclax were neurologic, including ataxia, mood alterations, somnolence, and cognitive dysfunction. The majority of these were grades 1 and 2 (88%). Two of five patients experienced dose-limiting grade 3 neurologic toxicity at a dose of 20 mg/m(2); no patients experienced grade 4 neurologic toxicities, and no other patients experienced grade 3 neurologic toxicity. Of the patients who experienced grade 3 neurologic events, one later developed febrile neutropenia, which was also a dose-limiting toxicity (DLT). After an additional three patients were treated without DLT at the previously tolerated dose of 14 mg/m(2) on day 1, the level was escalated to 14 mg/m(2) on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m(2) on days 1 and 3 was defined as the recommended phase II dose. Two patients with small-cell lung cancer (SCLC) achieved partial responses and four patients had stable disease. Median time to progression (TTP) was 12 weeks.
  
  
  CONCLUSIONS
  Obatoclax mesylate administered at 14 mg/m(2) IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m(2) IV on days 1-5 of an every 3-week cycle. A phase II trial to assess the efficacy of this combination for patients with relapsed SCLC is currently accruing patients.
authors.affiliation: Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Paik
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Andrew
authors.initials: A
authors.lastname: Brown
authors.forename: Naiyer A
authors.initials: NA
authors.lastname: Rizvi
authors.forename: Naoko
authors.initials: N
authors.lastname: Takebe
authors.forename: William
authors.initials: W
authors.lastname: Travis
authors.forename: Leonard
authors.initials: L
authors.lastname: James
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Ginsberg
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Juergens
authors.forename: Susan
authors.initials: S
authors.lastname: Markus
authors.forename: Leslie
authors.initials: L
authors.lastname: Tyson
authors.forename: Sara
authors.initials: S
authors.lastname: Subzwari
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Lee M
authors.initials: LM
authors.lastname: Krug
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008698:Mesylates / Q000008:administration & dosage; D008875:Middle Aged; D018579:Patient Selection; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D019772:Topotecan / Q000008:administration & dosage
chemical_list: D007211:Indoles; D008698:Mesylates; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D019772:Topotecan; C520962:obatoclax