title: Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer.
abstract: BACKGROUND
  AT-101 is an oral, pan Bcl-2 family protein inhibitor that has demonstrated activity in small cell lung cancer (SCLC) models. A phase I/II study was conducted combining AT-101 with topotecan in relapsed and refractory SCLC.
  
  
  METHODS
  An open-labeled multicenter phase I/II study was conducted of oral AT-101 with intravenous topotecan in patients with SCLC who had progressed on prior platinum-containing chemotherapy. The phase II portion was a two-stage design, and two cohorts of patients, sensitive relapsed and refractory, were analyzed. Primary endpoint in the two-stage phase II portion was response rate; secondary endpoints were duration of response and time to progression.
  
  
  RESULTS
  Thirty-six patients were enrolled. The most common toxicities were hematologic, as would be expected with topotecan and AT-101. The recommended phase II dose was 40 mg AT-101 days 1 to 5 with topotecan 1.25 mg/m(2) days 1 to 5 on a 21-day cycle. In the sensitive-relapsed cohort (n = 18), there were 0 complete response (CR), three partial response (PR), 10 stable disease (SD), and four progressive disease (PD). In the refractory cohort (n = 12), there were 0 CR/PR, five SD, and five PD. The study did not meet its prespecified endpoints to continue enrollment in the second stage of the phase II study. Median time to progression in the sensitive-relapsed cohort was 17.4 weeks and 11.7 weeks in the refractory cohort.
  
  
  CONCLUSIONS
  AT-101 can be safely combined with topotecan at a reduced dose of 1.25 mg/m(2). The response rates observed did not meet the criteria for additional enrollment; however, many patients had a best response of SD and the median time to progression in both cohorts was favorable. Additional trials of AT-101 in SCLC are ongoing.
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts 02114, USA. rheist@partners.org
authors.forename: Rebecca Suk
authors.initials: RS
authors.lastname: Heist
authors.forename: Jerry
authors.initials: J
authors.lastname: Fain
authors.forename: Bernard
authors.initials: B
authors.lastname: Chinnasami
authors.forename: Waseem
authors.initials: W
authors.lastname: Khan
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Temel
authors.forename: Panos
authors.initials: P
authors.lastname: Fidias
authors.forename: Valari
authors.initials: V
authors.lastname: Brainerd
authors.forename: Lance
authors.initials: L
authors.lastname: Leopold
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D016879:Salvage Therapy; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D019772:Topotecan / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D019772:Topotecan; D006072:Gossypol; C028178:gossypol acetic acid