title: A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer.
abstract: BACKGROUND
  A phase I, dose-escalation study of AT-101 with cisplatin and etoposide was conducted to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and pharmacokinetics in patients with advanced solid tumors, with an expanded cohort in patients with extensive-stage small cell lung cancer (ES-SCLC) to assess preliminary activity.
  
  
  METHODS
  In the dose escalation portion, increasing doses of AT-101 were administered orally BID on days 1-3 along with cisplatin on day 1 and etoposide on days 1-3 of a 21 day cycle. At the RP2D, an additional 7 patients with untreated ES-SCLC were enrolled.
  
  
  RESULTS
  Twenty patients were enrolled in the dose-escalation cohort, and 7 patients with ES-SCLC were enrolled in the expanded cohort. The MTD/RP2D was established at AT-101 40 mg BID days 1-3 with cisplatin 60 mg/m2 and etoposide 120 mg/m2 on day 1 of a 21 day cycle with pegfilgrastim support. Two DLTs of neutropenic fever were seen at dose level 1. After the addition of pegfilgrastim, no additional DLTs were observed. Grade 3/4 treatment-related toxicities included: diarrhea, increased AST, neutropenia, hypophosphatemia, hyponatremia, myocardial infarction and pulmonary embolism. No apparent PK interactions were observed between the agents. Preliminary activity was observed with PRs in patients with ES-SCLC, high-grade neuroendocrine tumor, esophageal cancer and NSCLC.
  
  
  CONCLUSIONS
  AT-101 with cisplatin and etoposide is well tolerated with growth factor support. Anti-tumor activity was observed in a variety of cancers including ES-SCLC, supporting further investigation with BH-3 mimetics in combination with standard chemotherapy for ES-SCLC.
authors.affiliation: University of Wisconsin Carbone Cancer Center, 600 Highland Avenue, K4/530 CSC, Madison, WI, 53792, USA, wrs@medicine.wisc.edu.
authors.forename: William R
authors.initials: WR
authors.lastname: Schelman
authors.forename: Tabraiz A
authors.initials: TA
authors.lastname: Mohammed
authors.forename: Anne M
authors.initials: AM
authors.lastname: Traynor
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Marnocha
authors.forename: Jens
authors.initials: J
authors.lastname: Eickhoff
authors.forename: Michael
authors.initials: M
authors.lastname: Keppen
authors.forename: Dona B
authors.initials: DB
authors.lastname: Alberti
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Naoko
authors.initials: N
authors.lastname: Takebe
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006072:Gossypol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D005047:Etoposide; D006072:Gossypol; D002945:Cisplatin; C028178:gossypol acetic acid