title: A phase II evaluation of bortezomib in the treatment of recurrent platinum-sensitive ovarian or primary peritoneal cancer: a Gynecologic Oncology Group study.
abstract: OBJECTIVE
  To determine the activity and pharmacodynamics (PD) of bortezomib in platinum-sensitive epithelial ovarian or primary peritoneal cancer (EOC/PPC).
  
  
  METHODS
  Eligible women with recurrent EOC/PPC progressing between 6 and 12 months after initial chemotherapy were treated with bortezomib on days 1, 4, 8, and 11 [1.5 (cohort I) and 1.3 (cohort II) mg/m(2)/dose]. Patients must have had initial chemotherapy only. Response Evaluation Criteria in Solid Tumors (RECIST) was assessed by computed tomography (CT) scan every 2 cycles. 20S proteasome activity was quantified in three pre-treatment and a 1-hour post-treatment (cycle one, day 1) whole blood lysates.
  
  
  RESULTS
  Initially, 26 evaluable patients were treated at the 1.5 mg/m(2)/dose level. Objective response rate was 3.8% (1/26), a partial response. An additional 10 patients (38.5%) had stable disease. Given concerns that treatment discontinuations due to toxicity limited drug exposure/activity a second cohort of 29 evaluable patients was accrued at 1.3 mg/m(2)/dose. The 1.3 mg/m(2)/dose regimen is currently approved as an indication for multiple myeloma and mantle cell lymphoma. Treatment was more tolerable, although objective responses remained low at 6.9% (2/29, partial responses). Second stage accrual was not warranted at either dose. Bortezomib effectively inhibited 20S proteasome activity in whole blood lysates between 37 and 92% in 24/25 (96%) patients in cohort I, and 14-84% in 27/28 (96%) patients in cohort II who provided satisfactory pre- and post-treatment specimens for testing.
  
  
  CONCLUSIONS
  Bortezomib has minimal activity as a single-agent in the treatment of recurrent platinum-sensitive EOC/PPC. Treatment with bortezomib at 1.5 mg/m(2)/dose was not feasible in this patient population due to excess toxicity. Bortezomib was well tolerated at 1.3 mg/m(2)/dose.
authors.affiliation: The Gynecologic Medical Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA. aghajanc@mskcc.org
authors.forename: Carol
authors.initials: C
authors.lastname: Aghajanian
authors.forename: John A
authors.initials: JA
authors.lastname: Blessing
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Darcy
authors.forename: Gary
authors.initials: G
authors.lastname: Reid
authors.forename: Koen
authors.initials: K
authors.lastname: DeGeest
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Rubin
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mannel
authors.forename: Jacob
authors.initials: J
authors.lastname: Rotmensch
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Schilder
authors.forename: William
authors.initials: W
authors.lastname: Riordan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001897:Boronic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069286:Bortezomib; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000201:enzymology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011719:Pyrazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex