title: Safety, Efficacy, and Biomarker Exploration in a Phase II Study of Bevacizumab, Oxaliplatin, and Gemcitabine in Recurrent Müllerian Carcinoma.
abstract: OBJECTIVE: To explore the safety, efficacy, and biomarkers of bevacizumab with gemcitabine and oxaliplatin in women with recurrent platinum-sensitive ovarian carcinoma.  METHODS: The patients received bevacizumab (10 mg/kg), gemcitabine (1000 mg/m(2)), and oxaliplatin (65 mg/m(2)) on days 1 and 15 in 28-day cycles. The patients with safely accessible tumor underwent intratumoral fluid pressure (IFP) measurements and positron-emission tomographies immediately and 2 weeks after treatment. Blood biomarkers were evaluated at 5 time points.  RESULTS: The trial was closed after enrolling 19 of the 53 projected patient accrual. Thirteen (68.5%) of 19 patients showed a response (1 complete response, 12 partial responses), and 6 patients showed stable disease (31.6%). Median progressive-free survival was 36.9 weeks (258.3 days), and the median overall survival was 112.3 weeks (633 days, not reached). Toxicity was acceptable, and there were no arterial thromboses, serious bleeding, gastrointestinal perforations, or complications from the invasive procedures. Bevacizumab with chemotherapy induced a substantial drop in tumor IFP after treatment. The regimen induced sustained elevation in circulating plasma vascular endothelial growth factor (VEGF), placental growth factor (PlGF), basic fibroblast growth factor (bFGF), soluable vascular endothelial growth factor receptor 2 (sVEGFR2), and circulating progenitor cells. Plasma PlGF, VEGFR2(+) monocytes, and urinary matrix metalloproteinase 2 activity showed differential associations with treatment outcome when evaluated at baseline and after 14 days of treatment.  CONCLUSIONS: Despite early termination of the study, the results indicate that the regimen was well tolerated and demonstrated activity in platinum-sensitive ovarian cancer. Biomarker evaluations showed that bevacizumab with chemotherapy significantly changed the levels of several circulating cellular and molecular biomarkers. The increases in plasma PlGF and VEGFR2(+) monocytes showed correlations with outcome. These exploratory data should be further evaluated in future studies of bevacizumab in ovarian cancer.
authors.affiliation: Gynecologic Oncology Program, Brigham and Women's Hospital, Boston, MA.
authors.forename: Neil S
authors.initials: NS
authors.lastname: Horowitz
authors.forename: Richard T
authors.initials: RT
authors.lastname: Penson
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: di Tomaso
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Cohen
authors.forename: Suzanne
authors.initials: S
authors.lastname: Berlin
authors.forename: Carolyn N
authors.initials: CN
authors.lastname: Krasner
authors.forename: Marsha A
authors.initials: MA
authors.lastname: Moses
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain