TY - JOUR
T1 - A phase I pharmacokinetic study of intraperitoneal bortezomib and carboplatin in patients with persistent or recurrent ovarian cancer
T2 - An NRG Oncology/Gynecologic Oncology Group study
AU - Jandial, Danielle A.
AU - Brady, William E.
AU - Howell, Stephen B.
AU - Lankes, Heather A.
AU - Schilder, Russell J.
AU - Beumer, Jan H.
AU - Christner, Susan M.
AU - Strychor, Sandra
AU - Powell, Matthew A.
AU - Hagemann, Andrea R.
AU - Moore, Kathleen N.
AU - Walker, Joan L.
AU - DiSilvestro, Paul A.
AU - Duska, Linda R.
AU - Fracasso, Paula M.
AU - Dizon, Don S.
PY - 2017/5
Y1 - 2017/5
N2 - Purpose Intraperitoneal (IP) therapy improves survival compared to intravenous (IV) treatment for women with newly diagnosed, optimally cytoreduced, ovarian cancer. However, the role of IP therapy in recurrent disease is unknown. Preclinical data demonstrated IP administration of the proteasome inhibitor, bortezomib prior to IP carboplatin increased tumor platinum accumulation resulting in synergistic cytotoxicity. We conducted this phase I trial of IP bortezomib and carboplatin in women with recurrent disease. Methods Women with recurrent ovarian cancer were treated with escalating doses of IP bortezomib - in combination with IP carboplatin (AUC 4 or 5) every 21 days for 6 cycles. Pharmacokinetics of both agents were evaluated in cycle 1. Results Thirty-three women participated; 32 were evaluable for safety. Two patients experienced dose-limiting toxicity (DLT) at the first dose level (carboplatin AUC 5, bortezomib 0.5 mg/m2), prompting carboplatin reduction to AUC 4 for subsequent dose levels. With carboplatin dose fixed at AUC 4, bortezomib was escalated from 0.5 to 2.5 mg/m2 without DLT. Grade 3/4 related toxicities included abdominal pain, nausea, vomiting, and diarrhea which were infrequent. The overall response rate in patients with measurable disease (n = 21) was 19% (1 complete, 3 partial). Cmax and AUC in peritoneal fluid and plasma increased linearly with dose, with a favorable exposure ratio of the peritoneal cavity relative to peripheral blood plasma. Conclusion IP administration of this novel combination was feasible and showed promising activity in this phase I trial of heavily pre-treated women with ovarian cancer. Further evaluation of this IP combination should be conducted.
AB - Purpose Intraperitoneal (IP) therapy improves survival compared to intravenous (IV) treatment for women with newly diagnosed, optimally cytoreduced, ovarian cancer. However, the role of IP therapy in recurrent disease is unknown. Preclinical data demonstrated IP administration of the proteasome inhibitor, bortezomib prior to IP carboplatin increased tumor platinum accumulation resulting in synergistic cytotoxicity. We conducted this phase I trial of IP bortezomib and carboplatin in women with recurrent disease. Methods Women with recurrent ovarian cancer were treated with escalating doses of IP bortezomib - in combination with IP carboplatin (AUC 4 or 5) every 21 days for 6 cycles. Pharmacokinetics of both agents were evaluated in cycle 1. Results Thirty-three women participated; 32 were evaluable for safety. Two patients experienced dose-limiting toxicity (DLT) at the first dose level (carboplatin AUC 5, bortezomib 0.5 mg/m2), prompting carboplatin reduction to AUC 4 for subsequent dose levels. With carboplatin dose fixed at AUC 4, bortezomib was escalated from 0.5 to 2.5 mg/m2 without DLT. Grade 3/4 related toxicities included abdominal pain, nausea, vomiting, and diarrhea which were infrequent. The overall response rate in patients with measurable disease (n = 21) was 19% (1 complete, 3 partial). Cmax and AUC in peritoneal fluid and plasma increased linearly with dose, with a favorable exposure ratio of the peritoneal cavity relative to peripheral blood plasma. Conclusion IP administration of this novel combination was feasible and showed promising activity in this phase I trial of heavily pre-treated women with ovarian cancer. Further evaluation of this IP combination should be conducted.
KW - Intraperitoneal
KW - Ovarian cancer
KW - Platinum
KW - Proteasome inhibition
UR - http://www.scopus.com/inward/record.url?scp=85016022620&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2017.03.013
DO - 10.1016/j.ygyno.2017.03.013
M3 - Article
C2 - 28341300
AN - SCOPUS:85016022620
VL - 145
SP - 236
EP - 242
JO - Gynecologic Oncology
JF - Gynecologic Oncology
SN - 0090-8258
IS - 2
ER -