A phase I pharmacokinetic study of intraperitoneal bortezomib and carboplatin in patients with persistent or recurrent ovarian cancer: An NRG Oncology/Gynecologic Oncology Group study.
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.



Women with recurrent ovarian cancer were treated with escalating doses of IP bortezomib - in combination with IP carboplatin (AUC 4 or 5) every 21days for 6cycles. Pharmacokinetics of both agents were evaluated in cycle 1.



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 0.5mg/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 2.5mg/m2without 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). Cmaxand AUC in peritoneal fluid and plasma increased linearly with dose, with a favorable exposure ratio of the peritoneal cavity relative to peripheral blood plasma.



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.
University of California Irvine Medical Center, United States.
Danielle A
DA
Jandial
NRG Statistics and Data Management Center - Buffalo Office, United States. Electronic address: bbrady@gogstats.org.
William E
WE
Brady
Moores UCSD Cancer Center, University of California, San Diego, United States. Electronic address: showell@ucsd.edu.
Stephen B
SB
Howell
NRG Statistics and Data Management Center - Buffalo Office, United States. Electronic address: hlankes@gogstats.org.
Heather A
HA
Lankes
Gynecologic Oncology, Thomas Jefferson Medical College, Philadelphia, PA, United States. Electronic address: russell.schilder@jefferson.edu.
Russell J
RJ
Schilder
University of Pittsburgh Cancer Institute, United States; University of Pittsburgh School of Pharmacy. United States; University of Pittsburgh School of Medicine, United States.
Jan H
JH
Beumer
University of Pittsburgh Cancer Institute, United States. Electronic address: christners@upmc.edu.
Susan M
SM
Christner
University of Pittsburgh Cancer Institute, United States. Electronic address: ssdk1106@comcast.net.
Sandra
S
Strychor
Washington University, St. Louis, United States. Electronic address: powellm@wudosis.wustl.edu.
Matthew A
MA
Powell
Washington University, St. Louis, United States. Electronic address: hagemanna@wudosis.wustl.edu.
Andrea R
AR
Hagemann
Oklahoma University Medical Center, United States. Electronic address: kathleen-moore@ouhsc.edu.
Kathleen N
KN
Moore
Oklahoma University Medical Center, United States. Electronic address: joan-walker@ouhsc.edu.
Joan L
JL
Walker
Women & Infants' Hospital of Rhode Island, United States. Electronic address: PDiSilvestro@Wihri.org.
Paul A
PA
DiSilvestro
UVA Cancer Center, University of Virginia, Charlottesville, VA, United States. Electronic address: lrd5d@hscmail.mcc.virginia.edu.
Linda R
LR
Duska
UVA Cancer Center, University of Virginia, Charlottesville, VA, United States. Electronic address: fracasso@virginia.edu.
Paula M
PM
Fracasso
Massachusetts General Hospital Cancer Center, United States. Electronic address: ddizon@partners.org.
Don S
DS
Dizon
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000069286:Bortezomib / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000077216:Carcinoma, Ovarian Epithelial; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D055815:Young Adult
D000069286:Bortezomib; D016190:Carboplatin
Intraperitoneal; Ovarian cancer; Platinum; Proteasome inhibition