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Gynecol Oncol. 2017 May;145(2):236-242. doi: 10.1016/j.ygyno.2017.03.013. Epub 2017 Mar 22.

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.

Author information

1
University of California Irvine Medical Center, United States.
2
NRG Statistics and Data Management Center - Buffalo Office, United States. Electronic address: bbrady@gogstats.org.
3
Moores UCSD Cancer Center, University of California, San Diego, United States. Electronic address: showell@ucsd.edu.
4
NRG Statistics and Data Management Center - Buffalo Office, United States. Electronic address: hlankes@gogstats.org.
5
Gynecologic Oncology, Thomas Jefferson Medical College, Philadelphia, PA, United States. Electronic address: russell.schilder@jefferson.edu.
6
University of Pittsburgh Cancer Institute, United States; University of Pittsburgh School of Pharmacy. United States; University of Pittsburgh School of Medicine, United States.
7
University of Pittsburgh Cancer Institute, United States. Electronic address: christners@upmc.edu.
8
University of Pittsburgh Cancer Institute, United States. Electronic address: ssdk1106@comcast.net.
9
Washington University, St. Louis, United States. Electronic address: powellm@wudosis.wustl.edu.
10
Washington University, St. Louis, United States. Electronic address: hagemanna@wudosis.wustl.edu.
11
Oklahoma University Medical Center, United States. Electronic address: kathleen-moore@ouhsc.edu.
12
Oklahoma University Medical Center, United States. Electronic address: joan-walker@ouhsc.edu.
13
Women & Infants' Hospital of Rhode Island, United States. Electronic address: PDiSilvestro@Wihri.org.
14
UVA Cancer Center, University of Virginia, Charlottesville, VA, United States. Electronic address: lrd5d@hscmail.mcc.virginia.edu.
15
UVA Cancer Center, University of Virginia, Charlottesville, VA, United States. Electronic address: fracasso@virginia.edu.
16
Massachusetts General Hospital Cancer Center, United States. Electronic address: ddizon@partners.org.

Abstract

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 21days for 6cycles. 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 0.5mg/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/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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01074411.

KEYWORDS:

Intraperitoneal; Ovarian cancer; Platinum; Proteasome inhibition

PMID:
28341300
PMCID:
PMC5706109
DOI:
10.1016/j.ygyno.2017.03.013
[Indexed for MEDLINE]
Free PMC Article

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