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

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.

Conflict of interest statement

Conflicts of interest

Dr. Bill Brady reports that he received grants from the NCI (1 U10 CA 180822-01, 5 U10 CA037517-29, P30 CA16056) during the conduct of the submitted work. Additionally, Dr. Brady reports that he has received a grant from Nektar Therapeutics and Advaxis outside the submitted work. Dr. Russell Schilder reports that has received personal fees from Celsion as Chair, IDMC. Jan Beumer reports that the pharmacologic work was supported in part by Millenium Pharmaceuticals. Dr. Matthew Powell reports serving as paid consultant/speaker for Roche/Genentech and AstraZeneca. Dr. Kathleen Moore repots serving on the Advisory Board of Genentech Roche, Astra Zeneca, Amgen, Immunogen, TESARO, Clovis, Advaxis.

Copyright © 2017. Published by Elsevier Inc.

Figures

Fig. 1

Peritoneal fluid (●) and plasma (○) bortezomib (A) and ultrafilterable platinum (B) concentrations of a patient treated with 2.1 mg/m2 bortezomib and carboplatin AUC 4.

Fig. 2

Bortezomib Cmax (A) and AUC0 – t (B) as a function of bortezomib dose, and the peritoneal fluid (PF) to peripheral blood plasma exposure ratios based on Cmax (C) and AUC0 – t (D) plotted on a semi-log y-axis as a function of bortezomib dose.