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.

• Authors: Danielle A Jandial, William E Brady, Stephen B Howell, Heather A Lankes, Russell J Schilder, Jan H Beumer, Susan M Christner, Sandra Strychor, Matthew A Powell, Andrea R Hagemann, Kathleen N Moore, Joan L Walker, Paul A DiSilvestro, Linda R Duska, Paula M Fracasso, Don S Dizon
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 145 Issue 2 Pg. 236-242 (05 2017) ISSN: 1095-6859 [Electronic] United States
• PMID: 28341300 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: Copyright © 2017. Published by Elsevier Inc.

Chemical References

• Bortezomib
• Carboplatin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, blood, pharmacokinetics)
• Bortezomib (administration & dosage, adverse effects, blood, pharmacokinetics)
• Carboplatin (administration & dosage, adverse effects, blood, pharmacokinetics)
• Carcinoma, Ovarian Epithelial
• Dose-Response Relationship, Drug
• Female
• Humans
• Infusions, Parenteral
• Middle Aged
• Neoplasm Recurrence, Local (blood, drug therapy, metabolism)
• Neoplasms, Glandular and Epithelial (blood, drug therapy, metabolism)
• Ovarian Neoplasms (blood, drug therapy, metabolism)
• Young Adult