GEN-1 in Combination with Neoadjuvant Chemotherapy for Patients with Advanced Epithelial Ovarian Cancer: A Phase I Dose-escalation Study. Clin Cancer Res 2021 Oct 15;27(20):5536-5545
Date
07/31/2021Pubmed ID
34326131Pubmed Central ID
PMC9338778DOI
10.1158/1078-0432.CCR-21-0360Scopus ID
2-s2.0-85117384884 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
PURPOSE: GEN-1 (phIL-12-005/PPC), an IL12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, has preclinical activity when combined with platinum-taxane intravenous chemotherapy and administered intraperitoneally in epithelial ovarian cancer (EOC) models. OVATION I was a multicenter, nonrandomized, open-label phase IB trial to evaluate the safety, preliminary antitumor activity, and immunologic response to GEN-1 in combination with neoadjuvant chemotherapy (NACT) carboplatin-paclitaxel in patients with advanced EOC.
PATIENTS AND METHODS: A total of 18 patients with newly diagnosed stage IIIC and IV EOC were enrolled. A standard 3+3 dose-escalation design tested four GEN-1 doses (36, 47, 61, 79 mg/m2) to determine the maximum tolerated dose and dose-limiting toxicities (DLTs). GEN-1 was administered in eight weekly intraperitoneal infusions starting at cycle 1 week 2 in combination with three 21-day cycles of NACT carboplatin AUC 6 and weekly paclitaxel 80 mg/m2.
RESULTS: The most common treatment-emergent adverse events at least possibly related were nausea, fatigue, abdominal pain/cramping, anorexia, diarrhea, and vomiting. Eight patients experience grade 4 neutropenia attributed to NACT. No DLTs occurred. A total of 14 patients were evaluable for response and 12 (85.7%) had radiological response (two complete response and 10 partial response) prior to debulking; nine were R0 at debulking and one patient had complete pathologic response. IL12 and its downstream cytokine, IFNγ, increased in peritoneal washings but not as much in blood. Increased levels of myeloid dendritic cells and T-effector memory cells in peritoneal fluid, plus elevated CD8+ T cells and reduced immunosuppression within the tumor microenvironment were found. A median time to treatment failure of 18.4 months (95% confidence interval, 9.2-24.5) was observed in the intention-to-treat population.
CONCLUSIONS: Adding GEN-1 to standard NACT is safe, appears active, and has an impact on the tumor microenvironment.
Author List
Thaker PH, Bradley WH, Leath CA 3rd, Gunderson Jackson C, Borys N, Anwer K, Musso L, Matsuzaki J, Bshara W, Odunsi K, Alvarez RDAuthor
William H. Bradley MD Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgedAntineoplastic Combined Chemotherapy Protocols
Carboplatin
Female
Humans
Middle Aged
Neoadjuvant Therapy
Neoplasm Staging
Ovarian Neoplasms
Paclitaxel