TY - JOUR
T1 - GEN-1 in Combination with Neoadjuvant Chemotherapy for Patients with Advanced Epithelial Ovarian Cancer
T2 - A Phase I Dose-escalation Study
AU - Thaker, Premal H.
AU - Bradley, William H.
AU - Leath, Charles A.
AU - Jackson, Camille Gunderson
AU - Borys, Nicholas
AU - Anwer, Khursheed
AU - Musso, Lauren
AU - Matsuzaki, Junko
AU - Bshara, Wiam
AU - Odunsi, Kunle
AU - Alvarez, Ronald D.
N1 - Funding Information:
Four centers in the United States participated in OVATION I. This study was sponsored by Celsion Corporation and registered with ClinicalTrials.gov (NCT02480374). The protocol was approved by the Institutional Review Board (IRB) or central IRB and biological safety committees of each institution, and all patients provided written informed consent before enrollment and performance of any study-related procedures. The study was conducted in compliance with the protocol, International Conference on Harmonization Good Clinical Practice Guidelines E6 (ICH-GCP), NIH Guidelines for Research Involving Recombinant DNA Molecules (April 2002) and with the Declaration of Helsinki and its amendments. The study was monitored for safety and dose escalation decisions by an independent Data Safety Monitoring Board (DSMB).
Funding Information:
This work was partially conducted at Roswell Park’s Pathology Network and Immune Analysis Shared Resources, P30CA016056. This study was funded by Celsion Corporation, Lawrenceville, NJ.
Funding Information:
This work was partially conducted at Roswell Park?s Pathology Network and Immune Analysis Shared Resources, P30CA016056. This study was funded by Celsion Corporation, Lawrenceville, NJ.
Publisher Copyright:
©2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/10/15
Y1 - 2021/10/15
N2 - 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 3þ3 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, IFNg, 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 CD8þ 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.
AB - 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 3þ3 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, IFNg, 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 CD8þ 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.
UR - http://www.scopus.com/inward/record.url?scp=85117384884&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-0360
DO - 10.1158/1078-0432.CCR-21-0360
M3 - Article
C2 - 34326131
AN - SCOPUS:85117384884
SN - 1078-0432
VL - 27
SP - 5536
EP - 5545
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -