TY - JOUR
T1 - A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers
T2 - An NRG Oncology/Gynecologic Oncology Group study
AU - Thaker, Premal H.
AU - Brady, William E.
AU - Lankes, Heather A.
AU - Odunsi, Kunle
AU - Bradley, William H.
AU - Moore, Kathleen N.
AU - Muller, Carolyn Y.
AU - Anwer, Khursheed
AU - Schilder, Russell J.
AU - Alvarez, Ronald D.
AU - Fracasso, Paula M.
N1 - Funding Information:
This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank ( CA 27469 ), and to the GOG Statistical and Data Center ( CA 37517 ) as well as NRG Oncology Operations grant number U10 CA180868 and NRG SDMC grant U10 CA180822 . The following GOG member institutions participated in this study: University of Alabama at Birmingham, Froedtert and the Medical College of Wisconsin, Washington University School of Medicine, University of Oklahoma Health Sciences Center and University of New Mexico.
Funding Information:
Dr. Thaker reports grants from Merck, personal fees from Celsion, outside of the submitted work. Dr. Kathleen Moore reports personal fees from Astra Zeneca, personal fees from Tesaro, personal fees from immunogen, and personal fees from VBL Therapeutics, outside of the submitted work. Dr. Muller reports that she is involved in other ovarian cancer clinical trials with other chemotherapy and immunotherapy agents through NCI and other industry sponsors. Dr. R. Schilder reports personal fees received from Celsion. Dr. Fracasso reports that she became an employee of Bristol-Myers Squibb Company (BMS) as of May 1, 2014, and as such, she has stock with the company. Prior to her employment with BMS, she was a Professor of Medicine and Obstetrics and Gynecology at the University of Virginia where she is now affiliated as a Visiting Professor of Medicine and Obstetrics and Gynecology. This clinical study was done while was a Professor at the University of Virginia and no activities in this work have any relationship to her work at BMS. All other authors report that there are no conflicts of interest to disclose.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/11
Y1 - 2017/11
N2 - Objective The study's purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC). Methods Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3 + 3 phase I dose escalation design with patients receiving intravenous PLD 40 mg/m2 (dose level 1 and 2) or 50 mg/m2 (dose level 3) every 28 days and intraperitoneal GEN-1 at 24 mg/m2 (dose level 1) or 36 mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28 day cycle. Cycles were repeated every 28 days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect. Results Sixteen evaluable patients received a median of 4 cycles (range 1–8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR = 21.4%; SD = 35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ and TNF-α levels were found in peritoneal fluid following GEN-1 treatment. Conclusions GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1.
AB - Objective The study's purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC). Methods Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3 + 3 phase I dose escalation design with patients receiving intravenous PLD 40 mg/m2 (dose level 1 and 2) or 50 mg/m2 (dose level 3) every 28 days and intraperitoneal GEN-1 at 24 mg/m2 (dose level 1) or 36 mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28 day cycle. Cycles were repeated every 28 days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect. Results Sixteen evaluable patients received a median of 4 cycles (range 1–8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR = 21.4%; SD = 35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ and TNF-α levels were found in peritoneal fluid following GEN-1 treatment. Conclusions GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1.
KW - GEN-1
KW - IL-12 plasmid
KW - Pegylated liposomal doxorubicin
KW - Primary peritoneal cancer
UR - http://www.scopus.com/inward/record.url?scp=85028062345&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2017.08.001
DO - 10.1016/j.ygyno.2017.08.001
M3 - Article
C2 - 28802766
AN - SCOPUS:85028062345
SN - 0090-8258
VL - 147
SP - 283
EP - 290
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 2
ER -