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: An NRG Oncology/Gynecologic Oncology Group study.

Abstract

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 40mg/m2 (dose level 1 and 2) or 50mg/m2 (dose level 3) every 28days and intraperitoneal GEN-1 at 24mg/m2 (dose level 1) or 36mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28day cycle. Cycles were repeated every 28days 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 4cycles (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.

• Authors: Premal H Thaker, William E Brady, Heather A Lankes, Kunle Odunsi, William H Bradley, Kathleen N Moore, Carolyn Y Muller, Khursheed Anwer, Russell J Schilder, Ronald D Alvarez, Paula M Fracasso
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 147 Issue 2 Pg. 283-290 (11 2017) ISSN: 1095-6859 [Electronic] United States
• PMID: 28802766 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• liposomal doxorubicin
• poly(ethylene glycol)-co-poly(ethyleneimine)
• Interleukin-12
• Polyethylene Glycols
• Doxorubicin
• Polyethyleneimine

Topics

• Aged
• Antibiotics, Antineoplastic (administration & dosage)
• Carcinoma, Ovarian Epithelial
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Doxorubicin (administration & dosage, analogs & derivatives)
• Fallopian Tube Neoplasms (drug therapy, genetics, therapy)
• Female
• Genetic Therapy (methods)
• Humans
• Interleukin-12 (administration & dosage, genetics)
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy, genetics)
• Neoplasms, Glandular and Epithelial (drug therapy, genetics, therapy)
• Ovarian Neoplasms (drug therapy, genetics, therapy)
• Peritoneal Neoplasms (drug therapy, genetics, therapy)
• Plasmids (administration & dosage, genetics)
• Polyethylene Glycols (administration & dosage)
• Polyethyleneimine (administration & dosage, analogs & derivatives)