Chemoimmunotherapy using pegylated liposomal Doxorubicin and interleukin-18 in recurrent ovarian cancer: a phase I dose-escalation study.

Abstract

Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m(2)) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 μg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy. Sixteen subjects were enrolled. One subject withdrew due to PLD hypersensitivity. Most subjects (82%) were platinum-resistant or refractory, and had received a median of three or more prior chemotherapy regimens. SB-485232 up to 100 μg/kg with PLD had an acceptable safety profile. Common drug-related adverse events were grade 1 or 2 (no grade 4 or 5 adverse events). Concomitant PLD administration did not attenuate the biologic activity of IL-18, with maximal SB-485232 biologic activity already observed at 3 μg/kg. Ten of 16 enrolled subjects (63%) completed treatment, whereas five (31%) subjects progressed on treatment. A 6% partial objective response rate and a 38% stable disease rate were observed. We provide pilot data suggesting that SB-485232 at the 3 μg/kg dose level in combination with PLD is safe and biologically active. This combination warrants further study in a phase II trial.

• Authors: Fiona Simpkins, Aurea Flores, Christina Chu, Jonathan S Berek, Joseph Lucci 3rd, Sharon Murray, John Bauman, Herbert Struemper, Fiona Germaschewski, Zdenka Jonak, Olivia Gardner, John Toso, George Coukos
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 1 Issue 3 Pg. 168-78 (Sep 2013) ISSN: 2326-6074 [Electronic] United States
• PMID: 24777679 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Adjuvants, Immunologic
• Interleukin-18
• liposomal doxorubicin
• Polyethylene Glycols
• Doxorubicin

Topics

• Adjuvants, Immunologic (therapeutic use)
• Adult
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Doxorubicin (administration & dosage, analogs & derivatives, therapeutic use)
• Drug Resistance, Neoplasm
• Female
• Humans
• Interleukin-18 (administration & dosage, therapeutic use)
• Maximum Tolerated Dose
• Middle Aged
• Ovarian Neoplasms (drug therapy)
• Polyethylene Glycols (administration & dosage, therapeutic use)