Recombinant interleukin-18 (IL-18; SB-485232) is an immunostimulatory cytokine, with demonstrated antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability and biological activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m2) on Day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 microg/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 >3 prior chemotherapy regimens. SB-485232 up to 100 microg/kg with PLD had an acceptable safety profile. Common drug-related AEs were grade 1 or 2 (no grade 4 or 5 AEs). Concomitant PLD administration did not attenuate the biological activity of IL-18, with maximal SB-485232 biological activity already observed at 3 microg/kg. Ten of 16 enrolled subjects (63%) completed treatment, while 5 (31%) subjects progressed on treatment. A 6% partial objective response rate, and a 38% stable disease rate were observed. We provide pilot data suggesting SB-485232 at the 3 microg/kg dose level in combination with PLD,is safe and biologically active. This combination warrants further study in a phase II trial.
- Received July 16, 2013.
- Accepted July 18, 2013.
- Copyright © 2013, American Association for Cancer Research.