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.