Background: LCL161 is a small molecule that triggers tumor cell apoptosis by selectively antagonizing inhibitor of apoptosis proteins (IAPs). Preclinical studies demonstrated antitumor efficacy of LCL161 alone or in combination with chemotherapeutic agents, acting synergistically with paclitaxel in breast cancer models. A Phase I study confirmed potent pharmacodynamic (PD) effects at well-tolerated doses of 1800 mg once weekly. The purpose of this Phase Ib study was to determine the maximum tolerated dose (MTD)/recommended phase II dose (RP2D), safety, pharmacokinetics (PK), PD, and preliminary antitumor activity of LCL161 in combination with weekly paclitaxel.

Methods: Patients with advanced/metastatic solid tumors were treated with paclitaxel 80 mg/m2 each week, immediately followed by escalating doses of LCL161 administered once weekly. PK and biomarker sampling was performed. Patients with breast or ovarian cancer were treated at the MTD/R2PD in the dose-expansion phase of the study.

Results: As of 4 June 2013, 61 patients have received LCL161 doses of 600 mg (n = 3), 1200 mg (n = 5), 1500 mg (n = 5), and 1800 mg (n = 48), including 26 patients with breast cancer and 19 patients with ovarian cancer. Median duration of exposure was 10 weeks. The most common LCL161-related adverse events (AEs) were diarrhea (53%), anemia (36%), and neutropenia (34%). Eleven patients experienced AEs indicated by the principal investigator as a toxicity requiring dose reduction or a change to a 3 week on/1 week off schedule (ten at 1800 mg and one at 1200 mg), seven of which were neutropenia or febrile neutropenia. The MTD was not reached, and 1800 mg was selected as the RP2D. In the safety expansion group of patients with breast cancer treated at 1800 mg, 17 (out of 20) patients were evaluable for response by investigator assessment using RECIST criteria; of these, 47% achieved a partial response, 35% had stable disease, and 18% developed progressive disease. Interestingly, responses were seen in patients with documented progression to prior taxane-based regimens. Of note, in the ovarian cancer cohort, one patient achieved a complete response. In the study overall, 26% achieved a partial response, and 30% experienced stable disease. No PK interaction between LCL161 and paclitaxel was observed.

Discussion: Combination therapy with LCL161 and paclitaxel is well tolerated, with manageable toxicities and encouraging clinical efficacy in breast cancer. Enrollment of additional patients with breast cancer resistant to paclitaxel is ongoing.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-7.