A Phase IB Combination Study of RO4929097 (RO), A Gamma-Secretase Inhibitor, and Temsirolimus (TEM) in Patients (PTS) with Advanced Solid Tumors

Background The notch signalling pathway has a critical role in regulating cellular differentiation, proliferation, and apoptosis. RO is a potent and selective gamma-secretase inhibitor with antitumor activity in animal models. Pre-clinical experiments indicate that the PI3K/AKT/mTOR pathway may mediate resistance to gamma secretase inhibitors, providing a rationale for combination therapy with RO and TEM. Methods A phase Ib dose-escalation study with a 3 + 3 design was conducted. Three dose levels (DLs) were planned. Objectives were to determine the recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the combination. Eligible pts received once daily oral RO on a 3 day on/4 day off schedule every week (QW), and intravenous QW TEM. Initial doses were 10 mg RO and 25 mg TEM. Cycles were every 21 days, except for cycle 1, which was 28 days. Treatment-related dose-limiting toxicities (DLTs) were evaluated during cycle 1. Results 17 pts (data cut-off 26-Apr-2012) have been treated on three DLs. Number of pts, DLTs and schedule are shown in Table 1. Demographics: M:F 6:11; median age: 60 yrs (range 28-84); ECOG 0/1:4/13. Pts received a median of 3 cycles (range 1-12). The most common adverse events (AEs) related to the study drug combination included: fatigue (82%; G3 6%), mucositis, (71%; G3 6%), neutropenia (59%; G3 12%), anemia (59%; G3 0%), and hypertriglyceridemia (59%, G3 0%).Two DLTs (G3 rash, G3 mucositis) were observed in the same patient in DL1 prompting dose expansion. No additional DLTs were observed. Of 15 patients evaluable for response, no objective responses were observed. 11 pts (73%) had stable disease (SD) as their best response; with 3 pts (sarcoma, neuroendocrine, non-small cell lung cancer) on therapy for ≥6 cycles. Conclusions RO can be safely combined with TEM. The RP2D was established as RO at 20 mg combined with 37.5 mg of TEM. PK and circulating angiogenic factors analyses will be presented. Dose Level RO Dose (mg) TEM Dose (mg) No. of pts treated No. of pts with DLT DLT 1 † 10 25 8 1 G3 rash, G3 mucositis 2 20 25 3 0 3 ∧ 20 37.5 6 0 † 2 pts were not evaluable for DLT ∧ DL3 (RP2D) was expanded to 6 pts Disclosure All authors have declared no conflicts of interest.