OT3-01-16: A Phase 2 Study of Ridaforolimus (RIDA) and Dalotuzumab (DALO) in Estrogen Receptor Positive (ER+) Breast Cancer.

Abstract

Abstract Background: Activation of the PI3K/AKT/mTOR pathway is common in breast cancer. Preclinical studies indicate that the dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A phase 1 study of the mTOR inhibitor RIDA and the anti-IGFR antibody DALO demonstrated that the combination was feasible and well-tolerated at doses that were nearly those used for the two single agents and with dose limiting toxicity of stomatitis, similar to RIDA as monotherapy. A preliminary signal of anti-tumor activity, including partial responses and prolonged progression free survival, was observed in ER+ breast cancer, especially in high proliferation tumors. This observation is supported by data from tumor profiling and preclinical data suggesting that ER+ high proliferation breast cancer may be responsive to the RIDA-DALO combination. Methods: This is a two-part, adaptive design study intended to first test the combination of RIDA-DALO against a standard agent, exemestane, for ER+ positive breast cancer that has progressed after aromatase inhibitors. The trial is a multi-center, international, randomized study with PFS as the primary endpoint. Patients (pts) are stratified into high and low proliferation strata based on baseline Ki67, and the low proliferation stratum is capped to ensure adequate enrollment of high proliferation pts. If Part A shows a PFS benefit for RIDA-DALO, Part B is intended to show the PFS benefit of the combination over the single agents by comparing RIDA-DALO to RIDA and DALO. Part B will be further adapted based on whether the PFS benefit in Part A is observed in all-comers or the high proliferation subset. Tumor tissue is collected for molecular profiling and analysis of intrinsic subtype, with an efficacy analysis based on classification of tumors using the genomic grade index (GGI) as an exploratory objective. This trial design is intended to establish proof of concept that RIDA-DALO can prolong PFS in ER+ breast cancer in all-comers or a high proliferation subset by Ki67, while efficiently addressing the development of two investigational agents in combination and leading to a two-arm Phase 3 design. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-16.