Abstract OT2-6-13: A randomized phase 2 study of the triplet combination of ridaforolimus (RIDA), dalotuzumab (DALO) and exemestane (EX) compared to the ridaforolimus, exemestane doublet in high proliferation, estrogen receptor positive (ER+) advanced breast cancer

Abstract

Abstract Background: The clinical benefit of combination of mTOR inhibition and anti-hormonal therapy has been previously established and represents a new standard of care for patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Preclinical evaluation of the mTOR pathway demonstrates that 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 completed phase 1 study of the combination of the mTOR inhibitor, RIDA and the anti-IGFR antibody, DALO demonstrated preliminary signals of anti-tumor activity. This was further evaluated in a recently completed phase 2 study of RIDA-DALO compared to exemestane in ER+ ABC. Final safety and efficacy results from that phase 2 study will be reported at this meeting (see Baselga et al). Building upon the clinical synergies of mTOR and EX as well as the biologic relationship of the mTOR and IGFR pathways, a clinical study has been initiated to evaluate the triplet combination of RIDA-DALO-EX compared to RIDA-EX. Methods: This is a multicenter, international, randomized phase 2 study of the triplet combination of RIDA (10 mg by mouth daily for 5 out of every 7 days), DALO (10 mg/kg IV weekly), and EX (25 mg QD) compared to RIDA (30 mg by mouth daily for 5 out of every 7 days) and EX (25 mg QD) in high KI67 (≥15%) expressing ER+, ABC. Approximately 84 patients will be randomized 1:1 to either triplet or doublet therapy. Key eligibility criteria include: HR+ and HER-2 negative measurable ABC, prior therapy with a non-steroidal aromatase inhibitor, and KI67 labeling index ≥15%. The primary endpoint of the study is progression free survival (PFS). Key secondary endpoints include evaluation of percent (%) reduction from baseline in the sum of imaging measurements (target lesion diameters or volumes) at 16 weeks between the two arms, and overall response rates. The sample size is event driven with a target of 38 PFS events, which provides approximately 80% power, at 1-sided alpha of 0.1, to detect a HR of 0.5, corresponding to an approximate 100% improvement in median PFS, from 10.6 to 21.2 months. Safety parameters or adverse experiences of special interest include hyperglycemia, stomatitis, mucosal inflammation, pneumonitis and hearing loss. Accrual has been completed with results expected in May 2014. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-13.