Abstract P2-16-04: A phase 2 study of ridaforolimus (RIDA) and dalotuzumab (DALO) in estrogen receptor positive (ER+) breast cancer
Authors: Baselga J , Morales SM , Awada A , Blum JL , Tan AR , Ewertz M , Cortes J , Moy B , Ruddy KJ , Haddad T , Ciruelos EM , Vuylsteke P , Ebbinghaus S , Im E , Eaton L , Prathiraja K , Gause C , Mauro D , Rugo HS 
Published: August 2014

Abstract
Background: 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. The dose limiting toxicity was stomatitis, similar to RIDA monotherapy. Preliminary signals of anti-tumor activity, including partial responses and prolonged progression free survival (PFS), were observed in ER+ advanced breast cancer (ABC), especially in high proliferation tumors (Ki67 ≥15%). Methods: The trial was a multi-center, international randomized study with PFS as the primary endpoint. Key eligibility included ABC with prior treatment with a non-steroidal aromatase inhibitor. The original phase 2 study design was a two-part, adaptive design intended to first test the combination of RIDA (30 mg by mouth daily for 5 out of every 7 days), -DALO (10 mg/kg IV weekly) against a standard agent, exemestane in Part A. Patients were stratified into high and low proliferation strata based on baseline Ki67. Following a demonstration of PFS benefit of the combination in Part A, Part B was intended to show the PFS benefit of the combination over each single agents by comparing RIDA-DALO to RIDA and DALO. Results: The study was initiated in October 2011. Accrual was suspended after the first 66 patients were randomized due to a higher than expected rate of stomatitis in the RIDA-DALO arm. Preliminary data indicated an overall incidence of any grade stomatitis was 68% (22/33 pts), and of grade 3 stomatitis was 35% (11/33 pts). In an effort to identify a more tolerable regimen, the study was amended to eliminate Part B and to evaluate two sequential reduced dose RIDA-DALO cohorts in a non-randomized design: 20mg and 10mg for 5 out of every 7 days. The dose of DALO was unchanged. Preliminary safety results of overall and grade 3 stomatitis in the 20 mg were 81.5% (22/27 pts) and 37% (10/27 pts), respectively. Although the incidence of overall stomatitis in the 10 mg cohort remained high, 88% (22/25 pts), grade 3 stomatitis was dramatically reduced to 8% (2/25 pts). Conclusion: Preliminary evaluation of safety from this phase 2 study demonstrates that the previously recommended phase 2 dose of RIDA-DALO was not tolerable. However lower doses of RIDA (10 mg) in combination with DALO appeared to be tolerable with markedly reduced rates of grade 3 stomatitis. Final results of efficacy, safety and RNA profiling analysis from the two RIDA-DALO dose cohorts as well as from the randomized portion of the study will be available at the time of the meeting.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-04.