A phase I study of the oral mTOR inhibitor ridaforolimus (RIDA) in combination with the IGF-1R antibody dalotozumab (DALO) in patients (pts) with advanced solid tumors.

Abstract

3008 Background: RIDA is a non-prodrug rapamycin analog mTOR inhibitor, and DALO is a humanized monoclonal antibody targeting the IGF-1R receptor. In preclinical models, dual mTOR/IGF1-R inhibition results in synergistic antitumor activity and inhibits feedback AKT activation due to TORC1 inhibition by rapamycin analogs. Methods: Pts with advanced cancers who failed standard therapy received RIDA at escalating doses of 10-40 mg/day QD×5/week combined with DALO at 10 mg/kg/week or 7.5 mg/kg every other week. RIDA was administered for one week prior to starting DALO to enable PK/PD assessment with and without DALO. PD parameters were assessed from PBMCs, skin biopsies, and tumor biopsies. Two dose levels were expanded to determine the optimal dose for future study. Results: 62 pts have been enrolled. During dose escalation, only one pt experienced a DLT (prolonged G2 stomatitis at dose level 1). RIDA 40 mg plus DALO 10 mg/kg/week (recommended doses for RIDA and DALO as single agents) was declared MTD. In an expansion cohort at the declared MTD, 4 DLTs were observed in 9 DLT-evaluable patients (G3 stomatitis, 3 pts; G3 fatigue, 1 pt) and cumulatively 4 of 15 (27%) pts at the declared MTD had DLTs. A 2nd expansion cohort at the next lower dose level (RIDA 30 mg plus DALO 10 mg/kg/week) is being evaluated, and there was 1 DLT in 17 DLT-evaluable pts so far. The most frequent treatment-related adverse events included stomatitis, fatigue, and hyperglycemia, mostly grade 1-2. Efficacy signals included 3 confirmed PRs (2 breast cancer [BCa], 1 parotid adenocarcinoma), 2 partial metabolic responses (PMRs) on FDG-PET scan (2 BCa), 2 prolonged SD > 6 months (1 BCa and 1 endometrial ca), and 3 pts with ≥50% decline in CA-125 (2 ovarian and 1 endometrial Ca). Of 23 BCa pts enrolled by December 1, 5 pts had efficacy signals (2 PRs, 1 SD for 9 months, and 2 PMRs); all 5 pts were ER+, and 4 had high Ki67 breast tumors. PK/PD assessments are currently underway and will be presented at the meeting. Conclusions: The combination of ridaforolimus and dalotuzumab is tolerable and has promising antitumor activity in heavily pretreated advanced cancer, particularly in ER+/high proliferation breast cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Merck Merck, Novartis