Abstract 2411: A combination trial of SGN-75 and everolimus in patients with CD70-positive metastatic renal cell carcinoma (RCC).
Authors: Nancy C. Whiting, Che-Leung Law, Tim Lewis
Journal: Cancer Research (2013)

Abstract Background. SGN-75 is an antibody-drug conjugate composed of a humanized anti-CD70 mAb conjugated to the microtubule-disrupting agent MMAF via a plasma-stable maleimidocaproyl linker. Upon binding to CD70, SGN-75 internalizes and releases cys-mcMMAF, which binds tubulin and induces G2/M arrest and apoptosis. In a phase 1, dose-escalation trial of SGN-75 in patients with CD70-positive relapsed/refractory NHL or metastatic RCC, single-agent activity of SGN-75 was observed in both NHL and RCC patients (Thompson 2011). In RCC, objective responses were observed with SGN-75 administered IV every 3 weeks at doses of 2 and 3 mg/kg. In vitro synergy in target cell killing was observed when SGN-75 was combined with mTOR inhibitors (everoliumus, temsirolimus, or sirolimus), a PI3K/mTOR inhibitor (NVP-BEZ235), or a dual mTORC1/mTORC2 inhibitor (PP242), as assessed by the Chou-Talalay method (Lewis 2011). Consistent with this observation, xenograft experiments using RCC cell lines (786-O and UM-RC-3) and a patient-derived RCC model (108963P) also demonstrated significantly improved antitumor activity with the combination of SGN-75 and everolimus compared to either agent alone. Based on the clinical activity of SGN-75 observed in patients with metastatic RCC and the synergistic effects observed in combination with mTOR inhibitors in preclinical models, a phase 1b study of the combination of SGN-75 and everolimus was initiated in patients with CD70-positive metastatic RCC (ClinicalTrials.gov #NCT01677390). Methods. The primary objective of this phase 1 study is to evaluate the safety and tolerability, and to identify the MTD, of SGN-75 in combination with everolimus. Pharmacokinetics, immunogenicity, and antitumor activity will also be evaluated. Eligible patients are ≥18 years old with pathologically confirmed CD70-positive metastatic RCC on archived or fresh tumor biopsy. Patients must have previously received treatment with 1 or 2 VEGF-receptor TKIs and must not have received prior treatment with any mTOR inhibitor. Patients must have measurable disease as defined in RECIST Version 1.1. SGN-75 will be administered IV every 3 weeks at protocol-defined doses up to 2 mg/kg in combination with everolimus 10 mg daily. After establishing the MTD, an expansion cohort of 15 efficacy-evaluable patients will be enrolled and treated with a dose at or below the MTD to further characterize the safety and pharmacokinetic profile and to obtain a preliminary estimate of antitumor activity of the combination. Patients who achieve CR, PR, or SD will be eligible to continue treatment in the study until disease progression. Patients who achieve a response of SD or better and discontinue study treatment prior to disease progression will be followed for progression-free survival and all patients will be followed for overall survival. Citation Format: Nancy C. Whiting, Che-Leung Law, Tim Lewis. A combination trial of SGN-75 and everolimus in patients with CD70-positive metastatic renal cell carcinoma (RCC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2411. doi:10.1158/1538-7445.AM2013-2411