(ChemotherapyAdvisor) – A first-in-human phase 1 monotherapy study of RG7212, a novel monoclonal antibody that targets TWEAK signaling—frequently active in advanced solid tumors—has “demonstrated excellent tolerability,” a study presented at the 24th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland, November 7, has found.

“Tumor Necrosis Factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast inducible factor 14 (Fn14) are a ligand-receptor pair of the TNF superfamily that are frequently overexpressed in solid tumors,” noted presenter Ulrik Lassen, MD, PhD, head of the oncology phase I unit at the Rigshospitalet, Copenhagen, Denmark.

The study was conducted between July 2011 and May 2012 in 38 patients with advanced solid tumors that expressed Fn14 (IHC ≥ 10%), who were enrolled in weekly (n=26; 6 dose cohorts from 200-3600mg) or every 3 weekly schedules (n=12; dose range 800-3200mg) using a 3+3 design.

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Mean number of treatment cycles was 3.4 (range 1-10); 7 patients remained on the study. No dose-limiting toxicities were observed and no patient discontinued RG7212 for related toxicities. Nearly 95% of related adverse events were limited to grade 1 or 2, Dr. Lassen noted; most common were fatigue (21%), nausea (18%), and fever (15%).

Pharmacokinetic data show dose proportionality for all cohorts tested, with T1/2 of approximately 7 to 10 days.

18F FDG-PET partial metabolic responses (PMR) were observed for five patients, he stated; one patient with refractory, BRAF wild type melanoma had tumor regression on CT (−14.4% reduction in 3D volume), along with 18F FDG-PET PMR and ≥70% reduction in tumor Ki-67 and pERK.

“Prolonged stable disease has been seen in several patients,” Dr. Lassen said. “Overall, 11 of the 38 patients (29%) have received more than 12 weeks of study treatment, with several receiving 18 or more weeks of RG7212 therapy, including those with refractory NSCLC, melanoma, mesothelioma, breast cancer, renal cell carcinoma, and biliary tract cancer.”

Investigators from four leading cancer research centers in Denmark, The Netherlands, and Canada are recruiting patients into the phase 2 trial, particularly those with advanced metastatic melanoma expressing Fn14.

The phase I data show that RG7212 is safe for multi-cycle administration in patients with advanced cancer, and results from tests of blood and tumor samples suggest that it would be feasible to administer over a prolonged period of time.

“These results are encouraging and support additional studies of RG7212 in combination with other treatments,” Dr. Lassen concluded.

Abstract (select abstract #29)