TY - JOUR
T1 - A phase I monotherapy study of RG7212, a first-in-class monoclonal antibody targeting TWEAK signaling in patients with advanced cancers
AU - Lassen, Ulrik N
AU - Meulendijks, Didier
AU - Siu, Lilian L
AU - Karanikas, Vaios
AU - Mau-Sorensen, Morten
AU - Schellens, Jan H M
AU - Jonker, Derek J
AU - Hansen, Aaron R
AU - Simcox, Mary E
AU - Schostack, Kathleen J
AU - Bottino, Dean
AU - Zhong, Hua
AU - Roessler, Markus
AU - Vega-Harring, Suzana M
AU - Jarutat, Tiantom
AU - Geho, David
AU - Wang, Ka
AU - DeMario, Mark
AU - Goss, Glenwood D
N1 - ©2014 American Association for Cancer Research.
PY - 2015/1/15
Y1 - 2015/1/15
N2 - Purpose: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand-receptor pair frequently overexpressed in solid tumors. TWEAK:Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFkB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1k monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14. Experimental Design: Dose escalations, over a 200- To 7,200- mgrange, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of TWEAK:Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics. Results: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment. Conclusion: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced TWEAK:Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212.
AB - Purpose: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand-receptor pair frequently overexpressed in solid tumors. TWEAK:Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFkB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1k monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14. Experimental Design: Dose escalations, over a 200- To 7,200- mgrange, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of TWEAK:Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics. Results: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment. Conclusion: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced TWEAK:Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212.
KW - Antibodies, Monoclonal
KW - Antineoplastic Agents
KW - Colorectal Neoplasms
KW - Female
KW - Fluorodeoxyglucose F18
KW - Humans
KW - Male
KW - Maximum Tolerated Dose
KW - Melanoma
KW - Middle Aged
KW - Radiopharmaceuticals
KW - Treatment Outcome
U2 - 10.1158/1078-0432.ccr-14-1334
DO - 10.1158/1078-0432.ccr-14-1334
M3 - Journal article
C2 - 25388164
SN - 1078-0432
VL - 21
SP - 258
EP - 266
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -
