A phase I monotherapy study of RG7212, a first-in-class monoclonal antibody targeting TWEAK signaling in patients with advanced cancers.
OBJECTIVE
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.
Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFκB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1κ monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14.


METHODS
Dose escalations, over a 200- to 7,200-mg range, 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
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.


CONCLUSIONS
RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced
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. Clin Cancer Res; 21(2); 258-66. ©2014 AACR.
Department of Oncology, The Finsen Centre, Rigshospitalet, Copenhagen, Denmark. ulrik.lassen@rh.regionh.dk.
Ulrik N
UN
Lassen
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Didier
D
Meulendijks
Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Lilian L
LL
Siu
Roche Pharmaceutical Research and Early Development, Translational Medicine Oncology, Roche Innovation Center Zurich, Schlieren, Switzerland.
Vaios
V
Karanikas
Department of Oncology, The Finsen Centre, Rigshospitalet, Copenhagen, Denmark.
Morten
M
Mau-Sorensen
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Jan H M
JH
Schellens
Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada.
Derek J
DJ
Jonker
Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Aaron R
AR
Hansen
Roche Translational Clinical Research Center Inc., New York, New York.
Mary E
ME
Simcox
Roche Translational Clinical Research Center Inc., New York, New York.
Kathleen J
KJ
Schostack
Roche Translational Clinical Research Center Inc., New York, New York.
Dean
D
Bottino
Roche Translational Clinical Research Center Inc., New York, New York.
Hua
H
Zhong
Roche Diagnostics GmbH, Penzberg, Germany.
Markus
M
Roessler
Roche Diagnostics GmbH, Penzberg, Germany.
Suzana M
SM
Vega-Harring
Roche Diagnostics GmbH, Penzberg, Germany.
Tiantom
T
Jarutat
Roche Translational Clinical Research Center Inc., New York, New York.
David
D
Geho
Roche Translational Clinical Research Center Inc., New York, New York.
Ka
K
Wang
Roche Translational Clinical Research Center Inc., New York, New York.
Mark
M
DeMario
Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada.
Glenwood D
GD
Goss
D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008875:Middle Aged; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000601202:RG7212; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18