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Exposure and Tumor Fn14 Expression as Determinants of Pharmacodynamics of the Anti-TWEAK Monoclonal Antibody RG7212 in Patients with Fn14-Positive Solid Tumors.
Meulendijks, Didier; Lassen, Ulrik N; Siu, Lillian L; Huitema, Alwin D R; Karanikas, Vaios; Mau-Sorensen, Morten; Jonker, Derek J; Hansen, Aaron R; Simcox, Mary E; Schostack, Kathleen J; Bottino, Dean; Zhong, Hua; Roessler, Markus; Vega-Harring, Suzana M; Jarutat, Tiantom; Geho, David; Wang, Karen; DeMario, Mark; Goss, Glenwood D; Schellens, Jan H M.
Affiliation
  • Meulendijks D; Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Lassen UN; Department of Oncology, The Finsen Centre, Rigshospitalet, Copenhagen, Denmark.
  • Siu LL; Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
  • Huitema AD; Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Karanikas V; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Zurich, Switzerland.
  • Mau-Sorensen M; Department of Oncology, The Finsen Centre, Rigshospitalet, Copenhagen, Denmark.
  • Jonker DJ; Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada.
  • Hansen AR; Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
  • Simcox ME; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
  • Schostack KJ; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
  • Bottino D; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
  • Zhong H; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
  • Roessler M; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Penzberg, Germany.
  • Vega-Harring SM; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Penzberg, Germany.
  • Jarutat T; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Penzberg, Germany.
  • Geho D; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
  • Wang K; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
  • DeMario M; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, New York, New York.
  • Goss GD; Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada.
  • Schellens JH; Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Pharmaceutical Sciences, Science Faculty, Utrecht University, Utrecht, the Netherlands. j.schellens@nki.nl.
Clin Cancer Res ; 22(4): 858-67, 2016 Feb 15.
Article in En | MEDLINE | ID: mdl-26446946
ABSTRACT

PURPOSE:

The TWEAK-Fn14 pathway represents a novel anticancer target that is being actively investigated. Understanding the relationship between pharmacokinetics of anti-TWEAK therapeutics and tumor pharmacodynamics is critical. We investigated exposure-response relationships of RG7212, an anti-TWEAK mAb, in patients with Fn14-expressing tumors. EXPERIMENTAL

DESIGN:

Patients with Fn14-positive tumors (IHC ≥ 1+) treated in a phase I first-in-human study with ascending doses of RG7212 were the basis for this analysis. Pharmacokinetics of RG7212 and dynamics of TWEAK were determined, as were changes in tumor TWEAK-Fn14 signaling in paired pre- and posttreatment tumor biopsies. The objectives of the analysis were to define exposure-response relationships and the relationship between pretreatment tumor Fn14 expression and pharmacodynamic effect. Associations between changes in TWEAK-Fn14 signaling and clinical outcome were explored.

RESULTS:

Thirty-six patients were included in the analysis. RG7212 reduced plasma TWEAK to undetectable levels at all observed RG7212 exposures. In contrast, reductions in tumor Fn14 and TRAF1 protein expression were observed only at higher exposure (≥ 300 mg*h/mL). Significant reductions in tumor Ki-67 expression and early changes in serum concentrations of CCL-2 and MMP-9 were observed exclusively in patients with higher drug exposure who had high pretreatment tumor Fn14 expression. Pretreatment tumor Fn14 expression was not associated with outcome, but a trend toward longer time on study was observed with high versus low RG7212 exposure.

CONCLUSIONS:

RG7212 reduced tumor TWEAK-Fn14 signaling in a systemic exposure-dependent manner. In addition to higher exposure, relatively high Fn14 expression might be required for pharmacodynamic effect of anti-TWEAK monoclonal antibodies.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colorectal Neoplasms / Biomarkers, Tumor / Receptors, Tumor Necrosis Factor / Antibodies, Monoclonal / Antineoplastic Agents Limits: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Language: En Journal: Clin Cancer Res Journal subject: NEOPLASIAS Year: 2016 Document type: Article Affiliation country: Netherlands

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colorectal Neoplasms / Biomarkers, Tumor / Receptors, Tumor Necrosis Factor / Antibodies, Monoclonal / Antineoplastic Agents Limits: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Language: En Journal: Clin Cancer Res Journal subject: NEOPLASIAS Year: 2016 Document type: Article Affiliation country: Netherlands