Trabectedin plus CD13-targeted tissue factor tTF-NGR against advanced relapsed or refractory soft tissue sarcoma: translational data, clinical safety and efficacy
Abstract
Abstract Trabectedin is standard for r/r soft tissue sarcomas. tTF-NGR accumulates in tumor vasculature leading to tumor vascular occlusion and tumor infarction. Both compounds in sequence could trap trabectedin inside tumors and increase its efficacy, which then optimizes the pro-coagulatory activity of tTF-NGR. This report summarizes translational data and results of the safety run-in patient cohort of the TRABTRAP trial combining trabectedin plus tTF-NGR. A dose of trabectedin of 1.5 mg/m 2 (24 h, day 1) combined with 1.0 mg/m 2 of tTF-NGR (1 h, days 2 and 3, q day 22) represents the approx. Maximum tolerated dose (MTD) and with 0.5 mg/m 2 tTF-NGR (days 2 and 3) the recommended starting dose for the randomized part of TRABTRAP. None of the 6 patients on 0.5 mg/m 2 tTF-NGR had dose-limiting toxicity (DLT). Higher doses or additional days of application of tTF-NGR led to grade 3 DLT including early troponin T high sensitivity increase, a reversible non-ST-elevation myocardial infarction in one patient, and reversible thromboembolic events. Pharmacokinetics explain the difference of the MTD between the phase I study and in TRABTRAP. Experimental and clinical efficacy and tolerability of the combination between trabectedin and tTF-NGR supports the active randomized part of TRABTRAP.
Article Details
Authors (28)
Kathrin Hessling
Caroline Brand
Christian Schwöppe
Mirjam Gerwing
Stefanie Pavelka
Andrew F. Berdel
Heike Hintelmann
Rainer Hamacher
Carsten Müller-Tidow
Gerlinde Egerer
Wolfgang Hartmann
Inga Grünewald
Lars H. Lindner
Ludwig Maximilian University Hospital, Munich, Germany
Dorit Di Gioia
Judith S. Hecker
Sabine Maurer
Daniel Pink
Marius Fried
Sergio A. Zapata Bonilla
Anne-Marie Scheuble
Florian Lordick
From Bielefeld University, Medical School and University Medical Center Ostwestfalen-Lippe, Campus Hospital Lippe, Detmold, Germany (J.H.); the Department of Radiation Oncology, Medical University of Graz, Graz, Austria (T.B.); the Clinical Trials Unit, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany (C.S.); the Institute of Surgical Pathology, University Medical Center Freiburg, Germany (P.B.); the Department of Surgery, University Medical Center Schleswig-Holstein–Campus Lübeck, Lübeck, Germany (B.K., T.K.); Comprehensive Cancer Center Augsburg, Faculty of Medicine, University of Augsburg, Augsburg, Germany (R.C.); the Department of General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany (S.U.); the Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg–Eppendorf, Hamburg, Germany (J.R.I.); the Department of Gastrointestinal Surgery, IRCCS San Raffaele Scientific Institute and San Raffaele Vita-Salute Universi...
Philipp Ivanyi
Manfred Fobker
Georg Lenz
Joachim Gerss
Torsten Kessler
Wolfgang E. Berdel
Christoph Schliemann