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Trabectedin plus CD13-targeted tissue factor tTF-NGR against advanced relapsed or refractory soft tissue sarcoma:
Kathrin Hessling1, Caroline Brand1, Christian Schwöppe1
1Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital of Muenster, Albert‑Schweitzer‑Campus 1, 48149, Muenster, Germany.
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/m2 (24 h, day 1) combined with 1.0 mg/m2 of tTF-NGR (1 h, days 2 and 3, q day 22) represents the approx. Maximum tolerated dose (MTD) and with 0.5 mg/m2 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/m2 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.
Insights
The TRABTRAP trial combined trabectedin and tTF-NGR for soft tissue sarcomas. The recommended starting dose showed good tolerability, supporting further randomized studies.
Area of Science:
- Oncology
- Pharmacology
- Translational Medicine
Background:
- Trabectedin is a standard treatment for relapsed/refractory soft tissue sarcomas.
- Tumor-targeting fusion NGR (tTF-NGR) targets tumor vasculature, causing occlusion and infarction.
- Sequential administration may enhance trabectedin's efficacy by trapping it within tumors.
Purpose of the Study:
- To evaluate the safety and tolerability of combining trabectedin with tTF-NGR.
- To determine the maximum tolerated dose (MTD) and recommended starting dose for the TRABTRAP trial.
- To summarize translational data and safety findings from the TRABTRAP trial's initial patient cohort.
Main Methods:
- Phase I safety run-in cohort of the TRABTRAP trial.
- Combination therapy of trabectedin and tTF-NGR administered sequentially.
- Dose escalation of tTF-NGR to identify dose-limiting toxicities (DLTs).
Main Results:
- A combination dose of trabectedin 1.5 mg/m² and tTF-NGR 0.5 mg/m² was identified as the recommended starting dose.
- No dose-limiting toxicities (DLTs) were observed in patients receiving the recommended starting dose.
- Higher doses or extended application of tTF-NGR resulted in Grade 3 DLTs, including myocardial infarction and thromboembolic events.
Conclusions:
- The combination of trabectedin and tTF-NGR is feasible and tolerable at the recommended dose.
- The identified MTD and recommended starting dose support the ongoing randomized portion of the TRABTRAP trial.
- Translational and clinical data support the continued investigation of this combination therapy for soft tissue sarcomas.
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