1. Efficacy: Prolongation of progression-free survival (PFS) according to iRECIST as judged by central radiology in a blinded fashion after end of trial. (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): The primary objective of the trial is to evaluate whether tTF-NGR in combination with standard trabectedin chemotherapy given for unresectable or metastatic soft tissue sarcoma after failure of anthracycline-containing first line therapy or with contraindications to these drugs prolongs progression-free survival, as compared with trabectedin alone.
The following efficacy endpoint (for the randomized phase III part) will be considered:
- Progression-free survival (PFS) according to iRECIST (Seymour L, Lancet Oncol. 2017) as judged by central radiology in a blinded fashion after end of trial.
Secondary outcome:
1. Evaluation of the efficacy of tTF-NGR in combination with standard trabectedin chemotherapy (OOR) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the efficacy, the following measurement will be considered:
Overall response rate (ORR, consisting of CR and PR)
2. Evaluation of the efficacy of tTF-NGR in combination with standard trabectedin chemotherapy (DCR) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the efficacy, the following measurement will be considered:
- Disease control rate (DCR, consisting of CR, PR, and stable disease (SD) for >18 weeks)
3. Evaluation of the efficacy of tTF-NGR in combination with standard trabectedin chemotherapy (mPFS) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the efficacy, the following measurement will be considered:
- Median progression-free survival (mPFS)
4. Evaluation of the efficacy of tTF-NGR in combination with standard trabectedin chemotherapy (mOS) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the efficacy, the following measurement will be considered:
- Median overall survival (mOS)
5. Evaluation of the efficacy of tTF-NGR in combination with standard trabectedin chemotherapy (OS) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the efficacy, the following measurement will be considered:
- Overall survival (OS) rate at 12 and 18 months
6. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (AE) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- Adverse Events (AEs) assessment based on CTCAE v.5.0.
7. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (Standard laboratory parameters) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- laboratory parameter: Troponin T hs [ng/l]
8. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (Physical examination: Height) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- Physical examination: Height [m]
9. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (Physical examination: Weight) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- Physical examination: Weight [kg]
10. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (Physical examination: Body surface) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- Physical examination: Body surface area [m2]
11. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (Vital sign: breathing) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- Physical examination: Vital sign: breathing rate by watching and counting [breaths per minute]
12. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (Vital sign: consciousness) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- Physical examination: Vital sign: consciousness by talking to the patient
13. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (Vital sign: heart rate) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- Physical examination: Vital sign: heart rate by pulse [beats per minute]
14. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (Physical examination: ECOG perfomance status) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- Physical examination: ECOG perfomance status
15. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (ECG) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- ECG (rythm, puls rate, Vector, P Wave, PQ time, QRS Complex, R progression from V1 to V6, QT Interval, PQ time, QRS time, T wave)
16. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (Echocardiography) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- Echocardiography (diameters of both atria and left and right cardiac chambers at end-diastolic and end-systolic times [mm], ejection fraction [%], wall diameters [mm])
17. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (PRO) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- Patient reported outcomes (PRO) by EORTC QLQ C30 questionnaire
18. Evaluation of the safety profile of tTF-NGR combined with standard trabectedin chemotherapy (PK) (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months): To assess the safety profile of tTF-NGR combined with trabectedin the following safety endpoint will be considered:
- pharmacokinetics: AUC [ng*h/ml]
Active Comparator: Arm 1: Standard chemotherapy with trabectidin (in-label) Patients will receive standard trabectedin 1.5 mg/m2 as a 24-hour central intravenous (IV) infusion on day 1, q d 22 x until disease progression or contraindications against further application.
Experimental: Arm 2: tTF-NGR added to standard trabectedin Patients will receive standard trabectedin according to arm 1 plus the safe dose according to safety run-in part of tTF-NGR (1-hour ratecontrolled infusion, port central venous access, 0.9 % NaCl ad 100 mL) per day for 4 or lower number of consecutive days following each trabectedin cycle (within 1 hour interval between end of trabectedin infusion and tTF-NGR: e.g.: trabectedin on monday 8 am to tuesday 8 am followed by tTF-NGR on tuesday 9 am and on the following days, q d 22 x until disease progression or contraindications against further application.
Trabectedin (Yondelis): Patients will receive standard trabectedin 1.5 mg/m2 as a 24-hour central intravenous (IV) infusion on day 1, q d 22 x until disease progression or contraindications against further application.
tTF-NGR: Patients will receive standard trabectedin according to arm 1 plus the safe dose according to safety run-in part of tTF-NGR (1-hour ratecontrolled infusion, port central venous access, 0.9 % NaCl ad 100 mL) per day for 4 or lower number of consecutive days following each trabectedin cycle (within 1 hour interval between end of trabectedin infusion and tTF-NGR: e.g.: trabectedin on monday 8 am to tuesday 8 am followed by tTF-NGR on tuesday 9 am and on the following days, q d 22 x until disease progression or contraindications against further application.
Quelle: ClinicalTrials.gov
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