tTF-NGR Randomized Study - STS (TRABTRAP)
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ClinicalTrials.gov Identifier: NCT05597917 |
Recruitment Status :
Recruiting
First Posted : October 28, 2022
Last Update Posted : December 22, 2023
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Condition or disease | Intervention/treatment | Phase |
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Soft Tissue Sarcoma | Drug: Trabectedin Biological: tTF-NGR | Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 126 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | Phase III Study Comparing Trabectedin (T) Versus T Plus tTF-NGR to Entrap T Inside the Tumor in Patients With Metastatic and/or Refractory Soft Tissue Sarcoma (STS) |
Actual Study Start Date : | October 26, 2021 |
Estimated Primary Completion Date : | December 2025 |
Estimated Study Completion Date : | December 2026 |
Arm | Intervention/treatment |
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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.
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Drug: Trabectedin
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.
Other Name: Yondelis |
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.
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Drug: Trabectedin
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.
Other Name: Yondelis Biological: 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. |
- 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.
- 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)
- 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)
- 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)
- 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)
- 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
- 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.
- 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]
- 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]
- 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]
- 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]
- 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]
- 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
- 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]
- 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
- 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)
- 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])
- 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
- 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]
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Ages Eligible for Study: | 18 Years to 75 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients of all genders (female, male, diverse), with no restriction regarding ethnic or religious background age 18 - 75 years.
- Patients with advanced or metastatic soft-tissue sarcoma after failure of anthracycline-containing first line therapy (or anthracycline-containing adjuvant therapy within 12 months before entry on study) or with contraindications to these drugs
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Patients must have histological evidence of high-grade advanced unresectable or metastatic soft tissue sarcoma (grade 2 - 3) according to the FNCLCC grading system. The following tumor types are included:
- Dedifferentiated liposarcoma
- Myxoid liposarcoma (high grade)
- Pleomorphic liposarcoma
- Adult fibrosarcoma
- Myxofibrosarcoma (high-grade)
- Leiomyosarcoma
- Rhabdomyosarcoma (alveolar, pleomorphic)
- Angiosarcoma
- Synovial sarcoma
- Undifferentiated sarcoma
Tumor types not listed above may be included upon communication with Coordinating Investigator.
The following tumor types will not be included:
- Gastrointestinal stromal tumors (GIST)
- Epitheloid sarcoma
- Alveolar soft part sarcoma
- Desmoplastic small round cell tumor
- Chondrosarcoma
- Osteosarcoma
- Ewing sarcoma (including CIC-rearranged sarcoma and Sarcoma with BCOR alterations)
- CD13 positivity with a score of ≥ 1 (20) by central pathology (GDI Münster)
- Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria 1.1. This lesion should not have been irradiated during previous treatments
- Life expectancy of at least 3 months
- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
- No contraindications for trabectedin (see attachment)
- Negative serum pregnancy test for females of childbearing potential* within 14 days of starting treatment
- Informed consent signed and dated to participate in the study
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Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures
- Women of childbearing potential (WOCBP) must be using, from the screening to 3 months following the last trabectedin (Arm 1) or the last last study drug (Arm 2) administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) and which include, for instance, progesteron-only or combined (estrogen- and progesteron-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated monthly. For men contraception methods should be performed for 5 months after the last application of trabectedin (Arm1) or study drug (Arm 2).Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy)
Exclusion Criteria:
- curative therapy available
- clinically significant unrelated illness, which in the judgement of the investigators could compromise the patient's ability to tolerate the IMP or be likely to interfere with the study procedures or results
- immobilized tumor patients (wheel chair etc.) with increased risk for DVT
- known hypersensitivity reactions to prior application of E. coli-derived material
- history of coronary heart disease, stroke, transitent ischemic attacks, pulmonary embolism, or deep vein thrombosis. For reason of mechanism of action of tTF-NGR, exclusion of patients with a history of any of the vascular conditions mentioned is important. Clinical suspicion of coronary heart disease must be further checked e.g. by cardiac MRI or myocardial scintigraphy to exclude coronary heart disease.
- known hereditary syndromes with elevated thromboembolic risk (FV Leiden and prothrombin mutations (G20210A), hereditary antithrombin, protein C and S deficiency, and antiphospholipid syndrome) after one or more clinical thromboembolic events
- patients with hereditary vascular disorders (such as Klippel-Trenauny-Weber syndrome) with increased thromboembolic risk.
- patients with a Khorana score of (Khorana AA, et al. J.Clin. Oncol. 2009, 27, 4839-4847, attached to this protocol) of > 3
- elevated Troponin T hs (> 50 ng/L) before entry on study
- presence of active central nervous system (CNS) disease and/or CNS vascular abnormalities detected by MRI
- no adequate bone marrow function, absolute neutrophil count (ANC) < 1.0 x 109/L, platelets < 50 x 109/L (for trabectedin actually < 100 x 109/L - to be decided by the investigator on an individual patient basis) and haemoglobin (Hb) < 8.0 g/dl.
- chronically impaired renal function or creatinine ≥ 2.0 x upper limit of normal (ULN).
- inadequate liver function (alanine aminotranserase (ALT), aspartate aminotranserase (AST), alkaline phosphatase (ALP) or total bilirubin ≥ 2.5 x ULN) unless due to liver metastasis (decision by the investigator)
- fibrinogen < 150 mg/dL, and/or International Normalized Ratio (INR) > 1,5 (global coagulation parameters can be discussed with the Coordinating Investigator prior to entry on study)
- female patients with child-bearing who do not agree to exclusion of potential pregnancy by adequate testing within 48 hours prior to entry on study
- females of childbearing potential as well as fertile males who do not agree to use a highly effective form of contraception (Pearl Index < 1) during the study and for 3 months (females) following the last trabectedin (Arm 1) or last study drug (Arm 2) administration and 5 months (males) following the last dose of trabectedin (Arm 1) or study drug (Arm 2)
- women with breast-feeding activity
- concomitant use of any other investigational agent (agent for which there is currently no approved indication from regulatory authorities) or any other anti-cancer drug
- concomitant enrolment in another clinical trial interfering with the endpoints of this study.
- any medical condition which could compromise participation in the study according to the investigator's assessment.
- prophylactic or therapeutic anticoagulation within the last 3 days (see 11)
- presence of active and uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study
- concurrent malignancies other than STS, unless the patient has been disease-free for at least 2 years
- serious, non-healing wound, ulcer or bone fracture; not completed wound healing from previous wounds and/or surgery
- no central venous port system in place (prerequisite for ARM 2; valid exceptions have to be discussed with the Coordinating Investigator).
NOTE: Outliers of laboratory values can be disregarded and set aside as exclusion criteria by a Coordinating Investigator´s decision. The conditions for the use of trabectedin as specified in the Summary of Product Characteristics are to be followed according to institutional guidelines for standard of care.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05597917
Contact: Christoph Schliemann, Prof. Dr. | +49 251 83 45363 | Christoph.Schliemann@ukmuenster.de | |
Contact: Torsten Kessler, PD Dr. | +49 251 83 45363 | Torsten.Kessler@ukmuenster.de |
Austria | |
Medizinische Universität Graz | Recruiting |
Graz, Austria, 8010 | |
Contact: Joanna Skandera, PD 0043 316 38513115 joanna.szkandera@medunigraz.at | |
Principal Investigator: Joanna Skandera, PD | |
Germany | |
HELIOS Klinikum Bad Saarow | Recruiting |
Bad Saarow, Germany, 15529 | |
Contact: Daniel Pink, Dr. +49 33631 73527 daniel.pink@helios-gesundheit.de | |
Principal Investigator: Daniel Pink, Dr. | |
Sub-Investigator: Daniel Schöndube, Dr. | |
Sub-Investigator: Antja West, Dr. | |
HELIOS Klinikum Berlin-Buch | Recruiting |
Berlin, Germany, 13125 | |
Contact: Peter Reihardt, PD Dr. +49 30 940114888 peter.reichardt@helios-gesundheit.de | |
Principal Investigator: Peter Reihardt, PD Dr. | |
Sub-Investigator: Nicolas Ziegenhagen | |
Sub-Investigator: Benjamin Unger | |
TU Dresden Medizinische Fakultät Carl Gustav Carus | Recruiting |
Dresden, Germany, 01307 | |
Contact: Stephan Richter, Dr. +49 351 458 7108 Stephan.Richter@uniklinikum-dresden.de | |
Principal Investigator: Stephan Richter, Dr. | |
Sub-Investigator: Martin Wermke, Dr. | |
Universitätsklinikum Frankfurt | Recruiting |
Frankfurt am Main, Germany, 60590 | |
Contact: Marit Ahrens, Dr. +49 69 6301 83359 Marit.Ahrens@kgu.de | |
Principal Investigator: Marit Ahrens, Dr. | |
Sub-Investigator: Björn Steffen, Dr. | |
Universitätsklinikum Heidelberg | Recruiting |
Heidelberg, Germany, 69120 | |
Contact: Gerlinde Egerer, Prof. Dr. +49 6221 568029 Gerlinde.Egerer@med.uni-heidelberg.de | |
Principal Investigator: Gerlinde Egerer, Prof. Dr. | |
Sub-Investigator: Susanne Hofmann, Dr. | |
Universitätsmedizin Mainz | Recruiting |
Mainz, Germany, 55131 | |
Contact: Marius Fried, Dr. +49 6131 175952 Marius.Fried@unimedizin-mainz.de | |
Principal Investigator: Marius Fried, Dr. med. | |
Sub-Investigator: Thomas Kindler, Prof. Dr. | |
LMU Klinikum | Recruiting |
Münich, Germany, 81377 | |
Contact: Lars Lindner, Prof. Dr. +49 89 4400 77773 Lars.Lindner@med.uni-muenchen.de | |
Principal Investigator: Lars Lindner, Prof. Dr. | |
Sub-Investigator: Dorit Di Gioia, PD Dr. | |
University Hospital Muenster, Germany | Recruiting |
Münster, Germany, 48149 | |
Contact: Christoph Schliemann, Prof. Dr. +49 251 83 45363 Christoph.Schliemann@ukmuenster.de | |
Contact: Torsten Kessler, PD Dr. +49 251 83 45363 Torsten.Kessler@ukmuenster.de | |
Principal Investigator: Christoph Schliemann, Prof. Dr. | |
Sub-Investigator: Torsten Kessler, PD Dr. |
Principal Investigator: | Christoph Schliemann, Prof. Dr. | University Hospital Muenster (Department of Medicine A), Germany |
Responsible Party: | Universität Münster |
ClinicalTrials.gov Identifier: | NCT05597917 |
Other Study ID Numbers: |
WWU19_0007 2020-005858-21 ( EudraCT Number ) |
First Posted: | October 28, 2022 Key Record Dates |
Last Update Posted: | December 22, 2023 |
Last Verified: | December 2023 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
Plan Description: | De-identified participant data for all primary and secondary outcome measurements will be made available within 6 months of study completion |
Supporting Materials: |
Study Protocol |
Time Frame: | within 6 months of study completion |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
tTF-NGR vascular targeting CD13 aminopeptidase N Trabectedin |
Sarcoma Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Neoplasms Trabectedin |
Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents |