Patients (18-75 years) with metastatic and/or refractory soft-tissue sarcoma after failure of anthracycline-containing 1st line therapy or with contraindications to anthracyclines (CD13 positivity: grade >/= 1+). MedDRA version: 20.0 Level: PT Classification code 10073135 Term: Dedifferentiated liposarcoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: HLT Classification code 10024628 Term: Liposarcomas malignant S
Conditions
Sponsors
Westfälische Wilhelms-Universität Münster c/o Universitätsklinikum Münster, Geschäftsbereich Recht u. Drittmittel
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients of all genders (female, male, diverse), with no restriction regarding ethnic or religious background age 18 – 75 years. 2. 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 3. 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) 4. CD13 positivity with a score of = 1 (20) by central pathology (GDI Münster) 5. 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 6. Life expectancy of at least 3 months 7. Eastern Cooperative Oncology Group (ECOG) Performance Status = 2 8. No contraindications for trabectedin (see attachment) 9. Negative serum pregnancy test for females of childbearing potential* within 14 days of starting treatment 10. Informed consent signed and dated to participate in the study 11. 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) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 106 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: 1. curative therapy available 2. 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 3. immobilized tumor patients (wheel chair etc.) with increased risk for DVT 4. known hypersensitivity reactions to prior application of E. coli-derived material 5. 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. 6. 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 7. patients with hereditary vascular disorders (such as Klippel-Trenauny- Weber syndrome) with increased thromboembolic risk. 8. patients with a Khorana score of (Khorana AA, et al. J.Clin. Oncol. 2009, 27, 4839–4847) of > 3 9. elevated Troponin T hs (> 50 ng/L) before entry on study 10. presence of active central nervous system (CNS) disease and/or CNS vascular abnormalities detected by MRI 11. no adequate bone marrow function, absolute neutrophil count (ANC) 1,5 (global coagulation parameters can be discussed with the Coordinating Investigator prior to entry on study) 15. 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 16. 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) 17. women with breast-feeding activity 18. 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 19. concomitant enrolment in another clinical trial interfering with the endpoints of this study. 20. any medical condition which could compromise participation in the study according to the investigator's assessment. 21. prophylactic or therapeutic anticoagulation within the last 3 days 22. 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 23. concurrent malignancies other than STS, unless the patient has been disease-free for at
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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. ;Secondary Objective: The secondary objective of the trial is to evaluate the efficacy of tTF-NGR in combination with standard trabectedin chemotherapy given for unresectable or metastatic STS after failure of anthracycline-containing first line therapy or with contraindications to these drugs with respect to the response rate and overall survival as well as to assess the safety profile of tTF-NGR combined with trabectedin.;Primary end point(s): The following primary efficacy endpoint will be considered (for the phase III randomized part): - Progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumours in cancer immunotherapy trials (iRECIST, Seymour L, Lancet Oncol. 2017) as judged by central blinded radiology. The reason for using the iRECIST modification of RECIST for evaluation rests in the observation within preclinical studies and clinical cases, that intratumoral swelling by blood pooling and vascular disruption can occur and lead to pseudoprogressions (22, IB, and see below). In particular, even if the assessment of PFS by a local investigator differs from the central blinded assessment, the latter assessment is considered the relevant primary efficacy endpoint. ;Timepoint(s) of evaluation of this end point: Progression-free survival (PFS) rate according to iRECIST at week 18 (after 6 cycles), then every 9 weeks (+/- 1 week, independent from cycle length of 3 weeks) thereafter until confirmed progression by iRECIST (iCPD). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): To assess the efficacy, the following measurements will be considered: - Overall response rate (ORR, consisting of CR and PR) - Disease control rate (DCR, consisting of CR, PR, and stable disease (SD) for > 15 weeks) - Median progression-free survival (mPSF) - Median overall survival (mOS) - Overall survival (OS) rate To assess the safety profile of tTF-NGR combined with trabectedin (for the phase II and phase III parts of the study). The following safety endpoints will be considered: - Adverse Events (AEs) assessment based on CTCAE v.5.0. - Standard laboratory parameters - Physical examination findings including assessment of vital signs - Analysis of patient reported outcomes (PRO);Timepoint(s) of evaluation of this end point: Overall response rate (ORR, consisting of CR and PR) Disease control rate (DCR, consisting of CR, PR, and stable disease (SD) for > 18 weeks) Median pregression-free survival (mPSF) Median overall survival (mOS) Overall survival (OS) rate at 12 and 18 months Adverse Events (AEs) assessment based on CTCAE v.5.0. continuously. | — |
Countries
Austria, Germany
Contacts
Public ContactDepartment of Medicine A
University Hospital Muenster
Outcome results
None listed