Newly diagnosed patients with metastatic (other than lung/pleura metastases only) Ewing sarcoma
Conditions
Interventions
Trade Name: Stivarga 40 mg film-coated tablets.
Product Name: Regorafenib, stivarga
Pharmaceutical Form: Tablet
Sponsors
Gustave Roussy
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or round cell sarcomas which are ‘Ewing’s-like’ but negative for EWSR1 gene rearrangement 2.Metastatic disease 3.Age =2 years and 60 ml/min/1.73 m2 - International normalized ratio (INR)/ Partial thromboplastin time (PTT). INR and PTT = 1.5 x ULN. INR & PTT = 1.5xULN 5.Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) =50%) at baseline, as determined by echocardiography 6.Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as: a BP 18 years old should have BP = 150/90 mm Hg. 7.No prior treatment for Ewing sarcoma other than surgery 8.Negative pregnancy test for female patients of childbearing potential within 7 days prior to study registration. 9.Patient agrees to use highly effective contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where applicable 10.Subject must be able to swallow and retain oral medication. 11.Written informed consent from the patient and/or the parent/legal guardian, according to local, regional or national regulation prior to any study specific procedures. 12.Patients must be affiliated to a social security system or beneficiary of the same, as per local regulatory requirements (France only) Are the trial subjects under 18? yes Number of subjects for this age range: 19 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 4 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: 1.Localized tumor or metastatic disease to lung/pleura only. 2.Contra-indication to the Ewing sarcoma standard multimodal treatment 3.Pregnant or breastfeeding women or intending to become pregnant during the study. 4.Follow-up not possible due to social, geographic or psychological reasons 5.Impairment of gastrointestinal (GI) function or GI disease that may significantly alter absorption of oral drugs 6.A clinically significant ECG abnormality, including a marked prolonged QTcF interval (eg, a repeated demonstration of a QTcF interval >480 msec) Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality, unstable angina, active coronary artery disease and myocardial infarction within 6 months before randomization.) Uncontrolled hypertension (systolic pressure >150 mm Hg or diastolic pressure > 90 mm Hg on repeated measurement) despite optimal medical management 7.Previous arterial or venous thromboembolisms Grade = 3 per CTCAE v5.0 8.Hypersensitivity to any active substance or to any excipients 9.Radiographic evidence of encasement or invasion of a major blood vessel or of intratumoral cavitation 10.Major surgical procedure or significant traumatic injury within 28 days before starting study treatment 11.Non-healing wound, ulcer or bone facture. 12.Interstitial lung disease with ongoing signs and symptoms. 13.Any other medical or other condition that, in the opinion of the investigator(s), would preclude the subject’s participation in this clinical study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the recommended Phase 2 dose (RP2D) of regorafenib in combination with standard backbone chemotherapy of VDC/IE in patients with newly diagnosed metastatic (other than lungs and/or pleura only) Ewing sarcoma.;Secondary Objective: To assess the survival outcome (PFS, OS) To assess the toxicity of the combination of regorafenib and VDC/IE chemotherapy To evaluate the radiological response of primary tumor, regional lymph nodes and/or other metastases. To evaluate the primary tumor histological response Translational objectives: To identify predictive biomarkers for regorafenib therapy response To develop non-invasive liquid biopsies for monitoring tumor response and relapse To define biological mechanisms of regorafenib resistance and response To describe regorafenib pharmacokinetics in pediatric patients ;Primary end point(s): Dose-limiting toxicity (DLT): DLT will be defined as any of the following haematological and non-haematological events (CTCAE v5.0) that occur during the DLT assessment period (4 weeks after the start of treatment = cycle 1) and are at least possibly related (possibly, probably, or definitely) attributable to VDC/IE + regorafenib: -Any cardiac toxicity grade = 3 -Any grade 3 or 4 hematological or non-hematological toxicity leading to delay of start of next course by > 7 days (i.e: starting > day 21). -Any dose interruption or reduction due to toxicity, which results in administration of less than 80% of the planned dose of regorafenib or, 75% of the planned dose of chemotherapy. -Any grade 3 or 4 toxicity resulting in discontinuation of chemotherapy with regorafenib -Any grade 5 toxicity at least possibly related to study treatment (death) ;Timepoint(s) of evaluation of this end point: 4 weeks after the start of treatment = cycle 1 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Overall Survival (OS) and progression-free survival (PFS) -Adverse events and toxicity, defined by CTCAE v5.0 -Histological response of the primary tumor to induction chemotherapy if surgery is performed as local control -Radiological response of primary tumor, regional lymph nodes and/or metastases Translational endpoints: -To analyze a validated novel 225 gene expression-based molecular risk-classifier Kinase Activity and Response in SARComa (KARSARC), which prospectively identifies long-term responders and survivors to MTKI therapy in sarcomas. -To analyze a pre-defined proteomics signature for regorafenib sensitivity, defined by kinase connectivity map (K-MAP) by mass spectrometry -To analyze the levels of circulating inflammatory cytokines and growth factors that are reported to be predictive of anti-angiogenic MTKI response in sarcomas and other cancers -Concentrations of regoragenib and its active metabolites M2 and M5 ;Timepoint(s) of evaluation of this end point: 4 weeks after the start of treatment = cycle 1 | — |
Countries
Denmark, European Union, France, Italy, Spain
Contacts
Public ContactAqsa YAR
Gustave Roussy
Outcome results
None listed