Phase Ib Study of the Combination of Regorafenib With Conventional Chemotherapy for the Treatment of Newly Diagnosed Patients With Multimetastatic Ewing Sarcoma
New drug efficacy in ES has been disappointing in the last decades and no new drugs have been successfully introduced up to now in front line treatment. Among the tested drugs, early clinical data suggest that strategies using multi-targeted tyrosine kinase inhibitors (TKI) with anti-angiogenic activities are among the most efficient and may be beneficial in the treatment of patients with ES. Several TKI have been and are currently being tested as single-agent in patients with relapsed/refractory ES with encouraging results in phase II trials. Regorafenib has shown promising activity in Ewing sarcoma relapse setting, Nevertheless, regorafenib has never been combined with the intensive chemotherapy VDC/IE schedule and therefore this combination needs to be evaluated in order to avoid dose reduction of the current standard treatment and hence its efficacy. The current clinical trial has been therefore designed to test the feasibility of regorafenib with ES conventional chemotherapy. It consists of a phase Ib that will only recruit patients with multi-metastatic (other than lungs/pleura only) ES, that present the highest unmet medical need (2 year EFS: 33%, similar to patients with relapse/refractory ES).
• 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
• Metastatic disease
• Age ≥2 years and \<50 years (from second birthday to 49 years 364 days)
• Patient assessed as medically fit to receive the Ewing sarcoma standard multimodal treatment and regorafenib, including:
‣ Absolute Neutrophil Count (ANC) ≥ 0.75x10\^9/L, platelets ≥ 75x10\^9/L.
⁃ Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 5×ULN
⁃ Bilirubin ≤ 2×ULN
⁃ Creatinine \< 2x ULN or creatinine clearance \>60 ml/min/1.73 m\^2
⁃ International normalized ratio (INR)/ Partial thromboplastin time (PTT). INR and PTT ≤ 1.5 x ULN. INR \& PTT ≤ 1.5xULN
• Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) ≥50%) at baseline, as determined by echocardiography
• Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as: a BP \<95th percentile for sex, age, and height at screening (as per National Heart Lung and Blood Institute \[NHLBI\] guidelines) and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1. Patients \>18 years old should have BP ≤ 150/90 mmHg.
• No prior treatment for Ewing sarcoma other than surgery
• Negative pregnancy test for female patients of childbearing potential within 7 days prior to study registration.
• 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
⁃ Subject must be able to swallow and retain oral medication.
⁃ 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.
⁃ Patients must be affiliated to a social security system or beneficiary of the same, as per local regulatory requirements (France only)