Eurosarc Trial of Linsitinib in Advanced Ewing Sarcoma

Inclusion Criteria

• Histological or cytological confirmed original (no new biopsy required) diagnosis of Ewing sarcoma, preferably with EWSR in situ hybridisation break apart probe.
• First, second or any relapse or refractory disease to conventional treatment
• Current disease state for which there either is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• Has recovered from prior chemotherapy-related toxicity to ≤ grade 2
• Male or female, Age ≥ 18 and ≤70 years
• Life expectancy of at least 4 months
• WHO performance score of 0-2
• Must be able to take oral medication
• Is willing and able to comply with the protocol for the duration of the study, and scheduled visits and examinations, including biopsies and PET-CT scans
• Written (signed and dated) informed consent
• Tumour at biopsy accessible site; in the case of lung metastases, accessible with VATS procedure
• Tumour progression documented with imaging in the 6 months prior to study entry
• At least one measurable lesion on CT scan performed in past 14 days of minimum size 1 cm and 18FDG uptake positive
• Cardiac Ejection Fraction (Echocardiogram) ≥45%
• Fasting glucose ≤ 150 mg/dL (8.3 mmol/L) with no history of diabetes. Concurrent use of non-insulinotropic anti-hyperglycaemic therapy for diabetes is permitted if the dose has been stable for ≥ 4 weeks at the time of enrolment
• 16. Haematological and biochemical indices within the specified ranges as below:
• Haemoglobin (Hb) ≥9 g/dL (Previous transfusion is allowed)
• Absolute neutrophil count (ANC) ≥1.0 x 109/L without growth factor support
• Platelet count > 80.x 109/L (Previous transfusion is allowed)
• Direct Bilirubin <1.5 times the upper limit of normal (ULN)
• Serum alanine aminotransferase (ALT) <2.5 x ULN for age and ≤ 5 x ULN if liver metastasis
• Aspartate aminotransferase (AST) <2.5 x ULN for age
• Alkaline phosphatase <2.5 x ULN for age
• CPK <2.5 x ULN for age
• Serum creatinine ≤1.5 x ULN for age
• Potassium, magnesium and calcium within normal limits (supplementation and re-testing is permitted)

Exclusion Criteria

• Females: Pregnant or breast-feeding, or of childbearing potential unless effective methods of contraception are used. Males: Unless effective methods of contraception are used.
• Significant active cardiac disease including: History (within last 6 months) of significant cardiovascular disease unless the disease is well-controlled. Significant cardiac disease includes second/third degree heart block; clinically significant ischemic heart disease; superior vena cava (SVC) syndrome; poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea).
• History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (≥ grade 3), left bundle branch block (LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients with atrial fibrillation controlled by medication are not excluded; uncontrolled high blood pressure (no greater than 2 SD above the mean for age for SBP and DBP), unstable angina, congestive heart failure, myocardial infarction within the previous 6 months, or serious cardiac arrhythmias
• Mean QTcF interval ≥ 450 msec based on analysis of screening visit and pre-dose ECGs.
• 5. Use of drugs that have a known risk of causing Torsades de Pointes (TdP) within 14 days prior to registration
• Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine within 7 days prior to registration. Linsitinib is primarily metabolized by CYP1A2 and inhibitors/inducers of CYP1A2 could alter the pharmacokinetics of linsitinib. Other less potent CYP1A2 inhibitors/inducers are not excluded
• Other psyc