Relapsed and/or refractory Ewing sarcoma MedDRA version: 18.1 Level: PT Classification code 10015560 Term: Ewing's sarcoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Linsitinib
Pharmaceutical Form: Tablet
INN or Proposed INN: linsitinib
CAS Number: 867160-71-2
Current Sponsor code: linsi
Sponsors
University of Oxford
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histological or cytological confirmed original (no new biopsy required) diagnosis of Ewing sarcoma, preferably with EWSR in situ hybridisation break apart probe. 2. First, second or any relapse or refractory disease to conventional treatment. 3. Current disease state for which there either is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life. 4. Has recovered from prior chemotherapy-related toxicity to = grade 2. 5. Male or female, Age = 18 and =70 years. 6. Life expectancy of at least 4 months. 7. WHO performance score of 0-2. 8. Must be able to take oral medication. 9. 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. 10. Written (signed and dated) informed consent. 11. Tumour at biopsy accessible site; in the case of lung metastases, accessible with VATS procedure. 12. Tumour progression documented with imaging in the 6 months prior to study entry. 13. At least one measurable lesion on CT scan performed in past 14 days of minimum size 1 cm and 18 FDG uptake positive 14. Cardiac Ejection Fraction (Echocardiogram) =45%. 15. Fasting glucose = 150 mg/dL (8.3 mmol/L) with no history of diabetes mellitus. Concurrent use of non-insulinotropic anti-hyperglycemic therapy 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. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 39 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 1
Exclusion criteria
Exclusion criteria: 1. Females: Pregnant or breast-feeding, or of childbearing potential unless effective methods of contraception are used. Males: Unless effective methods of contraception are used. 2. 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). 3. 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. 4. Mean QTcF interval = 450 msec based on analysis of screening visit ECGs; 5. Use of drugs that have a known risk of causing Torsades de Pointes (TdP) within 14 days prior to registration. 6. 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. 7. Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results. 8. Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions. 9. History of cerebrovascular accident (CVA) within 6 months prior to entry that resulted in ongoing neurologic instability. 10. Patients with symptomatic brain metastases. Patients with previously diagnosed brain metastases are eligible if they have completed their CNS treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable. 11. Major surgery within 4 weeks prior to study treatment. 12. Prior anti- IGF-1R treatment. 13. Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment. 14. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the effect of the trial drug (linsitinib) on the patient’s tumours in terms of changes in biomarker and PET scans. To establish the safety of the trial drug (linsitinib) in Ewing sarcoma at the dose and treatment schedule being used in the trial. ; Secondary Objective: To assess whether the trial drug improves the time to progression (progression free survival). To assess whether the trial drug improves life span of patients (disease specific survival). To assess whether the trial drug has an effect on patients tumour using CT scans. To further understand what the body does to the trial drug. ; Primary end point(s): As this trial utilises Bayensian analysis there are 2 primary endpoints: 1. Pharmacodynamic effects of linsitinib in the tumour measured by (a) FDG update (SUV) responses (b) Biomarker responses in tumour biopsies. 2. Safety: Adverse events and laboratory abnormalities. ; Timepoint(s) of evaluation of this end point: 1. Pharmacodynamic endpoints will be measured as follows: (a) FDG-PET - baseline and cycle 1 day 15 (b) Biopsies - baseline and cycle 1 day 17 2. Safety data will be collected during cycles 1-6. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Progression free survival 2. Disease specific survival 3. Objective responses (RECIST) 4. Pharmacokinetic assays ; Timepoint(s) of evaluation of this end point: 1. Time of progression. 2. Time of death or censored for at time last known alive for patient still alive at the end of the trial. 3. Baseline, cycle 1, 3 & 6. 4. Cycles 1-6 | — |
Countries
Italy, Netherlands, United Kingdom
Contacts
Public ContactClinical Trial Coordinator
University of Oxford
Outcome results
None listed