LINES: Eurosarc trial of LINsitinib in advanced Ewing Sarcoma

ISRCTN	ISRCTN94236001
DOI	https://doi.org/10.1186/ISRCTN94236001
EudraCT/CTIS number	2012-000616-28
ClinicalTrials.gov number	NCT02546544
Secondary identifying numbers	14859

Submission date: 05/03/2014
Registration date: 05/03/2014
Last edited: 08/08/2019

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://www.cancerresearchuk.org/about-cancer/trials/a-trial-looking-linsitinib-advanced-ewings-sarcoma-lines

Contact information

Ms Hannah Johnson
Scientific

Oncology Clinical Trials Office (OCTO) - Department of Oncology
Old Road Campus
Roosevelt Drive Headington
Oxford
OX3 7DQ
United Kingdom

Email	octo-eurosarc@oncology.oc.ac.uk

Study information

Study design	Non-randomised; Interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Non randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	Phase II trial of Linsitinib (anti-IGFR/IR) in patients with relapsed and/or refractory Ewing Sarcoma
Study acronym	LINES
Study objectives	An important development in ES has been the identification of IGF-1R pathway dependency. The reasons for the remarkable single agent efficacy observed in a small subset of patients remains unknown, as is the relative lack of efficacy in the majority of patients. There may be heterogeneity in response due to partial signal pathway inhibition at the tumour level, inherent resistance in ES cells or the presence of alternative pathway activation through IR-A receptor signalling. Here we aim to establish pharmacodynamic responses in ES tumours using functional imaging 18FDG-PET-CT and repeat post treatment biopsy for biomarker responses, toxicity and clinical outcome to the dual anti-IGF-1R/IR kinase blocking single agent linsitinib. This is a single arm phase 2 study utilising adaptive Bayesian analysis. Approximately 40 patients will be recruited the national bone sarcoma centre in 5 EU countries over 18 months. Eligible patients will take 4x 150 mg tablets once a day, days 1-3 of the week followed by 4 days off - repeated for 3 weeks = one treatment cycle. Patients can remain on treatment for as long as they gain clinical benefit. The primary objectives are to determine the effect of linsitinib on the patients tumours in terms of changes in biomarker and PET scans and to establish the safety of the trial drug (linsitinib) in Ewing sarcoma at the dose and treatment schedule being used in the trial. More details can be found at: http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=14859
Ethics approval(s)	South Central Oxford C, 22/08/2013, ref: 13/SC/0330
Health condition(s) or problem(s) studied	Topic: National Cancer Research Network; Subtopic: Sarcoma; Disease: Bone
Intervention	Linsitinib, Linsitinib is to be administered oally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg. Treatment should continue in patients with either radiological confirmed stable or responding disease until disease progression, unaccetable toxicity or at the patients request. Study Entry : Registration only
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Linsitinib
Primary outcome measure	FDG uptake (SUV) responses; Timepoint(s): FDG uptake (SUV) responses, measured using PET-CT at baseline, during cycles 1, 3, and 6
Secondary outcome measures	Safety and tolerability of Linsitinib; Timepoint(s): Adverse events and lab abnormalities (CTCAE v4 grade, timing, seriousness & relatedness) - all visit
Overall study start date	30/04/2014
Completion date	28/02/2015

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 40; UK Sample Size: 10
Total final enrolment	16
Key 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 3 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.
Key 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 conebiopsied in situ carcinoma of the cervix uteri and nonmelanoma 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.
Date of first enrolment	30/04/2014
Date of final enrolment	28/02/2015

Locations

Countries of recruitment

England
France
Germany
Italy
Netherlands
United Kingdom

Study participating centre

Oncology Clinical Trials Office (OCTO) - Department of Oncology

Oxford
OX3 7DQ
United Kingdom

Sponsor information

University of Oxford
University/education

CTRG
Joint Research Office
Block 60 Churchill Hospital
Headington
OX3 7LJ
England
United Kingdom

Website	http://www.ox.ac.uk
"ROR"	https://ror.org/052gg0110

Funders

Funder type

Government

European Commission - The Directorate-General for Research and Innovation; Grant Codes: 278742

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results			08/08/2019	No	No
HRA research summary			28/06/2023	No	No

Editorial Notes

08/08/2019: ClinicalTrials.gov number and link to basic results (scientific) added.
21/06/2019: Added clinicaltrialsregister.eu link to basic results (scientific). Added total final enrollment.
15/08/2016: Changed name of study contact