Plain English Summary
Trial website
Contact information
Type
Scientific
Primary contact
Ms Hannah Johnson
ORCID ID
Contact details
Oncology Clinical Trials Office (OCTO) - Department of Oncology
Old Road Campus
Roosevelt Drive Headington
Oxford
OX3 7DQ
United Kingdom
-
octo-eurosarc@oncology.oc.ac.uk
Additional identifiers
EudraCT number
2012-000616-28
ClinicalTrials.gov number
NCT02546544
Protocol/serial number
14859
Study information
Scientific title
Phase II trial of Linsitinib (anti-IGFR/IR) in patients with relapsed and/or refractory Ewing Sarcoma
Acronym
LINES
Study hypothesis
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
South Central Oxford C, 22/08/2013, ref: 13/SC/0330
Study design
Non-randomised; Interventional; Design type: Treatment
Primary study design
Interventional
Secondary study design
Non randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
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
Phase
Phase II
Drug names
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 trial start date
30/04/2014
Overall trial end date
28/02/2015
Reason abandoned (if study stopped)
Eligibility
Participant 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.
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 40; UK Sample Size: 10
Total final enrolment
16
Participant 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.
Recruitment start date
30/04/2014
Recruitment end date
28/02/2015
Locations
Countries of recruitment
France, Germany, Italy, Netherlands, United Kingdom
Trial participating centre
Oncology Clinical Trials Office (OCTO) - Department of Oncology
Oxford
OX3 7DQ
United Kingdom
Sponsor information
Organisation
University of Oxford
Sponsor details
CTRG
Joint Research Office
Block 60 Churchill Hospital
Headington
OX3 7LJ
United Kingdom
Sponsor type
University/education
Website
Funders
Funder type
Government
Funder name
European Commission - The Directorate-General for Research and Innovation; Grant Codes: 278742
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
See: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-000616-28/results (added 21/06/2019) and https://www.clinicaltrials.gov/ct2/show/results/NCT02546544 (added 08/08/2019)
Publication list