Condition category
Cancer
Date applied
05/03/2014
Date assigned
05/03/2014
Last edited
15/08/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

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

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 patient’s 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 measures

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

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

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

http://www.ox.ac.uk

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

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

15/08/2016: Changed name of study contact