Eurosarc Trial of Linsitinib in Advanced Ewing Sarcoma

NCT02546544 | Completed Phase 2 Results DMC

• 2 other identifiers: OCTO_0382012-000616-28
• Study Type: interventional
• Target: 16
• Locations: 5 countries
• Sites: 5

Brief Summary

This is an international, multi-centre, single arm Bayesian designed phase 2 study to identify and determine the safety and activity of anti-IGF-1/IR inhibition in patients with relapsed and/or refractory ESFT. Approximately 40 patients will be recruited from 5-7 European centres. Each patient will be treated with single agent linsitinib, 600 mg orally once a day for days 1-3, 8-10 and 15-17 on a 21 day cycle until disease progression or undue toxicity.

Conditions

Relapsed Ewing Sarcoma; Refractory Ewing Sarcoma

Keywords

Linsitinib; anti-IGF-1R/IR; Ewing Sarcoma; dual IGF-1R/IR inhibition; Relapsed Ewing Sarcoma; Refractory Ewing Sarcoma; Metastatic Ewing Sarcoma

Outcome Measures

Primary Outcomes (2)

• Number of Participants With a Metabolic Response as Evaluated by PERCIST v1.0

  Metabolic response measured by PERCIST v1.0 using SULpeak. This methodology used SULpeak to measure change in glucose uptake in the tumour. Complete Metabolic Response - Complete resolution of 18F-FDG uptake within measurable target lesion so that it is less than mean liver activity and indistinguishable from surrounding background blood-pool levels. Partial Metabolic Response - Reduction of minimum of 30% in target measurable tumour 18F-FDG SULpeak. Absolute drop in SUL must be at least 0.8 SUL units, as well. No new lesions. Positive Metabolic Response - Participants having either "Complete Metabolic Response" or "Partial Metabolic Response". Stable Metabolic Disease - Not CMR, PMR or PMD. Progressive metabolic disease - Increase of more than 30% in 18F-FDG SUL peak. OR: Visible increase in extent of 18F-FDG tumour uptake (75% in TLG volume with no decline in SUL. OR: New 18F-FDG-avid lesions that are typical of cancer and not related to treatment effect or infection.

  Pre- and Post- dose responses following 1 cycle (21 days) of treatment

• Number of Participants With a Toxic Event

  A patient is defined as having a toxic event if they experienced at least one grade 3 adverse event (CTCAE v4.0 grade)

  Following 6 cycles of treatment (up to 6 months)

Secondary Outcomes (4)

• Clinical Outcome (PFS, DSS)

  Duration of study (up to 18 months)

• Pharmacokinetics Assays of Following Linsitinib Treatment (Plasma Concentrations of Linsitinib)

  Cycle 1 days 1,15,17, Cycle 2 day 3, Cycle 3 days 1 and 3, Cycle 4 day 1, Cycle 5 day 1, Cycle 6 day 1 and End of Treatment.0

• Number of Participants With a Radiological Response as Evaluated by RECIST v1.1

  Measured cycle 1 day 15, cycle 3 and cycle 6

• Number of Participants With a Metabolic Response as Evaluated by EORTC 1.0

  Measured cycle 1 day 15

Study Arms (1)

Linsitinib

OTHER

Linsitinib is to be taken orally once a day on days 1-3, 8-10 and 15-17 on a 21 day cycle. The starting dose is 600 mg

Drug: Linsitinib

Interventions

Linsitinib DRUG

Also known as: OSI-906, ASP7487

Linsitinib

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• \. 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 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
• Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions
• History of cerebrovascular accident (CVA) within 6 months prior to entry that resulted in ongoing neurologic instability
• 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
• Major surgery within 4 weeks prior to study treatment
• Prior anti- IGF-1R treatment
• Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment
• Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV

Sponsors & Collaborators

• University of Oxford: lead
• European Organisation for Research and Treatment of Cancer - EORTC: collaborator
• European Commission: collaborator
• Astellas Pharma Inc: collaborator
• Oxford University Hospitals NHS Trust: collaborator

Study Sites (5)

Universitè Lyon 1 Claude Bernard

Lyon, France

Location

Pediatric Hematology and Oncology, University Hospital Münster

Münster, 48149, Germany

Location

Istituti Ortopedici Rizzoli

Bologna, 40136, Italy

Location

Department of Clinical Oncology, Leiden University Medical Center

Leiden, Postzone K1-P, P.O. Box 9600, Netherlands

Location

Oxford University Hospitals NHS Foundation Trust

Oxford, OX3 7LE, United Kingdom

Location

Related Links

• Information about the trial on the Oncology Clinical Trials Office (OCTO) website. OCTO run the trial on behalf of the sponsor, the University of Oxford
• ISRCTN registry

MeSH Terms

Conditions

Sarcoma, Ewing

Interventions

3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol

Condition Hierarchy (Ancestors)

Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Results Point of Contact

• Title: Joint Research Office
• Organization: University of Oxford

ctrg@admin.ox.ac.uk

+441865572245

Study Officials

• Andrew B Hassan, BMBCh FRCP

  University of Oxford

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 6, 2014
• First Posted: September 11, 2015
• Study Start: March 1, 2014
• Primary Completion: July 15, 2016
• Study Completion: July 15, 2016
• Last Updated: June 3, 2019
• Results First Posted: June 3, 2019

Record last verified: 2017-10

Locations

IT (1); DE (1); NL (1); FR (1); GB (1)