Eurosarc Trial of Linsitinib in Advanced Ewing Sarcoma
Condition: Relapsed Ewing Sarcoma; Refractory Ewing Sarcoma
MeSH terms: Sarcoma; Sarcoma, Ewing
Intervention: Linsitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Linsitinib; anti-IGF-1R/IR; Ewing Sarcoma; dual IGF-1R/IR inhibition; Relapsed Ewing Sarcoma; Refractory Ewing Sarcoma; Metastatic Ewing Sarcoma

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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

          -  16. Haematological and biochemical indices within the specified ranges as below:

               -  Haemoglobin (Hb) ≥9 g/dL (Previous transfusion is allowed)

               -  Absolute neutrophil count (ANC) ≥1.0 x 109/L without growth factor support

               -  Platelet count > 80.x 109/L (Previous transfusion is allowed)

               -  Direct Bilirubin <1.5 times the upper limit of normal (ULN)

               -  Serum alanine aminotransferase (ALT) <2.5 x ULN for age and ≤ 5 x ULN if liver
                  metastasis

               -  Aspartate aminotransferase (AST) <2.5 x ULN for age

               -  Alkaline phosphatase <2.5 x ULN for age

               -  CPK <2.5 x ULN for age

               -  Serum creatinine ≤1.5 x ULN for age

               -  Potassium, magnesium and calcium within normal limits (supplementation and
                  re-testing is permitted)

        Exclusion Criteria:

          -  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.

          -  5. 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