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    Summary
    EudraCT Number:2022-002874-10
    Sponsor's Protocol Code Number:2022-3545
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-11-02
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2022-002874-10
    A.3Full title of the trial
    Phase Ib study of the combination of regorafenib with conventional chemotherapy for the treatment of newly diagnosed patients with multimetastatic Ewing sarcoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase Ib study of the combination of regorafenib with conventional chemotherapy for the treatment of newly diagnosed patients with multimetastatic Ewing sarcoma
    A.3.2Name or abbreviated title of the trial where available
    REGO-INTER-EWING1
    A.4.1Sponsor's protocol code number2022-3545
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGustave Roussy
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGustave Roussy
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGustave Roussy
    B.5.2Functional name of contact pointAqsa YAR
    B.5.3 Address:
    B.5.3.1Street Address114 Rue Edouard Vaillant
    B.5.3.2Town/ cityVillejuif
    B.5.3.3Post code94800
    B.5.3.4CountryFrance
    B.5.4Telephone number33142116717
    B.5.5Fax number33142116290
    B.5.6E-mailbpp.regulatory@gustaveroussy.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Stivarga 40 mg film-coated tablets.
    D.2.1.1.2Name of the Marketing Authorisation holderBayer AG 51368 Leverkusen Germany
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRegorafenib, stivarga
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Newly diagnosed patients with metastatic (other than lung/pleura metastases only) Ewing sarcoma
    E.1.1.1Medical condition in easily understood language
    Newly diagnosed patients with metastatic (other than lung/pleura metastases only) Ewing sarcoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the recommended Phase 2 dose (RP2D) of regorafenib in combination with standard backbone chemotherapy of VDC/IE in patients with newly diagnosed metastatic (other than lungs and/or pleura only) Ewing sarcoma.
    E.2.2Secondary objectives of the trial
    To assess the survival outcome (PFS, OS)
    To assess the toxicity of the combination of regorafenib and VDC/IE chemotherapy
    To evaluate the radiological response of primary tumor, regional lymph nodes and/or other metastases.
    To evaluate the primary tumor histological response
    Translational objectives:
    To identify predictive biomarkers for regorafenib therapy response
    To develop non-invasive liquid biopsies for monitoring tumor response and relapse
    To define biological mechanisms of regorafenib resistance and response
    To describe regorafenib pharmacokinetics in pediatric patients
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or round cell sarcomas which are ‘Ewing’s-like’ but negative for EWSR1 gene rearrangement
    2.Metastatic disease
    3.Age ≥2 years and <50 years (from second birthday to 49 years 364 days)
    4.Patient assessed as medically fit to receive the Ewing sarcoma standard multimodal treatment and regorafenib, including:
    - Absolute Neutrophil Count (ANC) ≥ 0.75x109/L, platelets ≥ 75x109/L.
    - Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 5×ULN
    - Bilirubin ≤ 2×ULN
    - Creatinine < 2x ULN or creatinine clearance >60 ml/min/1.73 m2
    - International normalized ratio (INR)/ Partial thromboplastin time (PTT). INR and PTT ≤ 1.5 x ULN. INR & PTT ≤ 1.5xULN
    5.Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) ≥50%) at baseline, as determined by echocardiography
    6.Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as: a BP <95th percentile for sex, age, and height at screening (as per National Heart Lung and Blood Institute [NHLBI] guidelines) and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1. Patients >18 years old should have BP ≤ 150/90 mm Hg.
    7.No prior treatment for Ewing sarcoma other than surgery
    8.Negative pregnancy test for female patients of childbearing potential within 7 days prior to study registration.
    9.Patient agrees to use highly effective contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where applicable
    10.Subject must be able to swallow and retain oral medication.
    11.Written informed consent from the patient and/or the parent/legal guardian, according to local, regional or national regulation prior to any study specific procedures.
    12.Patients must be affiliated to a social security system or beneficiary of the same, as per local regulatory requirements (France only)
    E.4Principal exclusion criteria
    1.Localized tumor or metastatic disease to lung/pleura only.
    2.Contra-indication to the Ewing sarcoma standard multimodal treatment
    3.Pregnant or breastfeeding women or intending to become pregnant during the study.
    4.Follow-up not possible due to social, geographic or psychological reasons
    5.Impairment of gastrointestinal (GI) function or GI disease that may significantly alter absorption of oral drugs
    6.A clinically significant ECG abnormality, including a marked prolonged QTcF interval (eg, a repeated demonstration of a QTcF interval >480 msec)
    Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality, unstable angina, active coronary artery disease and myocardial infarction within 6 months before randomization.) Uncontrolled hypertension (systolic pressure >150 mm Hg or diastolic pressure > 90 mm Hg on repeated measurement) despite optimal medical management
    7.Previous arterial or venous thromboembolisms Grade ≥ 3 per CTCAE v5.0
    8.Hypersensitivity to any active substance or to any excipients
    9.Radiographic evidence of encasement or invasion of a major blood vessel or of intratumoral cavitation
    10.Major surgical procedure or significant traumatic injury within 28 days before starting study treatment
    11.Non-healing wound, ulcer or bone facture.
    12.Interstitial lung disease with ongoing signs and symptoms.
    13.Any other medical or other condition that, in the opinion of the investigator(s), would preclude the subject’s participation in this clinical study
    E.5 End points
    E.5.1Primary end point(s)
    Dose-limiting toxicity (DLT):
    DLT will be defined as any of the following haematological and non-haematological events (CTCAE v5.0) that occur during the DLT assessment period (4 weeks after the start of treatment = cycle 1) and are at least possibly related (possibly, probably, or definitely) attributable to VDC/IE + regorafenib:
    -Any cardiac toxicity grade ≥ 3
    -Any grade 3 or 4 hematological or non-hematological toxicity leading to delay of start of next course by > 7 days (i.e: starting > day 21).
    -Any dose interruption or reduction due to toxicity, which results in administration of less than 80% of the planned dose of regorafenib or, 75% of the planned dose of chemotherapy.
    -Any grade 3 or 4 toxicity resulting in discontinuation of chemotherapy with regorafenib
    -Any grade 5 toxicity at least possibly related to study treatment (death)
    E.5.1.1Timepoint(s) of evaluation of this end point
    4 weeks after the start of treatment = cycle 1
    E.5.2Secondary end point(s)
    -Overall Survival (OS) and progression-free survival (PFS)
    -Adverse events and toxicity, defined by CTCAE v5.0
    -Histological response of the primary tumor to induction chemotherapy if surgery is performed as local control
    -Radiological response of primary tumor, regional lymph nodes and/or metastases
    Translational endpoints:
    -To analyze a validated novel 225 gene expression-based molecular risk-classifier Kinase Activity and Response in SARComa (KARSARC), which prospectively identifies long-term responders and survivors to MTKI therapy in sarcomas.
    -To analyze a pre-defined proteomics signature for regorafenib sensitivity, defined by kinase connectivity map (K-MAP) by mass spectrometry
    -To analyze the levels of circulating inflammatory cytokines and growth factors that are reported to be predictive of anti-angiogenic MTKI response in sarcomas and other cancers
    -Concentrations of regoragenib and its active metabolites M2 and M5
    E.5.2.1Timepoint(s) of evaluation of this end point
    4 weeks after the start of treatment = cycle 1
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase Ib
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 19
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 10
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 9
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 4
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 24
    F.4.2.2In the whole clinical trial 24
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    NONE
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-12-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-12-14
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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