Overview

This is a randomized, double-blinded, 2 arms study concerning patients with high-grade bone sarcoma (HGBS) without complete remission after standard treatment at diagnosis or first relapse.

In the first arm, patients will be treated with regorafenib + best supportive care (BSC) for a maximum of 12 months as maintenance therapy after standard line therapy completion, whereas in the second arm, patients will be treated with placebo + BSC (standard of care).

The comparison between this two arms will allow to determine whether or not regorafenib and BSC is efficient for disease control, in terms of Progression-Free Survival improvement.

Eligibility

INCLUSION CRITERIA:

I1. Age ≥ 12 years at the day of consenting to the study;

        I2. Patients must have histologically confirmed high-grade sarcomas of bone primary
        localisation, including but not limited to: Osteosarcomas, Ewing sarcomas, Chondrosarcomas,
        Undifferenciated Pleomorphic Sarcomas (UPS), Leiomyosarcomas (LMS) and Angiosarcomas
        I3. Measurable residual disease not amenable to resection after multimodal treatment
        principles either at diagnosis (after standard multimodal treatment based on the
        histological subtype) or at relapse (chemotherapy)
        I4. Non progressive disease (defined by the investigator according to the RECIST version
        1.1 Appendix 1) at study entry;
        I5. Interval between the date of last anticancer treatment (chemotherapy or surgery) and
        the date of randomization: at least 4 weeks but no longer than 2 months;
        I6. Life expectancy of greater than 6 months;
        I7. Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky ≥ 70%)
        (Appendix 2);
        I8. Adequate bone marrow and organ function defined by the following laboratory results:
        a. Bone marrow: i. Absolute neutrophil count ≥ 1.5 Giga/l ii. Platelets ≥ 100 Giga/l iii.
        Haemoglobin≥ 9 g/dl
        b. Hepatic function: i. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT)
        ≤ 2.5 x Upper Limit of Normal (ULN) (≤ 5.0 × ULN for patients with liver involvement of
        their cancer) ii. Bilirubin ≤1.5 X ULN iii. Alkaline phosphatase ≤ 2.5 x ULN (≤ 5 x ULN in
        patient with liver involvement of their cancer). If Alkaline phosphatase > 2.5 ULN, hepatic
        isoenzymes 5-nucleotidase or gamma-glutamyltransferase (GGT) tests must be performed;
        hepatic isoenzymes 5-nucleotidase must be within the normal range and/or GGT < 1.5 x ULN.
        c. Renal function: i. Serum creatinine ≤ 1.5 x ULN ii. Glomerular Filtration Rate (GFR) ≥
        30 ml/min/1.73m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula
        iii. Spot urine must not show ≥ 1 "+" protein in urine or the patient will require a repeat
        urine analysis. If repeat urinalysis shows 1 "+" protein or more, a 24-hour urine
        collection will be required and must show total protein excretion < 1000 mg/24 hours
        d. Coagulation: International Normalized Ratio (INR)/Partial Thromboplastin Time (PTT) ≤1.5
        x ULN; Patients who are therapeutically treated with an agent such as warfarin or heparin
        will be allowed to participate provided that no prior evidence of underlying abnormality in
        coagulation parameters exists. Close monitoring of at least weekly evaluations will be
        performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the
        local standard of care;
        e. Pancreatic function: Lipase ≤ 1.5 x ULN
        I9. Recovery to anticancer-treatment related NCI-CTCAE v5 Grade 0 or 1 level or recovery to
        baseline preceding the prior treatment from any previous drug/procedure related toxicity
        (except alopecia, anaemia, and hypothyroidism);
        I10. Women of childbearing potential and male patients must agree to use adequate
        contraception (including at least the use of condoms) for the duration of treatment and for
        7 months (210 days) in women of childbearing potential or 4 months (120 days) in men
        sexually active with women of childbearing potential after the last dose of regorafenib
        I11. Patients, and their parents when applicable, must sign and date an informed consent
        document indicating that they have been informed of all the pertinent aspects of the trial
        prior to enrolment;
        I12. Patients must be willing and able to comply with scheduled visits, treatment plan,
        laboratory tests and other study procedures;
        I13. Patients affiliated to the Social Security System
        I14. Body Surface Area (BSA) ≥ 1.30m² at the time of consenting to the study
        EXCLUSION CRITERIA:
        E1. Prior treatment with any VEGFR inhibitor (thus, any prior exposure to regorafenib,
        sunitinib, sorafenib, pazopanib, bevacizumab, or other VEGFR inhibitor);
        E2. All soft tissue sarcomas (including but not limited to soft tissue osteosarcoma), and
        chordomas;
        E3. Prior history of malignancies other than study disease (except for basal cell or
        squamous cell carcinoma of the skin or carcinoma in situ of the cervix) within 3 years
        prior to randomization;
        E4. Cardiovascular dysfunction defined by:
          -  Left ventricular ejection fraction (LVEF) < 50%,
          -  Congestive heart failure ≥ New York Heart Association (NYHA) class 2,
          -  Myocardial infarction < 6 months prior to first study drug administration,
          -  Cardiac arrhythmias requiring therapy (beta blockers or digoxin are permitted),
          -  Unstable (angina symptoms at rest) or new-onset angina within the last 3 months prior
             to first study drug administration;
          -  Uncontrolled hypertension (systolic blood pressure > 150 mm Hg or diastolic pressure >
             90 mm Hg despite optimal treatment);
          -  Arterial or venous thrombotic or embolic events such as cerebrovascular accident
             (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism
             within the last 6 months before the first study drug administration;
        E5. Major surgical procedure, open biopsy or significant traumatic injury within 28 days
        before the first study drug administration;
        E6. Ongoing infection > Grade 2 according to NCI-CTCAE v5;
        E7. Known history of human immunodeficiency virus infection;
        Nota Bene: Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to
        participate in the study if they meet the following criteria :
          1. No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic
             infection within the past 12 months prior to enrolment;
          2. No history of AIDS-defining cancers (e.g. Kaposi's sarcoma, aggressive B-cell lymphoma
             and invasive cervical cancer);
          3. Subjects should be on established anti-retroviral therapy for at least 4 weeks and
             have an HIV viral load of < 400 copies/mL prior to enrolment;
        E8. Active or chronic hepatitis B or C requiring treatment with antiviral therapy; Nota
        Bene: Subjects with a history of hepatitis B or C who have normal alanine aminotransferase
        (ALT) and are hepatitis B surface antigen negative and/or have undetectable HCV RNA are
        eligible
        E9. Dehydration according to NCI-CTCAE v5 Grade >1;
        E10. Difficulties to swallow oral medication and/or any mal-absorption condition and/or any
        Gastrointestinal (GI) disease that may significantly alter the absorption of regorafenib
        (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption
        syndrome, or small bowel resection);
        E11. Patients with seizure disorder requiring medication;
        E12. Concurrent enrolment in another clinical trial in which investigational therapies are
        administered;
        E13. Known hypersensitivity to the active substance or to any of the excipients;
        E14. Pregnant women, women who are likely to become pregnant or are breast-feeding. Women
        of childbearing potential must have a negative serum β-Human Chorionic Gonadotropin (HCG)
        pregnancy test within 7 days prior randomization;
        E15. Patients with any psychological, familial, sociological or geographical condition
        potentially hampering compliance with the study protocol and follow-up schedule; those
        conditions should be discussed with the patient before registration in the trial;
        E16. Patients with history of non-compliance to medical regimens or unwilling or unable to
        comply with the protocol;
        E17. Interstitial lung disease with ongoing signs and symptoms at the time of informed
        consent;
        E18. Non-healing wound, non-healing ulcer, or non-healing bone fracture;
        E19. Patients with evidence or history of any bleeding diathesis, irrespective of severity;
        E20. Any haemorrhage or bleeding event ≥ CTCAE v5 Grade 3 within 4 weeks prior to the first
        study drug administration;
        E21. Clinically significant unrelated systemic illness (e.g., serious infection or
        significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise
        the patient's ability to tolerate study treatment or would likely interfere with study
        procedures or results;
        E22. Patients using prohibited concomitant and/or concurrent medications (see section
        "Prohibited concomitant/concurrent treatments);
        E23. Patients under tutorship or curatorship.