Efficacy of Regorafenib Combined With Best Supportive Care as Maintenance Treatment in High Grade Bone Sarcomas Patients

This is a multicenter phase II study.

Patients with evaluable unresectable residual disease will be accrued after they completed standard of care, consisting of:

• At diagnosis: standard multimodal treatment based on histological subtype
• At relapse: chemotherapy

Patients who meet the eligibility criteria will receive regorafenib + best supportive care (BSC) as maintenance treatment for a maximum 12 months period.

After their eligibility has been confirmed, patients will receive regorafenib until disease progression, or for a maximum of 12 months, or unacceptable toxicity or willingness to stop, whichever occurs first.

After the completion of the maintenance therapy (12 months) patients will be followed-up until the first radiological disease progression, unless a premature disease progression occurred. All patients will be followed-up until the data cut-off (12 months after the last inclusion).

The vital status will be updated once for all patients at 24 months after the last inclusion, based on patient's medical file.

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. Evaluable 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 start date of regorafenib: 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 :

• No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months prior to enrolment;
• No history of AIDS-defining cancers (e.g. Kaposi's sarcoma, aggressive B-cell lymphoma and invasive cervical cancer);
• 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.