Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas
Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas
This is a randomized, double-blinded, 2 arms study concerning patients with bone sarcoma
 after the first line therapy.

 In the first arm, patients will be treated with regorafenib for a maximum of 12 months as
 maintenance therapy after first line therapy (chemotherapy and surgery), whereas in the
 second arm, patients will be treated with placebo (standard of care).

 The comparison between this two arms will allow to determine whether or not regorafenib is
 efficient for disease control, in terms of Relapse-Free Survival improvement.
Bone sarcomas are rare primary bone cancers, although, their frequency has been increasing by
 0.3% per year over the last decade. They include a very large number of tumour types
 belonging to the family of primary malignant bone tumours and originate from bone as
 Osteosarcomas (OS), Chondrosarcomas (CS), Fibrosarcomas, Chordomas, …

 Current conventional treatments for OS combine chemotherapy and surgery. Compared with
 surgery alone, multimodal treatment of high-grade sarcomas increases disease-free survival
 probabilities from only 10%-20% to 50-65% depending on the bone sarcoma type. In general,
 despite second-line treatment, the prognosis of recurrent disease has remained poor, with
 long-term post-relapse survival of <20%.

 The outcome of bone sarcoma has been dramatically improved by the addition of chemotherapy in
 the 70' and 80' but has remained remarkably stable in the last 3 decades, with a survival
 rate largely plateaued, despite introduction of novel regimens, both in localized and
 metastatic disease, in children and in adults. Primary bone cancer presented challenges in
 new drug development partly because of their rarity and heterogeneity. Thus, improving
 treatments for these diseases is a high priority, but advances have been few in recent years.
 In this context, maintenance therapy may be an interesting option as a way to prolong the
 benefit of first-line chemotherapy.

 Regorafenib may play a role in the maintenance setting for bone sarcomas (as improved
 Progression-Free Survival and sustained responses were observed in the REGOBONE study) in
 maintaining the initial response to chemotherapy and delaying the need for further treatment
 at relapse, while exerting a manageable associated toxicity and minimal negative impact on
 health-related quality of life.

 Currently there is no available agent used as maintenance therapy after first-line
 chemotherapy. In the context of a clinical trial with close monitoring, it is, thus,
 acceptable to consider a placebo-control group.

 On this basis, this study propose to conduct a double-blinded randomized controlled trial to
 evaluate the efficacy of regorafenib versus placebo in the treatment of patients with bone
 sarcomas, who have no evidence of disease after neoadjuvant and/or adjuvant chemotherapies.

 The main goal of the present study is then to explore whether sequential addition of
 regorafenib after completion of a standard induction chemotherapy in patients with bone
 sarcomas would improve outcomes in term of event-free-survival (EFS) defined by local or
 distant recurrence of the disease.

 Results will be stratified on the "high-risk" versus "low-risk" of relapse. As response to
 neoadjuvant chemotherapy and metastatic status at time of diagnosis are known to be important
 on patient's outcome, stratification will rely on a combined criteria taking into account
 these two factors. Thus, "high-risk" of relapse will be defined by the group of patients who
 are poor responders to neoadjuvant chemotherapy and/or in metastatic setting at diagnosis,
 whereas "low-risk" of relapse will be defined by the group of patients who have no metastatic
 disease at time of diagnosis and are good responders to neoadjuvant chemotherapy.
INCLUSION CRITERIA :

 I1. Age ≥ 16 years at the day of consenting to the study;

 I2. Patients must have histologically confirmed diagnosis of primary bone sarcoma of one of
 the following histotypes:

 -  OS (conventional-intramedullary/central high grade, small cell, telangiectatic or
 high-grade surface OS);

 -  Bone sarcomas other than Ewing sarcoma, chondrosarcoma and chordoma;

 I3. Availability of archival Formalin-Fixed Paraffin Embedded (FFPE) block.

 I4. Prior treatment for localized or metastatic disease for bone sarcoma must have been
 completed. It should include:

 -  Neoadjuvant chemotherapy with documented assessment of histological response

 -  Local procedure: Surgery (or radiotherapy if tumour is unresectable)

 -  Adjuvant chemotherapy (Nota Bene: patients with histotype different from OS may not
 have received adjuvant treatment) For OS, excepted from head and neck, neoadjuvant
 and/or adjuvant chemotherapy should include methotrexate-based regimen for patients <
 18 years old or anthracycline and cisplatin-based regimen for patients ≥ 18 years old.

 For head and neck OS, neoadjuvant and/or adjuvant chemotherapy should include adriamycin,
 cisplatin or ifosfamide-based regimen.

 For non-OS, neoadjuvant and/or adjuvant chemotherapy should include adriamycin and/or
 cisplatin-based regimen.

 I5. Recovery to 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);

 I6. Interval between the last chemotherapy administration and the date of randomisation :
 at least 4 weeks but no longer than 2 months;

 I7. Confirmed complete remission or no evidence of disease (for metastatic disease);

 Patients with pulmonary micro nodules can be included provided they do not meet the
 following criteria:

 -  At least one lung nodule of 10 mm or more

 -  And/or at least two nodules well limited between 6-9 mm

 -  And/or at least 5 nodules well limited of 5 mm or less All the other situations will
 be considered as doubtful lesions except in case of metastatic disease confirmed
 during the lung surgery of the residual lung lesions after pre-operative chemotherapy.
 If no other metastatic localisation is detected at the initial staging, the patient
 will be considered as localised disease and eligible for randomisation.

 I8. Life expectancy of greater than 12 months;

 I9. Karnofsky Performance status ≥ 70 (patients younger than 18-year old) or Eastern
 Cooperative Oncology Group (ECOG) performance status < 2 (adult patients) (Cf. appendix 2);

 I10. Patients must have adequate bone marrow, renal, and hepatic function, as evidenced by
 the following within 7 days of study treatment initiation :

 -  Absolute neutrophil count ≥ 1.5 Giga/l

 -  Platelets ≥ 100 Giga/l

 -  Haemoglobin ≥ 9 g/dl

 -  Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN)

 -  Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73m2 according to the Modified Diet in
 Renal Disease (MDRD) abbreviated formula

 -  Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5.0
 × ULN for patients with liver involvement of their cancer)

 -  Bilirubin ≤ 1.5 X ULN

 -  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 GGT
 tests must be performed; hepatic isoenzymes 5-nucleotidase must be within the normal
 range and/or Gamma-Glutamyltransferase (GGT) < 1.5 x ULN.

 -  Lipase ≤ 1.5 x ULN

 -  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;

 I11. 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;

 I12. Women of childbearing potential and male patients must agree to use adequate
 contraception (Appendix 4) for the duration of study participation and up to 8 weeks
 following completion of therapy;

 I13. Women of childbearing potential must have a negative serum β-Human Chorionic
 Gonadotropin (HCG) pregnancy test within 7 days prior randomization and/or urine pregnancy
 test within 48 hours before the first administration of the study treatment;

 I14. 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;

 I15. Patients must be willing and able to comply with scheduled visits, treatment plan,
 laboratory tests and other study procedures;

 I16. Patients covered by a medical insurance.

 EXCLUSION CRITERIA :

 E1. Prior treatment with any VEGFR inhibitor (thus, any prior exposure to sunitinib,
 sorafenib, pazopanib, bevacizumab, or other VEGFR inhibitor);

 E2. All soft tissue sarcomas (including but not limited to soft tissue osteosarcoma and
 Ewing soft tissue sarcoma), and Ewing sarcoma, chondrosarcoma and chordoma;

 E3. Prior history of other 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:

 -  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 (begun within the last 3 months
 prior to first study drug administration);

 E5. Uncontrolled hypertension (systolic blood pressure > 150 mm Hg or diastolic pressure >
 90 mm Hg despite optimal treatment);

 E6. 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;

 E7. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
 before the first study drug administration;

 E8. Ongoing infection > Grade 2 according to NCI-CTCAE v5;

 E9. Known history of human immunodeficiency virus (HIV) infection;

 E10. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral
 therapy;

 E11. Dehydration according to NCI-CTCAE v5 Grade > 1;

 E12. 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);

 E13. Patients with seizure disorder requiring medication;

 E14. Concurrent enrolment in another clinical trial in which investigational therapies are
 administered;

 E15. Known hypersensitivity to the active substance or to any of the excipients;

 E16. Pregnant women, women who are likely to become pregnant or are breast-feeding;

 E17. 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;

 E18. Patients with history of non-compliance to medical regimens or unwilling or unable to
 comply with the protocol;

 E19. Interstitial lung disease with ongoing signs and symptoms at the time of informed
 consent;

 E20. Non-healing wound, non-healing ulcer, or non-healing bone fracture;

 E21. Patients with evidence or history of any bleeding diathesis, irrespective of severity;

 E22. Any haemorrhage or bleeding event ≥ NCI-CTCAE v5 Grade 3 within 4 weeks prior to the
 first study drug administration;

 E23. 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;

 E24. Patients using prohibited concomitant and/or concurrent medications (see section
 "Prohibited concomitant/concurrent treatments");

 E25. Patients under tutorship or curatorship.