Inclusion Criteria:
1. Patients must have histologically confirmed diagnosis of bone sarcoma (osteosarcoma, Ewing sarcoma of bone, chondrosarcoma or chordoma);
2. Patients with confirmed disease progression at study entry;
3. Metastatic disease not amenable to surgical resection or radiation with curative intent;
4. Patients must have measurable disease;
5. Prior treatment :
at least one, but no more than two prior chemotherapy regimen for metastatic disease for osteosarcoma, chondrosarcoma and Ewing sarcoma; neo-adjuvant /maintenance therapy are not counted towards this requirement. Chordoma not pretreated or with 1 or 2 prior (combination) chemotherapy regimen or with one or two prior molecularly targeted therapy, but no more than 2 prior lines of treatment (whatever the indication) can be included. At least 4 weeks since last chemotherapy (6 weeks in case of nitrosoureas and mitomycin C), immunotherapy or any other pharmacological treatment and/or radiotherapy;
6. Age ≥10 years for osteosarcomas, Ewing sarcomas and chondrosarcomas (for chordomas, patients must be ≥18 years);
7. Body Surface Area ≥1.30 m²;
8. Life expectancy of greater than 3 months;
9. Eastern Cooperative Oncology Group (ECOG) performance status \<2 (Karnofsky ≥60%) for adults patients;
10. Karnofsky scale ≥ 60% for children aged \>12 years old / Lansky scale ≥60% for children aged ≤12 years old;
11. Patients must have adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days of study treatment initiation: normal organ function as defined below:
* Absolute neutrophil count ≥1.5 Giga/L
* Platelets ≥100 Giga/L
* Hemoglobin ≥9 g/dL
* Serum creatinin ≤1.5 x upper limit of normal (ULN)
* Glomerular filtration rate (GFR) ≥30 ml/min/1.73 m² according to the modified Diet in Renal Disease (MDRD) abbreviated formula
* Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN
* 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 gamma-glutamyl transferase (GGT) tests must be performed; hepatic isoenzymes 5-nucleotidase must be within the normal range and/or GGT \<1.5 x ULN;
* lipase ≤1.5 x ULN;
* Spot urine must not show 1+ or more 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
12. International Normalized Ratio(INR)/ Partial Thromboplastin Time (PTT) ≤1.5 x ULN;
13. Recovery to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure related toxicity (except alopecia, anemia, and hypothyroidism);
14. Women of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy;
15. Women of childbearing potential must have a negative serum β-HCG pregnancy test within 7 days prior randomization and/or urine pregnancy test within 48 hours before the first administration of the study treatment;
16. Signed informed consent form by adult patients and/or patients parents/legal representatives (if age \<18 years) and age appropriate assent form by the patients' parents/legal representatives obtained before any study specific procedure is conducted;
17. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures;
18. Patients or parents/legal representatives affiliated to the Social Security System.
Exclusion Criteria:
1. Prior treatment with any VEGFR inhibitor;
2. Soft tissue sarcoma;
3. Other cancer (different histology) within 5 years prior to randomization;
4. Major surgical procedure, open biopsy, significant trauma, within the last 28 days before randomization;
5. Cardiovascular dysfunction:
* Left ventricular ejection fraction (LVEF) \<50%
* Congestive heart failure (New York Heart Association \[NYHA\]) ≥2
* Myocardial infarction \<6 months before study
* Cardiac arrhythmias requiring therapy
* Uncontrolled hypertension
* Unstable angina or new-onset angina
6. 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 randomization;
7. Severe hepatic impairment (Child-Pugh C);
8. Ongoing infection \> Grade 2 according to NCI-CTCAE v4.0;
9. Known history of human immunodeficiency virus (HIV) infection;
10. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy;
11. Difficulties with swallowing study tablets;
12. Prior anticancer therapy, including radiotherapy, endocrine therapy, immunotherapy, chemotherapy (CT) within the last 4 weeks (6 weeks for nitrosoureas and mitomycin C), or other investigational agents ; Concomitant antalgic palliative radiotherapy allowed;
13. Concurrent enrolment in another clinical trial in which investigational therapies are administered;
14. Known hypersensitivity to the active substance or to any of the excipients;
15. Pregnant women, women who are likely to become pregnant or are breast-feeding;
16. For adult patients, individual deprived of liberty or placed under the authority of a tutor;
17. 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;
18. Patients with history of non compliance to medical regimens or unwilling or unable to comply with the protocol;
19. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent;
20. Non-healing wound, non-healing ulcer, or non-healing bone fracture;
21. Patients with evidence or history of any bleeding diathesis, irrespective of severity;
22. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication;
23. Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks of study entry.
