| Eligibility |
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 ß-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.
|
