A Phase II Study Evaluating Efficacy and Safety of Regorafenib in Patients With Metastatic Bone Sarcomas

Prior treatment

• Prior treatment with any VEGFR inhibitor;
• Other cancer (different histology) within 5 years prior to randomization;
• Major surgical procedure, open biopsy, significant trauma, within the last 28 days before randomization;
• 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;
• Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy;
• 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;
• Concurrent enrolment in another clinical trial in which investigational therapies are administered;
• Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication;

Other illness

• Severe hepatic impairment (Child-Pugh C);
• Ongoing infection \> Grade 2 according to NCI-CTCAE v4.0;
• Known history of human immunodeficiency virus (HIV) infection;
• Known hypersensitivity to the active substance or to any of the excipients;
• 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;
• Patients with history of non compliance to medical regimens or unwilling or unable to comply with the protocol;
• Interstitial lung disease with ongoing signs and symptoms at the time of informed consent;
• Non-healing wound, non-healing ulcer, or non-healing bone fracture;
• Patients with evidence or history of any bleeding diathesis, irrespective of severity;

Lab values

• 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

Other

• Soft tissue sarcoma;
• Difficulties with swallowing study tablets;
• Pregnant women, women who are likely to become pregnant or are breast-feeding;
• For adult patients, individual deprived of liberty or placed under the authority of a tutor;
• Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks of study entry.

• Patients must have histologically confirmed diagnosis of bone sarcoma (osteosarcoma, Ewing sarcoma of bone, chondrosarcoma or chordoma);
• Patients with confirmed disease progression at study entry;
• Metastatic disease not amenable to surgical resection or radiation with curative intent;
• Patients must have measurable disease;
• 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;
• Age ≥10 years for osteosarcomas, Ewing sarcomas and chondrosarcomas (for chordomas, patients must be ≥18 years);
• Body Surface Area ≥1.30 m²;
• Life expectancy of greater than 3 months;
• Eastern Cooperative Oncology Group (ECOG) performance status \<2 (Karnofsky ≥60%) for adults patients;
• Karnofsky scale ≥ 60% for children aged \>12 years old / Lansky scale ≥60% for children aged ≤12 years old;
• 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
• International Normalized Ratio(INR)/ Partial Thromboplastin Time (PTT) ≤1.5 x ULN;
• 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);
• 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;
• 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;
• 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;
• Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures;
• Patients or parents/legal representatives affiliated to the Social Security System.