Phase II, multicentre, randomised, open-label trial with MAP +/- denosumab regimen for the treatment of patients with metastatic osteosarcoma

Prior treatment

• Medical contraindications to the use of the drugs in the protocol
• Previous history or evidence of osteonecrosis of the jaw
• Cardiovascular disease with NYHA status >2. History of myocardial infarction less than 6 months prior to the start of treatment. Patients with unstable angina and severe life-threatening arrhythmia are excluded
• Medical history of arterial thrombotic or embolic events such as cerebrovascular infarctions (including transient ischaemic attacks - TIA) or pulmonary embolisms in the 6 months prior to the start of trial treatment
• Active or chronic hepatitis B or C requiring treatment with antiviral drugs
• Previous treatment with denosumab or other bisphosphonates

Other illness

• Known history of HIV infection
• Evidence of any serious or unstable medical, psychological, or social illness or condition that may compromise the patient's safety and/or compliance with participation in the trial or evaluation of results
• Known hypersensitivity to the trial drug or its class or to excipients present in the formulation of the trial drugs

Lab values

• Hypocalcaemia not controlled with oral calcium supplementation
• Known hypersensitivity to calcium or vitamin D

Other

• Dental contraindications to the use of denosumab
• Pregnancy and/or breastfeeding at the time of diagnosis
• Any situation that might jeopardise treatment compliance
• Subjects with known Central Nervous System metastases

• The patient (or his/her legal representative) must be able to read and understand the informed consent form and must provide his/her written informed consent prior to any trial-specific procedure
• Histologically confirmed diagnosis of high-grade metastatic osteosarcoma at onset
• Age ≥ 12 years (or having reached skeletal maturity) and ≤ 40 years
• ECOG Performance status ≤ 2 or Lansky/Karnofsky Score ≥ 40%.
• Adequate bone marrow function defined as follows: White blood cells >3.0 x 109/L, Absolute neutrophil count >1.5 x 109/L, Platelets >100 x 109/L, Haemoglobin > 9 g/d
• Adequate liver and kidney function defined as follows: Total bilirubin < 2 Upper Limit of Normality (LSN), AST (SGOT) <3.0 x LSN, ALT (SGPT) <3.0 x LSN, GGT <2.5 x LSN, Blood calcium ≥ 8.0 mg/dl and ≤ 11.5 mg/dl, Creatinine: Creatininemia < 1.5 mg/mL or creatinine clearance of 60 mL/min/1.73m2 for patients with creatinine levels above the normal limit
• Left Ventricular Ejection Fraction > 50%
• female patients of childbearing age must have a negative pregnancy test in the 7 days prior to the start of each chemotherapy cycle. Any post-menopausal women must have been amenorrhoeic for at least 12 months to be considered potentially infertile. Potentially fertile male and female patients must agree to use an effective method of contraception during the study