Fight Osteosarcoma Through European Research evolving study platform from diagnosis to relapse (FOSTER evolving study platform)

Prior treatment

• For FOSTER-CabOS (first randomization) - 18. Use of prohibited concomitant and/or concurrent medications (see section “Prohibited concomitant/concurrent treatments)
• For FOSTER-CabOS (first randomization) - 2. Prior treatment with any Vascular Endothelial Growth Factor (VEGFR) inhibitor (thus, any prior exposure to sunitinib, sorafenib, pazopanib, regorafenib, bevacizumab, or other VEGFR inhibitor);
• For FOSTER-CabOS (first randomization) - 9. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy;
• For FOSTER-CabOS (first randomization) - 5. 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;
• For FOSTER-CabOS (first randomization) - 6. Major surgical procedure or significant traumatic injury within 3 weeks before the first study drug administration. Note: Adequate wound healing after major surgery must be clinically assessed, independent of time elapsed for eligibility.
• For FOSTER-CabOS (first randomization) - 7. Ongoing infection > Grade 2 according to NCI-CTCAE v5, unless fully recovered prior cycle1 day1;
• For FOSTER-CabOS (first randomization) - 16. Any haemorrhage or bleeding event ≥ CTCAE v5 Grade 3 within 4 weeks prior to the first study drug administration;

Other illness

• For FOSTER-CabOS (first randomization) - 17. 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;
• For FOSTER-CabOS (first randomization) - 1. Progressive disease at any site during initial pre- and/or post-operative chemotherapy, confirmed before randomisation time. With exception of patients with progressive disease limited to the primary tumour during pre-operative chemotherapy, if complete resection is achieved at surgery.
• For FOSTER-CabOS (first randomization) - 20. 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
• For FOSTER-CabOS (first randomization) - 21. Patients with history of non-compliance to medical regimens or unwilling or unable to comply with the protocol.
• For FOSTER-CabOS (first randomization) - 4. Uncontrolled hypertension > the 95th percentile despite optimal treatment (for adults, systolic blood pressure > 150mmHg or diastolic pressure > 90 mmHg despite optimal treatment)
• For FOSTER-CabOS (first randomization) - 8. Known history of human immunodeficiency virus (HIV) infection;
• For FOSTER-CabOS (first randomization) -23. Known hypersensitivity to the active substance Investigational Medicinal Product or to any of the excipients
• For FOSTER-CabOS (first randomization) - 11. Difficulties to swallow oral medication and/or any malabsorption condition and/or any Gastrointestinal (GI) disease that may significantly alter the absorption of cabozantinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel resection);
• For FOSTER-CabOS (first randomization) - 12. Patients with a seizure disorder requiring medication;
• For FOSTER-CabOS (first randomization) - 13. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent;
• For FOSTER-CabOS (first randomization) - 14. Non-healing wound, non-healing ulcer, or non-healing bone fracture
• For FOSTER-CabOS (first randomization) - 15. Patients with evidence or history of any bleeding diathesis, irrespective of severity;

Other

• For FOSTER evolving study platform - 1. Low-grade osteosarcoma, parosteal or periosteal osteosarcoma , small cell osteosarcome
• For FOSTER-CabOS (first randomization) - 19. Pregnant or breastfeeding women or intending to become pregnant during the clinical investigation.
• For FOSTER-CabOS (first randomization) - 22. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent
• For FOSTER-CabOS (first randomization) - 3. Cardiovascular dysfunction
• For FOSTER-CabOS (first randomization) - 10. Dehydration according to NCI-CTC v5 Grade >1

• For FOSTER evolving study platform - 1. Newly diagnosed, biopsy-proven, high-grade osteosarcoma
• For FOSTER-CabOS (first randomization) - 5. Performance status < 2 for patient adult, or >70 using Karnofsky or Lansky performance scores.
• For FOSTER-CabOS (first randomization) - 6. Interval between the last treatment either chemotherapy administration or surgical procedures or radiotherapy or thermoablation, (whichever occurred last) and the date of randomisation should be at least 4 weeks but no longer than 2 months
• For FOSTER-CabOS (first randomization) - 7. Disease in complete remission or with residual persistent stable disease according to RECIST criteria before randomisation (please refer 7.3.4 for the definition of the residual persistent stable disease)
• For FOSTER-CabOS (first randomization) - 8. Patient fit to undergo protocol treatment and follow-up
• For FOSTER-CabOS (first randomization) -9. Adequate cardiac function: Left Ventricular Ejection Fraction (LVEF) ≥50% and/or fractional shortening (FS) >28% at baseline as determined by echocardiography or multigated acquisition (MUGA) scan (performed only if echocardiography is not feasible)
• For FOSTER-CabOS (first randomization) - 10. Adequately controlled blood pressure (BP) with or without antihypertensive medications: BP 95th percentile for sex, age and height/length at screening (as per NHLBI (National Heart, Lung and Blood Institute) guidelines) and no change in antihypertensive medications within 1 week prior to start of treatment (C1D1). Patients aged >18 years should have a BP ≤150/90 mmHg at screening and no change in antihypertensive therapy within 1 week prior to C1D1
• For FOSTER-CabOS (first randomization) - 11. Screening laboratory values must meet the following criteria (according to CTCAE v5) and should be obtained within 7 days prior to randomisation - Absolute neutrophil count ≥ 1 x 109/L - Platelets ≥ 100 x 109/L - Haemoglobin ≥ 8.0 g/dL (a hemoglobin of less than 8.0 g/dl is acceptable if it is corrected by growth factor or transfusion before C1D1) - Serum creatinine ≤ 1.5 x ULN or based on age/gender. If serum creatinine is greater than maximum serum creatinine for age/gender as described, then creatinine clearance (or radioisotope Glomerular Filtration Rate (GFR)) must be >60 ml/min/1.73 m2 - Urine dipstick < 2+ for proteinuria. Patients who have ≥2+ proteinuria on dipstick urinalysis should undergo a spot Protein/Creatinine ratio test that should be grade 2 per CTCAE v5.0 - No clinical evidence of nephrotic syndrome - Alanine Aminotransferase/Aspartate Aminotransferase (ALT/AST) ≤ 2.5 x Upper limit of normal (ULN) in the absence of liver metastases or ≤ 5.0 x ULN in the presence of liver metastases - Total bilirubin ≤ 1.5 x ULN (except Gilbert Syndrome: < 3.0 mg/dL) or ≤ 5.0 x ULN in the presence of liver metastases - Alkaline phosphatase (PAL) ≤2.5 x ULN (≤5 x ULN in patient with liver involvement of their cancer). If Alkaline phosphatase > 2.5 ULN, Gamma-Glutamyl Transferase GGT tests must be performed; GGT < 1.5 x ULN - Lipase ≤1.5 x ULN - INR (International Normalized Ratio) /PTT (Partial Thromboplatin Time) ≤1.5 x ULN
• For FOSTER-CabOS (first randomization) - 12. Patients who are therapeutically treated with an agent such as warfarin or heparin/ Low-molecular-weight heparin (LMWH) will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists.
• For FOSTER-CabOS (first randomization) - 13. Women of childbearing potential or young women of chilbearing potential and who started their puberty (menarche) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of Human Chorionic Gonadotropin (HCG)) done within 7 days prior to randomisation.
• For FOSTER-CabOS (first randomization) - 14.Effective methods of contraception should be used by male and female patients and their partners during therapy, and for at least 4 months after completing therapy. Because oral contraceptives might not be considered as “effective methods of contraception”, they should be used together with another method, such as a barrier method, according to age and gynaecologist advice.
• For FOSTER evolving study platform - 2. Patient considered medically fit to receive systemic treatment
• For FOSTER-CabOS (first randomization) - 15. Provision of dated and signed written informed consent for the randomised trial prior to any study specific procedures, sampling and analyses.
• For FOSTER-CabOS (first randomization) - 16. Affiliation to a social insurance or equivalent regimen (if required in the country).
• For FOSTER evolving study platform - 3. Planned systemic therapy according to national guidelines and age
• For FOSTER evolving study platform - 4. Written informed consent from patients and/or their parents/ guardians before enrolment and any study-related procedure.
• For FOSTER evolving study platform - 5. Affiliation to a social insurance or equivalent regimen (if required in the country)
• For FOSTER-CabOS (first randomization)- 1. Patient with a histologically proven and confirmed high-grade osteosarcoma, according to the criteria described in the last World Health Organization (WHO) classification of Soft Tissue and Bone Tumours, after the exclusion of all potential differential diagnoses, either by local pathologists with expertise in bone sarcomas, or through centralized revision in a referral centre, according to national rules.
• For FOSTER-CabOS (first randomization) - 2. Age ≥ 4 years old (when able to swallow tablet) ; no upper age limit
• For FOSTER-CabOS (first randomization) - 3. First line systemic and local treatment of primary tumour (and metastasis when present) for localised or metastatic osteosarcoma must have been completed according to national guidelines (Mifamurtide is allowed according to centre’s practices)
• For FOSTER-CabOS (first randomization) - 4. Recovery to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5 Grade 0 or 1 level or recovery to baseline health status preceding the prior treatment from any previous drug/procedure related toxicity (except alopecia, anaemia, and hypothyroidism)