Randomized Phase II/III Study of Cabozantinib Maintenance Versus Best Supportive Care in Osteosarcoma Patients After First‑Line Chemotherapy (FOSTER‑CabOS)
- Trial ID
- 2023-505575-69-01
- Protocol
- 2025/4106
- Sponsor
- Institut Gustave Roussy
Trial statistics
Diseases & Conditions
Objectives
The primary objectives of the FOSTER evolving study platform are to determine the 3‑year event‑free survival rate of the overall cohort across different treatment sequences and, within the FOSTER‑CabOS randomisation, to compare the efficacy of cabozantinib versus best supportive care as maintenance therapy after first‑line chemotherapy, assessing improvement in event‑free survival among patients achieving complete remission and in the combined population that includes those with residual stable disease.
Secondary objectives address feasibility, efficacy, safety and translational outcomes, including:
- Evaluation of feasibility and compliance with first‑line conventional chemotherapy.
- Estimation of the proportion of patients who are event‑free and alive after first‑line chemotherapy.
- Assessment of 3‑year overall survival and 5‑year event‑free survival for the cohort.
- Characterisation of treatment sequences in relation to survival outcomes and adverse events.
- Quality‑of‑life measurement using EORTC QLQ‑C30, PedsQL and the Toronto Extremity Salvage Score.
- Prognostic analysis of clinical and biological factors, including the G1/G2 RNA‑seq signature.
- Exploration of differences in survival between sequential regimens as new evidence emerges.
- Implementation of biological sample collection (tumor tissue, blood, plasma) for circulating tumor DNA and protein studies.
- Creation of an imaging repository for future radiological and radiomic research.
- Evaluation of imaging and novel biomarkers (minimally invasive plasma assays, radiomic MRI features) as prognostic tools.
- Application of artificial‑intelligence methods to improve lung‑nodule characterisation.
- Investigation of the impact of standard treatments on height velocity and growth‑plate morphology in pediatric patients.
- Comparison of detailed patient‑reported outcomes using PROMIS and the Body Image Scale.
- Facilitation of a broad European collaborative network for further research.
- Safety assessment of cabozantinib, particularly when combined with mifamurtide.
- Definition of the benefit‑risk ratio of cabozantinib versus control using the Q‑TWiST approach.
- Prognostic and predictive evaluation of clinical, radiological and biological factors for event‑free survival, including subgroup analyses based on disease status, histological response, G1/G2 signature, chemotherapy type, mifamurtide use, age and metastatic status.
- Assessment of cabozantinib’s effect on longitudinal growth, wound healing, postoperative complications, and overall growth biology.
- Analysis of cabozantinib efficacy/resistance according to the G1/G2 diagnostic signature.
- Investigation of circulating tumor DNA as a predictive biomarker of cabozantinib efficacy or resistance.
- Identification of tumor and tumor‑microenvironment resistance phenotypes by comparing diagnostic and relapse specimens.
- Evaluation of cabozantinib’s influence on growth‑plate maturation and morphology.
Participants
The sponsor did not provide the total number of enrolled participants. The trial enrolled patients of both sexes with a confirmed diagnosis of high‑grade osteosarcoma. Eligible individuals were aged 4 years and older, with no upper age limit, and were required to be medically fit for systemic therapy, having completed first‑line chemotherapy and local treatment. Inclusion required a performance status better than 2 (Karnofsky/Lansky >70), adequate cardiac function (LVEF ≥ 50 %), and laboratory values within predefined limits. Participants could be in complete remission or have stable residual disease after initial therapy. Both male and female patients, including vulnerable populations, were considered, provided they met the health and organ‑function criteria; no specific dietary or physical‑activity restrictions were stipulated.
Plans and Procedures
The study is a phase 5, randomized, double‑blind, controlled trial comparing oral cabozantinib tablets (20 mg, 40 mg, or 60 mg) with best supportive care as maintenance therapy after completion of first‑line chemotherapy for high‑grade osteosarcoma. Recruitment is planned to begin on 6 July 2026 and continue until 6 July 2034, with each participant followed for up to three years to assess event‑free survival from the time of randomisation. Study visits include an initial screening visit to confirm eligibility, a baseline visit on the day of randomisation, regular follow‑up visits during the maintenance phase (typically every four weeks for safety and efficacy assessments), and a final end‑of‑study visit at three years or at the occurrence of an event. The total duration of involvement for an enrolled participant therefore spans the screening period plus approximately three years of follow‑up.
Treatment
The experimental arm utilizes cabozantinib supplied as CABOMETYX film‑coated tablets in three dosage strengths (20 mg, 40 mg, and 60 mg). The tablets are administered orally once daily as maintenance therapy following completion of first‑line chemotherapy. Dose selection is based on the patient's tolerability and may be adjusted within the available strengths while maintaining the once‑daily schedule.
The comparator arm consists of best supportive care (BSC) provided according to institutional standards and includes symptom management, nutritional support, and routine follow‑up without additional anticancer agents.
All study medications are dispensed in labeled containers, and participants receive written instructions on timing and adherence. Study staff perform pill counts and review patient diaries at each study visit to monitor compliance. Dose modifications, interruptions, or discontinuations are documented according to predefined criteria, and any missed doses are recorded for subsequent analysis.
Efficacy
Efficacy will be primarily evaluated by Event‑free survival (EFS), defined as the time from diagnosis (for the evolving study platform) or from randomisation (for the CabOS randomisation) to the first occurrence of disease progression or relapse (local, regional, or distant), a second primary malignancy, or death from any cause. Events are recorded by investigator assessment and, when available, confirmed by central review. Patients without an event are censored at the date of last follow‑up. The 3‑year EFS rate will be estimated using Kaplan–Meier methods, and comparative analyses between treatment sequences or between cabozantinib and best supportive care will employ Cox proportional‑hazards models with multivariable adjustment and log‑rank tests.
Secondary efficacy outcomes include Overall survival (OS), measured from diagnosis to death from any cause, and the proportion of disease‑free patients assessed clinically and radiologically between 6 and 10 months after the start of first‑line chemotherapy. Quality of life and functional outcome are captured with the EORTC QLQ‑C30, PedsQL, and the Toronto Extremity Salvage Score (TESS) at predefined study visits. Additional exploratory efficacy analyses incorporate ctDNA, radiomics, and imaging‑based assessments of lung metastases, with data integrated into multivariable Cox models to explore prognostic associations.
Inclusion and Exclusion Criteria
Inclusion Criteria
- For FOSTER evolving study platform - 1. Newly diagnosed, biopsy-proven, high-grade osteosarcoma
- For FOSTER evolving study platform - 2. Patient considered medically fit to receive systemic treatment
- 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)
- 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-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).
Exclusion Criteria
- For FOSTER evolving study platform - 1. Low-grade osteosarcoma, parosteal or periosteal osteosarcoma , small cell osteosarcome
- 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) - 10. Dehydration according to NCI-CTC v5 Grade >1
- 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;
- 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;
- 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) - 18. Use of prohibited concomitant and/or concurrent medications (see section “Prohibited concomitant/concurrent treatments)
- 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) - 19. Pregnant or breastfeeding women or intending to become pregnant during the clinical investigation.
- 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) - 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) - 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) - 3. Cardiovascular dysfunction
- 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) - 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) - 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Yet Recruiting | 06 Jul 2026 | 15 |
 Finland | Not Yet Recruiting | 06 Jul 2026 | 9 |
 France | Recruiting | 06 Jul 2026 | 207 |
 Italy | Not Yet Recruiting | 06 Jul 2026 | 61 |
 The Netherlands | Not Yet Recruiting | 06 Jul 2026 | — |
 Poland | Not Yet Recruiting | 06 Jul 2026 | 20 |
 Spain | Not Yet Recruiting | 06 Jul 2026 | 90 |
 Sweden | Not Yet Recruiting | 06 Jul 2026 | 41 |
| Netherlands | — | — | 65 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CABOMETYX 60 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 60 | 12 | PRD4382746 |
CABOMETYX 20 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 60 | 12 | PRD4381882 |
CABOMETYX 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 60 | 12 | PRD4382703 |