Randomized, Double-Blind, Placebo-Controlled Study of Regorafenib as Maintenance Therapy in Patients with Bone Sarcomas Post First-Line Treatment

Trial ID: 2024-514637-37-00
Protocol: ET18-272
Sponsor: Centre Leon Berard

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Diseases & Conditions

Bone sarcoma

Objectives

The primary objective of this study is to compare the **antitumor efficacy** of regorafenib versus placebo as maintenance treatment in patients with bone sarcomas. This is clinically relevant as it aims to determine the potential benefit of regorafenib in prolonging disease-free survival in patients who have no residual disease after their standard treatment sequence, potentially improving long-term outcomes.

Secondary objectives include:

Time to Treatment Failure (TTF), which assesses the duration until the treatment is deemed ineffective.
Overall Survival, evaluating the length of time from the start of treatment until death from any cause.
Quality of Life, measured using the EORTC QLQ-C30 questionnaire, to assess the impact of treatment on patients' well-being.
Safety profile, using the NCI-CTC AE version 5, to monitor adverse events and ensure patient safety.
Compliance to study treatment, to evaluate adherence to the prescribed treatment regimen.

Participants

The clinical trial involves participants diagnosed with **bone sarcomas** other than chordoma, who have no residual disease following their standard treatment regimen. The study population includes both male and female subjects aged 12 years and older. Participants are required to have a life expectancy of more than 12 months and must demonstrate adequate bone marrow, renal, and hepatic function. The trial does not include a vulnerable population. The selection criteria emphasize the necessity for participants to have completed prior treatment for localized or metastatic bone sarcoma, with a confirmed complete remission or no evidence of disease. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations. Key inclusion criteria include a histologically confirmed diagnosis of primary bone sarcoma and a body surface area of at least 1.30 m² at the time of consenting to the study.

Plans and Procedures

The clinical trial is designed as a **randomized**, **placebo-controlled**, **double-blind** study to evaluate the efficacy and safety of **regorafenib** as maintenance therapy in patients with bone sarcomas. The trial will span an estimated duration from February 11, 2020, to February 11, 2027. Participants will be randomly assigned to receive either regorafenib or a placebo, with the primary objective being to compare the antitumor efficacy of regorafenib versus placebo. The primary endpoint is Relapse-Free Survival (RFS), assessed according to RECISTv1.1, with events defined as the recurrence of the disease, either local or distant.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are confirmed, including age, histologically confirmed diagnosis of primary bone sarcoma, and completion of prior treatment. Participants must have a life expectancy greater than 12 months and adequate bone marrow, renal, and hepatic function. Following the screening, participants will undergo regular follow-up visits to monitor treatment efficacy and safety, with assessments including laboratory tests and imaging studies. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any adverse events.

Participant involvement is expected to last up to 12 months, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial is not categorized as low intervention and is conducted in multiple centers, ensuring a comprehensive evaluation of regorafenib's role in maintaining remission in bone sarcoma patients. The study adheres to rigorous ethical standards, requiring informed consent from all participants and, where applicable, their guardians.

Treatment

The clinical trial involves the administration of **regorafenib**, marketed under the product name BAY 73-4506, as the experimental medication. Regorafenib is provided in the form of a **film-coated tablet** and is intended for **oral use**. The maximum daily dose is 120 mg, with a total maximum dose of 43,800 mg over a treatment period of up to 12 months. The active substance, regorafenib, is of chemical origin and is manufactured by Bayer Healthcare AG. The dosing schedule is designed to ensure consistent administration, and participant compliance will be monitored throughout the study to maintain the integrity of the trial data.

The study also includes a **placebo** group, which will receive tablets identical in appearance to the regorafenib tablets. The placebo is referred to as the IMP Stivarga 40 mg film-coated tablets. These tablets are also administered orally, following the same dosing schedule as the experimental group. The use of a placebo is critical in maintaining the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias and enhancing the reliability of the study outcomes.

Efficacy

The efficacy of regorafenib as a maintenance therapy in patients with bone sarcomas will be assessed in this clinical trial. The primary endpoint for evaluating efficacy is **Relapse-Free Survival (RFS)**, which will be assessed according to RECISTv1.1 criteria. An event in this context is defined as the recurrence of the disease, either local or distant, as determined by the investigational staff at each site. The trial is designed as a randomized, placebo-controlled, double-blinded, multicentre study, ensuring a robust evaluation of the treatment's efficacy. The assessment of RFS will be conducted locally by the investigational staff, who will monitor for any signs of disease recurrence throughout the study period.

Inclusion and Exclusion Criteria

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Inclusion Criteria

I1. Age ≥ 12 years at the day of consenting to the study;
I2. Patients must have histologically confirmed diagnosis of primary bone sarcoma including but not limited to: Osteosarcomas, Ewing sarcomas, Chondrosarcomas, Undifferentiated Pleomorphic Sarcomas (UPS), Leiomyosarcomas (LMS) and Angiosarcomas;
I3. Prior treatment for localized or metastatic disease for bone sarcoma must have been completed, consisting of a standard multimodal treatment based on the histological subtype: For OS, (excepted head and neck localisations), neoadjuvant and/or adjuvant chemotherapy should include methotrexate-based regimen for patients < 18 years old; patients ≥ 18 years old may have received either methotrexate-based regimen or anthracycline and cisplatin-based regimen For head and neck OS, neoadjuvant and/or adjuvant chemotherapy should include adriamycin, cisplatin or ifosfamide-based regimen. For non-OS, neoadjuvant and/or adjuvant chemotherapy should include adriamycin and/or cisplatin-based regimen.
I4. Retour à un grade 0 ou 1 de la classification NCI-CTCAE v5 ou retour à l’état initial avant le dernier traitement ou la dernière procédure (à l’exception de l’alopécie, l’anémie et l’hypothyroïdie)
I5. Interval between the last chemotherapy administration and the date of randomisation: at least 4 weeks but no longer than 2 months;
I6. Confirmed complete remission or no evidence of disease (for metastatic disease); Patients with pulmonary micro nodules can be included provided they do not meet the following criteria: • At least one lung nodule of 10mm or more• And/or at least two nodules well limited between 6-9mm • And/or at least 5 nodules well limited of 5mm or less All the other situations will be considered as doubtful lesions except in case of metastatic disease confirmed during the lung surgery of the residual lung lesions after pre-operative chemotherapy. If no other metastatic localisation is detected at the initial staging, the patient will be considered as localised disease and eligible for randomisation.
I7. Life expectancy of greater than 12 months;
I8. Karnofsky Performance status ≥70 (patients younger than 18-year old) or ECOG performance status < 2 (adult patients) ;
I9. Patients must have adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days of study treatment initiation: - Absolute neutrophil count ≥ 1.5 Giga/l - Platelets ≥ 100 Giga/l - Haemoglobin≥ 9 g/dl - Serum creatinine ≤ 1.5 x ULN - Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula - AST and ALT ≤2.5 x ULN ( ≤5.0 × ULN for patients with liver involvement of their cancer) - 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 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 “+”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
I10. INR/PTT ≤1.5 x ULN; Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care;
I11. Women of childbearing potential and male patients must agree to use adequate contraception (Appendix 4) for the duration of treatment and for 7 months (210 days) in WOCBP or 4 months (120 days) in men sexually active with WOCBP after the last dose of regorafenib;
I12. 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;
I13. Patients, and their parents when applicable, must sign and date an informed consent document indicating that they have been informed of all the pertinent aspects of the trial prior to enrolment;
I14. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures;
I15. Patients covered by a medical insurance.
I16. Body Surface Area (BSA) ≥ 1.30m² at the time of consenting to the study.

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Exclusion Criteria

E1. Prior treatment with any VEGFR inhibitor (thus, any prior exposure to sunitinib, sorafenib, pazopanib, bevacizumab, or other VEGFR inhibitor);
E2. All soft tissue sarcomas (including but not limited to soft tissue osteosarcomas and Ewing soft tissue sarcomas) and chordomas;
E3. Prior history of other malignancies other than study disease (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) within 3 years prior to randomization;
E4. Cardiovascular dysfunction: • Left ventricular ejection fraction (LVEF) < 50%, • Congestive heart failure ≥ New York Heart Association (NYHA) class 2, • Myocardial infarction < 6 months prior to first study drug administration, • Cardiac arrhythmias requiring therapy (beta blockers or digoxin are permitted), • Unstable (angina symptoms at rest) or new-onset angina within the last 3 months prior to first study drug administration;
E5. Uncontrolled hypertension (systolic blood pressure > 150mmHg or diastolic pressure > 90 mmHg despite optimal treatment);
E6. 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;
E7. Major surgical procedure, open biopsy or significant traumatic injury within 28 days before the first study drug administration;
E8. Ongoing infection > Grade 2 according to NCI-CTCAE v5;
E9. Known history of human immunodeficiency virus (HIV) infection; Nota Bene: Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate in the study if they meet the following criteria: a. No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months prior to enrolment; b. No history of AIDS-defining cancers (e.g. Kaposi’s sarcoma, aggressive B-cell lymphoma and invasive cervical cancer); c. Subjects should be on established anti-retroviral therapy for at least 4 weeks and have an HIV viral load of < 400 copies/mL prior to enrolment
E10. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy; Nota Bene: Subjects with a history of hepatitis B or C who have normal alanine aminotransferase (ALT) and are hepatitis B surface antigen negative and/or have undetectable HCV RNA are eligible;
E11. Dehydration according to NCI-CTC v5 Grade >1;
E12. Difficulties to swallow oral medication and/or any mal-absorption condition and/or any Gastrointestinal (GI) disease that may significantly alter the absorption of regorafenib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel resection);
E13. Patients with seizure disorder requiring medication;
E14. Concurrent enrolment in another clinical trial in which investigational therapies are administered;
E15. Known hypersensitivity to the active substance or to any of the excipients;
E16. Pregnant women, women who are likely to become pregnant or are breast-feeding
E17. 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;
E18. Patients with history of non-compliance to medical regimens or unwilling or unable to comply with the protocol;
E19. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent;
E20. Non-healing wound, non-healing ulcer, or non-healing bone fracture;
E21. Patients with evidence or history of any bleeding diathesis, irrespective of severity;
E22. Any haemorrhage or bleeding event ≥ CTCAE v5 Grade 3 within 4 weeks prior to the first study drug administration;
E23. 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;
E24. Patients using prohibited concomitant and/or concurrent medications (see section “Prohibited concomitant/concurrent treatments);
E25. Patients under tutorship or curatorship.