Phase II Randomized, Placebo-Controlled Study on Regorafenib Efficacy and Safety in Metastatic Bone Sarcomas

Trial ID: 2024-513455-33-00
Protocol: UC-0150/1309
Sponsor: Unicancer

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Diseases & Conditions

Chondrosarcoma metastatic Osteosarcoma metastatic Chordoma Ewing's sarcoma metastatic

Objectives

The primary objective of this study is to evaluate the **antitumour activity** of regorafenib in patients with metastatic **bone sarcoma**. This assessment is conducted according to RECIST 1.1 criteria, based on a central radiological review. The clinical relevance of this objective lies in determining the efficacy of regorafenib as a potential therapeutic option for this patient population, which could lead to improved treatment outcomes.

Secondary objectives include:

Progression-free survival (PFS) according to RECIST 1.1 criteria.
Objective response rate, defined as complete response (CR) or partial response (PR) according to RECIST V 1.1 for all cohorts, and CHOI criteria for chordomas.
Overall survival, defined as the time from the date of randomization or start of treatment for cohort E to the date of death due to any cause.
Duration of response.
Disease control rate at 6 months, defined as the proportion of patients with a best response rating of CR, PR, or stable disease (SD) according to RECIST guidelines 1.1, with SD lasting at least 8 weeks.
Progression-free rates at 3 and 6 months (PFR-3 and PFR-6), and time to progression.
Treatment safety assessed using the NCI CTC-AE version 4.0.
Growth Modulation Index (GMI).
Identification and characterization of biomarkers.
Time to progression, measured from the date of randomization or start of treatment for cohort E until the date of first observation of progression.
Pain assessment for chordomas.
Progression-free survival according to CHOI criteria for chordomas.
Description of the untreated population registered in the study.

Participants

The clinical trial involves a study population diagnosed with **bone sarcoma**, specifically focusing on individuals with CIC-rearranged sarcoma. The trial includes both male and female participants, with an age range starting from 10 years and above. The participants are required to have a life expectancy of greater than three months and an ECOG performance status of less than 2, indicating a relatively stable general health status. The trial population was selected based on specific inclusion criteria, including a histologically and molecularly confirmed diagnosis, adequate organ function, and measurable disease as per RECIST V1.1 criteria. Participants must have experienced disease progression and have undergone no more than three prior chemotherapy regimens for metastatic or locally advanced disease. The trial also considers lifestyle factors such as the ability to comply with scheduled visits and treatment plans. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of **regorafenib** in patients with metastatic bone sarcomas. The trial aims to investigate the antitumor activity of regorafenib according to RECIST 1.1 criteria based on central radiological review. The study is expected to conclude by September 30, 2026, with recruitment having commenced on September 24, 2014. Participants will be involved in the study for a maximum treatment period of six months, with the primary efficacy endpoint being the non-progression rate at specified time points for different sarcoma types.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, involves confirming the diagnosis of CIC-rearranged sarcoma and assessing eligibility based on criteria such as adequate organ function and performance status. Follow-up visits are scheduled to monitor disease progression, treatment response, and any adverse events. The end-of-study visit will evaluate the overall outcomes and gather final data on the primary and secondary endpoints, including progression-free survival and overall survival.

Participants are expected to comply with scheduled visits, treatment plans, and laboratory tests throughout the study duration. Conditions that may lead to early termination from the study include significant disease progression, unacceptable toxicity, or withdrawal of consent. The trial's design ensures rigorous assessment of regorafenib's therapeutic potential in treating metastatic bone sarcomas, with a focus on safety and efficacy outcomes.

Treatment

The clinical trial involves the administration of **Stivarga** 40 mg film-coated tablets, which contain the active substance **regorafenib**. This medication is provided in the form of film-coated tablets and is administered orally. The maximum daily dose is 160 mg, with a total maximum dose of 20,160 mg over the treatment period. The treatment duration is set for a maximum of six months. **Regorafenib** is a chemically synthesized compound, and its primary role in the trial is to evaluate its antitumor activity in patients with metastatic bone sarcomas, as per the RECIST 1.1 criteria.

In this randomized Phase II, placebo-controlled, multicenter study, a placebo is used as the comparator treatment. The placebo is designed to match the experimental medication in appearance and administration route to ensure blinding. The placebo is administered orally in the same frequency and dosage schedule as the **Stivarga** tablets. This design allows for a controlled comparison of the efficacy and safety of **regorafenib** against a non-active treatment.

Participant compliance with the dosing schedule is monitored throughout the study. This includes regular assessments to ensure adherence to the prescribed regimen and to evaluate any potential deviations. The study protocol includes detailed instructions for the administration of both the experimental medication and the placebo, ensuring consistency and reliability in the trial outcomes.

Efficacy

The efficacy of regorafenib in the clinical trial will be assessed using several parameters. The primary efficacy endpoint is the non-progression rate at specific timepoints: 8 weeks for patients with osteosarcoma, Ewing sarcoma, and **CIC-rearranged sarcoma**; 12 weeks for chondrosarcoma patients; and 6 months for chordoma patients. This rate is defined as the proportion of patients without disease progression at the specified timepoint, confirmed by central radiological review using RECIST 1.1 criteria.

Secondary efficacy endpoints include Progression-Free Survival (PFS), which will be measured from the date of randomization or start of treatment until the date of radiological progression or death. The Objective Response Rate (ORR) will be evaluated as the proportion of patients achieving a complete response (CR) or partial response (PR) according to RECIST 1.1 and CHOI criteria for chordoma. The Disease Control Rate at 6 months will be assessed as the proportion of patients with a best response rating of CR, PR, or stable disease (SD), with SD lasting at least 8 weeks. Overall Survival (OS) will be determined from the date of randomization or start of treatment until death from any cause, with censoring at the database cut-off date if the patient is alive.

Additional secondary endpoints include the Duration of Response, Progression-Free Rate at 3 and 6 months, Time to Progression, and the Growth Modulation Index (GMI), which is the ratio of time to progression under regorafenib to time to progression under previous treatment. Biomarker identification and characterization, toxicity according to NCI-CTC V4.0, and pain assessment for chordomas will also be evaluated. All efficacy assessments for chordomas using CHOI criteria will be conducted by central radiological reviewers.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients must have a histologically and molecularly confirmed diagnosis of CIC-rearranged sarcoma (either bone or soft tissue) with available Formalin Fixed Paraffin Embedded (FFPE) blocks obtained for further research purposes;
Patients with confirmed disease progression at study entry. The “baseline” radiological evaluation should demonstrate disease progression by RECIST V 1.1 when compared to a prior disease assessment done within a prior period of 3 month prior to screening Note: radiographic progression of disease will be based on at least 2 sets of scans (either MRI or CT) in the 3-month to or during screening in which radiographic progression of disease, as defined by RECIST, is demonstrated. No central review of scans (either MRIs or CTs) will be required for study eligibility; these scans must be sent for central review within 10 days after start of treatment
Metastatic disease and/or locally advanced disease not amenable to surgical resection or radiation with curative intent;
Patients must have measurable disease (outside any previous irradiated field) defined as at least one unidimensionally lesion that can be accurately measured as ≥ 10 mm with CT scan according to RECIST V1.1 for all cohorts;
Prior treatment : no more than three prior chemotherapy regimen for metastatic disease or locally advanced for CIC-rearranged sarcoma (neo-adjuvant /maintenance therapy are not counted towards this requirement). First line patients must have been previously treated with a previous (neo)adjuvant chemotherapy regimen. 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
Body Surface Area ≥ 1.30 m²
Life expectancy of greater than 3 months
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 : a. Absolute neutrophil count ≥ 1.5 Giga/L b. Platelets ≥ 100 Giga/L c. Hemoglobin≥ 9 g/dL d. Serum creatinin ≤ 1.5 x ULN e. Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 according to the modified Diet in Renal Disease (MDRD) abbreviated formula f. AST and ALT ≤2.5 x ULN ( ≤5.0 × ULN for patients with liver involvement of their cancer g. Bilirubin ≤1.5 X ULN h. 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 i. lipase ≤1.5 x ULN. j. 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
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
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/orpatients 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.
REGISTRATION CRITERIA FOR CIC-REARRANGED SARCOMA: 1. Patients must have a histologically and molecularly confirmed diagnosis of CIC-rearranged sarcoma (either bone or soft tissue) 2. Prior treatment : no more than three prior chemotherapy regimen for metastatic disease or locally advanced for CIC-rearranged sarcoma; neo-adjuvant /maintenance therapy are not counted towards this requirement (les traitements néo- adjuvant / entretien ne sont pas pris en compte pour ce critère.) . 3. Patients with confirmed disease progression at study entry. The “baseline” radiological evaluation should demonstrate disease progression by RECIST V 1.1 when compared to a prior disease assessment done within a prior period of 3 month prior to screening 4. Patients who do not meet the inclusion/non inclusion criteria for study treatment or do not wish to participate to the therapeutic study 5. Patients who do not oppose to the collection of data (demographic data, disease characterisitics, disease related treatments, progression and survival) from their medical records.

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Exclusion Criteria

Prior treatment with any VEGFR inhibitor (thus, any prior exposure to sunitinib, sorafenib, pazopanib, bevacizumab, or other VEGFR inhibitor would render the patient ineligible for this study);
Other cancer (different histology) within 5 years prior to study treatment initiation;
Major surgical procedure, open biopsy, significant trauma, within the last 28 days before study treatment initiation;
Cardiovascular dysfunction: - Left ventricular ejection fraction (LVEF) < 50% - Congestive heart failure (New York Heart Association [NYAH]) ≥ 2 - Myocardial infarction <6 months before study - Cardiac arrhythmias requiring therapy (beta blockers or digoxin are permitted) - Uncontrolled hypertension (systolic blood pressure (SBP) > 150mmHg or diastolic blood pressure (DBP) > 90mmHg despite optimal treatment or for children/adolescents SBP and/or DBP > 95th percentile + 5 mmHg) - Unstable (angina symptoms at rest) or new-onset angina (begun within the last 3 months)
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 study treatment initiation;
Severe hepatic impairment (Child-Pugh C);
Ongoing infection > Grade 2 according to NCI-CTCAE v4.0;
Known history of human immunodeficiency virus (HIV) infection;
Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy ;
Difficulties with swallowing study tablets;
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;
Known hypersensitivity to the active substance or to any of the excipients;
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;
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
Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication
Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks of study entry.