Regorafenib in Patients With Refractory Primary Bone Tumors

Study Overview
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Brief Summary
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The aim of the project is to improve treatment outcomes in patients with primary malignant bone tumors, refractory to standard therapy, by increasing the availability of advanced therapy, as well as to develop treatment options using advanced molecular diagnostics for patients who have not responded to the standard therapeutic regimen, and to introduce modern diagnostics for risk stratification and for the use in molecularly targeted therapies.

Detailed Description
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The scope of the project is to cover the entire population of children, adolescents and young adults from the age of 9 to the age of 21, who progressed to first-line treatment or who presented with a recurrence of Ewing's sarcoma or osteosarcoma. Despite escalating doses of chemotherapy and radiotherapy, aggressive surgical procedures in patients with dissemination disease and negative prognostic factors, no improvement in treatment outcomes has been achieved for over 30 years. For this reason, other therapeutic options are being investigated. There have been no significant responses to immunotherapy. Although, the inclusion of tyrosine kinase inhibitors (TKIs) appears to be promising. The identification of new mutations in bone tumors has led to a better insight into the molecular basis of these tumors, which has resulted in a more significant role of genetic research in everyday practice. Although traditional histopathological examinations are currently the basis for the diagnosis of bone tumors, the developing techniques of molecular biology make it possible, in many cases, to refine the diagnosis and, in the near future, will become the basis for the classification of these neoplasms. Moreover, these technics are expected to enable the qualification of patients to modern molecularly targeted therapies. Based on the above data, the objectives of the project are as follows: 1. to estimate the nature and frequency of mutations in the tumor tissue, 2. to compare molecular test results with clinical data (which will allow for the initial assessment of the impact of the mutation status on the clinical condition, course of treatment and prognosis), 3. to include targeted treatment - broad spectrum tyrosine kinase inhibitor - regorafenib in standard therapy.

Official Title
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Evaluation of the Efficacy and Safety of Regorafenib in Patients With Refractory Primary Bone Tumors

Conditions
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Osteosarcoma, Ewing Sarcoma of Bone

Intervention / Treatment
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* Drug: Regorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >9 years ≤ 21 years. Histologically proven Ewing sarcoma or osteosarcoma. Failure of the treatment identified no earlier than 30 days prior to study treatment initiation (at least one of below needs to apply in order for this requirement to be satisfied): progression on the I line or next, or relapse. Signing of informed consent for trial participation (including for Regorafenib treatment) according with current legal regulations. Life expectancy of at least 12 weeks from the time informed consent was signed. Possibility of swallowing the tablet. Consent to the use of effective contraception throughout the period of the study and a minimum of 2 year after discontinuation of study treatment in patients at puberty and sexual maturity. Exclusion Criteria: Lack of inclusion criteria Previous treatment with Regorafenib. Pregnancy and breastfeeding. Hypersensitivity to the study drug or any of its ingredients. Simultaneous treatment with other drugs which might interact with Regorafenib. Persistent toxicity related to prior therapy, making it impossible to treat with Regorafenib. Diagnosis of other malignancies before study inclusion. Patients with uncontrolled hypertension. Patients with diseases of the coagulation system. Patients with heart defects and / or cardiac arrhythmias requiring permanent treatment with antiarrhythmic drugs. Other acute or persistent disorders, behaviors or abnormal laboratory test results, which might increase the risk related to the participation in this clinical trial or to taking the study drug, or which might influence the interpretation of the study results, or which, in the investigator's opinion, disqualify a patient from participating in the trial.

Ages Eligible for Study
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Minimum Age: 9 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R1 - Regorafenib Arm<br>R1 - the experimental group. Standard oncological treatment will be started. Additionally, patients will receive regorafenib orally at doses adjusted for age, body surface area and pharmacokinetics. Treatment with regorafenib will be continued for up to 1 year or until disease progression, patient death, unacceptable toxicity, or study closure. Pharmacokinetics and safety profile of the investigational product (IP) will be determined throughout the course therapy. | Drug: Regorafenib<br>* Patients will receive regorafenib orally at doses adjusted for age, body surface area and pharmacokinetics. Treatment with regorafenib will be continued for up to 1 year or until disease progression, patient death, unacceptable toxicity, or study closure. Pharmacokinetics and safety profile of the investigational product (IP) will be determined throughout the course therapy. In the event of progression or relapse, patients in the control group will have the option to receive the IP along with the standard treatment of the next line.<br>|
| No Intervention: R2 - Control Group<br>R2 - the control group - will receive only standard treatment. In the event of progression or relapse, patients in the control group will have the option to receive the IP along with the standard treatment of the next line. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFS - (Event-Free Survival). | To explore the efficacy in terms of EFS - (Event-Free Survival) | 1 year | 
| Determining the dose of the test substance in patients between 9 and 21 years of age, at which exposure to the drug will be similar to that recommended for adults. | Safety will be assessed by the rate of participants presenting with Adverse Events stratified by grade, category, affected organ or system, as number of serious adverse events (SAEs) | 1 year | 
| Determining the dose of the test substance in patients between 9 and 21 years of age, at which exposure to the drug will be similar to that recommended for adults. | Safety will be assessed by the rate of participants presenting with Adverse Events stratified by grade, category, affected organ or system, as number of adverse events (AEs), including events of special interest | from date of randomization, until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months. | 
| Determining the dose of the test substance in patients between 9 and 21 years of age, at which exposure to the drug will be similar to that recommended for adults. | Safety will be assessed by the rate of participants presenting with Adverse Events stratified by grade, category, affected organ or system, as incidence and severity of TEAEs (coded to preferred term and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA) and graded according to the National Cancer Institute Common -Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) | from date of randomization, until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months. | 
| Determining the dose of the test substance in patients between 9 and 21 years of age, at which exposure to the drug will be similar to that recommended for adults. | Safety will be assessed by the rate of participants presenting with Adverse Events stratified by grade, category, affected organ or system, as physical examination; vital signs | from date of randomization, until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months. | 
| Determining the dose of the test substance in patients between 9 and 21 years of age, at which exposure to the drug will be similar to that recommended for adults. | Safety will be assessed by the rate of participants presenting with Adverse Events stratified by grade, category, affected organ or system, as laboratory abnormalities graded according to NCI CTCAE v5.0. | from date of randomization, until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months. | 
| Determining the dose of the test substance in patients between 9 and 21 years of age, at which exposure to the drug will be similar to that recommended for adults. | Safety will be assessed by the rate of participants presenting with Adverse Events stratified by grade, category, affected organ or system, as ECGs to evaluate heart rate, atrial ventricular conduction, QTcF, and arrhythmias, and ECHO. | from date of randomization, until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS (Progression-Free Survival). |  | Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months. | 
| OS (Overall Survival). |  | Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months. | 
| ORR (Overall Response Rate). |  | Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months. | 
| Time to achieving sufficient drug concentration in serum. |  | Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months. | 
| Maximum serum concentration in steady state Cmaxs. |  | Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months. | 
| Minimum serum concentration in steady state Cminss. |  | Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months. | 
| Random serum concentration in steady state Css. |  | Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months. | 
| Drug exposure Ctau. |  | Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months. | 
| Time to achieving steady state drug concentration in serum. |  | Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TKI, refractory bone tumors, osteosarcoma, Ewing sarcoma, targeted treatment, solid tumor