Regorafenib in Patients With Refractory Primary Bone Tumors

Phase 1

Active, not recruiting

• Conditions: Osteosarcoma; Ewing Sarcoma of Bone
• Interventions: Drug: Regorafenib

• Registration Number: NCT05395741
• Lead Sponsor: Institute of Mother and Child, Warsaw, Poland

Brief Summary

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

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.

Study Timeline

• Study Start: 2022-04-28
• Study First Submitted: 2022-05-05
• Study First Submitted QC: 2022-05-24
• Study First Posted: 2022-05-27
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-09
• Last Update Posted: 2025-04-10
• Primary Completion: 2025-09-12
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

1. Age >9 years ≤ 21 years.

2. Histologically proven Ewing sarcoma or osteosarcoma.

3. 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):

   1. progression on the I line or next, or
   2. relapse.

4. Signing of informed consent for trial participation (including for Regorafenib treatment) according with current legal regulations.

5. Life expectancy of at least 12 weeks from the time informed consent was signed.

6. Possibility of swallowing the tablet.

7. 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

1. Lack of inclusion criteria
2. Previous treatment with Regorafenib.
3. Pregnancy and breastfeeding.
4. Hypersensitivity to the study drug or any of its ingredients.
5. Simultaneous treatment with other drugs which might interact with Regorafenib.
6. Persistent toxicity related to prior therapy, making it impossible to treat with Regorafenib.
7. Diagnosis of other malignancies before study inclusion.
8. Patients with uncontrolled hypertension.
9. Patients with diseases of the coagulation system.
10. Patients with heart defects and / or cardiac arrhythmias requiring permanent treatment with antiarrhythmic drugs.
11. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
R1 - Regorafenib Arm	Regorafenib	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.

Primary Outcome Measures

Name	Time	Method
Assessment of the safety of regorafenib	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.	Safety will be assessed by analyzing recorded vital signs, laboratory test results, echocardiography, and ECG.
EFS - (Event-Free Survival).	1 year	To explore the efficacy in terms of EFS - (Event-Free Survival)
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.	1 year	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)
Assessment of safety in terms of AEs	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.	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 adverse events of special interest

Secondary Outcome Measures

Name	Time	Method
ORR (Overall Response Rate).	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.	the percentage of patients who achieved the response to treatment defined in the protocol.
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.	Concentration parameters will come directly from the concentration values measured in PK samples.
Minimum serum concentration in steady state Cminss.	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.	Concentration parameters will come directly from the concentration values measured in PK samples.
Maximum serum concentration in steady state Cmaxs.	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.	Concentration parameters will come directly from the concentration values measured in PK samples.
Random serum concentration in steady state Css.	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.	Concentration parameters will come directly from the concentration values measured in PK samples.
OS (Overall Survival).	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.	overall survival - will be measured from randomization to death due to cancer.
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.	by monitoring the patient's clinical and molecular status
PFS (Progression-Free Survival).	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.	progression-free survival - will be measured from randomization to the detection of disease progression in imaging tests.
Drug exposure Ctau.	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.	by monitoring the patient's clinical and molecular status

Trial Locations

Locations (2)

the Institute of Mother and Child; 🇵🇱 Warsaw, Poland

Maria Sklodowska-Curie National Research Institute of Oncology; 🇵🇱 Warsaw, Poland