Regorafenib in Patients With Refractory Primary Bone Tumors

Osteosarcoma Clinical Trial

— Regbone  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05395741
• Other study ID #: Regbone
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: April 28, 2022
• Est. completion date: December 31, 2025

Study information

• Verified date: January 2024
• Source: Institute of Mother and Child, Warsaw, Poland
• Contact: Katarzyna Maleszewska
• Phone: +48 22 32 77 205
• Email: klinika.onkologii[@]imid.med.pl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 31, 2025
• Est. primary completion date: September 12, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 9 Years to 21 Years

Eligibility

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.

Related Conditions & MeSH terms

• Bone Neoplasms
• Ewing Sarcoma of Bone
• Osteosarcoma
• Sarcoma
• Sarcoma, Ewing

Intervention

Drug:
• Regorafenib
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.

Locations

Country	Name	City	State
Poland	Maria Sklodowska-Curie National Research Institute of Oncology	Warsaw
Poland	the Institute of Mother and Child	Warsaw

Sponsors (2)

Lead Sponsor	Collaborator
Institute of Mother and Child, Warsaw, Poland	Maria Sklodowska-Curie National Research Institute of Oncology

Country where clinical trial is conducted

Poland, 

References & Publications (9)

Agulnik M, Attia S. Growing Role of Regorafenib in the Treatment of Patients with Sarcoma. Target Oncol. 2018 Aug;13(4):417-422. doi: 10.1007/s11523-018-0575-0. — View Citation

Allard M, Khoudour N, Rousseau B, Joly C, Costentin C, Blanchet B, Tournigand C, Hulin A. Simultaneous analysis of regorafenib and sorafenib and three of their metabolites in human plasma using LC-MS/MS. J Pharm Biomed Anal. 2017 Aug 5;142:42-48. doi: 10. — View Citation

Berry V, Basson L, Bogart E, Mir O, Blay JY, Italiano A, Bertucci F, Chevreau C, Clisant-Delaine S, Liegl-Antzager B, Tresch-Bruneel E, Wallet J, Taieb S, Decoupigny E, Le Cesne A, Brodowicz T, Penel N. REGOSARC: Regorafenib versus placebo in doxorubicin- — View Citation

Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G — View Citation

Cardoso E, Mercier T, Wagner AD, Homicsko K, Michielin O, Ellefsen-Lavoie K, Cagnon L, Diezi M, Buclin T, Widmer N, Csajka C, Decosterd L. Quantification of the next-generation oral anti-tumor drugs dabrafenib, trametinib, vemurafenib, cobimetinib, pazopa — View Citation

Davis KL, Fox E, Merchant MS, Reid JM, Kudgus RA, Liu X, Minard CG, Voss S, Berg SL, Weigel BJ, Mackall CL. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, pha — View Citation

Davis LE, Bolejack V, Ryan CW, Ganjoo KN, Loggers ET, Chawla S, Agulnik M, Livingston MB, Reed D, Keedy V, Rushing D, Okuno S, Reinke DK, Riedel RF, Attia S, Mascarenhas L, Maki RG. Randomized Double-Blind Phase II Study of Regorafenib in Patients With Me — View Citation

Dirksen U, Brennan B, Le Deley MC, Cozic N, van den Berg H, Bhadri V, Brichard B, Claude L, Craft A, Amler S, Gaspar N, Gelderblom H, Goldsby R, Gorlick R, Grier HE, Guinbretiere JM, Hauser P, Hjorth L, Janeway K, Juergens H, Judson I, Krailo M, Kruseova — View Citation

Duffaud F, Mir O, Boudou-Rouquette P, Piperno-Neumann S, Penel N, Bompas E, Delcambre C, Kalbacher E, Italiano A, Collard O, Chevreau C, Saada E, Isambert N, Delaye J, Schiffler C, Bouvier C, Vidal V, Chabaud S, Blay JY; French Sarcoma Group. Efficacy and — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	EFS - (Event-Free Survival).	To explore the efficacy in terms of EFS - (Event-Free Survival)	1 year
Primary	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
Primary	Assessment of safety in terms of AEs	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	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.
Primary	Assessment of the safety of regorafenib	Safety will be assessed by analyzing recorded vital signs, laboratory test results, echocardiography, and ECG.	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	PFS (Progression-Free Survival).	progression-free survival - will be measured from randomization to the detection of disease progression in imaging tests.	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.
Secondary	OS (Overall Survival).	overall survival - will be measured from randomization to death due to cancer.	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.
Secondary	ORR (Overall Response Rate).	the percentage of patients who achieved the response to treatment defined in the protocol.	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.
Secondary	Time to achieving sufficient drug concentration in serum.	Concentration parameters will come directly from the concentration values measured in PK samples.	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.
Secondary	Maximum serum concentration in steady state Cmaxs.	Concentration parameters will come directly from the concentration values measured in PK samples.	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.
Secondary	Minimum serum concentration in steady state Cminss.	Concentration parameters will come directly from the concentration values measured in PK samples.	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.
Secondary	Random serum concentration in steady state Css.	Concentration parameters will come directly from the concentration values measured in PK samples.	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.
Secondary	Drug exposure Ctau.	by monitoring the patient's clinical and molecular status	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.
Secondary	Time to achieving steady state drug concentration in serum.	by monitoring the patient's clinical and molecular status	Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.