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Regorafenib in Patients With Refractory Primary Bone Tumors (Regbone)

Primary Purpose

Osteosarcoma, Ewing Sarcoma of Bone

Status

Recruiting

Phase

Phase 1

Locations

Poland

Study Type

Interventional

Intervention

Regorafenib

About this trial

This is an interventional treatment trial for Osteosarcoma focused on measuring TKI, refractory bone tumors, osteosarcoma, Ewing sarcoma, targeted treatment, solid tumor

Eligibility Criteria

9 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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):
1. progression on the I line or next, or
2. 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.

Sites / Locations

Mother and Child InstituteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

R1 - Regorafenib Arm

R2 - Control Group

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

EFS - (Event-Free Survival).

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.

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)

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

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)

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

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.

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.

Secondary Outcome Measures

PFS (Progression-Free Survival).

OS (Overall Survival).

ORR (Overall Response Rate).

Time to achieving sufficient drug concentration in serum.

Maximum serum concentration in steady state Cmaxs.

Minimum serum concentration in steady state Cminss.

Random serum concentration in steady state Css.

Drug exposure Ctau.

Time to achieving steady state drug concentration in serum.

Full Information

NCT ID

NCT05395741

First Posted

May 5, 2022

Last Updated

March 20, 2023

Sponsor

Institute of Mother and Child, Warsaw, Poland

Collaborators

Maria Sklodowska-Curie National Research Institute of Oncology

1. Study Identification

Unique Protocol Identification Number

NCT05395741

Brief Title

Regorafenib in Patients With Refractory Primary Bone Tumors

Acronym

Regbone

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 28, 2022 (Actual)

Primary Completion Date

September 12, 2025 (Anticipated)

Study Completion Date

December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Institute of Mother and Child, Warsaw, Poland

Collaborators

Maria Sklodowska-Curie National Research Institute of Oncology

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Osteosarcoma, Ewing Sarcoma of Bone

Keywords

TKI, refractory bone tumors, osteosarcoma, Ewing sarcoma, targeted treatment, solid tumor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

R1 - Regorafenib Arm

Arm Type

Experimental

Arm Description

Arm Title

R2 - Control Group

Arm Type

No Intervention

Arm Description

Intervention Type

Drug

Intervention Name(s)

Regorafenib

Intervention Description

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.

Primary Outcome Measure Information:

Title

EFS - (Event-Free Survival).

Description

To explore the efficacy in terms of EFS - (Event-Free Survival)

Time Frame

1 year

Title

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.

Description

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)

Time Frame

1 year

Title

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.

Description

Time Frame

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.

Title

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.

Description

Time Frame

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.

Title

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.

Description

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

Time Frame

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.

Title

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.

Description

Time Frame

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.

Title

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.

Description

Time Frame

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 Measure Information:

Title

PFS (Progression-Free Survival).

Time Frame

Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.

Title

OS (Overall Survival).

Time Frame

Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.

Title

ORR (Overall Response Rate).

Time Frame

Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.

Title

Time to achieving sufficient drug concentration in serum.

Time Frame

Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.

Title

Maximum serum concentration in steady state Cmaxs.

Time Frame

Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.

Title

Minimum serum concentration in steady state Cminss.

Time Frame

Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.

Title

Random serum concentration in steady state Css.

Time Frame

Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.

Title

Drug exposure Ctau.

Time Frame

Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.

Title

Time to achieving steady state drug concentration in serum.

Time Frame

Safety analyzes are planned in accordance with the schedule of intermediate analyzes, at least every 12 months.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

9 Years

Maximum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Facility Information:

Facility Name

Mother and Child Institute

City

Warsaw

State/Province

Mazovian

ZIP/Postal Code

01-211

Country

Poland

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Katarzyna Maleszewska

Phone

+48 22 32 77 205

klinika.onkologii@imid.med.pl

First Name & Middle Initial & Last Name & Degree

Anna Raciborska

12. IPD Sharing Statement

Citations:

PubMed Identifier

29931504

Citation

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.

Results Reference

result

PubMed Identifier

28494338

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: 10.1016/j.jpba.2017.04.053. Epub 2017 May 1.

Results Reference

result

PubMed Identifier

28295221

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-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis. Cancer. 2017 Jun 15;123(12):2294-2302. doi: 10.1002/cncr.30661. Epub 2017 Mar 10.

Results Reference

result

PubMed Identifier

27932229

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; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9. Epub 2016 Dec 6. Erratum In: Lancet. 2017 Jan 7;389(10064):36.

Results Reference

result

PubMed Identifier

29544202

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, pazopanib, regorafenib and two metabolites in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Apr 15;1083:124-136. doi: 10.1016/j.jchromb.2018.02.008. Epub 2018 Feb 8.

Results Reference

result

PubMed Identifier

32192573

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, phase 1-2 trial. Lancet Oncol. 2020 Apr;21(4):541-550. doi: 10.1016/S1470-2045(20)30023-1. Epub 2020 Mar 17.

Results Reference

result

PubMed Identifier

31013172

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 Metastatic Osteosarcoma. J Clin Oncol. 2019 Jun 1;37(16):1424-1431. doi: 10.1200/JCO.18.02374. Epub 2019 Apr 23.

Results Reference

result

PubMed Identifier

31553693

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 J, Kuehne T, Ladenstein R, Lervat C, Lessnick SL, Lewis I, Linassier C, Marec-Berard P, Marina N, Morland B, Pacquement H, Paulussen M, Randall RL, Ranft A, Le Teuff G, Wheatley K, Whelan J, Womer R, Oberlin O, Hawkins DS; Euro-E.W.I.N.G. 99 and Ewing 2008 Investigators. High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008. J Clin Oncol. 2019 Dec 1;37(34):3192-3202. doi: 10.1200/JCO.19.00915. Epub 2019 Sep 25.

Results Reference

result

PubMed Identifier

30477937

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 safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2019 Jan;20(1):120-133. doi: 10.1016/S1470-2045(18)30742-3. Epub 2018 Nov 23.

Results Reference

result

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Regorafenib in Patients With Refractory Primary Bone Tumors

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