Study describing the efficacy and safety of regorafenib as maintenance therapy after first-line treatment in patients with bone sarcomas

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Leon Berard

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Feb 2020 → ongoing

Decision date (initial)

2024-08-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Bayer AG

External identifiers

EU CT number

2024-514637-37-00

EudraCT number

2018-004045-16

ClinicalTrials.gov

NCT04055220

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

The primary objective is to determine the antitumor efficacy of regorafenib versus placebo as maintenance treatment in patients with bone sarcomas.

Secondary objectives 6

1. Relapse-Free Survival (RFS),
2. Duration of treatment (experimental arm),
3. Overall Survival,
4. Quality of Life (EORTC QLQ-C30),
5. Safety profile (NCI-CTC AE version 5),
6. Compliance to study treatment

Conditions and MedDRA coding

Patients with bone sarcomas other than chordoma, who have no residual disease after their standard treatment sequence.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. I1. Age ≥ 12 years at the day of consenting to the study;
2. I2. Patients must have histologically confirmed diagnosis of primary bone sarcoma including but not limited to: Osteosarcomas, Ewing sarcomas, Chondrosarcomas, Undifferentiated Pleomorphic Sarcomas (UPS), Leiomyosarcomas (LMS) and Angiosarcomas;
3. I3. Prior treatment for localized or metastatic disease for bone sarcoma must have been completed, consisting of a standard multimodal treatment based on the histological subtype: For OS, (excepted head and neck localisations), neoadjuvant and/or adjuvant chemotherapy should include methotrexate-based regimen for patients < 18 years old; patients ≥ 18 years old may have received either methotrexate-based regimen or anthracycline and cisplatin-based regimen For head and neck OS, neoadjuvant and/or adjuvant chemotherapy should include adriamycin, cisplatin or ifosfamide-based regimen. For non-OS, neoadjuvant and/or adjuvant chemotherapy should include adriamycin and/or cisplatin-based regimen.
4. I4. Retour à un grade 0 ou 1 de la classification NCI-CTCAE v5 ou retour à l’état initial avant le dernier traitement ou la dernière procédure (à l’exception de l’alopécie, l’anémie et l’hypothyroïdie)
5. I5. Interval between the last chemotherapy administration and the date of randomisation: at least 4 weeks but no longer than 2 months;
6. I6. Confirmed complete remission or no evidence of disease (for metastatic disease); Patients with pulmonary micro nodules can be included provided they do not meet the following criteria: • At least one lung nodule of 10mm or more• And/or at least two nodules well limited between 6-9mm • And/or at least 5 nodules well limited of 5mm or less All the other situations will be considered as doubtful lesions except in case of metastatic disease confirmed during the lung surgery of the residual lung lesions after pre-operative chemotherapy. If no other metastatic localisation is detected at the initial staging, the patient will be considered as localised disease and eligible for randomisation.
7. I7. Life expectancy of greater than 12 months;
8. I8. Karnofsky Performance status ≥70 (patients younger than 18-year old) or ECOG performance status < 2 (adult patients) ;
9. I9. Patients must have adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days of study treatment initiation: - Absolute neutrophil count ≥ 1.5 Giga/l - Platelets ≥ 100 Giga/l - Haemoglobin≥ 9 g/dl - Serum creatinine ≤ 1.5 x ULN - Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula - AST and ALT ≤2.5 x ULN ( ≤5.0 × ULN for patients with liver involvement of their cancer) - Bilirubin ≤1.5 X ULN - 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. - Lipase ≤1.5 x ULN - 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
10. I10. 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;
11. I11. Women of childbearing potential and male patients must agree to use adequate contraception (Appendix 4) for the duration of treatment and for 7 months (210 days) in WOCBP or 4 months (120 days) in men sexually active with WOCBP after the last dose of regorafenib;
12. I12. 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;
13. I13. Patients, and their parents when applicable, must sign and date an informed consent document indicating that they have been informed of all the pertinent aspects of the trial prior to enrolment;
14. I14. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures;
15. I15. Patients covered by a medical insurance.
16. I16. Body Surface Area (BSA) ≥ 1.30m² at the time of consenting to the study.

Exclusion criteria 25

1. E1. Prior treatment with any VEGFR inhibitor (thus, any prior exposure to sunitinib, sorafenib, pazopanib, bevacizumab, or other VEGFR inhibitor);
2. E2. All soft tissue sarcomas (including but not limited to soft tissue osteosarcomas and Ewing soft tissue sarcomas) and chordomas;
3. E3. Prior history of other malignancies other than study disease (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) within 3 years prior to randomization;
4. E4. Cardiovascular dysfunction: • Left ventricular ejection fraction (LVEF) < 50%, • Congestive heart failure ≥ New York Heart Association (NYHA) class 2, • Myocardial infarction < 6 months prior to first study drug administration, • Cardiac arrhythmias requiring therapy (beta blockers or digoxin are permitted), • Unstable (angina symptoms at rest) or new-onset angina within the last 3 months prior to first study drug administration;
5. E5. Uncontrolled hypertension (systolic blood pressure > 150mmHg or diastolic pressure > 90 mmHg despite optimal treatment);
6. E6. 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 the first study drug administration;
7. E7. Major surgical procedure, open biopsy or significant traumatic injury within 28 days before the first study drug administration;
8. E8. Ongoing infection > Grade 2 according to NCI-CTCAE v5;
9. E9. Known history of human immunodeficiency virus (HIV) infection; Nota Bene: Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate in the study if they meet the following criteria: a. No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months prior to enrolment; b. No history of AIDS-defining cancers (e.g. Kaposi’s sarcoma, aggressive B-cell lymphoma and invasive cervical cancer); c. Subjects should be on established anti-retroviral therapy for at least 4 weeks and have an HIV viral load of < 400 copies/mL prior to enrolment
10. E10. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy; Nota Bene: Subjects with a history of hepatitis B or C who have normal alanine aminotransferase (ALT) and are hepatitis B surface antigen negative and/or have undetectable HCV RNA are eligible;
11. E11. Dehydration according to NCI-CTC v5 Grade >1;
12. E12. Difficulties to swallow oral medication and/or any mal-absorption condition and/or any Gastrointestinal (GI) disease that may significantly alter the absorption of regorafenib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel resection);
13. E13. Patients with seizure disorder requiring medication;
14. E14. Concurrent enrolment in another clinical trial in which investigational therapies are administered;
15. E15. Known hypersensitivity to the active substance or to any of the excipients;
16. E16. Pregnant women, women who are likely to become pregnant or are breast-feeding
17. E17. 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;
18. E18. Patients with history of non-compliance to medical regimens or unwilling or unable to comply with the protocol;
19. E19. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent;
20. E20. Non-healing wound, non-healing ulcer, or non-healing bone fracture;
21. E21. Patients with evidence or history of any bleeding diathesis, irrespective of severity;
22. E22. Any haemorrhage or bleeding event ≥ CTCAE v5 Grade 3 within 4 weeks prior to the first study drug administration;
23. E23. Clinically significant unrelated systemic illness (e.g., serious infection or significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results;
24. E24. Patients using prohibited concomitant and/or concurrent medications (see section “Prohibited concomitant/concurrent treatments);
25. E25. Patients under tutorship or curatorship.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint will be the 36-month Relapse-Free Survival rate (36M-RFS). An event will be described as the recurrence of the disease, either local or distant, determined locally by the investigational staff.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Leon Berard

Sponsor organisation

Centre Leon Berard

Address

28 Rue Laennec

City

Lyon

Postcode

69008

Country

France

Scientific contact point

Organisation

Centre Leon Berard

Contact name

Pr BLAY Jean-Yves

Public contact point

Organisation

Centre Leon Berard

Contact name

Clinical trial manager

Locations

1 EU/EEA country · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications