A Phase II Study Evaluating Efficacy and Safety of Regorafenib in Patients With Metastatic Bone Sarcomas (REGOBONE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

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 Sep 2014 → ongoing

Decision date (initial)

2024-08-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

BAYER HealthCare AG

External identifiers

EU CT number

2024-513455-33-00

EudraCT number

2013-003910-42

ClinicalTrials.gov

NCT02389244

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy, Pharmacogenomic

The principal objective of the trial is to investigate the antitumour activity of regorafenib according to RECIST 1.1 criteria based on central radiological review.

Secondary objectives 13

1. The Progression free survival (PFS) according to RECIST 1.1 criteria
2. Objective response rate [defined as complete response (CR) or partial response (PR) according to RECIST V 1.1 for all cohorts, and CHOI criteria for chordomas]
3. Overall survival (defined as the time from the date of randomization or start of treatment for cohort E to the date of death due to any cause).
4. Duration of response.
5. Disease control rate at 6 months is defined as the proportion of patients who have a best response rating of CR, PR or stable disease [SD] according to RECIST guidelines 1.1. SD should be at least 8 weeks.
6. Progression-free rates at 3 and 6 months (PFR-3 and PFR-6), time to progression.
7. Treatment safety will be assessed using the NCI CTC-AE version 4.0 .
8. Growth Modulation Index (GMI).
9. Identification and characterization of biomarkers
10. Time to progression (measured from date of randomization or start of treatment for cohort E until the date of first observation of progression )
11. Pain assessment for chordomas
12. Progression Free Survival according to CHOI criteria for chordomas
13. To describe the untreated population registered in the study

Conditions and MedDRA coding

Bone sarcoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Patients must have a histologically and molecularly confirmed diagnosis of CIC-rearranged sarcoma (either bone or soft tissue) with available Formalin Fixed Paraffin Embedded (FFPE) blocks obtained for further research purposes;
2. Patients with confirmed disease progression at study entry. The “baseline” radiological evaluation should demonstrate disease progression by RECIST V 1.1 when compared to a prior disease assessment done within a prior period of 3 month prior to screening Note: radiographic progression of disease will be based on at least 2 sets of scans (either MRI or CT) in the 3-month to or during screening in which radiographic progression of disease, as defined by RECIST, is demonstrated. No central review of scans (either MRIs or CTs) will be required for study eligibility; these scans must be sent for central review within 10 days after start of treatment
3. Metastatic disease and/or locally advanced disease not amenable to surgical resection or radiation with curative intent;
4. Patients must have measurable disease (outside any previous irradiated field) defined as at least one unidimensionally lesion that can be accurately measured as ≥ 10 mm with CT scan according to RECIST V1.1 for all cohorts;
5. Prior treatment : no more than three prior chemotherapy regimen for metastatic disease or locally advanced for CIC-rearranged sarcoma (neo-adjuvant /maintenance therapy are not counted towards this requirement). First line patients must have been previously treated with a previous (neo)adjuvant chemotherapy regimen. At least 4 weeks since last chemotherapy (6 weeks in case of nitrosoureas and mitomycin C), immunotherapy or any other pharmacological treatment and/or radiotherapy;
6. Age ≥ 10
7. Body Surface Area ≥ 1.30 m²
8. Life expectancy of greater than 3 months
9. ECOG performance status < 2 (Karnofsky ≥ 60%) for adults patients
10. Karnofsky scale ≥ 60 % for children aged > 12 years old / Lansky scale ≥ 60 % for children aged ≤ 12 years old
11. Patients must have adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days of study treatment initiation : normal organ function as defined below : a. Absolute neutrophil count ≥ 1.5 Giga/L b. Platelets ≥ 100 Giga/L c. Hemoglobin≥ 9 g/dL d. Serum creatinin ≤ 1.5 x ULN e. Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 according to the modified Diet in Renal Disease (MDRD) abbreviated formula f. AST and ALT ≤2.5 x ULN ( ≤5.0 × ULN for patients with liver involvement of their cancer g. Bilirubin ≤1.5 X ULN h. 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 i. lipase ≤1.5 x ULN. j. 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
12. 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
13. Recovery to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure related toxicity (except alopecia, anemia, and hypothyroidism);
14. Women of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy;
15. 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;
16. Signed informed consent form by adult patients and/orpatients parents/legal representatives (if age < 18 years) and age appropriate assent form by the patients’ parents/legal representatives obtained before any study specific procedure is conducted
17. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures;
18. Patients or parents/legal representatives affiliated to the Social Security System.
19. REGISTRATION CRITERIA FOR CIC-REARRANGED SARCOMA: 1. Patients must have a histologically and molecularly confirmed diagnosis of CIC-rearranged sarcoma (either bone or soft tissue) 2. Prior treatment : no more than three prior chemotherapy regimen for metastatic disease or locally advanced for CIC-rearranged sarcoma; neo-adjuvant /maintenance therapy are not counted towards this requirement (les traitements néo- adjuvant / entretien ne sont pas pris en compte pour ce critère.) . 3. Patients with confirmed disease progression at study entry. The “baseline” radiological evaluation should demonstrate disease progression by RECIST V 1.1 when compared to a prior disease assessment done within a prior period of 3 month prior to screening 4. Patients who do not meet the inclusion/non inclusion criteria for study treatment or do not wish to participate to the therapeutic study 5. Patients who do not oppose to the collection of data (demographic data, disease characterisitics, disease related treatments, progression and survival) from their medical records.

Exclusion criteria 22

1. Prior treatment with any VEGFR inhibitor (thus, any prior exposure to sunitinib, sorafenib, pazopanib, bevacizumab, or other VEGFR inhibitor would render the patient ineligible for this study);
2. Other cancer (different histology) within 5 years prior to study treatment initiation;
3. Major surgical procedure, open biopsy, significant trauma, within the last 28 days before study treatment initiation;
4. Cardiovascular dysfunction: - Left ventricular ejection fraction (LVEF) < 50% - Congestive heart failure (New York Heart Association [NYAH]) ≥ 2 - Myocardial infarction <6 months before study - Cardiac arrhythmias requiring therapy (beta blockers or digoxin are permitted) - Uncontrolled hypertension (systolic blood pressure (SBP) > 150mmHg or diastolic blood pressure (DBP) > 90mmHg despite optimal treatment or for children/adolescents SBP and/or DBP > 95th percentile + 5 mmHg) - Unstable (angina symptoms at rest) or new-onset angina (begun within the last 3 months)
5. 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 study treatment initiation;
6. Severe hepatic impairment (Child-Pugh C);
7. Ongoing infection > Grade 2 according to NCI-CTCAE v4.0;
8. Known history of human immunodeficiency virus (HIV) infection;
9. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy ;
10. Difficulties with swallowing study tablets;
11. Prior anticancer therapy, including radiotherapy, endocrine therapy, immunotherapy, chemotherapy (CT) within the last 4 weeks (6 weeks for nitrosoureas and mitomycin C), or other investigational agents ; Concomitant antalgic palliative radiotherapy allowed;
12. Concurrent enrolment in another clinical trial in which investigational therapies are administered;
13. Known hypersensitivity to the active substance or to any of the excipients;
14. Pregnant women, women who are likely to become pregnant or are breast-feeding;
15. For adult patients, individual deprived of liberty or placed under the authority of a tutor;
16. 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;
17. Patients with history of non compliance to medical regimens or unwilling or unable to comply with the protocol
18. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
19. Non-healing wound, non-healing ulcer, or non-healing bone fracture
20. Patients with evidence or history of any bleeding diathesis, irrespective of severity
21. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication
22. Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks of study entry.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint is the non-progression rate at 8 weeks for osteosarcoma, Ewing sarcoma and CIC-rearranged sarcoma patients, at 12 weeks for chondrosarcoma patients and at 6 months for chordoma patients. The non-progression rate will be defined as the proportion of patients without disease progression at the defined timepoint after confirmation by central radiological review (using RECIST 1.1).

Secondary endpoints 12

1. Progression-Free Survival [defined using RECIST 1.1] will be measured from the date of randomization or start of treatment for cohort E until the date of radiological progression or death whatever the cause (if death occurs before progression).
2. Objective response rate [defined as complete response (CR) or partial response (PR) according to RECIST 2009, version 1.1, for all cohorts, and CHOI criteria for chordoma] ;
3. Disease control rate at 6 months (defined as the proportion of patients who a best response rating of CR, PR or stable disease [SD]), SD should be at least 8 weeks ;
4. Overall survival (defined as the time from the date of randomization or start of treatment for cohort E until the date of death due to any cause); if the patients is alive at the date of data base cut off then he will be censored at the data base cut off date;
5. Duration of response (defined as the time from date of first documented objective response of CR or PR, whichever is noted earlier, to first disease progression or death before progression ;
6. Progression-free rate at 3 and 6 months (PFR-3 and PFR-6), defined as the proportion of patients without progression at 3 and 6 months post randomization or start of treatment for cohort E;
7. Time to progression (measured from date of randomization or start of treatment for cohort E until the date of first observation of progression );
8. Growth Modulation Index (GMI) defined as ratio of time to PD under regorafenib to TTP under previous treatment. The GMI will be explored in patients receiving regorafenib after randomization or start of treatment for cohort E;
9. Identification and characterization of biomarkers
10. Toxicity according to NCI-CTC V4.0
11. Pain assessment for chordomas
12. Progression Free Survival according to CHOI criteria for chordomas All efficacy assessments using CHOI criteria (only for chordomas) will be performed by central radiological reviewers.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris Cedex 13

Postcode

75654

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 24 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 10 files

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

Application history

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