Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas

  • End date
    Oct 1, 2024
  • participants needed
  • sponsor
    Centre Leon Berard
Updated on 24 January 2021
glomerular filtration rate
neutrophil count
cancer chemotherapy
ewing's sarcoma
localized disease


This is a randomized, double-blinded, 2 arms study concerning patients with bone sarcoma after the first line therapy.

In the first arm, patients will be treated with regorafenib for a maximum of 12 months as maintenance therapy after first line therapy (chemotherapy and surgery), whereas in the second arm, patients will be treated with placebo (standard of care).

The comparison between this two arms will allow to determine whether or not regorafenib is efficient for disease control, in terms of Relapse-Free Survival improvement.


Bone sarcomas are rare primary bone cancers, although, their frequency has been increasing by 0.3% per year over the last decade. They include a very large number of tumour types belonging to the family of primary malignant bone tumours and originate from bone as Osteosarcomas (OS), Chondrosarcomas (CS), Fibrosarcomas, Chordomas,

Current conventional treatments for OS combine chemotherapy and surgery. Compared with surgery alone, multimodal treatment of high-grade sarcomas increases disease-free survival probabilities from only 10%-20% to 50-65% depending on the bone sarcoma type. In general, despite second-line treatment, the prognosis of recurrent disease has remained poor, with long-term post-relapse survival of <20%.

The outcome of bone sarcoma has been dramatically improved by the addition of chemotherapy in the 70' and 80' but has remained remarkably stable in the last 3 decades, with a survival rate largely plateaued, despite introduction of novel regimens, both in localized and metastatic disease, in children and in adults. Primary bone cancer presented challenges in new drug development partly because of their rarity and heterogeneity. Thus, improving treatments for these diseases is a high priority, but advances have been few in recent years. In this context, maintenance therapy may be an interesting option as a way to prolong the benefit of first-line chemotherapy.

Regorafenib may play a role in the maintenance setting for bone sarcomas (as improved Progression-Free Survival and sustained responses were observed in the REGOBONE study) in maintaining the initial response to chemotherapy and delaying the need for further treatment at relapse, while exerting a manageable associated toxicity and minimal negative impact on health-related quality of life.

Currently there is no available agent used as maintenance therapy after first-line chemotherapy. In the context of a clinical trial with close monitoring, it is, thus, acceptable to consider a placebo-control group.

On this basis, this study propose to conduct a double-blinded randomized controlled trial to evaluate the efficacy of regorafenib versus placebo in the treatment of patients with bone sarcomas, who have no evidence of disease after neoadjuvant and/or adjuvant chemotherapies.

The main goal of the present study is then to explore whether sequential addition of regorafenib after completion of a standard induction chemotherapy in patients with bone sarcomas would improve outcomes in term of event-free-survival (EFS) defined by local or distant recurrence of the disease.

Results will be stratified on the "high-risk" versus "low-risk" of relapse. As response to neoadjuvant chemotherapy and metastatic status at time of diagnosis are known to be important on patient's outcome, stratification will rely on a combined criteria taking into account these two factors. Thus, "high-risk" of relapse will be defined by the group of patients who are poor responders to neoadjuvant chemotherapy and/or in metastatic setting at diagnosis, whereas "low-risk" of relapse will be defined by the group of patients who have no metastatic disease at time of diagnosis and are good responders to neoadjuvant chemotherapy.

Condition Osteosarcoma, Sarcoma, Sarcoma of Bone, Sarcoma (Pediatric), Soft Tissue Sarcoma, bone sarcoma
Treatment Treatment by Regorafenib, Treatment by Placebo
Clinical Study IdentifierNCT04055220
SponsorCentre Leon Berard
Last Modified on24 January 2021


Yes No Not Sure

Inclusion Criteria

I1. Age 16 years at the day of consenting to the study
I2. Patients must have histologically confirmed diagnosis of primary bone
sarcoma of one of the following histotypes
OS (conventional-intramedullary/central high grade, small cell, telangiectatic or high-grade surface OS)
Bone sarcomas other than Ewing sarcoma, chondrosarcoma and chordoma
I3. Availability of archival Formalin-Fixed Paraffin Embedded (FFPE) block
I4. Prior treatment for localized or metastatic disease for bone sarcoma must
have been completed. It should include
Neoadjuvant chemotherapy with documented assessment of histological response
Local procedure: Surgery (or radiotherapy if tumour is unresectable)
Adjuvant chemotherapy (Nota Bene: patients with histotype different from OS may not have received adjuvant treatment) For OS, excepted from head and neck, neoadjuvant and/or adjuvant chemotherapy should include methotrexate-based regimen for patients < 18 years old or anthracycline and cisplatin-based regimen for patients 18 years old
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
I5. Recovery to NCI-CTCAE v5 Grade 0 or 1 level or recovery to baseline
preceding the prior treatment from any previous drug/procedure related
toxicity (except alopecia, anaemia, and hypothyroidism)
I6. Interval between the last chemotherapy administration and the date of
randomisation : at least 4 weeks but no longer than 2 months
I7. Confirmed complete remission or no evidence of disease (for metastatic
Patients with pulmonary micro nodules can be included provided they do not
meet the following criteria
At least one lung nodule of 10 mm or more
And/or at least two nodules well limited between 6-9 mm
And/or at least 5 nodules well limited of 5 mm 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
I8. Life expectancy of greater than 12 months
I9. Karnofsky Performance status 70 (patients younger than 18-year old) or
Eastern Cooperative Oncology Group (ECOG) performance status < 2 (adult
patients) (Cf. appendix 2)
I10. 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 Upper Limit of Normal (ULN)
Glomerular filtration rate (GFR) 30 ml/min/1.73m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula
Aspartate Aminotransferase (AST) and Alanine Aminotransferase (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 Gamma-Glutamyltransferase (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
I11. International Normalized Ratio (INR)/Partial Thromboplastin Time (PTT)
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
I12. Women of childbearing potential and male patients must agree to use
adequate contraception (Appendix 4) for the duration of study participation
and up to 8 weeks following completion of therapy
I13. Women of childbearing potential must have a negative serum -Human
Chorionic Gonadotropin (HCG) pregnancy test within 7 days prior randomization
and/or urine pregnancy test within 48 hours before the first administration of
the study treatment
I14. 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
I15. Patients must be willing and able to comply with scheduled visits
treatment plan, laboratory tests and other study procedures
I16. Patients covered by a medical insurance

Exclusion Criteria

E1. Prior treatment with any VEGFR inhibitor (thus, any prior exposure to
sunitinib, sorafenib, pazopanib, bevacizumab, or other VEGFR inhibitor)
E2. All soft tissue sarcomas (including but not limited to soft tissue
osteosarcoma and Ewing soft tissue sarcoma), and Ewing sarcoma, chondrosarcoma
and chordoma
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
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 (begun within the last 3 months prior to first study drug administration)
E5. Uncontrolled hypertension (systolic blood pressure > 150 mm Hg or
diastolic pressure > 90 mm Hg despite optimal treatment)
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
E7. Major surgical procedure, open biopsy, or significant traumatic injury
within 28 days before the first study drug administration
E8. Ongoing infection > Grade 2 according to NCI-CTCAE v5
E9. Known history of human immunodeficiency virus (HIV) infection
E10. Active hepatitis B or C or chronic hepatitis B or C requiring treatment
with antiviral therapy
E11. Dehydration according to NCI-CTCAE v5 Grade > 1
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
E13. Patients with seizure disorder requiring medication
E14. Concurrent enrolment in another clinical trial in which investigational
therapies are administered
E15. Known hypersensitivity to the active substance or to any of the
E16. Pregnant women, women who are likely to become pregnant or are breast-
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
E18. Patients with history of non-compliance to medical regimens or unwilling
or unable to comply with the protocol
E19. Interstitial lung disease with ongoing signs and symptoms at the time of
informed consent
E20. Non-healing wound, non-healing ulcer, or non-healing bone fracture
E21. Patients with evidence or history of any bleeding diathesis, irrespective
of severity
E22. Any haemorrhage or bleeding event NCI-CTCAE v5 Grade 3 within 4 weeks
prior to the first study drug administration
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
E24. Patients using prohibited concomitant and/or concurrent medications (see
section "Prohibited concomitant/concurrent treatments")
E25. Patients under tutorship or curatorship
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