Overview
This is a randomized, double-blinded, 2 arms study concerning patients with high-grade bone sarcoma (HGBS) without complete remission after standard treatment at diagnosis or first relapse.
In the first arm, patients will be treated with regorafenib + best supportive care (BSC) for a maximum of 12 months as maintenance therapy after standard line therapy completion, whereas in the second arm, patients will be treated with placebo + BSC (standard of care).
The comparison between this two arms will allow to determine whether or not regorafenib and BSC is efficient for disease control, in terms of Progression-Free Survival improvement.
Description
This is a randomized, placebo-controlled, double-blinded, prospective, comparative, multicentre phase II study.
Patients with measurable unresectable residual disease will be accrued after they completed standard of care, consisting of:
- At diagnosis: multimodal treatment with neoadjuvant chemotherapy, surgery and adjuvant chemotherapy
- At relapse: chemotherapy
Patients who meet the eligibility criteria will be randomly assigned (1:1) into one of the following treatment groups:
- Experimental arm: regorafenib + best supportive care (BSC) maintenance (12 months maximum)
- Standard arm: placebo + BSC (12 months maximum)
A randomization procedure (centralized implementation of concealed random permuted blocks) will be used to obtain a balanced distribution of the setting of the disease (stratification factor): residual disease at diagnosis or at relapse after standard multimodal treatment.
After their eligibility has been confirmed, patients will receive regorafenib or its matching placebo until disease progression, or for a maximum of 12 months, or unacceptable toxicity or willingness to stop, whichever occurs first.
In case of radiological disease progression during treatment period, patients from the standard arm (placebo) who have unresectable disease will be allow to switch to experimental arm (regorafenib). After the switch, patients will be treated with regorafenib until disease progression or unacceptable toxicity or willingness to stop which occurs first.
After the completion of the maintenance therapy (12 months) patients will be followed-up until the first radiological disease progression, unless a premature disease progression occurred. All patients will be followed-up until the data cut-off (12 months after the last randomization).
The vital status will be updated once for all patients at the end of the study, based on patient's medical file.
The end of the study will be 24 months after the last randomisation or at the end of treatment of the last patient under treatment (either blinded or open label) whichever occurs last.
Eligibility
INCLUSION CRITERIA:
I1. Age ≥ 12 years at the day of consenting to the study;
I2. Patients must have histologically confirmed high-grade sarcomas of bone primary
localisation, including but not limited to: Osteosarcomas, Ewing sarcomas, Chondrosarcomas,
Undifferenciated Pleomorphic Sarcomas (UPS), Leiomyosarcomas (LMS) and Angiosarcomas
I3. Measurable residual disease not amenable to resection after multimodal treatment
principles either at diagnosis (after standard multimodal treatment based on the
histological subtype) or at relapse (chemotherapy)
I4. Non progressive disease (defined by the investigator according to the RECIST version
1.1 Appendix 1) at study entry;
I5. Interval between the date of last anticancer treatment (chemotherapy or surgery) and
the date of randomization: at least 4 weeks but no longer than 2 months;
I6. Life expectancy of greater than 6 months;
I7. Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky ≥ 70%)
(Appendix 2);
I8. Adequate bone marrow and organ function defined by the following laboratory results:
a. Bone marrow: i. Absolute neutrophil count ≥ 1.5 Giga/l ii. Platelets ≥ 100 Giga/l iii.
Haemoglobin≥ 9 g/dl
b. Hepatic function: i. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT)
≤ 2.5 x Upper Limit of Normal (ULN) (≤ 5.0 × ULN for patients with liver involvement of
their cancer) ii. Bilirubin ≤1.5 X ULN iii. 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 gamma-glutamyltransferase (GGT) tests must be performed;
hepatic isoenzymes 5-nucleotidase must be within the normal range and/or GGT < 1.5 x ULN.
c. Renal function: i. Serum creatinine ≤ 1.5 x ULN ii. Glomerular Filtration Rate (GFR) ≥
30 ml/min/1.73m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula
iii. 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
d. Coagulation: International Normalized Ratio (INR)/Partial Thromboplastin Time (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;
e. Pancreatic function: Lipase ≤ 1.5 x ULN
I9. Recovery to anticancer-treatment related 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);
I10. Women of childbearing potential and male patients must agree to use adequate
contraception (including at least the use of condoms) for the duration of treatment and for
7 months (210 days) in women of childbearing potential or 4 months (120 days) in men
sexually active with women of childbearing potential after the last dose of regorafenib
I11. 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;
I12. Patients must be willing and able to comply with scheduled visits, treatment plan,
laboratory tests and other study procedures;
I13. Patients affiliated to the Social Security System
I14. Body Surface Area (BSA) ≥ 1.30m² at the time of consenting to the study
EXCLUSION CRITERIA:
E1. Prior treatment with any VEGFR inhibitor (thus, any prior exposure to regorafenib,
sunitinib, sorafenib, pazopanib, bevacizumab, or other VEGFR inhibitor);
E2. All soft tissue sarcomas (including but not limited to soft tissue osteosarcoma), and
chordomas;
E3. Prior history of 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 defined by:
- 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;
- Uncontrolled hypertension (systolic blood pressure > 150 mm Hg or diastolic pressure >
90 mm Hg despite optimal treatment);
- 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;
E5. Major surgical procedure, open biopsy or significant traumatic injury within 28 days
before the first study drug administration;
E6. Ongoing infection > Grade 2 according to NCI-CTCAE v5;
E7. Known history of human immunodeficiency virus infection;
Nota Bene: Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to
participate in the study if they meet the following criteria :
1. No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic
infection within the past 12 months prior to enrolment;
2. No history of AIDS-defining cancers (e.g. Kaposi's sarcoma, aggressive B-cell lymphoma
and invasive cervical cancer);
3. 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;
E8. Active 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
E9. Dehydration according to NCI-CTCAE v5 Grade >1;
E10. 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);
E11. Patients with seizure disorder requiring medication;
E12. Concurrent enrolment in another clinical trial in which investigational therapies are
administered;
E13. Known hypersensitivity to the active substance or to any of the excipients;
E14. Pregnant women, women who are likely to become pregnant or are breast-feeding. Women
of childbearing potential must have a negative serum β-Human Chorionic Gonadotropin (HCG)
pregnancy test within 7 days prior randomization;
E15. 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;
E16. Patients with history of non-compliance to medical regimens or unwilling or unable to
comply with the protocol;
E17. Interstitial lung disease with ongoing signs and symptoms at the time of informed
consent;
E18. Non-healing wound, non-healing ulcer, or non-healing bone fracture;
E19. Patients with evidence or history of any bleeding diathesis, irrespective of severity;
E20. Any haemorrhage or bleeding event ≥ CTCAE v5 Grade 3 within 4 weeks prior to the first
study drug administration;
E21. 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;
E22. Patients using prohibited concomitant and/or concurrent medications (see section
"Prohibited concomitant/concurrent treatments);
E23. Patients under tutorship or curatorship.