Efficacy of Regorafenib Combined With Best Supportive Care as Maintenance Treatment in High Grade Bone Sarcomas Patients

Study Overview
=================
Brief Summary
-----------------
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.

Detailed 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.

Official Title
-----------------
A Randomized, Placebo-controlled, Double-blinded, Phase II Study of Efficacy of Regorafenib as Maintenance Treatment in Patients With High Grade Bone Sarcomas at Diagnosis or Relapse and Without Complete Remission After Standard Treatment

Conditions
-----------------
Bone Sarcoma, Osteosarcoma

Intervention / Treatment
-----------------
* Drug: Treatment by regorafenib and best supportive care
* Drug: Treatment by placebo and best supportive care


Participation Criteria
=================
Eligibility Criteria
-----------------
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 : No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months prior to enrolment; No history of AIDS-defining cancers (e.g. Kaposi's sarcoma, aggressive B-cell lymphoma and invasive cervical cancer); 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.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regorafenib and best supportive care<br>Treatment will be divided in 28 days cycles, including a 21-day period of treatment by regorafenib and best supportive care followed by a 7-day period of rest. In case of toxicity, dose can be reduced or treatment interrupted according to Specific Product Characteristics (SPC). Patients can receive up to a maximum of 13 cycles (maximum treatment period : 12 Months). | Drug: Treatment by regorafenib and best supportive care<br>* Treatment for 13 cycles (12 months) maximum. During each cycle : patients ≥ 16 years old and patients <16 old with Body Surface Area (BSA) ≥ 1,70 m2 will take 3 tablets, once a day, corresponding to a total of 120 mg Regorafenib, during 21 days, followed by 7 days without treatment. patients < 16 years old with a 1,30 m2 ≤ BSA ≥ 1,70 m2 will take 2 tablets, once a day, corresponding to a total of 80 mg Regorafenib, during 21 days, followed by 7 days without treatment<br>* Other names: Experimental arm;|
| Placebo Comparator: Placebo and best supportive care<br>Treatment will be divided in 28 days cycles, including a 21-day period of treatment by placebo and best supportive care followed by a 7-day period of rest. In case of toxicity, dose can be reduced or treatment interrupted according to Specific Product Characteristics (SPC). Patients can receive up to a maximum of 13 cycles (maximum treatment period : 12 Months). | Drug: Treatment by placebo and best supportive care<br>* Treatment for 13 cycles (12 months) maximum. During each cycle : patients ≥ 16 years old and patients <16 old with Body Surface Area (BSA) ≥ 1,70 m2 will take 3 tablets, once a day, corresponding to a total of 120 mg Placebo, during 21 days, followed by 7 days without treatment. patients < 16 years old with a 1,30 m2 ≤ BSA ≥ 1,70 m2 will take 2 tablets, once a day, corresponding to a total of 80 mg Placebo, during 21 days, followed by 7 days without treatment<br>* Other names: Standard arm;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | The Progression-Free Survival (PFS) will be defined as the time from the date of randomization to the date of first documented disease progression (according to the RECIST V1.1) or the date of death due to any cause. Patients alive and progression-free at the time of data cut-off will be censored at the time of the latest tumour evaluation. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) from switch | In patients from the placebo arm who switched into the active treatment group, PFS will be studied from regorafenib initiation: PFS from switch will be defined as the time from the date of switch to the date of first documented disease progression (according to the RECIST V1.1) post-switch or the date of death due to any cause. | Up to 3 years | 
| Objective Response Rate (ORR) | The Objective Response Rate (ORR) will be defined as the proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR) (RECIST V1.1) | Up to 3 years | 
| Objective Response Rate (ORR) from switch | In patients from the placebo arm who switched into the active treatment group, the ORR will be studied from regorafenib initiation: The ORR from switch will be defined as the proportion of patients in the placebo arm with a best overall response of Complete Response (CR) or Partial Response (PR) from regorafenib initiation. | Up to 3 years | 
| Disease Control Rate (DCR) at 2 months | The Disease Control Rate (DCR) will be defined as the proportion of patients with a best overall response of CR, PR or Stable Disease (SD) (RECIST V1.1) 2 months after randomization | 2 months | 
| Disease Control Rate (DCR) at 4 months | The Disease Control Rate (DCR) will be defined as the proportion of patients with a best overall response of CR, PR or Stable Disease (SD) (RECIST V1.1) 4 months after randomization | 4 months | 
| Disease Control Rate (DCR) from switch at 2 months | In patients from the placebo arm who switched into the active treatment group, the DCR will be studied from regorafenib initiation: The DCR from switch will be defined as the proportion of patients in the placebo arm with a best overall response of CR, PR or Stable Disease (SD) 2 months after regorafenib initiation. | 2 months | 
| Disease Control Rate (DCR) from switch at 4 months | In patients from the placebo arm who switched into the active treatment group, the DCR will be studied from regorafenib initiation: The DCR from switch will be defined as the proportion of patients in the placebo arm with a best overall response of CR, PR or Stable Disease (SD) 4 months after regorafenib initiation. | 4 months | 
| Time to Treatment Failure (TTF) | The Time to Treatment Failure (TTF) will be defined as the time from the date of randomization to the date of permanent discontinuation of the study treatment, whichever is the cause. Patient not known to have withdrawn treatment before 12 months (study treatment duration) will be censored at the time of treatment stop. | Up to 1 year | 
| Overall Survival (OS) | The Overall Survival (OS) will be defined as the time from date of randomization to the date of death, from any cause. Patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive. | Up to 3 years | 
| Overall Survival (OS) from switch | In patients from the placebo arm who switched into the active treatment group, the OS will be studied from regorafenib initiation: The Overall Survival (OS) from switch will be defined as the time from date of switch to the date of death, from any cause. Patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive. | Up to 3 years | 
| Quality of Life (QoL) after 6 cycles of treatment | The patient's Quality of Life (QoL) will be assessed using the EORTC Quality Of Life Questionnaire (QLQ)-C30 file. Scores will be calculated at each time point according to the scoring manuals. Descriptive statistics will be used to evaluate baseline scores and evolution of scores from baseline to each time point. Data will be compared between arms using the Student's t-test. The QoL data will also be presented graphically if deemed relevant. | 6 months | 
| Quality of Life (QoL) after treatment completion | The patient's Quality of Life (QoL) will be assessed using the EORTC Quality Of Life Questionnaire (QLQ)-C30 file. Scores will be calculated at each time point according to the scoring manuals. Descriptive statistics will be used to evaluate baseline scores and evolution of scores from baseline to each time point. Data will be compared between arms using the Student's t-test. The QoL data will also be presented graphically if deemed relevant. | Up to 1 year | 
| Tolerance profile of treatment | The safety will be described mainly on the frequency of adverse events (AE) coded using the common toxicity criteria (NCI-CTCAE v5.0) grade. Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment. AE will be coded according to the MedDRA®. | Up to 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bone sarcoma, Osteosarcoma, Maintenance therapy, Regorafenib, Randomization, Double-blind, Placebo-controlled, Progression-free survival, Objective response rate, Disease control rate, Time to treatment failure, Overall survival, Quality of life, Tolerance, Tyrosine inhibitor kinase, Multitarget inhibitor, High-grade