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Tyrosine

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).

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).

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

Treatment by regorafenib and best supportive care

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

Treatment by placebo and best supportive care

Julien GAUTIER

Loïc CHAIGNEAU

Maud TOULMONDE

Alice HERVIEUX

Nicolas PENEL

Mehdi BRAHMI

Nelly FIRMIN

Morgane CLEIREC

Sophie PIPERNO-NEUMANN

Pascaline BOUDOU-ROUQUETTE

Emmanuelle BOMPAS

Claire BERGER

Natacha ENTZ WERLE

Justine GANTZER

Thibaud VALENTIN

Nathalie GASPAR

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.

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.

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

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

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.

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.

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)

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.

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

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

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.

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.

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.

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.

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.

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.

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®.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Efficacy of Regorafenib Combined With Best Supportive Care as Maintenance Treatment in High Grade Bone Sarcomas Patients	NCT04698785	Bone Sarcoma Osteosarcoma	Treatment by re... Treatment by pl...	12 Years -	Centre Leon Berard
Efficacy of Regorafenib Combined With Best Supportive Care as Maintenance Treatment in High Grade Bone Sarcomas Patients	NCT04698785	Bone Sarcoma Osteosarcoma	Treatment by re... Treatment by pl...	12 Years -	Centre Leon Berard

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