Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas
- Conditions
- LeiomyosarcomaBone SarcomaOsteosarcomaChondrosarcomaUndifferentiated Pleomorphic SarcomaEwing SarcomaAngiosarcoma
- Interventions
- Drug: Treatment by PlaceboDrug: Treatment by Regorafenib
- Registration Number
- NCT04055220
- Lead Sponsor
- Centre Leon Berard
- Brief Summary
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, 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.
- Detailed Description
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. Chemotherapy treatment is commonly given for OS over a period of 6-10 months, with a period of preoperative chemotherapy, to facilitate local surgical treatment. The conventional cocktail used in OS is composed by a minimum of three drugs (reference combination: methotrexate, doxorubicin and cisplatin (MAP)).
The currently recommended treatments for Ewing sarcomas (for both localized and metastatic diseases) consist of multimodal approaches including surgery and/or radiotherapy associated to neoadjuvant and adjuvant chemotherapy, comprising respectively from 3 to 6, and then from 6 to 10 cycles. Doxorubicin, cyclophosphamide, ifosfamide, vincristine, dactinomycin and etoposide are considered as the most active substances. Current trials require combination chemotherapies, and most of them are based on the combination of 5-6 of these substances.
Concerning chondrosarcomas, the treatment is adapted according to the subtype. Thus, the treatment regimen for mesenchymal chondrosarcomas and dedifferentiated chondrosarcomas differs. Indeed, an Ewing-type chemotherapy regimen is usually suggested to treat mesenchymal chondrosarcomas while dedifferentiated chondrosarcomas are often treated as high-grade bone sarcoma, with systemic and local therapies.
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 standard treatments 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 treatments. 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 standard multimodal treatments based on the histological subtype.
The main goal of the present study is then to explore whether sequential addition of regorafenib after completion of a standard treatment 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 168
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Treatment by Placebo Treatment will be divided in 28 days cycles, including a 21-day period of treatment by placebo 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). Regorafenib Treatment by Regorafenib Treatment will be divided in 28 days cycles, including a 21-day period of treatment by regorafenib 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).
- Primary Outcome Measures
Name Time Method Relapse-Free Survival (RFS) Up to 5 years RFS will be defined as the time from randomization to relapse, or death from any cause, whichever occurs first. Patients alive without relapse at the time of the analysis will be censored at the date of last tumour assessment. The Kaplan-Meier approach will be used to estimate median RFS for each study arm. The two-sided log-rank test, stratified on randomization stratification factors, will be used to compare RFS between the investigational arm and the control arm. The stratified Cox-regression (with proportional hazards) will be used to estimate the hazard ratio and to calculate the 95% confidence intervals of the hazard ratio.
- Secondary Outcome Measures
Name Time Method Time to Treatment Failure (TTF) Up to 1 year 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. TTF survival will be estimated using the Kaplan-Meier method, and will be described in terms of medians along with the associated 2-sided 95% confidence interval for the estimates.
Overall Survival (OS) Up to 5 years 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. OS survival will be estimated using the Kaplan-Meier method, and will be described in terms of medians along with the associated 2-sided 95% confidence interval for the estimates.
Safety profile Up to 5 years The safety will be described mainly on the frequency of adverse events coded using the common toxicity criteria (NCI-CTCAE v5.0) grade. Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment. Adverse events will be coded according to the MedDRA®.
Patient's Quality of Life (QoL) Up to 5 years The patient's Quality of Life will be assessed using the EORTC QLQ-C30. 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 (Every 3 months since baseline, then every 4 months after second year surveillance). Data will be compared between arms using the Student's t-test. The QoL data will also be presented graphically if deemed relevant.
Compliance To Treatment Up to 1 year The compliance to treatment will be described using the proportion of patients requiring dose reduction and temporary or permanent treatment discontinuation.
Trial Locations
- Locations (16)
Hôpital Jean Minjoz
🇫🇷Besançon, France
Institut Bergonié
🇫🇷Bordeaux, France
Centre Oscar Lambret
🇫🇷Lille, France
Centre Léon Bérard
🇫🇷Lyon, France
APHM - Hôpital Timone
🇫🇷Marseille, France
ICM Val d'Aurelle
🇫🇷Montpellier, France
Institut Curie
🇫🇷Paris, France
APHP Hôpital Cochin
🇫🇷Paris, France
Centre Hospitalier Universitaire de Poitiers
🇫🇷Poitiers, France
ICO René Gauducheau
🇫🇷Saint-Herblain, France
Centre Hospitalier Universitaire de Saint-Etienne (CHUSE)
🇫🇷Saint-Étienne, France
Institut de Cancérologie Strasbourg Europe
🇫🇷Strasbourg, France
Centre Hospitalier Régional de Strasbourg Hautepierre
🇫🇷Strasbourg, France
IUCT-Oncopole
🇫🇷Toulouse, France
ICL Alexis Vautrin
🇫🇷Vandœuvre-lès-Nancy, France
Institut Gustave Roussy
🇫🇷Villejuif, France