A Multicentre Exploratory Phase II Study Describing the Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 168
- 试验地点
- 16
- 主要终点
- Relapse-Free Survival (RFS)
研究概览
简要总结
Randomized, non-comparative, multicentre exploratory phase II study.
Two arms 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 kept under surveillance (standard of care). Regardless of their study arm, all the patients will be followed up until end of the study.
The comparison between these two arms will allow to determine whether or not regorafenib is efficient for disease control, in terms of Relapse-Free Survival improvement.
详细描述
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%.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 12 years at the day of consenting to the study;
- •Patients must have histologically confirmed diagnosis of primary bone sarcoma including but not limited to: Osteosarcomas, Ewing sarcomas, Chondrosarcomas, Undifferentiated Pleomorphic Sarcomas (UPS), Leiomyosarcomas (LMS) and Angiosarcomas;
- •Prior treatment for localized or metastatic disease for bone sarcoma must have been completed, consisting of a standard multimodal treatment based on the histological subtype:
- •For OS, (excepted head and neck localisations), neoadjuvant and/or adjuvant chemotherapy should include methotrexate-based regimen for patients < 18 years old; patients ≥ 18 years old may have received either methotrexate-based regimen or anthracycline and cisplatin-based regimen 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.
- •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);
- •Interval between the last chemotherapy administration and the date of randomisation: at least 4 weeks but no longer than 2 months;
- •Confirmed complete remission or no evidence of disease (for metastatic disease);
- •Patients with pulmonary micro nodules can be included provided they do not meet the following criteria:
- •At least one lung nodule of 10mm or more
- •And/or at least two nodules well limited between 6-9mm
- •And/or at least 5 nodules well limited of 5mm 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.
- •Life expectancy of greater than 12 months;
- •Karnofsky Performance status ≥70 (patients younger than 18-year old) or ECOG performance status < 2 (adult patients) ;
- •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 ULN
- •Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula
- •AST and 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 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
- •INR/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;
- •Women of childbearing potential and male patients must agree to use adequate contraception (Appendix 4) for the duration of treatment and for 7 months (210 days) in WOCBP or 4 months (120 days) in men sexually active with WOCBP after the last dose of regorafenib;
- •Women of childbearing potential must have a negative serum β-HCG pregnancy test within 7 days prior randomization and/or urine pregnancy test within 48 hours before the first administration of the study treatment;
- •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;
- •Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures;
- •Patients covered by a medical insurance.
- •Body Surface Area (BSA) ≥ 1.30m² at the time of consenting to the study.
- •NON-INCLUSION CRITERIA :
- •Prior treatment with any VEGFR inhibitor (thus, any prior exposure to sunitinib, sorafenib, pazopanib, bevacizumab, or other VEGFR inhibitor);
- •All soft tissue sarcomas (including but not limited to soft tissue osteosarcomas and Ewing soft tissue sarcomas) and chordomas;
- •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;
- •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 within the last 3 months prior to first study drug administration;
- •Uncontrolled hypertension (systolic blood pressure > 150mmHg or diastolic pressure > 90 mmHg 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;
- •Major surgical procedure, open biopsy or significant traumatic injury within 28 days before the first study drug administration;
- •Ongoing infection > Grade 2 according to NCI-CTCAE v5;
- •Known history of human immunodeficiency virus (HIV) 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);
- 另有 17 项未显示
排除标准
- 未提供
研究组 & 干预措施
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).
干预措施: Treatment by Regorafenib (Drug)
Surveillance
No intervention is performed for patients in this arm; however, they receive the identical surveillance as patients of the experimental arm.
干预措施: Surveillance (Other)
结局指标
主要结局
Relapse-Free Survival (RFS)
时间窗: 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.
次要结局
- Time to Treatment Failure (TTF)(Up to 1 year)
- Overall Survival (OS)(Up to 5 years)
- Safety profile(Up to 5 years)
- Patient's Quality of Life (QoL)(Up to 5 years)
- Compliance To Treatment(Up to 1 year)