NCT02389244已完成2 期
A Randomized Phase II, Placebo-controlled, Multicenter Study Evaluating Efficacy and Safety of Regorafenib in Patients With Metastatic Bone Sarcomas
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- UNICANCER
- 入组人数
- 163
- 试验地点
- 34
- 主要终点
- Non-progression rate
研究概览
简要总结
INDICATION:
Metastatic bone sarcomas: conventional high grade osteosarcoma, Ewing sarcoma of bone, intermediate or high-grade chondrosarcomas and chordomas and either bone or soft tissue metastatic CIC-rearranged sarcomas
详细描述
METHODOLOGY:
Randomized, placebo-controlled, multicentric, phase II study -This is a double-blind placebo-controlled trial, with 5 cohorts: cohort A: Osteosarcoma, cohort B: Ewing sarcoma, cohort C: Chondrosarcoma, cohort D : chondroma, cohort E: CIC-rearranged sarcoma. Cohort A, B and C will involve a total of 36 patients (24 Regorafenib + 12 placebo), cohort D a total of 24 evaluable patients (16 Regorafenib + 8 placebo) and cohort E will involve a total of 27 evaluable patients (18 Regorafenib + 9 placebo).
159 patients who meet the eligibility criteria will be randomly assigned in a 2:1 ratio to the following treatment groups :
The Arm A:
Regorafenib (160 mg/d) once daily for the 3 weeks on / 1 week off plus Best Supportive Care (BSC) until progression (according to RECIST 1.1), intolerance or withdrawal of consent .
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 10 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have histologically confirmed diagnosis of bone sarcoma (osteosarcoma, Ewing sarcoma of bone, chondrosarcoma or chordoma);
- •Patients with confirmed disease progression at study entry;
- •Metastatic disease not amenable to surgical resection or radiation with curative intent;
- •Patients must have measurable disease;
- •Prior treatment :
- •at least one, but no more than two prior chemotherapy regimen for metastatic disease for osteosarcoma, chondrosarcoma and Ewing sarcoma; neo-adjuvant /maintenance therapy are not counted towards this requirement. Chordoma not pretreated or with 1 or 2 prior (combination) chemotherapy regimen or with one or two prior molecularly targeted therapy, but no more than 2 prior lines of treatment (whatever the indication) can be included. At least 4 weeks since last chemotherapy (6 weeks in case of nitrosoureas and mitomycin C), immunotherapy or any other pharmacological treatment and/or radiotherapy;
- •Age ≥10 years for osteosarcomas, Ewing sarcomas and chondrosarcomas (for chordomas, patients must be ≥18 years);
- •Body Surface Area ≥1.30 m²;
- •Life expectancy of greater than 3 months;
- •Eastern Cooperative Oncology Group (ECOG) performance status <2 (Karnofsky ≥60%) for adults patients;
- •Karnofsky scale ≥ 60% for children aged >12 years old / Lansky scale ≥60% for children aged ≤12 years old;
- •Patients must have adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days of study treatment initiation: normal organ function as defined below:
- •Absolute neutrophil count ≥1.5 Giga/L
- •Platelets ≥100 Giga/L
- •Hemoglobin ≥9 g/dL
- •Serum creatinin ≤1.5 x upper limit of normal (ULN)
- •Glomerular filtration rate (GFR) ≥30 ml/min/1.73 m² according to the modified Diet in Renal Disease (MDRD) abbreviated formula
- •Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN
- •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 gamma-glutamyl transferase (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+ or more 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
- •International Normalized Ratio(INR)/ Partial Thromboplastin Time (PTT) ≤1.5 x ULN;
- •Recovery to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure related toxicity (except alopecia, anemia, and hypothyroidism);
- •Women of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy;
- •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;
- •Signed informed consent form by adult patients and/or patients parents/legal representatives (if age <18 years) and age appropriate assent form by the patients' parents/legal representatives obtained before any study specific procedure is conducted;
- •Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures;
- •Patients or parents/legal representatives affiliated to the Social Security System.
排除标准
- •Prior treatment with any VEGFR inhibitor;
- •Soft tissue sarcoma;
- •Other cancer (different histology) within 5 years prior to randomization;
- •Major surgical procedure, open biopsy, significant trauma, within the last 28 days before randomization;
- •Cardiovascular dysfunction:
- •Left ventricular ejection fraction (LVEF) <50%
- •Congestive heart failure (New York Heart Association [NYHA]) ≥2
- •Myocardial infarction <6 months before study
- •Cardiac arrhythmias requiring therapy
- •Uncontrolled hypertension
- •Unstable angina or new-onset angina
- •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 randomization;
- •Severe hepatic impairment (Child-Pugh C);
- •Ongoing infection > Grade 2 according to NCI-CTCAE v4.0;
- •Known history of human immunodeficiency virus (HIV) infection;
- •Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy;
- •Difficulties with swallowing study tablets;
- •Prior anticancer therapy, including radiotherapy, endocrine therapy, immunotherapy, chemotherapy (CT) within the last 4 weeks (6 weeks for nitrosoureas and mitomycin C), or other investigational agents ; Concomitant antalgic palliative radiotherapy allowed;
- •Concurrent enrolment in another clinical trial in which investigational therapies are administered;
- •Known hypersensitivity to the active substance or to any of the excipients;
- •Pregnant women, women who are likely to become pregnant or are breast-feeding;
- •For adult patients, individual deprived of liberty or placed under the authority of a tutor;
- •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;
- •Patients with history of non compliance to medical regimens or unwilling or unable to comply with the protocol;
- •Interstitial lung disease with ongoing signs and symptoms at the time of informed consent;
- •Non-healing wound, non-healing ulcer, or non-healing bone fracture;
- •Patients with evidence or history of any bleeding diathesis, irrespective of severity;
- •Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication;
- •Use of biological response modifiers, such as granulocyte colony stimulating factor (G-CSF), within 3 weeks of study entry.
研究组 & 干预措施
placebo
Placebo Comparator
Placebo plus BCS until progression (according to RECIST V1.1) intolerance or withdrawal of consent. Patients who have received placebo will receive open-label regorafenib after objective tumor progression.
干预措施: Placebo (Drug)
Regorafenib
Experimental
For adult patients (≥18 years old) : 160 mg/d once daily for the 3 weeks on / 1 week off plus Best Supportive Care (BSC) until progression (according to RECIST 1.1), intolerance or withdrawal of consent .
For children Age ≥10 years to <18 years old and BSA ≥1.30 m², regorafenib (82 mg/m²) once daily for the 3 weeks on/1 week off (without exceeding 160 mg/day) plus Best Supportive care (BSC) until progression (according to RECIST 1.1), intolerance or withdrawal of consent.
干预措施: Regorafenib (Drug)
结局指标
主要结局
Non-progression rate
时间窗: 8 weeks for cohorts A, B and E, 12 weeks for cohort C, 6 months for cohort D
Proportion of patients without disease progression at the defined timepoint after central radiological review (using RECIST 1.1)
次要结局
- Time to progression(from date of randomization until the date of first observation of progression (up to 6 months))
- Duration of response(expected average duration of 6 months)
- Progression-free rate at 3 and 6 months(at 3 and 6 months)
- Overall survival(2 years)
- Progression Free Survival(expected average duration of 3 months)
- Objective response rate(6 months)
- Disease control rate at 6 months(6 months)
- Growth Modulation Index defined as ratio of time to progressive disease (PD) under regorafenib to time to progression (TTP) under previous treatment(expected average duration of 3 months)
- Toxicity according to NCI-CTCAE V4-0(expected average duration of 6 months)
- Pain assessment using Visual analog scale (VAS), DN4 scale (Neuropathic Pain Diagnostic Questionnaire) and NPSI scale (Neuropathic Pain Symptom Inventory)(expected average duration of 6 months)
- PFS(from date of randomization until the date of first observation of progression (up to 6 months))
研究者
研究点 (34)
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