Phase I Clinical Trial of Olaratumab Plus Trabectedin in Advanced Soft-tissue Sarcoma Patients
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- To determine the maximum tolerated dose (MTD) or the recommended dose for phase II of Olaratumab plus Trabectedin.
研究概览
简要总结
Phase I, multicentre clinical trial of olaratumab plus trabectedin in patients with advanced soft-tissue sarcoma.
Olaratumab plus trabectedin could be synergistic and with a manageable toxicity profile in advanced STS.
The study is a phase I, non-randomised, one-armed, multicenter trial, open-label.
The dose escalation rules include patients in blocks of 3 o 6 patient. Treatment is a combination of unlimited cycles of oralatumab and trabectedin.
Primary clinical study endpoint of phase I:
- Determine the maximum tolerated dose (MTD) or the recommended dose of olaratumab combined with trabectedin in advanced soft tissue sarcoma
Secondary clinical study endpoints:
- Objective Response Rate (ORR): ORR is defined as the number of subjects with a Best Overall Response (BOR) according to RECIST 1.1.
- Progression free survival (PFS): time to progression or death from treatment initiation.
- Overall survival (OS): Time from treatment initiation until death. Efficacy measured through tumor response according to Choi criteria. The evaluation criteria will be based on the identification of target lesions in baseline and their follow-up until tumor progression.
- Correlation of clinical outcome with translational biomarkers.
- Quality of life (QoL) measured per QLQ-C30 questionnaire of EORTC
详细描述
PHASE I DESIGN
The number of evaluable patients to be included in this trial is 25. However 28 patients will be enrolled considering the possibility of 3 non-evaluable cases.
The dose escalation rules proceed as follows: escalating in cohorts of 3-6 patients per dose level. Three patients are treated at a given dose level. If at least 2 patients are observed to have dose-limiting toxicity (DLT), the prior dose level is defined as the maximum tolerable dosage (MTD) (unless only 3 patients have been treated at that level, in which case it is the tentative MTD). If 0 of the 3 patients are observed to have DLT, the dose level is escalated one step for the next cohort of 3 patients, and the process continues as above. If exactly 1 of the 3 patients treated show DLT, 3 additional patients are treated at the current dose level. If none of these additional 3 patients show DLT, the dose level is escalated for the next cohort of 3 patients, and the process continues as above; otherwise, the prior dose level is defined as the MTD.
Dose-limiting toxicity (DLT) is usually defined as cycle 1 grade 3 or above toxicity, excepting grade 3 neutropenia unaccompanied by either fever or infection. More specifically, for this clinical trial, DLT will be applied only to either of the following toxicities occurring during the first treatment cycle:
Hematological toxicity:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must provide written informed consent prior to performance of study specific procedures and must be willing to comply with treatment and follow-up.
- •Age: 18-80 years.
- •Histologic diagnosis of soft tissue sarcoma: liposarcoma (dedifferentiated and myxoid/round cell), leiomyosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma confirmed, before enrolment confirmation, by central pathology review by a paraffin embedded tumor tissue.
- •Metastatic/advanced disease in progression in the last 6 months.
- •Patients had previously received at least anthracyclines if clinically indicated.
- •Previous olaratumab administration is allowed.
- •Measurable disease according to RECIST 1.1 criteria.
- •ECOG Performance Status of 0-
- •Adequate hepatic, renal, cardiac, and hematologic function.
- •Laboratory tests as follows: Haemoglobin >9g/dl, Absolute neutrophil count ≥ 1,500/mm³, Platelet count ≥ 100,000/mm³, Total Bilirubin ≤ 1.5 mg/dL, PT≤ 1.5 ULN and INR ≤ 1.5, AST and ALT ≤ 2.5 times upper limit of normal, Creatinine
- •≤ 1.5 mg/dL Calcium ≤ 12 mg/dL and Blood glucose < 150 mg/dL, Urine protein assessment: <2+, and/or <3.5g protein/24h.
- •Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.
- •Having a central venous portal is mandatory before treatment initiation.
- •Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment. Females of child-bearing potential and males and must agree to use highly effective contraceptive precautions during the trial and up to 6 months following the last dose of study drug. A highly effective method of birth control is defined as one that results in a low failure rate (that is, <1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner.
- •Exceptions: Females not of child-bearing potential due to surgical sterilization (at least 6 weeks following surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by medical history or menopause. A "postmenopausal woman" is a woman meeting either of the following criteria:
- •spontaneous amenorrhea for at least 12 months, not induced by a medical condition such as anorexia nervosa and not taking medications during the amenorrhea that induced the amenorrhea (for example, oral contraceptives, hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen receptor modulators (SERMs), or chemotherapy
- •spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone (FSH) level >40 mIU/mL
- •Exclusion criteria:
- •More than 2 previous lines of chemotherapy for advanced disease. Previous trabectedin not allowed.
- •Hipersensitivity to olaratumab.
- •The following histologies are not included: Ewing Sarcoma, extraskeletal osteosarcoma, extraskeletal myxoid chondrosarcoma, Kaposi's sarcoma, rhabdomyosarcoma and gastrointestinal stromal tumor (GIST).
- •Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI-CTCAE] version 5.0 Grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= Grade 3).
- •Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
- •Other disease or illness within the past 6 months, including any of the following:
- •Myocardial infarction
- •Coronary or peripheral artery bypass graft
- •Cerebrovascular accident or transient ischemic attack
- •Pulmonary embolism
- •The patient has electively planned or will require major surgery during the course of the study
- •Social situation that would preclude study compliance.
- •Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
- •Hemorrhage ≥ Grade 3 in the past 4 weeks.
- •Females who are pregnant or breast-feeding.
排除标准
- 未提供
研究组 & 干预措施
Unlimited cycles of Olaratumab and Trabectedin
The study is a phase I, non-randomised, one-armed, multicenter trial, open-label,.
The dose escalation rules include patients in blocks of 3 o 6 patient. Treatment is a combination of unlimited cycles of oralatumab and trabectedin.
干预措施: Olaratumab and Trabectedin (Drug)
结局指标
主要结局
To determine the maximum tolerated dose (MTD) or the recommended dose for phase II of Olaratumab plus Trabectedin.
时间窗: Recruitment duration: 18 months
There will be determined the security profile for each dose level.
次要结局
- Objective Response Rate (ORR)(During recruitment and follow-up (30 months))
- Efficacy as per Choi criteria(During recruitment and follow-up (30 months))
- Correlation of clinical outcome with translational biomarkers (See Translational Section)(During recruitment and follow-up (30 months))
- Progression free survival (PFS)(During recruitment and follow-up (30 months))
- Overall survival (OS)(During recruitment and follow-up (30 months))
- QoL(Recruitment duration: 18 months)