A Phase Ib Study of Olaparib With Concomitant Radiotherapy in Locally Advanced/Unresectable Soft-tissue Sarcoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 41
- 试验地点
- 4
- 主要终点
- Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
A phase Ib study of Olaparib with concomitant radiotherapy in locally advanced/unresectable soft-tissue sarcoma.
详细描述
This is a multicenter, prospective phase Ib trial based on a dose escalation study design (3+3 traditional design) assessing four dose levels of Olaparib given with concomitant radiotherapy, followed by an expansion cohort.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histology: patients with soft-tissue sarcoma histologically confirmed by central review (Pr Coindre team), except if the diagnosis was already confirmed by the RRePS Network,
- •Upper/Lower limb or trunk wall soft-tissue sarcoma,
- •Age ≥ 18 years,
- •Locally advanced or locally recurrent primitive tumor, outside any previously irradiated field. Patients presenting operable locally Advanced or lacally recurrent tumor can be included. Patients with metastases can be included.
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2,
- •Life expectancy ≥ 6 months,
- •At least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements,
- •Adequate hematological, renal, metabolic and hepatic function:
- •Haemoglobin ≥ 9 g/dL and no blood transfusions in the 14 days prior to study entry
- •Absolute neutrophil count (ANc) ≥ 1.5 x 109/L
- •Platelets ≥ 100 x 109/L
- •Total bilirubin ≤ 1.5 x upper limit of normality (ULN),
- •Alanine aminotransferase (ALAT) or aspartate aminotransferase (ASAT) ≤ 2.5 x ULN,
- •Serum creatinine ≤ 150 μmol/L or creatinine clearance ≥ 50 mL/min (according to local institution) in case of serum creatinine > 150 μmol/L,
- •TP, INR ≤ 1.5 x ULN
- •Women of childbearing potential must have a negative serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day
- •Female patients of child bearing potential and their partners, who are sexually active, must agree to the use of two highly effective forms of contraception in combination throughout the period of taking study treatment and for at least 1 month after last dose of study drug. Males patients, who are sexually active, must agree to the use of two highly effective forms of contraception in combination throughout the period of taking study treatment and for at least 3 month after last dose of study drug. Acceptable birth control methods are described in appendix
- •Subjects of non-childbearing potential are those who have:
- •Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments,
- •LH and FSH levels in the post menopausal range for women under 50,
- •radiation-induced oophorectomy with last menses >1 year ago,
- •chemotherapy-induced menopause with >1 year interval since last menses,
- •or surgical sterilisation (bilateral oophorectomy or hysterectomy).
- •Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up,
- •Voluntary signed and dated written informed consent prior to any specific procedure,
- •Patients with a social security in compliance with the Law.
排除标准
- •Any previous treatment with a PARP inhibitor, including Olaparib,
- •Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication,
- •Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy,
- •Patients with known active hepatic disease (i.e., Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids,
- •Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent,
- •Patients with uncontrolled seizures,
- •Men or women of childbearing potential who are not using an effective method of contraception as previously describes; women who are pregnant or breast feeding,
- •No prior or concurrent malignant disease diagnosed or treated in the last 2 years, except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
- •Patients receiving any systemic chemotherapy within 2 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used),
- •Concomitant use of known CYP3A4 inhibitors such as ketokonazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir,
- •Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome,
- •Blood transfusions within 14 days prior to study start,
- •Patients with myelodysplastic syndrome/acute myeloid leukaemia,
- •Major surgery within 14 days of starting study treatment and patients must have recovered from any effects of any major surgery,
- •Participation to a study involving a medical or therapeutic intervention in the last 30 days,
- •Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons,
- •Previous enrollment in the present study,
- •Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
- •Patients who not have recovered from any effects of any major surgery
- •Individuals deprived of liberty or placed Under legal guardianship
- •Patients who have tumor in contact with, invading or encasing for more than 50% any major blood vessels
研究组 & 干预措施
Olaparib in association with concomitant radiotherapy
Olaparib will be administered per os bi-daily, as appropriate assigned dose level, during 7.5 weeks (D1 to D52). Olaparib should be started one week before the start of radiotherapy and will be continued until the last day of radiotherapy. Beyond this period, Olaparib could be continued at the investigator's discretion and after sponsor authorization, until progression. Radiotherapy consists of fractionated focal irradiation at a dose of 1.8 Grays (Gy) per fraction given once daily five days per week (Monday through Friday) over a period of 6.5 weeks, for a total dose of 59.4 Gy. Radiotherapy starts at D8.
干预措施: Concomitant Radiotherapy (Radiation)
Olaparib in association with concomitant radiotherapy
Olaparib will be administered per os bi-daily, as appropriate assigned dose level, during 7.5 weeks (D1 to D52). Olaparib should be started one week before the start of radiotherapy and will be continued until the last day of radiotherapy. Beyond this period, Olaparib could be continued at the investigator's discretion and after sponsor authorization, until progression. Radiotherapy consists of fractionated focal irradiation at a dose of 1.8 Grays (Gy) per fraction given once daily five days per week (Monday through Friday) over a period of 6.5 weeks, for a total dose of 59.4 Gy. Radiotherapy starts at D8.
干预措施: Olaparib (Drug)
结局指标
主要结局
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
时间窗: Until to six weeks after end of radiotherapy
We reported in the following the number of Participants who experienced DLT. A DLT is defined as an adverse event (AE) or laboratory abnormality that fulfills all the criteria below: 1/ Occurs during the period of observation of DLTs defined as the period between the first day of treatment administration and up to 6 weeks after the end of radiotherapy. 2/ Is considered to be at least possibly related to the treatment strategy (radiotherapy or Olaparib).3/ Is unrelated to disease, disease progression, inter-current illness, or concomitant medications. 4/ Meets some criteria (see protocole), graded according to NCI CTCAEv4.0
Maximum Tolerated Dose (MTD) of Olaparib in Association With Radiotherapy
时间窗: Up to 6 weeks after end of radiotherapy for each dosing cohort
MTD was determined by testing increasing doses up 150mg twice a day on dose escalation cohorts 1 to 4 with 3 to 11 participants each. MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in \> 33% of participants. DLTs were defined as any grade 3 or 4 adverse event according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) that could be related to treatment (reported in the following primary outcome measure).
次要结局
- Percentage of Participants With Non-progression at 6 Months as Per RECIST 1.1(up to 6-month after treatment onset)
- Percentage of Participants With Objective Responses at 6 Months as Per RECIST 1.1(up to 6-month after treatment onset)
- Best Response Under Treatment as Per RECIST 1.1(End of treatment, approximately 13.5 weeks atfer treatment onset)
- Progression-free Survival (PFS) as Per RECIST 1.1(1 year after treatment onset)
- Overall Survival (OS)(1 year after treatment onset)
- Musculoskeletal Tumor Society (MSTS) Functional Score(Two weeks after treatment onset)