Trabectedin Combined With Durvalumab (MEDI4736) in Patients With Advanced Pretreated Soft-tissue Sarcomas and Ovarian Carcinomas. A Phase Ib Study.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Dose Escalation Part: Establish the Recommended Phase II Dose (RP2D), the Maximum Tolerated Dose (MTD) Evaluated on the First Cycle (D1 to D21), the Safety Profile, and the Dose Limiting Toxicities (DLT) of Trabectedin Given in Combination With Durvalumab
研究概览
简要总结
A phase Ib trial study of trabectedin when prescribed in combination with durvalumab in locally advanced/unresectable soft-tissue sarcoma and ovarian carcinomas.
详细描述
This is a multicenter, prospective phase Ib trial based on a dose escalation study design (3+3 traditional design) assessing three dose levels of Trabectedin given with durvalumab, followed by two expansion cohorts once the MTD is established.
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
盲法说明
Open Label
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 :
- •Soft-tissue sarcoma histologically confirmed. In care outside a center of the RRePS Network, a central review is necessary (Pr. Coindre team),
- •histologically confirmed ovarian carcinoma (carcinosarcoma included), or ovarian carcinoma without known g/s BRCA mutation
- •Ovarian carcinoma must have received at least one line of platinum-containing regimen
- •Metastatic or unresectable locally advanced disease, not amenable to curative therapy
- •Age ≥ 18 years,
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1,
- •Life expectancy > 3 months,
- •Patients must have measurable disease (lesion in previously irradiated filed can be considered as measurable if progressive at inclusion according to RECIST 1.1) defined as per RECIST v1.1 with at least one lesion that can be measured in at least one dimension (longest diameter to be recorded) as > 10 mm with spiral CT scan.
- •Documented disease progression according to RECIST v1.1 before study entry,
- •Patient must comply with the collection of tumor biopsies,
- •At least 1 line of chemotherapy in the palliative setting with use of Anthracyclines (for STS),
- •At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,
- •Adequate hematological, renal, metabolic and hepatic function:
- •Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 109/l, and platelet count ≥ 100 x 109/l.
- •Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of extensive liver involvement) and alkaline phosphatase (AP) ≤ 2.5 x ULN.
- •Total bilirubin ≤ ULN.
- •Albumin ≥ 25 g/l.
- •Calculated creatinine clearance (CrCl) > 60 ml/min (according to Cockroft Gault formula).
- •Thyroid function within normal laboratory ranges (TSH, free T3, free T4).
- •Creatine Phosphokinase (CPK) ≤ 2.5 x ULN
- •Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of trial medication. Both women and men must agree to use a highly effective method of contraception throughout the treatment period and for six months after discontinuation of treatment.
- •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,
- •Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.0),
- •Voluntarily signed and dated written informed consent prior to any study specific procedure,
- •Patients with a social security in compliance with the French law .
排除标准
- •Previous treatment with Trabectedin or an anti-PD-1, anti-PD-L1, anti-PD-L2, including durvalumab
- •Current or prior use of immunosuppressive medication medication including any use of oral glucocorticoids, within 21 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses
- •Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis),
- •Has an active autoimmune disease requiring systemic treatment within the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insuddiciency) is not considered a form of systemic treatment,
- •Has evidence of active non-infectious pneumonitis,
- •Has an active infection requiring systemic therapy,
- •Currently active bacterial or fungus infection (> grade 2 CTC [CTCAE] HIV1, HIV2, hepatitis A or hepatitis B or hepatitis C infections,
- •Known central nervous system malignancy (CNS),
- •Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding,
- •Previous enrolment in the present study,
- •Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
- •Has received a live vaccine within 30 days prior to the first dose of trial treatment.
- •Note: the killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
- •Known hypersensitivity to any involved study drug or any of its formulation components,
- •Tumors not accessible for biopsy,
- •Known history of active tuberculosis
- •Person under judicial protection or deprived of liberty,
- •Cardiac dysfunction: LVEF < 40% at Baseline or clinically symptomatic cardiac dysfunction (any % of LVEF at Baseline)
- •Concomitant use of strong inhibitor or inductors of cytochrome CYP3A4 taken within 21 days prior to the first dose of study drug
研究组 & 干预措施
Combination of trabectedin with durvalumab
Trabectedin will be administered intraveinously, on day 1 of each cycle, every three weeks, as appropriate for assigned dose level.
Durvalumab will be administered intraveinously, at fixed doses of 1120 mg (equivalent to 15 mg/kg), on day 2 of each cycle, every three weeks.
干预措施: Combination of trabectedin with durvalumab (Drug)
结局指标
主要结局
Dose Escalation Part: Establish the Recommended Phase II Dose (RP2D), the Maximum Tolerated Dose (MTD) Evaluated on the First Cycle (D1 to D21), the Safety Profile, and the Dose Limiting Toxicities (DLT) of Trabectedin Given in Combination With Durvalumab
时间窗: During the first cycle (21 days)
A DLT is defined as an AE or laboratory abnormality that fulfills all the criteria below: * Begins on the first 21 days of treatment. * Is considered to be at least possibly related to the study treatment. * Meets one of the criteria below, graded as outlined or according to NCI-CTCAEv4.03 : * Any grade-4 toxicity (except for vomiting without maximal symptomatic/prophylactic treatment and if toxicity is transaminitis, but which have to be resolved at Day 21, i.e. return to Baseline or grade 1). * Grade-3 non-haematological toxicity lasting \> 7days. * Grade-3 hematologic toxicity lasting for \> 7days. * Grade 4 neutropenia with fever. * Grade \> 2 thrombocytopenia with bleeding. Endpoints: * Toxicity graded using the common toxicity criteria from the the NCI-CTCAE v4.03. * Incidence rate of DLT at each dose level during the first 21 days.
Expansion Cohorts : Evaluate Preliminary Signs of the Antitumor Activity of Trabectedin Given in Combination With Durvalumab in Terms of Objective Response Under Treatment.
时间窗: Tumor assessment were repeated every 8 weeks (±7 days, i.e Week 8, 16, 24, etc.) from the start of treatment and at least 4 weeks after the first CR or PR, even if there are treatment delays, an average of 5.1 months
Following RECIST v1.1 recommendations: * Objective response rate (ORR) is defined as the proportion of patients with complete or partial response (CR, PR) as per RECIST v1.1 criteria. * Objective response under treatment is recorded from study treatment initiation until the end of treatment and determined once all the data for the patient is known. * Claimed responses will have to be confirmed at least 4 weeks later to ensure responses identified are not the result of measurement errors. * Disease status under treatment, whatever the response observed, will be centrally reviewed for all patients, by an independent expert radiologist. Reviewed data will be used for the efficacy analysis.
次要结局
- Dose Escalation Part: Preliminary Signs of Antitumor Activity, Best Overall Response (BOR)(Tumor assessment were repeated every 8 weeks (±7 days, i.e Week 8, 16, 24, etc.) from the start of treatment and at least 4 weeks after the first CR or PR, even if there are treatment delays, an average of 5.1 months)
- Dose Escalation Part : Objective Response Rate (ORR)(Tumor assessment were repeated every 8 weeks (±7 days, i.e Week 8, 16, 24, etc.) from the start of treatment and at least 4 weeks after the first CR or PR, an average of 5.1 months and ORR at 6-month)
- Dose Escalation Part : 1-year Progression-free Survival (PFS)(1-year progression-free survival (PFS) rate as per RECIST v1.1)
- Dose Escalation Part : Progression-free Rate (PFR) at 6-month(6-month progression-free Rate (PFR) as per RECIST v1.1)
- Dose Escalation Part : 1-year Overall Survival (OS)(1-year Overall Survival (OS) as per RECIST v1.1)
- Expansion Cohorts: Preliminary Signs of Antitumor Activity, Best Overall Response (BOR)(Tumor assessment were repeated every 8 weeks (±7 days, i.e Week 8, 16, 24, etc.) from the start of treatment and at least 4 weeks after the first CR or PR, even if there are treatment delays, an average of 5.1 months)
- Expansion Cohorts : 6-month Objective Response Rate (ORR)(6-month Objective response rate (ORR) as per RECIST v1.1)
- Expansion Cohorts: 6-month Progression-free Rate (PFR)(6-month progression-free rate (PFR) as per RECIST v1.1)
- Expansion Cohort : 1-year Overall Survival (OS)(1-year Overall Survival (OS) as per RECIST v1.1)
- Expansion Cohorts: 1-year Progression-free Survival (PFS)(1-year Progression-free survival (PFS) as per RECIST v1.1)