A Phase 1/2 Study to Investigate the Safety, Pharmacokinetics and Efficacy of EDO-S101, a First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule, in Patients With Advanced Solid Tumors. Sub-study to Characterize the Effects of Tinostamustine at a Dose of 60mg/m2 Administered During a 60 Minutes Infusion on Cardiac Repolarization, in Patients With Advanced Solid Tumors. Sub-study to Characterize the Effects of Tinostamustine at a Dose of 80mg/m2 Administered During a 80 Minutes Infusion on Cardiac Repolarization, in Patients With Advanced Solid Tumors.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 71
- 试验地点
- 13
- 主要终点
- Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE V4.03 on Phase 1
研究概览
简要总结
Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor designed to improve drug access to deoxyribonucleic acid (DNA) strands, induce DNA damage and counteract its repair in cancer cells. The main purpose of this study is to assess the safety, tolerability and efficacy of Tinostamustine in subjects with advanced solid tumours. Subjects will be given Tinostamustine via intravenous infusion on Days 1 and 15 of a 4-week cycle, the dose and infusion time will vary depending on the phase of the study.
详细描述
The study consists of 2 phases and 2 sub-studies:
This study is a multi-centre, open-label phase 1/2 study of single agent EDO-S101 in subjects with advanced solid tumours.
Phase 1 part of the study is designed to determine the safety, tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and the Pharmacokinetic (PK) of EDO-S101 as a single agent in patients with solid tumours who have progressed after at least one (1) line of therapy and for whom no other standard therapy with proven clinical benefit is available.
Phase 2 part of the study is designed to evaluate the overall response rate (ORR) of the RP2D, plus the rate of patients with stable disease (SD) at 4 or 6 months, depending on the type of solid tumour. The RP2D was determined after phase 1 to be 80 mg/m2 of EDO-S101 administered over 1 hour on Day 1 and Day 15 of each 4-week treatment cycle.
In addition, two sub-studies are designed to better characterize the effect of EDO-S101: one at a dose of 60 mg/m2 administered over 60 minutes and the second at a dose of 80 mg/m2 administered over 80 minutes on cardiac repolarization (QTc) and other ECG parameters in the subjects with solid tumours.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Tinostamustine (EDO-S101) - Phase 1 - 80mg/m2 (30 min) cohort 2
干预措施: Tinostamustine 80mg/m2 over 30min (Drug)
Tinostamustine (EDO-S101) - Phase 1 - 60mg/m2 (30 min) cohort 1
干预措施: Tinostamustine 60mg/m2 over 30min (Drug)
Tinostamustine (EDO-S101) - Phase 1 - 100mg/m2 (30 min) cohort 3
干预措施: Tinostamustine 100mg/m2 over 30min (Drug)
Tinostamustine (EDO-S101) - Phase 1 - 60mg/m2 (60 min) cohort 4
干预措施: Tinostamustine 60mg/m2 over 60min (Drug)
Tinostamustine (EDO-S101) - Phase 1 - 80mg/m2 (60 min) cohort 5
干预措施: Tinostamustine 80mg/m2 over 60min (Drug)
Tinostamustine (EDO-S101) - Phase 1 - 100mg/m2 (60 min) cohort 6
干预措施: Tinostamustine 100mg/m2 over 60min (Drug)
Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) cohort
干预措施: Tinostamustine 80mg/m2 over 60min (Drug)
Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort
干预措施: Tinostamustine 80mg/m2 over 60min (Drug)
Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Triple Negative breast Cancer (TNBC) cohort
干预措施: Tinostamustine 80mg/m2 over 60min (Drug)
Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort
干预措施: Tinostamustine 80mg/m2 over 60min (Drug)
Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort
干预措施: Tinostamustine 80mg/m2 over 60min (Drug)
Tinostamustine (EDO-S101) - Sub study 1 (SS1)
干预措施: Tinostamustine 60mg/m2 over 60min (Drug)
Tinostamustine (EDO-S101) - Sub study 2 (SS2)
干预措施: Tinostamustine 80mg/m2 over 80min (Drug)
结局指标
主要结局
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE V4.03 on Phase 1
时间窗: From each patient's time of first dose administration to discontinuation of study drug (at any time or D28 of the last treatment cycle), up to 6 months.
All TEAEs was reported from the first dose of study drug through the time of study drug discontinuation (at any time or Day 28 of the last treatment Cycle). All treatment-related TEAEs was followed until resolution or stabilization. For the purpose of regulatory reporting requirements, causal relationships of definite, probable, and possible was considered treatment-related. Number of patients experiencing treatment-related adverse events (TEAE) as assessed by CTCAE v4.03. (June 2010).
Clinical Benefit Response Rate in Selected Solid Tumor Cohorts on Phase 2
时间窗: From start treatment and assessed after every 2 cycles until determination of stable disease and follow up for up to 84 days.
The Clinical Benefit Response Rate is calculated as the number of patients with Clinical Benefit Response divided by number of patients in the FAS (in the respective cohort). Clinical Benefit Response is defined as patients achieving stable disease with a duration of at least 12 weeks (84 days). Summary subjects analysed were 36.
Highest Change From Baseline in QTcF in Sub-studies
时间窗: From cycle 1 and at every cycle on treatment days D1 and D15, assessed pre-dose and post-start of infusion at 30 and 80mins (Substudy 2 - up to 6 months) and 30, 60, 90, 120 and 180mins (substudy 1 - up to 6 months).
QTcF: corrected QT interval \[QTc\] using Fridericia's formula) and other electrocardiogram (ECG) parameters in subjects with solid tumours who have progressed after at least 1 line of therapy and for whom no other standard therapy with proven clinical benefit is available. Within each cycle a Change from baseline (CfB) is calculated for QTcF relative to the baseline value of day 1 of the cycle. QTcF CfB= QTcF Post-dose value - QTcF pre-dose value of D1 ECG Parameters: 4-hours ECG holter monitoring in C1 and ECGs during EDO-S101 administration. Continuous variables the mean and standard deviation are presented together with the total number of observations and the number of missing and non-missing values.
次要结局
- Treatment-related Adverse Events on Phase 2 and Sub Studies(From each patient's time of informed consent to discontinuation of study drug (at any time or D28 of the last treatment cycle), up to 8 months)
- Progression Free Survival (PFS) Time for Phase 2 and Sub Studies(From patient's first dose until first documented progression/start of subsequent anti-cancer therapy/death from any cause, whichever came first, up to 26 months.)
- Overall Survival (OS) Time for Phase 2 and Sub Studies(From patient's first dose until first documented progression/start of subsequent anti-cancer therapy/death from any cause, whichever came first, up to 42 months.)
- Maximum Duration of Response (DoR) Time for Phase 2 and Sub Studies(From patient's first overall response of CR or PR, until disease progression/subsequent anti-cancer therapy/death from any cause, up to 24 months.)
- Objective Response Rate (ORR) and the Clinical Benefit Rate (CBR) That Persists for at Least Four (4) Months in Selected Solid Tumor Cohorts on Sub Studies(From start of treatment, assessed every 2 cycles, until first documented complete CR, PR or SD, up to 6 months. If SD, assessment continued every 2 cycles until CR/PR/death (up to 6 months))
- Number of Participants With Duration of Stable Disease (SD) That Persists for at Least 4 Months in Selected Solid Tumor Cohorts in Sub Studies.(From start of treatment, assessed every 2 cycles, until first documented complete CR, PR or SD, up to 6 months. If SD, assessment continued every 2 cycles until CR/PR/death (up to 6 months).)
- Maximum Plasma Concentration (Cmax) in Phase 2 and Sub Studies(Blood samples were collected over a period of 24hr (phase 2 and sub-study 1) and 30hr (sub-study 2) on Cycle 1 Day 1 and Day 15.)
- Area Under the Curve [AUC(0-t)] in Phase 2 and Sub Studies.(Blood samples were collected over a period of 24hr (phase 2 and sub-study 1) and 30hr (sub-study 2) on Cycle 1 Day 1 and Day 15.)
- Summary of Tmax in in Phase 2 and Sub Studies.(Blood samples were collected over a period of 24hr (phase 2 and sub-study 1) and 30hr (sub-study 2) on Cycle 1 Day 1 and Day 15.)
- Clearance of Tinostamustine and Metabolites in Phase 2 and Substudies(Blood samples were collected over a period of 24hr (phase 2 and sub-study 1) and 30hr (sub-study 2) on Cycle 1 Day 1 and Day 15.)
- Summary of Half-life of Tinostamustine in Phase 2 and Substudies.(Blood samples were collected over a period of 24hr (phase 2 and sub-study 1) and 30hr (sub-study 2) on Cycle 1 Day 1 and Day 15.)