A Phase 1A Dose Escalation and Phase 1B Expansion Study to Evaluate the Safety and Tolerability of ETC-1907206 in Combination With Dasatinib in Advanced Haematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 试验地点
- 6
- 主要终点
- Phase 1B PK: AUC from time zero to the last measureable concentration (AUC0-t)
研究概览
简要总结
This study evaluates the use of ETC-1907206 in combination with dasatinib in certain types of blood cancers. The first phase of the study (1A) is designed to find the highest tolerated dose of ETC-1907206, while the second phase (1B) will assess the safety and tolerability of the recommended dose of ETC-1907206. ETC-1907206 has been designed to block the activity of an enzyme of the body known as Mnk kinase, which is thought to be involved in the development of a variety of cancers.
详细描述
This study consists of two parts: a Phase 1A dose escalation to identify the MTD and the RD of ETC-1907206 administered in combination with dasatinib and a Phase 1B expansion at the RD.
Phase 1A: A dose escalation with an adaptive design model using ordinal continual reassessment method (oCRM) will be used to characterise the dose toxicity curve of ETC-1907206 when administered orally every other day (EOD) under fasted conditions in combination with oral once daily dasatinib (per locally approved product prescribing instructions) in order to identify the maximum tolerated dose (MTD) and recommended dose (RD) for Phase 1B.
Phase 1B: Open-label, non-randomised, to assess preliminary clinical activity and safety of ETC-1907206 administered orally EOD under fasted conditions at the RD identified in Phase 1A, in combination with dasatinib (per locally approved product prescribing instructions).
Patients will continue in the study until disease progression, the start of new anti-cancer therapy, unacceptable toxicity, death, or the completion of 12 separate 4-week treatment cycles, whichever occurs first.
As long as the Sponsor agrees to continue treatment, patients who complete 12 cycles of treatment and have no evidence of disease progression are allowed to continue on treatment past the end of treatment (EOT) visit until there is disease progression, unacceptable toxicity, the patient decides to withdraw, or it is judged not to be in the patient's interest to continue on the study.
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
Dose Escalation (Phase 1A)
An adaptive design using the ordinal Continual Reassessment Method (oCRM) will be used to determine the MTD and RD of ETC-1907206 in combination with dasatinib.
干预措施: dasatinib (Drug)
Dose Escalation (Phase 1A)
An adaptive design using the ordinal Continual Reassessment Method (oCRM) will be used to determine the MTD and RD of ETC-1907206 in combination with dasatinib.
干预措施: ETC-1907206 (Drug)
Dose Expansion (Phase 1B)
Once the MTD and/or RD has been determined in Phase 1A, an expansion cohort will be enrolled in order to characterize the safety, PK and preliminary clinical activity of ETC-1907206 in combination with dasatinib. Subjects may continue treatment in the study until disease progression, unacceptable toxicity, withdrawal of consent or it is judged not to be in the patient's interest to continue on the study.
干预措施: ETC-1907206 (Drug)
Dose Expansion (Phase 1B)
Once the MTD and/or RD has been determined in Phase 1A, an expansion cohort will be enrolled in order to characterize the safety, PK and preliminary clinical activity of ETC-1907206 in combination with dasatinib. Subjects may continue treatment in the study until disease progression, unacceptable toxicity, withdrawal of consent or it is judged not to be in the patient's interest to continue on the study.
干预措施: dasatinib (Drug)
结局指标
主要结局
Phase 1B PK: AUC from time zero to the last measureable concentration (AUC0-t)
时间窗: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing
Single-dose PK measurement of AUC0-t after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B PK: First-order rate constant for elimination of drug (kel)
时间窗: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing
Single-dose PK measurement of kel after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B Safety: Incidence of Adverse Events (AEs) during Phase 1B
时间窗: up to 44 months
Incidence and Severity of AEs
Phase 1B PK: Area under the drug concentration-time curve (AUC) from time zero to infinite time (AUC0-inf)
时间窗: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing
Single-dose PK measurement of AUC0-inf after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Maximum Tolerated Dose (MTD) (Phase 1A)
时间窗: the initial 28 days of treatment
The MTD is defined as the highest possible dose with a predicted probability of having DLT not exceeding the target toxicity rate. The target toxicity rate (or the target predicted probability of DLT) for this study is set at 25%.
Phase 1B PK: Time to reach maximum plasma concentration (Tmax)
时间窗: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing
Single-dose PK measurement of Tmax after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B PK: Time between drug administration and first observed concentration above lower limit if quantitation in plasma (Tlag)
时间窗: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing
Single-dose PK measurement of Tlag after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B PK: Total clearance (CL)
时间窗: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing
Single-dose PK measurement of CL after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B PK: Volume of distribution (Vd)
时间窗: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing
Single-dose PK measurement of Vd after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B PK: Half-life (T1/2)
时间窗: pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing
Single-dose PK measurement of T1/2 after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
次要结局
- Phase 1A PK: Total clearance (CL)(pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing)
- Phase 1A PK: Volume of distribution (Vd)(pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing)
- Phase 1A PK: Half-life (T1/2)(pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing)
- Phase 1B Clinical Activity: Best Overall Response (BOR)(through study completion (44 months))
- Phase 1B Clinical Activity: duration of complete remission (DOCRe)(through study completion (44 months))
- Phase 1B Clinical Activity: objective response rate (ORR)(through study completion (44 months))
- Phase 1B Clinical Activity: time to major molecular response (TTMMR)(through study completion (44 months))
- Phase 1B Clinical Activity: time to complete haematologic response (TTCHR)(through study completion (44 months))
- Phase 1B Clinical Activity: overall survival (OS)(through study completion (44 months))
- Phase 1A Safety: Incidence of Adverse Events (AEs) during Phase 1A(up to 24 months)
- Phase 1A PK: Area under the drug concentration-time curve (AUC) from time zero to infinite time (AUC0-inf)(pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing)
- Phase 1A PK: AUC from time zero to the last measureable concentration (AUC0-t)(pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing)
- Phase 1A PK: First-order rate constant for elimination of drug (kel)(pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing)
- Phase 1A PK: Time to reach maximum plasma concentration (Tmax)(pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing)
- Phase 1A PK: Time between drug administration and first observed concentration above lower limit if quantitation in plasma (Tlag)(pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing)
- Phase 1B Clinical Activity: time to objective response (TTR)(through study completion (44 months))
- Phase 1B Clinical Activity: time to complete remission (TTCRe)(through study completion (44 months))
- Phase 1B Clinical Activity: duration of objective response (DOR)(through study completion (44 months))
- Phase 1B Clinical Activity: duration of major molecular response (DOMMR)(through study completion (44 months))
- Phase 1B Clinical Activity: duration of complete haematologic response (DOCHR)(through study completion (44 months))
- Phase 1B Clinical Activity: progression-free survival (PFS)(through study completion (44 months))
- Phase 1B Clinical Activity: duration of complete cytogenetic response (DOCCyR)(through study completion (44 months))
- Phase 1B Clinical Activity: time to complete cytogenetic response (TTCCyR)(through study completion (44 months))