A Phase Ib Study of the Safety, Pharmacokinetic of Lisaftoclax (APG-2575) Single Agent and in Combination With Homoharringtonine or Azacitidine in Patients With Relapsed/Refractory AML
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 458
- 试验地点
- 12
- 主要终点
- Dose Limiting Toxicities (DLT)
研究概览
简要总结
The purpose of this study is to assess the safety, pharmacokinetic profile of Lisaftoclax (APG-2575) single agent and in combination with HHT/AZA in patients with relapsed/refractory AML and related myeloid malignancies.
详细描述
This is an open-label, multi-center Phase Ib study of safety, PK of Lisaftoclax (APG-2575) as single agent or in combination with HHT or AZA in relapsed/refractory AML and related myeloid malignancies patients.
This study consists of three stages: The first stage is the Lisaftoclax (APG-2575) single agent dose-escalation study. The second stage is the Lisaftoclax (APG-2575) combined with HHT/AZA dose-escalation study. The third stage is the MTD/RP2D expansion cohort study of the combination regimen.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Subjects who meet each of the following inclusion criteria are eligible to participate in this study:
- •In accordance with the World Health Organization (WHO) 2016 diagnostic criteria for relapsed or refractory acute myeloid leukemia (AML), Mixed phenotype acute leukemia(MPAL), Chronic myelomonocytic leukemia (CMML), Higher-risk myelodysplastic syndrome (HR-MDS) , Blastic plasmacytoid dendritic cell neoplasm (BPDCN) and naïve AML ineligible for treatment with a standard chemotherapy due to age or comorbidities.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 -2 (0 to 3 for participants >= 60 to 74 years of age who are evaluated as ineligible for treatment with standard chemotherapy).
- •Subjects can accept oral administration of Lisaftoclax (APG-2575).
- •Life expectancy ≥ 3 months.
- •Adequate renal and liver function.
- •Males, female patients of childbearing potential (postmenopausal women who must have been menopausal for at least 12 months to be considered infertile) and their partners voluntarily take contraception which the investigator considers effective during treatment and at least three months after the last dose of study drug.
- •Ability to understand and willingness to sign a written informed consent form (the consent form must be signed by the patient prior to any study-specific procedures).
- •Willingness and ability to comply with study procedures and follow-up examination.
排除标准
- •Patients who meet any of the following exclusion criteria are not to be enrolled in this study:
- •Patients diagnosed with acute promyelocytic leukemia or t(9;22)(q34.1;q11.2); BCR-ABL1 positive AML patients.
- •The persistent toxicities caused by previous chemotherapy or radiotherapy has not been restored to lower than grade 2 by CTCAE 5.0 (except for alopecia).
- •Known leukemia infiltration of the central nervous system.
- •Symptomatic active fungal, bacterial and/or viral infections.
- •Prior history of allogeneic hematopoietic stem cell transplantation or adoptive cell immunotherapy, autologous hematopoietic stem cell transplantation within 12 months.
- •Within 14 days before the first dose of study drug, received chemotherapy (hydroxyurea is permitted more than 24 hours before the first dose of study drug), radiotherapy, surgery, immunotherapy, targeted therapy, biological therapy or any investigational treatment.
- •Within 7 days before the first dose of study drug, received a strong and/or moderate CYP3A inducer and/or Inhibitor.
- •At the discretion of the investigator, gastrointestinal diseases that affect the absorption of Lisaftoclax (APG-2575).
- •Any other condition or circumstance, at the discretion of the investigator, that patients would be unsuitable for participation in the study.
研究组 & 干预措施
Lisaftoclax (APG-2575) single agent
Lisaftoclax (APG-2575) orally once daily starting from 200mg and will be increased in subsequent cohorts to 400mg, 600mg, 800mg, to determine the MTD/RP2D.
干预措施: Lisaftoclax (APG-2575) (Drug)
Lisaftoclax (APG-2575)+reduced-dose HHT
Lisaftoclax (APG-2575) MTD/RP2D-1 and MTD/RP2D combines with reduced-dose HHT in R/R AML, MPAL, BPDCN, CMML.
干预措施: Lisaftoclax (APG-2575) (Drug)
Lisaftoclax (APG-2575)+reduced-dose HHT
Lisaftoclax (APG-2575) MTD/RP2D-1 and MTD/RP2D combines with reduced-dose HHT in R/R AML, MPAL, BPDCN, CMML.
干预措施: Reduced-dose HHT (Drug)
Lisaftoclax (APG-2575)+ standard-dose HHT
Lisaftoclax (APG-2575) MTD/RP2D-1 and MTD/RP2D combines with standard-dose HHT in R/R AML, MPAL, BPDCN, CMML.
干预措施: Lisaftoclax (APG-2575) (Drug)
Lisaftoclax (APG-2575)+ standard-dose HHT
Lisaftoclax (APG-2575) MTD/RP2D-1 and MTD/RP2D combines with standard-dose HHT in R/R AML, MPAL, BPDCN, CMML.
干预措施: standard-dose HHT (Drug)
Lisaftoclax (APG-2575)+ AZA
Lisaftoclax (APG-2575) MTD/RP2D-1 and MTD/RP2D combines with AZA in R/R AML, MPAL, BPDCN, CMML.
干预措施: Lisaftoclax (APG-2575) (Drug)
Lisaftoclax (APG-2575)+ AZA
Lisaftoclax (APG-2575) MTD/RP2D-1 and MTD/RP2D combines with AZA in R/R AML, MPAL, BPDCN, CMML.
干预措施: Azacitidine (Drug)
Lisaftoclax (APG-2575)+ AZA(HR-MDS.)
Lisaftoclax (APG-2575) MTD/RP2D-1 and MTD/RP2D combines with AZA in HR-MDS.
干预措施: Azacitidine (Drug)
Lisaftoclax (APG-2575)+ AZA(HR-MDS.)
Lisaftoclax (APG-2575) MTD/RP2D-1 and MTD/RP2D combines with AZA in HR-MDS.
干预措施: Lisaftoclax (APG-2575) (Drug)
Lisaftoclax (APG-2575)+ AZA(Naïve AML.)
Lisaftoclax (APG-2575) MTD/RP2D-1 and MTD/RP2D combines with AZA in treatment naïve AML.
干预措施: Lisaftoclax (APG-2575) (Drug)
Lisaftoclax (APG-2575)+ AZA(Naïve AML.)
Lisaftoclax (APG-2575) MTD/RP2D-1 and MTD/RP2D combines with AZA in treatment naïve AML.
干预措施: Azacitidine (Drug)
Lisaftoclax (APG-2575)+AZA+Olverembatinib
Lisaftoclax (APG-2575) combines with AZA and Olverembatinib in R/R AML.
干预措施: Azacitidine (Drug)
Lisaftoclax (APG-2575)+AZA+Olverembatinib
Lisaftoclax (APG-2575) combines with AZA and Olverembatinib in R/R AML.
干预措施: Lisaftoclax (APG-2575) (Drug)
Lisaftoclax (APG-2575)+AZA+Olverembatinib
Lisaftoclax (APG-2575) combines with AZA and Olverembatinib in R/R AML.
干预措施: olverembatinib (Drug)
Lisaftoclax (APG-2575)+HHT+Olverembatinib
Lisaftoclax (APG-2575) combines with HHT and Olverembatinib in R/R AML.
干预措施: standard-dose HHT (Drug)
Lisaftoclax (APG-2575)+HHT+Olverembatinib
Lisaftoclax (APG-2575) combines with HHT and Olverembatinib in R/R AML.
干预措施: Lisaftoclax (APG-2575) (Drug)
Lisaftoclax (APG-2575)+HHT+Olverembatinib
Lisaftoclax (APG-2575) combines with HHT and Olverembatinib in R/R AML.
干预措施: olverembatinib (Drug)
结局指标
主要结局
Dose Limiting Toxicities (DLT)
时间窗: 28 days
DLT will be graded according to NCI CTCAE Version 5.0. DLT will be defined as clinically significant drug-related adverse events during cycle one.
Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose(RP2D)
时间窗: 28 days
MTD/RP2D will be determined based on DLTs observed during cycle one.
次要结局
- Maximum plasma concentration (Cmax)(28 days)
- duration of response (DOR)(Up to 2 years.)
- Area under the plasma concentration versus time curve (AUC)(28 days)
- Objective Response Rate (ORR)(Up to 6 cycles (each cycle is 28 days).)
- progression free survival (PFS)(Up to 2 years.)
- overall survival (OS)(Up to 2 years.)