Study of APG2575 Single Agent and Combination With Therapy in Patients Relapsed/Refractory AML
- Conditions
- Relapsed/Refractory Acute Myeloid LeukaemiaMyeloid Malignancy
- Interventions
- Registration Number
- NCT04501120
- Lead Sponsor
- Ascentage Pharma Group Inc.
- Brief Summary
The purpose of this study is to assess the safety, pharmacokinetic profile of APG-2575 single agent and in combination with HHT/AZA in patients with relapsed/refractory AML and related myeloid malignancies.
- Detailed Description
This is an open-label, multi-center Phase Ib study of safety, PK of 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 APG-2575 single agent dose-escalation study. The second stage is the APG-2575 combined with HHT/AZA dose-escalation study. The third stage is the MTD/RP2D expansion cohort study of the combination regimen.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 284
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 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.
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 APG-2575.
- Any other condition or circumstance, at the discretion of the investigator, that patients would be unsuitable for participation in the study.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description APG2575+ standard-dose HHT standard-dose HHT APG-2575 MTD/RP2D-1 and MTD/RP2D combines with standard-dose HHT in R/R AML, MPAL, BPDCN, CMML. APG2575+ AZA(Naïve AML.) APG-2575 APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in treatment naïve AML. APG2575+reduced-dose HHT Reduced-dose HHT APG-2575 MTD/RP2D-1 and MTD/RP2D combines with reduced-dose HHT in R/R AML, MPAL, BPDCN, CMML. APG2575+ AZA APG-2575 APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in R/R AML, MPAL, BPDCN, CMML. APG2575+ AZA(HR-MDS.) APG-2575 APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in HR-MDS. APG2575 single agent APG-2575 APG-2575 orally once daily starting from 200mg and will be increased in subsequent cohorts to 400mg, 600mg, 800mg, to determine the MTD/RP2D. APG2575+reduced-dose HHT APG-2575 APG-2575 MTD/RP2D-1 and MTD/RP2D combines with reduced-dose HHT in R/R AML, MPAL, BPDCN, CMML. APG2575+ standard-dose HHT APG-2575 APG-2575 MTD/RP2D-1 and MTD/RP2D combines with standard-dose HHT in R/R AML, MPAL, BPDCN, CMML. APG2575+ AZA(Naïve AML.) Azacitidine APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in treatment naïve AML. APG2575+ AZA Azacitidine APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in R/R AML, MPAL, BPDCN, CMML. APG2575+ AZA(HR-MDS.) Azacitidine APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in HR-MDS.
- Primary Outcome Measures
Name Time Method Dose Limiting Toxicities (DLT) 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) 28 days MTD/RP2D will be determined based on DLTs observed during cycle one.
- Secondary Outcome Measures
Name Time Method Area under the plasma concentration versus time curve (AUC) 28 days AUC of APG-2575 will be assessed in the patients in single agent or combo study.
Maximum plasma concentration (Cmax) 28 days Cmax of APG-2575 will be assessed in the patients in single agent or combo study.
Objective Response Rate (ORR) Up to 6 cycles (each cycle is 28 days). ORR is defined by CR+ CRi + PR(according to IWG AML(2003)).Response will be evaluated on cycle 1 and every even cycles till completing 6 cycles treatment or end of treatment.
progression free survival (PFS) Up to 2 years. From date of treatment start until the date of progression or the date of death due to any cause.
duration of response (DOR) Up to 2 years. From date of response until the date of progression.
overall survival (OS) Up to 2 years. From date of treatment start until the date of death due to any cause.
Trial Locations
- Locations (12)
Peking University People's Hospital
🇨🇳Beijing, Beijing, China
Sun Yat-sen University Cancer Center
🇨🇳Guangzhou, Guandong, China
Henan Tumor Hospital
🇨🇳Zhengzhou, Henan, China
Union Hospital medical college Huazhong University of Science and Technology
🇨🇳Wuhan, Hubei, China
The First affiliated hospital of Soochow University
🇨🇳Suzhou, Jiangsu, China
Chongqing University Cancer Hospital
🇨🇳Chongqing, Chongqing, China
Xiangya Hospital Central South University
🇨🇳Changsha, Hunan, China
Guangdong Provincial People's Hospital
🇨🇳Guangzhou, Guangdong, China
the First Affiliated Hospital, College of Medicine, Zhejiang University
🇨🇳Hangzhou, Zhejiang, China
Zhongnan Hospital of Hunan university
🇨🇳Wuhan, Hubei, China
Shanghai The Sixth People' s Hospital
🇨🇳Shanghai, Shanghai, China
West China Hospital of Sichuan University
🇨🇳Chengdu, Sichuan, China