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Study of APG2575 Single Agent and Combination With Therapy in Patients Relapsed/Refractory AML

Primary Purpose

Relapsed/Refractory Acute Myeloid Leukaemia, Myeloid Malignancy

Status
Recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
APG-2575
Reduced-dose HHT
standard-dose HHT
Azacitidine
APG-2575
Sponsored by
Ascentage Pharma Group Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsed/Refractory Acute Myeloid Leukaemia focused on measuring APG-2575, Acute Myeloid Leukaemia (AML), Bcl-2 Inhibitor, Myeloid Malignancy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Subjects who meet each of the following inclusion criteria are eligible to participate in this study:

  1. Age ≥18 years old.
  2. 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) and Blastic plasmacytoid dendritic cell neoplasm (BPDCN).
  3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 -2.
  4. Subjects can accept oral administration of APG-2575.
  5. Life expectancy ≥ 3 months.
  6. Adequate renal and liver function.
  7. 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.
  8. 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).
  9. Willingness and ability to comply with study procedures and follow-up examination.

Exclusion Criteria:

Patients who meet any of the following exclusion criteria are not to be enrolled in this study:

  1. Patients diagnosed as acute promyelocytic leukemia (FAB classification AML-M3 or WHO diagnosis classification APL with PML-RARα) or t(9;22)(q34.1;q11.2); BCR-ABL1 positive AML patients.
  2. White blood cell (WBC) ≥100×109/L when screening.
  3. 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).
  4. Known leukemia infiltration of the central nervous system.
  5. Symptomatic active fungal, bacterial and/or viral infections, including but not limited to active human immunodeficiency virus (HIV), viral hepatitis B or C (type B or C).
  6. Prior history of allogeneic hematopoietic stem cell transplantation or adoptive cell immunotherapy or autologous hematopoietic stem cell transplantation within 12 months.
  7. Requirement of therapeutic doses of anticoagulants and antiplatelet drugs, but allow the use of low doses of anticoagulants to maintain the opening of the central venous catheter.
  8. Within 14 days before the first dose of study drug, received chemotherapy (hydroxyurea is permitted more than 48 hours before the first dose of study drug), radiotherapy, surgery, immunotherapy, hormone therapy, targeted therapy, biological therapy or Chinese herbal therapy or any investigational treatment.
  9. Within 7 days before the first dose of study drug, received a strong and/or moderate CYP3A inducer and/or Inhibitor.
  10. Within 7 days before the first dose of study drug, received hematopoietic cytokines (granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), or erythropoietin) .
  11. Failure to recover adequately, at the discretion of the investigator, from prior surgical procedures, including patients who have had major surgery within 28 days before the first dose of study drug, and patients who have had minor surgery (excluding pathological biopsy) within 14 days before the beginning of study.
  12. At the discretion of the investigator, gastrointestinal diseases that affect the absorption of APG-2575.
  13. Unstable angina, myocardial infarction, coronary artery reconstruction, or severe gastrointestinal bleeding occurred during the 180 days before the start of study.
  14. Uncontrolled complications include but not limited to: uncontrollable severe infections, symptomatic congestive heart failure, unstable angina, arrhythmia, or mental illness/social environment that may affect compliance.
  15. The last treatment before signing the informed consent was a Bcl-2 inhibitor (subjects who had been treated with a Bcl-2 inhibitor but had not developed drug resistance could be enrolled in this study).
  16. Any other condition or circumstance, at the discretion of the investigator, that patients would be unsuitable for participation in the study.

Sites / Locations

  • Peking University People's HospitalRecruiting
  • Chongqing University Cancer Hospital
  • Sun Yat-sen University Cancer CenterRecruiting
  • Guangdong Provincial People's HospitalRecruiting
  • Henan Tumor HospitalRecruiting
  • Union Hospital medical college Huazhong University of Science and TechnologyRecruiting
  • Zhongnan Hospital of Hunan universityRecruiting
  • Xiangya Hospital Central South UniversityRecruiting
  • The First affiliated hospital of Soochow UniversityRecruiting
  • Shanghai The Sixth People' s Hospital
  • West China Hospital of Sichuan UniversityRecruiting
  • the First Affiliated Hospital, College of Medicine, Zhejiang UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

APG2575 single agent

APG2575+reduced-dose HHT

APG2575+ standard-dose HHT

APG2575+ AZA

APG2575+ AZA(HR-MDS.)

APG2575+ AZA(Naïve AML.)

Arm Description

APG-2575 orally once daily starting from 200mg and will be increased in subsequent cohorts to 400mg, 600mg, 800mg, to determine the MTD/RP2D.

APG-2575 MTD/RP2D-1 and MTD/RP2D combines with reduced-dose HHT in R/R AML, MPAL, BPDCN, CMML.

APG-2575 MTD/RP2D-1 and MTD/RP2D combines with standard-dose HHT in R/R AML, MPAL, BPDCN, CMML.

APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in R/R AML, MPAL, BPDCN, CMML.

APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in HR-MDS.

APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in treatment naïve AML.

Outcomes

Primary Outcome Measures

Dose Limiting Toxicities (DLT)
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)
MTD/RP2D will be determined based on DLTs observed during cycle one.

Secondary Outcome Measures

Maximum plasma concentration (Cmax)
Cmax of APG-2575 will be assessed in the patients in single agent or combo study.
Area under the plasma concentration versus time curve (AUC)
AUC of APG-2575 will be assessed in the patients in single agent or combo study.
Objective Response Rate (ORR)
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)
From date of treatment start until the date of progression or the date of death due to any cause.
duration of response (DOR)
From date of response until the date of progression.
overall survival (OS)
From date of treatment start until the date of death due to any cause.

Full Information

First Posted
August 3, 2020
Last Updated
March 10, 2023
Sponsor
Ascentage Pharma Group Inc.
Collaborators
Suzhou Yasheng Pharmaceutical Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT04501120
Brief Title
Study of APG2575 Single Agent and Combination With Therapy in Patients Relapsed/Refractory AML
Official Title
A Phase Ib Study of the Safety, Pharmacokinetic of APG-2575 Single Agent and in Combination With Homoharringtonine or Azacitidine in Patients With Relapsed/Refractory AML
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 28, 2020 (Actual)
Primary Completion Date
August 2024 (Anticipated)
Study Completion Date
August 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ascentage Pharma Group Inc.
Collaborators
Suzhou Yasheng Pharmaceutical Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsed/Refractory Acute Myeloid Leukaemia, Myeloid Malignancy
Keywords
APG-2575, Acute Myeloid Leukaemia (AML), Bcl-2 Inhibitor, Myeloid Malignancy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
284 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
APG2575 single agent
Arm Type
Experimental
Arm Description
APG-2575 orally once daily starting from 200mg and will be increased in subsequent cohorts to 400mg, 600mg, 800mg, to determine the MTD/RP2D.
Arm Title
APG2575+reduced-dose HHT
Arm Type
Experimental
Arm Description
APG-2575 MTD/RP2D-1 and MTD/RP2D combines with reduced-dose HHT in R/R AML, MPAL, BPDCN, CMML.
Arm Title
APG2575+ standard-dose HHT
Arm Type
Experimental
Arm Description
APG-2575 MTD/RP2D-1 and MTD/RP2D combines with standard-dose HHT in R/R AML, MPAL, BPDCN, CMML.
Arm Title
APG2575+ AZA
Arm Type
Experimental
Arm Description
APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in R/R AML, MPAL, BPDCN, CMML.
Arm Title
APG2575+ AZA(HR-MDS.)
Arm Type
Experimental
Arm Description
APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in HR-MDS.
Arm Title
APG2575+ AZA(Naïve AML.)
Arm Type
Experimental
Arm Description
APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in treatment naïve AML.
Intervention Type
Drug
Intervention Name(s)
APG-2575
Intervention Description
APG-2575 orally once daily, every 28 days as a cycle.
Intervention Type
Drug
Intervention Name(s)
Reduced-dose HHT
Intervention Description
1mg IV QD on Days 1-14 (28-day cycle).
Intervention Type
Drug
Intervention Name(s)
standard-dose HHT
Intervention Description
2mg/m^2 IV QD on Days 1-7 (28-day cycle).
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Intervention Description
75 mg/m^2 SC or Iv gtt QD on Days 1- 7 (28-day cycle).
Intervention Type
Drug
Intervention Name(s)
APG-2575
Intervention Description
APG-2575 orally once daily for 14 days, every 28 days as a cycle.
Primary Outcome Measure Information:
Title
Dose Limiting Toxicities (DLT)
Description
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.
Time Frame
28 days
Title
Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose(RP2D)
Description
MTD/RP2D will be determined based on DLTs observed during cycle one.
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Maximum plasma concentration (Cmax)
Description
Cmax of APG-2575 will be assessed in the patients in single agent or combo study.
Time Frame
28 days
Title
Area under the plasma concentration versus time curve (AUC)
Description
AUC of APG-2575 will be assessed in the patients in single agent or combo study.
Time Frame
28 days
Title
Objective Response Rate (ORR)
Description
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.
Time Frame
Up to 6 cycles (each cycle is 28 days).
Title
progression free survival (PFS)
Description
From date of treatment start until the date of progression or the date of death due to any cause.
Time Frame
Up to 2 years.
Title
duration of response (DOR)
Description
From date of response until the date of progression.
Time Frame
Up to 2 years.
Title
overall survival (OS)
Description
From date of treatment start until the date of death due to any cause.
Time Frame
Up to 2 years.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Exclusion Criteria: 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jie Jin, M.D.
Phone
+86 571-87236896
Email
jiej0503@163.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yifan Zhai, M.D., Ph.D.
Organizational Affiliation
Suzhou Yasheng Pharmaceutical Co., Ltd.
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Jie Jin, M.D.
Organizational Affiliation
the First Affiliated Hospital, College of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Peking University People's Hospital
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100044
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Qiang Jiang, Professor
Facility Name
Chongqing University Cancer Hospital
City
Chongqing
State/Province
Chongqing
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yi Gong, M.D.
Facility Name
Sun Yat-sen University Cancer Center
City
Guangzhou
State/Province
Guandong
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yang Liang, Professor
Facility Name
Guangdong Provincial People's Hospital
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
510080
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jianyu Wong, M.D.
Facility Name
Henan Tumor Hospital
City
Zhengzhou
State/Province
Henan
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Xudong Wei, Professor
Facility Name
Union Hospital medical college Huazhong University of Science and Technology
City
Wuhan
State/Province
Hubei
ZIP/Postal Code
430022
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Qiubo Li, Professor
Facility Name
Zhongnan Hospital of Hunan university
City
Wuhan
State/Province
Hubei
ZIP/Postal Code
430071
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Fuling Zhou, Professor
First Name & Middle Initial & Last Name & Degree
Jianying Zhou, Professor
Facility Name
Xiangya Hospital Central South University
City
Changsha
State/Province
Hunan
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yajing Xu, Master
First Name & Middle Initial & Last Name & Degree
Qun He, Master
Facility Name
The First affiliated hospital of Soochow University
City
Suzhou
State/Province
Jiangsu
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Suning Chen, M.D.
Facility Name
Shanghai The Sixth People' s Hospital
City
Shanghai
State/Province
Shanghai
Country
China
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chunkang Chang, Professor
Facility Name
West China Hospital of Sichuan University
City
Chengdu
State/Province
Sichuan
ZIP/Postal Code
610044
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Xiao Shuai, M.D.
Phone
18980606797
Email
5397781@qq.com
Facility Name
the First Affiliated Hospital, College of Medicine, Zhejiang University
City
Hangzhou
State/Province
Zhejiang
ZIP/Postal Code
310003
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jie Jin, M.D.
Phone
+86 571-87236896
Email
jiej0503@163.com

12. IPD Sharing Statement

Learn more about this trial

Study of APG2575 Single Agent and Combination With Therapy in Patients Relapsed/Refractory AML

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