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

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ClinicalTrials.gov Identifier: NCT04501120
Recruitment Status : Recruiting
First Posted : August 6, 2020
Last Update Posted : October 1, 2021
Sponsor:
Collaborator:
Suzhou Yasheng Pharmaceutical Co., Ltd.
Information provided by (Responsible Party):
Ascentage Pharma Group Inc.

Brief Summary:
The purpose of this study is to assess the safety, pharmacokinetic of APG-2575 single agent and in combination with HHT/AZA in patients with relapsed/refractory AML.

Condition or disease Intervention/treatment Phase
Relapsed/Refractory Acute Myeloid Leukaemia Drug: APG-2575 Drug: reduced-dose HHT Drug: standard-dose HHT Drug: Azacitidine Phase 1 Phase 2

Detailed Description:

This is an open-label, multi-center Phase Ib study of safety, PK of APG-2575 as a single agent or in combination with HHT or AZA in relapsed/refractory AML patients.

This study consists of three stages: The first stage is the APG-2575 single agent escalation study. The second stage is the APG-2575 combined with HHT/AZA escalation study. The third stage is the MTD/RP2D expansion cohort study of the combination regimen.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 105 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 28, 2020
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : August 2023


Arm Intervention/treatment
Experimental: APG2575 single agent
APG-2575 orally once daily starting from 200mg and will be increased in subsequent cohorts to 400mg, 600mg, 800mg, to determine the MTD/RP2D.
Drug: APG-2575
APG-2575 orally once daily, every 28 days as a cycle.

Experimental: APG2575+ reduced-dose HHT
APG-2575 MTD/RP2D-1 and MTD/RP2D combines with reduced-dose HHT.
Drug: reduced-dose HHT
1mg IV QD on Days 1-14 (28-day cycle).

Experimental: APG2575+ standard-dose HHT
APG-2575 MTD/RP2D-1 and MTD/RP2D combines with standard-dose HHT.
Drug: standard-dose HHT
2mg/m^2 IV QD on Days 1-7 (28-day cycle).

Experimental: APG2575+ AZA
APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA.
Drug: Azacitidine
75 mg/m^2 SC QD on Days 1- 7 (28-day cycle).




Primary Outcome Measures :
  1. Dose Limiting Toxicities (DLT) [ Time Frame: 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 the cycle one.

  2. Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose(RP2D) [ Time Frame: 28 days ]
    MTD/RP2D will be determined based on DLTs observed during cycle one.


Secondary Outcome Measures :
  1. Maximum plasma concentration (Cmax) [ Time Frame: 28 days ]
    Cmax of APG-2575 will be assessed in the patients in single agent or combo study.

  2. Area under the plasma concentration versus time curve (AUC) [ Time Frame: 28 days ]
    AUC of APG-2575 will be assessed in the patients in single agent or combo study.

  3. Objective Response Rate (ORR) [ Time Frame: 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.

  4. progression free survival (PFS) [ Time Frame: Up to 2 years. ]
    From date of treatment start until the date of progression or the date of death due to any cause.

  5. duration of response (DOR) [ Time Frame: Up to 2 years. ]
    From date of response until the date of progression.

  6. overall survival (OS) [ Time Frame: Up to 2 years. ]
    From date of treatment start until the date of death due to any cause.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 primary AML, patients diagnosed as R/R AML (blasts in bone marrow >5%) after treatment, except for acute promyelocytic (APL) and t(9;22) AML.
  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 BCR-ABL 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 radiotherapy, surgery, immunotherapy, hormone therapy, targeted therapy, biological therapy or Chinese herbal therapy or any investigational treatment.
  9. Within 14 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) .
  10. 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.
  11. At the discretion of the investigator, gastrointestinal diseases that affect the absorption of APG-2575.
  12. Unstable angina, myocardial infarction, coronary artery reconstruction, or severe gastrointestinal bleeding occurred during the 180 days before the start of study.
  13. 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.
  14. 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).
  15. Any other condition or circumstance, at the discretion of the investigator, that patients would be unsuitable for participation in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04501120


Contacts
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Contact: Jie Jin, M.D. +86 571-87236896 jiej0503@163.com

Locations
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China, Beijing
Peking University People's Hospital Recruiting
Beijing, Beijing, China, 100044
Contact: Qiang Jiang, Professor         
China, Guandong
Sun Yat-sen University Cancer Center Recruiting
Guangzhou, Guandong, China
Contact: Yang Liang, Professor         
China, Henan
Henan Tumor Hospital Recruiting
Zhengzhou, Henan, China
Contact: Xudong Wei, Professor         
China, Hubei
Union Hospital medical college Huazhong University of Science and Technology Recruiting
Wuhan, Hubei, China, 430022
Contact: Qiubo Li, Professor         
Zhongnan Hospital of Hunan university Recruiting
Wuhan, Hubei, China, 430071
Contact: Fuling Zhou, Professor         
Contact: Jianying Zhou, Professor         
China, Hunan
Xiangya Hospital Central South University Recruiting
Changsha, Hunan, China
Contact: Yajing Xu, Master         
Contact: Qun He, Master         
China, Zhejiang
the First Affiliated Hospital, College of Medicine, Zhejiang University Recruiting
Hangzhou, Zhejiang, China, 310003
Contact: Jie Jin, M.D.    +86 571-87236896    jiej0503@163.com   
Sponsors and Collaborators
Ascentage Pharma Group Inc.
Suzhou Yasheng Pharmaceutical Co., Ltd.
Investigators
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Study Director: Yifan Zhai, M.D., Ph.D. Suzhou Yasheng Pharmaceutical Co., Ltd.
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Responsible Party: Ascentage Pharma Group Inc.
ClinicalTrials.gov Identifier: NCT04501120    
Other Study ID Numbers: APG2575AC101
First Posted: August 6, 2020    Key Record Dates
Last Update Posted: October 1, 2021
Last Verified: October 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ascentage Pharma Group Inc.:
APG-2575
Acute Myeloid Leukaemia (AML)
Bcl-2 Inhibitor
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Neoplasms by Histologic Type
Neoplasms
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors