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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Myeloid Malignancy; Relapsed/Refractory Acute Myeloid Leukaemia
• Intervention / Treatment: Drug: APG-2575; Drug: standard-dose HHT; Drug: Azacitidine; Drug: APG-2575; Drug: Reduced-dose HHT

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.

• Study Type: Interventional
• Enrollment (Anticipated): 284
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Jie Jin, M.D.; Phone Number: +86 571-87236896; Email: jiej0503@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100044
      • Recruiting
      • Peking University People's Hospital
      • Contact: Qiang Jiang, Professor
  • Chongqing
    • Chongqing, Chongqing, China
      • Not yet recruiting
      • Chongqing University Cancer Hospital
      • Contact: Yi Gong, M.D.
  • Guandong
    • Guangzhou, Guandong, China
      • Recruiting
      • Sun Yat-Sen University Cancer Center
      • Contact: Yang Liang, Professor
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Recruiting
      • Guangdong Provincial People's Hospital
      • Contact: Jianyu Wong, M.D.
  • Henan
    • Zhengzhou, Henan, China
      • Recruiting
      • Henan Tumor Hospital
      • Contact: Xudong Wei, Professor
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Recruiting
      • Union Hospital medical college Huazhong University of Science and Technology
      • Contact: Qiubo Li, Professor
    • Wuhan, Hubei, China, 430071
      • Recruiting
      • Zhongnan Hospital of Hunan university
      • Contact: Fuling Zhou, Professor
      • Contact: Jianying Zhou, Professor
  • Hunan
    • Changsha, Hunan, China
      • Recruiting
      • Xiangya Hospital Central South University
      • Contact: Yajing Xu, Master
  • Jiangsu
    • Suzhou, Jiangsu, China
      • Recruiting
      • The First Affiliated Hospital Of Soochow University
      • Contact: Suning Chen, M.D.
  • Shanghai
    • Shanghai, Shanghai, China
      • Not yet recruiting
      • Shanghai The Sixth People' s Hospital
      • Contact: Chunkang Chang, Professor
  • Sichuan
    • Chengdu, Sichuan, China, 610044
      • Recruiting
      • West China Hospital of Sichuan University
      • Contact: Xiao Shuai, M.D.; Phone Number: 18980606797; Email: 5397781@qq.com
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Recruiting
      • The First Affiliated Hospital, College of Medicine, Zhejiang University
      • Contact: Jie Jin, M.D.; Phone Number: +86 571-87236896; Email: jiej0503@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

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

1. 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.
2. 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).
3. Subjects can accept oral administration of APG-2575.
4. Life expectancy ≥ 3 months.
5. Adequate renal and liver function.
6. 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.
7. 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).
8. 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 with acute promyelocytic leukemia or t(9;22)(q34.1;q11.2); BCR-ABL1 positive AML patients.
2. 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).
3. Known leukemia infiltration of the central nervous system.
4. Symptomatic active fungal, bacterial and/or viral infections.
5. Prior history of allogeneic hematopoietic stem cell transplantation or adoptive cell immunotherapy, autologous hematopoietic stem cell transplantation within 12 months.
6. 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.
7. Within 7 days before the first dose of study drug, received a strong and/or moderate CYP3A inducer and/or Inhibitor.
8. At the discretion of the investigator, gastrointestinal diseases that affect the absorption of APG-2575.
9. Any other condition or circumstance, at the discretion of the investigator, that patients would be unsuitable for participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / 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.; Drug: APG-2575; APG-2575 orally once daily for 14 days, every 28 days as a cycle.
Experimental: APG2575+reduced-dose HHT; APG-2575 MTD/RP2D-1 and MTD/RP2D combines with reduced-dose HHT in R/R AML, MPAL, BPDCN, CMML.	Drug: APG-2575; APG-2575 orally once daily, every 28 days as a cycle.; Drug: APG-2575; APG-2575 orally once daily for 14 days, every 28 days as a cycle.; 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 in R/R AML, MPAL, BPDCN, CMML.	Drug: APG-2575; APG-2575 orally once daily, every 28 days as a cycle.; Drug: standard-dose HHT; 2mg/m^2 IV QD on Days 1-7 (28-day cycle).; Drug: APG-2575; APG-2575 orally once daily for 14 days, every 28 days as a cycle.
Experimental: APG2575+ AZA; APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in R/R AML, MPAL, BPDCN, CMML.	Drug: APG-2575; APG-2575 orally once daily, every 28 days as a cycle.; Drug: Azacitidine; 75 mg/m^2 SC or Iv gtt QD on Days 1- 7 (28-day cycle).; Drug: APG-2575; APG-2575 orally once daily for 14 days, every 28 days as a cycle.
Experimental: APG2575+ AZA(HR-MDS.); APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in HR-MDS.	Drug: APG-2575; APG-2575 orally once daily, every 28 days as a cycle.; Drug: Azacitidine; 75 mg/m^2 SC or Iv gtt QD on Days 1- 7 (28-day cycle).; Drug: APG-2575; APG-2575 orally once daily for 14 days, every 28 days as a cycle.
Experimental: APG2575+ AZA(Naïve AML.); APG-2575 MTD/RP2D-1 and MTD/RP2D combines with AZA in treatment naïve AML.	Drug: APG-2575; APG-2575 orally once daily, every 28 days as a cycle.; Drug: Azacitidine; 75 mg/m^2 SC or Iv gtt QD on Days 1- 7 (28-day cycle).; Drug: APG-2575; APG-2575 orally once daily for 14 days, every 28 days as a cycle.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax)	Cmax of APG-2575 will be assessed in the patients in single agent or combo study.	28 days
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.	28 days
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.	Up to 6 cycles (each cycle is 28 days).
progression free survival (PFS)	From date of treatment start until the date of progression or the date of death due to any cause.	Up to 2 years.
duration of response (DOR)	From date of response until the date of progression.	Up to 2 years.
overall survival (OS)	From date of treatment start until the date of death due to any cause.	Up to 2 years.

Collaborators and Investigators

• Sponsor: Ascentage Pharma Group Inc.
• Collaborators: Suzhou Yasheng Pharmaceutical Co., Ltd.
• Investigators: Study Director: Yifan Zhai, M.D., Ph.D., Suzhou Yasheng Pharmaceutical Co., Ltd.; Principal Investigator: Jie Jin, M.D., the First Affiliated Hospital, College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2020
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): August 1, 2025

Study Registration Dates

• First Submitted: August 3, 2020
• First Submitted That Met QC Criteria: August 3, 2020
• First Posted (Actual): August 6, 2020

Study Record Updates

• Last Update Posted (Actual): March 14, 2023
• Last Update Submitted That Met QC Criteria: March 10, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: APG-2575; Acute Myeloid Leukaemia (AML); Bcl-2 Inhibitor; Myeloid Malignancy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Leukemia; Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: APG2575AC101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No