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

Sponsor

Ascentage Pharma Group Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04501120

Collaborator

Suzhou Yasheng Pharmaceutical Co., Ltd. (Industry)

132

Enrollment

Locations

Arms

58.1

Anticipated Duration (Months)

13.2

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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 and related myeloid malignancies.

Condition or Disease	Intervention/Treatment	Phase
Relapsed/Refractory Acute Myeloid Leukaemia Myeloid Malignancy	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 and related myeloid malignancies 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

132 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 :

Sep 28, 2020

Anticipated Primary Completion Date :

Aug 1, 2024

Anticipated Study Completion Date :

Aug 1, 2025

Arms and Interventions

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 or Iv gtt QD on Days 1- 7 (28-day cycle).

Outcome Measures

Primary Outcome Measures

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 the 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

Maximum plasma concentration (Cmax) [28 days]
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) [28 days]
AUC 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Age ≥18 years old.
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).
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 -2.
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 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.
White blood cell (WBC) ≥100×109/L when screening.
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, including but not limited to active human immunodeficiency virus (HIV), viral hepatitis B or C (type B or C).
Prior history of allogeneic hematopoietic stem cell transplantation or adoptive cell immunotherapy or autologous hematopoietic stem cell transplantation within 12 months.
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.
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.
Within 7 days before the first dose of study drug, received a strong and/or moderate CYP3A inducer and/or Inhibitor.
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) .
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.
At the discretion of the investigator, gastrointestinal diseases that affect the absorption of APG-2575.
Unstable angina, myocardial infarction, coronary artery reconstruction, or severe gastrointestinal bleeding occurred during the 180 days before the start of study.
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.
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).
Any other condition or circumstance, at the discretion of the investigator, that patients would be unsuitable for participation in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Peking University People's Hospital	Beijing	Beijing	China	100044
2	Sun Yat-sen University Cancer Center	Guangzhou	Guandong	China
3	Guangdong Provincial People's Hospital	Guangzhou	Guangdong	China	510080
4	Henan Tumor Hospital	Zhengzhou	Henan	China
5	Union Hospital medical college Huazhong University of Science and Technology	Wuhan	Hubei	China	430022
6	Zhongnan Hospital of Hunan university	Wuhan	Hubei	China	430071
7	Xiangya Hospital Central South University	Changsha	Hunan	China
8	The First affiliated hospital of Soochow University	Suzhou	Jiangsu	China
9	West China Hospital of Sichuan University	Chengdu	Sichuan	China	610044
10	the First Affiliated Hospital, College of Medicine, Zhejiang University	Hangzhou	Zhejiang	China	310003

Sponsors and Collaborators

Ascentage Pharma Group Inc.
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