A Phase Ib Study of APG-115 Single Agent or in Combination With Azacitidine or Cytarabine in Patients With AML and MDS.

A Phase Ib Study to Investigate the Safety, Pharmacokinetics and Pharmacodynamics of APG-115 as a Single Agent or in Combination With Azacitidine or Cytarabine in Patients With Relapse/Refractory AML and Relapsed/Progressed High/Very High Risk MDS

Acute myeloid leukemia is a malignant disorder characterized by the rapid, uncontrolled proliferation of malignant clonal hematopoietic stem cells that accumulate as immature, undifferentiated cells (blasts) in the bone marrow and circulation.

APG-115 is a potent and orally active small-molecule MDM2 inhibitor, it binds to MDM2 protein and shows potent cell growth inhibitory activity in vitro with low nanomolar potencies in a subset of human cancer cell lines. APG-115 has demonstrated its strong antitumor activities with either daily or less frequent dosing-schedules in the acute leukemia xenograft models.

This is a phase 1b, open-label, three-stages study that will initially evaluate the safety and PK/PD profile of APG-115 as a single agent, followed by a combination of APG-115 + azacytidine or cytarabine in R/R AML or MDS subjects.

Patients will continue treatment for maximally 6 cycles or until progression of disease or unacceptable toxicity is observed or administrative discontinuation whichever occurs first. Patients who continue to be benefit after 6 cycles' treatment will receive additional cycles of treatment until progression of disease, unacceptable toxicity is observed or administrative discontinuation. (As long as it is proven safe).

Study Overview

• Status: Recruiting
• Conditions: Myelodysplastic Syndromes (MDS); Acute Myeloid Leukemia (AML)
• Intervention / Treatment: Drug: APG-115; Drug: Cytarabine; Drug: Azacitidine

Detailed Description

Stage 1: This will be a 3+3 dose escalation to determine the DLTs and MTD/RP2D of APG-115 given according to the different dose levels once daily from Days 1 to 7 every 28 days.

Stage 2: After stage 1 of APG-115 single agent dose escalation first cycle is completed, stage 2 can be initiated with the combination regimen. This will be a 3+3 dose escalation to determine the MTD/RP2D and DLTs of APG-115 + AZA(arm A)/Cytarabine (arm B)combination.

Stage 3: dose expansion of the combination regimes.

• Study Type: Interventional
• Enrollment (Estimated): 102
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Junyuan Qi, M.D.; Phone Number: +86-18622662361; Email: qi_jy@yahoo.com
• Study Contact Backup: Name: Bo Jiang, M.D.; Phone Number: +86-22-23909067; Email: jianbo044@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100034
      • Not yet recruiting
      • The First Hospital of Peking University
      • Contact: Qian Jiang, Ph.D
      • Principal Investigator: Qian Jiang, Ph.D
  • Guangdong
    • Guangzhou, Guangdong, China
      • Recruiting
      • Nanfang Hospital of Southern Medical University
      • Contact: Yu Zhang, Master
      • Contact: Chongyuan Xu Professor; Phone Number: 86-020-62786845; Email: nfyygcp@126.com
    • Guangzhou, Guangdong, China
      • Recruiting
      • Guangzhou Panyu Central Hospital
      • Contact: Shuqin Cheng, Master
      • Contact: Hui Yang Professor
  • Henan
    • Zhengzhou, Henan, China
      • Recruiting
      • Henan Provincial Oncology Hospital
      • Contact: Xudong Wei, M.D.
  • Hubei
    • Wuhan, Hubei, China
      • Recruiting
      • Zhongnan Hospital of Wuhan University
      • Contact: Fuling Zhou, M.D.
      • Contact: Jianying Huang Director
    • Wuhan, Hubei, China
      • Recruiting
      • Union Hospital medical college Huazhong University of Science and Technology
      • Contact: Qiubo Li, Doctor
  • Hunan
    • Changsha, Hunan, China
      • Recruiting
      • Xiangya Hospital Central South University
      • Contact: Qun Qin, M.D.
      • Contact: Qun He, Master
  • Jiangsu
    • Suzhou, Jiangsu, China
      • Recruiting
      • The First Affiliated Hospital of Soochow University
      • Contact: Xiaowen Tang, Doctor
    • Suzhou, Jiangsu, China, 215636
      • Not yet recruiting
      • The First Affilated Hospital of Ganzhou Medical University
      • Contact: Liping Liu, Ph.D.
      • Principal Investigator: Liping Liu, Ph.D.
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • Not yet recruiting
      • The First Affiliated Hospital of Nanchang University
      • Contact: Fei Li, Ph.D.
      • Principal Investigator: Fei Li, Ph.D.
  • Jilin
    • Changchun, Jilin, China
      • Recruiting
      • First Hospital of Jilin University
      • Contact: Sujun Gao, M.D.
  • Shanghai
    • Shanghai, Shanghai, China
      • Recruiting
      • Shanghai Sixth People's Hospital
      • Contact: Chunkang Chang Professor
    • Shanghai, Shanghai, China
      • Recruiting
      • Shanghai Jiao Tong University school of medicine Ruijing Hospital
      • Contact: Junmin Li Professor
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Recruiting
      • Blood Diseases Hospital Chinese Academy of Medical Sciences
      • Contact: Jianxiang Wang, MD; Phone Number: +86 22-23909120; Email: wangjx@ihcams.ac.cn
      • Contact: Junyuan Qi, MD; Phone Number: +86 18622662361; Email: qi_jy@yahoo.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients with a diagnosis of histologically confirmed relapsed or refractory (R/R) acute myeloid leukemia by WHO classification or relapsed/progressed high/very high risk MDS (score≥4.5) according to IPSS-R risk stratification
2. Age >/= 18 years.
3. Adequate organ function
4. Subject must have a projected life expectancy of at least 12 weeks.
5. ECOG performance status of 0-1.
6. Patient must have the ability to understand the requirements of the study and signed informed consent. A signed informed consent by the patient or his legally authorized representative is required prior to their enrollment on the protocol.
7. Subject has a white blood cell count< 50 × 109/L. Note: Hydroxyurea is permitted to meet this criterion.

Exclusion Criteria:

1. Subject has acute promyelocytic leukemia.
2. Patients must not have had leukemia biotherapy 4 weeks prior to starting investigational drug, or less than 5 half-lives small molecular targeted drug therapy, or 28 days any anti-cancer therapy (whichever is longer)
3. Uncontrolled intercurrent illness including, but not limited to active uncontrolled infection, symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
4. Active infection requiring systemic antibiotic/antifungal medication, known clinically active hepatitis B or C, or HIV infection.
5. Participants who have received allogeneic HSCT, or autologous HSCT within 12 months.
6. Patients with active, uncontrolled CNS leukemia will not be eligible.
7. Any prior systemic MDM2-p53 inhibitor treatment
8. Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.

9. Subject has a history of other malignancies within 2 years prior to study entry, with the exception of:

   • Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
   • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
   • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intention: requires discussion with sponsor.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: APG-115/APG-115+Cytarabine in Relapse/Refractory AML	Drug: APG-115; APG-115 orally once daily from Days 1 to 7 every 28 days.; Drug: Cytarabine; 1g/m^2 IV QD on Days 3-7 (28-day cycle)
Experimental: APG-115/APG-115+Aza in relapsed/progressed high risk MDS	Drug: APG-115; APG-115 orally once daily from Days 1 to 7 every 28 days.; Drug: Azacitidine; 75 mg/m^2 SC QD on Days 1- 7 (28-day cycle)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicities (DLT)	DLT will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 5) by organ system. DLT will be defined as clinically significant drug-related adverse events during the Cycle one.	From day 1 to the end of cycle 1 (each cycle is 28 days).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR is defined by CR + CRi+ PR (according to IWG AML（2003）and IWG MDS（2006）criteria)	Evaluated for response by the end of cycle 1 and cycle 2, and then 2 months thereafter till complete 6 cycles treatment or 1 month after last dose (each cycle is 28 days).
Overall survival (OS)	From date of treatment start until the date of death due to any cause or date of termination of the study, whichever came first. Termination of the Study: The last subject has completed at least 6 cycle's treatment or the subject discontinues treatment for any reason.	Measured up to 6 months after the last subject has received treatment.

Collaborators and Investigators

• Sponsor: Ascentage Pharma Group Inc.
• Collaborators: Suzhou Yasheng Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Jianxiang Wang, M.D., Blood Diseases Hospital Chinese Academy of Medical Sciences

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2020
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: February 5, 2020
• First Submitted That Met QC Criteria: February 18, 2020
• First Posted (Actual): February 19, 2020

Study Record Updates

• Last Update Posted (Actual): August 30, 2023
• Last Update Submitted That Met QC Criteria: August 28, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: AML; MDS; APG-115
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Leukemia; Leukemia, Myeloid; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Preleukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Azacitidine; Cytarabine
• Other Study ID Numbers: APG115AC101

Drug and device information, study documents

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