A Study of APG-2575 in Combination With Azacitidine in Patients With Acute Myeloid Leukemia (AML)

A Phase Ib/II Study of APG-2575 in Combination With Azacitidine in Patients With Acute Myeloid Leukemia (AML), Mixed Phenotype Acute Leukemia (MPAL), Chronic Myelomonocytic Leukemia (CMML) and Higher-Risk Myelodysplastic Syndrome (MDS

This is a Phase Ib/II, open-label, multi-center study evaluating the safety, tolerability, efficacy and PK of APG-2575 in combination with Azacitidine in the patients with AML/MPAL or MDS/CMML. The study consists of dose escalation (Part I) and dose expansion phase (Part II)

Study Overview

• Status: Recruiting
• Conditions: AML, Adult
• Intervention / Treatment: Drug: APG 2575 ramp up arm

Detailed Description

The patients with histologically confirmed relapsed or refractory (R/R) AML/MPAL/CMML or relapsed/refractory Higher-Risk MDS by WHO classification for which no available standard therapies are indicated or anticipated to result in a durable response will be enrolled.

This will be a 3+3 dose escalation to determine the DLTs and MTD/RP2D of APG-2575 (see dose escalation table) given in combination with Azacitidine

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Angela Kaiser; Phone Number: 301-509-0357; Email: Angela.Kaiser@ascentage.com

Study Locations

• Australia
  • Queensland
    • Benowa, Queensland, Australia, 4217
      • Recruiting
      • Pindara Private Hospital
      • Principal Investigator: Hanlon Sia, MD
    • Birtinya, Queensland, Australia, 4575
      • Recruiting
      • Sunshine Coast University Hospital
      • Principal Investigator: Joshua Richmond, MD
  • Victoria
    • Epping, Victoria, Australia, 3076
      • Recruiting
      • The Northern Hospital
      • Principal Investigator: Chong C Chua, MD
  • Western Aus
    • Perth, Western Aus, Australia, 6000
      • Recruiting
      • Royal Perth Hospital
      • Principal Investigator: Michael Leahy, MD
• United States
  • California
    • Los Angeles, California, United States, 94101
      • Recruiting
      • UCLA Medical cetner Division of Hematology
      • Principal Investigator: Caspian Oliai, MD
  • North Carolina
    • Charlotte, North Carolina, United States, 28413
      • Recruiting
      • Novant Health
      • Principal Investigator: Patricia Kropf, MD
    • Winston-Salem, North Carolina, United States, 27103
      • Recruiting
      • Novant Health
      • Principal Investigator: James Dugan, MD
      • Contact: Patricia Kropf, MD; Phone Number: 980-302-4560
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MDACC
      • Contact: Debra B Linderman; Phone Number: 713-614-2069; Email: DLBull@mdanderson.org
      • Principal Investigator: Tapan Kadia, MD
  • Washington
    • Seattle, Washington, United States, 98104
      • Recruiting
      • Swedish Medical Center
      • Principal Investigator: Daniel Egan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients with a diagnosis of histologically confirmed relapsed or refractory (R/R) acute myeloid leukemia (AML) or mixed phenotype acute leukemia (MPAL) or Chronic Myelomonocytic Leukemia (CMML) or relapsed/refractory Higher-Risk MDS by 2016 WHO classification for which no available standard therapies are indicated or anticipated to result in a durable response.

• MPAL will include biphenotypic leukemia, bilineal leukemia, undifferentiated leukemia, mixed lineage leukemia, leukemia of ambiguous lineage, T/myeloid leukemia, B/myeloid leukemia, or other diagnosis indicating the presence of multiple lineages within the cell population.
• Relapsed/refractory MDS will be defined as prior receipt of 4 cycles of HMA therapy with failure to attain a response, or progression of disease or relapse at any time after prior response to HMA therapy with Overall Revised International Prognostic Scoring System (IPSS-R) score > 3 (intermediate, high or very high).

Exclusion Criteria:

1. Pregnant women.
2. 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.

3. Have had leukemia therapy within 14 days prior to starting investigational drug.

   However, patients with rapidly proliferative disease may receive hydroxyurea as needed until 24 hours prior to starting therapy on this protocol and during the first cycle of study.

4. Have taken strong inhibitors or inducers of CYP3A4 within 7 days prior to the first dose of APG-2575.
5. Have acute promyelocytic leukemia (French-American-British Class M3 AML or WHO classification APL with PML-RARA) or AML/MPAL with BCR-ABL1 positive.
6. Active infection requiring systemic antibiotic/antifungal medication, known clinically active hepatitis B or C, or HIV infection or active COVID-19. (Patients who have received COVID-19 vaccination will be considered as eligible for the study.)
7. Have active/ongoing graft-versus host disease (GVHD) or require continued treatment with systemic immunosuppressive agents (calcineurin inhibitors within 4 weeks prior to the first dose).
8. Myeloablative therapy with autologous or allogeneic hematopoietic stem cell rescue within 6 months of study treatment initiation.
9. Documented hypersensitivity to any of the components of the therapy program.
10. Active, uncontrolled CNS leukemia.
11. Men and women of childbearing potential who do not practice contraception. Women of childbearing potential and men must agree to use at least 1 form of barrier birth control (such as condom) prior to study entry and for the duration of study participation.

12. 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.
13. Failure to have recovered (Grade > 1) from prior treatment (including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, or surgery), except for alopecia.
14. Unable to swallow tablets or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
15. Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval (QTc) ≥470 msec.
16. Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: APG2575 + Azacitidine; 200 mg APG2575 dose ramp up +AZA	Drug: APG 2575 ramp up arm; APG2575 ramp up + Azacitidine; Other Names: APG2575

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DLT	Dose-limiting toxicity (DLT) rate at each dose level DLT will be assessed within the first 28-day cycle of study treatment via CTCAE version 5.0	28 days

Collaborators and Investigators

• Sponsor: Ascentage Pharma Group Inc.
• Investigators: Principal Investigator: Qian Niu, MD, Ascentage Pharma

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2021
• Primary Completion (Estimated): July 30, 2024
• Study Completion (Estimated): October 30, 2024

Study Registration Dates

• First Submitted: June 23, 2021
• First Submitted That Met QC Criteria: July 6, 2021
• First Posted (Actual): July 16, 2021

Study Record Updates

• Last Update Posted (Actual): October 25, 2023
• Last Update Submitted That Met QC Criteria: October 23, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia, Myeloid; Leukemia; Leukemia, Myeloid, Acute
• Other Study ID Numbers: APG2575AU101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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