A Study Evaluating APG-115 as a Single Agent or in Combination With APG-2575 in Subjects With T-PLL

A Phase IIa Study Evaluating the Pharmacokinetics, Safety and Efficacy of APG-115 as a Single Agent or in Combination With APG-2575 in Subjects With Relapsed/Refractory T-cell Prolymphocytic Leukemia (R/R T-PLL)

This is a multi-center, open-label, phase IIa study to evaluate the pharmacokinetics (PK), safety, and efficacy of APG-115 as a single agent or in combination with APG-2575 in patients with T-PLL. The study consists of two parts. A total of 24-36 T-PLL patients will be enrolled.

Study Overview

• Status: Recruiting
• Conditions: T-Prolymphocytic Leukemia
• Intervention / Treatment: Drug: APG-115; Drug: APG-2575

Detailed Description

In Part 1, 12-18 participants will be enrolled using a 3+3 dose escalation design. Patients receive APG-115 orally once every day (QD) with meal on Days 1 to 5, and 23 days off in the 28-day cycles.

In Part 2, patients receive APG-115 orally QD on Days 1 to 5, followed by 23 days off in a 28-day cycle. APG-115 dose escalation will use a standard 3+3 design starting from 150 mg, followed by 200 mg, then 250 mg. APG-2575 will be administered at 800 mg after ramp-up period. To prevent tumor lysis syndrome (TLS), APG-2575 needs to follow a 3-day daily ramp-up schedule from 200 mg before the fixed dose 800 mg is reached.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

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

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope
      • Contact: Melissa Banez; Phone Number: 626-218-8276; Email: mbanez@coh.org
      • Principal Investigator: Geoffrey Shouse, DO, PhD
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University
      • Contact: Hemalatha Rao; Phone Number: 614-685-1976; Email: Hemalatha.Rao@osumc.edu
      • Principal Investigator: Jonathan Brammer, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson
      • Contact: Kelly Quagliato; Phone Number: 713-614-2069; Email: krquagliato@mdanderson.org
      • Principal Investigator: Tapan Kadia, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age ≥ 18 years old
2. Patients with relapsed/refractory T-PLL who have active disease and have received at least one prior therapy
3. Patients must not have had chemotherapy or antibody therapy for 7 days prior to starting APG-115 and/or APG-2575. However, patients with rapidly proliferative disease may receive hydroxyurea or decadron until 24 hours prior to starting therapy on this protocol.
4. Absolute neutrophil count (ANC) ≥ 500/mm˄3; hemoglobin ≥ 60 g/L; platelet count ≥ 30,000/mm˄3
5. Total bilirubin ≤ 1.5 × upper limit of normal (ULN), unless related to leukemic involvement
6. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 3× ULN or ≤ 5 × ULN unless related to leukemic involvement
7. Adequate kidney function, defined as a calculated creatinine clearance ≥ 50 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula
8. Require laboratory TLS parameters to be within acceptable range and clinical TLS parameters no higher than grade 2 at study baseline, with or without TLS treatment, before initiation of study treatment.
9. Known cardiac ejection fraction of ≥ 45% within the past 3 months, no need to perform again at screening if this can be found in medical documents
10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
11. Has no malignancies other than T-PLL that: 1) currently require systemic therapies; 2) were not previously treated with curative intention (unless the malignant disease is in a stable remission according to the discretion of the treating physician); 3) or developed signs of progression after curative treatment
12. A negative serum pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling in this trial. Women of childbearing potential and men must agree to use contraception prior to study entry and for the duration of study participation.
13. 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/her legally authorized representative is required prior to their enrollment on the protocol.

Exclusion Criteria:

1. Uncontrolled intercurrent illness including, but not limited to active uncontrolled infection, symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
2. Patient with documented hypersensitivity to any of the components of the therapy program.
3. Patient previously treated with a murine double minute 2 (MDM2) inhibitor.
4. Known active, uncontrolled central nervous system (CNS) malignancy
5. Patients require graft versus host therapy, or require continued treatment with systemic immunosuppressive agents (calcineurin inhibitors within 4 weeks prior to the first dose of study drug).
6. Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies)
7. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection that requires treatment or at risk for HBV reactivation. Hepatitis B virus deoxyribonucleic acid (DNA) and HCV ribonucleic acid (RNA) must be undetectable upon testing. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis B core antibody positive. Prior test results obtained as part of standard of care that confirm a subject is immune and not at risk for reactivation (i.e., hepatitis B surface antigen negative, surface antibody positive) may be used for purposes of eligibility and tests do not need to be repeated. Subjects with prior positive serology results must have negative polymerase chain reaction results. Subjects whose immune status is unknown or uncertain must have results confirming immune status before enrollment.
8. Patients with COVID-19 who are tested with positive swab.
9. Failure to have recovered (Grade > 1) (except alopecia and pigmentation) from prior treatment (including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, or surgery)
10. Significant screening electrocardiogram (ECG) abnormalities including corrected QT interval (Fridericia) (QTcF) > 470 msec
11. Patients who have any conditions or illness that, according to the opinions of the Investigators or the medical monitor, would compromise patient safety or interfere with the evaluation of safety and efficacy to the study drug(s).
12. Patients who have used strong CYP2C8 inhibitors, or moderate or strong CYP3A4 inhibitors or inducers within washout period of 14 days or 7 half-lives before the first administration of study drugs, whichever is longer.

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 monotherapy; APG-115 will be given alone	Drug: APG-115; APG-115 given orally for first 5 consecutive days each cycle
Experimental: APG-115 + APG-2575 combination; APG-115 is given in combination with APG-2575	Drug: APG-115; APG-115 given orally for first 5 consecutive days each cycle; Drug: APG-2575; APG-2575 given orally each day in cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose of APG-115	To evaluate the safety of APG-115 as a single agent	28 days
Maximum tolerated dose of APG-115+APG-2575	To evaluate the maximum tolerated dose of APG-115 and APG-2575 in combination	28 days

Collaborators and Investigators

• Sponsor: Ascentage Pharma Group Inc.
• Investigators: Study Chair: Yifan Zhai, MD, PhD, Ascentage Pharma Group Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2021
• Primary Completion (Estimated): May 31, 2024
• Study Completion (Estimated): May 31, 2025

Study Registration Dates

• First Submitted: July 22, 2020
• First Submitted That Met QC Criteria: July 29, 2020
• First Posted (Actual): August 3, 2020

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, Lymphoid; Leukemia, T-Cell; Leukemia; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell
• Other Study ID Numbers: APG115TU101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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