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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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T-Prolymphocytic Leukemia

Intervention / Treatment
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* Drug: APG-115
* Drug: APG-2575


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old Patients with relapsed/refractory T-PLL who have active disease and have received at least one prior therapy 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. Absolute neutrophil count (ANC) ≥ 500/mm˄3; hemoglobin ≥ 60 g/L; platelet count ≥ 30,000/mm˄3 Total bilirubin ≤ 1.5 × upper limit of normal (ULN), unless related to leukemic involvement Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 3× ULN or ≤ 5 × ULN unless related to leukemic involvement 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 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. 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 Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 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 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. 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: 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. Patient with documented hypersensitivity to any of the components of the therapy program. Patient previously treated with a murine double minute 2 (MDM2) inhibitor. Known active, uncontrolled central nervous system (CNS) malignancy 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). Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies) 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. Patients with COVID-19 who are tested with positive swab. Failure to have recovered (Grade > 1) (except alopecia and pigmentation) from prior treatment (including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, or surgery) Significant screening electrocardiogram (ECG) abnormalities including corrected QT interval (Fridericia) (QTcF) > 470 msec 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). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study consists of Part 1 APG-115 as monotherapy and Part 2 APG-2575 in combination with APG-115. APG-115 and APG-2575 will be orally administrated on 28-day cycles. Totally 12-18 participants will be enrolled using a 3+3 dose escalation design in each part. Patients receive APG-115 orally once every day (QD) with meal on Days 1 to 5, 23 days off on the 28-day cycles.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APG-115 monotherapy<br>APG-115 will be given alone | Drug: APG-115<br>* APG-115 given orally for first 5 consecutive days each cycle<br>|
| Experimental: APG-115 + APG-2575 combination<br>APG-115 is given in combination with APG-2575 | Drug: APG-115<br>* APG-115 given orally for first 5 consecutive days each cycle<br>Drug: APG-2575<br>* APG-2575 given orally each day in cycle<br>|

What is the study measuring?
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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 |