A Phase Ib/II Study of APG-2575 as a Single Agent or in Combination with Other Therapeutic Agents in Patients with Relapsed and/or Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ascentage Pharma Group Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

20 Dec 2021 → ongoing

Decision date (initial)

2024-09-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Ascentage Pharma Group Inc.

External identifiers

EU CT number

2024-515654-25-00

EudraCT number

2020-002736-73

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Therapy, Pharmacodynamic, Safety, Pharmacokinetic

Phase Ib
To assess the safety and tolerability, identify dose-limiting toxicities (DLT) and determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of APG-2575, administered orally as monotherapy or in combination with rituximab or acalabrutinib in patients with relapsed and/or refractory
CLL/SLL.
Phase II
To assess the safety and efficacy of APG-2575 alone or in combination with other therapeutic agents such as rituximab, acalabrutinib, ibrutinib or zanubrutinib in patients with relapsed and/or refractory or treatment naïve CLL/SLL. (Efficacy assessment parameters will include: ORR, CR, PR, PR-L, DOR, PFS,
OS, MRD by 8-color flow cytometry with a minimum sensitivity of 10-4 (0.01%) in peripheral blood and bone marrow, time to CR and/or MRD negativity.)

Secondary objectives 1

1. A- Determine the pharmacokinetics (PK) of APG-2575 when administered as: a single agent or in combination with, a) rituximab, b) acalabrutinib, c) ibrutinib, or d) zanubrutinib. B- To evaluate the relationship between exploratory and prognostic biomarkers (including BH3 profiling) for CLL/SLL and response to APG-2575 when administered as a single agent and in combinations with rituximab, acalabrutinib, ibrutinib or zanubrutinib.

Conditions and MedDRA coding

Relapsed and/or Refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. ≥18 years of age.
2. Histologically confirmed chronic lymphocytic leukemia or small lymphocytic leukemia (CLL/SLL) according to the 2018 international workshop (IW) CLL criteria who must have relapsed or be refractory to at least one prior therapy for CLL/SLL and require treatment by 2018 IWCLL criteria. In addition, for APG-2575, 600 plus acalabrutinib combination may be (1) treatment naïve or (2) refractory to venetoclax. Patients in APG-2575 plus ibrutinib Cohort C and in APG-2575 plus zanubrutinib Cohort D may be relapsed/refractory or treatment naïve.
3. Eastern Cooperative Oncology Group (ECOG) score ≤ 2.
4. Patients must have objectively documented evidence of disease progression prior to study entry such as: escalating lymphocytes count with an increase > 50% over a period of two months or doubling time in less than 6 months; enlarging adenopathy or splenomegaly; increasing cytopenias; clinical B symptoms night sweats, fatigue, > 10 % weight loss in 6 months, fevers > 100.50 F or 38.00 C for ≥ one month without infection.
5. Adequate bone marrow function independent of growth factor: • Absolute neutrophil count (ANC)≥ 1.0× 109/L. • Platelet count ≥ 50 x 109/L (entry platelet count must be independent of transfusion within 7 days of first dose of study drug). • Hemoglobin ≥ 8.0 g/dL independent of transfusion within 7 days of first dose of study drug.
6. Adequate renal and hepatic function as indicated by: a. Creatinine clearance must be ≥ 50 mL/min, calculated using the Cockcroft and Gault formula(140-Age) x mas (kg)/ (72x creatinine mg/dL); multiply by 0.85 if female (Cockcroft 1976) or measured by 24-hour urine collection. b. Total bilirubin ≤1.5 x ULN, except patient with known Gilbert’s syndrome or resolving hemolytic anemia. c. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <3 x ULN. Alkaline phosphatase < 3×ULN
7. Females of childbearing potential (i.e. not postmenopausal for at least 2 years or surgically sterile) must have negative results for pregnancy test performed: a. At screening on a serum sample obtained within 14 days prior to the first study drug administration. b. Prior to dosing on a urine sample obtained on the first day of study drug administration, if it has been＞7 days since obtaining the serum pregnancy test results.
8. Females of childbearing potential and non-sterile males must practice at least one of the following methods of birth control with partner(s) throughout the study and for 90 days after discontinuing study drug: a. Total abstinence from sexual intercourse as the preferred lifestyle of the patient; periodic abstinence is not acceptable; b. Surgically sterile partner(s); acceptable sterility surgeries are vasectomy, bilateral tubal ligation, bilateral oophorectomy or hysterectomy; c. Intrauterine device (IUD); d. Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal jellies or cream AND a condom); e. Hormonal contraceptives (oral, parenteral, vaginal ring or transdermal) for at least 3 months prior to study drug administration. If hormonal contraceptives are used, the specific contraceptive must have been used for at least 3 months prior to study drug administration.
9. Male patients must refrain from sperm donation, from initial study drug administration until 90 days after the last dose of study drug.
10. 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).
11. Willingness and ability to comply with study procedures and follow-up examination.

Exclusion criteria 22

1. Patient has undergone allogeneic stem cell transplant < 90 days.
2. Patient has active graft-versus-host disease or requires immunosuppressive therapy.
3. Patient has undergone CAR-T therapy < 30 days.
4. Active Richter’s Syndrome (patients with previously treated Richter’s Syndrome will be permitted if they are in remission).
5. Prior anti-Bcl-2 treatment (except patients who discontinued treatment for reasons other than disease progression and patients in the APG-2575 plus BTKi cohorts).
6. For the BTKi and APG-2575 combination cohorts: (1) Patients who discontinued due to a specific BTKi toxicity may not be retreated with that BTKi (Note: Patients who received a BTKi therapy may participate whether or not they progressed following BTKi treatment). (2) Patients in the cohort receiving acalabrutinib with the capsule formulation and not tablet formulation, who require concomitant treatment with a proton pump inhibitor (e.g., omeprazole esomeprazole, lansoprazole, etc.) at study entry. (Patients receiving proton pump inhibitors who switch to H2 receptor antagonists or antacids are eligible for enrollment into this study arm.) (3) Requires or is receiving anticoagulation therapy with warfarin or equivalent vitamin K antagonists within 7 days of first dose of the study drug(s).
7. Active pathogen infections including human immunodeficiency virus syndrome (HIV) infection.
8. Active hepatitis B infection, as defined seropositivity for Hep B surface antigen (HBsAg) or known active Hepatitis C infection as determined by Hepatitis C antibody with elevated liver enzymes as defined in the inclusion criteria or any other evidence of active Hepatitis C such as currently on treatment; or active COVID-19 infection. (Patients who have received COVID-19 vaccination will be considered as eligible for the study).
9. Has known central nervous system (CNS) involvement.
10. Prior malignancy that requires treatment, with exception of hormonal therapy and any cancer with recurrence within 2 years of screening (except for non-melanoma skin cancer or adequately treated carcinoma in situ of cervix or breast). Cancer treated within 2 years with curative intent and without recurrence as well as prostate cancer on active surveillance are allowed.
11. Concurrent treatment with an investigational agent, received biologics (≤14 days), or small molecule targeted therapies (≤5 half-life) or other anti-cancer therapies (including chemotherapy) ≤14 days of first dose of study drug.
12. Patient is pregnant or breastfeeding.
13. Has received the following within 7 days prior to the first dose of study drug: a. Steroid therapy at a dose greater than prednisone 20 mg daily (or equivalent) for antineoplastic intent; b. CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin; c. Potent CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John’s wort;
14. Radiation within 14 days of study entry.
15. Continuance of toxicities due to prior radiotherapy or chemotherapy agents that have not recovered to ≤ grade 1 or baseline, except alopecia or neuropathy.
16. Failure to recover adequately, as judged by the investigator, from prior surgical procedures. Patients with active wound healing, patients who have had major surgery within 28 days from 1st dose of study drug.
17. Has a cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea or anginal pain.
18. Unstable angina or myocardial infarction within 3 months of enrollment.
19. QTcF interval＞ 480ms (Bazetts or Fredericia) or other remarkable abnormality of ECG, including second-degree type II atrioventricular block, third-degree atrioventricular block or bradycardia (ventricular rate consistently less than 50 beats per minute).
20. Unable to swallow capsules or have gastrointestinal conditions that could affect the absorption of APG-2575 in the opinion of the investigator.
21. Uncontrolled concurrent illness including, but not limited to: uncontrolled diabetes mellitus, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with the study requirements.
22. Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary endpoints include characterizing safety and tolerability, defining the MTD and recommended phase 2 dose (RP2D).

Secondary endpoints 1

1. Secondary endpoints include determining the effectiveness of APG-2575 as monotherapy and in combination with other anticancer agents in patients with relapsed and/or refractory CLL by determining ORR (CR and PR) and MRD negativity.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ascentage Pharma Group Inc.

Sponsor organisation

Ascentage Pharma Group Inc.

Address

700 King Farm Boulevard

City

Rockville

Postcode

20850-5736

Country

United States

Scientific contact point

Organisation

Ascentage Pharma Group Inc.

Contact name

Yifan Zhai, M.D., Ph.D.

Public contact point

Organisation

Ascentage Pharma Group Inc.

Contact name

Yifan Zhai, M.D., Ph.D.

Third parties 5

Locations

2 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications