Inclusion Criteria:

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 treated with APG-2575 200 mg QD plus acalabrutinib cohort may be relapsed or refractory to prior BTKi with del17p and/or p53 mutation and/or unmutated IGHV.

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× 10^9 /L;

• Platelet count ≥ 50 x 10^9 /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)/ (72 x 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:

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 acalabrutinib cohort).

6. For the acalabrutinib and APG-2575 combination cohort: (1) Patients who discontinued due to acalabrutinib toxicity

(Note: Patients who received a BTK inhibitor therapy may participate whether, or not, they progressed following BTK inhibitor treatment). (2) Requires treatment with proton pump inhibitors (e.g., omeprazole esomeprazole, lansoprazole etc) at study entry. (Patients receiving proton pump inhibitors who switch to H2 receptors antagonists or antacids are eligible for enrollment to this study arm.) (3) Requires or receiving anticoagulation therapy with warfarin or equivalent vitamin K antagonists within 7 days of first dose of the study drug(s).

7. Active pathogen infection 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.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/30/23. Questions regarding updates should be directed to the study team contact.