Study of APG-2575 as a Single Agent or in Combination With Other Therapeutic Agents for CLL/SLL

Inclusion Criteria:

1. ≥18 years of age.

2. Histologically confirmed chronic lymphocytic leukemia (CLL) or small lymphocyticleukemia (SLL) according to the 2018 international workshop (IW) CLL criteria whomust have relapsed or be refractory to at least one prior therapy for CLL/SLL andrequire treatment by 2018 IWCLL criteria. In addition, lisaftoclax (600 mg) plusacalabrutinib combination cohort may include patients who are: (1) treatment-naïve,or (2) refractory to venetoclax.

3. Eastern Cooperative Oncology Group (ECOG) ≤ 2.

4. Patient must have objectively documented evidence of disease progression prior tostudy entry such as: escalating lymphocytes count with an increase > 50% over aperiod of two months or doubling time in less than 6 months; enlarging adenopathy orsplenomegaly; increasing cytopenias; clinical B symptoms -night sweats, fatigue, > 1% weight loss in 6 months, fevers > 100.50F for ≥ one month without infection.

5. Adequate bone marrow function independent of growth factor:

6. Absolute neutrophil count (ANC) ≥1.0× 109/L in patient without bone marrowinvolvement. This criterion does not apply to patients with bone marrowinvolvement by CLL/SLL.

7. Platelets count ≥30 x 109/L (entry platelet count must be independent oftransfusion within 7 days of first dose of lisaftoclax).

8. Adequate renal and hepatic function as indicated by:

9. Serum creatinine ≤1.5×upper limit of normal (ULN); if serum creatinine is >1.5×ULN, creatinine clearance must be ≥ 50 mL/min, calculated using theCockcroft and Gault formula(140-Age)x mas (kg)/(72x creatinine mg/dL); multiplyby 0.85 if female (Cockcroft 1976).

10. Total bilirubin ≤1.5 x ULN, except patients with known Gilbert's syndrome.

11. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <2.5 x ULN,Alkaline phosphatase<2.5×ULN.

12. International normalized Ratio (INR), Prothrombin Time (PT) or ActivatedPartial Thromboplastin time (APTT) ≤1.5×ULN unless the patient is receivinganticoagulant therapy as long as PT or APTT is within therapeutic range ofintended use of anticoagulants.

13. Females of childbearing potential (i.e., not postmenopausal for at least 2 years orsurgically sterile) must have negative results for pregnancy test performed:

14. At screening on a serum sample obtained within 14 days prior to the firstlisaftoclax administration;

15. Prior to dosing on a urine sample obtained on the first day of lisaftoclaxadministration, if it has been >7 days since obtaining the serum pregnancy testresults.

16. Females of childbearing potential and non-sterile males must practice at least oneof the following methods of birth control with partner(s) throughout the study andfor 90 days after discontinuing lisaftoclax:

17. Total abstinence from sexual intercourse as the preferred lifestyle of thepatient; periodic abstinence is not acceptable;

18. Surgically sterile partner(s); acceptable sterility surgeries are: vasectomy,bilateral tubal ligation, bilateral oophorectomy or hysterectomy

19. Intrauterine device (IUD);

20. Double-barrier method (contraceptive sponge, diaphragm or cervical cap withspermicidal fellies or cream AND a condom);

21. Hormonal contraceptives (oral, parenteral, vaginal ring or transdermal) for atleast 3 months prior to lisaftoclax administration. If hormonal contraceptivesare used, the specific contraceptive must have been used for at least 3 monthsprior to lisaftoclax administration.

22. Male patients must refrain from sperm donation, from initial lisaftoclaxadministration until 90 days after the last dose of lisaftoclax.

23. Ability to understand and willingness to sign a written informed consent form (theconsent form must be signed by the patient prior to any study-specific procedures).

24. 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 require immunosuppressive therapy.

3. Patient has undergone CAR-T cell therapy < 30 days.

4. Richter's Syndrome (patients with previously treated Richter's syndrome will bepermitted if they are in remission).

5. Prior anti-BCL-2 treatment (except patients who discontinued treatment for reasonsother than disease progression and patients in the lisaftoclax plus acalabrutinibcohort).

6. For the acalabrutinib and lisaftoclax combination cohort: (1) Patients whodiscontinued due to acalabrutinib toxicity (Note: Patients who received a BTKinhibitor therapy may participate whether, or not, they progressed following BTKinhibitor treatment). (2) Patients who require treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, etc.) at study entry. (Patientsreceiving proton pump inhibitors who switch to H2 receptor antagonists or antacidsare eligible for enrollment to this study arm.) (3) Patients who require or arereceiving anticoagulation therapy with warfarin or equivalent vitamin K antagonistswithin 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 antibodywith elevated liver enzymes as defined in the inclusion criteria or any otherevidence of active Hepatitis C such as currently on treatment; or active COVID-19infection. (Patients who have received COVID-19 vaccination will be considered aseligible for the study).

9. Has known central nervous system (CNS) involvement.

10. Prior malignancy that required treatment and has shown recurrence within 2 years ofscreening (except for non-melanoma skin cancer or adequately treated carcinoma insitu of cervix or breast). Cancer treated within 2 years with curative intent andwithout recurrence as well as prostate cancer on active surveillance are allowed.

11. Concurrent treatment with any other investigational agent, received biologics (≤28days), or small molecule targeted therapies (≤5 half-life) or other anti-cancertherapies (including chemotherapy) ≤14 days of first dose of lisaftoclax.

12. Patient is pregnant or breast feeding.

13. Has received the following within 7 days prior to the first dose of lisaftoclax:

14. Steroid therapy at a dose greater than prednisone 20 mg daily (or equivalent)for anti-neoplastic intent

15. CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin

16. Potent CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St.John's wort.

17. Radiation within 14 days of study entry.

18. Continuance of toxicities due to prior radiotherapy or chemotherapy agents that havenot recovered to ≤ grade 1 or baseline, except alopecia or neuropathy.

19. Failure to recover adequately, as judged by the Investigator, from prior surgicalprocedures. For example, patients with active wound healing; patients who have hadmajor surgery within 28 days from 1st dose of lisaftoclax.

20. 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 butordinary physical activity results in fatigue, palpitations, dyspnea or anginalpain.

21. Unstable angina or myocardial infarction within 3 months of enrollment.

22. QTc interval> 480ms (Bazett or Fredericia formulae) or other remarkable abnormal ECGfindings, including second-degree type II atrioventricular block, third-degreeatrioventricular block or bradycardia (ventricular rate of less than 50 beats perminute).

23. Unable to swallow capsules or have gastrointestinal conditions that could affect theabsorption of lisaftoclax in the opinion of the Investigator.

24. Uncontrolled concurrent illness including, but not limited to: uncontrolled diabetesmellitus, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith the study requirements.

25. Any other condition or circumstance that would, in the opinion of the Investigator,make the patient unsuitable for participation in the study.