Study of APG-2575 as a Single Agent or in Combination With Other Therapeutic Agents for CLL/SLL
Study of APG-2575 as a Single Agent or in Combination With Other Therapeutic Agents for CLL/SLL
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.
The study will be conducted in two (2) parts and each part will consist of a ramp-up period,
 dose escalation and dose expansion portions. The duration of the ramp-up period will depend
 on the dose schedule being tested and will be conducted for both monotherapy and combination
 therapy. The ramp-up will consist of treatment with APG-2575 given once a day starting at 20
 mg on Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, 400 mg on Day 5¸ 600 mg on Day
 6, 800 mg on Day 7, 1000 mg on Day 8 and 1200 mg on Day 9. Scheduled maximum cohort doses for
 evaluation will start at 200 mg of APG-2575 to a maximum of 1200 mg of APG-2575.
 Consequently, patients with a scheduled maximum dose of 200 mg will have a 3-day ramp-up
 period, those scheduled at 400 mg, a 4-day ramp-up, and those scheduled at 600 mg, a 5-day
 ramp-up, etc, see Figure 1. Part 1 will study APG-2575 at different dose levels as
 monotherapy using a 3+3 dose escalation design with dose expansion at RP2D. Part 2 will be
 combination of APG-2575 with rituximab or acalabrutinib or voruciclib Part 2 will be a 3+3
 dose escalation of combination APG-2575 plus rituximab or acalabrutinib or voruciclib.
 Expansion cohorts at RP2D for the respective combinations will be conducted to further
 evaluate safety and anticancer activity
Inclusion Criteria:

 -  1. ≥18 years of age. 2. Histologically confirmed chronic lymphocytic leukemia (CLL) or
 small lymphocytic leukemia (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.

 3. ECOG) ≤2. 4. Patient 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, > 1% weight loss in 6 months, fevers > 100.50F for ≥ one month
 without infection.

 5. In Part 1 of the APG-2575 monotherapy dose escalation portion, patients eligible
 for dose expansion at doses lower than MTD will have received ≤ 3 prior systemic lines
 of therapy.

 6. Adequate bone marrow function independent of growth factor:

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

 2. Platelets count ≥30 x 109/L (entry platelet count must be independent of
 transfusion within 7 days of first dose of study drug).

 7. Adequate renal and hepatic function as indicated by:

 a. 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 the Cockcroft and Gault
 formula(140-Age)x mas (kg)/(72x creatinine mg/dL); multiply by 0.85 if female
 (Cockcroft 1976) b. Total bilirubin ≤1.5 x ULN, except patients with known Gilbert's
 syndrome. c. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <2.5
 x ULN, Alkaline phosphatase<2.5×ULN d. International normalized Ratio (INR),
 Prothrombin Time (PT) or Activated Partial Thromboplastin time (APTT)≤1.5×ULN unless
 the patient is receiving anticoagulant therapy as long as PT or APTT is within
 therapeutic range of intended use of anticoagulants.

 8. 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.

 9. 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:

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

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

 3. Intrauterine device (IUD);

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

 5. 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.

 10. Male patients must refrain from sperm donation, from initial study drug
 administration until 90 days after the last dose of study drug.

 11. 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).

 12. 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. Richter's Syndrome. 4. Prior anti-Bcl-2 treatment (except patients who discontinued
 treatment for reasons other than disease progression) 5. For combination cohorts:

 1. In the acalabrutinib and APG-2575 cohort, patients who are on anticoagulants or
 patients that 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. Prior CDK-9 inhibitor in the voruciclib plus APG-2575 cohort 6. Known human
 immunodeficiency virus syndrome (HIV) infection 7. Known active hepatitis B
 infection, as defined seropositivity for Hep B surface antigen (HBsAg) or known
 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 8. Has known central nervous system
 (CNS) involvement. 9. Prior malignancy that required treatment and has shown
 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.

 10. Concurrent treatment with an investigational agent, received biologics (≤28
 days), or small molecule targeted therapies (≤5 half-life) or other anti-cancer
 therapies (including chemotherapy) ≤14 days of first dose of study drug 11.
 Patient is pregnant or breast feeding 12. Has received the following within 7
 days prior to the first dose of study drug:

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

 2. CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin;

 3. Potent CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's
 wort; 13. Radiation within 14 days of study entry 14. Continuance of toxicities
 due to prior radiotherapy or chemotherapy agents that have not recovered to ≤
 grade 1 or baseline, except alopecia or neuropathy.

 15. Failure to recover adequately, as judged by the investigator, from prior
 surgical procedures. Patient with active wound healing, patients who have had
 major surgery within 28 days from 1st dose of study drug 16. 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.

 17. Unstable angina or myocardial infarction within 3 months of enrollment 18.
 QTc interval> 480ms (Bazett or Fredericia formulae) or other remarkable abnormal
 ECG findings, including second-degree type II atrioventricular block,
 third-degree atrioventricular block or bradycardia (ventricular rate of less than
 50 beats per minute).

 19. Has gastrointestinal conditions that could affect the absorption of APG-2575
 in the opinion of the Investigator.

 20. 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.

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