This is a Phase I, multicenter, open-label, two-stage study of APG-3288 monotherapy, aiming to determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of APG-3288 administered orally once daily in patients with relapsed/refractory (R/R) hematologic malignancies.

Part 1 (Dose Escalation Phase): Patients will receive orally administered APG-3288 at specified doses once daily in 28-day cycles. This phase aims to determine the MTD or RP2D of APG-3288 for patients who have failed standard therapy and for whom no standard therapy offering clinical benefit is available.

Part 2 (Dose Expansion Phase): Following the completion of Part 1, Part 2 will be initiated to further evaluate dose safety. Doses will be determined based on a comprehensive assessment of the pharmacokinetic (PK), pharmacodynamic (PD), safety, and efficacy data of APG-3288 from Part 1. In Part 2, up to 60 patients per chosen indication will be enrolled and randomly assigned in equal proportions to 2 or 3 dose cohorts to evaluate dose safety.

Key Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) status ≤ 1 in Part 1 (dose escalation), and ≤ 2 in Part 2 (dose expansion).
• Part 1 (Dose Escalation): histologically or cytologically confirmed diagnosis of R/R CLL/SLL, DLBCL (including Richter Transformation), MCL, WM, MZL, or FL.
• Prior systemic therapy: at least 2 prior lines of systemic therapy (including BTK inhibitor for approved indications) and who have failed or are not eligible for available therapies with established clinical benefit.
• Measurable disease per response criteria specific to the malignant condition.
• Adequate organ and bone marrow function.

Key Exclusion Criteria:

• Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, targeted therapy, biologic therapy, with the exception of hormones for hypothyroidism or estrogen replacement therapy, anti-estrogen analogs, agonists required to suppress serum testosterone levels).

• Any investigational therapy within 14 days prior to the first dose of study drug or within 5 half-lives of the respective investigational drug (whichever is shorter).

• Persistent toxicities from prior radiotherapy, targeted therapy, immunotherapy, or chemotherapy agents that have not recovered to Grade <2 (except for alopecia or vitiligo).

• Symptomatic brain metastases due to tumor involvement of the central nervous system (CNS). Patients with CNS tumors who have been treated, are asymptomatic, and who have discontinued steroids (for the treatment of CNS tumors) for > 28 days may be enrolled.

• Use of therapeutic-dose anticoagulants or antiplatelet agents. (Use of low-dose anticoagulants to maintain central venous catheter patency is permitted)

• Biological growth factors within 7 days prior to the first dose of study drug.

• Patients who, in the investigator's judgment, have not adequately recovered from prior surgery, or have undergone major surgery within 28 days prior to enrollment, or minor surgery within 14 days prior to enrollment.

• Significant cardiac disease defined as:

  1. New York Heart Association class III or IV cardiac disease, including pre-existing uncontrolled, clinically-significant arrhythmia, congestive heart failure, or cardiomyopathy.
  2. Unstable angina, myocardial infarction, or a coronary revascularization procedure within ≤ 3 months prior to initiation of study treatment.
  3. History of left ventricular ejection fraction < 50%.
  4. Poorly controlled hypertension, or history of poor compliance with antihypertensive drug regimens.

• Clinically active and uncontrolled symptomatic infection; well-controlled human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection may be considered for enrollment.

• Autoimmune diseases, active inflammatory bowel disease, chronic infections, or any other disease or condition associated with chronic inflammation.

• Concurrent use of QT-prolonging medications or history of torsades de pointes.

• Concurrent malignancy other than the one being treated in this study with the exception of the following: cured malignancy without recurrence within 3 years prior to study entry; completely resected basal cell and squamous cell skin cancer; completely resected carcinoma in situ of any type.

• Any severe and/or uncontrolled medical condition that, in the investigator's opinion, may compromise the individual's safety or the evaluation of study results.

• Prior treatment with: BTK degrader treatment or allogeneic stem cell transplant