Background: BCL2 inhibition as a means of targeting intrinsic apoptotic pathways that confer a survival advantage to leukemic blasts has become a key therapeutic strategy for patients with myeloid malignancies. LP-108 is an oral highly potent and selective inhibitor of BCL-2 with comparable or more potent in vitro inhibitory activity as compared to the FDA approved oral BCL-2 inhibitor venetoclax. We propose to investigate LP-108 as monotherapy and in combination with azacitidine in patients with relapsed or refractory (r/r) MDS, CMML or AML. Methods: The primary objectives of the trial are 1.) To determine the safety, tolerability and determine the maximum tolerated dose (MTD) and the recommended phase 2 dose / optimal biological dose (OBD) of LP-108 as a single agent (Arm 1) and in combination with azacitidine (Arm 2) in patients with relapsed/refractory MDS/CMML/AML; 2.) To characterize the pharmacokinetic profile of LP-108 as monotherapy and in combination with a fixed dose of azacitidine. The secondary objectives of the trial are 1.) To evaluate the objective response rate of LP-108 (monotherapy or combination therapy) in r/r MDS/CMML/AML as well as progression free survival, duration of response and overall survival. In Arm 1 patients will be enrolled according to a 3+3 design with escalating doses of LP-108 for a 28 day cycle (firs table). DLTs will be determined in the first 28 days. In Arm 2 patients will be enrolled according to a 3+3 design with escalating doses of LP-108 in combination with a fixed dose of azacitidine (second table). DLTs will be determined in the first 28 days. DLT for both arms is defined as some ≥ Grade 3 non-hematological toxicities or prolonged myelosuppression. Patients may continue treatment until disease progression, unacceptable toxicity, or per investigator discretion. Patients age ≥ 18 years with r/r MDS with excess or blasts or with high or very-high risk disease per the R-IPSS, or r/r MDS for Arm 2, r/r AML, or frontline older and/or unfit AML for Arm 2, or r/r CMML may enroll. Patients with prior hypomethylating agents or venetoclax exposure may enroll. The blast count at the time of starting therapy must be ≤ 30 x 10⁹ cells/L. Hydroxyurea is allowed prior to and during treatment. Ejection fraction ≥ 50% is required. Calculated creatinine clearance shall be ≥ 30 mL/min. Strong CYP3A4 inducers and inhibitors are prohibited. Patients on weak/moderate azole antifungals were allowed to enroll. Enrollment to Arm 1 is complete and there have been no DLTs to date. Enrollment to Arm 2 is pending. Arm 1 Dose Escalation Scheme (LP-108 monotherapy). Clinical trial information: NCT04139434.