This is a Phase 1, open-label, multicenter, dose-escalation & expansion study to evaluate the safety,tolerability and pharmacokinetics (PK) of LP-108, a BCL-2 inhibitor, combined with azacitidine, to determine the dose limiting toxicity (DLT) and the recommended Phase 2 dose (RP2D), and to assess the preliminary efficacy of this combination.

This Phase 1 study will look at different doses and different treatment schedules in order to better understand the effects of the combined regimens on the newly diagnosed or refractory/relapsed adult participants with AML ,MDS or CMML. The procedures include screening for eligibility, study treatments, and blood & bone marrow tests. All the safety events will be record, pharmacokinetic parameters (Tmax, Cmax,T1/2, AUC et al.) will be calculated, response and survival will be assess during the study. Participants will be treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.

Inclusion Criteria:

• Subject must has a diagnosis of one of the following: relapsed or refractory (R/R) or untreated ineligible for treatment with a standard induction chemotherapy acute myeloid leukemia (AML) ; R/R myelodysplastic syndrome(MDS) or untreated MDS with excess blasts defined as ≥ 5% blasts in either bone marrow or blood or with high risk (high and very high-risk groups according to IPSS-R) ;CMML-1 or 2 by WHO, no requirements for prior therapy.
• ECOG performance status ≤ 2.
• Estimated survival ≥ 12 weeks.
• Baseline white blood cell count (WBC) ≤ 25 x 109/L.
• Subject must has adequate organ function as defined below: Aspartate transaminase (AST) and alanine transaminase (ALT)≤3 x ULN; Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin); adequate renal function as demonstrated by a creatinine clearance ≤1.5 x ULN ; calculated by the Cockcroft Gault formula; APTT ≤ 1.5 x ULN, INR ≤ 1.5 x ULN.
• Prior treatment-related toxicities must be grade 1 or baseline except for alopecia.
• If subject is sexually active, he/she must agree to carry out birth control throughout the study and 90 days after the last dose of LP-108. Subject must agree to have a negative serum β-HCG test result within 7 days prior to study drug.
• Subject must voluntarily sign and date an informed consent.

Exclusion Criteria:

• Subject is allergic to LP-108, Azacitidine or excipients, or with poor tolerance to Azacitidine.
• Subject has received prior therapy with a BH3 mimetic.
• Subject has acute promyelocytic leukemia.
• Subject has t(9;22) karyotype abnormality or positive BCR/ABL1 fusion gene.
• Subject has known and active CNS involvement.
• Subject has myeloid sarcoma but no bone marrow involvement.
• Subject has Acute unidentified leukemia.
• Subject has treatment related MDS or AML.
• Subject has AML/MDS/CMML with myelofibrosis ≥ grade 2.
• Subject has received allogeneic Hematopoietic Stem Cell Transplantation (HSCT) or autologous HSCT within 3 months prior to the first dose of study drug.
• Subject must be at least 4 weeks from antitumor therapy, major surgery, radiation therapy, or participation in other investigational trials.
• Subject has received a strong and/or moderate CYP3A inhibitor or inducer, P-gp inhibitor or CYP2C8 substrate within 14 days prior to the initiation of study treatment.
• Subject has received drugs with a potential to cause prolonged QT intervals or torsade de pointes.
• Administration or consumption of any of the following within 3 days prior to the first dose of study drug: Grapefruit or grapefruit products; Seville oranges (including marmalade containing Seville oranges); Star fruit.
• Subject has known malignancy within 3 years prior to the first dose of study drug, with the exception of: Adequately treated basal skin cancers, in situ carcinoma of the cervix uteri or breast, localized squamous cell carcinoma.
• Subject has serious and/or uncontrolled systemic diseases, in the opinion of the investigator, the subject is inappropriate for enrollment into this study (serious active infection with grade ≥ 2(based on CTCAE), high blood pressure that cannot be controlled by medication, diabetes, unstable angina, congestive heart failure, Respiratory diseases requiring continuous oxygen intake, severe vascular embolism, uncontrolled massive bleeding or bleeding from vital organs, severe liver, kidney or metabolic diseases, such as cirrhosis, kidney failure, etc.).
• Subject has myocardial infarction or stroke within 6 months prior to the first dose of study drug.
• Subject has a cardiac history including the following: History of CHF requiring treatment or Ejection Fraction <50% or a cardiovascular disability status of New York Heart Association.
• Subject has uncontrolled and/or active systemic infection (viral, bacterial or fungal).
• Subject has difficulty to swallow pills or has conditions that affect drug absorption or pharmacokinetics.
• Strong and/or moderate CYP3A inhibitor or inducer and CYP2C8 substrate cannot be discontinued during the study.
• Vaccination with live, attenuated vaccines ≤4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study or 4 weeks after the last dose of study drug.
• Subject has an autoimmune disease that requires immunosuppressive therapy In the opinion of the investigator, the subject is inappropriate for enrollment into this study.