Overview

This is a Phase Ib/II, open-label, multi-center study evaluating the safety, tolerability, efficacy and PK of APG-2575 in combination with Azacitidine in the patients with AML/MPAL or MDS/CMML. The study consists of dose escalation (Part I) and dose expansion phase (Part II)

Eligibility

Inclusion Criteria:

        Patients with a diagnosis of histologically confirmed relapsed or refractory (R/R) acute
        myeloid leukemia (AML) or mixed phenotype acute leukemia (MPAL) or Chronic Myelomonocytic
        Leukemia (CMML) or relapsed/refractory Higher-Risk MDS by 2016 WHO classification for which
        no available standard therapies are indicated or anticipated to result in a durable
        response.
          -  MPAL will include biphenotypic leukemia, bilineal leukemia, undifferentiated leukemia,
             mixed lineage leukemia, leukemia of ambiguous lineage, T/myeloid leukemia, B/myeloid
             leukemia, or other diagnosis indicating the presence of multiple lineages within the
             cell population.
          -  Relapsed/refractory MDS will be defined as prior receipt of 4 cycles of HMA therapy
             with failure to attain a response, or progression of disease or relapse at any time
             after prior response to HMA therapy with Overall Revised International Prognostic
             Scoring System (IPSS-R) score > 3 (intermediate, high or very high).
        Exclusion Criteria:
          1. Pregnant women.
          2. Uncontrolled intercurrent illness including, but not limited to active uncontrolled
             infection, symptomatic congestive heart failure (NYHA Class III or IV), unstable
             angina pectoris, clinically significant cardiac arrhythmia, or psychiatric
             illness/social situations that would limit compliance with study requirements.
          3. Have had leukemia therapy within 14 days prior to starting investigational drug.
             However, patients with rapidly proliferative disease may receive hydroxyurea as needed
             until 24 hours prior to starting therapy on this protocol and during the first cycle
             of study.
          4. Have taken strong inhibitors or inducers of CYP3A4 within 7 days prior to the first
             dose of APG-2575.
          5. Have acute promyelocytic leukemia (French-American-British Class M3 AML or WHO
             classification APL with PML-RARA) or AML/MPAL with BCR-ABL1 positive.
          6. Active infection requiring systemic antibiotic/antifungal medication, known clinically
             active hepatitis B or C, or HIV infection or active COVID-19. (Patients who have
             received COVID-19 vaccination will be considered as eligible for the study.)
          7. Have active/ongoing graft-versus host disease (GVHD) or require continued treatment
             with systemic immunosuppressive agents (calcineurin inhibitors within 4 weeks prior to
             the first dose).
          8. Myeloablative therapy with autologous or allogeneic hematopoietic stem cell rescue
             within 6 months of study treatment initiation.
          9. Documented hypersensitivity to any of the components of the therapy program.
         10. Active, uncontrolled CNS leukemia.
         11. Men and women of childbearing potential who do not practice contraception. Women of
             childbearing potential and men must agree to use at least 1 form of barrier birth
             control (such as condom) prior to study entry and for the duration of study
             participation.
         12. History of other malignancies within 2 years prior to study entry, with the exception
             of:
               -  Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
                  breast.
               -  Basal cell carcinoma of the skin or localized squamous cell carcinoma of the
                  skin.
               -  Previous malignancy confined and surgically resected (or treated with other
                  modalities) with curative intention requires discussion with sponsor.
         13. Failure to have recovered (Grade > 1) from prior treatment (including chemotherapy,
             targeted therapy, immunotherapy, experimental agents, radiation, or surgery), except
             for alopecia.
         14. Unable to swallow tablets or malabsorption syndrome, disease significantly affecting
             gastrointestinal function, or resection of the stomach or small bowel, symptomatic
             inflammatory bowel disease or ulcerative colitis, or partial or complete bowel
             obstruction.
         15. Significant screening electrocardiogram (ECG) abnormalities including left bundle
             branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or
             corrected QT interval (QTc) ≥470 msec.
         16. Any other condition or circumstance that would, in the opinion of the investigator,
             make the patient unsuitable for participation in the study.