Strategic considerations

Acute myeloid leukemia (AML) is one of the most aggressive blood cancers, with a very low survival rate and few options for participants who are unable to undergo intensive chemotherapy, the current standard of care. This study is to evaluate how safe lemzoparlimab is and how it moves within the body when used along with azacitidine and/or venetoclax in adult participants with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Adverse events and maximum tolerated dose (MTD) of lemzoparlimab will be assessed.

Lemzoparlimab (TJ011133) is being evaluated in combination with azacitidine and venetoclax for the treatment of acute myeloid leukemia (AML) and with azacitidine with/without venetoclax for myelodysplastic syndrome (MDS). Study doctors place the participants in 1 of 5 groups, called treatment arms. Each group receives a different treatment. Adult participants with a diagnosis of AML or MDS will be enrolled. Around 80 participants will be enrolled in the study in approximately 50 sites worldwide.

Participants will receive lemzoparlimab (IV) once weekly (Q1W), venetoclax oral tablets once daily (QD) for 28 days (AML participants) or 14 days (MDS participants) and Azacitidine by SC or IV route QD for 7 days of each 28-day cycle.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests and checking for side effects.

Inclusion Criteria:

• Documented confirmation of acute myeloid leukemia (AML) according to the World Health Organization (WHO) criteria, previously untreated [OR]

• Documented diagnosis of previously untreated de novo myelodysplastic syndrome (MDS) according to the 2017 WHO classification with presence of < 20% bone marrow blasts per marrow biopsy/aspirate.

• Participants with documented MDS must meet the following disease activity criteria:

  • Overall revised international prognostic scoring system (IPSS-R) score > 3 (intermediate, high, or very high);
  • Eastern cooperative oncology group (ECOG) performance status of 0 to 2;
  • Hematopoietic stem cell transplant (HSCT) ineligible, or participant who chooses not to undergo HSCT.

• Participants with documented AML with adverse cytogenetic and/or molecular risk, and must be considered ineligible for induction therapy defined by the following:

  • >= 75 years of age; [OR]

  • >= 18 to 74 years of age with at least one of the following comorbidities: --- Eastern cooperative oncology group (ECOG) performance status of 2 to 3; --- Cardiac history of congestive heart failure requiring treatment or ejection fraction <= 50% or chronic stable angina;

    • Diffusion capacity of lung (DLCO) <= 65% or forced expiratory volume during the first second (FEV1) <= 65%;
    • Creatinine clearance >= 30 mL/min to < 45 mL/min;
    • Moderate hepatic impairment with total bilirubin > 1.5 to <= 3.0 × upper limit of normal (ULN);
    • Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy or the participant declines to receive intensive chemotherapy.

Japan Safety Lead-In Phase:

• Documented confirmation of AML according to WHO criteria, relapsed or refractory (R/R) disease without other standard of care treatments.

• Documented diagnosis of MDS according to the 2017 WHO classification with presence of < 20% bone marrow blasts per marrow biopsy/aspirate, with intermediate- and high-risk relapsed/refractory MDS.

• Documented MDS must meet the following disease activity criteria:

  • ECOG performance status of 0 to 2.

Exclusion Criteria:

• Participants with documented AML with acute promyelocytic leukemia and considered eligible for induction therapy.

• Participant with documented AML having prior diagnosis of:

  -- known active central nervous system involvement with AML.

• Participants with documented MDS having prior diagnosis of:

  • MDS evolving from a pre-existing myeloproliferative neoplasm (MPN);
  • MDS/MPN including chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia and unclassifiable MDS/MPN.

• History of allogeneic HSCT or solid organ transplantation.

• Previous exposure to anti-CD47 therapies.

• History of an active malignancy within the past 2 years prior to Screening, with the exception of:

  -- Adequately treated carcinoma in situ of the cervix uteri or carcinoma in situ of the breast;

  • Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin;
  • Asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy;
  • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.

• Conditions that could interfere with drug absorption including but not limited to short bowel syndrome.

Japan Safety Lead-In Phase:

• Documented AML have Acute Promyelocytic Leukemia.

• Participant with documented AML having prior diagnosis of:

  -- Chronic myeloid leukemia with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation.

• Participants with documented MDS having prior diagnosis of:

  • Therapy-related MDS.