A Study Comparing Venetoclax and Azacitidine Plus Cusatuzumab to Venetoclax and Azacitidine in Newly Diagnosed AML Ineligible for Intensive Therapy

Inclusion Criteria:

• Men and women ≥18 years old

• Must sign an informed consent form (ICF) indicating that he or she understands thepurpose of, and procedures required for the study and is willing to participate inthe study

• Diagnosis of AML according to ICC 2022 (with the exclusion of MDS/AML with 10-19%blasts)

• Previously untreated AML except may have received emergency leukapheresis,hydroxyurea before study entry to control hyperleukocytosis

• Deemed unfit for intensive chemotherapy by meeting at least 1 of the followingcriteria:

1. Participant is ≥75 years of age with Eastern Cooperative Oncology Group (ECOG)performance status of 0 to 2 OR

2. Participant is ≥18 to 74 years of age and has any of the followingcomorbidities:

3. ECOG performance status of 2 or 3

4. Cardiac status including any one of the following: congestive heartfailure requiring treatment or ejection fraction ≤50% or chronic stableangina

5. Known history of diffusion capacity of lung for carbon monoxide (DLCO) ≤65% of forced expiratory volume in the first second (FEV1) ≤65%

6. Creatinine clearance (CrCl) ≥15 mL/min to <45 mL/min

7. Hepatic disorder with total bilirubin >1.5 to 3x the upper limit of normal (ULN)

8. Any other comorbidity that the investigators determine to be incompatiblewith conventional intensive chemotherapy

• Adequate liver and renal function defined as:

1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3xULN; forparticipants with leukemic infiltration of the liver (documented by biopsy orimaging), AST and ALT <5xULN is permitted

2. Total bilirubin ≤1.5xULN, unless bilirubin rise is due to Gilbert's syndrome orof nonhepatic origin. Participants who are <75 years of age may have abilirubin up to 3xULN.

3. Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 (by theModification of Diet in Renal Disease [MDRD] formula). Participants who are <75years of age may have an eGFR ≥15 mL/min/1.73 m2.

• Women of childbearing potential (WOCBP), defined as fertile women between menarcheand post menopause unless permanently sterile, must have a negative highly sensitiveserum β-human chorionic gonadotropin (β-hCG) or urine pregnancy test at screening

• Must be willing to use contraception as consistent with institutional guidelinesregarding the use of contraceptive methods for participants participating inclinical studies

1. WOCBP must agree to adhere to the following birth control measures whilereceiving study treatment continuing to 3 months after the last dose of studydrug:

2. Must be practicing a highly effective method of birth control (failurerate of <1% per year when used consistently and correctly) as determinedby institutional standards

3. Must agree to not donate eggs (ova, oocytes) for the purposes of assistedreproduction

4. Must not be breastfeeding and not planning to become pregnant

5. Male participants who are sexually active with WOCBP, and male partners ofstudy participants who are WOCBP, and who are not surgically or otherwisesterile must agree to adhere to the following birth control measures whilereceiving study treatment and for 3 months after the last dose of study drug:

6. Must agree to use a barrier method of birth control (e.g., either condomwith spermicidal foam/gel/film/cream/suppository or partner with occlusivecap [diaphragm or cervical/vault caps] with spermicidal foam, gel, film,cream, or suppository)

7. Must not donate sperm

8. Must no plan to father a child

• Participants with HIV infection are eligible for the trial if the following criteriaare met:

1. CD4+ T-cell count ≥200 cells/μL

2. No prior history of AIDS-defining opportunistic infection within the past 12months

3. Receiving treatment with antiretroviral therapy

4. Undetectable viral load within 6 months of screening

Exclusion Criteria:

• Any prior treatment for AML (except those outlined in inclusion criterion #4)

• Participant has received a hypomethylating agent (HMA) or venetoclax for MDS ormyeloproliferative neoplasm

• Leukemic involvement in the central nervous system

• Participants with acute promyelocytic leukemia (APL)

• ECOG performance status of 4 for participants 18 to 74 years of age and ECOGperformance status of 3 or 4 for participants ≥75 years of age

• Use of immune suppressive agents ≤4 weeks before the first administration ofcusatuzumab. Participants may be included if free of systemic corticosteroids >5days before the first administration of cusatuzumab with the exception ofcorticosteroids at physiologic replacement doses.

• Received a live, attenuated vaccine within 4 weeks prior to initiation of study drug

• Active malignancies (i.e., progressing or requiring treatment change in the last 24months) other than the disease being treated under study. Exceptions to thisexclusion criterion include the following:

1. Nonmelanoma skin cancer treated within the last 24 months that is consideredcompletely cured

2. Adequately treated breast lobular carcinoma in situ and breast ductal carcinomain situ

3. Adequately treated cervical carcinoma in situ and breast ductal carcinoma insitu

4. History of localized breast cancer and receiving anti-hormonal agents, orhistory of localized prostate cancer (N0M0) and receiving androgen depravationtherapy

5. A malignancy that is considered cured with minimal risk of recurrence

• Any active systemic infection

• History of prior HSCT (allogeneic or autologous transplants)

• Active hepatitis B or C infection or other clinically active liver diseases addefined below:

1. Seropositivity for hepatitis B is defined by a positive test for hepatitis Bsurface antigen (HBsAg)

2. Participants with resolved infection (i.e., participants who are HBsAg negativewith antibodies to total hepatitis B core antigen [anti-HBc] with or withoutthe presence of hepatitis B surface antibody [anti-HBs]) must be screened usingPCR measurement of hepatitis B virus (HBV) DNA levels. Those who are PCRpositive will be excluded.

• Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history ofprior HBV vaccination, do not need to be tested for HBV DNA by PCR

3. Active hepatitis C infection as defined by being positive for a nucleic acidtest for hepatitis C virus (HCV) RNA

• Congestive hear failure severity that is New York Heart Association Class III or IV

• Unstable angina

• Known allergies, hypersensitivity, or intolerance to cusatuzumab, venetoclax, orazacitidine or their excipients (e.g., mannitol, an excipient of azacitidine)

• Inability or difficulty swallowing capsules/tablets, malabsorption syndrome, or anydisease or medical condition significantly affecting gastrointestinal function

• Any condition for which, in the investigator's opinion, participation would not bein the best interest of the participant (e.g., compromise the well-being) orphysical limitations that could prevent, limit, or confound the protocol-specifiedassessments

• Major surgery (e.g., requiring general anesthesia) ≤4 weeks prior to initiation ofstudy treatment