IMGN632 as Monotherapy or With Venetoclax and/or Azacitidine for Participants With CD123-Positive Acute Myeloid Leukemia

Inclusion Criteria:

• Patient must be ≥ 18 years of age.

• Patients must have confirmed diagnosis of AML (excluding acute promyelocyticleukemia) based on World Health Organization classification (Arber 2016).

• Disease characteristics and allowable prior therapy:

• Patients must be evaluated for any available standard of care therapies (including induction, consolidation chemotherapy and/or transplant) and, in theopinion of the treating physician, be deemed appropriate for this experimentaltherapy.

• Treatment-naïve (untreated) patients will be allowed in the Expansion Phase forRegimen C (Triplet) (IMGN632 + azacitidine + venetoclax). No prior treatmentswith hypomethylating agents (HMAs) for MDS are allowed.

• Patients must have CD123-positive AML as confirmed by local flow cytometry (orimmunohistochemistry [IHC]).

• Patients may have received prior CD123-targeted therapies, except IMGN632, aslong as CD123 remains detectable during screening.

• Relapsed or refractory CD123-positive AML patients will be allowed to enroll inthe Escalation Phase of Regimens A, B, and C (Triplet (IMGN632 + azacitidine,venetoclax, or azacitidine + venetoclax, respectively) and relapsedCD123-positive AML patients will be allowed to enroll the Expansion Phase ofRegimens A-C. Note: Patients may also have received up to 2 prior lines oftherapy, eg, frontline treatment (induction, consolidation [includingtransplant], and maintenance) and 1 salvage regimen.

• Patients enrolling in Regimen D must be in CR (CR/CRh/CRp/ CRi) and be MRD+ atthe time of screening, confirmed by central laboratory testing. Patients mayhave no more than 2 prior lines of therapy (which may include stem celltransplant), ie, frontline or first salvage. Note: Fit patients who receivedintensive treatment (eg 3+7, HiDAC) are eligible for Regimen D Cohort D1. Unfitpatients who received non-intensive treatment (eg, HMA, low dose cytarabine)are eligible for Regimen D Cohort D2.

• Previous treatment-related toxicities must have resolved to Grade 1 or baseline (excluding alopecia).

• For patients enrolling in Regimens A-D, total WBC count must < 25 × 10^9 cells/L.Hydroxyurea may be used to control blood counts before Cycle 1 Day 1, at thediscretion of the treating physician, according to institutional practice. Duringthe Escalation Phase in Regimens A-C, hydroxyurea may also be used during Cycle 1.

• Liver enzymes (AST and ALT) ≤ 3 × the upper limit of normal (ULN).

• Total bilirubin ≤ 1.5 × the ULN; patients with Gilbert syndrome must have totalbilirubin < 3.0 × ULN with direct bilirubin < 1.0 × ULN at the time of enrollment.

• An estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73 m2 or creatinineclearance of > 30 mL/min.

• Left ventricular ejection fraction (LVEF) ≥ 45% for patients enrolling in RegimensA-D based on locally available assessment, eg, echocardiogram or other modality.

• Patients with prior autologous or allogeneic bone marrow transplant are eligible.Patients with an allogeneic transplant must meet the following conditions: Thetransplant must have been performed more than 120 days before the date of dosing onthis study, the patient must not have active ≥ Grade 2 graft versus host disease (GvHD), or extensive chronic GvHD of any severity, and must be off allimmunosuppression for at least 2 weeks prior to first dose of IMGN632.

• Participants or their legally authorized representative must voluntarily sign anddate an informed consent, approved by an Institutional Review Board/IndependentEthics Committee (IRB/IEC), before performance of any study-related procedure notpart of normal medical care.

• Women of childbearing potential (WCBP), defined as sexually mature women who havenot undergone surgical sterilization or who have not been naturally postmenopausalfor at least 12 consecutive months (ie, who have had menses any time in thepreceding 12 consecutive months), must agree to use acceptable contraceptive methodswhile on study drug and for at least 7 months after the last dose of IMGN632.

• WCBP must have a negative pregnancy test within 3 days before the first dose ofstudy drug.

• Male patients who are able to father children must agree to use acceptable methodsof contraception throughout the study and for at least 4 months after the last doseof study drug(s).

• Patients with prior malignancy are eligible; however, the patient's malignancy mustbe well-controlled or stable and have completed all systemic chemotherapy andradiotherapy for the prior malignancy at least 6 months before enrollment, and alltreatment-related toxicities must have resolved to ≤ Grade 1 (excluding alopecia).Note: patients with prostate cancer or breast cancer on adjuvant hormonal therapyare eligible and may or may not be on long-term maintenance treatment that isunlikely to interfere with study therapy. Note: patients with tumors with anegligible risk for metastasis or death (eg, adequately controlled basal cellcarcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervixor breast) are eligible.

• Patients in expansion Cohorts C1 and C2 must be considered ineligible for intensiveinduction therapy defined by the following:

• ≥ 75 years of age OR

• < 75 years of age with at least one of the following co-morbidities documentedwithin 28 days of Cycle 1 Day 1:

• ECOG performance status of 2 or 3

• History of congestive heart failure requirement treatment or ejection fraction ≤ 50% or chronic stable angina

• Diffusing capacity of the lung for carbon monoxide ≤ 65% or forced expiratoryvolume in 1 second ≤ 65%

• Creatinine clearance ≥ 30 mL/min to < 45 mL/min

• Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × ULN

• Patients in Cohort C1 and C2 must have an ECOG performance status of 0 to 2 forthose ≥ 75 years of age OR 0 to 3 for < 75 years of age.

• Patients must not be incarcerated and must be freely willing and able to provideinformed consent. Examples of patients unable to freely provide informed consent mayinclude some adults under legal protection measure (eg, underguardianship/curatorship) or unable to express their consent and select adults underpsychiatric care. Investigator's discretion should be applied.

Exclusion Criteria:

• Patients who have received any anticancer therapy, including investigational agents,within 14 days (or within 28 days for checkpoint inhibitors) before drugadministration on this study (hydroxyurea is allowed before beginning studytreatment). Patients must have recovered to baseline from all acute toxicity fromthis prior therapy.

• Patients who have been previously treated with IMGN632.

• Patients with myeloproliferative neoplasm-related secondary AML are excluded fromthe Dose Expansion Phase of the study.

• Patients with active central nervous system (CNS) AML will be excluded. A lumbarpuncture does not need to be performed unless there is clinical suspicion of CNSinvolvement per investigator judgement. Concurrent therapy for CNS prophylaxis orcontinuation of therapy for controlled CNS AML is allowed with the approval of thesponsor.

• Patients with a history of sinusoidal obstruction syndrome/venous occlusive diseaseof the liver.

• Myocardial infarction within 6 months before enrollment or New York HeartAssociation Class III or IV heart failure, uncontrolled angina, severe uncontrolledventricular arrhythmias, or electrocardiographic evidence of acute ischemia oractive conduction system abnormalities before study entry.

• Clinically relevant active infection including known active hepatitis B or C, HIVinfection, or cytomegalovirus or any other known concurrent infectious disease that,in the judgment of the investigator, would make a patient inappropriate forenrollment into this study (testing not required).

• Patients who have undergone a major surgery within 4 weeks (or longer if not fullyrecovered) before study enrollment.

• Serious or poorly controlled medical conditions that could be exacerbated bytreatment or that would seriously compromise safety assessment or compliance withthe protocol, in the judgment of the investigator.

• Women who are pregnant or breastfeeding

• Prior known hypersensitivity reactions to monoclonal antibodies (≥ Grade 3).

• Prior known hypersensitivity reactions to study drugs and/or any of theirexcipients.

• Patients who have a history of allergy to IMGN632 (or any of its excipients),azacitidine, or venetoclax.