A Multi-Site Break Through Cancer Trial: Targeting Measurable Residual Disease in Patients with Acute Myeloid Leukemia: A Phase 1/2 Study of Tagraxofusp, Azacitidine, and Venetoclax

The purpose of this research study is to test the safety and efficacy of a new drug
combination with three agents, azacitidine, venetoclax and tagraxofusp. Leftover
(residual) leukemia disease that is not visible by eye can be increase the chance of
disease recurrence. This research study is to determine if the combination therapy can
safely help to control residual Acute Myeloid Leukemia (AML) and to prevent disease
recurrence.

The names of the study drugs involved in this study are:

- Tagraxofusp (a type of CD123-directed cytotoxin)

- Azacitidine (a type of standard of care cytidine nucleoside analog)

- Venetoclax (a type of standard of care BCL-2 inhibitor)

Inclusion Criteria:

- Age ≥ 18 years.

- History of known diagnosis of Acute Myeloid Leukemia (including de novo, secondary
or AML arising from MDS).

- Subjects must be in CR, CRi, or CRh with <5% morphologic blasts in bone marrow

- Any evidence of CD123+ by central assessment.

- Participants must have measurable disease, defined as ≥ 0.1% by multiparametric flow
cytometric assay as assessed by central laboratory

- ECOG performance status ≤2 (see Appendix A).

- Subjects must have adequate organ and marrow function as defined below:

- total bilirubin ≤ 1.5 x institutional upper limit of normal unless due to
Gilbert or non-hepatic in origin

- AST(SGOT) and ALT(SGPT) ≤ 3.0 × institutional upper limit of normal

- Creatinine clearance ≥ 45 ml/min GFR by MDRD

- Albumin ≥ 3.2 g/dL

- Left ventricular ejection fraction ≥ institutional lower limit of normal by MUGA or
echocardiogram within 30 days of first protocol treatment. This can be locally
assessed.

- Pregnancy potential: Female subjects of childbearing potential must have negative
results for pregnancy test. Females with reproductive potential are advised to use
effective contraception during study treatment and for at least 6 months after last
dose. Similarly, males with female partners of reproductive potential are advised to
use effective contraception during treatment and for at least 3 months after the
last dose. Men must agree to abstain from donating sperm.

- Subject is able and willing to adhere to the study visit schedule and other protocol
requirements

Exclusion Criteria:

- Prior treatment with CD123-targeted therapy

- Known diagnosis of acute promyelocytic leukemia.

- Subjects who received intensive anti-leukemic chemotherapy within 2 weeks from first
dose of study. If on venetoclax, subjects must be off venetoclax for at least 5 days

- Subjects pre-arranged for SCT are only excluded if it is imminent.

- History of prior allogeneic stem cell transplant

- Subject has uncontrolled, clinically significant pulmonary disease (e.g. COPD,
pulmonary hypertension, etc.) that in the opinion of the Investigator would put the
subject at significant risk for pulmonary complications during the study.

- Subject has experienced Grade 3 or Grade 4 capillary leak syndrome (CLS) in the past
for any reason

- Subjects with known HBV and/or HCV infection must have undetectable viral load
during screening (HBV and HCV testing are not required.) Participants with serologic
evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen
negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody
negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may
participate.

- Subjects with known HIV positivity are permitted provided they have undetectable
viral load at the time of screening (HIV testing is not required).

- Subject has a concurrent malignancy or prior malignancy within the 6-month period
before screening. To be eligible, subjects must be in remission from the prior
malignancy at least 6 months prior to screening and all treatment-related toxicities
must have resolved to ≤ Grade 1 except for alopecia. Exceptions include adequately
treated basal or squamous cell skin cancer, superficial bladder cancer, adequately
treated carcinoma in situ of the cervix or uterus, or carcinoma in situ of the
breast, previous malignancy confined and surgically resected (or successfully
treated with other modalities) with curative intent, which are permissible for
inclusion. Maintenance therapy, hormonal therapy, or steroid therapy for a
well-controlled concurrent malignancy is allowed.

- Subject has uncontrolled systemic fungal, bacterial, or viral infection, defined as
ongoing signs/symptoms related to the infection without improvement despite
appropriate antibiotics, antivirals, or antifungals, either IV or oral. However,
subjects with controlled infection still requiring anti-infectives are eligible.

- Subjects with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, that have New York Heart Association Functional
Class III or IV symptoms.

- Subject has evidence of ongoing alcohol or drug abuse

- Subjects with known active/symptomatic CNS involvement. CNS prophylaxis allowed

- Subjects receiving moderate or strong P450 3A (CYP3A) inducers within 7 days of
start of study therapy. See Appendix B for examples

- Subjects with uncontrolled intercurrent illness.

- 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

- Pregnant women are excluded from this study because of the potential for teratogenic
or abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with trial therapy,
breastfeeding should be discontinued if the mother is treated on trial.