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)

This phase 1/2 study, single-arm, multi-center, open-labeled clinical trial 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.

A Phase 1/2 clinical trial tests the safety and effectiveness of an investigational drug combination to learn whether the drug combination works in treating a specific disease. The Phase 1 safety run-in part of the study will determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for tagraxofusp in combination with Azacitidine and Venetoclax. Phase 2 will test the RP2D for Tagraxofusp in combination with azacitidine and venetoclax.

The U.S. Food and Drug Administration (FDA) has approved the doublet combination of venetoclax and azacitidine for the treatment of AML.

The U. S. FDA has approved Tagraxofusp monotherapy as a therapy for another type of leukemia called blastic plasmacytoid dendritic cell neoplasm.

The U.S. Food and Drug Administration (FDA) has not approved the combination of azacitidine, venetoclax and tagraxofusp as a treatment for AML.

The research study procedures include screening for eligibility, in-clinic visits, blood tests, Computerized Tomography (CT) scans, Magnetic Resonance Imaging (MRI) scans, or Positron Emission (PET) scans, X-rays, echocardiograms (ECGs), electrocardiograms (EKGs), and bone marrow biopsies and aspirations.

Participation in this research study is expected to last about 4 years.

It is expected that about 31 people will take part in this research study.

Stemline Therapeutics is supplying the study drug, Tagraxofusp. Break Through Cancer is providing funding to support the laboratory services.

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.

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Data can be shared no earlier than 1 year following the date of publication

Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu