This is a 4-stage, non-randomized, open-label, dose escalation and expansion, multicenter study. A cycle of therapy is 21 days. Stage 1 was a dose-escalation stage. During Stages 2-4, patients are treated at the MTD or maximum tested dose at which multiple DLTs are not observed during Stage 1.

Study 0114 is a multi-stage, non-randomized, open-label, multicenter study of Tagraxofusp in First line and Relapsed/Refractory (R/R) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) and Acute Myeloid Leukemia (AML) patients divided into 4 stages.

Each study stage has its own unique objectives and patient population, with Stage 1 representing the dose escalation phase and Stage 3 the pivotal phase.

In Stages 1 and 2, both patients with BPDCN (first-line and R/R) and AML were enrolled; Stage 3 enrolled previously untreated (first-line) BPDCN patients only. A separate stage, Stage 4, enrolled First-line and R/R BPDCN patients to further characterize safety and efficacy of Tagraxofusp.

The primary study objectives are reported below by stage:

Stage 1: to determine the Maximum Tolerated Dose (MTD) (or Maximum Tested Dose, MTeD where multiple DLTs were not observed) of Tagraxofusp administered at the following dose levels 7, 9, 12, 16 µg/kg/day

Stage 2: cohort expansion to determine the efficacy and safety of Tagraxofusp at the MTD selected in Stage 1

Stage 3 (pivotal): to determine the efficacy and safety of Tagraxofusp in patients with First-line BPDCN

Stage 4: to further characterize the efficacy and safety of Tagraxofusp in patients with both First-line and R/R BPDCN

Inclusion Criteria:

1. The patient has a diagnosis of AML (Protocol Stages 1 and 2) or BPDCN (Protocol Stages 1-4) according to WHO classification (AML; excluding acute promyelocytic leukemia [APL, FAB M3]) or confirmed by hematopathology (BPDCN) (Facchetti et al. 2008).

2. The patient must meet one of the following (a) or (b) or (c):

   1. Has evidence of persistent or recurrent AML (Protocol Stages 1 and 2) in the peripheral blood and/or bone marrow that is refractory to, or has relapsed from, their most recent prior line of treatment.

      • A prior line of treatment is considered an induction regimen if it involves an approved or investigational cytotoxic chemotherapy agent, biological agent, and/or hypomethylating agent administered alone or in a combination regimen, with the intent to induce robust cytoreduction (i.e., CR).
      • The previous induction regimen may have been a SCT with intent to induce a CR.
      • Consolidation and/or maintenance (including SCT) may have been given in CR/CRi, but are not counted as a line of treatment.
      • Hydroxyurea will not be considered a prior line of treatment.

   2. Has previously untreated AML (Protocol Stages 1 and 2) and is considered to be at high risk for disease progression and/or is unlikely to derive more than transient benefit from standard therapy by having at least one of the following:

      • Treatment-related AML, except if it is associated with favorable cytogenetics (e.g., inversion 16, t[16;16], t[8;21], t[15;17]), and not a candidate for SCT in their current disease state.
      • AML with antecedent hematological disease (e.g., MDS, myelofibrosis, polycythemia vera) and not a candidate for SCT.

   3. Has histological and/or cytological evidence of BPDCN by pathologic assessment at the investigative site according to WHO classification (Facchetti et al. 2008) by a pathologist with expertise in hematologic malignancies, that can be measured for treatment response and is either:

      • Previously untreated (i.e., first-line) (Protocol Stages 2-4).
      • Persistent or recurrent in the peripheral blood, bone marrow, spleen, lymph nodes, skin, or other sites after previous treatment with at least 1 line of systemic therapy for BPDCN, e.g., stem cell transplant or chemotherapy (Protocol Stages 1, 2, and 4). A pathology specimen must be available for central pathology review for all BPDCN patients enrolled in Protocol Stages 2-4.

3. The patient is ≥ 18 years old.

4. The patient has an ECOG performance score (PS) of 0-2.

5. The patient has adequate baseline organ function, including cardiac, renal, and hepatic function:

   • Left ventricular ejection fraction (LVEF) ≥ institutional lower limit of normal as measured by MUGA scan or 2-D ECHO within 28 days prior to start of therapy and no clinically significant abnormalities on a 12-lead ECG
   • Serum creatinine ≤ 1.5 mg/dl
   • Serum albumin ≥ 3.2 g/dl
   • Bilirubin ≤ 1.5 mg/dl
   • AST and ALT ≤ 2.5 times the upper limit of normal (ULN)

6. If the patient is a woman of child bearing potential (WOCBP), she has had a negative serum or urine pregnancy test within 1 week prior to treatment.

7. The patient has signed informed consent prior to initiation of any study-specific procedures or treatment.

8. The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment.

9. The patient (male and female) agrees to use acceptable contraceptive methods for the duration of time on the study, and continue to use acceptable contraceptive methods for 2 months after the last infusion of Tagraxofusp.

Exclusion Criteria:

1. The patient has a diagnosis of acute promyelocytic leukemia (APL; FAB M3).
2. The patient has persistent clinically significant toxicities Grade ≥ 2 from previous chemotherapy (excluding alopecia, nausea, fatigue, and liver function tests (as mandated in the inclusion criteria)).
3. The patient has received treatment with chemotherapy, wide-field radiation, or biologic therapy within 14 days of study entry.
4. The patient has received treatment with another investigational agent within 14 days of study entry.
5. The patient has previously received treatment with Tagraxofusp.
6. The patient has an active malignancy and/or cancer history (excluding AML, BPDCN, or antecedent MDS) that may confound the assessment of the study endpoints. Patients with a past cancer history (within 2 years of entry) with substantial potential for recurrence and/or ongoing active malignancy must be discussed with the Sponsor before study entry. Patients with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, cervical intraepithelial neoplasia, organ-confined prostate cancer with no evidence of progressive disease.
7. The patient has clinically significant cardiovascular disease (e.g., uncontrolled or any NYHA Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction or stroke within 6 months of study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
8. The patient has uncontrolled, clinically significant pulmonary disease (e.g., COPD, pulmonary hypertension) that in the opinion of the investigator would put the patient at significant risk for pulmonary complications during the study.
9. The patient has known active or suspected CNS leukemia. If suspected, CNS leukemia should be ruled out with relevant imaging and/or examination of cerebrospinal fluid.
10. The patient is receiving immunosuppressive therapy - with the exception of low-dose prednisone (≤ 10 mg/day) - for treatment or prophylaxis of graft-versus-host disease (GVHD). If the patient has been on immunosuppressive treatment or prophylaxis for GVHD, the treatment(s) must have been discontinued at least 14 days prior to study treatment and there must be no evidence of Grade ≥ 2 GVHD.
11. The patient has uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, DIC, or psychiatric illness/social situations that would limit compliance with study requirements.
12. The patient is pregnant or breast feeding.
13. The patient has known positive status for human immunodeficiency virus (HIV) active or chronic Hepatitis B or Hepatitis C.
14. The patient is oxygen-dependent.
15. The patient has any medical condition which in the opinion of the investigator places the patient at an unacceptably high risk for toxicities.