Tagraxofusp in Patients With Blastic Plasmacytoid Dendritic Cell Neoplasm or Acute Myeloid Leukemia

Tagraxofusp in Patients With Acute Myeloid Leukemia (AML) and Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

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 Overview

• Status: Completed
• Conditions: Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN); Acute Myeloid Leukemia (AML)
• Intervention / Treatment: Drug: Tagraxofusp

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 138
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
  • Florida
    • Tampa, Florida, United States, 12902
      • H. Lee Moffiitt Cancer Center & Research Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center Presbyterian Shady Side
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: First-Line Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN); Intervention: Tagraxofusp	Drug: Tagraxofusp; Other Names: SL-401
Experimental: Relapse/Refractory Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN); Intervention: Tagraxofusp	Drug: Tagraxofusp; Other Names: SL-401
Experimental: Acute Myeloid Leukemia; Intervention: Tagraxofusp	Drug: Tagraxofusp; Other Names: SL-401

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD (Stage 1)	Maximum tolerated dose (MTD) in both patients with BPDCN and AML. MTD defined as the highest dose level where less than 2/3 or 2/6 patients experienced a DLT	21-day period after the first dose (cycle 1)
CR Rate in First-line BPDCN (Stage 3, Pivotal Cohort)	Complete response (CR) rate, defined as the percentage who achieved CR+ CR(clinical) with minimal residual skin abnormality (CRc) after treatment with Tagraxofusp. CR criteria according to Cheson BD et al, The International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-586: Marrow: normalization of blast percentage (≤5%). Peripheral blood: normalization of neutrophil count (≥ 1,000/µL) and platelet count (≥ 100,000/µL) - absence of leukemic blasts Skin: 100% clearance of all skin lesions from baseline; no new lesions in patients without lesions at baseline Nodal masses: regression to normal size on CT Spleen, liver: not palpable, nodules disappeared CRc criteria: all the above except for skin: marked clearance of all skin lesions from baseline; residual hyperpigmentation or abnormality with BPDCN identified on biopsy (or no biopsy performed)	at pre-defined treatment cycle intervals from randomization up to disease progression, up to 3.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CR Rate in First-line BPDCN, R/R BPDCN and AML	CR rate, defined as the percentage of patients who achieved CR+ CR with minimal residual skin abnormality (CRc) after treatment with Tagraxofusp. CR criteria according to Cheson BD et al, The International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-586: Marrow: normalization of blast percentage (≤5%) Peripheral blood: normalization of neutrophil count (≥ 1,000/µL) and platelet count (≥ 100,000/µL) - absence of leukemic blasts Skin: 100% clearance of all skin lesions from baseline; no new lesions in patients without lesions at baseline Nodal masses: regression to normal size on CT Spleen, liver: not palpable, nodules disappeared CRc criteria: all the above except for skin: marked clearance of all skin lesions from baseline; residual hyperpigmentation or abnormality with BPDCN identified on biopsy (or no biopsy performed)	at pre-defined treatment cycle intervals from randomization up to disease progression, up to 5 years
Duration of CR in First-line BPDCN, R/R BPDCN and AML	Duration of complete response (CR) defined as the time from when the criteria are first met for CR+CRc (whichever was recorded first) until the date that the criteria for relapse after CR+CRc are met, according to the previously reported criteria for CR and CRc and following criteria of relapse after CR+CRc (Cheson BD et al. J Clin Oncol 2007;25:579-586.): Marrow: blast percentage >5% (if no peripheral blasts, then confirmation aspirate required ≥ 1week later) Peripheral blood: presence of leukemic blasts Skin: increase in skin score greater than the sum of nadir plus 50% baseline score Nodal masses: appearance of a new lesion(s) >1.5 cm in any axis, ≥50% increase from nadir in SPD of more than one node, or ≥50% increase from nadir in longest diameter of a previously identified node >1cm in short axis Spleen, liver: >50% increase from nadir in the SPD of any previous lesions	at pre-defined treatment cycle intervals from randomization up to disease progression, up to 5 years
ORR in First-line BPDCN, R/R BPDCN and AML	Objective response rate (ORR) defines as the percentage of patients who achieved CR (CR+CRc), CR with incomplete blood count recovery (CRi), or partial response (PR) after treatment with Tagraxofusp according to the previously reported definitions of CR, CRc and the following one of CRi and PR: CRi: CR with incomplete of neutrophil and/or platelet count and absence of leukemic blast in the peripheral blood Marrow: PR defined as decrease by ≥50% in blast percentage to 5-25% Peripheral blood: PR defined as normalization of neutrophil count (≥ 1,000/µL) and platelet count (≥ 100,000/µL) Skin: 50%-<100% clearance of all skis lesions from baseline; no new lesions in patients without lesions at baseline Nodal masses: ≥50% decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes Spleen, liver: ≥50% in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen	at pre-defined treatment cycle intervals from randomization up to disease progression, up to 5 years
OS in First-line BPDCN, R/R BPDCN and AML	Overall survival (months) defined as the time from the date of first infusion of Tagraxofusp to the date of death from any cause	From first infusion to treatment discontinuation when survival is assessed every 90 days up to end of follow-up or death, up to 5 years
Bridge to SCT in First-line BPDCN, R/R BPDCN and AML	Bridge to Stem Cell Transplant (SCT) defined as the percentage of patients who received SCT subsequent to achieving an Investigator-determined outcome from Tagraxofusp that was deemed by the Investigator to enable an SCT	at pre-defined intervals up to achievement of outcome enabling an SCT for a period, up to 5 years

Collaborators and Investigators

• Sponsor: Stemline Therapeutics, Inc.
• Collaborators: The Leukemia and Lymphoma Society

Publications and helpful links

General Publications

• Pemmaraju N, Sweet KL, Stein AS, Wang ES, Rizzieri DA, Vasu S, Rosenblat TL, Brooks CL, Habboubi N, Mughal TI, Kantarjian H, Konopleva M, Lane AA. Long-Term Benefits of Tagraxofusp for Patients With Blastic Plasmacytoid Dendritic Cell Neoplasm. J Clin Oncol. 2022 Sep 10;40(26):3032-3036. doi: 10.1200/JCO.22.00034. Epub 2022 Jul 12.
• Pemmaraju N, Lane AA, Sweet KL, Stein AS, Vasu S, Blum W, Rizzieri DA, Wang ES, Duvic M, Sloan JM, Spence S, Shemesh S, Brooks CL, Balser J, Bergstein I, Lancet JE, Kantarjian HM, Konopleva M. Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med. 2019 Apr 25;380(17):1628-1637. doi: 10.1056/NEJMoa1815105.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): February 1, 2020
• Study Completion (Actual): March 12, 2020

Study Registration Dates

• First Submitted: March 13, 2014
• First Submitted That Met QC Criteria: April 10, 2014
• First Posted (Estimated): April 15, 2014

Study Record Updates

• Last Update Posted (Actual): August 1, 2024
• Last Update Submitted That Met QC Criteria: July 8, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Hematologic Diseases; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: STML-401-0114