Tagraxofusp and Low-Intensity Chemotherapy for CD123-Positive Relapsed or Refractory AML

Tagraxofusp and Low-Intensity Chemotherapy for the Treatment of CD123-Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)

To determine the efficacy of the combination of tagraxofusp, cladribine, and cytarabine.

Study Overview

• Status: Recruiting
• Conditions: Refractory Acute Myeloid Leukemia; Relapsed Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Cladribine (CLAD); Drug: Cytarabine; Drug: Tagraxofusp

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Woo In (Yustina) Cho; Phone Number: 650-721-2443; Email: wooin@stanford.edu

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Recruiting
      • Stanford University
      • Contact: Woo In (Yustina) Cho; Phone Number: 650-721-2443; Email: wooin@stanford.edu
      • Principal Investigator: Gabriel Mannis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Documented diagnosis of relapsed or refractory acute myeloid leukemia (AML) according to World Health Organization (WHO) 2022 criteria
• Expression of CD123 by either flow cytometry or immunohistochemical staining with no minimum threshold for positivity
• Must have received initial therapy with venetoclax in combination with a hypomethylating agent (either azacitidine or decitabine) with no subsequent therapy unless mutations in the IDH or FLT3 genes.

If mutations in the IDH or FLT3 genes, treatment with IDH or FLT3 inhibitors after initial failure of venetoclax plus HMA is allowed, but not required.

• Age ≥ 18 years of age
• ECOG ≤ 2
• Albumin ≥ 3.2 g/dL at time of screening (note that albumin supplementation is not permitted to enable eligibility)
• Left ventricular ejection fraction ≥ 50%
• No clinically significant abnormalities on 12-lead electrocardiogram (ECG) including: complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250ms, or QTcF (Friderica's method) >450ms in 3 successive measurements
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Females of reproductive potential need to either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with highly effective contraception without interruption prior to starting treatment, during the study therapy, and for 30 days after last dose of study therapy
• For males of reproductive potential: agreement to use of condoms
• Adequate hepatic/renal function defined as:

Hepatic function: total bilirubin ≤ 1.5 x ULN (unless attributable to Gilbert's disease or leukemic involvement) AND AST or ALT ≤ 3 x ULN

Renal function: creatinine clearance > 30 mL/minute, calculated by Cockcroft Gault formula

• Women of childbearing potential must have a negative urine or serum pregnancy test
• Ability to understand and the willingness to provide written informed consent.

Exclusion Criteria:

• Prior therapy apart from Venetoclax in combination with a hypomethylating agent, or Venetoclax in combination with a hypomethylating agent followed by monotherapy with IDH or FLT3 inhibitors
• Patients who received systemic anti-cancer therapy <14 days prior to their first day of study drug administration.
• Patients who received systemic anti-cancer therapy <14 days prior to their first day of study drug administration. Concurrent hydroxyurea will be allowed. Hydroxyurea use will be allowed only during the first cycle if needed for disease control.
• Significant cardiac disease (any NYHA Class 3 or 4 CHF, uncontrolled angina, history of MI, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension, or clinically significant arrhythmias not controlled by medication)
• Any uncontrolled bacterial, fungal, viral or other infection.
• Known HIV+ or active hepatitis B or C infection, defined as positive viral load for HBV or HCV or a positive surface antigen (HBsAg) test for hepatitis B.
• The patient has persistent clinically significant toxicities Grade >/= 2 from previous therapies not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue).
• The patient has an active malignancy and/or cancer history that may confound the assessment of the study endpoints. Patients with a past cancer history (within 2 years of study entry) with substantial potential for recurrence and/or ongoing active malignancy must be discussed with study team 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.
• The patient has uncontrolled, clinically significant pulmonary disease (e.g. chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study.
• The patient has known active or suspected CNS disease. If suspected, CNS disease should be ruled out with relevant imaging and/or examination of cerebrospinal fluid.
• The patient is receiving immunosuppressive therapy - with the exception of low-dose prednisone (</= 10 mg/day).
• Received allogenic stem cell transplant prior to the treatment.
• The patient has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant or breast feeding

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose level 1 (DL1); DL1 will consist of cladribine 5mg/m2 IV once daily on days 1-3, cytarabine 20mg/m2 IV daily days 1-5, and tagraxofusp 12 mcg/kg IV daily days 4-6. If a DLT is encountered in the first 2 participants, 3 more will be enrolled at the same dose.	Drug: Cladribine (CLAD); Cladribine 5mg/m2 IV once daily on days 1-3 (DL1) Cladribine 5mg/m2 IV once daily on days 1-4 (DL2) Cladribine 5mg/m2 IV once daily on days 1-5 (DL3); Drug: Cytarabine; Cytarabine 20mg/m2 IV daily days 1-5 (DL1) Cytarabine 20mg/m2 IV daily days 1-7(DL2) cytarabine 20mg/m2 IV daily days 1-10 (DL3); Drug: Tagraxofusp; Tagraxofusp is administered by intravenous infusion (IV) over 15 minutes for 3 consecutive days of a 28-day cycle. (days 4-6)
Experimental: Dose level 2 (DL2); DL2 will consist of cladribine 5mg/m2 IV once daily on days 1-4, cytarabine 20mg/m2 IV daily days 1-7, and tagraxofusp 12 mcg/kg IV daily days 4-6. If a DLT is encountered in the first 2 participants, 3 more will be enrolled at the same dose.	Drug: Cladribine (CLAD); Cladribine 5mg/m2 IV once daily on days 1-3 (DL1) Cladribine 5mg/m2 IV once daily on days 1-4 (DL2) Cladribine 5mg/m2 IV once daily on days 1-5 (DL3); Drug: Cytarabine; Cytarabine 20mg/m2 IV daily days 1-5 (DL1) Cytarabine 20mg/m2 IV daily days 1-7(DL2) cytarabine 20mg/m2 IV daily days 1-10 (DL3); Drug: Tagraxofusp; Tagraxofusp is administered by intravenous infusion (IV) over 15 minutes for 3 consecutive days of a 28-day cycle. (days 4-6)
Experimental: Dose level 3 (DL3); DL3 will consist of cladribine 5mg/m2 IV once daily on days 1-5, cytarabine 20mg/m2 IV daily days 1-10, and tagraxofusp 12 mcg/kg IV daily days 4-6. If a DLT is encountered in the first 2 participants, 3 more will be enrolled at the same dose.	Drug: Cladribine (CLAD); Cladribine 5mg/m2 IV once daily on days 1-3 (DL1) Cladribine 5mg/m2 IV once daily on days 1-4 (DL2) Cladribine 5mg/m2 IV once daily on days 1-5 (DL3); Drug: Cytarabine; Cytarabine 20mg/m2 IV daily days 1-5 (DL1) Cytarabine 20mg/m2 IV daily days 1-7(DL2) cytarabine 20mg/m2 IV daily days 1-10 (DL3); Drug: Tagraxofusp; Tagraxofusp is administered by intravenous infusion (IV) over 15 minutes for 3 consecutive days of a 28-day cycle. (days 4-6)
Experimental: Dose Level -1 (DL-1); DL -1 will consist of cladribine 5mg/m2 IV once daily on days 1-2, cytarabine 20mg/m2 IV daily days 1-4, and tagraxofusp 12mcg/kg IV daily days 4-6.	Drug: Cladribine (CLAD); Cladribine 5mg/m2 IV once daily on days 1-3 (DL1) Cladribine 5mg/m2 IV once daily on days 1-4 (DL2) Cladribine 5mg/m2 IV once daily on days 1-5 (DL3); Drug: Cytarabine; Cytarabine 20mg/m2 IV daily days 1-5 (DL1) Cytarabine 20mg/m2 IV daily days 1-7(DL2) cytarabine 20mg/m2 IV daily days 1-10 (DL3); Drug: Tagraxofusp; Tagraxofusp is administered by intravenous infusion (IV) over 15 minutes for 3 consecutive days of a 28-day cycle. (days 4-6)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase 2 dose	Determination of the recommended Phase 2 dose based on the safety of tagraxofusp in combination with cladribine and low-dose cyatarabine, as determined by DLT evaluation.	up 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite complete response (CR+CRi +CRh)	Composite complete response will be determined by the proportion of study subjects achieving CR, CRi, or CRh, as defined by the ELN 2022 AML Response Criteria.	up 2 years
Incidence of drug-related adverse events	The Incidence of Drug-Related Adverse Events is a safety endpoint used to evaluate the frequency and severity of adverse events (AEs) that are attributed to the study drug All grades of adverse events determined to be treatment-related will be summarized descriptively.	up 2 years
Overall response rate (ORR)	ORR will be determined by the proportion of study subjects achieving Complete Remission (CR), Complete remission with incomplete hematologic recovery (CRi), Complete remission with partial hematologic recovery (CRh), Morphological leukemia-free state (MLFS), or (Partial Response (PR), as defined by the ELN 2022 AML response criteria.	up 2 years
Complete response	Complete Response will be determined by the proportion of study subjects achieving CR, as defined by the ELN 2022 AML Response Criteria.	up 2 years
Rate of Minimal Residual Disease (MRD) negativity in responders	Rate of MRD negativity in responders, as measured by multi-parameter flow cytometry.	up 2 years
Duration of overall survival	Overall survival (OS) will be measured as the date of enrollment in the study to the date of death from any cause.	up 2 years

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: Stemline Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: August 16, 2024
• First Submitted That Met QC Criteria: August 16, 2024
• First Posted (Actual): August 19, 2024

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 12, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: cytarabine; cladribine; tagraxofusp
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nucleic Acids, Nucleotides, and Nucleosides; Purines; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Ribonucleosides; Arabinonucleosides; Deoxyribonucleosides; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Deoxyadenosines; Cytarabine; Cladribine; tagraxofusp
• Other Study ID Numbers: IRB-76512; NCI-2025-01963 (Registry Identifier: National Cancer Institute: Clinical Trials Reporting Program)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No