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

NCT07148180 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 25-330
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 2

Brief Summary

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)

Conditions

Blood Cancers; Acute Myeloid Leukaemia (AML); Leukemia; Blood Cancer

Keywords

Acute Myeloid Leukemia; AML; Measurable Residual Disease; Myeloid Neoplasms; Blood Cancer; Blood Cancers

Outcome Measures

Primary Outcomes (3)

• Recommended phase II dose (RP2D) of tagraxofusp in combination with fixed dose of Azacitidine and Venetoclax [Phase I]

  Definition of RP2D is outlined in protocol section 5.4.

  Up to 28 days

• Number of Participants Experienced Dose-Limiting Toxicity (DLT) [Phase I]

  Definition of Dose Limiting Toxicity (DLT) is outlined in protocol section 5.4.

  Up to 28 days

• Measurable Residual Disease (MRD) conversion rate [Phase II]

  MRD conversion rate is defined as the proportion of participants that achieve multi-parametric flow cytometry (MFC) MRD conversion (positive to negative) within the first four cycles of therapy. MRD negativity will be defined according to 2021 ELN MRD Working Party Consensus Guidelines and central lab MRD will be used to make this determination: CR with negative MFC-MRD negative refers to achievement of flow MRD negativity: MFC-MRD negative in bone marrow defined as \<0.1% (same as \<10\^-3).

  Up to 4 months

Secondary Outcomes (7)

• Duration of Remission (DOR)

  Disease response assessments will be conducted at baseline, day 1 of cycles 2, 4, 6, 9, and 12, then every 3 cycles thereafter during treatment, and at end of treatment (2 years) or upon suspected relapse. Each cycle is 28 days.

• Median Overall Survival (OS)

  Participants off protocol treatment but remaining on study will have survival status assessed every 12 weeks for up to 2 years. Maximum treatment duration is 2 years.

• Median Relapse-free survival (RFS)

  Disease response assessments will be conducted at baseline, day 1 of cycles 2, 4, 6, 9, and 12, then every 3 cycles thereafter during treatment, and at end of treatment (2 years) or upon suspected relapse. Each cycle is 28 days.

• Median Event-free Survival (EFS)

  Disease response assessments will be conducted at baseline, day 1 of cycles 2, 4, 6, 9, and 12, then every 3 cycles thereafter during treatment, and at end of treatment (2 years) or upon suspected relapse. Each cycle is 28 days.

• Bridge to Transplantation Rate

  Maximum treatment duration is 2 years.

Study Arms (2)

Arm 1: Phase 1 Dose Escalation

EXPERIMENTAL

Up to 12 participants will be enrolled in a standard 3+3 design to determine the maximum tolerated dose/RP2D for Tagraxofusp in combination with azacitidine and venetoclax starting at Dose Level 1 and escalating to Dose Level 2 according to dose-limiting toxicity rules. * Baseline visit * Cycles 1 through 2 (28 day cycles): * Days 1 through 7: Predetermined dose of Azacitidine 1x daily. * Days 4 through 6: Predetermined dose of Tagraxofusp 1x daily. * Days 1 and 14: Predetermined dose of Venetoclax 1x daily * Day 28: bone marrow aspiration and biopsy * Cycles 3 through 24 (28 day cycles): * Days 1 through 7: Predetermined dose of Azacitidine 1x daily. * Days 4 through 6: Predetermined dose of Tagraxofusp 1x daily. * Days 1 and 14: Predetermined dose of Venetoclax 1x daily * Bone marrow aspirations/biopsies on Day 1 of Cycles 4, 6, 9, 12, and then every 3 cycles. * End of treatment visit with bone marrow aspiration and biopsy * Follow up for up to 2 years

Drug: Tagraxofusp; Drug: Azacitidine (AZA); Drug: Venetoclax

Arm 2: Phase 2 Dose Expansion

EXPERIMENTAL

19 Participants will receive Tagraxofusp at the RP2D in combination with Azacitidine and Venetoclax and will complete: * Baseline visit * Cycles 1 through 2 (28 day cycles): * Days 1 through 7: Predetermined dose of Azacitidine 1x daily. * Days 4 through 6: Predetermined dose of Tagraxofusp 1x daily. * Days 1 and 14: Predetermined dose of Venetoclax 1x daily * Day 28: bone marrow aspiration and biopsy * Cycles 3 through 24 (28 day cycles): * Days 1 through 7: Predetermined dose of Azacitidine 1x daily. * Days 4 through 6: Predetermined dose of Tagraxofusp 1x daily. * Days 1 and 14: Predetermined dose of Venetoclax 1x daily * Bone marrow aspirations/biopsies on Day 1 of Cycles 4, 6, 9, 12, and then every 3 cycles. * End of treatment visit with bone marrow aspiration and biopsy * Follow up for up to 2 years

Drug: Tagraxofusp; Drug: Azacitidine (AZA); Drug: Venetoclax

Interventions

Tagraxofusp DRUG

A CD123-directed cytotoxin, Single-use vial, via intravenous (into the vein) infusion per protocol.

Also known as: ELZONRIS, SL-401

Arm 1: Phase 1 Dose Escalation; Arm 2: Phase 2 Dose Expansion

Azacitidine (AZA) DRUG

A cytidine nucleoside analog, single-use vial, via intravenous infusion or subcutaneous (under the skin) injection per standard of care.

Also known as: VIDAZA, Onureg

Arm 1: Phase 1 Dose Escalation; Arm 2: Phase 2 Dose Expansion

Venetoclax DRUG

A BCL-2 inhibitor, tablet, via orally per standard of care.

Also known as: VENCLEXTA, C45H50ClN7O7S

Arm 1: Phase 1 Dose Escalation; Arm 2: Phase 2 Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Jacqueline Garcia, MD: lead
• Stemline Therapeutics, Inc.: collaborator
• Break Through Cancer Foundation: collaborator

Study Sites (2)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia; Hematologic Neoplasms; Neoplasm, Residual

Interventions

tagraxofusp; Azacitidine; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms by Site; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Jacqueline Garcia, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jacqueline Garcia, MD

CONTACT

617-632-6349; jacqueline_garcia@dfci.harvard.edu

Jacqueline Garcia, MD

CONTACT

jacqueline_garcia@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Model Details: The study includes a phase 1 dose-escalation phase to determine the MTD and RP2D, followed by a phase 2 dose-expansion phase

Study Record Dates

• First Submitted: August 20, 2025
• First Posted: August 29, 2025
• Study Start: February 2, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2030
• Last Updated: February 5, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (2)