Testing the Combination of Targeted Radiotherapy With Anti-Cancer Drugs, Venetoclax and ASTX-727, to Improve Outcomes for Adults With Newly Diagnosed Acute Myeloid Leukemia

NCT06802523 | Suspended Phase 1 FDA Drug

• 3 other identifiers: NCI-2025-0057510653UM1CA186689
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial tests the safety, side effects, and best dose of lintuzumab-Ac225 in combination with venetoclax and ASTX-727, and how well they work in treating patients with newly diagnosed acute myeloid leukemia (AML). Lintuzumab-Ac225 is a monoclonal antibody, called lintuzumab, linked to a radioactive agent called actinium Ac 225. Lintuzumab attaches to CD33 positive cancer cells in a targeted way and delivers actinium Ac 225 to kill them. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. ASTX-727 is a combination of two drugs, cedazuridine and decitabine. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Giving lintuzumab-Ac225 in combination with venetoclax and ASTX-727 may be safe and tolerable in treating patients with newly diagnosed AML and may improve the chance of going into remission and staying in remission for a longer period of time.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Incidence of dose limiting toxicities

  Adverse events (AEs) will be described and graded using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

  Up to 28 days after the start of induction (up to 42 days for persistent neutropenia and thrombocytopenia)

• Overall response rate (ORR)

  Will include patients with complete remission (CR), complete remission with partial hematologic recovery (CRh), and complete remission with incomplete hematologic recovery (CRi). ORR and its 95% confidence interval will be calculated.

  Up to 5 years

Secondary Outcomes (20)

• Maximum tolerated dose of lintuzumab Ac-225 when used in combination with venetoclax and ASTX-727

  Up to completion of dose-escalation phase (Part A)

• Frequency and severity of AEs

  Up to 30 days after last dose of study treatment

• CR rate

  Up to 5 years

• Time to CR

  Up to 5 years

• CRh rate

  Up to 5 years

Other Outcomes (2)

• Correlate CD33 expression on acute myeloid leukemia cells with response to lintuzumab-Ac225 in combination with venetoclax and ASTX-727

  Up to 5 years

• CD33 isoforms as a variable for response to lintuzumab-Ac225 in combination with venetoclax and ASTX-727

  Up to 5 years

Study Arms (2)

Schedule 1 (lintuzumab-Ac225, venetoclax, ASTX-727)

EXPERIMENTAL

INDUCTION: Patients receive lintuzumab-Ac225 IV over 30 minutes on day 8, venetoclax PO QD on days 1-28 and ASTX-727 PO QD on days 1-5 of cycle 1. RE-INDUCTION: Patients with CR,PR or NR after cycle 1 receive lintuzumab-Ac225 IV over 30 minutes on day 8, venetoclax PO QD on days 1-28 and ASTX-727 PO QD on days 1-5 of cycle 2. MAINTENANCE/CONSOLIDATION: Patients with CRi, CRh, or MLFS after cycle 1 receive venetoclax PO QD on days 1-28 and ASTX-727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and biopsy and blood sample collection throughout the study.

Radiation: Actinium Ac 225 Lintuzumab; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Drug: Decitabine and Cedazuridine; Drug: Venetoclax

Schedule 2 (lintuzumab-Ac225, venetoclax, ASTX-727)

EXPERIMENTAL

INDUCTION: Patients receive lintuzumab-Ac225 V over 30 minutes on day 1, venetoclax PO QD on days 1-28 and ASTX-727 PO QD on days 1-5 of cycle 1. RE-INDUCTION: Patients with CR, PR or NR receive lintuzumab-Ac225 IV over 30 minutes on day 1, venetoclax PO QD on days 1-28 and ASTX-727 PO QD on days 1-5 of cycle 2. MAINTENANCE/CONSOLIDATION: Patients with CRi, CRh, or MLFS after cycle 1 receive venetoclax PO QD on days 1-28 and ASTX-727 PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and biopsy and blood sample collection throughout the study.

Radiation: Actinium Ac 225 Lintuzumab; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Drug: Decitabine and Cedazuridine; Drug: Venetoclax

Interventions

Actinium Ac 225 Lintuzumab RADIATION

Given IV

Also known as: 225Ac-HuM195, Actimab-A, Actinium (225Ac) Lintuzumab Satetraxetan, Actinium-225-Labeled Humanized Anti-CD33 Monoclonal Antibody HuM195, LINTUZUMAB SATETRAXETAN AC-225, SGN-33 AC-225

Schedule 1 (lintuzumab-Ac225, venetoclax, ASTX-727); Schedule 2 (lintuzumab-Ac225, venetoclax, ASTX-727)

Venetoclax DRUG

Given PO

Also known as: ABT 199, ABT-0199, ABT-199, ABT199, GDC 0199, GDC-0199, GDC0199, RG7601, Venclexta, Venclyxto

Schedule 1 (lintuzumab-Ac225, venetoclax, ASTX-727); Schedule 2 (lintuzumab-Ac225, venetoclax, ASTX-727)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Schedule 1 (lintuzumab-Ac225, venetoclax, ASTX-727); Schedule 2 (lintuzumab-Ac225, venetoclax, ASTX-727)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow aspiration and biopsy

Schedule 1 (lintuzumab-Ac225, venetoclax, ASTX-727); Schedule 2 (lintuzumab-Ac225, venetoclax, ASTX-727)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow aspiration and biopsy

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Schedule 1 (lintuzumab-Ac225, venetoclax, ASTX-727); Schedule 2 (lintuzumab-Ac225, venetoclax, ASTX-727)

Decitabine and Cedazuridine DRUG

Given PO

Also known as: ASTX 727, ASTX-727, ASTX727, C-DEC, CDA Inhibitor E7727/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Tablet, DEC-C, Inaqovi, Inqovi

Schedule 1 (lintuzumab-Ac225, venetoclax, ASTX-727); Schedule 2 (lintuzumab-Ac225, venetoclax, ASTX-727)

Eligibility Criteria

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

You may qualify if:

• Patients must have histologically or cytologically confirmed diagnosis of acute myeloid leukemia (AML) according to 2022 World Health Organization (WHO) criteria
• Evidence of CD33 expression in more than 25% of bone marrow blasts by flow cytometry determined by local assessment
• Patients must be considered ineligible for induction therapy defined by the following
• ≥ 75 years of age; OR
• \<75 years of age with at least one of the following co-morbidities or high-risk genetic features. Geriatric assessment and other tools to assess frailty have not been validated in patients with AML, and therefore will not be used to assess eligibility
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3;
• Cardiac history of congestive heart failure (CHF) requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina;
• Diffusion capacity of lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume in 1 second (FEV1) ≤ 65%;
• Moderate hepatic impairment with total bilirubin \> 1.5 to ≤ 3.0 × upper limit of normal (ULN)
• Patents with high risk genetic features based on local testing
• inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)
• t(3q26.2;v)
• or del(5q); -7; -17/abnormal(17p)
• Complex karyotype or monosomal karyotype as defined by ELN 2022
• Mutated TP53

You may not qualify if:

• Acute promyelocytic leukemia (APL)
• Patients with favorable risk AML per the European LeukemiaNet (ELN) 2022 criteria
• Active central nervous system (CNS) involvement of AML requiring therapy
• Prior therapy with radiopharmaceuticals or external beam radiation therapy (EBRT)
• Previous therapy with venetoclax or other BCL-2 directed therapy
• Patients with Fridericia-corrected QT interval (QTcF) \> 450ms at screening. QTcF will be calculated as the mean of the QTcF value from three separate electrocardiography (EKGs)
• Receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to venetoclax or ASTX-727
• Uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous per investigators opinion
• Pregnant women are excluded from this study because lintuzumab-Ac225 is a radiotherapy agent with 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 lintuzumab-Ac225, breastfeeding should be discontinued if the mother is treated with lintuzumab-Ac225. These potential risks may also apply to other agents used in this study
• Women of child-bearing potential must agree to use adequate contraception (hormonal birth control or abstinence) prior to study entry and for the duration of study participation, and for 6 months following completion of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception (latex or synthetic condom or abstinence) prior to the study, for the duration of study participation, and 3 months after completion of the study
• Patients unable to swallow tablets/capsules and patients with malabsorption syndrome or other conditions that may interfere with the oral administration of medications are not eligible
• Patients who have had chemotherapy, targeted small molecule therapy (aside from imatinib, dasatinib, or nilotinib, hydroxyurea, cytarabine or ATRA),within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study are not eligible
• Prior allogenic stem cell transplant
• Patients who received a live vaccine within 30 days of planned start of study therapy

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

Yale University Cancer Center LAO

New Haven, Connecticut, 06520, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Actinium; Specimen Handling; Biopsy; decitabine and cedazuridine drug combination; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Actinoid Series Elements; Elements, Radioactive; Elements; Inorganic Chemicals; Metals, Heavy; Radioisotopes; Isotopes; Metals; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative

Study Officials

• Manu Pandey

  Yale University Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2025
• First Posted: January 31, 2025
• Study Start: April 21, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028
• Last Updated: April 13, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share

Locations

US (1)