Targeted Radiotherapy + Anti-Cancer Drugs for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Radiopharmaceuticals, BCL-2 therapy

Disqualifiers: APL, CNS involvement, Favorable risk AML, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

53 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for acute myeloid leukemia (AML), a type of blood cancer. It examines the safety and effectiveness of using a targeted radiotherapy called lintuzumab-Ac225 with two anti-cancer drugs, venetoclax and ASTX-727 (a combination of decitabine and cedazuridine). The goal is to determine if this combination can safely help more patients achieve and maintain remission. Suitable candidates include those newly diagnosed with AML, who have specific disease characteristics, such as CD33 positive cells, and are not eligible for standard aggressive chemotherapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, certain medications like hydroxyurea and ATRA are allowed before starting the study treatment. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that lintuzumab-Ac225, which targets certain cancer cells, was generally safe in earlier studies. Some patients experienced blood-related side effects, common among those with extensive treatment histories. Studies on venetoclax, a cancer drug that stops cancer cells from growing, found it well tolerated, especially in older patients. Previous research on the combination of decitabine and cedazuridine, which helps cancer medicine remain in the body longer, showed a safety profile similar to other treatments in its category. However, some serious side effects, such as infections and bleeding, occurred in a few cases. Overall, while some side effects have been noted with these treatments, past research suggests they are generally well-tolerated by patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining targeted radiotherapy with anti-cancer drugs like Decitabine, Cedazuridine, Lintuzumab-Ac225, and Venetoclax for treating Acute Myeloid Leukemia (AML) because of its unique approach. Unlike traditional chemotherapy, which broadly attacks rapidly dividing cells, this treatment uses Lintuzumab-Ac225 to deliver radioactive particles directly to leukemia cells, potentially reducing harm to healthy cells. Venetoclax works by targeting a protein that helps cancer cells survive, while ASTX-727 (a combination of Decitabine and Cedazuridine) inhibits DNA methylation, potentially making cancer cells more vulnerable to treatment. This combination could offer a more precise and effective attack on AML cells, making it a promising alternative to current therapies.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that adding lintuzumab-Ac225 to chemotherapy yields promising results for treating acute myeloid leukemia (AML). This trial evaluates two different schedules of this combination. In both schedules, lintuzumab-Ac225 targets specific cancer cells and uses a radioactive substance to destroy them. Venetoclax, a drug that blocks a protein aiding cancer cell survival, is included in both schedules. Studies have found that venetoclax can halt cancer growth in AML patients, with more than half of the patients achieving remission. ASTX-727, a combination of two drugs, helps create healthy blood cells and eliminate abnormal ones, with many patients reaching complete remission. Together, these treatments may improve remission rates for patients newly diagnosed with AML. ^{1 6 7 8 9}

Who Is on the Research Team?

Manu Pandey

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed acute myeloid leukemia (AML) who haven't had prior chemotherapy for related conditions. Participants must have AML cells that show CD33, normal bilirubin levels (unless due to Gilbert syndrome), and liver enzymes within acceptable limits. They should have a kidney function with a GFR of at least 60 ml/min/1.73 m^2, can be HIV-positive if on effective therapy, and not fit enough for intensive chemo as per their doctor's opinion.

Inclusion Criteria

I have chronic hepatitis B but it's under control with medication.

I had hepatitis C but am now cured or have no detectable virus while on treatment.

I have another cancer that won't affect this treatment's safety or results.

Exclusion Criteria

Receiving any other investigational agents

Pregnant or breastfeeding women

Consumed specific fruits within 3 days prior to study treatment initiation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive lintuzumab-Ac225, venetoclax, and ASTX-727 according to one of two schedules to determine the recommended phase 2 dose and assess initial response

4 weeks

Multiple visits for drug administration and monitoring

Re-Induction

Patients with CR, PR, or NR after cycle 1 receive a second cycle of treatment to enhance response

4 weeks

Multiple visits for drug administration and monitoring

Maintenance/Consolidation

Patients with CRi, CRh, or MLFS continue treatment cycles to maintain remission

28 days per cycle, repeated in absence of disease progression

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 3 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine and Cedazuridine
• Lintuzumab-Ac225
• Venetoclax

Trial Overview The trial tests the combination of lintuzumab-Ac225 (a targeted radioactive antibody), venetoclax (a BCL-2 inhibitor that may stop cancer cell growth), and ASTX-727 (cedazuridine plus decitabine to help bone marrow produce healthy blood cells). It aims to determine safety, side effects, best dose, and effectiveness in treating AML.

How Is the Trial Designed?

Group I: Schedule 2 (lintuzumab-Ac225, venetoclax, ASTX-727) Experimental Treatment 6 Interventions

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.

Group II: Schedule 1 (lintuzumab-Ac225, venetoclax, ASTX-727) Experimental Treatment 6 Interventions

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.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6551

Phase II trial of 10-day ASTX727 (decitabine/cedazuridine ... In this prospective clinical trial, we investigate the efficacy of a novel 10-day induction regimen with fully oral combination therapy for pts with R/R AML.

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/2896/533121/Fully-Oral-Combination-of-Decitabine-Cedazuridine

Fully Oral Combination of Decitabine/Cedazuridine (ASTX727 ... The median follow-up time was 20 months. The ORR was 40/60 (67%), including 24 (40%) complete remission (CR), 13 (22%) CR with incomplete count ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40051275/

A plain language summary of the ASCERTAIN trial Among people treated with oral DEC-C, the median overall survival was 31.8 months. Overall, people lived without developing AML for a median of ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123081417

Oral Decitabine/Cedazuridine Vs Intravenous ... The best response was complete response (CR) in 19/87 (21.8%, 95% CI: 13.7, 32.0%); CR with incomplete blood cell count recovery (CRi) in 5 patients (5.7%); and ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04817241

Testing Oral Decitabine and Cedazuridine (ASTX727) in ... This phase Ib/II trial studies the effects of ASTX727 (decitabine and cedazuridine) in combination with venetoclax in treating patients with higher-risk ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38452788/

Oral decitabine and cedazuridine plus venetoclax for older or ... Three deaths occurred in patients in remission (one sepsis, one gastrointestinal haemorrhage, and one respiratory failure) and were potentially treatment ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04657081

Study Details | NCT04657081 | Pharmacokinetics, Safety, ... The Phase 1 portion of this study is a single-arm, open-label, multicenter, non-randomized interventional study to evaluate the pharmacokinetic (PK) ...

8. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4277/534135/Personalized-Oral-Maintenance-Therapy-with

Personalized Oral Maintenance Therapy with Decitabine ... Conclusions: Combination targeted oral maintenance is feasible in AML and demonstrates encouraging RFS. Myelosuppression is universal in ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124056489

Fully Oral Combination of Decitabine/Cedazuridine ... 3 deaths occurred on study treatment in patients in remission and were potentially treatment-related (1 from bleeding and 2 from infections). Conclusions: ...