Genomic Assessment for Mutation Clearance in Acute Myeloid Leukemia

Recruiting at 2 trial locations

Overseen By Meagan Jacoby, M.D., Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Disqualifiers: APL, Therapy-related AML, Secondary AML, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12-16 weeks

107 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators will prospectively determine whether the relapse-free and overall survival in patients who have cleared their leukemia-associated mutations treated with standard consolidation chemotherapy is superior to what is expected based on historical controls. The investigators will also prospectively determine the relapse-free and overall survival of patients who have not cleared their mutations. Because the relapse rate of patients with persistent mutations is expected to be high, treatment with either standard of care consolidation therapy alone or alloSCT will be permitted, at the discretion of the treating physician.

Do I have to stop taking my current medications for this trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with your doctor or the trial coordinators.

What data supports the effectiveness of the treatment Allogeneic stem cell transplant, Bone marrow aspiration, Cytarabine, Cytosar-U, Depocyt, Tarabine PFS, Punch skin biopsy for Acute Myeloid Leukemia?

High-dose cytarabine, a component of the treatment, is an established therapy for relapsed or refractory acute myeloid leukemia, with a complete remission rate of 58% in a study of 172 patients. Additionally, genetic profiling and next-generation sequencing are increasingly used to tailor treatments, potentially improving outcomes for patients with specific genetic mutations. ^{1 2 3 4 5}

Is cytarabine generally safe for humans?

Cytarabine, a key drug for treating acute myeloid leukemia, has been studied for its safety and effectiveness. Some genetic variations can affect how patients respond to the drug, leading to different levels of side effects like toxicities in the kidneys, liver, lungs, and skin. Understanding these genetic factors can help predict who might experience more side effects. ^{6 7 8 9 10}

What makes the drug Cytarabine unique for treating acute myeloid leukemia?

Cytarabine is unique because it is a chemotherapy drug that specifically targets and disrupts the DNA of cancer cells, which can help in reducing the number of leukemia cells. Unlike some other treatments, it is often used in combination with genomic assessments to monitor mutation clearance, making it a part of a more personalized treatment approach. ^{1 11 12 13 14}

Research Team

Meagan Jacoby, M.D., Ph.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for adults aged 18-60 with previously untreated, non-M3 Acute Myeloid Leukemia (AML) of intermediate risk or normal cytogenetics with specific mutations. Participants must be in remission post-induction therapy and agree to use contraception. Excluded are those with AML due to prior chemo/radiation, other hematological malignancies, significant medical issues affecting compliance, known HIV/HBV/HCV infections, or pregnancy.

Inclusion Criteria

I am considered a good candidate for intensive chemotherapy.

My AML is untreated, not M3 type, and is intermediate-risk or has specific genetic features.

My blood cancer is in remission but my blood counts haven't fully recovered.

Exclusion Criteria

History of allergic reaction to compounds of similar chemical or biologic composition to cytarabine

Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 3 days of signing consent

Has medical or psychosocial conditions that would prevent study compliance

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard consolidation chemotherapy or alloSCT based on mutation clearance status

12-16 weeks

Multiple visits for chemotherapy cycles

Follow-up

Participants are monitored for relapse-free and overall survival

Up to 5 years

Treatment Details

Interventions

• Allogeneic stem cell transplant
• Bone marrow aspiration
• Cytarabine
• Punch skin biopsy

Trial Overview The study tests if clearing leukemia-associated mutations using standard chemotherapy improves survival compared to historical data. It also assesses outcomes for patients whose mutations persist and may receive either chemotherapy or a stem cell transplant based on the physician's discretion.

Participant Groups

Group I: Cohort B: Investigator's choice (HiDAC, AlloSCT) Experimental Treatment 5 Interventions

* At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq * Patients who have persistent leukemia-associated mutations, defined as a LAM VAF ≥2.5% will be assigned to the investigator's choice arm. * Patients assigned to this arm may received either HiDAC or AlloSCT. * HiDAC = Standard regimen of cytarabine 1.5 g/m\^2 or 3 g/m\^2 over 2-3 hours twice a day on Days 1, 3, \& 5 of each 28 day cycle for 3-4 cycles. Can be replaced by Onureg with permission from PI. * The source of stem cell product, donor selection, conditioning regimen, graft-versus-host-prophylaxis, and supportive care will be at the discretion of the treatment physician * For patients with the FLT3-ITD or a FLT3-TKD mutation, therapy with the FDA-approved FLT3 inhibitor midostaurin is permitted at the discretion of the treating physician.

Group II: Cohort A: HiDAC Experimental Treatment 4 Interventions

* At the time of diagnostic bone marrow biopsy, samples will be clinically sequenced via ClinSeq * Patients who have clearance of their leukemia-associated mutations, defined as a LAM VAF \<2.5% will be assigned to the high-dose cytarabine consolidation (HiDAC) arm. * HiDAC = Standard regimen of cytarabine 1.5 g/m\^2 or 3 g/m\^2 over 2-3 hours twice a day on Days 1, 3, \& 5 of each 28 day cycle for 3-4 cycles. Can be replaced by Onureg with permission from PI. * For patients with the FLT3-ITD or a FLT3-TKD mutation, therapy with the FDA-approved FLT3 inhibitor midostaurin is permitted at the discretion of the treating physician.

Cytarabine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia
• Meningeal leukemia

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

American Society of Hematology

Collaborator

Trials

14

Recruited

20,800+

Findings from Research

A new diagnostic approach combining karyotyping and mutational screening using next-generation sequencing allows for rapid and accurate risk stratification in acute myeloid leukemia, significantly speeding up treatment decisions.

In a validation study with 22 patient samples, this method correctly identified 97% of copy number variations and accurately classified all tested karyotypes, demonstrating its potential to enhance subtype-specific therapies for leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive genetic diagnosis of acute myeloid leukemia by next-generation sequencing. Mack, EKM., Marquardt, A., Langer, D., et al.[2020]

Acute myeloid leukemia (AML) is becoming more common, especially in older populations, and traditional chemotherapy treatments are often ineffective for most patients, highlighting the need for more personalized approaches.

Recent advancements in molecular technologies have identified new genetic mutations and changes in AML, which can help tailor more effective, individualized treatment strategies that combine targeted therapies with conventional methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute Myeloid Leukemia: Biologic, Prognostic, and Therapeutic Insights. Khaled, S., Al Malki, M., Marcucci, G.[2021]

Next generation sequencing (NGS) has significantly advanced the understanding of acute myeloid leukemia (AML) by identifying genetic mutations and precursor lesions, which are now influencing treatment decisions and patient stratification.

The integration of genetic profiling into clinical practice is expected to enhance diagnosis, risk assessment, and the development of personalized treatment plans, including the use of recently approved drugs targeting specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next Generation Sequencing in AML-On the Way to Becoming a New Standard for Treatment Initiation and/or Modulation? Leisch, M., Jansko, B., Zaborsky, N., et al.[2020]

The MiSeq next-generation sequencing platform effectively screened 54 cancer-related genes in 63 samples from patients with acute myeloid leukemia, showing complete concordance with results from other established testing methods.

MiSeq demonstrated high accuracy in detecting mutations at low frequencies (as low as 1.5%) and offers advantages such as a quick 4-day turnaround time and the ability to assess both routine and emerging genetic markers, making it a promising tool for clinical applications in monitoring and treating acute myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring. Luthra, R., Patel, KP., Reddy, NG., et al.[2021]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Comprehensive genetic diagnosis of acute myeloid leukemia by next-generation sequencing. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Acute Myeloid Leukemia: Biologic, Prognostic, and Therapeutic Insights. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Next Generation Sequencing in AML-On the Way to Becoming a New Standard for Treatment Initiation and/or Modulation? [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Reassessing the role of high dose cytarabine and mitoxantrone in relapsed/refractory acute myeloid leukemia. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

[Acute myeloid leukemia]. [2021]

6. Japan pubmed.ncbi.nlm.nih.gov

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Combined interaction of multi-locus genetic polymorphisms in cytarabine arabinoside metabolic pathway on clinical outcomes in adult acute myeloid leukaemia (AML) patients. [2013]

8. United States pubmed.ncbi.nlm.nih.gov

Impact of novel polymorphisms related to cytotoxicity of cytarabine in the induction treatment of acute myeloid leukemia. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Genetic factors influencing cytarabine therapy. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Cytarabine dose of 36 g/m² compared with 12 g/m² within first consolidation in acute myeloid leukemia: results of patients enrolled onto the prospective randomized AML96 study. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Can chemotherapy cause cancer relapse? [2012]

12. United States pubmed.ncbi.nlm.nih.gov

Sequential Targeted Treatment for a Geriatric Patient with Acute Myeloid Leukemia with Concurrent FLT3-TKD and IDH1 Mutations. [2021]

13. Italy pubmed.ncbi.nlm.nih.gov

Next-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring. [2021]

14. United States pubmed.ncbi.nlm.nih.gov

Subclonal patterns in follow-up of acute myeloid leukemia combining whole exome sequencing and ultrasensitive IBSAFE digital droplet analysis. [2022]