Treosulfan for Acute Myeloid Leukemia

Recruiting at 2 trial locations

Overseen By Clinical Trial Information

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: medac GmbH

Disqualifiers: Severe renal, pulmonary, hepatic impairment, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 7 days

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how the drug treosulfan affects individuals with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), particularly those with impaired kidney function. Researchers aim to determine if race or ethnicity influences how the body processes the drug and to establish a safe dose for those with kidney issues. The study includes participants preparing for a stem cell transplant who have a compatible donor. Eligible participants must have either AML or MDS and require this specific conditioning treatment before their transplant. As a Phase 1 trial, the research focuses on understanding the treatment's effects in people, offering participants the chance to be among the first to receive this potentially groundbreaking therapy.

Will I have to stop taking my current medications?

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

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

Research has shown that treosulfan, when combined with fludarabine, is generally well-tolerated by patients and has a good safety record, with serious side effects being rare. This suggests that patients can undergo the treatment without major problems.

In studies comparing treosulfan to other treatments, results were encouraging. Treosulfan improved the success of stem cell transplants for patients with conditions like acute myeloid leukemia (AML). This indicates that the combination is both effective and safe in similar situations.

Although this trial is in its early stages, testing treosulfan at this level reflects existing confidence in its safety. The study aims to determine the safest dose for people with kidney issues and to identify any differences based on race or ethnicity. Existing data supports its use, but this trial seeks to ensure it is safe for everyone. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard chemotherapy options for acute myeloid leukemia (AML), which typically include drugs like cytarabine and daunorubicin, the combination of treosulfan and fludarabine offers a unique approach. Treosulfan is a newer active ingredient that has been shown to have a different mechanism of action, potentially leading to fewer side effects and increased effectiveness in preparing patients for stem cell transplantation. Researchers are excited about this treatment because it might improve outcomes for AML patients by providing a more targeted and less toxic alternative to traditional regimens.

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

Research has shown that treatments using treosulfan are effective for acute myeloid leukemia (AML). Studies have found that patients receiving treosulfan tend to live longer and experience milder side effects. One study highlighted that treosulfan is safe, even for older patients or those with other health issues. In this trial, participants will receive a combination of treosulfan and fludarabine. Fludarabine, when combined with other treatments, has successfully helped AML patients achieve remission. Overall, the combination of treosulfan and fludarabine offers promising results for treating AML, providing a good balance of effectiveness and safety. ^{6 7 8 9 10}

Who Is on the Research Team?

Ute Eckenbach

Principal Investigator

SyntheractHCR

Are You a Good Fit for This Trial?

Adults aged 18-80 with acute myeloid leukemia or myelodysplastic syndrome, eligible for stem cell transplant and treosulfan treatment. Must have a compatible donor, adequate kidney function (creatinine clearance >=30 mL/min), and agree to use effective birth control. Excludes pregnant women.

Inclusion Criteria

I have a donor who matches me closely for a transplant.

I have AML or MDS and am eligible for a specific transplant prep treatment.

Participants must have a negative pregnancy test

Exclusion Criteria

My cancer has spread to my brain or spinal cord.

I cannot have a stem cell transplant soon due to a severe illness.

I have had more than one bone marrow transplant from a donor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive treosulfan and fludarabine before undergoing allogeneic hematopoietic stem cell transplantation

7 days

Daily visits for drug administration

Engraftment Monitoring

Participants are monitored for engraftment success and adverse events

28 days

Regular visits for blood tests and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Fludarabine
• Treosulfan

Trial Overview The study is testing how kidney function and race/ethnicity affect the body's handling of Treosulfan in patients receiving it as part of their conditioning regimen before stem cell transplantation for certain blood disorders.

How Is the Trial Designed?

Group I: Treosulfan and Fludarabine Experimental Treatment 2 Interventions

Participants will receive treosulfan 10 gram per square meter (g/m\^2), intravenous (IV) infusion, given over 2 hours once daily on three consecutive days (day -4 to day -2), followed by fludarabine, 30 milligram per square meter (mg/m\^2) IV infusion once daily on 5 consecutive days (days -6 to -2), preceding allogeneic haematopoietic stem cell transplantation (alloHSCT) on Day 0.

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

Approved in European Union as Fludara for:

• Chronic lymphocytic leukemia
• Mantle-cell lymphoma
• Non-Hodgkin's lymphoma

Approved in United States as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Stem Cell Transplant Conditioning

Approved in Canada as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

medac GmbH

Lead Sponsor

Trials

40

Recruited

9,300+

Synteract, Inc.

Industry Sponsor

Trials

21

Recruited

5,900+

Published Research Related to This Trial

In a study of 476 patients with active relapsed/refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation, the FLAMSA-Bu conditioning regimen showed a significantly lower relapse incidence (38% vs 49%) and improved leukemia-free survival (42% vs 29%) compared to the FluBu2 regimen.

While FLAMSA-Bu was associated with a higher risk of acute graft-versus-host disease (36% vs 20%), it also resulted in better overall survival rates (47% vs 39%), indicating that FLAMSA-Bu may be a beneficial but more complex treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmented FLAMSA-Bu versus FluBu2 reduced-intensity conditioning in patients with active relapsed/refractory acute myeloid leukemia: an EBMT analysis. Rodríguez-Arbolí, E., Labopin, M., Eder, M., et al.[2022]

The treosulfan-based conditioning regimen (FluTreo) demonstrated significantly better overall survival (76% vs. 57%) and disease-free survival (79% vs. 38%) compared to the busulfan-based regimen (FluBuATG) in patients with acute myeloid leukemia and myelodysplastic syndrome.

FluTreo showed a favorable safety profile with no severe organ toxicities and a low relapse mortality rate (7.4% vs. 42.3% for FluBuATG), indicating it is a promising option for medically infirm patients undergoing hematopoietic cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival Advantage and Comparable Toxicity in Reduced-Toxicity Treosulfan-Based versus Reduced-Intensity Busulfan-Based Conditioning Regimen in Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation. Sakellari, I., Mallouri, D., Gavriilaki, E., et al.[2018]

In a study of 60 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS), the combination of treosulfan and fludarabine for conditioning before allogeneic hematopoietic cell transplantation was well tolerated, with a low nonrelapse mortality (NRM) of 5% at 100 days and 8% at 2 years.

The 2-year relapse-free survival (RFS) rate was 58% overall, and 88% for patients without high-risk cytogenetics, indicating that this regimen may provide effective disease control, particularly in lower-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conditioning with treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. Nemecek, ER., Guthrie, KA., Sorror, ML., et al.[2021]

Treosulfan, a drug similar to busulfan, shows comparable effectiveness in myeloablation with fewer serious side effects, making it a promising candidate for FDA approval in combination with fludarabine for use before hematopoietic stem cell transplantation.

A new rapid and accurate assay has been developed to simultaneously measure treosulfan and fludarabine levels in human plasma, which is crucial for therapeutic drug monitoring to optimize treatment efficacy and minimize toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of Treosulfan and Fludarabine in Plasma by Turbulent Flow Liquid Chromatography-Tandem Mass Spectrometry (TFLC-MS/MS). Hutcherson, SM., Schofield, RC., Carlow, DC.[2023]

The combination of treosulfan and fludarabine (Treo-Flu) shows a good safety profile for patients undergoing hematopoietic stem cell transplantation, with a low risk of severe complications like hepatic venoocclusive disease, despite common grade 4 hematologic toxicities such as leukopenia and neutropenia.

Treo-Flu demonstrates significant myelosuppressive effects, leading to full donor chimerism in most transplant recipients, making it a promising option among reduced-intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treosulfan in combination with fludarabine as part of conditioning treatment prior to allogeneic hematopoietic stem cell transplantation. Ussowicz, M.[2020]

In a study comparing two conditioning regimens for hematopoietic stem cell transplantation, FT14 (fludarabine and treosulfan) was found to have higher relapse rates and lower leukemia-free survival in patients under 55 years old compared to FB4 (fludarabine and busulfan).

For patients aged 55 and older, while FB4 showed a higher incidence of acute graft-versus-host disease (GVHD), there were no significant differences in other outcomes, suggesting that FB4 may be a better option for younger patients with acute myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative study of treosulfan plus Fludarabine (FT14) with busulfan plus Fludarabine (FB4) for acute myeloid leukemia in first or second complete remission: An analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP). Gavriilaki, E., Labopin, M., Sakellari, I., et al.[2022]

The treosulfan-fludarabine combination regimen was found to be safe and feasible for patients with hematological malignancies who are not eligible for conventional transplants, with a low transplant-related mortality rate of 9% at 100 days and 15% at 7 months.

In this study of 46 patients, the regimen resulted in high rates of engraftment and complete chimerism, with estimated overall survival at 51% and progression-free survival at 38% after a median follow-up of 20 months, indicating its potential effectiveness for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treosulfan/fludarabine as an allogeneic hematopoietic stem cell transplant conditioning regimen for high-risk patients. Baronciani, D., Rambaldi, A., Iori, AP., et al.[2016]

A novel conditioning regimen using Treosulfan, Fludarabine, and Cytarabine (Treo/Flu/AraC) was found to be effective and tolerable for patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasms (MPN), with a median follow-up of 3.2 years.

The 3-year relapse-free survival rate was 37.6%, and overall survival was 45.4%, indicating that this treatment approach can provide significant benefits even in patients with advanced disease states.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of treosulfan, fludarabine and cytarabine as conditioning in patients with acute myeloid leukemia, myelodysplastic syndrome and myeloproliferative neoplasms. O'Hagan Henderson, S., Frietsch, JJ., Hilgendorf, I., et al.[2022]

The fludarabine and treosulfan regimen was tested in 24 patients with AML and MDS, showing a 60% two-year disease-free survival rate and a low relapse rate of 15%, indicating effective antileukemia activity.

The treatment demonstrated relatively limited extramedullary toxicity and manageable rates of graft-versus-host disease (GVHD), suggesting it is a safer alternative for patients not eligible for standard myeloablation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and treosulfan: a novel modified myeloablative regimen for allogeneic hematopoietic stem-cell transplantation with effective antileukemia activity in patients with acute myeloid leukemia and myelodysplastic syndromes. Shimoni, A., Hardan, I., Shem-Tov, N., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39635952/

Comparing Outcomes Between CPX-351 and Fludarabine ... The aim of this study was to further disclose the mechanisms of higher efficacy of CPX-351 in s-AML, with a focus on MRD.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/9009438/

High efficacy of fludarabine-containing therapy (FLAG ... Overall, 30 patients (59%) achieved CR, 6 (11%) PR and 10 (20%) were refractory; 5 (10%) experienced early death (cerebral hemorrhage or infection). The length ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05917405

NCT05917405 | Study Comparing the Efficacy of 2 RIC ... Retrospective studies have shown that clofarabine can achieve impressive results compared to the use of fludarabine in acute myeloid leukemia (AML) as part of ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2213048921000029?via%3Dihub

Fludarabine-based salvage therapy for refractory/relapsed ... This retrospective study found the 30-day mortality rate for Fludarabine-based regimens for adult acute leukemias to be 8%, complete remission in 51% of the ...

5. haematologica.org haematologica.org/article/view/haematol.2023.282912

Fludarabine, cytarabine, and idarubicin with or without ... Thirty-seven and 81 sequentially treated patients received FLAVIDA and FLA-IDA, respectively, and had safety and efficacy outcomes reported.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2974965/

Conditioning with Treosulfan and Fludarabine Followed by ... The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% ...

7. ashpublications.org ashpublications.org/bloodadvances/article/9/11/2691/535645/Long-term-outcomes-and-quality-of-life-with

Long-term outcomes and quality of life with treosulfan-based ... New regimens, including treosulfan (Treo), a busulfan analog, have demonstrated effectiveness while having a favorable acute toxicity profile.

8. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121037514

Comparative Study of Treosulfan Plus Fludarabine (FT14 ... This led to lower 2-year leukemia-free survival (LFS 52.2% versus 62.4%, p=0.002, 1C), overall survival (OS 63.2% versus 72.9%, p=0.038, 1D), and GVHD free, ...

9. nature.com nature.com/articles/s41409-024-02241-2

A clinical trial to registry data comparison Treosulfan compared with reduced-intensity busulfan improves allogeneic hematopoietic cell transplantation outcomes of older acute myeloid ...

10. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/ajh.26620

American Journal of Hematology | Blood Research Journal EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2–66.1) vs.