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

Trial Summary

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.

What data supports the effectiveness of the drug Treosulfan for treating Acute Myeloid Leukemia?

Research shows that a combination of Treosulfan and Fludarabine is effective for patients with Acute Myeloid Leukemia, with a 2-year relapse-free survival rate of 58% and a low non-relapse mortality rate. This combination is well-tolerated and provides encouraging survival and disease control. ^{1 2 3 4 5}

Is Treosulfan safe for use in humans?

Treosulfan, when used in combination with fludarabine, has been shown to have fewer serious side effects compared to other similar treatments and is considered a reduced-toxicity regimen for patients not eligible for conventional transplants. Studies indicate that it has acceptable toxicity levels, with limited nonhematological (not related to blood) side effects, making it a viable option for high-risk patients. ^{2 3 6 7 8}

How is the drug Treosulfan for Acute Myeloid Leukemia different from other treatments?

Treosulfan, when combined with fludarabine, offers a unique conditioning regimen for stem cell transplantation in patients with acute myeloid leukemia, providing effective antileukemia activity with reduced toxicity compared to traditional myeloablative treatments. This combination is particularly beneficial for patients not eligible for standard myeloablation, as it maintains a good safety profile while achieving full donor chimerism in most cases. ^{1 2 3 7 9}

What is the purpose of this trial?

This study aim is to assess, if treosulfan pharmacokinetics are influenced by declined renal function and by race/ethnicity of patients. The study also aims to determine an appropriate safe dose of treosulfan, when patient's renal function is impaired. The participants of this study are undergoing allogenic hematopoietic stem cell transplantation for treatment of acute myeloid leukemia or myelodysplastic syndrome.

Research Team

Ute Eckenbach

Principal Investigator

SyntheractHCR

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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 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]

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]

References

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

Conditioning with treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. [2021]

2. United States 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. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

Combination of treosulfan, fludarabine and cytarabine as conditioning in patients with acute myeloid leukemia, myelodysplastic syndrome and myeloproliferative neoplasms. [2022]

4. England 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. [2022]

5. United States 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. [2018]

6. England 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). [2022]

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

Determination of Treosulfan and Fludarabine in Plasma by Turbulent Flow Liquid Chromatography-Tandem Mass Spectrometry (TFLC-MS/MS). [2023]

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

Treosulfan/fludarabine as an allogeneic hematopoietic stem cell transplant conditioning regimen for high-risk patients. [2016]

9. Spain pubmed.ncbi.nlm.nih.gov

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