Treosulfan-Based vs Clofarabine-Based Conditioning for Leukemia

Overseen By Phuong Vo

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Research Center

Must not be taking: Amphotericin B, Active triazoles

Disqualifiers: Circulating blasts, Organ dysfunction, CNS leukemia, 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

Compensation: Varies

Number of Visits: 28

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores which of two chemotherapy combinations works better for individuals preparing for a stem cell transplant to treat myelodysplastic syndromes (a group of bone marrow disorders) or acute myeloid leukemia (a type of blood cancer). Researchers compare treosulfan-based and clofarabine-based regimens to determine which is more effective at killing cancer cells and making room for healthy donor cells. The trial seeks participants diagnosed with these conditions, who have less than 5% cancerous cells in their bone marrow, and are set to receive a donor stem cell transplant.

As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in cancer treatment.

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 to get specific guidance based on your situation.

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

Research has shown that both treosulfan and clofarabine have been studied for safety in treating blood cancers.

For treosulfan, studies indicate it is generally well-tolerated, especially in patients with myelodysplastic syndromes (a group of disorders where blood cells are not formed properly) and acute myeloid leukemia (a type of cancer affecting blood and bone marrow). Treatments using treosulfan have improved overall survival rates and shown fewer serious side effects, such as acute graft-versus-host disease (a condition where the donor's immune cells attack the patient's body).

Clofarabine, however, has been linked to some side effects. One study found that 83.5% of patients experienced side effects, mostly affecting blood cells. Despite these side effects, clofarabine has effectively lowered the risk of the disease returning.

This trial is in phase 2, indicating it is still early in testing, but some previous data on safety exists. Both drugs have undergone prior testing, providing doctors with some confidence in their safety. However, effects can vary, so discussing any concerns with a healthcare provider before joining a trial is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer innovative conditioning regimens for leukemia patients undergoing hematopoietic cell transplantation (HCT). Unlike the standard of care, which often involves busulfan-based conditioning, these treatments explore alternative agents like treosulfan and clofarabine. Treosulfan is noteworthy for its potential to reduce toxicity compared to traditional options, potentially leading to fewer side effects. Clofarabine, on the other hand, is valued for its unique mechanism of action that targets leukemia cells more effectively. These novel approaches aim to improve patient outcomes and expand the therapeutic options available for leukemia.

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

This trial will compare two treatment regimens for leukemia. Previous studies have shown promising results with treatments using clofarabine, which participants in Arm B of this trial may receive. For example, patients with high-risk acute myeloid leukemia (AML) had a survival rate of 83.3% over two years. Similarly, treatments using treosulfan, which participants in Arm A may receive, have proven effective for older AML patients, leading to better long-term survival and a good safety record. Treosulfan has successfully helped donor cells grow in the patient's bone marrow with low side effects. Both treatments have demonstrated strong potential in improving survival and reducing the return of leukemia. ^{6 7 8 9 10}

Who Is on the Research Team?

Phuong Vo

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

Adults aged 18-70 with myelodysplastic syndromes or acute myeloid leukemia, having less than 5% marrow blasts and a Karnofsky performance score of at least 60%. Participants must have compatible donors for stem cell transplant. Exclusions include severe non-cancer illnesses, active infections, HIV/hepatitis positivity, certain heart/lung/kidney diseases, pregnant or breastfeeding women, and those unwilling to use contraception.

Inclusion Criteria

My donor matches me closely in genetic markers for transplant.

Patients with previous autologous or allogeneic HCT may enroll

Able to give informed consent

Exclusion Criteria

My fungal infection has worsened despite treatment.

Known hypersensitivity to specific drugs

I am unable to understand and agree to the study's details on my own.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Patients receive chemotherapy and total-body irradiation followed by hematopoietic cell transplantation

7 days

Daily visits for chemotherapy administration and transplantation

Follow-up

Participants are monitored for safety and effectiveness after transplantation

5 years

Visits at days 28, 56, 84, 180, years 1 and 1.5, then annually

What Are the Treatments Tested in This Trial?

Interventions

• Clofarabine
• Hematopoietic Cell Transplantation
• Total-Body Irradiation
• Treosulfan

Trial Overview

The trial compares two pre-transplant chemotherapy regimens: treosulfan-based vs clofarabine-based conditioning. These treatments aim to eliminate cancer cells and make space in the bone marrow for donor stem cells which can regenerate healthy blood cells and help destroy any remaining cancer.

How Is the Trial Designed?

Group I: Arm B (clofarabine, TBI, HCT) Experimental Treatment 9 Interventions

Patients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.

Group II: Arm A (treosulfan, fludarabine, TBI, HCT) Experimental Treatment 10 Interventions

Patients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.

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

Approved in United States as Clolar for:

• Acute lymphoblastic leukemia (ALL) in pediatric patients

Approved in European Union as Evoltra for:

• Acute lymphoblastic leukemia (ALL) in pediatric patients

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Research Center

Lead Sponsor

Trials

444

Recruited

148,000+

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

Medexus Pharma, Inc.

Industry Sponsor

Trials

4

Recruited

190+

Published Research Related to This Trial

In a multicenter trial involving 56 patients with hematologic malignancies, treosulfan was safely administered as a conditioning agent for stem-cell transplantation, with no cases of engraftment failure and low nonrelapse mortality (20%) over 2 years.

The study found that treosulfan at a dose of 14 g/m² showed promising results, combining low toxicity with a lower incidence of relapse, making it a candidate for further research in conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning. Casper, J., Wolff, D., Knauf, W., et al.[2019]

In a phase I clinical trial involving 15 patients with recurrent/refractory leukemia, clofarabine was well tolerated at a dose of 50 mg/m/d for 5 days, showing minimal treatment-related mortality in this high-risk group.

The treatment led to quick hematopoietic recovery, with median times to neutrophil and platelet engraftment of 11 and 16 days, respectively, although 73.3% of patients ultimately died, primarily due to disease relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical Donor Transplantation Using a Novel Clofarabine-containing Conditioning Regimen for Very High-risk Hematologic Malignant Neoplasms. Sharma, A., Kang, G., Sunkara, A., et al.[2019]

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]

Treosulfan, used in combination with fludarabine, shows a favorable toxicity profile and effective engraftment in allogeneic hematopoietic stem cell transplantation (SCT), with non-relapse mortality rates between 9-28%.

The regimen demonstrates low relapse rates (5-30%) and promising survival outcomes (40-80%), particularly in patients with myelodysplastic syndrome (36-70% survival) and leukemia in remission (60-70% survival), indicating its potential as a safer alternative to standard conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. Danylesko, I., Shimoni, A., Nagler, A.[2013]

In a phase II trial involving 65 children with various hematological malignancies, treosulfan-based conditioning demonstrated a high rate of complete donor chimerism (98.4%) and a low non-relapse mortality rate (3.1%) at 36 months, indicating its safety and efficacy.

The overall survival rate was 83.0% at 36 months, with manageable rates of acute and chronic graft-versus-host disease, supporting the recommendation of treosulfan/fludarabine/thiotepa for myeloablative conditioning in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treosulfan-fludarabine-thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies. Kalwak, K., Mielcarek, M., Patrick, K., et al.[2021]

In a Phase II study involving 44 patients with hematologic malignancies, the conditioning regimen of clofarabine and treosulfan before allogeneic hematopoietic stem cell transplantation (allo-HSCT) demonstrated feasibility, achieving a 1-year overall survival rate of 78% in patients with low-intermediate Disease Risk Index scores.

The study reported a 100-day nonrelapse mortality rate of 18%, primarily due to bacterial infections, highlighting the need for improved strategies to manage infection risks and reduce relapse rates, especially in patients with high-very high Disease Risk Index scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine and Treosulfan as Conditioning for Matched Related and Unrelated Hematopoietic Stem Cell Transplantation: Results from the Clo3o Phase II Trial. Peccatori, J., Mastaglio, S., Giglio, F., et al.[2021]

A new reduced-toxicity conditioning regimen using treosulfan and fludarabine was tested in 75 patients with acute myeloid leukemia (AML), showing promising safety and efficacy with a 2-year overall survival rate of 61%.

The regimen resulted in primary engraftment of neutrophils after a median of 20 days, with manageable adverse events, including a 21% incidence of acute graft-versus-host disease (GVHD) and a 34% relapse rate after 2 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic SCT in patients with AML following treosulfan/fludarabine conditioning. Casper, J., Holowiecki, J., Trenschel, R., et al.[2013]

Clofarabine is a nucleoside analog effective for treating pediatric relapsed or refractory acute lymphoblastic leukemia, with pharmacokinetics showing rapid absorption and a bioavailability of 57.5%.

The pharmacokinetics of clofarabine differ significantly between adults and children, with adults experiencing higher drug exposure at similar doses, indicating that dose adjustments may be necessary for patients with renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with cancer. Bonate, PL., Cunningham, CC., Gaynon, P., et al.[2018]

Clofarabine-based reduced intensity conditioning (RIC) for allogeneic stem cell transplantation showed promising 2-year survival rates for patients with acute myeloid leukemia (AML), with an overall survival rate of 64.5% and disease-free survival rate of 57.2% among 84 patients studied over a median follow-up of 31 months.

For patients with AML in complete remission, the 2-year overall survival rate was even higher at 74.2%, indicating that the CloB2A1/A2 RIC regimen could be an effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine/busulfan-based reduced intensity conditioning regimens provides very good survivals in acute myeloid leukemia patients in complete remission at transplant: a retrospective study on behalf of the SFGM-TC. Le Bourgeois, A., Labopin, M., Leclerc, M., et al.[2023]

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