Sorafenib + Chemotherapy for Acute Myeloid Leukemia

Overseen By Uday R. Popat

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A4 inducers, Anticoagulants

Disqualifiers: Uncontrolled hypertension, Cardiac disease, others

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

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of sorafenib, a drug that may inhibit cancer cell growth, when combined with the chemotherapy drugs busulfan (Busulfex or Myleran) and fludarabine (Fludara or Oforta). It targets individuals with acute myeloid leukemia, a type of blood cancer, that has returned or is unresponsive to treatment, and who are preparing for a stem cell transplant. Participants must have a human leukocyte antigen (HLA)-matched donor available and should not have certain health conditions, such as uncontrolled high blood pressure. As a Phase 1 trial, the research focuses on understanding how the treatment works 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 does not specify if you need to stop taking your current medications, but you cannot participate if you have used strong CYP3A4 inducers (like certain anti-seizure medications and herbal supplements) within 28 days before starting the trial. If you are on therapeutic anticoagulation with certain blood thinners, you may not be eligible, but low-dose aspirin or warfarin is allowed.

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

Research has shown that sorafenib is generally well-tolerated by patients with acute myeloid leukemia, particularly those with FLT3 mutations. Studies have found it improves health outcomes without major safety concerns, though some patients might experience side effects like skin rash, diarrhea, or tiredness.

Busulfan, often used with other drugs, is usually safe for patients with acute myeloid leukemia. It is an effective chemotherapy drug but can cause side effects such as low blood cell counts and liver problems.

Fludarabine is used in various leukemia treatments and generally has manageable side effects. Common side effects include low blood cell counts and a higher risk of infections.

These drugs have been studied separately, and each has a reasonable safety record in treating leukemia. However, discussing potential risks with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of sorafenib with chemotherapy for treating acute myeloid leukemia (AML) because it offers a novel approach that targets the problem from multiple angles. Unlike standard AML treatments that typically focus on chemotherapy alone, this regimen incorporates sorafenib, which is a targeted therapy that inhibits certain proteins that help cancer cells grow. Additionally, by integrating sorafenib with busulfan and fludarabine before a stem cell transplant, this approach could potentially enhance the effectiveness of the transplant and improve patient outcomes. This treatment's ability to target cancer more precisely while supporting the transplant process is a key reason for the enthusiasm surrounding it.

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

Research shows that sorafenib, one of the treatments in this trial, may help treat acute myeloid leukemia (AML) by blocking certain processes that allow cancer cells to grow. Studies indicate that sorafenib can improve outcomes for children with a specific genetic mutation in AML. In this trial, participants will receive a combination of sorafenib, busulfan, and fludarabine before undergoing a stem cell transplant. When busulfan combines with another drug, it has been associated with better survival rates in AML patients. Treatments that include fludarabine have demonstrated that more than 50% of patients with relapsed or resistant AML achieve complete remission. Together, these treatments could potentially enhance the effectiveness of stem cell transplants in fighting AML. ^{1 4 5 6 7}

Who Is on the Research Team?

Uday R. Popat

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults aged 18-70 with recurrent or unresponsive acute myeloid leukemia, suitable for donor stem cell transplant. Must have a matched sibling or unrelated donor, normal organ function tests, and agree to contraception. Excludes those with certain heart conditions, bleeding disorders, other cancers within 3 years (except some skin/bladder cancers), major surgery within the last month, and inability to take oral medication.

Inclusion Criteria

Direct bilirubin less than or equal to 1 mg/dL

Alanine transaminase (ALT) less than or equal to 3 x upper limit of normal

Serum creatinine less than or equal to 1.5 x the upper limit of normal

Exclusion Criteria

I have no other cancers except possibly treated skin, cervical, or superficial bladder cancer, or any cancer cured over 3 years ago.

My leukemia is in its first full remission and is considered low risk.

My blood pressure is high despite taking medication.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Stem Cell Infusion

Patients receive sorafenib, busulfan, and fludarabine before stem cell transplantation

19 days

Multiple visits for drug administration

Stem Cell Infusion

Patients receive allogeneic hematopoietic stem cell transplant

1 day

1 visit (in-person)

Post-Stem Cell Infusion

Patients receive cyclophosphamide, tacrolimus, filgrastim, and sorafenib post-transplant

Up to 1 year

Regular follow-up visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 years

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Fludarabine
• Sorafenib

Trial Overview The trial is testing the effectiveness of sorafenib combined with busulfan and fludarabine in patients undergoing stem cell transplants for acute myeloid leukemia that has returned or is treatment-resistant. It aims to find the best dose of sorafenib that can block cancer growth when used alongside chemotherapy drugs.

How Is the Trial Designed?

Group I: Treatment (sorafenib, busulfan, fludarabine, HSCT) Experimental Treatment 8 Interventions

PRE-STEM CELL INFUSION: Patients receive sorafenib orally PO QD or BID on days -24 to -5, busulfan IV over 3 hours on days -20 and -13 and -6 and -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression or unacceptable toxicity. STEM CELL INFUSION: Patients receive allogeneic HSCT IV in the absence of disease progression or unacceptable toxicity. POST-STEM CELL INFUSION: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4, tacrolimus PO BID beginning day 5 for about 50 days, filgrastim SC on day 7 and sorafenib PO BID beginning between days +30 and +120 for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients with matched unrelated donor receive mycophenolate mofetil PO TID or IV over 2 hours TID beginning on day 5 for up to 90 days for longer.

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

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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]

In a study of 32 patients with acute myeloid leukemia in first complete remission, the busulfan/fludarabine (Bu/Flu) conditioning regimen resulted in significantly lower transplant-related toxicity compared to the busulfan/cyclophosphamide (Bu/Cy) regimen, with a lower incidence of severe side effects (68.8% vs. 25.0%).

Both regimens showed similar efficacy in terms of overall survival and event-free survival rates, indicating that Bu/Flu is a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia]. Liu, H., Fan, ZP., Jiang, QL., et al.[2014]

In a study of 148 acute myeloid leukemia patients undergoing hematopoietic stem cell transplantation, myeloablative conditioning with fludarabine and higher doses of busulfan (FluBu4) resulted in lower relapse rates compared to reduced intensity conditioning (FluBu2), particularly in patients with poor risk cytogenetics and those over 50 years old.

Despite the higher intensity of the FluBu4 regimen, the rates of nonrelapse mortality were similar to those of the FluBu2 group, suggesting that the myeloablative approach can improve overall survival (53% vs 34% at 5 years) without increasing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic transplantation with myeloablative FluBu4 conditioning improves survival compared to reduced intensity FluBu2 conditioning for acute myeloid leukemia in remission. Magenau, JM., Braun, T., Reddy, P., et al.[2015]

The combination of intravenous busulfan and fludarabine as a conditioning therapy for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) demonstrated a high complete remission rate of 85% in patients with active disease.

This regimen showed low regimen-related (1%) and treatment-related (3%) mortality rates, indicating improved safety, while achieving a 1-year overall survival rate of 65% and event-free survival rate of 52% for all patients, suggesting it is an effective and reduced-toxicity option for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. de Lima, M., Couriel, D., Thall, PF., et al.[2021]

The study compared outcomes of 67 patients treated with intravenous busulfan-cyclophosphamide to 148 patients treated with busulfan-fludarabine before allogeneic stem cell transplantation, finding that the busulfan-fludarabine regimen resulted in significantly improved safety and recovery from side effects.

Patients receiving the busulfan-fludarabine treatment had extremely low one-year treatment-related mortality and high overall and event-free survival rates, suggesting that this regimen may be a better option than conventional chemotherapy for those in first complete remission of acute myeloid leukemia or myelodysplastic syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-toxicity conditioning therapy with allogeneic stem cell transplantation for acute leukemia. Andersson, BS., de Lima, M., Thall, PF., et al.[2021]

Combining the alkylating agents busulfan and 4-hydroperoxycyclophosphamide, or busulfan and fludarabine, with the BCL2 inhibitor ABT199/venetoclax significantly enhances cytotoxic effects and apoptosis in acute myeloid leukemia (AML) cells, indicating a promising strategy for treatment.

The study demonstrated that these drug combinations not only increased cell death but also inhibited pro-survival pathways, suggesting they could be effective pre-transplant conditioning regimens for AML patients without compromising safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells. Valdez, BC., Murray, D., Yuan, B., et al.[2023]

Citations

1. tandfonline.com tandfonline.com/doi/full/10.1080/10428194.2025.2560086?src=exp-la

favorable outcome of a 3-day busulfan based regimen ... Optimal conditioning intensity: favorable outcome of a 3-day busulfan based regimen in younger acute myeloid leukemia patients. Hyunkyung ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3854108/

Better leukemia-free and overall survival in AML in first ... In combination with cyclophosphamide, intravenous busulfan is associated with better leukemia-free and overall survival in AML than TBI.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40571195/

High-Dose Melphalan Followed by Busulfan and ... In summary, our data suggest that sequential conditioning with melphalan followed by busulfan and fludarabine is effective and tolerable in elderly patients ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124102510

Outcomes of Melphalan Versus Busulfan with Fludarabine ... Our findings suggest that melphalan, compared to busulfan, with fludarabine RIC allo-HCT significantly decreases relapse rates; however, the overall survival ...

5. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/7073/501231/The-Efficacy-of-Modified-Melphalan-and-Busulfan

The Efficacy of Modified Melphalan and Busulfan-Based ... We aim to investigate the efficacy of MCBA conditioning regimen for auto-HSCT in low-risk and intermediate-risk AML patients who achieved CR after one course ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.e19032

Busulfan versus treosulfan conditioning for acute myeloid ... Treosulfan was superior in terms of OS, EFS and NRM, whereas both regimens were comparable in terms of relapse, aGvHD and cGvHD.

7. astctjournal.org astctjournal.org/article/S2666-6367(23)01469-0/fulltext

Myeloablative Dose of Busulfan and Fludarabine ... FB4 can safely offer durable remission of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in patients age 55 with HCT-CI <2.