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

74 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment Sorafenib + Chemotherapy for Acute Myeloid Leukemia?

Research shows that using busulfan and fludarabine together as part of a treatment plan for acute myeloid leukemia can improve survival rates and reduce the chance of the disease coming back, while keeping side effects manageable. ^{1 2 3 4 5}

Is the combination of Sorafenib, Busulfan, and Fludarabine safe for treating acute myeloid leukemia?

The combination of Busulfan and Fludarabine has been studied for safety in treating acute myeloid leukemia, showing reduced toxicity and good tolerability in patients. Common side effects include temporary liver issues, mouth sores, and nausea, but serious treatment-related deaths were low. Sorafenib's safety in this combination isn't detailed here, but Busulfan and Fludarabine are generally considered safe in this context. ^{1 2 4 5 6}

What makes the drug Sorafenib + Chemotherapy unique for treating acute myeloid leukemia?

The combination of Sorafenib with chemotherapy, including Busulfan and Fludarabine, is unique because Sorafenib is a multikinase inhibitor that has shown effectiveness in improving outcomes for patients with a specific genetic mutation (FLT3-ITD) in acute myeloid leukemia, potentially enhancing the effects of chemotherapy. ^{1 3 7 8 9}

What is the purpose of this trial?

This trial tests the best dose of sorafenib combined with busulfan and fludarabine for patients with hard-to-treat acute myeloid leukemia. Sorafenib blocks enzymes needed for cancer growth, while busulfan and fludarabine kill or stop the spread of cancer cells. Sorafenib has shown potential in early studies for treating acute myeloid leukemia.

Research Team

Uday R. Popat

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

References

1. China 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]. [2014]

2. Germany 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. [2015]

3. 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]

4. United States 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. [2021]

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

Reduced-toxicity conditioning therapy with allogeneic stem cell transplantation for acute leukemia. [2021]

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

Clofarabine and busulfan conditioning facilitates engraftment and provides significant antitumor activity in nonremission hematologic malignancies. [2021]

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

Sorafenib plus intensive chemotherapy improves survival in patients with newly diagnosed, FLT3-internal tandem duplication mutation-positive acute myeloid leukemia. [2020]

8. China pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Sorafenib Combined with Low Dose Cytarabine for Treating Patients with FLT3+ Relapsed and Refractory Acute Myeloid Leukemia]. [2018]

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

ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells. [2023]