Bortezomib + Sorafenib + Decitabine for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents, HAART

Disqualifiers: Active CNS disease, Serious cardiac conditions, Advanced solid tumors, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and the best dose of bortezomib and sorafenib tosylate when given together with decitabine in treating patients with acute myeloid leukemia. Bortezomib and sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving bortezomib and sorafenib tosylate together with decitabine may work better in treating acute myeloid leukemia.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot participate if you are taking medications that strongly interact with the trial drugs. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Bortezomib, Sorafenib, and Decitabine for treating Acute Myeloid Leukemia?

Research shows that Decitabine, one of the drugs in the combination, has been effective in improving survival and response rates in patients with Acute Myeloid Leukemia (AML), especially those who are not eligible for standard chemotherapy. Although adding Bortezomib to Decitabine did not improve outcomes in one study, Decitabine alone has shown promise as a treatment option for AML. ^{1 2 3 4 5}

Is the combination of Bortezomib and Decitabine safe for treating acute myeloid leukemia?

In a study with older patients with acute myeloid leukemia, adding Bortezomib to Decitabine did not lead to unexpected toxicities, and the most common side effect was febrile neutropenia (fever with low white blood cell count). Decitabine alone has been generally well tolerated in patients with acute myeloid leukemia. ^{1 3 4 5 6}

What makes the drug combination of Bortezomib, Sorafenib, and Decitabine unique for treating acute myeloid leukemia?

This drug combination is unique because it combines Bortezomib, a proteasome inhibitor, with Sorafenib, a kinase inhibitor, and Decitabine, a hypomethylating agent, potentially offering a multi-targeted approach to treat acute myeloid leukemia, which is different from traditional chemotherapy regimens that typically focus on a single mechanism of action. ^{1 3 7 8 9}

Research Team

Alison R. Walker

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with acute myeloid leukemia (AML) who are either aged 60+ and can't have standard treatment, or those with high-risk AML types. It's also open to adults 18+ with relapsed/refractory AML. Participants need a performance status of <=2, acceptable liver/kidney function, no severe heart disease or active central nervous system involvement, and must agree to use contraception.

Inclusion Criteria

I am 60 or older with AML and cannot or choose not to undergo standard treatment, or I have high-risk AML.

I am 18 or older with AML that has come back or didn't respond to treatment, and I haven't been treated with a 10-day decitabine schedule.

My kidney function is normal, with creatinine levels below 2.0 mg/dL or clearance above 60 mL/min.

Exclusion Criteria

I haven't had chemotherapy or radiotherapy in the last 2 weeks.

I do not have any severe illnesses or heart problems that my doctor says are uncontrolled.

I have active brain disease or my only cancer is in my granulocytes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive bortezomib, sorafenib tosylate, and decitabine in a dose-escalation study. Treatment repeats every 28 days for up to 4 courses.

16 weeks

Multiple visits for drug administration and monitoring

Maintenance Therapy

Patients achieving complete response or incomplete complete response receive maintenance therapy with decitabine.

28 days per course, ongoing in absence of disease progression

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

At least 30 days

Treatment Details

Interventions

• Bortezomib
• Decitabine
• Sorafenib Tosylate

Trial Overview The trial tests the combination of bortezomib and sorafenib tosylate with decitabine in treating AML. Bortezomib/sorafenib may halt cancer cell growth by blocking enzymes they need, while decitabine could kill or stop cancer cells from dividing/spreading. The study aims to find the best dose and assess side effects.

Participant Groups

Group I: Treatment (bortezomib, sorafenib tosylate, decitabine) Experimental Treatment 5 Interventions

STEP A: Patients receive bortezomib SC on days 1 and 4, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 5-14. STEP B: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 9-18 or 12-21. STEP C: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 5-14. Treatment repeats every 28 days for up to 4 courses in the absence of unacceptable toxicity. Patients achieving CR or CRi receive maintenance therapy comprising decitabine IV on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in United States as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Canada as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Japan as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Decitabine maintenance therapy significantly improves overall survival (34.7 months) and relapse-free survival (30.1 months) in patients with medium- and low-risk acute myeloid leukemia compared to a control group, indicating its efficacy as a treatment option.

The therapy enhances the immune response by increasing CD3+ T cells, CD8+ T cells, and NK cells while reducing regulatory T cells, suggesting a mechanism of action that boosts the body's ability to fight cancer, with a low incidence of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effectiveness and Mechanism of Decitabine Maintenance Therapy in Patients with Medium and Low-risk Acute Myeloid Leukemia]. Dong, Y., Wang, J., Tao, QS., et al.[2022]

A new low-intensity treatment regimen combining cladribine and low-dose cytarabine alternating with decitabine showed promising results in elderly or unfit patients with acute myeloid leukaemia (AML), with a median disease-free survival of 10.8 months and a median overall survival of 13.8 months based on a study of 118 patients.

The regimen was well tolerated, with only 1% of patients experiencing early death within the first 4 weeks, indicating a favorable safety profile compared to traditional therapies, which often have higher toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial. Kadia, TM., Cortes, J., Ravandi, F., et al.[2019]

Decitabine is an effective hypomethylating agent for treating acute myeloid leukemia (AML), significantly improving overall survival and response rates compared to standard care, based on results from the phase 3 DACO-016 trial with adult patients who are not eligible for standard chemotherapy.

The treatment is generally well tolerated and remains effective even in patients with adverse-risk karyotypes or TP53 mutations, making it a valuable option for those unfit for more intensive therapies, with potential for future combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. Santini, V., Lübbert, M., Wierzbowska, A., et al.[2022]

The D-CAG regimen, which combines decitabine with a modified chemotherapy approach, achieved a complete remission (CR) rate of 69.4% in 59 elderly patients (≥70 years) with newly diagnosed acute myeloid leukemia (AML), indicating its efficacy in this age group.

The treatment was found to be safe, with major adverse reactions including grade 3-4 myelosuppression and infections, but it significantly improved overall survival (OS) and event-free survival (EFS) for patients who achieved CR, with median OS of 19.8 months compared to 6.4 months for those who did not respond.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia]. Cao, L., Jiang, ZQ., Liu, WJ., et al.[2023]

In a study of 8 geriatric patients with acute myeloid leukemia, treatment with decitabine, with or without low-dose cytarabine, resulted in a 50% overall response rate, with 25% achieving complete remission and 25% achieving partial remission.

The treatment showed a median overall survival time of 9.5 months, with some patients surviving over a year, although it was associated with significant side effects, including severe myelosuppression in 87.5% of patients and pneumonia in 50%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. Zhou, HW., Zhou, MH., Wang, ZH., et al.[2019]

Current frontline treatments for acute myeloid leukemia (AML) using ara-C and topoisomerase II agents achieve complete response rates of 70%, but long-term survival remains low at 25%.

Newer agents like nucleoside analogs and hypomethylating agents show promise, with combination therapies yielding higher complete response rates, particularly when used alongside traditional treatments like ara-C.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New chemotherapeutic agents in acute myeloid leukemia. Kantarjian, HM., Estey, EH., Keating, MA.[2013]

The combination of CLAG (cladribine, cytarabine, granulocyte colony-stimulating factor) and imatinib mesylate (IM) showed a 37% overall response rate in a phase II study involving 38 patients with relapsed or refractory acute myeloid leukemia (AML), indicating potential efficacy in this challenging patient population.

The treatment was well tolerated, with a median overall survival of 11.1 months and a median progression-free survival of 4.9 months, suggesting that this regimen could be a viable option for patients with poor-risk AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of CLAG Regimen Combined With Imatinib Mesylate for Relapsed or Refractory Acute Myeloid Leukemia. Mirza, AS., Lancet, JE., Sweet, K., et al.[2018]

References

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

Randomized trial of 10 days of decitabine ± bortezomib in untreated older patients with AML: CALGB 11002 (Alliance). [2020]

2. China pubmed.ncbi.nlm.nih.gov

[Effectiveness and Mechanism of Decitabine Maintenance Therapy in Patients with Medium and Low-risk Acute Myeloid Leukemia]. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial. [2019]

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

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. [2022]

5. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia]. [2023]

6. China pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. [2019]

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

Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients. [2021]

8. England pubmed.ncbi.nlm.nih.gov

New chemotherapeutic agents in acute myeloid leukemia. [2013]

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

A Phase II Study of CLAG Regimen Combined With Imatinib Mesylate for Relapsed or Refractory Acute Myeloid Leukemia. [2018]