Bortezomib + Sorafenib for Acute Myeloid Leukemia

Recruiting at 232 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Disqualifiers: Fanconi anemia, Concurrent malignancy, Pregnancy, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

1645 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in treating patients with newly diagnosed 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 work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib and sorafenib tosylate together with combination chemotherapy may be an effective treatment for acute myeloid leukemia.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does require that hydroxyurea and ATRA be discontinued before starting the trial treatment. If you are on these medications, you will need to stop them before participating.

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

Sorafenib, when used with chemotherapy, has shown mild side effects like skin issues, elevated liver enzymes, and high blood pressure, but it is generally considered safe. Bortezomib's safety was tested in children with AML, but specific safety details were not provided in the study. ^{1 2 3 4 5}

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

The combination of Bortezomib and Sorafenib for acute myeloid leukemia is unique because it targets specific pathways involved in cancer cell survival and proliferation, potentially offering a novel approach compared to traditional chemotherapy. Bortezomib is a proteasome inhibitor, while Sorafenib is a kinase inhibitor, and their combined use may enhance treatment effectiveness by attacking the cancer cells from different angles. ^{6 7 8 9 10}

Research Team

Richard Aplenc

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for patients newly diagnosed with acute myeloid leukemia (AML) who haven't had any previous antileukemic therapy, except hydroxyurea, ATRA, corticosteroids, or IT cytarabine at diagnosis. Eligible participants include those with >=20% bone marrow blasts or certain genetic abnormalities characteristic of AML. Pregnant or breastfeeding women and individuals with other malignancies or specific syndromes are excluded.

Inclusion Criteria

My physical condition does not limit my eligibility for this trial.

I've only had specific treatments like hydroxyurea or ATRA for my leukemia, and I've stopped them before starting this trial.

I've tried or cannot safely undergo a bone marrow test but can provide a blood sample with specific testing conditions.

Exclusion Criteria

I have been diagnosed with juvenile myelomonocytic leukemia.

I have a condition that affects my bone marrow's ability to produce blood cells.

I am not pregnant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction I

Patients receive cytarabine IT and ADE chemotherapy, with additional treatments depending on the arm

4 weeks

Multiple visits for chemotherapy administration

Induction II

Continuation of chemotherapy with adjustments based on risk and arm, including bortezomib or sorafenib

4 weeks

Multiple visits for chemotherapy administration

Intensification I

Patients receive high-dose cytarabine and etoposide, with additional treatments based on arm

4 weeks

Multiple visits for chemotherapy administration

Intensification II

Further chemotherapy with high-dose cytarabine and additional treatments based on risk and arm

4 weeks

Multiple visits for chemotherapy administration

Stem Cell Transplantation (SCT)

Eligible high-risk patients undergo allogeneic SCT with conditioning regimen and GVHD prophylaxis

Approximately 2 weeks for conditioning and transplantation

Inpatient stay for transplantation

Maintenance

Patients receive sorafenib tosylate for one year post-intensification or SCT

1 year

Regular follow-up visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Monthly for 6 months, every 2 months for 6 months, every 4 months for 1 year, every 6 months for 1 year, then yearly

Treatment Details

Interventions

• Bortezomib
• Sorafenib Tosylate

Trial Overview The study tests the effectiveness of bortezomib and sorafenib tosylate combined with chemotherapy in treating new cases of AML. It aims to see if these drugs can stop cancer growth by inhibiting enzymes needed for cell division. The trial includes a pharmacological study and assessments of quality-of-life impacts.

Participant Groups

Group I: Arm D Experimental Treatment 7 Interventions

See Detailed Description. May reassigned to Arm C.

Group II: Arm C (Cohort 3) Experimental Treatment 10 Interventions

See Detailed Description. Different dose.

Group III: Arm C (Cohort 2) Experimental Treatment 10 Interventions

See Detailed Description.

Group IV: Arm C (Cohort 1) Experimental Treatment 10 Interventions

See Detailed Description

Group V: Arm B Experimental Treatment 10 Interventions

See Detailed Description

Group VI: Arm A Experimental Treatment 9 Interventions

See Detailed Description

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

Midostaurin, a multikinase inhibitor, was found to have a manageable safety profile in a study of 103 patients with FLT3 mutation-positive acute myeloid leukemia, with no new safety events reported during treatment.

The treatment showed promising outcomes, including high rates of transplant success and low relapse rates during maintenance therapy, indicating its efficacy when combined with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program. Roboz, GJ., Strickland, SA., Litzow, MR., et al.[2021]

Bortezomib combined with chemotherapy was found to be tolerable for pediatric patients with relapsed acute myeloid leukemia (AML), with complete response rates of 29% for those with lower prior anthracycline exposure and 43% for those with higher exposure.

Despite the tolerability, the treatment regimens did not meet the predetermined efficacy thresholds for continued patient enrollment, indicating that while bortezomib may help deplete leukemia initiating cells, it may not significantly improve overall response rates in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 2 study of bortezomib combined with either idarubicin/cytarabine or cytarabine/etoposide in children with relapsed, refractory or secondary acute myeloid leukemia: a report from the Children's Oncology Group. Horton, TM., Perentesis, JP., Gamis, AS., et al.[2021]

The BCL2 inhibitor venetoclax, when combined with low-dose cytarabine or hypomethylating agents, is both safe and effective for older patients with newly diagnosed acute myeloid leukemia (AML) who cannot undergo intensive chemotherapy.

New targeted therapies, such as glasdegib and CPX-351, have shown improved survival rates in specific patient populations, highlighting the importance of genomic characterization in selecting the most effective treatment for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-agent and combination biologics in acute myeloid leukemia. Richard-Carpentier, G., DiNardo, CD.[2022]

In a phase I study involving patients with acute myeloid leukemia (AML), the combination of the tyrosine kinase inhibitor midostaurin with bortezomib and chemotherapy showed a 56.5% complete response (CR) rate and an 82.5% overall response rate, indicating significant efficacy in treating refractory or relapsed AML.

While the treatment was effective, it was also associated with expected drug-related toxicities, including peripheral neuropathy, decreased ejection fraction, and diarrhea, particularly at higher dose levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia. Walker, AR., Wang, H., Walsh, K., et al.[2022]

Midostaurin combined with intensive chemotherapy is now the standard treatment for younger patients with acute myeloid leukemia (AML) who have FLT3 mutations, highlighting the importance of genetic testing in treatment planning.

For older patients, the combination of venetoclax with hypomethylating agents or low-dose AraC has significantly improved treatment outcomes, showcasing the advancements in targeted therapies for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What to use to treat AML: the role of emerging therapies. Thol, F.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Leukoreductive response to the combination of sorafenib and chemotherapy in hyperleukocytosis of FLT3-ITD mutated pediatric AML. [2022]

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

Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program. [2021]

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

Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. [2022]

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

Survey and analysis of the efficacy and prescription pattern of sorafenib in patients with acute myeloid leukemia. [2022]

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

A Phase 2 study of bortezomib combined with either idarubicin/cytarabine or cytarabine/etoposide in children with relapsed, refractory or secondary acute myeloid leukemia: a report from the Children's Oncology Group. [2021]

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

Single-agent and combination biologics in acute myeloid leukemia. [2022]

7. 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]

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

Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Which novel agents hold the greatest promise in AML? [2020]

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

What to use to treat AML: the role of emerging therapies. [2022]