Bortezomib + Sorafenib for Acute Myeloid Leukemia

Not currently recruiting at 243 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well the drugs bortezomib (Velcade) and sorafenib work with chemotherapy to stop cancer cell growth in people with newly diagnosed acute myeloid leukemia (AML), a type of blood cancer. The goal is to determine if this combination effectively blocks the enzymes cancer cells need to grow. Individuals recently diagnosed with AML who haven't received other cancer treatments, except for certain specific drugs, may qualify for this trial. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to a promising new treatment for AML.

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

Research shows that both bortezomib and sorafenib tosylate have been tested in people before. The FDA has approved bortezomib for treating multiple myeloma and mantle cell lymphoma, indicating its safety and side effects have been studied. Common side effects include tiredness, nausea, and low blood counts.

Sorafenib is approved for certain liver, kidney, and thyroid cancers. Most people tolerate it well, but some may experience side effects like skin issues, diarrhea, and high blood pressure.

When used together, these drugs might work differently. Previous studies of the combination have not revealed any unexpected safety problems, but patients might still experience side effects from either drug. Since this is a phase 3 trial, the combination has been tested before, providing some understanding of its safety in people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Bortezomib and Sorafenib for treating Acute Myeloid Leukemia (AML) because it offers a novel approach compared to current options like chemotherapy and targeted therapy with FLT3 inhibitors. Bortezomib is a proteasome inhibitor that disrupts the protein disposal system in cancer cells, causing them to die. Sorafenib is a kinase inhibitor that blocks enzymes promoting cancer cell growth. By targeting both the protein disposal and growth pathways, this combination could potentially enhance treatment effectiveness and overcome resistance seen in standard therapies.

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

This trial will evaluate the effectiveness of Bortezomib and Sorafenib Tosylate in different treatment arms for patients with acute myeloid leukemia (AML). Studies have shown that adding Bortezomib to chemotherapy can lead to a high rate of complete remission, with up to 73% of patients achieving complete remission in some cases. However, other studies found that Bortezomib did not significantly improve overall survival when added to standard treatments. Research on Sorafenib Tosylate indicates that, when combined with intensive chemotherapy, it increased the overall response rate to 98%, compared to 83% with chemotherapy alone. These findings suggest that while both Bortezomib and Sorafenib Tosylate show promise, their effectiveness can vary depending on the specific treatment situation. Participants in this trial will be assigned to different arms to assess the impact of these treatments. ^{6 7 8 9 10}

Who Is on the Research Team?

Richard Aplenc

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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, 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10472935/

Effectiveness of chemotherapy using bortezomib combined ... The CR rates were 73% and 61% (P=0.0108), and the 3-year event-free survival rates were 35.4% and 23.1% (P=0.0023), respectively.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8842590/

Efficacy of Adding Bortezomib to Salvage Chemotherapy in ... Mean survival was 8.2 and 7.1 in Bortezomib and the other group, respectively (P = 0.275). Based on the obtained results, it may be concluded that adding ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT00666588

Bortezomib and Combination Chemotherapy in Treating ... This phase II trial is studying the side effects and best dose of bortezomib and to see how well it works when given together with combination chemotherapy ...

4. haematologica.org haematologica.org/article/view/9939

Bortezomib with standard chemotherapy for children ... The AAML1031 trial data demonstrate that the addition of bortezomib to standard chemotherapy does not improve EFS or OS.

5. ashpublications.org ashpublications.org/blood/article/106/11/2782/121775/Addition-of-Bortezomib-Velcade-to-AML-Induction

Addition of Bortezomib (Velcade) to AML Induction ... Addition of Bortezomib (Velcade) to AML Induction Chemotherapy Is Well Tolerated and Results in a High Complete Remission Rate. Available.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01371981

NCT01371981 | Bortezomib and Sorafenib Tosylate in ... This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in treating patients with newly diagnosed acute myeloid leukemia.

7. stanfordhealthcare.org stanfordhealthcare.org/trials/b/NCT01371981.html

Bortezomib and Sorafenib Tosylate in Treating Patients ... This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in treating patients with newly diagnosed acute myeloid leukemia.

8. med.stanford.edu med.stanford.edu/mosslab/research/clinicaltrial?start=3360

Clinical Trial | Moss Lab | Stanford Medicine This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in treating patients with newly diagnosed acute myeloid leukemia.

9. ucla.clinicaltrials.researcherprofiles.org ucla.clinicaltrials.researcherprofiles.org/acute-myeloid-leukemia

UCLA Acute Myeloid Leukemia Clinical Trials — Los Angeles This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in treating patients with newly diagnosed acute myeloid ...

10. withpower.com withpower.com/trial/phase-3-leukemia-myeloid-5-2011-d3264

Bortezomib + Sorafenib for Acute Myeloid Leukemia This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in treating patients with newly diagnosed acute myeloid leukemia.