Chemotherapy with Bortezomib + Vorinostat for Acute Lymphoblastic Leukemia

Recruiting at 17 trial locations

Overseen By Tanja Gruber, MD, PhD

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: Prior therapy, Mature B-cell ALL, AML, Down syndrome, others

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

Compensation: Varies

Number of Visits: Unknown

50 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the good and bad effects of the study drugs bortezomib and vorinostat when they are given in combination with chemotherapy commonly used to treat acute lymphoblastic leukemia (ALL) in infants. For example, adding these drugs could decrease the number of leukemia cells, but it could also cause additional side effects. Bortezomib and vorinostat have been approved by the US Food and Drug Administration (FDA) to treat other cancers in adults, but they have not been approved for treating children with leukemia. With this research, we plan to meet the following goals: PRIMARY OBJECTIVE: * Determine the tolerability of incorporating bortezomib and vorinostat into an ALL chemotherapy backbone for newly diagnosed infants with ALL. SECONDARY OBJECTIVES: * Estimate the event-free survival and overall survival of infants with ALL who are treated with bortezomib and vorinostat in combination with an ALL chemotherapy backbone. * Measure minimal residual disease (MRD) positivity using both flow cytometry and PCR. * Compare end of induction, end of consolidation, and end of reinduction MRD levels to Interfant99 (ClinicalTrials.gov registration ID number NCT00015873) participant outcomes.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that only limited prior therapy is allowed. It's best to discuss your current medications with the trial team to see if they are compatible with the study requirements.

What data supports the effectiveness of the drug combination Bortezomib and Vorinostat for treating Acute Lymphoblastic Leukemia?

Research shows that Vorinostat, one of the drugs in the combination, has shown promise in treating various types of leukemia and lymphoma, including acute leukemias, by improving responses when used with other chemotherapy drugs. Additionally, Vorinostat has been effective in treating cutaneous T-cell lymphoma, suggesting its potential in other blood cancers. ^{1 2 3 4 5}

Is the combination of Bortezomib and Vorinostat safe for humans?

Vorinostat, also known as SAHA, has been studied for safety in patients with various types of leukemia. Common side effects include mild to moderate diarrhea, nausea, fatigue, and loss of appetite, while more severe side effects can include significant fatigue, low platelet counts, and diarrhea. No deaths related to the drug were reported in the study. ^{1 3 5 6 7}

How does the drug combination of Bortezomib and Vorinostat differ from other treatments for acute lymphoblastic leukemia?

The combination of Bortezomib and Vorinostat is unique because it combines a proteasome inhibitor (Bortezomib) and a histone deacetylase inhibitor (Vorinostat), which work together to enhance the killing of leukemia cells. This combination has shown promise in preclinical studies for its ability to overcome drug resistance and improve treatment effectiveness in leukemia. ^{3 5 8 9 10}

Research Team

Sima C. Jeha

Principal Investigator

St. Jude Children's Research Hospital

Tanja Gruber, MD, PhD

Principal Investigator

Lucile Packard Children's Hospital Stanford University

Eligibility Criteria

This trial is for infants under the age of 1 with newly diagnosed acute lymphoblastic leukemia (ALL) or similar conditions, with a significant number of leukemia cells in their bone marrow. Infants who have received very limited prior treatment and do not have mature B-cell ALL, AML, or Down syndrome can participate.

Inclusion Criteria

I was diagnosed before turning 1 year old.

Written informed consent following Institutional Review Board, NCI, FDA, and Office for Human Research Protections (OHRP) Guidelines

I have been newly diagnosed with a specific type of leukemia with a high number of cancer cells in my bone marrow.

Exclusion Criteria

Inability or unwillingness of legal guardian/representative to give written informed consent

I have been diagnosed with mature B-cell ALL or AML.

I have received treatments not listed in the trial's accepted therapies.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Remission Induction

Chemotherapy is administered to induce remission in leukemia. Drugs include ITMHA, dexamethasone, vorinostat, bortezomib, PEG-asparaginase, mitoxantrone, cyclophosphamide, cytarabine, and 6-mercaptopurine.

6 weeks

Consolidation

Therapy is given to eliminate remaining leukemia cells. Drugs include ITMHA, high-dose methotrexate, and 6-mercaptopurine.

8 weeks

Reinduction

Aims to improve overall response by inducing remission again. Drugs include ITMHA, mitoxantrone, peg-asparaginase, dexamethasone, bortezomib, and vorinostat.

5 months

Maintenance

Participants receive maintenance therapy to prevent leukemia recurrence. Drugs include ITMHA, dexamethasone, vincristine, 6-mercaptopurine, and methotrexate. Each cycle lasts 28 days and is repeated up to 20 times.

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

3-5 years

Treatment Details

Interventions

• Bortezomib
• Vorinostat

Trial Overview The study tests bortezomib and vorinostat combined with standard chemotherapy to treat infant ALL. These drugs are FDA-approved for adult cancers but not yet for children's leukemia. The goal is to see if they're tolerable and effective at reducing leukemia cells without causing too many side effects.

Participant Groups

Group I: Treatment Experimental Treatment 14 Interventions

Participants who meet eligibility requirements will receive remission induction, consolidation treatment, reinduction, reintensification and maintenance therapy. Interventions: ITMHA, dexamethasone, mitoxantrone, pegaspargase or asparaginase Erwinia chrysanthemi, bortezomib, vorinostat, cyclophosphamide, mercaptopurine, methotrexate, leucovorin calcium, cytarabine, etoposide, and vincristine.

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?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Gateway for Cancer Research

Collaborator

Trials

47

Recruited

2,500+

Baylor College of Medicine

Collaborator

Trials

1,044

Recruited

6,031,000+

Findings from Research

Vorinostat, when used sequentially before cytosine arabinoside (ara-C), showed mostly synergistic effects in killing leukemia cells, suggesting a promising treatment strategy for acute leukemias.

The combination of vorinostat with etoposide was found to be additive to synergistic, especially when etoposide was administered after vorinostat, indicating that the timing of drug administration is crucial for maximizing therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical studies of vorinostat (suberoylanilide hydroxamic acid) combined with cytosine arabinoside and etoposide for treatment of acute leukemias. Shiozawa, K., Nakanishi, T., Tan, M., et al.[2018]

Vorinostat, a histone deacetylase inhibitor, was well tolerated in a phase I trial with 10 Japanese patients suffering from various types of malignant lymphoma, showing only one dose-limiting toxicity at 200 mg.

The treatment resulted in a 40% overall response rate, with notable complete responses in follicular lymphoma and mantle cell lymphoma, suggesting that vorinostat could be a promising option for further studies in these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphoma. Watanabe, T., Kato, H., Kobayashi, Y., et al.[2018]

Vorinostat, a histone deacetylase inhibitor, was found to be safe and tolerable in a phase 1 study involving 41 patients with various types of leukemia and myelodysplastic syndromes, with a maximum tolerated dose of 200 mg twice daily or 250 mg thrice daily.

The treatment led to hematologic improvements in 7 patients, including 2 complete responses, and increased histone acetylation was observed, suggesting its potential efficacy in treating acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Garcia-Manero, G., Yang, H., Bueso-Ramos, C., et al.[2021]

Vorinostat's solubility was significantly enhanced when complexed with cyclodextrins, particularly with randomly methylated-β-cyclodextrin (RM-β-CD), which increased its solubility from 0.724 mm to 70.8 mm, making it nearly 100 times more soluble.

Molecular simulations supported these findings and suggested that using cyclodextrins could improve vorinostat's delivery methods, indicating potential for better oral absorption and parenteral delivery in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Solubilization of vorinostat by cyclodextrins. Cai, YY., Yap, CW., Wang, Z., et al.[2018]

Vorinostat, a histone deacetylase inhibitor, did not cause maternal toxicity or major fetal malformations in Sprague-Dawley rats and Dutch Belted rabbits, indicating a relatively safe profile during pregnancy at lower doses.

However, at high doses, vorinostat was associated with developmental toxicity, such as decreased fetal weight and skeletal variations, suggesting that while it is generally safe, caution is needed with higher dosages due to potential adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch Belted rabbits. Wise, LD., Turner, KJ., Kerr, JS.[2018]

References

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

Preclinical studies of vorinostat (suberoylanilide hydroxamic acid) combined with cytosine arabinoside and etoposide for treatment of acute leukemias. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphoma. [2018]

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

The synergic effect of vincristine and vorinostat in leukemia in vitro and in vivo. [2018]

4. Germany pubmed.ncbi.nlm.nih.gov

Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma or leukemia. [2018]

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

Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Solubilization of vorinostat by cyclodextrins. [2018]

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

Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch Belted rabbits. [2018]

8. Germany pubmed.ncbi.nlm.nih.gov

Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. [2015]

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

A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-cell Lymphoma. [2019]

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

Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: a case series illustrating utility in clinical practice. [2018]