Chemotherapy with Bortezomib + Vorinostat for Acute Lymphoblastic Leukemia

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding two drugs, bortezomib (Velcade) and vorinostat (Zolinza), to standard chemotherapy can help treat acute lymphoblastic leukemia (ALL) in infants. The goal is to determine if these drugs can reduce leukemia cells and improve survival rates, while also assessing their side effects. The study seeks infants newly diagnosed with ALL who have had very limited prior treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering a unique opportunity to contribute to groundbreaking research.

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.

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

A previous study administered bortezomib with chemotherapy to children whose acute lymphoblastic leukemia (ALL) had returned. Most children tolerated the drug well, though some experienced manageable side effects. However, the study did not clearly demonstrate the drug's benefits for these children.

Research has shown that vorinostat has been tested in people with various types of cancer. In a study of 498 individuals with solid tumors or blood cancers, most tolerated vorinostat well. Severe side effects were rare, and no deaths were attributed to the drug.

The FDA has approved both bortezomib and vorinostat for treating other cancers in adults, suggesting a degree of safety. However, their effects on children with leukemia remain under investigation. This clinical trial is in the early stages and primarily aims to assess how well these drugs are tolerated when combined with standard chemotherapy for infants with ALL. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Bortezomib and Vorinostat for treating Acute Lymphoblastic Leukemia because these drugs introduce a novel approach compared to traditional chemotherapy. Unlike standard treatments that primarily target rapidly dividing cells, Bortezomib works by inhibiting a protein complex known as the proteasome, which plays a crucial role in cancer cell survival. Vorinostat, on the other hand, is a histone deacetylase inhibitor, which can alter gene expression and potentially enhance the effectiveness of other cancer therapies. Together, these mechanisms offer a fresh strategy by directly targeting the cellular machinery and regulatory pathways that support cancer cell growth, making them a promising addition to leukemia treatment options.

What evidence suggests that the combination of bortezomib and vorinostat with chemotherapy could be effective for acute lymphoblastic leukemia?

Research indicates that vorinostat, one of the drugs in this trial's combination, shows promise in treating various blood cancers, including acute lymphoblastic leukemia (ALL). Early studies have found that drugs like vorinostat can combat tumors in several childhood cancers, including leukemia. Another drug in this trial, bortezomib, has demonstrated strong effects against certain cancer cells in early research. Although limited information exists about its use in children, both bortezomib and vorinostat have been safely used in adults for other cancers. This combination might help reduce leukemia cells when added to standard chemotherapy, but it could also increase side effects. ^{6 7 8 9 10}

Who Is on the 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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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, 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'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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01312818?term=NCT00154349%20NCT00388895%20NCT01222013%20NCT01312818%20NCT03023046&rank=2

Bortezomib, Vorinostat and Dexamethasone for Relapsed/ ... This is a phase II study of bortezomib 1.3 mg/m^2 by intravenous pyelogram (IVP) on days 1, 4, 8, and 11, vorinostat 180 mg/m^2 by mouth (PO) per day (not to ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01312818?term=Dexamethasone%20AND%20blast&viewType=Table&checkSpell=&rank=5

Study Details | Bortezomib, Vorinostat and Dexamethasone ... Both of bortezomib and vorinostat have identified Phase II doses for pediatric and adult patients of which no grade 4 dose limiting toxicities have been ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11673799/

A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell ... The results of the present trial revealed a modest overall response rate. Background: The proteasome inhibitor bortezomib has demonstrated marked preclinical ...

4. withpower.com withpower.com/trial/phase-2-precursor-cell-lymphoblastic-leukemia-lymphoma-2016-47c61

Chemotherapy with Bortezomib + Vorinostat for Acute ... Research shows that Vorinostat, one of the drugs in the combination, has shown promise in treating various types of leukemia and lymphoma, including acute ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3511610/

A Phase I Trial of Vorinostat and Bortezomib in Children with ... Preclinical studies have demonstrated that HDAC inhibitors, including vorinostat, have anti-tumor activity in a variety of pediatric cancers including leukemia ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6785345/

Efficacy and safety of a bortezomib and reduced intensity ... Of 55 children with rALL 23 received supportive care and 7 refused treatment, with a median survival of 2 (IQR 1-6) months. Twenty-two (88%) of 25 treated ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT00440726

Bortezomib With Chemotherapy for Relapsed Pediatric ... This is a Phase I/II study of a drug called bortezomib given in combination with chemotherapy drugs used to treat acute lymphoblastic leukemia (ALL) that ...

8. bloodresearch.or.kr bloodresearch.or.kr/journal/view.html?uid=2699&vmd=Full

Efficacy of bortezomib combined with Hyper-CVAD in ... ResultsOf the 20 patients with positive MRD included in this study, 60% (n = 12) exhibited MRD negative results after combination treatment, 30% ...

9. ashpublications.org ashpublications.org/blood/article/120/2/285/30407/Bortezomib-with-chemotherapy-is-highly-active-in

Bortezomib with chemotherapy is highly active in advanced B ... Investigators from the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) consortium retrospective study found remission rates of 44%, 27%, and 12% ...

10. fda.gov fda.gov/files/advisory%20committees/published/velcade-pediatric-postmarketing-pharmacovigilance-review.pdf

Velcade Pediatric Postmarketing Pharmacovigilance Review safety and effectiveness of bortezomib in pediatric patients was not established in the trial as no clinical benefit was demonstrated in ...