Vorinostat for Graft-versus-Host Disease Prevention

Recruiting at 6 trial locations

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Waitlist Available

Sponsor: University of Michigan Rogel Cancer Center

Must not be taking: Valproic acid

Disqualifiers: Uncontrolled illness, HIV, Hepatitis, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine the recommended phase 2 dose of the drug Vorinostat in children, adolescents and young adults following allogeneic blood or marrow transplant (BMT) and determine whether the addition of Vorinostat to the standard graft versus host disease (GVHD) prophylaxis will reduce the incidence of GVHD.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on another GVHD treatment or prevention trial, you cannot participate in this study.

What data supports the effectiveness of the drug Vorinostat for preventing Graft-versus-Host Disease?

Vorinostat has shown clinical activity in treating various cancers, including T-cell lymphoma and leukemia, by inhibiting histone deacetylase, which can affect gene expression. Its effectiveness in these conditions suggests potential benefits in preventing Graft-versus-Host Disease, although direct evidence for this specific use is not provided. ^{1 2 3 4 5}

Is vorinostat generally safe for humans?

Vorinostat has been tested in humans for various conditions, and common side effects include tiredness, nausea, vomiting, and diarrhea, which are usually mild to moderate. Serious side effects can include fatigue, low platelet counts (thrombocytopenia), and diarrhea, but no drug-related deaths were reported in the studies. ^{2 4 5 6 7}

How is the drug Vorinostat unique for preventing graft-versus-host disease?

Vorinostat is unique because it is a histone deacetylase inhibitor, which means it works by affecting the way genes are expressed in cells, and it has been primarily used in cancer treatments. Its novel mechanism of action and previous use in oncology make it different from other treatments for graft-versus-host disease. ^{1 3 5 8 9}

Research Team

Sung Choi, MD

Principal Investigator

University of Michigan

Eligibility Criteria

This trial is for children, adolescents, and young adults aged 3 to 39 who are undergoing allogeneic BMT for various blood cancers and diseases. They must have a matched donor, be able to take oral medication, use contraception if of reproductive age, understand consent forms in English (if participating in cognitive assessments), have a performance score of at least 70%, and expect to live more than six months.

Inclusion Criteria

I am a candidate for a bone marrow transplant from a donor for my blood cancer.

My brain-related disease is currently in remission.

My donor and I are a complete or half HLA match.

Exclusion Criteria

I don't have any serious illnesses or social situations that would stop me from following the study's requirements.

I am not pregnant or breastfeeding, and will not become pregnant during the study.

I am HIV positive or have HTLV1/HTLV2.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Transplantation

Participants undergo allogeneic blood or marrow transplant (BMT) according to local site institutional practice

Up to 28 days

Inpatient stay for transplantation

Treatment

Participants receive Vorinostat in addition to standard GVHD prophylaxis

100 days

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Periodic follow-up visits

Treatment Details

Interventions

• Vorinostat (Histone Deacetylase Inhibitor)

Trial Overview The study tests whether Vorinostat can prevent Graft vs Host Disease when added to standard prevention treatments after an allogeneic BMT. The goal is also to find the safest dose of Vorinostat for phase 2 trials in these patients.

Participant Groups

Group I: Vorinostat Experimental Treatment 6 Interventions

Who Is Running the Clinical Trial?

University of Michigan Rogel Cancer Center

Lead Sponsor

Trials

303

Recruited

20,700+

National Center for Advancing Translational Sciences (NCATS)

Collaborator

Trials

394

Recruited

404,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

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]

In a study involving 18 Japanese patients with solid tumors, vorinostat was administered in escalating doses, and while dose-limiting toxicities like thrombocytopenia and fatigue were observed, a maximum tolerated dose was not established.

Vorinostat showed a pharmacokinetic profile similar to that in non-Japanese patients, and doses of 200 mg twice daily or 500 mg once daily were well tolerated, making them suitable candidates for further phase II trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of vorinostat (suberoylanilide hydroxamic acid) in Japanese patients with solid tumors. Fujiwara, Y., Yamamoto, N., Yamada, Y., et al.[2018]

Vorinostat (SAHA) shows varying effectiveness in treating breast cancer, with some tumors and cell lines being resistant due to differences in gene expression related to cell adhesion and glutathione metabolism.

Depleting glutathione with buthionine sulfoximine (BSO) can enhance the effectiveness of SAHA, suggesting that evaluating antioxidant gene expression may help predict which tumors will respond to this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer. Chiaradonna, F., Barozzi, I., Miccolo, C., 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]

Vorinostat, the first FDA-approved HDAC inhibitor, has shown safety and efficacy in treating cutaneous T-cell lymphoma (CTCL) with an overall response rate of 24-30% in advanced, refractory cases during Phase II trials.

Common side effects of vorinostat include gastrointestinal issues, fatigue, and thrombocytopenia, with thrombosis being the most serious adverse event reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Duvic, M., Vu, J.[2022]

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]

In a phase I/II trial involving 33 patients with EGFR-mutated non-small cell lung cancer (NSCLC) who progressed after tyrosine kinase inhibitors, the combination of vorinostat and erlotinib was found to be safe, with a maximum tolerated dose established for the treatment regimen.

Despite the safety of the drug combination, the study reported no significant therapeutic responses, with a progression-free survival rate of only 28% at 12 weeks, indicating that this treatment may not be effective for patients who have already progressed on other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression. Reguart, N., Rosell, R., Cardenal, F., et al.[2022]

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

Phase I and pharmacokinetic study of vorinostat (suberoylanilide hydroxamic acid) in Japanese patients with solid tumors. [2018]

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

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer. [2018]

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

Solubilization of vorinostat by cyclodextrins. [2018]

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. [2022]

8. 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]

9. Ireland pubmed.ncbi.nlm.nih.gov

Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression. [2022]