Vorinostat for Graft-versus-Host Disease Prevention

Not currently recruiting at 6 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Michigan Rogel Cancer Center

Must not be taking: Valproic acid

Disqualifiers: Uncontrolled illness, HIV, Hepatitis, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 100 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called Vorinostat to determine if it can prevent graft-versus-host disease (GVHD), a condition that may occur after a bone marrow transplant when the donor's immune cells attack the recipient's body. The study aims to find the best dose for young patients who have undergone a blood or bone marrow transplant for certain blood cancers. Individuals may qualify if they are between 3 and 39 years old, have been diagnosed with specific blood cancers like leukemia or lymphoma, and plan to receive a matching donor transplant. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to contribute to groundbreaking medical research.

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.

Is there any evidence suggesting that Vorinostat is likely to be safe for humans?

Research has shown that Vorinostat has been tested in patients with certain blood cancers and maintains a good safety record. A daily dose of 400 mg proved easiest for patients to handle. For those undergoing a blood or marrow transplant, Vorinostat has been safely used to help prevent graft-versus-host disease (GVHD), a condition where transplanted cells attack the body. Studies have reported that the drug is safe and results in a low occurrence of GVHD. Overall, current research suggests that Vorinostat is well-tolerated. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Vorinostat is unique because it represents a new approach to preventing graft-versus-host disease (GVHD), a common complication following stem cell transplants. Unlike standard treatments such as immunosuppressants, which broadly dampen the immune system, Vorinostat is a histone deacetylase inhibitor that specifically targets and modulates gene expression, potentially reducing GVHD while preserving immune function. Researchers are excited about Vorinostat because of its targeted mechanism, which might offer a more precise and potentially safer way to prevent GVHD without the intense side effects often seen with traditional therapies.

What evidence suggests that Vorinostat might be an effective treatment for graft-versus-host disease?

Research has shown that Vorinostat, the treatment under study in this trial, might help prevent graft-versus-host disease (GVHD) after a bone marrow transplant. Studies have found that using Vorinostat with standard treatments for preventing GVHD can lower the risk of developing this condition. Vorinostat blocks certain enzymes that influence cell growth and survival. By doing so, it may maintain the transplant's positive effects while reducing harmful side effects. Early results are promising, suggesting that Vorinostat could be a valuable addition to current methods for preventing GVHD. ^{1 5 6 7 8}

Who Is on the Research Team?

Sung Choi, MD

Principal Investigator

University of Michigan

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Vorinostat

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.

How Is the Trial Designed?

Group I: Vorinostat Experimental Treatment 6 Interventions

Vorinostat is already approved in United States, European Union for the following indications:

Approved in United States as Zolinza for:

• Cutaneous T-cell lymphoma

Approved in European Union as Zolinza for:

• Cutaneous T-cell lymphoma

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+

Published Research Related to This Trial

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, 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, 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 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]

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]

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 (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 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. withpower.com withpower.com/trial/phase-2-hematologic-diseases-1-2020-bf6c7

Vorinostat for Graft-versus-Host Disease Prevention Trial Overview The study tests whether Vorinostat can prevent Graft vs Host Disease when added to standard prevention treatments after an allogeneic BMT. The ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT00132028?cond=Nodular%20lymphocyte%20predominant%20Hodgkin%20lymphoma&viewType=Table&rank=10

Vorinostat in Treating Patients With Relapsed or Refractory ... Patients receive oral vorinostat twice daily on days 1-14. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

3. ashpublications.org ashpublications.org/blood/article/130/15/1760/36380/Vorinostat-plus-tacrolimus-methotrexate-to-prevent

Vorinostat plus tacrolimus/methotrexate to prevent GVHD after ... HDAC inhibition with vorinostat shows potential efficacy for GVHD prevention and should be investigated in a randomized phase 3 trial. Subjects:.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC374345/

Histone deacetylase inhibitor suberoylanilide hydroxamic ... Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1785068/

Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic ... Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc Natl ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03842696

Study Details | NCT03842696 | Vorinostat for Graft vs Host ... 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 ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26827693/

The safety profile of vorinostat (suberoylanilide hydroxamic ... This review highlights the safety of HDAC inhibitors currently approved or being investigated for the treatment of hematologic malignancies.

8. sciencedirect.com sciencedirect.com/science/article/pii/S0006497120328019

Vorinostat plus tacrolimus/methotrexate to prevent GVHD ... The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute graft-versus-host disease (GVHD) ...