Vorinostat + Azacitidine for Head and Neck Cancers

Recruiting at 6 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Sodium valproate, others

Disqualifiers: CNS involvement, Uncontrolled illness, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of vorinostat when given together with azacitidine in treating patients with nasopharyngeal cancer or nasal natural killer T-cell lymphoma that has recurred (come back) at or near the same place as the original (primary) tumor, usually after a period of time during which the cancer could not be detected or has spread to other parts of the body. Drugs used in chemotherapy, such as vorinostat and azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Vorinostat and azacitidine also may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving vorinostat together with azacitidine may kill more cancer cells.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had chemotherapy or radiotherapy within 4 weeks before starting the trial. Also, you should not have taken sodium valproate for at least 2 weeks prior to enrollment.

What data supports the effectiveness of the drug Vorinostat in combination with Azacitidine for head and neck cancers?

Research shows that Vorinostat, when combined with standard chemoradiation therapy, was highly effective in treating advanced head and neck cancers, with a high rate of complete response in patients. This suggests potential effectiveness when combined with other treatments like Azacitidine. ^{1 2 3 4 5}

Is the combination of Vorinostat and Azacitidine safe for humans?

Vorinostat has been studied in various trials and is generally well tolerated, but it can cause side effects like fatigue, nausea, diarrhea, and low blood cell counts. In combination with chemoradiation therapy for head and neck cancer, it showed a high rate of complete response with manageable side effects. Azacitidine, also known as Vidaza, is commonly used in treating certain blood disorders and has its own safety profile, but specific safety data for the combination with Vorinostat in head and neck cancers is not detailed in the provided studies. ^{1 2 5 6 7}

How is the drug combination of Vorinostat and Azacitidine unique for treating head and neck cancers?

The combination of Vorinostat and Azacitidine is unique because Vorinostat is a histone deacetylase inhibitor that can sensitize cancer cells to other treatments, potentially enhancing the effectiveness of Azacitidine, which is a DNA methylation inhibitor. This combination aims to target cancer cells more effectively by using two different mechanisms of action, which is different from standard treatments that typically use single agents. ^{1 2 4 5 8}

Research Team

Wen-Son Hsieh

Principal Investigator

Johns Hopkins Singapore

Eligibility Criteria

This trial is for adults with nasopharyngeal cancer or nasal natural killer T-cell lymphoma that has returned or spread, who have already tried at least one chemotherapy treatment. They must be in good enough health to participate, not pregnant, willing to use contraception, and not have any serious illnesses that could interfere with the study.

Inclusion Criteria

My cancer has come back in the same area but cannot be treated with radiation to cure it.

I have cancer that has spread or returned and was treated with chemotherapy after it came back.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

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

Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with 5AC and SAHA

I do not have chronic active hepatitis B.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive azacitidine subcutaneously on days 1-10 and vorinostat orally twice daily on days 1-14. Treatment repeats every 28 days for 4 courses.

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Extension

Patients with responding disease may continue treatment at the discretion of the principal investigator.

Treatment Details

Interventions

• Azacitidine
• Vorinostat

Trial Overview The trial is testing the combination of two chemotherapy drugs, Vorinostat and Azacitidine. It aims to find the safest doses and see how well they work together against recurrent or metastatic nasopharyngeal cancer or nasal NK T-cell lymphoma by blocking enzymes needed for cell growth.

Participant Groups

Group I: Treatment (azacitidine, vorinostat) Experimental Treatment 4 Interventions

Patients receive azacitidine SC on days 1-10 and vorinostat PO BID on days 1-14. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 (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, 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]

In a phase I study involving 23 advanced-stage cancer patients, vorinostat was found to be safe and tolerable, with common side effects including mild to moderate nausea and fatigue.

The study revealed that a high-fat meal slightly increased the absorption of vorinostat but did not significantly impact its overall effectiveness, suggesting that vorinostat can be administered with or without food in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. Rubin, EH., Agrawal, NG., Friedman, EJ., et al.[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]

References

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

Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. [2021]

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

A phase 1 trial of Vorinostat in combination with concurrent chemoradiation therapy in the treatment of advanced staged head and neck squamous cell carcinoma. [2020]

3. 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]

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

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer. [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. 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. United States pubmed.ncbi.nlm.nih.gov

A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. [2018]

8. 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]