Vorinostat + Azacitidine for Myelodysplastic Syndrome / Acute Myeloid Leukemia

Recruiting at 6 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Interferon, Retinoids, others

Disqualifiers: Chemotherapy, Radiotherapy, CNS involvement, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

135 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of vorinostat and azacitidine and to see how well they work in treating patients with myelodysplastic syndromes or acute myeloid leukemia. Vorinostat may stop the growth of cancer or abnormal cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer or abnormal cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vorinostat together with azacitidine may kill more cancer or abnormal cells.

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking certain medications like corticosteroids, interferon, retinoids, and specific growth factors at least one month before joining. You also need to stop taking valproic acid or similar drugs two weeks before starting. If you're on any investigational drugs, you must stop them 28 days before the trial.

What data supports the effectiveness of the drug combination Vorinostat and Azacitidine for treating Myelodysplastic Syndrome and Acute Myeloid Leukemia?

Research shows that Vorinostat, when used alone, has shown some effectiveness in treating acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with some patients experiencing complete responses. However, a study combining Azacitidine and Vorinostat did not show a significant improvement in overall response rates compared to Azacitidine alone for higher-risk MDS. ^{1 2 3 4 5}

Is the combination of Vorinostat and Azacitidine safe for treating myelodysplastic syndrome or acute myeloid leukemia?

Vorinostat has been studied for safety in patients with various types of leukemia and myelodysplastic syndromes. Common side effects include fatigue, nausea, vomiting, and diarrhea, which were generally mild to moderate. Serious side effects like severe fatigue and low platelet counts occurred in some patients, but no deaths were related to the drug. ^{1 2 3 6 7}

What makes the drug combination of Vorinostat and Azacitidine unique for treating myelodysplastic syndrome or acute myeloid leukemia?

The combination of Vorinostat and Azacitidine is unique because Vorinostat is a histone deacetylase inhibitor that can modify gene expression, potentially reversing abnormal patterns seen in these blood disorders, while Azacitidine is a chemotherapy drug that helps restore normal blood cell production. This combination targets the disease at a genetic level, which is different from traditional chemotherapy approaches. ^{1 2 3 5 8}

Research Team

Lewis R Silverman

Principal Investigator

Montefiore Medical Center - Moses Campus

Eligibility Criteria

This trial is for adults with certain types of blood disorders, including various forms of leukemia and myelodysplastic syndromes. Participants should have specific disease characteristics, not be on certain medications recently, and must have a life expectancy over 2 months. They need to be in relatively good health otherwise (ECOG <=2), with normal organ function tests. Pregnant women or those who've had recent cancer treatments are excluded.

Inclusion Criteria

I have AML and haven't used certain medications recently.

Patients must meet performance status, life expectancy, laboratory values, and contraceptive use requirements

I have been diagnosed with MDS or AML according to specific medical criteria.

Exclusion Criteria

I haven't had chemotherapy, radiotherapy, or been diagnosed with another cancer in the last 3 years.

I do not have brain involvement, allergies to study drugs, serious illnesses, heart failure, high myeloblasts, HIV, infections, or liver tumors.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive azacitidine subcutaneously once daily on days 1-7 and vorinostat orally 2-3 times daily on days 3-5, 3-9, or 3-16. Treatment repeats every 28 days for at least 4 courses.

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with monthly follow-ups for 6 months and then every 2 months thereafter.

6 months

Treatment Details

Interventions

• Azacitidine
• Vorinostat

Trial Overview The study is testing the combination of two drugs: Vorinostat and Azacitidine. It aims to find the safest doses and see how effective they are against different blood disorders like acute myeloid leukemia and myelodysplastic syndromes by blocking enzymes that allow abnormal cells to grow or by directly killing them.

Participant Groups

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

Patients receive azacitidine SC QD on days 1-7 and vorinostat PO 2-3 times daily on days 3-5, 3-9, or 3-16. Treatment repeats every 28 days for at least 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 2 trial involving 37 patients with relapsed or untreated acute myeloid leukemia, vorinostat showed minimal efficacy, with a complete remission rate of only 4.5% in one treatment arm and 0% in another, leading to early discontinuation of therapy for many patients.

The study suggests that vorinostat as a monotherapy is not effective for this patient population, indicating a need for future research to explore its potential in combination with other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 study of vorinostat in acute myeloid leukemia. Schaefer, EW., Loaiza-Bonilla, A., Juckett, M., et al.[2022]

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]

In a study involving 277 patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), azacitidine combined with lenalidomide showed a higher overall response rate (ORR) of 68% in CMML patients compared to 28% for azacitidine alone, indicating a potential benefit for this specific group.

Overall, the combination therapies (azacitidine plus lenalidomide and azacitidine plus vorinostat) did not significantly outperform azacitidine monotherapy in terms of ORR, suggesting that while combinations may be beneficial for certain patients, they may also be impacted by dose modifications and other factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117. Sekeres, MA., Othus, M., List, AF., et al.[2022]

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 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]

References

1. Italy pubmed.ncbi.nlm.nih.gov

A phase 2 study of vorinostat in acute myeloid leukemia. [2022]

2. 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]

3. 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]

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

Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117. [2022]

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

Vorinostat induces apoptosis and differentiation in myeloid malignancies: genetic and molecular mechanisms. [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. England pubmed.ncbi.nlm.nih.gov

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

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

Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. [2021]