Vorinostat + Azacitidine for Myelodysplastic Syndrome / Acute Myeloid Leukemia

Not currently recruiting at 8 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of two drugs, vorinostat and azacitidine, to evaluate their effectiveness in treating myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The researchers aim to determine the optimal dose and understand any side effects while assessing how effectively these drugs inhibit cancer cell growth. Vorinostat may block enzymes necessary for cancer cell growth, and azacitidine is a chemotherapy drug that kills or stops the spread of cancer cells. Individuals diagnosed with MDS or AML who have not previously received azacitidine or similar drugs might be suitable candidates for this trial. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

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.

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

Research is examining the safety and effectiveness of combining vorinostat and azacitidine for treating myelodysplastic syndromes and acute myeloid leukemia. Previous studies show that patients usually tolerate this combination well. Azacitidine alone often serves as a first-line treatment for these conditions and is known for its safety.

Early results suggest that adding vorinostat might introduce some side effects. One study found that some patients experienced dose-limiting side effects, such as high bilirubin levels in the blood. However, many patients completed their treatment without major issues.

In summary, while some side effects exist, ongoing research aims to find the optimal dosage that balances effectiveness and tolerability. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of azacitidine and vorinostat for treating Myelodysplastic Syndrome and Acute Myeloid Leukemia because this treatment offers a unique approach. Unlike traditional treatments that primarily focus on chemotherapy, this combo includes vorinostat, a histone deacetylase inhibitor that can modify the expression of certain genes involved in cancer progression. Additionally, azacitidine is a hypomethylating agent that can help restore normal function to cancer cells. Together, they offer a novel way to target the disease at the genetic level, which could potentially improve outcomes for patients who don't respond well to standard treatments.

What evidence suggests that vorinostat and azacitidine might be an effective treatment for myelodysplastic syndrome or acute myeloid leukemia?

Research has shown that azacitidine helps people with myelodysplastic syndromes (MDS) live longer. Vorinostat, a pill that inhibits certain enzymes necessary for cell growth, might help prevent cancer from spreading. In this trial, participants will receive a combination of azacitidine and vorinostat. Studies comparing azacitidine alone to the combination of azacitidine and vorinostat found that the combination did not outperform azacitidine alone for acute myeloid leukemia (AML). However, researchers continue to investigate whether using both drugs together could be more effective for MDS. The aim is to determine if the two drugs can kill more cancer cells together than each can alone. ^{2 6 7 8 9}

Who Is on the Research Team?

Lewis R Silverman

Principal Investigator

Montefiore Medical Center - Moses Campus

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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, 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 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]

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]

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, 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01617226

NCT01617226 | Randomised Study of Azacitidine Versus ... This is a multicentre, open-label, randomised phase II trial comparing azacitidine monotherapy with combined azacitidine and vorinostat in patients with newly ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2948932/

Safety and efficacy of azacitidine in myelodysplastic ... Azacitidine is the first drug FDA-approved for the treatment of myelodysplastic syndromes that has demonstrated improvements in overall survival.

3. patlynk.com patlynk.com/trial/NCT00392353

Vorinostat and Azacitidine in Treating Patients ... Giving vorinostat together with azacitidine may kill more cancer or abnormal cells. PRIMARY OBJECTIVES: I. To evaluate the safety and toxicity of vorinostat in ...

4. cancerresearchuk.org cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-azacitidine-with-or-without-vorinostat-for-aml-that-has-come-back-ravva

A trial of azacitidine with or without vorinostat for acute ... Summary of results. This trial showed that the combination of azacitidine and vorinostat was not better than azacitidine alone for acute myeloid leukaemia (AML) ...

5. ascopubs.org ascopubs.org/doi/10.1200/jco.2008.26.15_suppl.7000

A phase I/II study of vorinostat, an oral histone deacetylase ... A phase I/II study of vorinostat, an oral histone deacetylase inhibitor, in combination with azacitidine in patients with the myelodysplastic ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT00392353

Study Details | NCT00392353 | Vorinostat and Azacitidine ... 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 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4332848/

Translational Phase I Trial of Vorinostat (Suberoylanilide ... Results. Eighteen of 21 patients with acute myelogenous leukemia (AML) treated on study completed planned therapy. Dose-limiting toxicities [hyperbilirubinemia/ ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2727156/

Future Directions in Myelodysplastic Syndrome These early results suggest that decitabine plus vorinostat is safe and has shown some efficacy in the treatment of relapse/refractory leukemia. In addition, ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0145212624002042

Combination therapy involving azacitidine for acute ... Clinical trials have indicated that hypomethylating agents can serve as first-line therapy for MDS and AML patients, demonstrating good safety and efficacy[15], ...