Vorinostat + Azacitidine for Acute Myeloid Leukemia

Overseen By Benjamin Oshrine, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Johns Hopkins All Children's Hospital

Must not be taking: Coumarins, Valproic acid

Disqualifiers: Chronic myelogenous leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

15 Participants Needed

Trial Summary

What is the purpose of this trial?

The objective of this study is to evaluate the maximum tolerated (MTD) of vorinostat used in combination with low-dose azacitidine after allogeneic hematopoietic cell transplantation (alloHCT) for prevention of relapse of childhood myeloid malignancies.

Will I have to stop taking my current medications?

The trial requires that you do not take coumarin-derived anticoagulants or valproic acid while participating. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug Vorinostat + Azacitidine for Acute Myeloid Leukemia?

Research shows that azacitidine improves survival in patients with certain types of blood disorders, including acute myeloid leukemia, while vorinostat has shown promising results in preclinical studies and some clinical trials for leukemia, suggesting potential effectiveness when combined. ^{1 2 3 4 5}

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

Vorinostat has been studied in various trials for leukemia and other conditions, showing common side effects like fatigue, nausea, vomiting, and diarrhea, which were generally mild to moderate. Serious side effects included fatigue, low platelet count, and diarrhea, but no drug-related deaths were reported. The combination with other drugs like idarubicin was generally tolerable, suggesting that Vorinostat is relatively safe for use in humans. ^{2 5 6 7 8}

How does the drug Vorinostat + Azacitidine differ from other treatments for acute myeloid leukemia?

Vorinostat + Azacitidine is unique because it combines two types of drugs that target cancer cells in different ways: vorinostat, a histone deacetylase inhibitor that affects gene expression, and azacitidine, a DNA methyltransferase inhibitor that alters DNA methylation. This combination aims to enhance the effectiveness of treatment by attacking the cancer cells through multiple mechanisms. ^{2 3 5 6 9}

Research Team

Cassandra Josephson, MD

Principal Investigator

Johns Hopkins All Children's Hospital

Eligibility Criteria

This trial is for children and young adults aged 1 to 21 with certain myeloid malignancies who've had a stem cell transplant. They must understand the study, not be breastfeeding or pregnant, use contraception, and can't be on other leukemia treatments or have chronic myelogenous leukemia.

Inclusion Criteria

I agree not to breastfeed while participating in the study.

I am between 1 and 21 years old.

I am a woman able to have children and my pregnancy test is negative.

Exclusion Criteria

I am currently taking blood thinners or valproic acid.

I have chronic myelogenous leukemia.

I am part of a clinical trial for new post-transplant medications.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment

Participants receive 2 cycles of standard post-transplant azacitidine at a dose of 32mg/m2/dose IV/subcutaneous for 5 days, in 28-day cycles

8 weeks

Dose-Escalation Treatment

Participants receive vorinostat orally at different dose levels, in addition to azacitidine, following a 3+3 dose-escalation design

up to 28 weeks

Follow-up

Participants are monitored for dose-limiting toxicities and other outcomes such as relapse, GVHD, and survival

1 year

Treatment Details

Interventions

• Azacitidine Injection
• Vorinostat

Trial Overview The study tests increasing doses of Vorinostat combined with low-dose Azacitidine after stem cell transplants in young patients to prevent cancer relapse. The goal is to find the highest dose that's safe without causing severe side effects.

Participant Groups

Group I: Combined therapy Experimental Treatment 2 Interventions

Patients will be enrolled in blocks of 3, with vorinostat dose-escalation according to 3+3 study design. Low-dose azacitidine will be administered in a fixed dose to all patients, for days 1-5 of each 28 day cycle.

Who Is Running the Clinical Trial?

Johns Hopkins All Children's Hospital

Lead Sponsor

Trials

47

Recruited

5,009,000+

Findings from Research

In the AZA-001 trial, azacitidine significantly improved survival in patients with high-risk myelodysplastic syndrome and acute myeloid leukemia, with 91 out of 179 patients responding to treatment after a median of 14 cycles.

Continued treatment with azacitidine beyond the first response led to an improved response category in 48% of patients, suggesting that ongoing therapy can enhance clinical benefits for those who initially respond.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Silverman, LR., Fenaux, P., Mufti, GJ., et al.[2022]

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, 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 of 149 patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), azacitidine treatment resulted in a median progression-free survival (PFS) of 10.9 months and an overall survival (OS) of 14.1 months, demonstrating its effectiveness in a real-world clinical setting.

The safety profile of azacitidine was consistent with previous clinical trials, and factors such as Eastern Cooperative Oncology Group (ECOG) performance status and red blood cell transfusion prior to treatment were identified as predictive factors for better PFS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Wehmeyer, J., Zaiss, M., Losem, C., et al.[2019]

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 trial involving 41 patients with refractory leukaemia, the combination of vorinostat and idarubicin showed a 17% response rate, indicating that this treatment can be effective for patients with advanced leukaemia.

The 3-day dosing schedule of vorinostat was better tolerated than the 14-day schedule, with the maximum tolerated dose established at 400 mg TID for 3 days, suggesting a safer administration method for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia. Kadia, TM., Yang, H., Ferrajoli, A., et al.[2021]

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]

In a phase I/II trial involving 52 adults with acute myeloid leukemia, the combination of vorinostat, azacitidine, and gemtuzumab ozogamicin showed a promising overall response rate of 41.9%, with 10 patients achieving complete remission.

Patients who achieved complete remission had a significantly longer median overall survival of 224.5 days compared to 95 days for those who did not respond to the treatment, highlighting the potential efficacy of this combination therapy in a challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study. Walter, RB., Medeiros, BC., Gardner, KM., et al.[2021]

References

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

Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. [2022]

2. Italy pubmed.ncbi.nlm.nih.gov

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

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. England pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). [2019]

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. England pubmed.ncbi.nlm.nih.gov

A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia. [2021]

8. England pubmed.ncbi.nlm.nih.gov

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

9. Italy pubmed.ncbi.nlm.nih.gov

Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study. [2021]