Iadademstat + Venetoclax + Azacitidine for Acute Myeloid Leukemia

Recruiting at 4 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Antidepressants, Strong CYP3A inhibitors

Disqualifiers: Intensive chemotherapy, CNS involvement, others

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

Compensation: Varies

Number of Visits: 3

45 Participants Needed

Trial Summary

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take drugs that target the 5HT2B receptor or the sigma nonspecific receptor, except if they are essential and monitored. You also cannot use strong CYP3A inhibitors, except for certain antifungals with dose adjustments. It's best to discuss your current medications with the trial team.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that you should not use certain drugs that target specific receptors, like some antidepressants, unless they are essential for your care. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the idea that Iadademstat + Venetoclax + Azacitidine for Acute Myeloid Leukemia is an effective drug?

The available research shows that the combination of Venetoclax and Azacitidine is effective for treating Acute Myeloid Leukemia, especially in older patients or those who cannot undergo intensive chemotherapy. Studies have shown that this combination improves remission rates and survival compared to using Azacitidine alone. For example, one study reported a complete response rate of 78.6% in newly diagnosed patients. Although specific data on Iadademstat combined with Venetoclax and Azacitidine is not provided, the effectiveness of Venetoclax and Azacitidine together suggests potential benefits when combined with Iadademstat. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination Iadademstat, Venetoclax, and Azacitidine for treating Acute Myeloid Leukemia?

Research shows that the combination of Venetoclax and Azacitidine improves remission rates and survival in older or unfit patients with acute myeloid leukemia compared to Azacitidine alone. Additionally, studies have found that Venetoclax-based therapies, including those combined with Azacitidine, are effective in treating newly diagnosed and relapsed acute myeloid leukemia, with favorable response rates and survival outcomes. ^{1 2 3 4 5}

What safety data exists for the treatment of Iadademstat, Venetoclax, and Azacitidine in AML?

The safety data for Venetoclax and Azacitidine combinations in AML show that hematologic toxicities are common, but the treatment is generally well-tolerated. Studies have shown that Venetoclax combined with Azacitidine is effective in older patients or those ineligible for intensive chemotherapy. In various trials, common adverse events included hematological and gastrointestinal toxicities. Higher doses of Venetoclax were found to be tolerable, but did not show significant clinical improvement. Outpatient induction with low-dose Venetoclax plus Azacitidine was feasible and safe. However, specific safety data for the combination including Iadademstat is not detailed in the provided studies. ^{1 2 4 5 6}

Is the combination of Iadademstat, Venetoclax, and Azacitidine safe for treating acute myeloid leukemia?

The combination of Venetoclax and Azacitidine has been studied for safety in patients with acute myeloid leukemia, showing common side effects like blood-related issues and stomach problems. These studies suggest that the treatment is generally safe, but specific safety data for Iadademstat in combination with these drugs is not provided. ^{1 2 4 5 6}

Is the drug combination of Azacitidine, Iadademstat, and Venetoclax promising for treating Acute Myeloid Leukemia?

Yes, the combination of Azacitidine and Venetoclax is promising for treating Acute Myeloid Leukemia, especially in older patients or those who can't undergo intensive chemotherapy. Studies show it improves remission rates and survival compared to using Azacitidine alone. ^{1 2 3 4 7}

What makes the drug combination of Iadademstat, Venetoclax, and Azacitidine unique for treating acute myeloid leukemia?

This drug combination is unique because it includes Iadademstat, which is not commonly used in standard treatments for acute myeloid leukemia. Venetoclax and Azacitidine are already known to improve remission rates and survival in older or unfit patients, but the addition of Iadademstat may offer a novel approach to enhance treatment effectiveness. ^{1 2 3 4 7}

What is the purpose of this trial?

This phase I trial tests safety, side effects and best dose of iadademstat with azacitidine and venetoclax for the treatment of patients with acute myeloid leukemia (AML) who have not receive treatment (treatment naive). Chemotherapy drugs, such as iadademstat 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. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving iadademstat with azacitidine and venetoclax may be safe and tolerable in treating patients with treatment naive AML.

Research Team

Natalie Galanina

Principal Investigator

University of Pittsburgh Cancer Institute LAO

Eligibility Criteria

This trial is for adults over 18 with newly diagnosed Acute Myeloid Leukemia (AML) who haven't started treatment, except possibly hydroxyurea. They should have a white blood cell count below a certain level, be able to swallow pills, weigh at least 50 kg, and have normal liver and kidney function tests.

Inclusion Criteria

My leukemia diagnosis matches the 2022 European standards.

I have AML and haven't been treated, except possibly with hydroxyurea or ATRA.

I can swallow pills.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive iadademstat, venetoclax, and azacitidine in cycles to determine the recommended phase 2 dose and safety profile

12 weeks

Multiple visits per cycle for drug administration and monitoring

Consolidation

Patients continue to receive iadademstat, venetoclax, and azacitidine in cycles for up to 2 years to maintain remission

Up to 2 years

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 3-4 months

Treatment Details

Interventions

• Azacitidine
• Iadademstat
• Venetoclax

Trial Overview The trial is testing the safety and optimal dosage of Iadademstat combined with Azacitidine and Venetoclax in treating AML. These drugs work differently to stop cancer cells from growing by killing them or blocking proteins they need to survive.

Participant Groups

Group I: Treatment (iadademstat, venetoclax, azacitidine) Experimental Treatment 6 Interventions

INDUCTION: Patients receive iadademstat PO QD on days 1-5, 8-12, and may also receive it on days 15-19, venetoclax PO QD on days 1-14 or 1-21 and azacitidine IV over 10-40 minutes or SC on days 1-7 or 1-5 and 8-9 of each cycle. Cycles repeat every 28 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo buccal swab collection on study. CONSOLIDATION: Patients receive iadademstat PO QD on days 1-5, 8-12 and may also receive it on days 15-19, venetoclax PO QD on days 1-7 or 1-14 and azacitidine IV over 10-40 minutes or SC on days 1-7 or 1-5 and 8-9 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection and may undergo bone marrow aspiration throughout the study.

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 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

In a study of 50 adults with acute myeloid leukemia (AML) in Mexico and Peru, venetoclax-based therapy showed a high complete response rate of 78.6% in newly diagnosed patients and 45.5% in those with relapsed/refractory disease, indicating its efficacy in treating AML.

The median overall survival was 9.6 months for newly diagnosed patients and 8 months for relapsed/refractory patients, suggesting that venetoclax is a viable treatment option even in real-world settings, despite common hematologic toxicities and dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. Gómez-De León, A., Demichelis-Gómez, R., Pinedo-Rodríguez, A., et al.[2022]

Outpatient induction therapy using low-dose venetoclax combined with itraconazole and azacitidine is feasible and safe for newly diagnosed acute myeloid leukemia (ND-AML) patients, with 77.7% of participants completing the first treatment cycle as outpatients.

The treatment showed promising efficacy, with a composite complete response rate of 53.9% after the first cycle and 85.7% after the second cycle, indicating that this regimen could be a viable option for patients eligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. De la Garza-Salazar, F., Colunga-Pedraza, PR., Gómez-Almaguer, D., et al.[2023]

In the HiDDAV study involving 42 newly diagnosed AML patients, higher doses of venetoclax (600 mg daily) were found to be tolerable but did not show significant clinical improvement compared to the standard 400 mg dose.

The study revealed that using minimal residual disease (MRD) status to guide the discontinuation of azacitidine did not lead to better outcomes in terms of duration of response or overall survival, suggesting that alternative strategies are needed to optimize treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia. Gutman, JA., Winters, A., Kent, A., et al.[2023]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]

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

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. [2023]

6. Italy pubmed.ncbi.nlm.nih.gov

Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. [2023]