Iadademstat + Azacitidine + Venetoclax for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: OHSU Knight Cancer Institute

Must not be taking: MAO inhibitors, P-gp inhibitors

Disqualifiers: Active malignancy, CNS involvement, others

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

Compensation: Varies

Number of Visits: 4

Duration: Average of 1 year

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to determine the safest and most effective dose of iadademstat when combined with azacitidine and venetoclax for treating newly diagnosed acute myeloid leukemia (AML). Iadademstat targets a protein that can inhibit cancer cell growth. Azacitidine and venetoclax are chemotherapy drugs that kill cancer cells or prevent their spread. This trial is for individuals with AML who have not received prior treatment and cannot undergo standard intensive chemotherapy, particularly if certain health conditions make intense treatment risky. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking anticoagulation or antiplatelet therapy at least 14 days before starting the treatment. Additionally, you must not be on certain medications like monoamine oxidase inhibitors, P-gp inhibitors, or strong/moderate CYP3A4 inducers or inhibitors close to the start of the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research has shown that combining the drugs iadademstat, azacitidine, and venetoclax might be safe and manageable for patients with newly diagnosed acute myeloid leukemia (AML). Early results from studies indicate that this combination is under evaluation to ensure it doesn't cause serious side effects. So far, the data appears promising, suggesting the treatment works well without causing harm. However, this combination is still being tested to confirm these safety results and determine the optimal dose. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Iadademstat, Azacitidine, and Venetoclax for treating Acute Myeloid Leukemia (AML) because it offers a new approach compared to standard chemotherapy options like cytarabine and anthracyclines. Iadademstat is a novel LSD1 inhibitor that targets leukemia cells differently by interfering with their gene expression, potentially making it a powerful partner with Azacitidine and Venetoclax. Venetoclax, a BCL-2 inhibitor, helps in inducing cancer cell death, while Azacitidine modifies the DNA of cancer cells to prevent their growth. Together, this combination aims to enhance effectiveness and offer hope for improved outcomes in AML patients.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that combining iadademstat, azacitidine, and venetoclax may help treat acute myeloid leukemia (AML). In this trial, participants will receive different dose levels of this combination to evaluate its effectiveness. Iadademstat blocks a protein called LSD1, potentially slowing cancer cell growth. Azacitidine prevents cancer cells from growing and dividing. Venetoclax blocks a protein called Bcl-2, which cancer cells need to survive. Studies suggest that using venetoclax with azacitidine has already helped many AML patients live longer. Early evidence indicates that adding iadademstat to this combination could be effective for people who cannot undergo intensive chemotherapy. ^{1 2 6 7 8}

Who Is on the Research Team?

Curtis A Lachowiez

Principal Investigator

OHSU Knight Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed acute myeloid leukemia (AML) who can't have intensive chemotherapy. Participants must be in good physical condition, with no major heart problems, and not have had certain treatments before.

Inclusion Criteria

Ability to comprehend the investigational nature of the study and provide written informed consent

Uncorrected INR or aPTT of < 1.5 x ULN

Willingness to adhere to study schedule and requirements

Exclusion Criteria

Recent investigational therapy

Prior allergic response to study medications

Serology positive for HIV under certain conditions

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive iadademstat, azacitidine, and venetoclax in cycles of 28 days, with specific dosing schedules for each drug

Average of 1 year

Multiple visits per cycle for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Iadademstat
• Venetoclax

Trial Overview

The trial tests the safety and best dose of iadademstat combined with azacitidine and venetoclax in AML patients. It studies how these drugs work together to inhibit cancer cell growth by targeting specific proteins that cancer cells need to survive.

How Is the Trial Designed?

Group I: Treatment Dose Level 2 (iadademstat, azacitidine, venetoclax) Experimental Treatment 8 Interventions

Iadademstat (150 mcg, 5+2 days, 2 out of 4 weeks per cycle), Venetoclax (400 mg, day 1-21), Azacitidine (75 mg/m2, day 1-7) Patients receive iadademstat PO QD on days 1-5 of cycle 0 and then days 1-5, 8-12, and 15-19. Patients also receive venetoclax PO QD days 1-21 and azacitidine SC QD days 1-7. Patients with CR, CRh, CRi, or MLFS after cycle 1 continue to receive IADA PO QD on days 1-5, 8-12, and 15-19, azacitidine SC QD days 1-7 and venetoclax PO QD days 1-21 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening as clinically indicated on study. Patients under bone marrow biopsy throughout the trial. Additionally, patients undergo blood sample collection during screening and on the trial.

Group II: Treatment Dose Level 1 (iadademstat, azacitidine, venetoclax) Experimental Treatment 8 Interventions

Iadademstat (100 mcg, 5+2 days, 2 out of 4 weeks per cycle), Venetoclax (400 mg, day 1-21), Azacitidine (75 mg/m2, day 1-7) Patients receive iadademstat PO QD on days 1-5 of cycle 0 and then days 1-5, 8-12, and 15-19. Patients also receive venetoclax PO QD days 1-21 and azacitidine SC QD days 1-7. Patients with CR, CRh, CRi, or MLFS after cycle 1 continue to receive IADA PO QD on days 1-5, 8-12, and 15-19, azacitidine SC QD days 1-7 and venetoclax PO QD days 1-21 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening as clinically indicated on study. Patients under bone marrow biopsy throughout the trial. Additionally, patients undergo blood sample collection during screening and on the trial.

Group III: Treatment Dose Level -2 (iadademstat, azacitidine, venetoclax) Experimental Treatment 8 Interventions

Iadademstat (75 mcg, 5+2 days, 2 out of 4 weeks per cycle), Venetoclax (400 mg, day 1-7), Azacitidine (50 mg/m2, day 1-7). Patients receive iadademstat PO QD on days 1-5 of cycle 0 and then days 1-5, 8-12, and 15-19. Patients also receive venetoclax PO QD days 1-21 azacitidine SC QD days 1-7. Patients with CR, CRh, CRi, or MLFS after cycle 1 continue to receive IADA PO QD on days 1-5, 8-12, and 15-19, azacitidine SC QD days 1-7 and venetoclax PO QD days 1-21 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening as clinically indicated on study. Patients under bone marrow biopsy throughout the trial. Additionally, patients undergo blood sample collection during screening and on the trial.

Group IV: Treatment Dose Level -1 (iadademstat, azacitidine, venetoclax) Experimental Treatment 8 Interventions

Iadademstat (75 mcg, 5+2 days, 2 out of 4 weeks per cycle), Venetoclax (400 mg, day 1-14), Azacitidine (75 mg/m2, day 1-7) Patients receive iadademstat PO QD on days 1-5 of cycle 0 and then days 1-5, 8-12, and 15-19. Patients also receive venetoclax PO QD days 1-21 and azacitidine SC QD days 1-7. Patients with CR, CRh, CRi, or MLFS after cycle 1 continue to receive IADA PO QD on days 1-5, 8-12, and 15-19, azacitidine SC QD days 1-7 and venetoclax PO QD days 1-21 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening as clinically indicated on study. Patients under bone marrow biopsy throughout the trial. Additionally, patients undergo blood sample collection during screening and on the trial.

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?

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

Oryzon Genomics S.A.

Industry Sponsor

Trials

5

Recruited

350+

Published Research Related to This Trial

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]

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 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 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]

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]

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 patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[2023]

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The goal is to see if this experimental drug called iadademstat is safe and helpful for people with newly diagnosed AML who can't have regular chemotherapy.