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

Trial Summary

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.

What data supports the effectiveness of the drug combination Iadademstat, Azacitidine, and Venetoclax 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, Venetoclax plus Azacitidine significantly prolonged overall survival in patients ineligible for intensive chemotherapy. ^{1 2 3 4 5}

Is the combination of Iadademstat, Azacitidine, and Venetoclax 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 digestive problems. These studies suggest that the treatment is generally safe, but side effects are possible, and the combination is often used for patients who cannot undergo intensive chemotherapy. ^{1 2 4 6 7}

What makes the drug combination of Iadademstat, Azacitidine, and Venetoclax 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 8}

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of iadademstat when given together with azacitidine and venetoclax in treating patients with newly diagnosed acute myeloid leukemia (AML). Iadademstat inhibits the LSD1 protein and may lead to inhibition of cell growth in LSD1-overexpressing cancer cells. Chemotherapy drugs, such as 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, tolerable and/or effective in treating patients with newly diagnosed AML who cannot undergo intensive chemotherapy.

Research Team

Curtis A Lachowiez

Principal Investigator

OHSU Knight Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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 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 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+

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]

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]

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]

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

TP53 or Not TP53: That Is the Question. [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. England pubmed.ncbi.nlm.nih.gov

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

8. 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]