AOH1996 + Venetoclax + Azacitidine for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A4 inducers, CYP3A inhibitors

Disqualifiers: Stem cell transplant, CNS disease, others

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

Compensation: Varies

Number of Visits: 30

Duration: Up to 48 weeks

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires stopping certain medications before starting, such as strong and moderate CYP3A4 inducers and strong CYP3A inhibitors, as well as strong inhibitors or inducers of CYP2C9, within 7 days prior to the trial. Foods and supplements that affect these enzymes, like grapefruit and St. John's wort, should also be avoided within 3 days before and during the study. Check with the trial team about your specific medications.

What data supports the effectiveness of the drug combination AOH1996, Azacitidine, and Venetoclax for treating Acute Myeloid Leukemia?

Research shows that the combination of venetoclax and azacitidine improves survival and remission rates in patients with acute myeloid leukemia, especially those who are older or cannot undergo intensive chemotherapy. ^{1 2 3 4 5}

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

The combination of Venetoclax and Azacitidine has been studied in patients with acute myeloid leukemia, and it is generally considered safe, with similar side effects to other treatments. However, the specific safety of adding AOH1996 to this combination has not been detailed in the available research. ^{4 5 6 7 8}

What makes the drug combination of AOH1996, Venetoclax, and Azacitidine unique for treating acute myeloid leukemia?

The combination of AOH1996 with Venetoclax and Azacitidine is unique because it introduces a novel component, AOH1996, to the existing standard regimen of Venetoclax and Azacitidine, which is typically used for patients who cannot undergo intensive chemotherapy. This new combination may offer a different mechanism of action or enhanced effectiveness, although specific details about AOH1996's role are not provided in the available research. ^{1 2 4 5 8}

What is the purpose of this trial?

This phase 1 trial tests safety, side effects, and best dose of AOH1996 for the treatment of patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or AML that has not responded to previous treatment (refractory). AOH1996 is in a class of medications called PCNA inhibitors. It inhibits cancer growth and induces deoxyribonucleic acid (DNA) damage. This may help keep cancer cells from growing and damage cancer cell DNA. Giving AOH1996 may be safe, tolerable and/or effective in treating patients with AML.

Research Team

Amanda Blackmon

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with Acute Myeloid Leukemia that has either returned after treatment or hasn't responded to past treatments. Participants should meet specific health conditions, but the exact inclusion and exclusion criteria are not provided.

Inclusion Criteria

Aspartate aminotransferase (AST) =< 3.0 x ULN (within 14 days prior to day 1 of protocol therapy)

International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN (within 14 days prior to day 1 of protocol therapy)

Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (within 14 days prior to day 1 of protocol therapy)

Exclusion Criteria

Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

I haven't had cancer treatments except hydroxyurea in the last 14 days.

I haven't consumed grapefruit, Seville oranges, starfruit, or St. John's wort in the last 3 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AOH1996 alone or in combination with venetoclax with or without azacitidine. Treatment cycles repeat every 28 days for up to 12 cycles.

Up to 48 weeks

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, including assessments of overall survival and progression-free survival.

Up to 1 year

Follow-up visits at 30 days and periodically up to 1 year

Treatment Details

Interventions

• AOH1996
• Azacitidine
• Venetoclax

Trial Overview The trial is testing AOH1996 alone or combined with Venetoclax, with or without Azacitidine. It aims to determine safety, side effects, and optimal dosages in treating relapsed or refractory AML by targeting cancer cell growth and survival mechanisms.

Participant Groups

Group I: Cohort I (AOH1996) Experimental Treatment 5 Interventions

Patients receive AOH1996 PO BID on days 1 - 28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients that attain a CR/CRh/CRi with transfusion independence (TI) by the end of cycle 2 continue cycles every 28 days for up to 12 total cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo bone marrow aspiration and blood sample collection throughout the trial.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 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 a study of 6 children with refractory or relapsed acute myeloid leukemia (AML), the combination of venetoclax, azacitidine, and cladribine (VAC regimen) resulted in significant treatment responses, with 4 achieving complete remission and 1 showing partial remission.

Despite severe side effects like grade IV neutropenia and thrombocytopenia, there were no treatment-related deaths or infections, indicating that the VAC regimen is both effective and safe for this vulnerable patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. DU, WW., Liu, SX., Wang, Y., 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 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 treatment-naïve patients with IDH1/2-mutant acute myeloid leukemia (AML), the combination of venetoclax and azacitidine resulted in a high composite complete remission rate of 79% and a median overall survival of 24.5 months, significantly outperforming the azacitidine-only group, which had an 11% remission rate and 6.2 months of survival.

The treatment was found to be safe, with no unexpected toxicities reported, and the favorable outcomes for patients with IDH1/2 mutations were consistent regardless of their cytogenetic risk, indicating a robust efficacy of this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax and Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia and IDH1/2 Mutations. Pollyea, DA., DiNardo, CD., Arellano, ML., et al.[2023]

In a study of 57 elderly patients (average age 69.9 years) with acute myeloid leukemia, the combination of venetoclax and azacitidine (VEN + AZA) showed a high overall response rate of 87.5% and a complete remission (CR) rate of 68.8%, indicating strong efficacy in this population.

The treatment was associated with a median overall survival (OS) of 11.5 months, and achieving minimal residual disease (MRD) negativity (<0.1%) was more common with VEN + AZA compared to traditional chemotherapy, although older patients (≥75 years) and those with higher ECOG scores faced more challenges in achieving MRD negativity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. Yu, H., Wang, C., Lei, Y., 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]

References

1. 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]

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

TP53 or Not TP53: That Is the Question. [2023]

3. China pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. [2023]

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

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

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

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

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

Impact of Venetoclax and Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia and IDH1/2 Mutations. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. [2023]

8. Italy pubmed.ncbi.nlm.nih.gov

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