HC-7366 + Azacitidine + Venetoclax for AML

Overseen By Abhishek Maiti, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Cytotoxic chemotherapy

Disqualifiers: CNS leukemia, Active infections, Heart failure, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

18 Participants Needed

Trial Summary

What is the purpose of this trial?

To find a recommended dose of HC-7366 to patients with AML. The safety and effects of this drug combination will also be studied.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have used any cytotoxic chemotherapy, targeted therapy, radiation therapy, immunotherapy, or other clinical trial therapies within 2 weeks before starting the study treatment. You may continue using hydroxyurea or cytarabine to control white blood cell count during this period.

What data supports the effectiveness of the drug combination HC-7366, Azacitidine, and Venetoclax for treating acute myeloid leukemia (AML)?

Research shows that the combination of venetoclax and azacitidine improves remission rates and survival in older or unfit patients with newly diagnosed AML compared to azacitidine alone. Additionally, venetoclax-azacitidine significantly prolonged overall survival in patients ineligible for intensive chemotherapy. ^{1 2 3 4 5}

Is the combination of HC-7366, Azacitidine, and Venetoclax safe for humans?

The combination of Venetoclax and Azacitidine has been studied in patients with acute myeloid leukemia (AML) and is generally considered safe, though common side effects include blood-related issues. These studies did not include HC-7366, so its safety in combination with the other two drugs is not addressed. ^{2 6 7 8 9}

What makes the drug combination of HC-7366, Azacitidine, and Venetoclax unique for treating AML?

The combination of HC-7366 with Azacitidine and Venetoclax is unique because it adds a novel component, HC-7366, to the existing regimen of Azacitidine and Venetoclax, which is already used for older or unfit patients with acute myeloid leukemia (AML) to improve remission rates and survival. This combination may offer a new option for patients who do not benefit from the standard Azacitidine and Venetoclax treatment, especially those with specific genetic mutations like TP53. ^{1 4 10 11 12}

Research Team

Abhishek Maiti, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults (≥18 years) with relapsed or refractory Acute Myeloid Leukemia (AML), excluding acute promyelocytic leukemia, who have no standard treatment options left. They must understand the study and consent to it, have good liver and kidney function, use contraception, and may join post-bone marrow transplant under certain conditions.

Inclusion Criteria

Participants must agree to use adequate contraception.

My liver and kidneys are working well.

I have been diagnosed with AML or MDS/AML with 10-19% blasts.

Exclusion Criteria

A known hypersensitivity or severe allergy to study drug components or diluents.

Pregnant women and breastfeeding women are excluded from this study.

First-degree relatives of the investigator, study staff or industry sponsor are excluded.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive HC-7366 once daily while fasting, on days 1-28

4 weeks

Daily administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Monitoring for adverse events and survival outcomes

Up to 1 year

Treatment Details

Interventions

• Azacitidine
• HC-7366
• Venetoclax

Trial Overview The trial is testing a new drug combination for AML: HC-7366 with azacitidine and venetoclax. The goal is to determine the safest dose of HC-7366 that can be used alongside these drugs while assessing their combined effects on AML.

Participant Groups

Group I: Dose Escalation Experimental Treatment 1 Intervention

If you are found to be eligible to take part in this study, you will be assigned to a dose level of HC-7366 based on when you join this study. Participants enrolled will receive HC-3766 single agent. HC-3766 will be taken once daily while fasting, 1 hour before or 2 hours after a meal, on days 1-28.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

HiberCell, Inc.

Industry Sponsor

Trials

20

Recruited

860+

Findings from Research

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]

The combination of venetoclax, azacitidine, and homoharringtonine (VAH) resulted in a high composite complete remission rate of 70.8% in patients with relapsed or refractory acute myeloid leukemia (R/R AML), indicating strong efficacy of this treatment regimen.

Patients treated with VAH had a median overall survival of 22.1 months and a 1-year overall survival rate of 61.5%, suggesting that this regimen not only effectively induces remission but also improves survival outcomes in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Combined with Azacitidine and Homoharringtonine in Relapsed/Refractory AML: A Multicenter, Phase 2 Trial. Jin, H., Zhang, Y., Yu, S., et al.[2023]

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 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 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

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]

Venetoclax, when combined with azacitidine, has shown effectiveness in treating a 73-year-old patient with acute myeloid leukemia (AML) who was undergoing dialysis and ineligible for standard therapies.

The combination of venetoclax and azacitidine appears to be a safe and feasible treatment option for AML patients with comorbidities, such as those requiring dialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration of combined venetoclax and azacitidine in a patient with acute myeloid leukemia and multiple comorbidities undergoing dialysis: A case report. Akagi, Y., Yamashita, Y., Kosako, H., 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]

In a study of 12 older adults (median age 74) with acute myeloid leukemia (AML), individualized dosing of venetoclax using therapeutic drug monitoring (TDM) showed that many patients had higher plasma concentrations than previously reported, suggesting a need for dose adjustments based on individual factors.

The study found a negative correlation between body surface area (BSA) and venetoclax concentrations, indicating that smaller patients, particularly those over 75 years old, may benefit from TDM to optimize treatment and enhance safety, especially when taking CYP3A4 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utility of therapeutic drug monitoring of venetoclax in acute myeloid leukemia. Kobayashi, M., Yasu, T., Suzaki, K., et al.[2022]

References

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

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

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

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

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

Venetoclax Combined with Azacitidine and Homoharringtonine in Relapsed/Refractory AML: A Multicenter, Phase 2 Trial. [2023]

4. 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]

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

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

6. England pubmed.ncbi.nlm.nih.gov

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

7. England pubmed.ncbi.nlm.nih.gov

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

8. China pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Administration of combined venetoclax and azacitidine in a patient with acute myeloid leukemia and multiple comorbidities undergoing dialysis: A case report. [2023]

11. 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]

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

Utility of therapeutic drug monitoring of venetoclax in acute myeloid leukemia. [2022]