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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of a new drug, HC-7366, for treating certain types of acute myeloid leukemia (AML). Researchers are evaluating the safety and effects of HC-7366 in combination with two other drugs, Azacitidine (a chemotherapy drug) and Venetoclax (a targeted therapy). The trial seeks adults with AML that hasn't responded to standard treatments or has recurred after treatment. Participants should have experienced frequent setbacks or relapses that affect their daily lives.

As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

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.

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

Research has shown that HC-7366 has promising results in early studies for treating acute myeloid leukemia (AML). The FDA has fast-tracked this drug, indicating potential benefits and safety. Although detailed safety data is not yet available, researchers are closely monitoring participants' responses due to the early phase of the study. This phase focuses on finding a safe dosage, so they are carefully observing any side effects.

Azacitidine and Venetoclax, already approved for other uses, have been shown to be safe in those contexts. However, their use with HC-7366 is new. Overall, while data remains limited, these treatments are being studied with safety as a top priority. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for acute myeloid leukemia (AML), which often include chemotherapy or targeted therapies like azacitidine and venetoclax, HC-7366 introduces a novel approach. Researchers are excited about HC-7366 because it has a unique mechanism of action that could potentially enhance the effectiveness of existing treatments. This drug is taken orally, which can be more convenient compared to traditional intravenous methods. By potentially offering a new way to tackle AML, HC-7366 might help improve outcomes for patients who do not respond well to current options.

What evidence suggests that this trial's treatments could be effective for AML?

Research has shown that HC-7366, which participants in this trial may receive, holds promise for treating acute myeloid leukemia (AML). In animal studies, the cancer completely disappeared in all cases. HC-7366 activates a protein called GCN2, which helps kill cancer cells. It has also reduced cancer cells in models using patient samples. The FDA has fast-tracked HC-7366, recognizing its potential for patients whose AML has returned or not responded to other treatments. ^{1 2 3 4 6}

Who Is on the Research Team?

Abhishek Maiti, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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]

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 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]

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 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 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 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06285890

Phase I Study of HC-7366 for Acute Myeloid Leukemia Primary Objective: - To evaluate safety of HC-7366. Secondary Objectives: To estimate rate of CR/CRh/CRi by 4 cycles; To estimate overall response rate (ORR) ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123095459

Activation of GCN2 By HC-7366 Results in Significant Anti ... The in vivo efficacy of HC-7366 in both CDX and PDX models was independent of TP53 mutation, resulting in 100% complete response and 100% tumor ...

3. targetedonc.com targetedonc.com/view/fda-fast-tracks-hc-7366-in-relapsed-refractory-acute-myeloid-leukemia

FDA Fast Tracks HC-7366 in Relapsed/Refractory Acute ... The FDA has granted fast track designation to HC-7366 for the treatment of adult patients with relapsed/refractory acute myeloid leukemia (AML).

4. hibercell.com hibercell.com/wp-content/uploads/2023/01/GCN2-Poster-AACR-AML-2023-with-fonts.pdf

activation of gcn2 by hc-7366 results in significant anti- ... Furthermore, we tested HC-7366 in a xenotransplantable model of patient- derived AML and found that HC-7366 significantly reduced mature myeloid (CD33+) AML.

5. onclive.com onclive.com/view/fda-grants-fast-track-designation-to-hc-7366-in-relapsed-refractory-aml

FDA Grants Fast Track Designation to HC-7366 ... - OncLive HC-7366 has received FDA fast track designation for the treatment of adult patients with relapsed/refractory acute myeloid leukemia.

6. hibercell.com hibercell.com/news/hibercell-maps-forward-path-for-novel-gcn2-activator-hc-7366-in-acute-myeloid-leukemia-aml/

HiberCell Maps Forward Path for Novel GCN2 Activator ... HiberCell Maps Forward Path for Novel GCN2 Activator, HC-7366 in Acute Myeloid Leukemia (AML). In vitro and in vivo results demonstrated ...