Pembrolizumab + Azacitidine + Venetoclax for Acute Myeloid Leukemia

Recruiting at 38 trial locations

Overseen By Amer Zeidan

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Monoclonal antibodies, Corticosteroids

Disqualifiers: CBF-AML, APL, Active CNS disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 7

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining three drugs—azacitidine, venetoclax, and pembrolizumab—in treating newly diagnosed acute myeloid leukemia (AML) in older patients. Azacitidine and venetoclax are chemotherapy drugs that inhibit cancer cell growth, while pembrolizumab is an immunotherapy that aids the immune system in fighting cancer. Researchers aim to determine if adding pembrolizumab can enhance treatment outcomes. This trial is open to patients newly diagnosed with AML who have not yet received intensive chemotherapy. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in AML treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, certain medications like hydroxyurea and ATRA should be discontinued before starting the study therapy. It's best to discuss your specific medications with the trial team.

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

Research shows that azacitidine and venetoclax are generally well-tolerated by patients with acute myeloid leukemia (AML). These drugs already treat newly diagnosed AML in patients who cannot undergo intensive chemotherapy. Patients taking these drugs report manageable side effects, making them a good option for many.

The safety of adding pembrolizumab to this treatment is still under study. Early results suggest this combination might cause some additional side effects, but they are usually not serious. These side effects may include fatigue and nausea. Overall, evidence suggests this combination is relatively safe, but further research is underway to confirm its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute myeloid leukemia because they bring together unique mechanisms that could enhance how the immune system fights cancer. Pembrolizumab is an immune checkpoint inhibitor that helps the body's immune cells recognize and attack cancer cells. Unlike standard chemotherapy, this combination also includes azacitidine and venetoclax, which work to disrupt cancer cell growth and survival. This multi-faceted approach aims to improve outcomes by not only directly targeting cancer cells but also boosting the immune response, offering hope for more effective treatment options.

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

Research has shown that using azacitidine and venetoclax together can help treat patients with newly diagnosed acute myeloid leukemia (AML), particularly those unable to undergo intensive treatments. Azacitidine stops cancer cells from growing, while venetoclax targets a protein that helps these cells survive. In this trial, one group of participants will receive this combination of azacitidine and venetoclax.

Another group will receive azacitidine, venetoclax, and pembrolizumab. Pembrolizumab boosts the immune system to help the body fight cancer. Adding pembrolizumab might improve treatment by enhancing patient response and reducing the chance of leukemia recurrence. However, studies have not shown significant improvement when pembrolizumab is added to azacitidine and venetoclax. This trial aims to determine if pembrolizumab can offer additional benefits in treating AML. ^{1 2 4 6 7}

Who Is on the Research Team?

Amer M. Zeidan

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for patients aged 60 or older with newly diagnosed acute myeloid leukemia who are unfit for intensive chemotherapy. They should have an ECOG performance status of 0-3, specific risk profiles of AML, and adequate organ function. Pregnant women, those unwilling to use contraception, and individuals with certain medical conditions or prior treatments are excluded.

Inclusion Criteria

My AML is not considered low risk, except for a good-risk cytogenetic profile.

Bone marrow biopsy, aspirate or peripheral blood obtained up to 3 weeks before signing consent allowed for confirming AML diagnosis

Willingness to use adequate contraception for female and male patients with partners of childbearing potential

Exclusion Criteria

I don't have any health issues that could affect the trial's results or my participation.

You have a mental illness or social situation that might make it difficult for you to follow the study guidelines.

I have or had lung inflammation treated with steroids.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction Therapy

Patients receive azacitidine and venetoclax with or without pembrolizumab for up to 6 cycles

24 weeks

Weekly visits for drug administration

Maintenance Therapy

Patients continue azacitidine and venetoclax with or without pembrolizumab for up to 24 cycles

Up to 3 years

Monthly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Pembrolizumab
• Venetoclax

Trial Overview The study tests azacitidine and venetoclax combined with pembrolizumab (an immunotherapy drug) against the same chemotherapy drugs without pembrolizumab. The goal is to see if adding pembrolizumab improves treatment outcomes in these patients by helping the immune system fight cancer more effectively.

How Is the Trial Designed?

Group I: Arm II (AZA, VEN, pembrolizumab) Experimental Treatment 9 Interventions

See Detailed Description

Group II: Arm I (AZA, VEN) Active Control 8 Interventions

See Detailed Description

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 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 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 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 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 nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., 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]

A lower dosage of Venetoclax (100 mg) combined with Azacitidine showed favorable outcomes in newly diagnosed acute myeloid leukemia (AML) patients, with a median overall survival of 17 months and an overall response rate of 69.4% based on a study of 36 patients.

The study suggests that even with dose reductions of Venetoclax, the combination therapy remains effective, indicating a potential strategy to manage therapy-related toxicity while still achieving significant treatment responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia. Cui, J., Chen, X., Li, C., et al.[2023]

Citations

1. onclive.com onclive.com/view/dr-shallis-on-data-for-pembrolizumab-plus-venetoclax-azacitidine-in-aml

Dr Shallis on Data for Pembrolizumab Plus Venetoclax ... Shallis concludes that although the addition of pembrolizumab to azacitidine and venetoclax did not improve outcomes, the findings underscore ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04284787

NCT04284787 | BLAST MRD AML-2: BLockade of PD-1 ... Giving azacitidine and venetoclax with pembrolizumab may increase the rate of deeper/better responses and reduce the chance of the leukemia coming back in ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12135334/

Efficacy and safety of venetoclax and azacitidine for acute ... Venetoclax (VEN) and azacitidine (AZA) are used to treat patients with newly diagnosed acute myeloid leukaemia (AML) who are unfit for intensive ...

4. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper210370.html

Paper: Efficacy and Safety of Pembrolizumab Added to ... We report results of a randomized, phase II trial of AZA+VEN +/- PD-1 inhibition for pts with AML ineligible for intensive induction (NCI10334, ...

5. cancernetwork.com cancernetwork.com/view/mipletamig-soc-achieved-complete-remission-rates-in-front-line-aml

Mipletamig/SOC Achieved Complete Remission Rates in ... Results from the RAINIER trial showed that mipletamig, venetoclax, and azacitidine achieved a complete remission rate of 90% in patients with AML.

6. cancernetwork.com cancernetwork.com/view/venetoclax-azacitidine-yields-sustained-survival-in-aml

Venetoclax/Azacitidine Yields Sustained Survival in AML Long-term survival improved with the use of venetoclax (Venclexta) plus azacitidine (Vidaza) for patients with newly diagnosed acute myeloid leukemia (AML).

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6624910/

Novel therapy in Acute myeloid leukemia (AML) This paper reviews the novel therapies approved for AML as well as the pipeline of compounds likely to affect treatment in the near future.