Pembrolizumab + Decitabine with or without Venetoclax for Acute Myeloid Leukemia or Myelodysplastic Syndrome

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Steroids, Immunosuppressants, CYP3A4 inducers

Disqualifiers: Previous transplant, Active CNS disease, others

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

Compensation: Varies

Number of Visits: 7

Duration: Up to 1 year

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new ways to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) using a combination of medicines. It examines how well pembrolizumab, an immunotherapy drug, works with decitabine, a chemotherapy drug, and sometimes venetoclax, to combat these blood cancers. The goal is to determine the safest and most effective dose of pembrolizumab when combined with the other drugs. This trial may suit individuals with AML or MDS that is newly diagnosed, has returned, or does not respond to current treatments. Participants should have symptoms affecting daily life but should not be suitable candidates for certain intense treatments like stem cell transplants.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot use certain medications like systemic steroids or strong CYP3A4 inducers before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research has shown that the combination of pembrolizumab and decitabine has been tested in patients with hard-to-treat blood cancers. Some studies found that this combination is generally well-tolerated. However, like any treatment, side effects can occur, such as tiredness, nausea, and low blood cell counts.

Researchers have also studied adding venetoclax to this mix. Venetoclax is already approved for some blood cancers, and when used with decitabine, it has been administered to patients outside of the hospital. This suggests it is somewhat safe, though side effects like low blood counts and infections have been reported.

Since this trial is in an early stage, it focuses on finding the best dose and identifying side effects. While there is some evidence of safety, more research is needed to fully understand how people handle these treatments together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) because they combine innovative drugs to potentially enhance treatment outcomes. Unlike standard chemotherapy, which mainly targets rapidly dividing cells, this approach uses pembrolizumab, an immune checkpoint inhibitor that unleashes the body's immune system to attack cancer cells. Adding decitabine, a hypomethylating agent, may further enhance this effect by modifying the expression of genes involved in cancer growth. In one arm of the trial, venetoclax is included, which blocks a protein that helps cancer cells survive, offering a multi-pronged attack on the disease. This combination strategy might provide a more effective treatment with the potential for longer-lasting remissions compared to existing options.

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

Research has shown that combining pembrolizumab and decitabine may help treat blood cancers like acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In earlier studies, this combination helped some patients whose AML had returned. Pembrolizumab boosts the immune system to fight cancer cells, while decitabine aids in creating normal blood cells and kills cancer cells. In this trial, some participants will receive pembrolizumab and decitabine alone, while others will receive an additional treatment with venetoclax. Adding venetoclax blocks a protein that cancer cells need to survive, potentially enhancing the treatment's effectiveness. Early results are promising, with some patients showing better response rates and longer survival. ^{1 2 3 6 7}

Who Is on the Research Team?

Vaibhav Agrawal

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults with newly-diagnosed, recurrent, or treatment-resistant acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Participants must be in good physical condition (ECOG status <=1), have a life expectancy of at least 3 months, and cannot be candidates for stem cell transplantation within the next 90 days. They should not have had certain previous treatments that were unsuccessful and must agree to use effective contraception.

Inclusion Criteria

My AML or MDS has not responded to previous treatments and I am not a candidate for a stem cell transplant or curative chemotherapy.

I am capable of becoming pregnant or fathering a child.

My AML has returned or didn't respond to treatment, and I can't have a stem cell transplant or curative chemo.

Exclusion Criteria

I haven't taken strong or moderate CYP3A4 inducers in the last 14 days.

I have a heart condition.

I have not been treated with drugs targeting PD-1, PD-L1, PD-L2, or similar.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive pembrolizumab and decitabine, with or without venetoclax, in cycles of 42 days for up to 8 cycles or 1 year

Up to 1 year

Visits on days 1, 5, 10, and 22 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

2 years

Follow-up at 6, 12, and 24 months post-treatment start; every 3 months if progressed

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Pembrolizumab
• Venetoclax

Trial Overview The trial is testing the safety and optimal dosage of pembrolizumab combined with decitabine, with or without venetoclax. Pembrolizumab is an immunotherapy drug; decitabine helps produce normal blood cells by affecting DNA; venetoclax targets proteins essential for cancer cell survival. The goal is to see how well these drugs work together against AML/MDS.

How Is the Trial Designed?

Group I: Cohort II (pembrolizumab, decitabine) Experimental Treatment 2 Interventions

Patients with MDS receive pembrolizumab IV over 30 minutes on days 1 and 22 and decitabine over 1 hour on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.

Group II: Cohort I Arm II (pembrolizumab, decitabine, venetoclax) Experimental Treatment 3 Interventions

Patients with pembrolizumab IV over 30 minutes on days 1 and 22 and decitabine IV over 1 hour on days 1-10 or 1-5. Patients who achieve a CR receive decitabine on days 1-5. Patients also receive venetoclax PO QD on days 1-14. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.

Group III: Cohort I Arm I (pembrolizumab, decitabine) Experimental Treatment 2 Interventions

Patients receive pembrolizumab IV over 30 minutes on days 1 and 22 and decitabine IV over 1 hour on days 1-10. Patients who achieve a CR receive decitabine on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.

Decitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

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+

Published Research Related to This Trial

In a phase 2 trial involving 168 patients with acute myeloid leukaemia (AML), the combination of venetoclax and a 10-day regimen of decitabine resulted in a high overall response rate of 74%, with particularly impressive results in newly diagnosed AML patients (89%).

The treatment demonstrated a manageable safety profile, with common adverse events including neutropenia and infections, and a 30-day mortality rate of only 3.6%, indicating that this combination therapy is both effective and relatively safe for older patients or those unfit for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. DiNardo, CD., Maiti, A., Rausch, CR., et al.[2021]

Older patients with acute myeloid leukemia, especially those deemed unfit, face poor outcomes due to high early mortality from intensive treatments; however, recent advancements in genetic technology have led to mutation-targeted therapies that improve treatment options.

Targeted therapies, including FLT3, Bcl-2, IDH inhibitors, and anti-CD33 antibody-drug conjugates, offer new hope for unfit patients by potentially reducing toxicity and overcoming drug resistance, thus changing the treatment landscape for this challenging group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment options for older unfit patients with acute myeloid leukemia. Tang, H., Jia, S., Bi, L., et al.[2021]

In a 24-week study involving 358 patients with rheumatoid arthritis who did not respond adequately to methotrexate, decernotinib (VX-509) significantly improved symptoms, with ACR20 response rates of up to 68.1% compared to 18.3% in the placebo group.

While VX-509 showed efficacy in reducing disease activity, safety concerns included headaches and elevated liver enzymes, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VX-509 (Decernotinib), an Oral Selective JAK-3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis. Genovese, MC., van Vollenhoven, RF., Pacheco-Tena, C., et al.[2016]

Decitabine, administered at a dose of 20 mg/m² for 5 consecutive days, has been approved for older patients (≥65 years) with acute myeloid leukaemia (AML) who cannot undergo standard treatment, showing clinically meaningful improvements in overall survival after extended follow-up.

In a pivotal phase III trial, decitabine demonstrated significantly higher complete remission rates compared to standard treatment options like cytarabine, with a safety profile similar to cytarabine, including common side effects like fever and low blood cell counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine: a review of its use in older patients with acute myeloid leukaemia. Curran, MP.[2021]

Low-dose decitabine has been shown to improve the overall response rate in elderly patients with acute myeloid leukemia (AML) compared to standard treatment options, although the median overall survival remains less than one year.

The combination of low-dose decitabine with venetoclax significantly enhances both the overall response rate and median overall survival in elderly AML patients, indicating a promising treatment strategy for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The history of oral decitabine/cedazuridine and its potential role in acute myeloid leukemia. Briski, R., Garcia-Manero, G., Kantarjian, H., et al.[2023]

The optimal biologic dose (OBD) of decitabine for treating acute myeloid leukemia (AML) was determined to be 20 mg/m²/day, which showed limited nonhematologic toxicity and promising clinical activity, with a response rate of 44% among 25 patients.

Combining decitabine with valproic acid (VA) resulted in dose-limiting encephalopathy at lower doses of VA, indicating safety concerns, while the clinical responses were similar whether patients received decitabine alone or in combination with VA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. Blum, W., Klisovic, RB., Hackanson, B., et al.[2019]

In a study involving 145 older patients (median age 74) with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of venetoclax with decitabine or azacitidine resulted in a high complete remission (CR) rate of 67%, demonstrating its efficacy in this challenging population.

The treatment was well tolerated, with no cases of tumor lysis syndrome reported, and the median overall survival was 17.5 months, indicating that venetoclax combined with hypomethylating agents is a promising option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. DiNardo, CD., Pratz, K., Pullarkat, V., et al.[2021]

JAK inhibitors (jakinibs) like tofacitinib, upadacitinib, and others have shown significant efficacy in treating moderate-to-severe rheumatoid arthritis (RA) in patients who did not respond to conventional or biological treatments, with upadacitinib demonstrating the best overall results.

While most jakinibs are generally safe, tofacitinib was associated with 11 deaths in clinical studies, indicating a need for caution, especially in patients with severe liver and kidney disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current jakinibs for the treatment of rheumatoid arthritis: a systematic review. Rocha, CM., Alves, AM., Bettanin, BF., et al.[2021]

In a phase 1b study involving 57 elderly patients with acute myeloid leukaemia, the combination of venetoclax with hypomethylating agents (decitabine or azacitidine) showed promising efficacy, with 61% of patients achieving complete remission or complete remission with incomplete marrow recovery.

The treatment was generally well-tolerated, with the most common serious adverse events being febrile neutropenia and thrombocytopenia, but no cases of tumor lysis syndrome were observed, indicating a favorable safety profile for this novel regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. DiNardo, CD., Pratz, KW., Letai, A., et al.[2023]

Decitabine has been approved for treating older patients (65 years and older) with newly diagnosed acute myeloid leukemia (AML) who cannot undergo standard chemotherapy, showing a median overall survival of 7.7 months compared to 5.0 months for those receiving low-dose cytarabine or supportive care.

The treatment demonstrated improved response rates and progression-free survival, with a manageable safety profile, making it a valuable option for older patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use. Nieto, M., Demolis, P., Béhanzin, E., et al.[2018]

In a study comparing older adults with newly diagnosed acute myeloid leukemia (AML), those treated with the combination of decitabine (DEC) and venetoclax (VEN) had a significantly longer median overall survival of 13.4 months compared to 8.3 months for those receiving DEC alone.

The combination therapy also resulted in a higher response rate of 70.3% versus 24.3% for DEC monotherapy, indicating that DEC+VEN is more effective in treating AML without increasing short-term mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. Kwag, D., Cho, BS., Bang, SY., et al.[2022]

In randomized clinical trials, treatment of rheumatoid arthritis with biologic DMARDs (b-DMARDs) or tofacitinib does not significantly increase the overall risk of malignancies, with odds ratios indicating no heightened risk for most treatments.

Long-term extension studies showed some numerical differences in the incidence of specific malignancies, but the overall findings suggest that ongoing monitoring of patients is necessary to ensure safety in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: Systematic review, meta-analysis, and network meta-analysis. Maneiro, JR., Souto, A., Gomez-Reino, JJ.[2022]

JAK inhibitors, such as tofacitinib and baricitinib, show superior efficacy compared to methotrexate in treating early rheumatoid arthritis (RA) patients who have not previously received treatment, and they are equally or more effective than adalimumab in certain cases.

While JAK inhibitors are effective, they carry a risk of serious infections similar to other advanced RA therapies, with a notably higher incidence of herpes zoster reactivation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Janus kinase inhibitors in the treatment of rheumatoid arthritis: a systemic literature review. Jegatheeswaran, J., Turk, M., Pope, JE.[2020]

In a study of 22 heavily pre-treated patients with relapsed or refractory acute myeloid leukaemia (RR-AML), the combination of venetoclax and decitabine resulted in a 45.5% overall response rate, with 40.9% achieving complete remission, demonstrating its efficacy in a real-world setting.

While the treatment was effective, it was associated with significant side effects, including grade IV neutropenia and thrombocytopenia in all patients, but no deaths were attributed to the treatment side effects, indicating that the adverse effects were manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. Tong, J., Zhao, N., Hu, X., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8753450/

Pembrolizumab and decitabine for refractory or relapsed ... The feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML).

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03969446

Pembrolizumab and Decitabine With or Without Venetoclax ... This phase Ib trial studies the side effects and best dose of pembrolizumab and how well it works in combination with decitabine with or without venetoclax ...

3. ashpublications.org ashpublications.org/bloodadvances/article/9/15/3907/546402/Targeting-PD-1-for-HCT-relapse-an-immunologic

Targeting PD-1 for HCT relapse: an immunologic knife's edge What is clear from the data is that the potential benefit of PD-1 checkpoint inhibition for the treatment of MDS/AML relapse after HCT must be ...

4. tandfonline.com tandfonline.com/doi/full/10.1080/10428194.2022.2034155

Pembrolizumab for myelodysplastic syndromes after failure ... The phase 1b multicohort KEYNOTE-013 study assessed the safety and antitumor activity of pembrolizumab given at 10 mg/kg/day every 2 weeks for up to 2 years.

5. rarediseaseadvisor.com rarediseaseadvisor.com/features/immunotherapeutics-emerge-promising-treatments-myelodysplastic-syndromes/

Immunotherapeutics Emerge as Promising Treatments for ... Preclinical studies and early-phase clinical trials have shown encouraging results, indicating improved overall responses and survival rates in ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8475606/

Myelodysplastic syndrome and immunotherapy novel to next ... This next section will focus on safety and efficacy outcomes reported from CPI-based clinical trials. Only select CPI trials with preliminary or completed data ...

7. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT05703542?draw=2&rank=1

BXCL701 Phase 1 R/R Acute Myeloid Leukemia or ... The goal of this research study is to find the safest and most effective dose of the study drug, BXCL701, for the treatment of Acute Myeloid Leukemia (AML) ...