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

Trial Summary

What is the purpose of this trial?

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 in treating patients with acute myeloid leukemia or myelodysplastic syndrome that is newly-diagnosed, has come back (recurrent), or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. This trial may help doctors find the best dose of pembrolizumab that can be safely given in combination with decitabine with or without venetoclax, and to determine what side effects are seen with this treatment.

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.

What data supports the effectiveness of the drugs Pembrolizumab, Decitabine, and Venetoclax for treating Acute Myeloid Leukemia or Myelodysplastic Syndrome?

The review on treatment options for older unfit patients with acute myeloid leukemia highlights the use of mutation-targeted therapies, such as Bcl-2 inhibitors like Venetoclax, which have significantly changed the treatment landscape for this condition, suggesting potential effectiveness in combination strategies. ^{1 2 3 4 5}

Is the combination of Pembrolizumab, Decitabine, and Venetoclax safe for humans?

Decitabine and Venetoclax have been studied in older patients with acute myeloid leukemia (AML) and are generally well tolerated, with common side effects including nausea, diarrhea, and low blood cell counts. No tumor lysis syndrome (a serious condition caused by the rapid breakdown of cancer cells) was observed in the study of Venetoclax with Decitabine. ^{6 7 8 9 10}

What makes the drug combination of Pembrolizumab, Decitabine, and Venetoclax unique for treating Acute Myeloid Leukemia or Myelodysplastic Syndrome?

This treatment is unique because it combines Pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with Decitabine and Venetoclax, which are known to work well together in older patients or those unfit for intensive chemotherapy, potentially offering a more effective option for high-risk patients. ^{7 11 12 13 14}

Research Team

Vaibhav Agrawal

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 (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]

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Treatment options for older unfit patients with acute myeloid leukemia. [2021]

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

VX-509 (Decernotinib), an Oral Selective JAK-3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis. [2016]

3. United States 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. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Current jakinibs for the treatment of rheumatoid arthritis: a systematic review. [2021]

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

Comparison of Janus kinase inhibitors in the treatment of rheumatoid arthritis: a systemic literature review. [2020]

6. New Zealand pubmed.ncbi.nlm.nih.gov

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

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

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. [2021]

8. England pubmed.ncbi.nlm.nih.gov

The history of oral decitabine/cedazuridine and its potential role in acute myeloid leukemia. [2023]

9. England 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. [2018]

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

Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. [2019]

11. England 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. [2021]

12. New Zealand 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. [2022]

13. England 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. [2023]

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

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. [2022]