Pembrolizumab + Decitabine with or without Venetoclax for Acute Myeloid Leukemia or Myelodysplastic Syndrome
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: City of Hope Medical Center
Must not be taking: Steroids, Immunosuppressants, CYP3A4 inducers
Disqualifiers: Previous transplant, Active CNS disease, others
No Placebo Group
Breakthrough Therapy
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.
12345Is 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.
678910What 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.
711121314Eligibility 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.
+25 more
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.
+27 more
Trial 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
Participant Groups
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.
3Treatment groups
Experimental Treatment
Group I: Cohort II (pembrolizumab, decitabine)Experimental Treatment2 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 Treatment3 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 Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope Comprehensive Cancer CenterDuarte, CA
City of Hope Medical CenterDuarte, CA
Loading ...
Who Is Running the Clinical Trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Treatment options for older unfit patients with acute myeloid leukemia. [2021]Older acute myeloid leukemia patients usually experience a bleak outcome, especially those in the unfit group. For this unfit category, intensive chemotherapy and allogeneic stem cell transplantation are usually accompanied by higher early mortality, which results from higher risk genetic profiles and worse psychological and physiological conditions. The significant improvement in genetic technology recently has driven the appearance of several mutation-targeted therapies, such as FLT3, Bcl-2, IDH and Hedgehog pathway inhibitors and an anti-CD33 antibody-drug conjugate, which have changed enormously the therapeutic landscape of acute myeloid leukemia. This review describes the treatment dilemma of the unfit group and discusses the objective clinical data of each targeted drug and mechanisms of resistance, with a focus on combination strategies with fewer toxicities and abrogation of drug resistance.
VX-509 (Decernotinib), an Oral Selective JAK-3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis. [2016]To assess the efficacy and safety of decernotinib (VX-509), an oral selective inhibitor of JAK-3, in patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate.
Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: Systematic review, meta-analysis, and network meta-analysis. [2022]To summarize and compare the risks of malignancies accompanying biologic DMARDs (b-DMARDs) and tofacitinib in rheumatoid arthritis (RA) in randomized clinical trials (RCTs) and long-term extension studies (LTEs).
Current jakinibs for the treatment of rheumatoid arthritis: a systematic review. [2021]One-third of patients with severe rheumatoid arthritis (RA) do not achieve remission or low disease activity, or they have side effects from cDMARD and bDMARD. They will need a new treatment option such as the small molecule JAK inhibitors. In this systematic review, we evaluate the efficacy and safety data of the current jakinibs: tofacitinib, peficitinib, decernotinib, upadacitinib, baricitinib and filgotinib in patients in whom treatment with conventional or biological disease-modifying antirheumatic drugs (cDMARD and/or bDMARD) failed.
Comparison of Janus kinase inhibitors in the treatment of rheumatoid arthritis: a systemic literature review. [2020]Several Janus kinase (JAK) inhibitors, oral targeted disease-modifying drugs, will be approved for the treatment of rheumatoid arthritis (RA) and other diseases. This review compares and contrasts the efficacy of JAK inhibitors (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib and decernotinib) in RA including: early RA methotrexate-naive patients, post methotrexate failure and post biologics. Trials in monotherapy, combination with disease modifying drugs such as methotrexate, and comparing with adalimumab in biologic-naive patients were studied. The efficacy is superior to methotrexate in naive patients and equal or superior to adalimumab depending on the drug and dose. There is a class effect of adverse events. Serious infections occur at a rate similar to other advanced therapies in RA, although more reactivation of herpes zoster occurs.
Decitabine: a review of its use in older patients with acute myeloid leukaemia. [2021]Decitabine (Dacogen(®)) is a deoxynucleoside analogue of cytidine that selectively inhibits DNA methyltransferases. Decitabine administered at a dose of 20 mg/m(2) by a 1-h intravenous infusion for 5 consecutive days of a 4-week cycle has been approved by the European Medicines Agency (EMA) for use in adult patients aged ≥65 years with de novo or secondary acute myeloid leukaemia (AML) who are not candidates for standard induction therapy. Decitabine, compared with treatment choice (cytarabine or supportive care), did not result in a statistically significant improvement in median overall survival (OS) in older patients with AML at the pre-specified primary endpoint of a pivotal phase III trial. However, the improvement in OS was considered by the EMA to be clinically meaningful. After a further year of follow-up, an analysis of the mature survival data demonstrated a statistical significance in median OS in favour of decitabine over treatment choice. Complete remission (CR) rates in the phase III trial were significantly improved with decitabine versus treatment choice. The overall safety profile of decitabine in older patients with AML was generally similar to that of cytarabine, with pyrexia, thrombocytopenia and anaemia being the most commonly reported adverse events. In conclusion, low-dose decitabine may be considered as an effective and generally well tolerated alternative treatment to cytarabine or supportive care in older patients with AML who are not candidates for standard induction therapy.
Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. [2021]Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).
The history of oral decitabine/cedazuridine and its potential role in acute myeloid leukemia. [2023]Decitabine, a member of the 5-azanucleosides, has a dose-dependent mechanism of action in vitro: termination of DNA replication at high doses, and inhibition of DNA methyltransferase at low doses. The alteration of DNA methylation patterns by low-dose decitabine is hypothesized to upregulate genes, which promote myeloblast differentiation. In a phase III clinical trial, low-dose decitabine achieved a superior overall response rate (ORR) when compared with 'treatment choice' [consisting of low-dose cytarabine (80%) and supportive care (20%)] as a frontline treatment for elderly patients with acute myeloid leukemia (AML). Despite an improved ORR, the median overall survival (OS) for elderly patients with AML was poor, <1 year. In turn, venetoclax was added to low-dose decitabine, the combination of which significantly improved the ORR and median OS in elderly patients with AML. Currently, hypomethylating agents are being combined with other novel therapies as investigational strategies for elderly and unfit patients with AML. They are also being evaluated as components of maintenance therapy in patients achieving remission. An oral formulation of decitabine has been developed which relies on the concomitant use of oral cedazuridine to protect against first pass metabolism. This oral formulation, which has been approved in myelodysplastic syndrome, is intended to increase convenience of use and therefore compliance in patients. This review characterizes the evolution of decitabine, its oral formulation, and its future in the treatment of AML.
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]: On September 20, 2012, a marketing authorization valid throughout the European Union (EU) was issued for decitabine for the treatment of adult patients aged 65 years and older with newly diagnosed de novo or secondary acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy. Decitabine is a pyrimidine analog incorporated into DNA, where it irreversibly inhibits DNA methyltransferases through covalent adduct formation with the enzyme. The use of decitabine was studied in an open-label, randomized, multicenter phase III study (DACO-016) in patients with newly diagnosed de novo or secondary AML. Decitabine (n = 242) was compared with patient's choice with physician's advice (n = 243) of low-dose cytarabine or supportive care alone. The primary endpoint of the study was overall survival. The median overall survival in the intent-to-treat (ITT) population was 7.7 months among patients treated with decitabine compared with 5.0 months for those in the control arm (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.04; p = .1079). Mature survival data after an additional year of follow-up were consistent with these results, with a median overall survival of 7.7 months in patients treated with decitabine and 5.0 months in the control arm (HR, 0.82; 95% CI, 0.68-0.99; p = .0373). Secondary endpoints, including response rates, progression-free survival, and event-free survival, were increased in favor of decitabine when compared with control treatment. The most common adverse drug reactions reported during treatment with decitabine are pyrexia, anemia, thrombocytopenia, febrile neutropenia, neutropenia, nausea, and diarrhea. This paper summarizes the scientific review of the application leading to approval of decitabine in the EU. The detailed scientific assessment report and product information (including the summary of product characteristics) for this product are available on the EMA website (http://www.ema.europa.eu).
Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. [2019]To determine an optimal biologic dose (OBD) of decitabine as a single agent and then the maximum-tolerated dose (MTD) of valproic acid (VA) combined with decitabine in acute myeloid leukemia (AML).
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]Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukaemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine that has shown promising results in patients with high-risk AML in phase 2 trials. We hypothesised that venetoclax with 10-day decitabine could have improved activity in patients with newly diagnosed AML and those with relapsed or refractory AML, particularly in high-risk subgroups.
Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. [2022]We report the efficacy and safety of venetoclax plus decitabine-based treatment in heavily pre-treated relapsed or refractory acute myeloid leukaemia (RR-AML) in a real-world setting.
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]Elderly patients (aged ≥65 years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study.
Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. [2022]Venetoclax (VEN) combined with azacitidine (AZA) or decitabine (DEC) has been approved for older adults with acute myeloid leukemia (AML) unfit for intensive chemotherapy based on the pivotal VIALE-A trial. However, this trial only compared AZA + VEN with AZA monotherapy. Therefore, we compared the outcomes of consecutive older adults (65 years or older) with newly diagnosed AML who received DEC (n = 230) or DEC + VEN (n = 74) after propensity score matching to construct a one-to-one matched cohort by the nearest neighbor algorithm. The median overall survival was longer in the DEC + VEN group than in the DEC group (13.4 months vs. 8.3 months, p = 0.01). The median event-free survivals were 8.6 and 5.8 months in the DEC + VEN and DEC groups, respectively (p = 0.02). The response rate (complete response, complete response with incomplete hematologic recovery, and morphologic leukemia-free state) was significantly higher in the DEC + VEN group than in the DEC group (70.3% vs. 24.3%, p