Trametinib + Azacitidine for Myelomonocytic Leukemia

Recruiting at 3 trial locations

Overseen By Ben Brookhart

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Therapeutic Advances in Childhood Leukemia Consortium

Must not be taking: MEK inhibitors

Disqualifiers: Infections, Noonan syndrome, Down syndrome, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 12 months for lower-risk, up to 2 months for high-risk

58 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot have had prior leukemia-directed therapy, except for certain medications like hydroxyurea and 6-mercaptopurine shortly before starting the trial. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Trametinib + Azacitidine for Myelomonocytic Leukemia?

Azacitidine has been shown to improve survival in patients with chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS), and it is considered a standard treatment for higher-risk MDS. Combining Azacitidine with other drugs has been suggested to potentially enhance outcomes, although specific data on Trametinib in this combination is not provided. ^{1 2 3 4 5}

Is the combination of Trametinib and Azacitidine safe for treating myelomonocytic leukemia?

Azacitidine has been studied extensively and is generally considered safe for treating conditions like myelomonocytic leukemia, though it can cause side effects such as anemia (low red blood cell count), neutropenia (low white blood cell count), and fatigue. Most side effects can be managed with additional medications, and treatment discontinuation due to side effects is rare. ^{6 7 8 9 10}

What makes the drug combination of Trametinib and Azacitidine unique for treating myelomonocytic leukemia?

The combination of Trametinib and Azacitidine is unique because it combines a MEK inhibitor (Trametinib) with a hypomethylating agent (Azacitidine), potentially offering a novel mechanism of action compared to traditional treatments. This combination may provide enhanced efficacy by targeting different pathways involved in leukemia cell growth and survival. ^{2 8 11 12 13}

What is the purpose of this trial?

This clinical trial will test the safety and efficacy of combining trametinib and azacitidine in patients with juvenile myelomonocytic leukemia (JMML). Newly diagnosed lower-risk JMML patients will receive trametinib and azacitidine. High-risk JMML patients will receive trametinib, azacitidine, fludarabine, and cytarabine.

Eligibility Criteria

This trial is for children and young adults up to 21 years old with newly diagnosed juvenile myelomonocytic leukemia (JMML). Participants must meet specific diagnostic criteria, including spleen enlargement, high monocyte counts, and no BCR/ABL fusion gene. They should also have a RAS mutation or clinical diagnosis of neurofibromatosis type 1.

Inclusion Criteria

I can do most activities by myself if I am 16 or older.

I have not received treatment for leukemia, except as specifically allowed.

My liver tests for bilirubin and ALT levels are within normal ranges.

Exclusion Criteria

I have been diagnosed with Noonan syndrome.

I have previously used growth factors, biologics, or radiation therapy.

I have an infection that hasn't improved with treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Lower-risk patients receive daily azacitidine for 5 days and trametinib for 28 days per course for up to 12 courses. High-risk patients receive daily azacitidine, fludarabine, and cytarabine for 5 days and trametinib for 28 days per course for up to 2 courses.

Up to 12 months for lower-risk, up to 2 months for high-risk

Follow-up

Participants are monitored for safety and effectiveness after treatment, including the incidence of dose limiting toxicities (DLTs) after the 1st course of therapy.

4 weeks

Treatment Details

Interventions

• Azacitidine
• Cytarabine
• Fludarabine
• Trametinib

Trial Overview The trial is testing the combination of trametinib and azacitidine in lower-risk JMML patients. High-risk patients will additionally receive fludarabine and cytarabine. It aims to determine how safe this treatment is and how effective it is at treating the disease.

Participant Groups

Group I: Lower-risk patients Experimental Treatment 2 Interventions

Lower-risk patients are defined as having a mutational burden of one clonal alteration AND a low DNA methylation classification.

Group II: High-risk patients Experimental Treatment 4 Interventions

High-risk patients are defined as having as having a mutational burden of more than one clonal alteration AND/OR an intermediate or high DNA methylation classification.

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?

Therapeutic Advances in Childhood Leukemia Consortium

Lead Sponsor

Trials

21

Recruited

680+

Findings from Research

A retrospective study of 54 patients with chronic myelomonocytic leukemia (CMML) and secondary acute myeloid leukemia (sAML) showed that a treatment regimen combining cladribine, low-dose cytarabine, and hypomethylating agents (CLAD/LDAC/HMA) resulted in a 33% overall response rate in CMML, with higher efficacy in patients who had not previously failed hypomethylating agents (50% response).

The median overall survival was significantly better for HMA-naive patients, with 14.4 months for HMA-naive CMML compared to only 8.8 months for those who had experienced HMA failure, indicating that CLAD/LDAC/HMA regimens may be particularly beneficial for newly diagnosed patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective study of cladribine and low-dose cytarabine-based regimens for the treatment of chronic myelomonocytic leukemia and secondary acute myeloid leukemia. Bazinet, A., Darbaniyan, F., Kadia, TM., et al.[2023]

In a study of 168 chronic myelomonocytic leukemia (CMML) patients over three decades, the median overall survival improved significantly from 10 months before 2000 to 23 months after, indicating advancements in treatment efficacy.

Patients treated with azacitidine (AZA) showed a notable survival benefit compared to those who did not receive AZA, particularly in subgroups with higher hemoglobin levels, monocytosis, and specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment options and survival in real life during the past three decades in patients with chronic myelomonocytic leukemia. Reiser, J., Geissler, K.[2023]

In a study of 91 patients with chronic myelomonocytic leukemia (CMML) treated with azacitidine (AZA), the overall response rate was 58% between cycles 4 and 6, indicating that AZA is effective for this patient group.

Nearly half of the patients achieved transfusion independence, and one quarter experienced clinical benefits, suggesting that AZA can be a viable treatment option for various CMML subtypes, including those with lower-risk profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to azacitidine in patients with chronic myelomonocytic leukemia according to overlap myelodysplastic/myeloproliferative neoplasms criteria. Triguero, A., Xicoy, B., Zamora, L., et al.[2022]

Azacitidine (AZA) is the standard frontline treatment for higher-risk myelodysplastic syndrome (MDS) and has been shown to significantly improve overall survival compared to conventional care in a phase III trial.

There is a need for further research to identify better prognostic factors for response to AZA and to explore combination therapies with other effective drugs to enhance treatment outcomes for patients with MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of advanced myelodysplastic syndrome with demethylating agents: azacitidine. Adès, L., Itzykson, R., Fenaux, P.[2013]

In a retrospective analysis of 5 boys with juvenile myelomonocytic leukemia (JMML) treated with azacitidine (AZA) in Japan, all patients tolerated the treatment well, with hematological toxicity being the main side effect.

Out of the 5 patients, 2 achieved a partial response to AZA, while 3 did not respond, highlighting the need for further studies to explore combination therapies for better outcomes in high-risk JMML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective analysis of azacitidine treatment for juvenile myelomonocytic leukemia. Honda, Y., Muramatsu, H., Nanjo, Y., et al.[2022]

In a study of 1406 patients receiving azacitidine, the most common severe adverse events were hematologic, with grade 3-4 anemia occurring in 43.4% of patients, which was higher than reported in clinical trials.

Despite the high frequency of adverse events, treatment discontinuation due to these events was low (5.1%), indicating that with proper management, azacitidine can be safely administered to most patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events in 1406 Patients Receiving 13,780 Cycles of Azacitidine within the Austrian Registry of Hypomethylating Agents-A Prospective Cohort Study of the AGMT Study-Group. Leisch, M., Pfeilstöcker, M., Stauder, R., et al.[2022]

Azacitidine (AZA) was found to be more effective than conventional care in treating patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), with overall response rates of 27% for MDS, 20% for AML, and 20% for CMML among 83 patients studied.

The treatment showed a median overall survival of 75% at 12 months for MDS and CMML patients, and 60% for AML patients, indicating a promising efficacy, although the most common side effects included myelosuppression and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real Life Data on Efficacy and Safety of Azacitidine Therapy for Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia. Helbig, G., Chromik, K., Woźniczka, K., et al.[2021]

In a study of 149 patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), azacitidine treatment resulted in a median progression-free survival (PFS) of 10.9 months and an overall survival (OS) of 14.1 months, demonstrating its effectiveness in a real-world clinical setting.

The safety profile of azacitidine was consistent with previous clinical trials, and factors such as Eastern Cooperative Oncology Group (ECOG) performance status and red blood cell transfusion prior to treatment were identified as predictive factors for better PFS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Wehmeyer, J., Zaiss, M., Losem, C., et al.[2019]

In a real-life study of 49 patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), azacitidine demonstrated a clinically acceptable safety profile, with 67.3% of patients experiencing treatment-related adverse events.

Efficacy results showed that 41.4% of MDS and CMML patients achieved a complete or partial response, and 43.8% of transfusion-dependent patients became transfusion-independent, with a median overall survival of 490 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. Beguin, Y., Selleslag, D., Meers, S., et al.[2015]

In a phase 1b/2b trial involving 113 patients with higher-risk myelodysplastic syndromes (MDS), the combination of panobinostat (PAN) and azacitidine (AZA) resulted in a higher rate of composite complete responses compared to AZA alone (27.5% vs 14.3%).

However, the combination treatment did not significantly improve overall survival or time to progression compared to AZA monotherapy, and it was associated with a higher incidence of severe adverse events and on-treatment deaths, indicating a need for further optimization of the treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts. Garcia-Manero, G., Sekeres, MA., Egyed, M., et al.[2018]

Current frontline treatments for acute myeloid leukemia (AML) using ara-C and topoisomerase II agents achieve complete response rates of 70%, but long-term survival remains low at 25%.

Newer agents like nucleoside analogs and hypomethylating agents show promise, with combination therapies yielding higher complete response rates, particularly when used alongside traditional treatments like ara-C.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New chemotherapeutic agents in acute myeloid leukemia. Kantarjian, HM., Estey, EH., Keating, MA.[2013]

Azacitidine is an effective and well-tolerated treatment for patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients who are ineligible for stem cell transplants, as demonstrated in pivotal phase 3 trials.

It is the only approved hypomethylating agent that has been shown to prolong overall survival compared to conventional care, making it the recommended first-line treatment for most patients with higher-risk MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. Scott, LJ.[2022]

Azacitidine (Vidaza) is the only drug approved in the EU that significantly prolongs survival in adults with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), making it a crucial treatment option for patients not eligible for stem cell transplantation.

The treatment is associated with a lower risk of AML progression and higher rates of remission and blood transfusion independence, while maintaining an acceptable safety profile, with peripheral cytopenias being the most common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2021]

References

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

A retrospective study of cladribine and low-dose cytarabine-based regimens for the treatment of chronic myelomonocytic leukemia and secondary acute myeloid leukemia. [2023]

2. Austria pubmed.ncbi.nlm.nih.gov

Treatment options and survival in real life during the past three decades in patients with chronic myelomonocytic leukemia. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Response to azacitidine in patients with chronic myelomonocytic leukemia according to overlap myelodysplastic/myeloproliferative neoplasms criteria. [2022]

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

Treatment of advanced myelodysplastic syndrome with demethylating agents: azacitidine. [2013]

5. Japan pubmed.ncbi.nlm.nih.gov

A retrospective analysis of azacitidine treatment for juvenile myelomonocytic leukemia. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events in 1406 Patients Receiving 13,780 Cycles of Azacitidine within the Austrian Registry of Hypomethylating Agents-A Prospective Cohort Study of the AGMT Study-Group. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Real Life Data on Efficacy and Safety of Azacitidine Therapy for Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia. [2021]

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

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). [2019]

9. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. [2015]

10. England pubmed.ncbi.nlm.nih.gov

A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts. [2018]

11. England pubmed.ncbi.nlm.nih.gov

New chemotherapeutic agents in acute myeloid leukemia. [2013]

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

Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. [2022]

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

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. [2021]