Trametinib + Azacitidine for Myelomonocytic Leukemia
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Therapeutic Advances in Childhood Leukemia Consortium
Must not be taking: MEK inhibitors
Disqualifiers: Infections, Noonan syndrome, Down syndrome, others
No Placebo Group
Breakthrough Therapy
Trial Summary
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.
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.12345
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.678910
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.28111213
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.
See 6 more
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.
See 6 more
Trial 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 (Nucleoside Analog)
- Cytarabine (Nucleoside Analog)
- Fludarabine (Nucleoside Analog)
- Trametinib (MEK Inhibitor)
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Group I: Lower-risk patientsExperimental Treatment2 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 patientsExperimental Treatment4 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, Australia 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
🇦🇺 Approved in Australia as Vidaza for:
- Myelodysplastic syndromes
- Acute myeloid leukemia
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's Hospital Los AngelesLos Angeles, CA
University of California San FranciscoSan Francisco, CA
Cincinnati Children's Hospital Medical CenterCincinnati, OH
Children's National Medical CenterWashington, United States
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Who Is Running the Clinical Trial?
Therapeutic Advances in Childhood Leukemia ConsortiumLead Sponsor
References
A retrospective study of cladribine and low-dose cytarabine-based regimens for the treatment of chronic myelomonocytic leukemia and secondary acute myeloid leukemia. [2023]Patients with higher risk chronic myelomonocytic leukemia (CMML) have limited therapeutic options beyond hydroxyurea and hypomethylating agents (HMAs). Regimens based on a backbone of cladribine (CLAD), low-dose cytarabine (LDAC), and an HMA are effective low-intensity therapies for acute myeloid leukemia (AML).
Treatment options and survival in real life during the past three decades in patients with chronic myelomonocytic leukemia. [2023]The impact of treatment on the outcome of chronic myelomonocytic leukemia (CMML) patients over a longer period of time and the potential role of predictive factors are not well defined. In a retrospective observational study, we analyzed 168 CMML patients regarding treatment options and survival during the past three decades. The proportion of patients treated with hydroxyurea (HU), intensive chemotherapy, and azacitidine (AZA) was 65/19/0% before 2000, 51/25/32% from 2000-2010, and 36/12/53% after 2010, respectively. Median overall survival (OS) increased from 10 months before 2000 to 23 months thereafter (p = 0.021). AZA-treated patients but not patients treated with other treatment options had improved survival as compared to CMML patients without AZA therapy (19 vs. 25 months, p = 0.041). When looking at subgroups, the following patient cohorts had a significant survival benefit in association with AZA therapy: patients with Hb > 10 g/dL, patients with monocytosis > 10 G/L, and patients with mutations in RASopathy genes.
Response to azacitidine in patients with chronic myelomonocytic leukemia according to overlap myelodysplastic/myeloproliferative neoplasms criteria. [2022]Azacitidine (AZA) is approved for the treatment of high-risk chronic myelomonocytic leukemia (CMML) of myelodysplastic (MD) subtype. Data of response rates using the specific response criteria for this disease are scarce. The aim of this study was to evaluate the response to AZA in patients diagnosed with CMML from the Spanish Registry of Myelodysplastic Syndromes (MDS) applying the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) response criteria.
Treatment of advanced myelodysplastic syndrome with demethylating agents: azacitidine. [2013]Azacitidine (AZA) improves long-term outcomes of higher-risk myelodysplastic syndrome (MDS) and is now the reference frontline therapy of higher-risk MDS not eligible for allogeneic stem cell transplant. Notably, in a phase III randomized trial, AZA significantly prolonged overall survival (OS) compared to conventional care regimens, in all cytogenetic subgroups. Nevertheless, further improvement of outcome for those patients is warranted, partly by researching for better prognostic factors of response to AZA, and also by developing new therapeutic strategies, in particular by combining AZA and other drugs known to have an effect in MDS. We review the prognostic factors of response and survival of patients treated with AZA, the combination of AZA with other drugs, and the use of AZA in specific situations, such as therapy-related MDS, chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), and in MDS/AML occurring in the course of myeloproliferative neoplasms (MPN).
A retrospective analysis of azacitidine treatment for juvenile myelomonocytic leukemia. [2022]Juvenile myelomonocytic leukemia (JMML) is a pediatric hematological malignancy with a poor prognosis. Although several case series have been published describing hematological and molecular responses to azacitidine (AZA) treatment in patients with JMML, the efficacy and safety profile of AZA is not well investigated, especially in Asian children and children undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed 5 patients who received a total of 12 cycles (median 2 cycles) of AZA treatment in Japan. All five patients were boys and their ages at the time of treatment were 21, 23, 24, 26, and 46 months, respectively. All five patients tolerated AZA treatment, including four patients who received AZA after HSCT. Therapeutic toxicity with AZA was mostly limited to hematological toxicity. The only serious non-hematological adverse event was hyperbilirubinemia (grades III-IV) observed in a patient who received AZA after a second HSCT. Two out of five patients treated with AZA achieved a partial response (PR), while three patients treated for post-transplant relapse did not have an objective response. Future prospective studies should be conducted to develop combination therapies with AZA and other molecular targeted drugs for high-risk patients.
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]Background: Azacitidine is the treatment backbone for patients with acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia who are considered unfit for intensive chemotherapy. Detailed reports on adverse events in a real-world setting are lacking. Aims: To analyze the frequency of adverse events in the Austrian Registry of Hypomethylating agents. To compare real-world data with that of published randomized clinical trials. Results: A total of 1406 patients uniformly treated with a total of 13,780 cycles of azacitidine were analyzed. Hematologic adverse events were the most common adverse events (grade 3-4 anemia 43.4%, grade 3-4 thrombopenia 36.8%, grade 3-4 neutropenia 36.1%). Grade 3-4 anemia was significantly more common in the Registry compared to published trials. Febrile neutropenia occurred in 33.4% of patients and was also more common in the Registry than in published reports. Other commonly reported adverse events included fatigue (33.4%), pain (29.2%), pyrexia (23.5%), and injection site reactions (23.2%). Treatment termination due to an adverse event was rare (5.1%). Conclusion: The safety profile of azacitidine in clinical trials is reproducible in a real-world setting. With the use of prophylactic and concomitant medications, adverse events can be mitigated and azacitidine can be safely administered to almost all patients with few treatment discontinuations.
Real Life Data on Efficacy and Safety of Azacitidine Therapy for Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia. [2021]The administration of azacitidine (AZA) was found to be more effective than conventional care regimen (CCR) in patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) with lower blast count. We designed a study to determine efficacy and safety of AZA therapy in "real life" patients with MDS, CMML and AML. The study included 83 patients (65% male) with a median age at diagnosis of 68 years. 43 patients were diagnosed with higher-risk MDS, 30 had AML and 10-CMML. Median AZA dose was comparable between treated groups. AZA dose reduction was required for 44% of MDS, 17% of AML and 25% of CMML patients. Complete remission (CR) was achieved in 14% of MDS, 7% of AML and 10% of CMML patients. Overall response rate was following: 27% for MDS, 20% for AML and 20% for CMML. Estimated OS at 12 months was 75% for MDS, 60% for AML and 75% for CMML. Median follow-up for MDS/AML/CMML from AZA initiation to last follow-up was 9.0, 9.4 and 9.4 months, respectively. The most common toxicity of AZA therapy was myelosuppression and infections. AZA treatment was effective in a limited number of patients with acceptable safety profile.
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]Label="OBJECTIVE" NlmCategory="OBJECTIVE">Azacitidine (Vidaza® ) is the standard treatment for patients with higher-risk myelodysplastic syndromes (MDS) not eligible for allogeneic stem cell transplantation. In the noninterventional study PIAZA, we evaluated the effectiveness and safety of azacitidine treatment in 149 patients with higher-risk MDS, chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) in routine clinical practice.
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]We evaluated azacitidine (Vidaza(®)) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed.
A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts. [2018]Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6-43.9%)) vs AZA (14.3% (5.4-28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50-80%); AZA, 70% (50-80%)) or time to progression (PAN+AZA, 70% (40-90%); AZA, 70% (40-80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.
New chemotherapeutic agents in acute myeloid leukemia. [2013]Only two classes of chemotherapeutic agents have shown activity in acute myeloid leukemia (AML): ara-C and topoisomerase II reactive agents. Frontline combinations of these agents produce complete response (CR) rates of 70% and long-term event free survival rates of 25%. New agents with different mechanisms of action are being explored. Nucleoside analogs such as chlorodeoxyadenosine (2-CdA) or fludarabine have shown single-agent efficacy and may be synergistic with ara-C. Combination therapy with ara-C and nucleoside analogs have shown promising results both as salvage therapy and in newly diagnosed patients. Combinations of topotecan with ara-C, VP16, and anthracyclines are being pursued, as is testing of other Topo-I inhibitors. Hypomethylating agents (5-azacytidine, decitabine) are showing activity in AML, producing CR rates of 5% to 30% as AML salvage therapy as a single agent, and 40%-60% in combinations. Decitabine may be synergistic with topo I inhibitors, biologic agents, and differentiating agents. Homoharringtonine has modest anti-AML activity, with CR rates of 10% to 30% as salvage therapy. Other classes of agents worthy of continuing investigation are platinum analogs and agents with novel mechanisms of action such as tallimustine.
Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. [2022]Azacitidine (Vidaza(®)) is a pyrimidine nucleoside analogue of cytidine and is approved in the EU for use in patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients (aged ≥65 years) with AML with >30 % bone marrow blasts (BMB) who are ineligible for haematopoietic stem cell transplant. This article reviews the clinical efficacy and tolerability of azacitidine in the treatment of these patient populations, as well as summarizing its pharmacological properties. In pivotal, international, phase 3 trials, subcutaneous azacitidine was an effective and well tolerated treatment in patients with higher-risk MDS or AML, including older patients with AML with >30 % BMB, with extensive evidence from the real-world setting confirming its efficacy and safety in these patient populations. Azacitidine is the only approved hypomethylating agent that has been shown to prolong overall survival compared with conventional care regimens and thus, it is recommended as the first-line hypomethylating agent for most patients with higher-risk MDS. Hence, azacitidine remains and important agent for use in the treatment of higher-risk MDS and AML, including in older patients with AML with >30 % BMB.
Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. [2021]Azacitidine (Vidaza) is a pyrimidine nucleoside analogue of cytidine. Subcutaneous azacitidine was recently approved in the EU for the treatment of adults who are not eligible for haematopoietic stem cell transplantation and who have intermediate-2-risk or high-risk myelodysplastic syndromes (MDS) [according to International Prognostic Scoring System (IPSS) criteria], chronic myelomonocytic leukaemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder, or acute myeloid leukaemia (AML) with 20-30% blasts and multilineage dysplasia (according to the WHO classification). Subcutaneous azacitidine is the only drug shown to significantly prolong survival in patients with higher-risk MDS or WHO-defined AML, compared with conventional care (i.e. best supportive care, low-dose cytarabine or intensive chemotherapy). In addition, azacitidine is associated with a lower risk of AML progression and higher rates of complete remission, partial remission, haematological improvement and red blood cell (RBC) transfusion independence. Azacitidine has an acceptable tolerability profile; peripheral cytopenias are the most commonly occurring adverse event. Thus, azacitidine is a valuable option for the first-line treatment of patients with higher-risk MDS/AML.