Selumetinib + Azacitidine for Leukemia

Overseen By Cancer Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Chicago

Must not be taking: MEK inhibitors

Disqualifiers: Active malignancy, Cardiac conditions, Ophthalmologic conditions, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Indefinite, as long as benefit is derived

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of two drugs, selumetinib and azacitidine, to evaluate their effectiveness in treating certain types of leukemia and related blood disorders. The goal is to determine the optimal dose of selumetinib when combined with azacitidine. Suitable participants have specific blood disorders that have recurred or not responded to other treatments and experience issues like low blood counts or require regular blood transfusions. The study aims to offer a new option for those who haven’t found success with current treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, giving participants the opportunity 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, but you cannot have received any anti-cancer therapy within 14 days before starting the study, except for hydroxyurea, which can be continued if needed.

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

Research has shown that azacitidine is safe and effective for treating certain blood cancers, such as higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). It has been tested in people, providing a clear understanding of its safety.

Studies have examined the use of selumetinib with azacitidine to find the best dose and ensure safety. As this is an early-phase study, the primary focus is on determining safe dosage levels and identifying any side effects. The combination is currently being tested to assess tolerability.

The combination of selumetinib and azacitidine remains under study for safety and effectiveness. Participants in these studies receive close monitoring to manage any side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of selumetinib and azacitidine for treating leukemia because it introduces a novel approach compared to traditional treatments. Most leukemia treatments focus on chemotherapy or targeted therapies that aim at specific genetic mutations. However, selumetinib is a MEK inhibitor that targets a different pathway involved in cell growth and survival, potentially offering a new avenue for treatment. When combined with azacitidine, which helps to restore normal function to genes controlling cell growth, this duo could enhance treatment effectiveness and overcome resistance seen in standard therapies. This unique combination approach could lead to better outcomes for patients with leukemia.

What evidence suggests that selumetinib combined with azacitidine could be an effective treatment for leukemia?

Research has shown that using selumetinib and azacitidine together, as studied in this trial, may help treat certain blood cancers. In earlier studies, 41.4% of patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) experienced complete or partial cancer improvement with this treatment. Additionally, 43.8% of patients who required blood transfusions no longer needed them after receiving this treatment. Azacitidine alone has been proven to help patients with some types of leukemia live longer. These results suggest that this combination could be effective against leukemia, but more research is needed to confirm these findings. ^{1 4 5 6 7}

Who Is on the Research Team?

Olatoyosi M. Odenike

Principal Investigator

University of Chicago

Are You a Good Fit for This Trial?

Adults with high-risk chronic blood cancers like Myeloid Leukemia, who haven't been treated with MEK inhibitors before, can join. They should have certain levels of disease severity and organ function, no recent cancer treatments except possibly hydroxyurea, and not be pregnant or breastfeeding. Participants must use effective birth control.

Inclusion Criteria

My myelofibrosis is high risk, and I can't tolerate or didn't respond to JAK inhibitor therapy.

I can take care of myself and do some daily activities.

My liver tests are within the required range.

Exclusion Criteria

Any uncontrolled concurrent illness that may put the patient at undo risk

Pregnant or lactating patients

I haven't taken any cancer treatments in the last 14 days, except hydroxyurea.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive azacitidine subcutaneously on days 1-7 and selumetinib on days 8-21 in 28-day cycles

Indefinite, as long as benefit is derived

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Long-term follow-up

Participants are monitored for long-term outcomes and survival

Up to 100 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Selumetinib

Trial Overview The trial is testing the combination of Selumetinib and Azacitidine to find the maximum tolerated dose. It's an early-phase study where patients receive treatment within 28 days after screening and continue indefinitely if beneficial, unless they experience unacceptable side effects or choose to leave.

How Is the Trial Designed?

Group I: Azacitidine and selumetinib Experimental Treatment 2 Interventions

Subjects will receive azacitidine subcutaneously on days 1-7. Selumetinib will be administered on days 8-21. Subjects will continue on this schedule in cycles of 28 days duration in the absence of disease progression.

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?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Published Research Related to This Trial

Sunitinib, a treatment for metastatic renal cell carcinoma, was analyzed in a meta-analysis of 12 studies involving 5,658 patients, revealing that common adverse events included skin rash (81%), fatigue (52%), and diarrhea (45%).

The analysis found that patients who had prior systemic therapy experienced a higher incidence of adverse events compared to those receiving sunitinib as a first-line treatment, indicating that previous treatments may influence the side effects experienced.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sunitinib adverse events in metastatic renal cell carcinoma: a meta-analysis. Ibrahim, EM., Kazkaz, GA., Abouelkhair, KM., et al.[2021]

The Vidaza Access Program in Belgium successfully facilitated access to azacitidine treatment for 175 patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) by streamlining the approval process for patient dossiers.

Out of the 175 patient dossiers submitted, 163 were approved by Celgene, demonstrating the program's effectiveness in ensuring timely treatment initiation without financial risk to hospitals, which is crucial for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. Meers, S., Selleslag, D., Potier, H., et al.[2018]

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]

A large analysis of adverse event reports revealed that tofacitinib/XR had significantly higher rates of cardiovascular-related (14.1%) and blood clot-related (14.8%) events compared to baricitinib and upadacitinib, indicating potential safety concerns for this medication.

Baricitinib was associated with the highest proportions of death (7.2%) and cancer-related (4.1%) adverse events, suggesting that while all three drugs are in the same class, their safety profiles may differ significantly, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics of adverse event reporting of Xeljanz/Xeljanz XR, Olumiant, and Rinvoq to the US Food and Drug Administration. Qian, J., Xue, X., Shannon, J.[2023]

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]

In a study of 466 metastatic renal cell carcinoma (mRCC) patients treated between 2007 and 2011, 85.8% experienced at least one adverse event (AE), with fatigue, vomiting, and diarrhea being the most common.

The study revealed that younger patients (<65 years) had higher rates of AEs compared to older patients, highlighting the importance of closely monitoring and managing AEs in real-world settings, as their frequency and severity can differ from those reported in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of "Real-World" data to describe adverse events during the treatment of metastatic renal cell carcinoma in routine clinical practice. Hirsch, BR., Harrison, MR., George, DJ., 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 phase Ib trial involving 23 patients with newly diagnosed IDH1-mutant acute myeloid leukemia, the combination of ivosidenib and azacitidine resulted in a high overall response rate of 78.3% and a complete remission rate of 60.9%.

The treatment was well tolerated, with a safety profile similar to that of each drug alone, and 71.4% of patients achieving complete remission showed clearance of the mIDH1 mutation in their bone marrow.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia. DiNardo, CD., Stein, AS., Stein, EM., et al.[2022]

A review of seven targeted cancer therapies (sunitinib, pazopanib, bevacizumab, temsirolimus, axitinib, everolimus, and sorafenib) revealed that all these medications are associated with adverse events, highlighting the importance of monitoring patients closely.

Effective management strategies for these side effects can prevent them from becoming severe, which is crucial to maintaining the full efficacy of the treatments and avoiding unnecessary dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A contemporary update on rates and management of toxicities of targeted therapies for metastatic renal cell carcinoma. Alasker, A., Meskawi, M., Sun, M., et al.[2022]

A comprehensive analysis of azacitidine's adverse events (AEs) using data from the Japanese Adverse Event Reporting Database identified 34 significant AEs, with hematologic toxicities and infections being the most common, both associated with high mortality rates.

The study found that many AEs occurred within the first month of treatment, highlighting the need for careful monitoring and supportive care to manage serious AEs like cardiac failure and tumor lysis syndrome, which can lead to treatment discontinuation before the drug's therapeutic effects are realized.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Event Profile of Azacitidine: Analysis by Route of Administration Using Japanese Pharmacovigilance Database. Yamaoka, K., Fujiwara, M., Uchida, M., et al.[2023]

Azacitidine significantly improves response rates and overall survival in patients with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with a median survival increase of 9.4 months compared to conventional care in higher-risk patients.

The treatment is generally well tolerated, with peripheral cytopenias being the most common side effect, along with gastrointestinal issues and injection-site reactions, making it a viable option for elderly patients as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2022]

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]

Citations

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AML-063: A Randomized, Double-Blind, Placebo ... We evaluated efficacy of Azacitidine (AZA)+Venetoclax (VEN) combination vs. AZA+Placebo (PBO) in treatment-naïve patients with acute myeloid leukemia (AML) ...

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A drug, selumetinib, in combination with azacitidine to treat ... If the combination of selumetinib and azacitidine is safe and works well to treat MDS, MDS/MPN, or myelofibrosis. You may be able to join this ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10987864/

Innovations in conditioning and post-transplant maintenance ... Tolerability and clinical activity of post-transplantation azacitidine in patients allografted for acute myeloid leukemia treated on the RICAZA trial. Biol ...