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

Trial Summary

What is the purpose of this trial?

This is a phase I, open-label, dose-escalation study to determine the MTD of selumetinib when combined with the standard dose of azacitidine. Treatment will begin within 28 days of screening procedures. Treatment will continue indefinitely, provided that the patient continues to derive benefit. A patient will be taken off study for reasons described in detail in section 3.12 including disease progression, unacceptable toxicity, inter-current illness, withdrawal of consent, or at the discretion of the investigator. Patients will be followed for 12 weeks after the last dose of study drug, until any study treatment related toxicities have stabilized, or until death. The total duration of the study is expected to be approximately 24 months.

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.

What data supports the effectiveness of the drug Azacitidine for leukemia?

Azacitidine has been shown to be effective and safe in treating higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), including in older patients, by prolonging overall survival compared to conventional care. It is recommended as the first-line treatment for most patients with higher-risk MDS. ^{1 2 3 4 5}

What safety data exists for Azacitidine in humans?

Azacitidine, used for myelodysplastic syndromes and acute myeloid leukemia, has shown adverse events like blood-related issues and infections in clinical trials. ^{6 7 8 9 10}

What makes the drug Selumetinib + Azacitidine unique for treating leukemia?

The combination of Selumetinib and Azacitidine is unique because it combines a MEK inhibitor (Selumetinib) with a hypomethylating agent (Azacitidine), potentially offering a novel approach to targeting leukemia cells by affecting different pathways involved in cancer cell growth and survival. ^{1 3 5 11 12}

Research Team

Olatoyosi M. Odenike

Principal Investigator

University of Chicago

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

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 (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]

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]

References

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

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]

2. 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]

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

Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia. [2022]

4. 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]

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

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

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

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

7. Japan pubmed.ncbi.nlm.nih.gov

Sunitinib adverse events in metastatic renal cell carcinoma: a meta-analysis. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

A contemporary update on rates and management of toxicities of targeted therapies for metastatic renal cell carcinoma. [2022]

9. United States 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. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Event Profile of Azacitidine: Analysis by Route of Administration Using Japanese Pharmacovigilance Database. [2023]

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

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

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

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