Omacetaxine + Azacitidine for Myelodysplastic Syndrome

Overseen By Ashley Visser

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Colorado, Denver

Disqualifiers: HIV, Hepatitis B/C, Heart failure, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates the effectiveness and safety of combining two treatments, omacetaxine and azacitidine (both types of chemotherapy), for patients with high-grade myelodysplastic syndromes (MDS), a blood disorder. The study consists of two phases: the first tests different doses of omacetaxine, and the second uses the optimal dose identified in phase one. Participants should have MDS with excess blasts or chronic myelomonocytic leukemia and must not have received certain MDS treatments previously. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

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

Research has shown that omacetaxine is generally safe, but it can cause serious side effects. In one study, 26% of patients experienced infections, 10% had fever with a low white blood cell count, and 7% had bleeding. Despite these risks, researchers considered the treatment safe to use.

Azacitidine is also used to treat myelodysplastic syndromes (MDS) and has been known to help patients live longer. However, many of its side effects are serious, and some can be life-threatening. Most reports come from healthcare professionals, highlighting the need for careful monitoring.

Both treatments show promise, but they require close supervision due to the potential for serious side effects. Participants should discuss these risks with their healthcare provider before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Omacetaxine and Azacitidine for treating Myelodysplastic Syndrome because it introduces a unique approach compared to current treatments. Omacetaxine works by inhibiting protein synthesis, which is different from most standard treatments that typically focus on modifying DNA or disrupting cell division. This distinct mechanism could potentially overcome resistance seen with conventional therapies like lenalidomide or hypomethylating agents alone. Additionally, combining Omacetaxine with Azacitidine, which is already a standard therapy, might enhance effectiveness by attacking the disease from two angles, offering new hope for better outcomes.

What evidence suggests that this trial's treatments could be effective for myelodysplastic syndrome?

In this trial, participants will receive a combination of omacetaxine and azacitidine to treat myelodysplastic syndromes (MDS). Previous studies have shown that these drugs hold promise, particularly for patients with an excess of immature blood cells, a potential cancer indicator. Research indicates that combining omacetaxine, which inhibits protein production in cancer cells, with azacitidine, which alters DNA to prevent cancer growth, can effectively target the stem cells causing MDS. Early results suggest that this combination can improve outcomes for previously untreated patients. Additionally, real-world evidence supports azacitidine's effectiveness in treating MDS by extending patient survival and reducing the need for blood transfusions. Overall, this combination could offer a more targeted approach to managing MDS, especially in high-risk patients. ^{6 7 8 9 10}

Who Is on the Research Team?

Daniel Pollyea, MD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

This trial is for adults over 18 with high grade myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia who haven't been treated before, or have tried a treatment but it didn't work. They should be relatively healthy otherwise, with good kidney and liver function, and not have other serious illnesses or active infections.

Inclusion Criteria

My condition is either high-grade MDS or chronic leukemia with more than 5% bone marrow blasts.

I can take care of myself and am up and about more than half of my waking hours.

Subject must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures

Exclusion Criteria

Subject has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to: New York Heart Association heart failure > class 2, Renal, neurologic, psychiatric, endocrine, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia, Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal). Patients on antibiotics with controlled systemic symptoms will not be excluded, Subject has uncontrolled diabetes, Subject has had a recent major hemorrhage or has a bleeding diathesis associated with a high risk of bleeding, Pregnant and breastfeeding females

Subject is known to be positive for HIV. HIV testing is not required

I had cancer before, but it was either skin cancer, treated breast or cervical cancer, prostate cancer not needing treatment, or any cancer that was completely removed or treated.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Dose escalation study where patients receive various doses of omacetaxine with azacitidine over a 28-day cycle

28 days per cycle

Phase II Treatment

Patients receive the maximum tolerated dose of omacetaxine with azacitidine over a 28-day cycle

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Omacetaxine

Trial Overview The study tests the combination of two drugs, omacetaxine mepesuccinate and azacitidine, in treating patients with untreated high-grade MDS. It aims to see how well these drugs work together as an initial therapy or after other treatments failed.

How Is the Trial Designed?

Group I: Phase II Experimental Treatment 2 Interventions

Up to 33 patients will be enrolled to receive the maximum tolerated dose (determined in phase I) over a 28 day cycle. Azacitidine will be given at the standard dose over a 28 day cycle.

Group II: Phase I Experimental Treatment 2 Interventions

Up to 18 patients will be enrolled to one of three cohorts to receive various doses of omacetaxine over a 28 day cycle. Azacitidine will be given at the standard dose over a 28 day cycle.

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 Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Published Research Related to This Trial

In a phase 1b study involving 44 patients with relapsed/refractory higher-risk myelodysplastic syndromes (MDS), the combination of venetoclax and azacitidine demonstrated significant activity, with a median overall survival of 12.6 months after prior treatment failure with hypomethylating agents.

The treatment resulted in hematological improvements, including complete remission in 7% of patients and transfusion independence in 36%, indicating that venetoclax plus azacitidine can provide meaningful clinical benefits for patients with limited options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Zeidan, AM., Borate, U., Pollyea, DA., et al.[2023]

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 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]

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]

Azacitidine significantly improves overall survival in patients with myelodysplastic syndromes and related disorders, with a median survival of 24.5 months compared to 15 months for conventional care, based on a trial of 358 patients.

While azacitidine offers a viable treatment option when stem cell transplantation is not possible, it carries risks of severe toxicity and other side effects, highlighting the need for careful patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine. Poor-prognosis myelodysplasia: promising, but more data needed. [2013]

Azacitidine was approved by the FDA for treating all subtypes of myelodysplastic syndrome (MDS) based on a randomized controlled trial showing a 16% overall response rate, with sustained responses lasting up to 17 months.

The treatment demonstrated a favorable safety profile, with no deaths attributed to azacitidine, although common side effects included gastrointestinal issues and hematologic complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Kaminskas, E., Farrell, AT., Wang, YC., et al.[2013]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12547833/

Omacetaxine and azacitidine for untreated patients with ... Patients with myelodysplastic syndromes (MDS) with excess blasts (MDS-EB) have poor long-term outcomes. Our preclinical studies showed ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02835794?id=%22NCT02835794%22OR%22NCT03564873%22&viewType=Table&rank=2

A Clinical Trial of Omacetaxine, Azacitidine, and Growth ... The purpose of this study is to determine the safety and establish the maximum tolerated dose (MTD) of omacetaxine in combination with azacitidine and G-CSF in ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121045572

Targeting MDS Stem Cells with Omacetaxine and ... Combination treatment with the protein synthesis inhibitor omacetaxine (oma) and the hypomethylating agent (HMA) azacitidine (aza) efficiently targeted MDS ...

4. researchgate.net researchgate.net/publication/386463527_Omacetaxine_and_Azacitidine_for_Newly_Diagnosed_Patients_with_Myelodysplastic_Syndromes_and_Excess_Blasts?_tp=eyJjb250ZXh0Ijp7InBhZ2UiOiJzY2llbnRpZmljQ29udHJpYnV0aW9ucyIsInByZXZpb3VzUGFnZSI6bnVsbH19

Omacetaxine and Azacitidine for Newly Diagnosed ... We report clinical outcomes and detailed correlative data from this single-institution trial (NCT03564873). Methods Subjects were eligible if ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9395485/

Real-world data on efficacy and safety of azacitidine therapy ... Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2948932/

Safety and efficacy of azacitidine in myelodysplastic ... Azacitidine has been reported to prolong survival in MDS patients. Azacitidine has been studied in different dosing schedules and combination therapies with the ...

7. hematologyadvisor.com hematologyadvisor.com/news/azacitidine-myelodysplastic-syndrome-mds-adverse-events-safety-concerns/

New Adverse Events Highlight Safety Concerns With ... Most AEs (95.78%) were classified as serious, and 40.87% resulted in death. Health professionals submitted nearly 90% of the reports, with the ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2817034/

5-azacitidine prolongs overall survival in patients with ... Patients with intermediate-2 and high-risk myelodysplastic syndrome (MDS) have a survival rate of 0.4 to 1.2 years as well as a high risk of their disease ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.6509

Preliminary safety and efficacy of oral azacitidine (Oral-AZA ... Here, we report safety and preliminary efficacy data from phase 2 of the ASTREON study, which evaluated 14-day Oral-AZA regimens in pts with Low ...

10. ashpublications.org ashpublications.org/blood/article/145/11/1126/534406/Efficacy-and-safety-of-venetoclax-plus-azacitidine

Efficacy and safety of venetoclax plus azacitidine for patients ... Venetoclax (14 days) + azacitidine regimen was well tolerated in patients with treatment-naive HR MDS, with no unexpected safety findings.