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

28 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will treat patients with previously untreated high grade myleodysplastic syndromes (MDS) with both omacetaxine mepesuccinate and azacitidine.

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.

What data supports the effectiveness of the drug azacitidine for treating myelodysplastic syndrome?

Azacitidine has been shown to improve survival time in patients with myelodysplastic syndromes, with one study reporting a median overall survival of 24.5 months compared to 15 months for those receiving conventional care. It also reduces the need for blood transfusions, making it a viable option when stem cell transplantation is not possible. ^{1 2 3 4 5}

Is the combination of Omacetaxine and Azacitidine safe for treating myelodysplastic syndrome?

Azacitidine, also known as Vidaza, has been used safely in patients with myelodysplastic syndromes and related conditions. Common side effects include low blood cell counts, nausea, and injection site reactions, but serious side effects are rare. Omacetaxine, also known as Synribo, is not specifically mentioned in the provided studies, so its safety profile in combination with Azacitidine is not detailed here. ^{2 3 6 7 8}

How is the drug combination of Omacetaxine and Azacitidine unique for treating Myelodysplastic Syndrome?

The combination of Omacetaxine and Azacitidine is unique because it targets patients with Myelodysplastic Syndrome who have not responded to standard hypomethylating agents, offering a new option where no standard treatment exists. Omacetaxine is administered subcutaneously and has shown effectiveness in patients with specific genetic profiles, while Azacitidine helps correct abnormal gene expression, potentially improving survival and reducing the need for transfusions. ^{1 2 9 10 11}

Research Team

Daniel Pollyea, MD

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

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.

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

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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 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]

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]

References

1. 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]

2. France pubmed.ncbi.nlm.nih.gov

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

3. 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]

4. Netherlands pubmed.ncbi.nlm.nih.gov

New therapeutic approaches in myelodysplastic syndromes: Hypomethylating agents and lenalidomide. [2021]

5. England pubmed.ncbi.nlm.nih.gov

The role of hypomethylating agents in myelodysplastic syndrome: changing the management paradigm. [2018]

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. England pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. [2013]

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

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

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

A phase II study of omacetaxine mepesuccinate for patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia after failure of hypomethylating agents. [2020]

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

Azacitine (vidaza) for myelodysplastic syndrome. [2013]

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

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. [2023]