Azacitidine +/− Lenalidomide/Vorinostat for Higher-Risk MDS/CMML

Not currently recruiting at 337 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Lenalidomide, Azacitidine, Vorinostat, Decitabine

Disqualifiers: AML, Radiation, Transplant, Neurotoxicity, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of azacitidine (also known as Vidaza or 5-azacytidine) alone or combined with lenalidomide (Revlimid) or vorinostat in treating higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia. These conditions result in the bone marrow not producing enough healthy blood cells. The study aims to determine if combining azacitidine with the other drugs inhibits cancer cell growth more effectively than azacitidine alone. Individuals diagnosed with myelodysplastic syndromes or chronic myelomonocytic leukemia who have not yet received certain treatments might be suitable for the trial. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that certain medications be stopped before participation. Specifically, any hematopoietic growth factors must be stopped for at least 14 days, low-dose cytarabine for at least 28 days, and hydroxyurea for at least 7 days before joining the trial. Other medications like lenalidomide, azacitidine, vorinostat, decitabine, and certain epilepsy medications must not have been used prior to the trial.

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

Research has shown that azacitidine is usually well-tolerated by patients with certain blood disorders, such as higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Studies have found that when combined with lenalidomide, patients can manage the treatment, but it does not significantly improve survival rates compared to azacitidine alone. This indicates that while patients can handle the side effects, adding lenalidomide does not necessarily lead to better outcomes.

When azacitidine is paired with vorinostat, early research has shown promising responses in patients. This suggests that the combination is safe and might be effective, but further research is needed to determine how it compares to azacitidine alone.

In summary, azacitidine, whether used alone or with lenalidomide or vorinostat, is generally safe and manageable for most patients. Like any treatment, side effects can occur, but these combinations have been tested and are usually considered tolerable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for higher-risk MDS/CMML because they offer a fresh approach compared to standard therapies like supportive care and hypomethylating agents. Azacitidine, a key part of all treatment arms, is known for its ability to interfere with the growth of abnormal blood cells, potentially improving patient outcomes. The addition of lenalidomide in one arm may enhance the immune system's response and work synergistically with azacitidine. Meanwhile, vorinostat, included in another arm, is a histone deacetylase inhibitor that might disrupt cancer cell growth in a novel way. These combinations aim to tackle the disease from multiple angles, potentially offering more comprehensive control than existing treatments.

What evidence suggests that this trial's treatments could be effective for higher-risk MDS/CMML?

Research has shown that combining azacitidine with lenalidomide, one of the treatment arms in this trial, effectively treats higher-risk myelodysplastic syndromes (MDS). Studies have found that this combination is generally well-tolerated and leads to lasting improvements in patients. Another arm in this trial examines the addition of vorinostat to azacitidine. Some research suggests that this combination might control MDS better than azacitidine alone, though the overall success rates are similar to using azacitidine by itself, which is being tested in a separate arm. While azacitidine alone is already an effective treatment, these combinations are being studied in this trial to determine if they can provide additional benefits. ^{1 2 3 5 6}

Who Is on the Research Team?

Mikkael A Sekeres

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

This trial is for adults with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia. Participants must have a specific diagnosis, not received certain treatments recently, and have an acceptable level of overall health and organ function. They should not be on anticoagulation therapy or have had previous stem cell transplants.

Inclusion Criteria

Patients must meet specific criteria regarding prior treatments and medical history

Patients must have specific laboratory measurements within 28 days prior to registration

All patients must be counseled about pregnancy precautions and risks of fetal exposure

Exclusion Criteria

I am not currently using blood thinners like warfarin or heparin.

I have never had a bone marrow or stem cell transplant from another person.

I do not have any major health, lab, or mental health issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive azacitidine with or without lenalidomide or vorinostat. Treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Up to 5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months.

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Lenalidomide
• Vorinostat

Trial Overview The study is testing the effectiveness of azacitidine alone versus in combination with either lenalidomide or vorinostat in treating patients. It aims to determine which treatment stops cancer growth more effectively by comparing these different drug combinations.

How Is the Trial Designed?

Group I: Arm III (azacitidine and vorinostat) Experimental Treatment 3 Interventions

Patients receive azacitidine as in Arm I and vorinostat PO BID on days 3-9. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (azacitidine) Experimental Treatment 2 Interventions

Patients receive azacitidine as in Arm I. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Group III: Arm I (azacitidine and lenalidomide) Experimental Treatment 3 Interventions

Patients receive azacitidine SC or IV on days 1-7 or days 1-5 and 8-9, and lenalidomide PO QD on days 1-21. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 involving 277 patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), azacitidine combined with lenalidomide showed a higher overall response rate (ORR) of 68% in CMML patients compared to 28% for azacitidine alone, indicating a potential benefit for this specific group.

Overall, the combination therapies (azacitidine plus lenalidomide and azacitidine plus vorinostat) did not significantly outperform azacitidine monotherapy in terms of ORR, suggesting that while combinations may be beneficial for certain patients, they may also be impacted by dose modifications and other factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117. Sekeres, MA., Othus, M., List, AF., et al.[2022]

In a phase II trial involving 160 patients with higher risk myelodysplastic syndromes and related conditions, the combination of azacitidine and lenalidomide did not show improved clinical benefits or survival rates compared to azacitidine alone.

Both treatment groups experienced similar rates of adverse events and maintained good adherence to the treatment protocol, indicating that while the combination therapy was tolerable, it did not enhance efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine with or without lenalidomide in higher risk myelodysplastic syndrome & low blast acute myeloid leukemia. Kenealy, M., Hertzberg, M., Benson, W., et al.[2020]

The combination therapy of lenalidomide and azacitidine showed a high overall response rate of 72% in patients with higher-risk myelodysplastic syndromes (MDS), with 44% achieving a complete response and a median duration of complete response lasting over 17 months.

This treatment was well-tolerated, although some patients experienced significant adverse events, such as febrile neutropenia in 22% of cases, indicating that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Sekeres, MA., Tiu, RV., Komrokji, R., et al.[2021]

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

1. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/4617/503020/Azacitidine-Combination-with-Lenalidomide-in

Azacitidine Combination with Lenalidomide in Treating Higher ... This trial demonstrated that the combination of azacytidine with a lenalidomide regimen is an effective therapy for higher-risk MDS patients, with high ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6442982/

Azacitidine with or without lenalidomide in higher risk ... Although the combination of lenalidomide and azacitidine was tolerable, there was no improvement in clinical benefit, response rates or overall survival in ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3525020/

Phase 2 study of the lenalidomide and azacitidine ... In conclusion, the combination of lenalidomide and azacitidine is well-tolerated and highly effective in higher-risk MDS patients, with sustained responses seen ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123112183

Azacitidine Combination with Lenalidomide in Treating ... This trial demonstrated that the combination of azacytidine with a lenalidomide regimen is an effective therapy for higher-risk MDS patients, with high ...

5. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(22)01719-0/fulltext

Azacitidine Monotherapy in Patients With Treatment-Naïve ... We assessed and synthesized clinical outcomes of azacitidine (AZA) monotherapy in treatment-naïve patients with higher-risk MDS.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06004765

NCT06004765 | Efficacy and Safety of Lenalidomide ... A Phase III, randomized, placebo-controlled trial of oral AZA in lower-risk MDS reported higher rates of hemoglobin and platelet hematological improvement in ...