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

Recruiting at 327 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

282 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Azacitidine combined with Lenalidomide or Vorinostat for higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML)?

The combination of Azacitidine and Lenalidomide showed a higher overall response rate (ORR) of 49% compared to Azacitidine alone, which had an ORR of 38%, particularly benefiting patients with CMML, where the ORR was 68% compared to 28% for Azacitidine alone. However, the combination with Vorinostat did not show a significant improvement in ORR. ^{1 2 3 4 5}

Is the combination of Azacitidine with Lenalidomide or Vorinostat safe for humans?

The combination of Azacitidine with Lenalidomide or Vorinostat has been studied in patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Serious side effects were similar across treatment groups, but patients on combination treatments were more likely to need dose adjustments. Common severe side effects included infections, lung issues, heart problems, and skin reactions, but the treatments were generally well-tolerated. ^{1 3 4 6 7}

How does the drug azacitidine differ from other treatments for higher-risk MDS/CMML?

Azacitidine is a standard first-line drug for higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), and it can be combined with lenalidomide or vorinostat to potentially improve response rates. The combination with lenalidomide, in particular, has shown a higher response rate in patients with CMML compared to azacitidine alone, making it a unique option for these patients. ^{1 4 6 7 8}

What is the purpose of this trial?

This randomized phase II/III trial studies how well azacitidine works with or without lenalidomide or vorinostat in treating patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, stopping them from dividing, or by stopping them from spreading. Lenalidomide may stop the growth of cancer cells by stopping blood flow to the cancer. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether azacitidine is more effective with or without lenalidomide or vorinostat in treating myelodysplastic syndromes or chronic myelomonocytic leukemia.

Research Team

Mikkael A Sekeres

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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 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]

References

1. United States 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. [2022]

2. 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]

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

Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. [2021]

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

Azacitidine in Lower-Risk Myelodysplastic Syndromes: A Meta-Analysis of Data from Prospective Studies. [2023]

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

Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. [2021]

7. Italy pubmed.ncbi.nlm.nih.gov

Azacitidine with or without lenalidomide in higher risk myelodysplastic syndrome & low blast acute myeloid leukemia. [2020]

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

Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes. [2020]