Nivolumab + Ipilimumab + Azacitidine for Myelodysplastic Syndrome

Overseen By Guillermo Garcia-Manero

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: High dose steroids

Disqualifiers: Second malignancy, Uncontrolled diabetes, Cardiovascular disease, Autoimmune diseases, Hepatitis, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 24-30 weeks

99 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the side effects of nivolumab and/or ipilimumab with or without azacitidine and to see how well they work in treating patients with myelodysplastic syndrome. Monoclonal antibodies, such as nivolumab and ipilimumab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab and/or ipilimumab with or without azacitidine may work better in treating myelodysplastic syndrome.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on high-dose steroids or immune suppression medications, you may not be eligible to participate.

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

Azacitidine has been shown to significantly improve survival in patients with higher-risk myelodysplastic syndromes compared to conventional care, with studies reporting longer median overall survival times and reduced transfusion needs. ^{1 2 3 4 5}

Is the combination of Nivolumab, Ipilimumab, and Azacitidine safe for humans?

Azacitidine has been studied for safety in patients with myelodysplastic syndrome and other blood disorders, showing some common side effects like pneumonia, joint pain, and constipation. In combination with other drugs, it has been generally safe with manageable side effects, but specific safety data for the combination with Nivolumab and Ipilimumab is not provided in the available research. ^{1 6 7 8 9}

How is the drug combination of Nivolumab, Ipilimumab, and Azacitidine unique for treating Myelodysplastic Syndrome?

This drug combination is unique because it combines immune checkpoint inhibitors (Nivolumab and Ipilimumab) with Azacitidine, a drug that affects DNA methylation, potentially offering a novel approach by enhancing the immune system's ability to fight cancer cells in Myelodysplastic Syndrome, a condition with limited standard treatment options. ^{10 11 12 13 14}

Research Team

Guillermo Garcia-Manero

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with Myelodysplastic Syndrome (MDS) who have previously been treated with hypomethylating agents but didn't respond well or the disease came back. They should not have had a stem cell transplant, any other cancer treatments, or major surgery within 2 weeks before starting the study. Participants need to be relatively healthy otherwise and can't be pregnant, breastfeeding, or have certain autoimmune diseases.

Inclusion Criteria

I will use effective birth control during and for 31 weeks after the study.

Patients or their legally authorized representative must provide written informed consent

Creatinine =< 2.0 x upper limit of normal (ULN)

Exclusion Criteria

I am not pregnant or breastfeeding.

I haven't had major surgery or cancer treatment in the last 2 weeks.

Patients with any other known concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes; cardiovascular disease including congestive heart failure New York Heart Association [NYHA] class III or IV, myocardial infarction within 6 months, and poorly controlled hypertension; chronic renal failure; or active uncontrolled infection) which, in the opinion of the investigator could compromise participation in the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab, ipilimumab, and/or azacitidine based on cohort assignment. Treatment cycles repeat every 3-4 weeks depending on the cohort.

24-30 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Azacitidine
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing how effective and safe it is to use Nivolumab and/or Ipilimumab with or without Azacitidine in treating MDS. These drugs include monoclonal antibodies that may block cancer growth by targeting specific cells and chemotherapy that stops cancer cells from growing.

Participant Groups

Group I: Cohort VI (azacitidine, nivolumab, ipilimumab) Experimental Treatment 4 Interventions

Patients receive azacitidine IV over 10-40 minutes on days 1-5 and nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 6. Treatment with ipilimumab repeats every 4 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. Cycles with nivolumab and azacitidine repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Group II: Cohort V (azacitidine, ipilimumab) Experimental Treatment 3 Interventions

Patients receive azacitidine IV over 10-40 minutes on days 1-5 and ipilimumab IV over 30 minutes on day 6. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Group III: Cohort IV (azacitidine, nivolumab) Experimental Treatment 3 Interventions

Patients receive azacitidine IV over 10-40 minutes on days 1-5 and nivolumab IV over 30 minutes on days 6 and 20. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Group IV: Cohort III (nivolumab, ipilimumab) Experimental Treatment 3 Interventions

Patients receive nivolumab IV over 30 minutes on days 1 and 15 and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 4 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes every 2 weeks (or every 4 weeks if patients receive azacitidine) in the absence of disease progression or unacceptable toxicity. Patients with disease progression may receive ipilimumab, nivolumab, and azacitidine at the discretion of the treating physician.

Group V: Cohort II (ipilimumab) Experimental Treatment 2 Interventions

Patients receive ipilimumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients with disease progression may receive ipilimumab and azacitidine at the discretion of the treating physician.

Group VI: Cohort I (nivolumab) Experimental Treatment 2 Interventions

Patients receive nivolumab IV over 30 minutes on days 1 and 15. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with disease progression may receive nivolumab and azacitidine at the discretion of the treating physician.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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]

Azacitidine has been shown to significantly prolong the time to progression to acute myeloid leukemia or death in myelodysplastic syndromes (MDS) patients, with a median time of 21 months compared to 13 months for supportive care in a study of 191 patients.

In a larger trial with 358 patients, azacitidine also significantly improved overall survival, extending it to 24.5 months compared to 15.0 months with conventional care, establishing it as a key first-line treatment for higher-risk MDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of azacitidine trials in Intermediate-2-and High-risk myelodysplastic syndromes. Fenaux, P., Ades, L.[2022]

Azacitidine is the only approved hypomethylating agent in Europe for treating int-2-/high-risk myelodysplastic syndromes, significantly improving patient survival compared to conventional care.

Despite its effectiveness, many patients do not respond to azacitidine, and most responders experience relapse, highlighting the need for established treatment options after azacitidine failure and the importance of optimizing initial treatment and identifying biomarkers for monitoring response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minimizing risk of hypomethylating agent failure in patients with higher-risk MDS and practical management recommendations. Santini, V., Prebet, T., Fenaux, P., 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]

In two large phase III trials involving 325 patients with myelodysplastic syndrome (MDS), azacitidine was associated with common adverse events (AEs) such as cytopenias and gastrointestinal issues, but most were transient and manageable, allowing patients to continue treatment.

The frequency of hematologic AEs decreased over time, and effective management strategies, including dosing delays and supportive medications, helped patients tolerate azacitidine better, maximizing the potential benefits of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*. Santini, V., Fenaux, P., Mufti, GJ., et al.[2021]

In a phase 1b study involving 46 patients with relapsed/refractory or HMA-naïve myelodysplastic syndrome, atezolizumab alone or in combination with azacitidine showed a high early death rate, with 61.9% of patients in cohort C experiencing death, raising safety concerns.

The study found poor efficacy, with no responses in cohort A and only 14.3% response in cohort B, leading to the conclusion that the risk-benefit profile for atezolizumab in these patient populations is unfavorable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome. Gerds, AT., Scott, BL., Greenberg, P., et al.[2022]

In a phase II trial involving 37 patients with myelodysplastic syndromes (MDS), the combination of azacitidine and pembrolizumab showed a high overall response rate of 76% in previously untreated patients, indicating promising efficacy.

The treatment was found to be safe with manageable toxicities, including pneumonia and immune-related adverse events, suggesting that this combination therapy warrants further investigation in earlier treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome. Chien, KS., Kim, K., Nogueras-Gonzalez, GM., et al.[2021]

In a phase 1 study involving 78 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab as first-line therapy demonstrated a tolerable safety profile with no treatment-related deaths and manageable adverse events, such as increased lipase and pneumonitis.

The treatment showed promising efficacy, with confirmed objective response rates of 47% in the ipilimumab every-12-weeks cohort and 38% in the every-6-weeks cohort, suggesting potential benefits over anti-PD-1 monotherapy and warranting further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Hellmann, MD., Rizvi, NA., Goldman, JW., et al.[2022]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

In a phase 3 trial with patients suffering from advanced melanoma, the combination of nivolumab and ipilimumab resulted in significantly longer overall survival rates (58% at 3 years) compared to ipilimumab alone (34%).

The safety profile of the combination therapy was consistent with previous reports, showing that 59% of patients experienced severe treatment-related adverse events, indicating that while effective, the combination therapy has a higher risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. Wolchok, JD., Chiarion-Sileni, V., Gonzalez, R., et al.[2023]

Nivolumab, a targeted cancer therapy, can lead to rare cutaneous side effects such as plaque morphea, as demonstrated in a case study of a 48-year-old female patient with metastatic melanoma.

The plaque morphea lesion responded well to treatment with topical corticosteroids and calcipotriol, highlighting the importance of monitoring for less common skin reactions in patients receiving PD-1 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-induced plaque morphea in a malign melanoma patient. Acar, A., Oraloglu, G., Yaman, B., et al.[2021]

Combining ipilimumab with nivolumab can significantly improve treatment outcomes for advanced melanoma patients, but ipilimumab alone is not effective for those resistant to nivolumab.

A case study demonstrated that a nivolumab-resistant patient with multiple in-transit melanomas responded well to a combination of ipilimumab and topical imiquimod, suggesting a potential new treatment strategy for similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod. Fujimura, T., Kambayashi, Y., Sato, Y., et al.[2020]

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

Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Review of azacitidine trials in Intermediate-2-and High-risk myelodysplastic syndromes. [2022]

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

Minimizing risk of hypomethylating agent failure in patients with higher-risk MDS and practical management recommendations. [2022]

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*. [2021]

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

Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. [2022]

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

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021]

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

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. [2023]

13. England pubmed.ncbi.nlm.nih.gov

Nivolumab-induced plaque morphea in a malign melanoma patient. [2021]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod. [2020]