Sirolimus + Azacitidine for Myelodysplastic Syndrome

Recruiting at 4 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University

Must not be taking: Antibiotics, Antifungals, Antivirals, others

Disqualifiers: Second malignancy, Cardiac issues, HIV, 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: 28 days per cycle

57 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well sirolimus and azacitidine works in treating patients with high-risk myelodysplastic syndrome or recurrent acute myeloid leukemia. Sirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Sirolimus and azacitidine may kill more cancer cells.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, you must stop taking some drugs like Carbamazepine, Rifampin, and St. John's Wort at least 72 hours before starting Sirolimus. Check with the trial team about any other medications you are currently taking.

What data supports the effectiveness of the drug combination Sirolimus + Azacitidine for Myelodysplastic Syndrome?

Azacitidine has been shown to improve survival in patients with high-risk myelodysplastic syndromes compared to conventional care, with a median overall survival of 24.5 months versus 15 months. It is also effective in treating related conditions like chronic myelomonocytic leukemia and acute myeloid leukemia, with response rates of up to 57% in some patient groups. ^{1 2 3 4 5}

Is the combination of Sirolimus and Azacitidine safe for treating Myelodysplastic Syndrome?

Azacitidine, also known as Vidaza, has been shown to be generally safe in humans, with common side effects including nausea, vomiting, and low blood cell counts. Serious side effects can include severe blood cell toxicity and liver or kidney issues, but no deaths have been directly attributed to it. Sirolimus, also known as Rapamune, is not specifically mentioned in the provided research, so its safety in combination with Azacitidine is not detailed here. ^{2 5 6 7 8}

What makes the drug combination of Sirolimus and Azacitidine unique for treating myelodysplastic syndrome?

The combination of Sirolimus and Azacitidine is unique because it combines Sirolimus, which is known for its immune-suppressing properties, with Azacitidine, a drug that blocks DNA synthesis and is already used to improve survival in higher-risk myelodysplastic syndromes. This novel combination may offer a new approach by potentially enhancing the effects of Azacitidine, although more research is needed to confirm its benefits. ^{2 5 9 10 11}

Research Team

Margaret Kasner, MD

Principal Investigator

Sidney Kimmel Cancer Center at Thomas Jefferson University

Eligibility Criteria

Adults with high-risk myelodysplastic syndrome or recurrent acute myeloid leukemia not suitable for intensive chemo. Must be over 18, have a life expectancy of at least 4 weeks, able to take oral meds, and have acceptable organ function. Excludes those with severe diseases, active infections, HIV/AIDS, pregnant/breastfeeding women, or on certain drugs.

Inclusion Criteria

Patients must be ≥ 18 years old

Patients may have had a prior stem cell transplant (autologous or allogeneic), however they may not have active GvHD, nor be on any immunosuppression

Patients must have a diagnosis of one of the following:

Exclusion Criteria

Patients must not be receiving growth factors.

Patients with a current second malignancy requiring systemic therapy, other than non-melanoma skin cancers, are not eligible. If a patient has had a prior second malignancy that is not currently requiring active treatment, the patient will be considered eligible.

Patients with uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure, myocardial infarction within the past 6 months or serious uncontrolled cardiac arrhythmia are not eligible.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sirolimus orally on days 1-10 or 1-12 and azacitidine intravenously on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 3 months.

Up to 5 years

Treatment Details

Interventions

• Azacitidine
• Sirolimus

Trial Overview The trial is testing the effectiveness of sirolimus (an inhibitor of cell growth) combined with azacitidine (a chemotherapy drug) in patients who either haven't responded well to other treatments or can't tolerate them.

Participant Groups

Group I: MDS or AML with prior Azacitadine therapy Experimental Treatment 2 Interventions

Patients receive sirolimus PO on days 1-10 or 1-12 and azacitidine IV on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: High risk Myleodysplastic Syndrome (MDS) Experimental Treatment 2 Interventions

Patients receive sirolimus PO on days 1-10 or 1-12 and azacitidine IV on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Group III: Acute Myeloid Leukemia (AML) Experimental Treatment 2 Interventions

Patients receive sirolimus PO on days 1-10 or 1-12 and azacitidine IV on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days 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?

Sidney Kimmel Cancer Center at Thomas Jefferson University

Lead Sponsor

Trials

164

Recruited

10,900+

Findings from Research

In a study of 196 patients with higher-risk myelodysplastic syndromes (MDS) and low blast count acute myeloid leukemia (AML), azacitidine treatment showed a higher response rate (63% complete or partial remission) when administered at the standard dose of 75 mg/m² for 7 days compared to a higher dose of 100 mg for 5-7 days (29% response).

The median overall survival for patients was 17.1 months, with better survival rates linked to lower MDS-comorbidity index scores and achieving complete or partial remission, highlighting the importance of treatment duration and dosing in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Standard dose and prolonged administration of azacitidine are associated with improved efficacy in a real-world group of patients with myelodysplastic syndrome or low blast count acute myeloid leukemia. Voso, MT., Niscola, P., Piciocchi, A., et al.[2016]

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 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 study of 90 patients with high-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), and acute myeloid leukaemia (AML), azacitidine showed an overall response rate of 57% in low-risk MDS and 39% in AML, indicating its efficacy across different risk groups.

The median overall survival for patients treated with azacitidine was 13 months, with factors like circulating blasts and poor risk cytogenetics identified as predictors for survival, while a doubling of platelets after the first treatment cycle was a positive indicator for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme. van der Helm, LH., Alhan, C., Wijermans, PW., et al.[2013]

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]

In a study of 38 elderly patients with myelodysplastic syndromes (MDS), azacitidine treatment resulted in a complete remission rate of 18% and a median overall survival of 16.4 months, indicating its efficacy in this population.

The treatment was generally safe, with only mild non-hematologic side effects reported, although 55% of patients experienced hematologic toxicities, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-azacitidine efficacy and safety in patients aged >65 years with myelodysplastic syndromes outside clinical trials. Breccia, M., Loglisci, G., Salaroli, A., 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]

Azacitidine (Vidaza) is the only drug approved in the EU that significantly prolongs survival in adults with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), making it a crucial treatment option for patients not eligible for stem cell transplantation.

The treatment is associated with a lower risk of AML progression and higher rates of remission and blood transfusion independence, while maintaining an acceptable safety profile, with peripheral cytopenias being the most common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2021]

Azacitidine is the first drug to significantly improve survival rates in patients with higher risk myelodysplastic syndrome (MDS), marking a shift from previous treatments that had lower complete remission rates.

While azacitidine is not a curative treatment, its effectiveness serves as a foundation for future combination studies and potential use in various treatment settings, such as before or after stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypomethylating agents and chemotherapy in MDS. Adès, L., Santini, V.[2014]

References

1. England pubmed.ncbi.nlm.nih.gov

Standard dose and prolonged administration of azacitidine are associated with improved efficacy in a real-world group of patients with myelodysplastic syndrome or low blast count acute myeloid leukemia. [2016]

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

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

3. England pubmed.ncbi.nlm.nih.gov

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

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

Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme. [2013]

5. 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]

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

5-azacitidine efficacy and safety in patients aged >65 years with myelodysplastic syndromes outside clinical trials. [2022]

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

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

9. Japan pubmed.ncbi.nlm.nih.gov

[Treatment of higher risk myelodysplastic syndromes]. [2019]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. [2021]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Hypomethylating agents and chemotherapy in MDS. [2014]