Sirolimus + Azacitidine for Myelodysplastic Syndrome

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of combining two drugs, sirolimus and azacitidine, in treating certain blood cancers, specifically high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Sirolimus (Rapamune) may slow cancer growth by blocking certain enzymes, while azacitidine (Vidaza or 5-azacytidine) aims to kill cancer cells or stop them from dividing. Different trial groups exist for patients with high-risk MDS or those previously treated with azacitidine. The trial suits individuals with high-risk MDS who have more than 5% blasts in their bone marrow or specific genetic changes and have previously received azacitidine treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Earlier studies have examined the safety and effectiveness of sirolimus and azacitidine for treating myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Azacitidine, a chemotherapy drug, is generally well-tolerated and can extend the lives of MDS patients. Sirolimus blocks certain enzymes to inhibit cancer cell growth and has shown promising results in similar blood disorders.

Researchers have tested the combination of sirolimus and azacitidine for safety in adults with these conditions. Only a few patients experienced significant side effects, indicating that the combination is generally well-tolerated. However, as this is a Phase 2 study, the long-term safety is still under investigation. Further research will clarify the safety of this combination for broader use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Sirolimus and Azacitidine for treating high-risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) because it offers a novel approach compared to current treatments like chemotherapy or hypomethylating agents alone. What sets this combination apart is Sirolimus's unique mechanism of action, which targets the mTOR pathway, potentially enhancing the effectiveness of Azacitidine. This dual approach could improve patient outcomes by tackling the disease from multiple angles, offering hope for better management of these challenging conditions.

What evidence suggests that sirolimus and azacitidine could be effective for high-risk myelodysplastic syndrome or recurrent acute myeloid leukemia?

Research has shown that using sirolimus and azacitidine together may help treat high-risk myelodysplastic syndrome (MDS) and recurrent acute myeloid leukemia (AML). This trial will administer a combination of sirolimus and azacitidine to participants. Sirolimus blocks certain proteins that cancer cells need to grow, while azacitidine stops cancer cells from dividing or kills them directly. Previous studies found that some patients with MDS experienced more than a 40% reduction in harmful cells after taking sirolimus. Azacitidine alone has extended the lives of patients with high-risk MDS. The combination of these drugs aims to kill more cancer cells and improve outcomes for patients with these challenging conditions. ^{1 2 3 6 7}

Who Is on the Research Team?

Margaret Kasner, MD

Principal Investigator

Sidney Kimmel Cancer Center at Thomas Jefferson University

Are You a Good Fit for This Trial?

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 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:

MDS (Arm A): High-risk MDS defined as: >5% blasts in bone marrow and/or the following cytogenetic categories: presence of inv(3)/t(3q)/del(3q), -7/del(7q), complex cytogenetics (3 or more abnormalities)

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 (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]

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 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 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]

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 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 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01869114

Sirolimus and Azacitidine in Treating Patients With High ... This phase II trial studies how well sirolimus and azacitidine works in treating patients with high-risk myelodysplastic syndrome or recurrent acute myeloid ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0006497119847833

A Phase II Study of Azacitidine and Sirolimus for the ... Only 5/12 MDS patients had >40% reduction in pS6 blasts after sirolimus. Correlation with clinical response is ongoing. Summary: Sirolimus and azacitidine ...

3. clinicaltrial.be clinicaltrial.be/en/details/174832?per_page=20&only_recruiting=0&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_eligible=0&only_active=0

Sirolimus and Azacitidine in Treating Patients With High... PRIMARY OBJECTIVE: I. To characterize the rate of response to azacitidine and sirolimus in adults with high-risk myelodysplastic syndrome (MDS), ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2817034/

5-azacitidine prolongs overall survival in patients with ... Patients with intermediate-2 and high-risk myelodysplastic syndrome (MDS) have a survival rate of 0.4 to 1.2 years as well as a high risk of their disease ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3768115/

Outcome of acute myeloid leukaemia following ... The prognosis of these secondary AML (sAML) cases is poor with frequent resistance to conventional chemotherapy and an overall survival of <1 year (Nimer, 2008) ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2948932/

Safety and efficacy of azacitidine in myelodysplastic ... Azacitidine has been reported to prolong survival in MDS patients. Azacitidine has been studied in different dosing schedules and combination therapies with the ...

7. researchgate.net researchgate.net/publication/8008720_Activity_of_sirolimus_in_patients_with_myelodysplastic_syndrome_-_Results_of_a_pilot_study

Activity of sirolimus in patients with myelodysplastic ... In hematological malignancies, sirolimus has shown antineoplastic activity against myelodysplastic syndrome [21] , acute myeloid leukemia (AML), ...