Tamibarotene + Azacitidine for Myelodysplastic Syndrome

Recruiting at 196 trial locations

Overseen By Tiffany Crowell

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Syros Pharmaceuticals

Must not be taking: Hypomethylating agents, Lenalidomide

Disqualifiers: Prior MDS treatment, Stem cell transplant, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 11

Duration: 28-day cycles

246 Participants Needed

Trial Summary

What is the purpose of this trial?

This study compares the efficacy of Tamibarotene in combination with azacitidine to azacitidine in combination with placebo in participants who are Retinoic Acid Receptor Alpha (RARA) positive, and newly diagnosed with higher-risk myelodysplastic syndrome (HR-MDS), and who have not received treatment for this diagnosis. The primary goal of the study is to compare the complete remission rate between the two treatment arms.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Azacitidine has been shown to improve survival time and reduce the need for blood transfusions in patients with higher-risk myelodysplastic syndromes, as demonstrated in clinical trials. It is the first drug approved by the FDA for this condition, providing benefits like normalization of blood counts and reducing transfusion dependence. ^{1 2 3 4 5}

Is the combination of Tamibarotene and Azacitidine safe for treating myelodysplastic syndrome?

Azacitidine, also known as Vidaza or 5-azacytidine, has been shown to be generally safe in humans, with common side effects including nausea, vomiting, and changes in blood cell counts. Serious side effects like liver function abnormalities and renal failure have been reported but are rare. There is no specific safety data available for the combination of Tamibarotene and Azacitidine. ^{1 4 5 6 7}

How is the drug combination of Tamibarotene and Azacitidine unique for treating myelodysplastic syndrome?

The combination of Tamibarotene and Azacitidine is unique because it pairs a retinoid (Tamibarotene) with a hypomethylating agent (Azacitidine), potentially offering a novel approach by targeting different pathways in the treatment of myelodysplastic syndrome, compared to standard treatments that typically use Azacitidine alone. ^{1 3 5 7 8}

Research Team

Medical Director

Principal Investigator

Syros Pharmaceuticals Inc.

Eligibility Criteria

This trial is for adults over 18 with newly diagnosed higher-risk myelodysplastic syndrome (HR-MDS) who test positive for RARA and haven't been treated before. They should be able to perform daily activities with some limitations (ECOG ≤2). Those planning a stem cell transplant or who've had certain MDS treatments can't join.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

My MDS is classified as very high, high, or intermediate risk according to WHO.

My cancer is RARA-positive according to a specific test.

Exclusion Criteria

I agree to have a stem cell transplant from a donor.

I have received treatment for MDS with specific drugs or a stem cell transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-screening

Assessment of the RARA biomarker for study eligibility through blood sample collection

1 week

1 visit (in-person)

Treatment

Participants receive Tamibarotene plus azacitidine or placebo plus azacitidine in 28-day cycles

28-day cycles

7 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Azacitidine
• Tamibarotene

Trial Overview The study tests Tamibarotene combined with Azacitidine against Azacitidine plus a placebo in patients with HR-MDS. The main focus is to see which group has more complete remission of the disease.

Participant Groups

Group I: Tamibarotene + Azacitidine Experimental Treatment 2 Interventions

Tamibarotene: 6 mg administered orally twice per day (BID) on Days 8 through 28 of each 28-day treatment cycle. Azacitidine: 75 mg/m\^2 administered intravenously or subcutaneously each day on Days 1 through 7 of each 28-day treatment cycle.

Group II: Tamibarotene Matched Placebo + Azacitidine Placebo Group 2 Interventions

Placebo: Tamibarotene-matching tablets administered orally BID on Days 8 through 28 of each 28-day treatment cycle. Azacitidine: 75 mg/m\^2 administered intravenously or subcutaneously each day on Days 1 through 7 of each 28-day treatment cycle.

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?

Syros Pharmaceuticals

Lead Sponsor

Trials

6

Recruited

1,000+

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]

A randomized 'pick-a-winner' study evaluated the effectiveness of adding lenalidomide, valproic acid, or idarubicin to azacitidine in patients with higher-risk myelodysplastic syndromes, which is the current standard treatment.

The study aimed to determine if these combinations could improve outcomes compared to azacitidine alone, highlighting the potential for enhanced treatment strategies in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancing our chances of picking a winner in higher-risk myelodysplastic syndromes. Wei, AH., Seymour, JF.[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]

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]

Azacitidine, a DNA methyltransferase inhibitor, has significantly improved survival rates in patients with high-risk myelodysplastic syndromes, which typically have a poor prognosis of around 1 year.

To maximize the benefits of azacitidine, it is crucial to manage its adverse effects, especially during the initial treatment cycles, using transfusions, growth factors, and antiemetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects of azacitidine: onset, duration, and treatment. Martínez-Francés, A.[2013]

The Vidaza Access Program in Belgium successfully facilitated access to azacitidine treatment for 175 patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) by streamlining the approval process for patient dossiers.

Out of the 175 patient dossiers submitted, 163 were approved by Celgene, demonstrating the program's effectiveness in ensuring timely treatment initiation without financial risk to hospitals, which is crucial for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. Meers, S., Selleslag, D., Potier, H., et al.[2018]

In a study of 24 patients with higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the combination of 5-azacytidine (AZA) and valproate (VPA) resulted in a 37% overall response rate, with a notably higher response of 57% in previously untreated patients, particularly those with MDS (64%).

The treatment led to complete remission (CR) in 29% of patients, with some achieving complete cytogenetic remission, indicating that VPA may enhance the efficacy of AZA, although further randomized trials are needed to confirm the role of HDAC inhibitors in this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid. Kuendgen, A., Bug, G., Ottmann, OG., et al.[2021]

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

Enhancing our chances of picking a winner in higher-risk myelodysplastic syndromes. [2022]

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

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

5. 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]

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

Adverse effects of azacitidine: onset, duration, and treatment. [2013]

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

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]

8. Germany pubmed.ncbi.nlm.nih.gov

Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid. [2021]