Tamibarotene + Azacitidine for Myelodysplastic Syndrome

No longer recruiting at 205 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for individuals newly diagnosed with higher-risk myelodysplastic syndrome (HR-MDS), a type of blood cancer. Researchers aim to determine if adding Tamibarotene, a retinoid therapy, to Azacitidine helps more patients achieve complete remission compared to Azacitidine with a placebo. Participants must be RARA-positive, indicating a specific gene marker, and must not have received any prior treatment for HR-MDS. The trial includes two groups: one receives both Tamibarotene and Azacitidine, while the other receives Azacitidine with a placebo. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

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.

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

Research shows that tamibarotene combined with azacitidine is under evaluation for its effectiveness and safety in treating higher-risk myelodysplastic syndrome (HR-MDS). Earlier studies found that this combination can significantly reduce cancer cells. However, like many treatments, it carries some risks.

Reports of serious side effects exist, but they are rare. Some patients have experienced liver and kidney problems. Notably, tamibarotene has received fast track designation from the FDA, indicating its promise and potential to meet an unmet medical need in HR-MDS.

Overall, while the treatment remains under study, evidence suggests it is generally well-tolerated, though not without possible side effects. Participants should weigh these risks and benefits when considering joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for myelodysplastic syndrome?

Researchers are excited about the combination of Tamibarotene and Azacitidine for treating Myelodysplastic Syndrome because it introduces a unique dual approach. Tamibarotene, an oral retinoic acid receptor alpha agonist, works by promoting the differentiation of blood cells, which is different from the standard treatments that primarily focus on directly targeting abnormal cells. When paired with Azacitidine, a chemotherapy drug that modifies DNA to stop cancer cells from growing, the combination aims to enhance the effectiveness of treatment by addressing multiple pathways involved in the disease. This innovative approach has the potential to improve outcomes and offer new hope for patients with this condition.

What evidence suggests that this trial's treatments could be effective for higher-risk myelodysplastic syndrome?

Research has shown that combining tamibarotene and azacitidine may be promising for treating higher-risk myelodysplastic syndrome (HR-MDS). In studies, patients with Retinoic Acid Receptor Alpha (RARA) positive disease had a 67% overall response rate, with 61% achieving complete remission. This suggests strong potential effectiveness in this group. In this trial, one group of participants will receive tamibarotene and azacitidine, while another group will receive azacitidine with a tamibarotene-matched placebo. Azacitidine alone has been proven to help patients with myelodysplastic syndromes live longer. When combined with tamibarotene, the treatment might enhance these benefits, especially in newly diagnosed patients. ^{1 3 4 6 7}

Who Is on the Research Team?

Medical Director

Principal Investigator

Syros Pharmaceuticals Inc.

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

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 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]

Citations

1. onclive.com onclive.com/view/tamibarotene-azacitidine-combination-under-investigation-in-higher-risk-mds

Tamibarotene/Azacitidine Combination Under Investigation ... The combination of tamibarotene (formerly SY-1425) and azacitidine (Vidaza) represents a potentially effective and tolerable addition to the higher-risk ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40334070/

Pivotal results of SELECT-MDS-1 phase 3 study ... Tamibarotene with azacitidine (AZA) showed complete remission (CR) rates in myeloid leukemia. SELECT-MDS-1 was a phase 3 study comparing the ...

3. withpower.com withpower.com/trial/tamibarotene-azacitidine-for-myelodysplastic-syndrome-96a32

Tamibarotene + Azacitidine for Myelodysplastic Syndrome Azacitidine significantly improves overall survival in patients with myelodysplastic syndromes and related disorders, with a median survival of 24.5 months ...

4. onclive.com onclive.com/view/dr-marconi-on-the-investigation-of-tamibarotene-plus-azacitidine-in-higher-risk-mds

Dr Marconi on the Investigation of Tamibarotene Plus ... In this trial, the patients with RARA-positive disease had an overall response rate (ORR) of 67%, with 61% of patients achieving a complete ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06085638?cond=Leukemia,%20Myelomonocytic,%20Chronic&rank=3

Phase I/II Study of SY-1425 (Tamibarotene) in Combination ... Primary Objectives: Cohort 1: Characterize the safety and toleratbility of the combination of azacitidine and tamibarotene in newly diagnosed CMML.

6. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/58/NCT02807558/Prot_000.pdf

STUDY PROTOCOL SY-1425-201 One case of overdose with azacitidine was reported during clinical trials (VIDAZA Prescribing ... Biomarker-Directed Phase 2 Trial of SY-1425 in Combination with ...

7. cancernetwork.com cancernetwork.com/view/fda-gives-tamibarotene-fast-track-designation-for-high-risk-mds

FDA Gives Tamibarotene Fast Track Designation for High- ... Tamibarotene has received fast track designation from the FDA for the treatment of patients with higher-risk myelodysplastic syndrome (MDS), ...