Phase 3 Randomized, Double-blind, Placebo-controlled Study of Tamibarotene and Azacitidine in RARA-positive Higher-risk Myelodysplastic Syndrome
- Trial ID
- 2023-510361-97-00
- Protocol
- SY-1425-301
- Sponsor
- Syros Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to **characterize and compare the complete remission/complete response rate** of tamibarotene plus azacitidine versus placebo plus azacitidine in newly diagnosed adult patients with RARA-positive higher-risk myelodysplastic syndrome. This objective is clinically relevant as achieving complete remission or response is a critical indicator of treatment efficacy in myelodysplastic syndromes, potentially leading to improved patient outcomes.
Secondary objectives include:
- Characterizing and comparing the overall survival (OS) of tamibarotene + azacitidine versus placebo + azacitidine.
- Characterizing and comparing the transfusion independence (TI) rate of tamibarotene + azacitidine versus placebo + azacitidine.
- Characterizing and comparing the overall response rate (ORR) of tamibarotene + azacitidine versus placebo + azacitidine.
- Characterizing the duration of complete response (DOCR) and duration of overall response of tamibarotene + azacitidine or placebo + azacitidine.
- Characterizing the time to complete remission/complete response (CR) and time to initial response of tamibarotene + azacitidine versus placebo + azacitidine.
- Characterizing and comparing the event-free survival (EFS) of tamibarotene + azacitidine versus placebo + azacitidine.
- Comparing changes in health-related quality of life (HRQOL) of tamibarotene + azacitidine versus placebo + azacitidine.
- Characterizing the safety of tamibarotene + azacitidine versus placebo + azacitidine.
Participants
The clinical trial involves a total of **133 participants** who are **newly diagnosed RARA-positive adult patients with higher-risk myelodysplastic syndrome (HR-MDS)**. The study population includes both male and female subjects, aged 18 years and older, with a focus on those classified under the WHO classification and IPSS-R risk category as Very High, High, or Intermediate risk. Participants were selected based on their diagnosis and measurable disease criteria, including bone marrow blasts greater than 5% at the screening visit. The trial population is characterized by an **ECOG Performance Status** of 2 or less and adequate organ function, as defined by specific laboratory parameters. Lifestyle considerations such as diet and physical activity are not specified, but participants must be willing to comply with study visits, treatment plans, and laboratory tests. The trial includes a vulnerable population, and all participants are required to provide informed consent. The sponsor has not provided additional information regarding specific lifestyle factors or habits.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** Phase 3 study to evaluate the efficacy of **tamibarotene** plus **azacitidine** versus placebo plus azacitidine in newly diagnosed adult patients with RARA-positive higher-risk **myelodysplastic syndrome**. The primary objective is to characterize and compare the complete remission/complete response rate between the two treatment groups. The trial is expected to run from February 2021 to February 2031, with participants involved for the duration of their treatment cycles, which may vary based on individual response and tolerance.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, RARA-positivity, and disease classification according to the WHO and IPSS-R risk categories. Following successful screening, participants will be randomized to receive either the investigational treatment or placebo. The treatment period involves administration of the study drugs, with **azacitidine** given subcutaneously or intravenously and **tamibarotene** administered orally. The maximum treatment period for azacitidine is 7 days per cycle, while tamibarotene is administered for up to 21 days per cycle.
Follow-up visits will be scheduled to monitor the participants' response to treatment, assess any adverse events, and perform necessary laboratory tests. The primary endpoint is the complete remission/complete response rate, while secondary endpoints include overall survival, transfusion independence, and overall response. The end-of-study visit will occur after the final treatment cycle or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent.
Participants are expected to comply with scheduled visits and treatment plans, and any deviation from these requirements may lead to early termination from the study. The trial aims to provide comprehensive data on the safety and efficacy of the investigational treatment in this patient population, contributing valuable insights into the management of higher-risk myelodysplastic syndrome.
Treatment
The clinical trial involves the administration of **Azacitidine**, a chemical compound used for its antineoplastic effects, believed to act through multiple mechanisms. The experimental medication, Azacitidin Zentiva 25 mg/mL, is provided as a **suspension for injection**. It is administered via **subcutaneous and intravenous use**. The dosing regimen includes a maximum daily dose of 75 mg/m² and a total maximum dose of 525 mg/m² over a treatment period of 7 days. The pharmaceutical form is a powder for suspension, manufactured by Zentiva, K.S., and is not a pediatric formulation.
Another formulation of **Azacitidine** used in the trial is a 25 mg/mL powder for suspension for injection, also administered subcutaneously and intravenously. This formulation follows the same dosing schedule as the Zentiva product, with a maximum daily dose of 75 mg/m² and a total maximum dose of 525 mg/m² over 7 days. It is produced by Zentiva Pharma UK Limited and is similarly not intended for pediatric use.
The trial also includes the administration of **Tamibarotene**, marketed as SY-1425, which is a potent and selective RARA agonist. It is provided in **tablet** form and is administered orally. The dosing schedule for Tamibarotene involves a maximum daily dose of 12 mg and a total maximum dose of 252 mg over a 21-day treatment period. This compound is manufactured by Syros Pharmaceuticals Inc. and is designated as an orphan drug.
A **placebo** for Tamibarotene (SY-1425) is also utilized in the study. The placebo is intended to match the administration route and form of Tamibarotene, although specific details regarding its pharmaceutical form and active ingredients are not applicable. The placebo is used to maintain the double-blind nature of the trial, ensuring unbiased comparison between the treatment and control groups.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the **complete remission/complete response rate** of tamibarotene plus azacitidine compared to placebo plus azacitidine. This primary endpoint will be determined by the investigator using the modified International Working Group (IWG) criteria for Myelodysplastic Syndromes (MDS). Secondary endpoints include overall survival, transfusion independence, overall response, duration of complete response, duration of overall response, time to complete remission/complete response, time to initial response, event-free survival, and changes in health-related quality of life. These will also be assessed using the modified IWG MDS criteria and additional tools such as the EORTC QLQ-30 and EQ-5D-5L for quality of life measurements.
Data collection will occur at specified intervals throughout the trial, with key timepoints including the date of randomization, the last dose of study drug, and the initiation of post-treatment therapy. The analysis will involve comparing the rates and durations of responses, survival times, and quality of life changes between the treatment and placebo groups. Adverse events and changes in clinical laboratory values, electrocardiogram results, and vital sign measurements will also be monitored to ensure comprehensive assessment of the treatment's efficacy and safety.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients must be at least 18 years old at the time of signing of an informed consent
- Patients must be RARA-positive based on the investigational assay
- Patients must be newly diagnosed with HR-MDS as follows: Diagnosis of MDS according to the WHO classification (Arber 2016) and classified by the IPSS-R risk category as: a. Very High (risk score >6), b. High (risk score >4.5 to 6), OR c. Intermediate (risk score >3 to 4.5).
- Patients must have measurable disease with bone marrow blasts >5% at the Screening Visit.
- Patients must have ECOG Performance Status of ≤2.
- Patients must have adequate organ function, as defined by: a. total bilirubin ≤3.0 × the ULN b. ALT and AST ≤3 × ULN, and c. creatinine clearance ≥30 mL/min based on the Cockcroft-Gault Glomerular Filtration Rate estimation.
- Patients must have a serum/high-sensitivity urine pregnancy test (for females of childbearing potential) that is negative at the Screening Visit and immediately prior to initiation of treatment (first dose of study drug).
- Patients must be willing and able to comply with the scheduled study visits, treatment plans, laboratory tests, use of 2 methods of birth control (including a barrier method) for WOCBP and male patients (as described in Appendix 4), and other procedures.
- Patients must be capable of giving signed and dated IRB or IEC approved informed consent document.
Exclusion Criteria
- Patients are suitable for and agree to undergo allogeneic HSCT at the time of screening.
- Patients received prior treatment for MDS with any hypomethylating agent, chemotherapy (including lenalidomide), or allogeneic HSCT, with the exception of prior treatment with growth factors or hydroxyurea. Growth factor treatment must be discontinued at least 2 weeks prior to starting study drug. Hydroxyurea treatment must be discontinued prior to starting study drug.
- Patients with history of cancer are excluded if they are in active treatment (with radiation, chemotherapy, antibodies, immunotherapies, or molecularly targeted therapies) or unless they are disease free for at least 2 years prior to the Screening Visit, following completion of a prior treatment. Exceptions include: localized prostate cancer treated with hormone monotherapy; localized breast cancer treated with adjuvant hormone monotherapy; or localized basal cell carcinoma, non-melanoma skin cancer, or cervical carcinoma in situ.
- Patients have an active, life-threatening, or clinically-significant, uncontrolled systemic infection requiring hospitalization.
- Patients have a known malabsorption syndrome or other condition that may impair absorption of study medication (e.g., gastrectomy).
- Immunocompromised patients with increased risk of opportunistic infections, including known HIV-positive patients with CD4 counts < or =350 cells/mm3 or history of opportunistic infection in the last 12 months. Note: To ensure that effective ART, when used in eligible HIV-positive patients, is tolerated and that toxicities are not confused with investigational drug toxicities, patients should be on an established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to the Screening Visit.
- Patients have a known active or chronic hepatitis B or active HCV infection. Patients with a history of HCV infection who have completed curative therapy for HCV at least 12 weeks before the Screening Visit and have a documented undetectable viral load at the Screening Visit are eligible for enrollment.
- Patients have other severe acute or chronic medical conditions (and/or psychiatric conditions or laboratory abnormalities) that may increase the expected risk to the patient (i.e., the risk associated with the study participation or investigational product administration), or that may interfere with the interpretation of study results or, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
- Patients received prior treatment with ATRA or systemic retinoid for a hematologic malignancy.
- Patients have not adequately recovered from a major surgery within 4 weeks of starting study drug administration.
- Patients with a diagnosis of hypervitaminosis A or patients taking vitamin A supplements >10,000 IU/day, unless treatment is discontinued at least 7 days prior to the first dose of the study drug.
- Patients known to be refractory to platelet or packed red blood cell transfusions per Institutional Guidelines, or patients who refuse blood product support.
- Patients received strong inducers of CYP3A4 within 2 weeks prior to the first tamibarotene/placebo administration.
- Patients received any other investigational agents within 4 weeks of the Screening Visit, or <5 half-lives since completion of previous investigational therapy have elapsed, whichever is shorter.
- Patients require concurrent treatment with any investigational or approved oncology agent, other than the agents described in exclusion criterion #3.
- Patients with > or = 20% blasts in peripheral blood or bone marrow or evidence of myeloid sarcoma (extramedullary AML).
- Patients with Grade > or = 2 hypertriglyceridemia, defined as >300 mg/dL (CTCAE, version 5)
- QTc >450 msec for male patients, QTc >470 msec for female patients, or QTc >480 msec in male or female patients with bundle branch block based on triplicate electrocardiogram (ECG) readings at the Screening Visit. NOTE: The QTc in this study should be the QT interval corrected for heart rate according to Fridericia formula (QTcF).
- Pregnant females, breastfeeding females, and males not willing to comply with contraceptive requirements or females of childbearing potential not willing to comply with contraceptive requirements.
- Patients who have a hypersensitivity to tamibarotene, azacitidine, or to any of their excipients
- Patients for whom treatment with tamibarotene or azacitidine is contraindicated.
- Patients with clinically significant cardiovascular disease, including unstable angina, acute myocardial infarction within 3 months prior to the start of study drug administration, or New York Heart Association Class III or IV congestive heart failure, cerebral vascular accident within 3 months prior to the start of study drug administration, or cardiac arrhythmia associated with hemodynamic instability.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Feb 2021 | 20 |
 Belgium | Not Recruiting | 01 Feb 2021 | 23 |
 Czechia | Not Recruiting | 01 Feb 2021 | 15 |
 France | Not Recruiting | 01 Feb 2021 | 130 |
 Germany | Not Recruiting | 01 Feb 2021 | 24 |
 Hungary | Not Recruiting | 01 Feb 2021 | 20 |
 Italy | Not Recruiting | 01 Feb 2021 | 75 |
 Poland | Not Recruiting | 01 Feb 2021 | 20 |
 Spain | Not Recruiting | 01 Feb 2021 | 90 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Azacitidin Zentiva 25 mg/ml Pulver zur Herstellung einer Injektionssuspension | Test | PULVER ZUR HERSTELLUNG EINER INJEKTIONSSUSPENSION | SUBCUTANEOUS AND INTRAVENOUS USE | 75 | 7 | PRD8106659 |
Azacitidine 25 mg/mL powder for suspension for injection | Test | POWDER FOR SUSPENSION FOR INJECTION | SUBCUTANEOUS AND INTRAVENOUS USE | 75 | 7 | PRD7942023 |
SY-1425 | Test | TABLET | ORAL | 12 | 21 | PRD5647808 |
Placebo for TamibaroteneSY-1425 | Placebo | N/A | — | — | — | N/A |
AZACITIDINE | Test | — | SUBCUTANEOUS AND INTRAVENOUS USE | 75 | 7 | SUB05624MIG |