Phase 3 Study of Tamibarotene Plus Azacitidine in Patients Selected for RARA-positive Higher-risk MDS (SELECT-MDS-1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Syros Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

completed 12 Nov 2024

Decision date (initial)

2024-06-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Syros Pharmaceuticals, Inc.

External identifiers

EU CT number

2023-510361-97-00

EudraCT number

2020-004528-40

ClinicalTrials.gov

NCT04797780

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Therapy, Safety

Characterize and compare the complete remission/complete response rate of tamibarotene plus azacitidine vs. placebo plus azacitidine

Secondary objectives 8

1. Characterize and compare the overall survival (OS) of tamibarotene + azacitidine vs. placebo + azacitidine
2. Characterize and compare the transfusion independence (TI) rate of tamibarotene + azacitidine vs. placebo + azacitidine
3. Characterize and compare the overall response rate (ORR) of tamibarotene + azacitidine vs. placebo + azacitidine
4. Characterize the duration of complete response (DOCR) and duration of overall response of tamibarotene + azacitidine or placebo + azacitidine
5. Characterize the time to complete remission/complete response (CR) and time to initial response of tamibarotene + azacitidine vs. placebo + azacitidine
6. Characterize and compare the event-free survival (EFS) of tamibarotene + azacitidine vs. placebo + azacitidine
7. Compare changes in health-related quality of life (HRQOL) of tamibarotene + azacitidine vs. placebo + azacitidine
8. Characterize the safety of tamibarotene + azacitidine vs. placebo + azacitidine

Conditions and MedDRA coding

Newly Diagnosed RARA-positive Adult Patients with Higher-risk Myelodysplastic Syndrome

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Patients must be at least 18 years old at the time of signing of an informed consent
2. Patients must be RARA-positive based on the investigational assay
3. 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).
4. Patients must have measurable disease with bone marrow blasts >5% at the Screening Visit.
5. Patients must have ECOG Performance Status of ≤2.
6. 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.
7. 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).
8. 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.
9. Patients must be capable of giving signed and dated IRB or IEC approved informed consent document.

Exclusion criteria 22

1. Patients are suitable for and agree to undergo allogeneic HSCT at the time of screening.
2. 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.
3. 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.
4. Patients have an active, life-threatening, or clinically-significant, uncontrolled systemic infection requiring hospitalization.
5. Patients have a known malabsorption syndrome or other condition that may impair absorption of study medication (e.g., gastrectomy).
6. 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.
7. 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.
8. 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.
9. Patients received prior treatment with ATRA or systemic retinoid for a hematologic malignancy.
10. Patients have not adequately recovered from a major surgery within 4 weeks of starting study drug administration.
11. 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.
12. Patients known to be refractory to platelet or packed red blood cell transfusions per Institutional Guidelines, or patients who refuse blood product support.
13. Patients received strong inducers of CYP3A4 within 2 weeks prior to the first tamibarotene/placebo administration.
14. 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.
15. Patients require concurrent treatment with any investigational or approved oncology agent, other than the agents described in exclusion criterion #3.
16. Patients with > or = 20% blasts in peripheral blood or bone marrow or evidence of myeloid sarcoma (extramedullary AML).
17. Patients with Grade > or = 2 hypertriglyceridemia, defined as >300 mg/dL (CTCAE, version 5)
18. 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).
19. 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.
20. Patients who have a hypersensitivity to tamibarotene, azacitidine, or to any of their excipients
21. Patients for whom treatment with tamibarotene or azacitidine is contraindicated.
22. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Complete remission/complete response rate as determined by the investigator per the modified IWG MDS criteria.

Secondary endpoints 10

1. Overall survival (OS), defined as the time from the date of randomization to the date of death due to any cause;
2. Transfusion independence (TI), defined as a period of at least 56 days with no RBC or platelet transfusion since the date of randomization to the last dose of study drug +30 days, the initiation of post-treatment therapy, or death, whichever occurs first
3. Overall response, defined as achieving complete remission/complete response (CR), partial remission/partial response (PR), marrow complete remission/complete response (mCR), or hematologic improvement (HI) as determined by the investigator per the modified IWG MDS criteria
4. Duration of complete response, defined as the duration from the date of first documented evidence of complete remission/complete response to the date of documented relapse of disease as determined by the investigator per the modified IWG MDS criteria, or death due to any cause, whichever occurs first
5. Duration of overall response defined as the duration from the date of first documented evidence of complete remission/complete response, partial remission/partial response, marrow complete remission/complete response, or hematologic improvement to the date of documented disease progression, relapse of disease as determined by the investigator per the modified IWG MDS criteria, or death due to any cause, whichever occurs first
6. Time to complete remission/complete response, defined as the duration from the date of randomization to the date of the first documented evidence of complete remission/complete response as determined by the investigator per the modified IWG MDS criteria
7. Time to initial response, defined as the duration from the date of randomization to the date of the first documented evidence of complete remission/complete response, partial remission/partial response, marrow complete remission/complete response, or hematologic improvement as determined by the investigator per the modified IWG MDS criteria
8. Event-free survival (EFS), defined as the time from the date of randomization to the date of transformation to AML or death due to any cause, whichever occurs first
9. Change in Health-related quality of life (HRQOL) as measured by the EORTC QLQ-30 and EQ-5D-5L
10. Adverse events and changes in clinical laboratory values, electrocardiogram results, and vital sign measurements

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Syros Pharmaceuticals Inc.

Sponsor organisation

Syros Pharmaceuticals Inc.

Address

35 Cambridgepark Drive Floor 4

City

Cambridge

Postcode

02140-2325

Country

United States

Scientific contact point

Organisation

Syros Pharmaceuticals Inc.

Contact name

Senior Clinical Trial Manager

Public contact point

Organisation

Syros Pharmaceuticals Inc.

Contact name

Senior Clinical Trial Manager

Third parties 7

Locations

9 EU/EEA countries · 97 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 46 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications