Tamibarotene/Venetoclax/Azacitidine in Previously Untreated Patients Selected for RARA-positive AML (SELECT-AML-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

1 Apr 2022 → 12 Nov 2024

Decision date (initial)

2024-04-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Syros Pharmaceuticals, Inc.

External identifiers

EU CT number

2024-510939-21-00

EudraCT number

2021-003910-38

ClinicalTrials.gov

NCT04905407

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Pharmacokinetic, Efficacy

Part 1
Characterize the safety and tolerability of tamibarotene/venetoclax/azacitidine combination in RARA-positive, previously untreated AML patients to inform Part 2 dose and regimen of the tamibarotene/venetoclax/azacitidine therapy
Part 2
Characterize and compare the CR/CRi rate of tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine

Secondary objectives 7

1. Part 1 Characterize the ORR of tamibarotene/venetoclax/azacitidine combination
2. Part 1 Characterize PK of tamibarotene when administered as a part of tamibarotene/venetoclax/azacitidine therapy
3. Part 2 Characterize the safety and tolerability of tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine in RARA-positive, previously untreated AML patients
4. Part 2 Characterize and compare CR rate and CR/CRh rate of tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine
5. Part 2 Characterize duration of CR, duration of CR/CRi, and duration of CR/CRh of tamibarotene/venetoclax/azacitidine combination versus venetoclax/azacitidine
6. Part 2 Characterize time to CR, time to CR/CRi, and time to CR/CRh of tamibarotene/venetoclax/azacitidine combination versus venetoclax/azacitidine
7. Part 2 Characterize and compare the ORR of tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine

Conditions and MedDRA coding

RARA-positive acute myeloid leukemia

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. All patients must have obtained a blood sample for RARA biomarker investigational assay testing prior to starting treatment on Cycle 1 Day 1. The results of the investigational biomarker assay for all patients must be confirmed as RARA-positive by Cycle 1 Day 8 to enroll (Part 1) or to be randomized (Part 2) in the study
3. Patients must have ND, previously untreated non-APL AML with a bone marrow or peripheral blood blast count ≥20% and must be unlikely to tolerate standard intensive chemotherapy at the time of Cycle 1 Day 1 Visit due to age, performance status, or comorbidities based on at least one of the following criteria (Ferrara 2013): a. age ≥75 years old OR b. age <75 years old, with at least one of the following: o Eastern Cooperative Oncology Group (ECOG) performance status of 3 o cardiac history of congestive heart failure (CHF) or documented ejection fraction (EF) ≤50% o pulmonary disease with diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% or forced expiratory volume in one second (FEV1) ≤65% o creatinine clearance ≥30 mL/min to <45 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation o hepatic impairment with total bilirubin >1.5 to ≤3.0 × upper limit of normal (ULN) o any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy, and reviewed and approved by the sponsor
4. Patients must have ECOG of 0 to 3 (if <75 years old) or 0 to 2 (if ≥75 years old)
5. Patients must have a white blood cell (WBC) count <25,000/μL at the time of initiation of study drug (leukapheresis may be performed and/or hydroxyurea may be administered to decrease the WBC count to <25,000/μL)
6. Patients must have minimum baseline organ function, as defined by: a. total bilirubin ≤3.0 × ULN (if <75 years old) or ≤1.5 × ULN (if ≥75 years old) b. alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤3 × ULN or ≤5 × ULN (if documented liver infiltration with leukemia cells) c. creatinine clearance ≥30 mL/min (if <75 years old) or ≥45 mL/min (if ≥75 years old) based on the Cockcroft-Gault glomerular filtration rate estimation
7. Patients must have a high-sensitive urine or serum 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 women of childbearing potential (WOCBP) and male patients (as described in Appendix 4), and other procedures
9. Patients must be capable of giving signed and dated Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent

Exclusion criteria 20

1. Patients have APL
2. Patients have known active central nervous system involvement with AML
3. Participants with a history of other cancers must not be receiving active treatment (with radiation or chemotherapy) and must be free of disease for 2 years prior to the Screening Visit with the exception of localized prostate cancer treated with hormone therapy, breast cancer treated with hormone therapy, localized basal cell carcinoma, nonmelanoma 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 human immunodeficiency virus (HIV)-positive patients with CD4 counts ≤350 cells/mm3 or history of opportunistic infection in the last 12 months. Note: To ensure that effective anti-retroviral therapy (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 hepatitis C virus (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 study drug 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 all-trans retinoic acid (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. Prior treatment (before Cycle 1 Day1) for the diagnosis of AML, MDS, or antecedent hematologic malignancy with any hypomethylating agent, venetoclax, chemotherapy, or hematopoietic stem cell transplantation (HSCT), with the exception of prior treatment with hydroxyurea.
12. 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.
13. 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.
14. Patients require concurrent treatment with any investigational or approved oncology agent, except for hydroxyurea.
15. Patients with Grade ≥2 hypertriglyceridemia, defined as >300 mg/dL (Common Terminology Criteria for Adverse Events [CTCAE], version 5).
16. 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).
17. 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.
18. Patients who have a hypersensitivity to tamibarotene, azacitidine, venetoclax or to any of their excipients.
19. Patients for whom treatment with tamibarotene, azacitidine, or venetoclax is contraindicated
20. Protected persons (legally protected adults [under judicial protection, guardianship, or supervision] and persons deprived of their liberty).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part 1 Incidence of AEs, changes in clinical laboratory values, ECGs, and vital sign measurements
2. Part 2 CR/CRi assessment; CR/CRi rate is estimated by the proportion of patients who achieve CR/CRi (as determined by the investigator)

Secondary endpoints 12

1. Part 1 Overall response assessment, comprised of CR, CRi, CRh, MLFS, or PR (as determined by the investigator); ORR is estimated by the proportion of patients who achieve overall response
2. Part 1 Tamibarotene PK parameters
3. Part 2 Incidence of AEs, changes in clinical laboratory values, ECGs, and vital sign measurements
4. Part 2 CR assessment; CR rate is estimated by the proportion of patients who achieve CR (as determined by the investigator)
5. Part 2 CR/CRh assessment; CR/CRh rate is estimated by the proportion of patients who achieve CR/CRh (as determined by the investigator)
6. Part 2 Duration of CR, defined as duration from the date of first documented evidence of CR to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first.
7. Part 2 Duration of CR/CRi, defined as duration from the date of first documented evidence of CR/CRi to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first
8. Part 2 Duration of CR/CRh, defined as duration from the date of first documented evidence of CR/CRh to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first
9. Part 2 Time to CR, defined as the duration from the date of Cycle 1 Day 1 Visit to the date of the first documented evidence of CR as determined by the investigator
10. Part 2 Time to CR/CRi, defined as the duration from the date of Cycle 1 Day 1 Visit to the date of the first documented evidence of CR/CRi as determined by the investigator
11. Part 2 Time to CR/CRh, defined as the duration from the date of Cycle 1 Day 1 Visit to the date of the first documented evidence of CR/CRh as determined by the investigator
12. Part 2 Overall response assessment, comprised of CR, CRi, CRh, MLFS, or PR (as determined by the investigator); ORR is estimated by the proportion of patients who achieve overall response

Investigational products

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

Test 5

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

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 5 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