A Biomarker-Directed Phase 2 Trial of SY-1425, a Selective Retinoic Acid Receptor Alpha Agonist, in Adult Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

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] - Neoplasms [C04]

Trial duration

6 Jun 2018 → 21 Nov 2024

Decision date (initial)

2024-09-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Syros Pharmaceuticals, Inc.

External identifiers

EU CT number

2024-516281-11-00

EudraCT number

2017-000783-14

ClinicalTrials.gov

NCT02807558

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic

- Characterize the clinical activity of SY-1425 in biomarker positive patients by the overall response rate (ORR) in patients in Arms 1, 2A, 2B, and 5, and by the transfusion independence rate (TIR) in patients in Arm 3
- Characterize the safety and tolerability of the combination of SY-1425 and daratumumab in Arm

Secondary objectives 8

1. Characterize the clinical act of SY-1425 in patients positive for the RARA super-enhancer associated biomarker by the ORR in Arms 1, 2A, 2B, and 5, and by TIR in Arm3
2. Characterize the clinical act of SY-1425 in patients positive for the IRF8 biomarker and negative for the RARA super-enhancer associated biomarker by the ORR in Arms1, 2A, 2B and 5, and by TIR in Arm3
3. Characterize the clinical act of the combination of SY-1425 and azacitidine by the ORR in patients in Arm2B
4. Characterize the clinical act of the combination of SY-1425 and daratumumab by ORR in Arm4
5. Characterize the clinical act by patients in Arms 1, 2A, 2B, 3, 4, and 5, based on event-free survival (EFS), relapse-free survival (RFS), duration of response (DOR), overall survival (OS), hematologic improvement (HI).
6. For all patients, evaluate the measures secondary to cytopenias
7. Characterize the safety and tolerability of SY-1425 as a single agent in Arms 1, 2A, and 3, and in combination with azacitidine in Arms 2B and 5
8. Characterize the (PK) of SY-1425 after single and multiple doses

Conditions and MedDRA coding

Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Patients must be at least 18 years of age.
2. Patients must have: a. Relapsed and/or refractory non-APL AML that has failed to achieve a CR or PR following standard induction therapy, or has relapsed after any duration of CR or PR i. measurable disease with bone marrow blasts ≥5% at screening. b.Relapsed and/or refractory higher-risk MDS (High / Very High Risk, as defined by the Revised International Prognostic Scoring System (IPSSR)) patients that have failed to achieve a CR or PR, or any HI (per IWG 2006 criteria) after standard therapy with hypomethylating agents (eg, azacitidine, decitabine), or have relapsed after any duration of CR or PR or HI i. measurable disease with bone marrow blasts >5% at screening.
3. Patients must have: c. Newly diagnosed, treatment-naïve non-APL AML in patients who, at the time of study entry are unlikely to tolerate standard intensive chemotherapy due to age, performance status, or comorbidities based on at least one of the following criteria (Ferrara et al, 2013): i. Age ≥ 75-years-old ii. Eastern Cooperative Oncology Group (ECOG) Performance Status of 3 iii. Cardiac history of congestive heart failure (CHF) or documented ejection fraction (EF) ≤ 50% iv. Pulmonary disease with DLCO ≤ 65% or FEVI ≤ 65% v. Creatinine clearance ≥ 30 mL/min to < 45 mL/min vi. Hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 x upper limit of normal (ULN) vii. Any other comorbidity that the Investigator judges to be incompatible with intensive chemotherapy, and reviewed and approved by the Sponsor prior to enrollment
4. Patients must have: d. Transfusion dependent lower-risk MDS without the del 5q abnormality, in patients refractory to erythropoietin treatment or unlikely to respond to EPO treatment (EPO >500). i. Lower-risk MDS: Very Low /Low / Intermediate Risk, as defined by IPSS-R. ii. Red blood cell (RBC) transfusion dependent anemia defined as no 8 consecutive weeks without RBC transfusions within the 16 weeks prior to study entry, or ≥4 RBC transfusions within the 8 weeks prior to study entry. iii. Refractory to or ineligible for ESAs is defined as RBC-Transfusion Dependence despite ESA treatment of ≥40,000 units/week recombinant human erythropoietin for 8 weeks or an equivalent dose of darbepoetin (150 µg/week) or serum EPO level >500 mU/mL in patients not previously treated with ESAs.
5. Patients must be evaluated for the RARA super-enhancer associated biomarker or IRF8 biomarker as measured by RT-qPCR with a centralized test of peripheral blood at the time of study screening. a. Patients in arms 1, 2A, 3, 4 and 5 must be positive for the biomarker as defined by a predetermined cutoff to be eligible for enrollment.
6. Must be amenable to serial bone marrow aspirates and peripheral blood sampling during the study.
7. ECOG Performance Status (PS) of 0, 1 or 2. For newly diagnosed AML patients < 75 years of age, ECOG 0 to 3; for ≥ 75 years of age, ECOG 0 to 2
8. Adequate organ function as defined by: a. Total bilirubin ≤ 1.5 x the upper limit of normal (ULN), unless suspected to have Gilbert's disease. For newly diagnosed AML patients < 75 years of age, total bilirubin ≤ 3.0 x ULN; for ≥ 75 years of age, total bilirubin ≤ 1.5 x ULN. b. ALT and AST ≤ 3 x ULN or ≤ 5 x ULN if documented liver infiltration with leukemia cells. c. Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 45 mL/min based on the Cockroft-Gault GFR estimation. For newly diagnosed AML patients < 75 years of age, creatinine clearance ≥ 30 mL/min; for ≥ 75 years of age, creatinine clearance ≥ 45 mL/min.
9. Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 2 weeks prior to first study treatment, with the exception of hydroxyurea.
10. No investigational agents within 2 weeks prior to first study treatment.
11. Resolved acute effects of any prior AML/MDS therapy to baseline or ≤Grade 1 CTCAE severity.
12. Serum/urine pregnancy test (for females of childbearing potential) that is negative at screening and immediately prior to initiation of treatment (first dose).
13. Willingness and ability to comply with the scheduled study visits, treatment plans, laboratory tests and other procedures.
14. Fully-executed, signed and dated Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent document.

Exclusion criteria 22

1. APL (M3 subtype of AML) or patients with a t(9:22) cytogenetic translocation.
2. QTc interval >480 msec based on triplicate ECG readings using the Fridericia (QTcF), with the exception of patients with Right Bundle Branch Block or Left Bundle Branch Block.
3. Patients with an active, life-threatening or clinically-significant uncontrolled systemic infection.
4. Patients with known active uncontrolled central nervous system (CNS) leukemia.
5. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness or hepatitis B or hepatitis C infection. a. Arm 4 only: Patients with resolved infection (ie, patients who are HBsAg negative but positive for antiHBs or antiHBc) must also be screened using PCR measurement of HBV DNA levels. Patients who are PCR positive for HBV will be excluded. b. Arm 4 only: Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR.
6. Known malabsorption syndrome or other condition that may impair absorption of study medication (eg, gastrectomy).
7. Major surgery within 4 weeks prior to starting study treatment.
8. Patients taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to first dose of study drug, or having hypervitaminosis A.
9. Concurrent treatment with any investigational or approved oncology agents (unless specified in the protocol, such as hydroxyurea) or herbal reparations.
10. Arm 4 only: Known allergies, hypersensitivity, or intolerance to mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products.
11. Arm 4 only: Vaccination with live attenuated vaccines within 4 weeks of first study drug administration.
12. Hyperleukocytosis (leukocytes ≥ 25 x 10^9/L) at study entry. These patients may be treated with hydroxyurea according to routine practice, and enroll in the study when the leukocyte count falls below 25 x 10^9/L.
13. Current illicit drug or alcohol abuse.
14. Patients known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.
15. Prior treatment with ATRA or systemic retinoid for the treatment of hematologic malignancy.
16. Arm 4 only – Prior or concurrent exposure to daratumumab or other CD38 therapies
17. Arm 4 only – Subject has either of the following: a. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of predicted normal. b. Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
18. Patients with other active malignancy (not including basal cell carcinoma, non- melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer treated with hormone therapy). Patients with history of other cancers should be free of disease for at least 2 years.
19. Patients with hypertriglyceridemia defined as >1000 mg/dL (CTCAE v4.03 Grade 4).
20. Any clinically significant cardiac disease including one of the following currently or in the previous 6 months: myocardial infarction, unstable cardiac function due to unstable angina or congestive heart failure, congenital long QT syndrome, torsades de pointes or clinically significant ventricular arrhythmias.
21. Other severe acute or chronic medical condition such as refractory congestive heart failure, pulmonary disease associated with dyspnea at rest or requiring oxygen therapy, kidney dialysis, liver cirrhosis (Child B or C), or psychiatric condition or laboratory abnormality that may increase the risk to the patient associated with study participation or investigational product administration or which 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.
22. Pregnant females; breastfeeding females; and males and females of childbearing potential not willing to use two highly effective methods of birth control, one being barrier method. Intrauterine devices and birth control pills are not barrier methods, but are highly effective especially when combined with a barrier method (eg, latex condom or a diaphragm or cervical cap) while taking study drug (SY-1425, azacitidine and daratumumab) and continuing contraception use for at least 90 days after the last dose of study drug. Men/women should not donate sperm or ova during this timeframe. a.Non-childbearing potential is defined as menopausal for at least 2 years or documented oophorectomy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. ORR for biomarker positive patients with AML or higher-risk MDS (Arms 1, 2A, 2B, 5)
2. TIR for patients with lower-risk MDS (Arm 3)
3. Safety and tolerability of SY-1425 in combination with daratumumab assessed by the type and frequency of AEs and SAEs using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.03, as well as changes in clinically significant clinical laboratory values, electrocardiogram (ECG) parameters and vital sign measurement (Arm 4)

Secondary endpoints 12

1. ORR for AML or higher-risk MDS patients positive for the RARA super-enhancer associated biomarker (Arms 1, 2A, 2B, and 5)
2. TIR for lower-risk MDS patients positive for the RARA super-enhancer associated biomarker (Arm 3)
3. Response rate (ORR + TIR) for patients positive for the IRF8 biomarker and negative for the RARA super-enhancer associated biomarker treated with SY-1425 as a single agent (Arms 1, 2A, and 3)
4. ORR for AML or higher-risk MDS patients positive for the IRF8 biomarker and negative for the RARA super-enhancer associated biomarker (Arms 1, 2A, 2B, and 5)
5. TIR for lower-risk MDS patients positive for the IRF8 biomarker and negative for the RARA super-enhancer associated biomarker (Arm 3)
6. ORR for AML patients who are treated with SY-1425 in combination with azacitidine (Arm 2B)
7. ORR for AML or higher-risk MDS patients treated with SY-1425 in combination with daratumumab (Arm 4)
8. Clinical activity as measured by EFS, RFS, DOR, OS, and HI in Arms 1, 2A, 2B, 4, and 5
9. Clinical activity as measured by DOR and HI in Arm 3
10. Proportion of patients requiring supportive measures secondary to cytopenias, as measured by changes in transfusion rates, incidence and duration of growth factor support and antibiotics use, and number of hospitalizations associated with febrile neutropenia and/or thrombocytopenic bleeding
11. Characterize the safety and tolerability of SY-1425 as a single agent and in combination with azacitidine by assessing the type and frequency of AEs and SAEs using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.03, as well as changes in clinically significant clinical laboratory values, electrocardiogram (ECG) parameters and vital sign measurements (Arms 1, 2A, 2B, 3, and 5)
12. PK parameters of SY-1425, as single agent and in combination with azacitidine or daratumumab, after single and multiple doses by performing PK analysis to define time to maximum concentration (tmax), Cmax, minimum plasma concentration (Cmin), AUC, total body clearance (CL/F) and half-life (t1/2), where the data permits

Investigational products

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

Test 2

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 2

Locations

1 EU/EEA country · 1 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

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