A Biomarker-Directed Phase 2 Trial of SY-1425 in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome

Inclusion Criteria:

Patients must be at least 18 years of age.

Patients must have:

a. Relapsed and/or refractory non-APL AML that has failed to achieve a complete remission (CR) or partial remission (PR) following standard induction therapy, or has relapsed after any duration of CR or PR i. Patients must have 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 (IPSS-R)) that has failed to achieve a CR or PR, or any hematologic improvement (HI, per IWG 2006 criteria) after standard therapy with hypomethylating agents (e.g., azacitidine, decitabine), or has relapsed after any duration of CR or PR or HI i. Patients must have measurable disease with bone marrow blasts >5% at screening

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 (PS) 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

d. Transfusion dependent lower-risk MDS without the del 5q abnormality, in patients refractory to erythropoietin treatment or unlikely to respond to erythropoietin 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 eight 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.

Patients must be evaluated for the RARA super-enhancer associated biomarker or RARA pathway associated biomarker at the time of study screening.

a. Patients in arms 1, 2A, 3, and 4 must be positive as defined by a pre-determined cut-off

1. Must be amenable to serial bone marrow aspirates and peripheral blood sampling during the study.
2. ECOG Performance Status (PS) of 0, 1 or 2. For newly diagnosed AML patients < 75 years of age, ECOG 0-3; for ≥ 75 years of age, ECOG 0-2.

Adequate organ function as defined by:

1. 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 x ULN; for ≥ 75 years of age, total bilirubin ≤ 1.5 x ULN.
2. ALT and AST ≤ 3 x ULN or ≤ 5 x ULN if documented liver infiltration with leukemia cells
3. 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.
4. Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 2 weeks prior to first study treatment, with the exception of hydroxyurea.
5. No investigational agents within 2 weeks prior to first study treatment.
6. No strong inducers of CYP3A4 (see Appendix 13.5) within 2 weeks prior to first study treatment.
7. Resolved acute effects of any prior AML/MDS therapy to baseline or ≤ Grade 1 CTCAE severity.
8. Serum/urine pregnancy test (for females of childbearing potential) that is negative at screening and immediately prior to initiation of treatment (first dose).

Exclusion Criteria:

1. Acute promyelocytic leukemia (APL, M3 subtype of AML) or patients with a t(9:22) cytogenetic translocation.
2. Hyperleukocytosis (leukocytes ≥25 x 109/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 109/L.
3. Patients known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.
4. Prior treatment with all-trans retinoic acid (ATRA) or systemic retinoid for the treatment of hematologic malignancy.
5. SY-1425 and daratumumab combination only - Prior or concurrent exposure to daratumumab or other CD38 therapies5.

SY-1425 and daratumumab combination only - Subject has either of the following:

1. 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.
2. 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.
3. Patients with 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.
4. Patients with hypertriglyceridemia defined as >1000 mg/dL (CTCAE Grade 4).
5. Patients with 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 significant ventricular arrhythmias .
6. Patients with known active uncontrolled central nervous system (CNS) leukemia.
7. Patients taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to first dose of study drug, or having hypervitaminosis A.
8. 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 (IUD) and birth control pills are not barrier methods, but are highly effective especially when combined with a barrier method (e.g. latex condom or a diaphragm or cervical cap) while taking investigational product (SY-1425) 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 time frame.