The purpose of this study is to determine the activity of SY-1425 in relapsed/refractory
acute myeloid leukemia (AML) patients (SY-1425 administered as a monotherapy or in
combination with azacitidine), relapsed/refractory higher-risk myelodysplastic syndrome (MDS)
patients (SY-1425 administered as a monotherapy or in combination with daratumumab), newly
diagnosed treatment naïve AML patients who are unlikely to tolerate standard intensive
chemotherapy (SY-1425 administered as a monotherapy or in combination with azacitidine), or
lower-risk myelodysplastic syndrome (MDS) patients (SY-1425 administered as a monotherapy).
This is a phase 2, multi-center, open-label study exploring the activity of SY-1425 in
patients with relapsed or refractory non-APL AML, relapsed or refractory higher-risk MDS,
newly diagnosed treatment naïve AML, or transfusion dependent, lower-risk MDS. All patients
must be evaluated for the RARA super-enhancer associated biomarker or RARA pathway biomarker
at the time of the study screening evaluation. Patients will accrue to each of the six arms
based on diagnosis, prior treatment, risk group, and investigator choice of treatment
(SY-1425 single agent or in combination with azacitidine or daratumumab). SY-1425 will be
administered at 6 mg/m2/day orally divided in two doses. SY-1425 will be given on a 28-day
treatment cycle and dosing will be continuous. For those newly diagnosed treatment naïve and
relapsed refractory AML patients receiving the combination of SY-1425 and azacitidine,
azacitidine will be administered at 75 mg/m2/day IV or SC days 1-7, and SY-1425 will be
administered at 6 mg/m2/day orally divided in two doses days 8-28 on a 28-day treatment
cycle. For those relapsed or refractory non-APL AML and relapsed or refractory higher-risk
MDS patients receiving the combination of SY-1425 and daratumumab, SY-1425 daily dosing (dose
level described above) will begin with a 7-day lead-in followed by continuous dosing on a
28-day treatment cycle. Daratumumab will be administered at a dose of 16 mg/kg starting on
Cycle 1 Day 1 weekly for 8 weeks (8 dose total), followed by dosing every 2 weeks for 16
weeks (8 doses total), followed by dosing every 4 weeks.
Dosing will continue unless: the patient experiences unacceptable toxicity, disease
progression/relapse, pursues post-remission therapy other than SY-1425 (single agent or in
combination with azacitidine or daratumumab), or the Investigator determines it is in the
best interest of the patient to discontinue treatment. Newly diagnosed AML patients who
achieve a CR/CRi or PR while on SY-1425 single agent treatment and then relapse, or who fail
to achieve a CR/CRi or PR after completing at least 4 cycles of SY-1425 single agent
treatment, are eligible to receive SY-1425 in combination with azacitidine.
Lower-risk MDS patients will be withdrawn from the study at week 24 if they do not have at
least a minor erythroid response. Lower-risk MDS patients who in the opinion of the
investigator are receiving clinical benefit, but do not meet the minor erythroid response
criteria can remain on study with sponsor approval. Lower-risk MDS patients who continue past
week 24 will continue to receive treatment until erythroid relapse, disease progression, or
unacceptable toxicity.
An end of treatment visit will be conducted for all AML and higher-risk MDS patients within
30 days of the last dose of study drug, but prior to the start of any subsequent therapies to
monitor for safety and resolution of adverse events. For lower-risk MDS patients, the end of
treatment visit will also be the end of study visit which will be conducted 30 days after the
last dose of study drug. All AML and higher-risk MDS patients will be followed every three
months for survival for up to 2 years and patients who are withdrawn prior to relapse will
also follow-up for event free survival.
Inclusion Criteria:
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 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.
3. 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
4. Must be amenable to serial bone marrow aspirates and peripheral blood sampling during
the study.
5. 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.
6. 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.
7. Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 2
weeks prior to first study treatment, with the exception of hydroxyurea.
8. No investigational agents within 2 weeks prior to first study treatment.
9. No strong inducers of CYP3A4 (see Appendix 13.5) within 2 weeks prior to first study
treatment.
10. Resolved acute effects of any prior AML/MDS therapy to baseline or ≤ Grade 1 CTCAE
severity.
11. 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.
6. 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.
7. 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.
8. Patients with hypertriglyceridemia defined as >1000 mg/dL (CTCAE Grade 4).
9. 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 .
10. Patients with known active uncontrolled central nervous system (CNS) leukemia.
11. Patients taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to
first dose of study drug, or having hypervitaminosis A.
12. 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.
