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agent treatment, are eligible to receive SY-1425 in combination with azacitidine.~Lower-risk MDS patients will be withdrawn from the study at week 24 if they do not have at least a minor erythroid response.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.
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).