Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs

Inclusion Criteria

• Adult participants ≥18 years of age who are able to understand and comply with study procedures and provide written informed consent before any study-specific procedure.
• Cytologically or histologically confirmed diagnosis of MDS or CMML according to the 2008 World Health Organization (WHO) classification.
• Performance status (ECOG) of 0-2.
• Previously treated MDS or CMML, defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) for intermediate or high risk MDS or CMML whose disease progressed or relapsed as follows:
• Participant received HMA for at least 6 cycles and was still transfusion dependent.
• Participant received HMA for at least 2 complete cycles and had disease progression prior to Cycle 6 defined as

i. ≥50% increase in bone marrow blasts from pre-HMA-treatment levels or from nadir post-HMA-treatment levels to >5% (for participants with pretreatment or nadir blasts ≤5%) or to >10% (for participants with pretreatment or nadir blasts >5%), and/or ii. Transfusion dependent and ≥2 gram/deciliter (g/dL) reduction of Hgb from pre-HMA-treatment levels.

Other prior treatments for MDS such as lenalidomide, cytarabine, intensive chemotherapy, hydroxyurea, erythropoietin and other growth factors, or hematopoietic cell transplant (HCT) are allowed.

• Participants must have either:
• Bone marrow blasts >5% at randomization, OR
• Transfusion dependence, defined as having had transfusion (in the setting of active disease) of 2 or more units of RBC or platelets within 8 weeks prior to randomization.
• Creatinine clearance or glomerular filtration rate ≥30 milliliter/minute (mL/min) estimated by the Cockroft-Gault (C-G) or other medically acceptable formulas such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration).
• Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential and men with female partners of childbearing potential must agree to practice 2 highly effective contraceptive measures of birth control and must agree not to become pregnant or father a child (a) while receiving treatment with guadecitabine and for at least 3 months after completing treatment and (b) while receiving treatment with LDAC or IC and for at least 6 months after completing treatment or for the duration specified in local prescribing information, whichever is longer.

Exclusion Criteria

• Participants who have been diagnosed as having AML with peripheral blood or bone marrow blasts of ≥20%.
• Participants who may still be sensitive to repeated treatment with decitabine or azacitidine such as participants who had response to prior decitabine or azacitidine treatment, but relapsed >6 months after stopping treatment with these agents.
• Prior treatment with guadecitabine.
• Hypersensitivity to decitabine, guadecitabine, or any of their excipients.
• Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.
• Treated with any investigational drug within 2 weeks of the first dose of study treatment.
• Total serum bilirubin >2.5 × upper limit of normal (ULN) (except for participants with Gilbert's Syndrome for whom direct bilirubin is 2 liters per minute oxygen.
• Life expectancy of less than one month
• Participants with TP53 mutations