Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs
Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs
A Phase 3, randomized, open-label, parallel-group, multicenter study designed to evaluate the
 efficacy and safety of guadecitabine in subjects with MDS or CMML who failed or relapsed
 after adequate prior treatment with azacitidine, decitabine, or both. This global study will
 be conducted in approximately 15 countries. Approximately 408 subjects from approximately 100
 study centers will be randomly assigned in a 2:1 ratio to either guadecitabine (approximately
 272 subjects) or Treatment Choice (approximately 136 subjects). The study consists of a
 14-day screening period, a treatment period, a safety follow-up visit, and a long-term
 follow-up period. The study is expected to last more than 2 years, and the duration of
 individual subject participation will vary. Subjects may continue to receive treatment for as
 long as they continue to benefit.
Multicenter, randomized, open-label, parallel-group study of guadecitabine vs Treatment
 Choice (TC). Approximately 408 subjects will be randomly assigned 2:1 to either guadecitabine
 or TC.

 -  Guadecitabine: approximately 272 subjects.

 -  TC: approximately 136 subjects.

 Before randomization, the investigator will assign each subject to one of the following TC
 options:

 -  Low dose cytarabine (LDAC).

 -  Standard Intensive Chemotherapy (IC) of a 7+3 regimen.

 -  Best Supportive Care (BSC) only. BSC will be provided to all subjects as per standard
 and institutional practice. Subjects randomized to TC will not be allowed to cross over
 to guadecitabine. Data will be reviewed by an independent Data Monitoring Committee at
 regular intervals, primarily to evaluate safety during study conduct. Randomization will
 be stratified by disease category (MDS vs CMML), bone marrow (BM) blasts (BM blasts >10%
 vs BM blasts ≤10%), TC option (LDAC vs IC vs BSC), and study center region.

 Guadecitabine: 60 mg/m2 given SC daily on Days 1-5 in 28-day cycles (delayed as needed to
 allow blood count recovery). Treatment should be given for at least 6 total cycles in the
 absence of unacceptable toxicity or disease progression requiring alternative therapy. Beyond
 6 cycles, treatment should continue as long as the subject continues to benefit. BSC should
 be given according to standard and institutional practice.

 Treatment Choice (TC): Before randomization, the investigator will assign each subject to one
 of the following TC options:

 -  Low dose cytarabine (LDAC) given as 20 mg/m2 SC or IV once daily for 14 days in 28-day
 cycles (delayed as needed to allow blood count recovery). Treatment should be given for
 at least 4 cycles in the absence of disease progression or unacceptable toxicity.

 -  Standard Intensive Chemotherapy (IC) of a 7+3 regimen: given as cytarabine 100-200
 mg/m2/day given as continuous infusion for 7 days and an anthracycline given as per
 institutional standard practice such as daunorubicin (45-60 mg/m2/day), or idarubicin
 (9-12 mg/m2/day), or mitoxantrone (8-12 mg/m2/day) by intravenous infusion for 3 days.

 -  Best Supportive Care (BSC) only: given according to standard and institutional practice.
 BSC includes, but is not limited to blood transfusions (RBCs or platelets), growth
 factors including erythropoiesis stimulating agents (ESA), granulocyte stimulating
 factors (GSFs), iron chelating therapy, and broad spectrum antibiotics and/or
 antifungals.
Inclusion Criteria:

 -  Adult subjects ≥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:

 1. Subject received HMA for at least 6 cycles and was still transfusion dependent
 (as defined in 5b below).

 2. Subject had disease progression prior to Cycle 6 defined as ≥50% increase in bone
 marrow blasts from pretreatment levels to >5%, or ≥2 g/dL reduction of Hgb from
 pretreatment levels with transfusion dependence after at least 2 cycles of HMA.

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

 -  Subjects must have either:

 1. Bone marrow blasts >5% at randomization, OR

 2. 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 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 while receiving treatment with guadecitabine, LDAC, or IC and for at
 least 3 months after completing treatment.

 Exclusion criteria:

 -  Subjects who have been diagnosed as having AML with peripheral blood or bone marrow
 blasts of ≥20%.

 -  Subjects who may still be sensitive to repeated treatment with decitabine or
 azacitidine such as subjects 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 ULN (except for subjects with Gilbert's Syndrome for whom
 direct bilirubin is <2.5×ULN), or liver cirrhosis or chronic liver disease Child-Pugh
 Class B or C.

 -  Known active HIV, HBV, or HCV infection. Inactive hepatitis carrier status or low
 viral hepatitis titer on antivirals is allowed.

 -  Known significant mental illness or other condition such as active alcohol or other
 substance abuse or addiction that, in the opinion of the investigator, predisposes the
 subject to high risk of noncompliance with the protocol.

 -  Refractory congestive heart failure unresponsive to medical treatment, active
 infection resistant to all antibiotics, or advanced non-MDS associated pulmonary
 disease requiring >2 liters per minute oxygen.

 -  Life expectancy of less than one month

 -  subjects with TP53 mutations