Phase 3 Randomized, Open-Label Study of Guadecitabine vs Treatment Choice in Previously Treated Acute Myeloid Leukemia

This Phase 3, randomized, open-label, parallel-group multicenter study of the efficacy and
safety of guadecitabine in adults with previously treated AML will be conducted in
approximately 20 countries. There will be 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
approximately 2 years. Duration of individual subject participation will vary, and subjects
may continue to receive treatment for as long as they continue to benefit.

Approximately 404 subjects from approximately 100 study centers will be randomly assigned to
either guadecitabine or treatment choice (TC) in a 1:1 ratio (approximately 202 subjects per
group). TC is as follows:

- High intensity: intermediate or high dose cytarabine (HiDAC); mitoxantrone, etoposide,
and cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida).

- Low intensity: low dose cytarabine (LDAC), decitabine, or azacitidine.

- Best Supportive Care (BSC).

Guadecitabine will be given SC at a dose of 60 mg/m2 in 28-day cycles. In Cycle 1,
guadecitabine will be given for 10 days on Days 1-5 and Days 8-12. Cycle 2 will be either the
5-day regimen (Days 1-5) or 10-day regimen (Days 1-5 and 8-12) based on assessment of disease
response and hematologic recovery at the end of Cycle 1. In subsequent cycles, guadecitabine
treatment will be for 5 days only (Days 1-5).

Inclusion Criteria:

1. Adult subjects ≥18 years of age who are able to understand study procedures, comply
with them, and provide written informed consent before any study-specific procedure.

2. History of cytologically or histologically confirmed diagnosis of AML (except acute
promyelocytic leukemia) according to the 2008 World Health Organization (WHO)
classification (bone marrow [BM] or peripheral blood [PB] blast counts ≥20%).

3. Performance status (Eastern Cooperative Oncology Group; ECOG) of 0-2.

4. Subjects with AML previously treated with initial induction therapy using a standard
intensive chemotherapy regimen, including cytarabine and an anthracycline, and who are
refractory to initial induction (primary refractory) or in relapse after such initial
induction with or without prior HCT.

5. Subjects must have either PB or BM blasts ≥5% at time of randomization.

6. Creatinine clearance or glomerular filtration rate ≥30 mL/min as 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).

7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a
negative pregnancy test at screening. Women of child-bearing potential and men with
female partners of child-bearing 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 of guadecitabine, decitabine, or
azacitidine and for at least 3 months after completing treatment and (b) while
receiving treatment with high-intensity TC or LDAC and for at least 6 months after
completing treatment.

Exclusion Criteria:

1. Known clinically active central nervous system (CNS) or extramedullary AML, except
leukemia cutis.

2. Subjects who are in first relapse after initial induction, if they had a response
duration of >12 months from date when first response first documented or if they are
good candidates for HCT.

3. BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).

4. Second malignancy currently requiring active therapy, except breast or prostate cancer
stable on or responding to endocrine therapy.

5. Grade 3 or higher Graft Versus Host Disease (GVHD), or GVHD on either a calcineurin
inhibitor or prednisone more than 5 mg/day.

6. Prior treatment with guadecitabine for any indication, or more than 2 cycles of prior
decitabine or azacitidine.

7. Hypersensitivity to decitabine, guadecitabine, or any of their excipients.

8. Treated with any investigational therapy within 2 weeks of the first dose of study
treatment.

9. Total serum bilirubin >2.5 × upper limit of normal (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.

10. Known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis
C virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis
titer on antivirals is allowed.

11. 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.

12. Refractory congestive heart failure unresponsive to medical treatment; active
infection resistant to all antibiotics; or non-AML-associated pulmonary disease
requiring >2 liters per minute (LPM) oxygen, or any other condition that puts the
subject at an imminent risk of death.

13. Subjects with high PB blasts >50% AND poor ECOG PS of 2.