Phase 3 Randomized, Open-Label Study of Guadecitabine vs Treatment Choice in Previously Treated Acute Myeloid Leukemia
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: guadecitabine; Treatment Choice (TC)
Intervention description: In Cycle 1, guadecitabine will be given for 10 days on Days 1-5 and Days 8-12. In Cycle 2, the guadecitabine dose will be 60 mg/m^2 for either 10 days (Days 1-5 and 8-12) or 5 days (Days 1-5 only) based on assessment of disease response, and hematological recovery by Day ≥28.; 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).
Intervention MeSH terms: Guadecitabine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 302.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: AML, acute myeloid leukemia, guadecitabine, SGI-110, Phase 3

Summary:

      Multicenter, randomized, open-label, parallel-group study of guadecitabine vs treatment
      choice (TC). Participants will be randomly assigned in a 1:1 ratio to either guadecitabine or
      TC. TC options include the 8 high or low intensity, locally available regimens below; or Best
      supportive Care (BSC) alone:

        -  High intensity (intermediate or high dose cytarabine [HiDAC]; mitoxantrone, etoposide,
           and cytarabine [MEC]; or fludarabine, cytarabine, granulocyte colony stimulating factor
           [G-CSF], +/- idarubicin [FLAG/FLAG-Ida]).

        -  Low intensity (low dose cytarabine [LDAC], decitabine, or azacitidine).

        -  BSC.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Adult participants ≥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. Participants 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. Participants 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. Participants 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 participants 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
             participant 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
             participant at an imminent risk of death.

         13. Participants with high PB blasts >50% AND poor ECOG PS of 2.