Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs
Condition: Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic
MeSH terms: Leukemia; Preleukemia; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Syndrome
Intervention: Guadecitabine; Treatment Choice
Intervention description: BSC: according to standard/institutional practice; included RBC or platelet transfusions; growth factors, i.e. erythropoiesis stimulating agents, granulocyte stimulating factors, iron chelating therapy; broad spectrum antibiotics and/or antifungals.
LDAC: 20 mg/m^2 SC or IV once daily (QD) for 14 days in 28-day cycles. Other schedules were allowed per institutional practice. Treatment for ≥4 cycles absent disease progression/toxicity. BSC per institutional/standard practice.
Standard Intensive Chemotherapy: recommended regimen of 7+3 was given as cytarabine 100-200 mg/m^2/day continuous infusion for 7 days and an anthracycline for 3 days. Anthracyclines per institutional practice included daunorubicin (45-60 mg/m^2/day) or idarubicin (9-12 mg/m^2/day) or mitoxantrone (8-12 mg/m^2/day) by IV infusion. Participants with complete or partial response after IC induction received ≥1 additional cycles with reduced cytotoxic doses then BSC per standard /institutional practice.
Intervention MeSH terms: Guadecitabine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 417.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      A Phase 3, randomized, open-label, parallel-group, multicenter study designed to evaluate the
      efficacy and safety of guadecitabine in participants 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 participants from approximately
      100 study centers will be randomly assigned in a 2:1 ratio to either guadecitabine
      (approximately 272 participants) or Treatment Choice (approximately 136 participants). The
      study consists of a 21-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 participant participation will vary. Participants may continue to
      receive treatment for as long as they continue to benefit.
    

Eligibility criteria:

        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:

               1. Participant received HMA for at least 6 cycles and was still transfusion
                  dependent.

               2. 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:

               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 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 <2.5×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
             participant 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

          -  Participants with TP53 mutations