SGI-110 in Participants With Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML)

DNA LINE-1 demethylation is defined as the largest percent decrease from baseline in methylation values within a participant between Day 8 and Day 22 of the first treatment cycle. BED was assessed based on DNA LINE-1 demethylation results and defined as the smallest dose that achieves the maximum biological pharmacodynamic (PD) effect (LINE-1 demethylation) in at least 3 successive dose levels.

DNA LINE-1 demethylation is defined as the largest percent decrease from baseline in methylation values within a participant between Day 8 and Day 22 of the first treatment cycle. BED was assessed based on DNA LINE-1 demethylation results and defined as the smallest dose that achieves the maximum biological pharmacodynamic (PD) effect (LINE-1 demethylation) in at least 3 successive dose levels.

DNA LINE-1 demethylation is defined as the largest percent decrease from baseline in methylation values within a participant between Day 8 and Day 22 of the first treatment cycle. BED was assessed based on DNA LINE-1 demethylation results and defined as the smallest dose that achieves the maximum biological pharmacodynamic (PD) effect (LINE-1 demethylation) in at least 3 successive dose levels.

DNA LINE-1 demethylation is defined as the largest percent decrease from baseline in methylation values within a participant between Day 8 and Day 22 of the first treatment cycle. BED was assessed based on DNA LINE-1 demethylation results and defined as the smallest dose that achieves the maximum biological pharmacodynamic (PD) effect (LINE-1 demethylation) in at least 3 successive dose levels.

The MTD was defined as the largest dose for which less than 33% of subjects experienced a dose limiting toxicity (DLT) during Cycle 1 of guadecitabine administration at each dose level. DLTs were defined using the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).

Composite complete response (CRc) rate is defined as the percentage of participants whose best response is complete remission [CR], CR with incomplete platelet recovery [CRp], or CR with incomplete hematological recovery [CRi]) after treatment with study drug. CR as per AML response criteria is defined as peripheral blood absolute neutrophil count (ANC) ≥1.0×10^9/L, Platelets ≥100×10^9/L, independence from red blood cell (RBC) and platelet transfusions over the past week, no myeloblasts and <5% myeloblasts in bone marrow. CRp as per AML response criteria is defined as peripheral blood ANC ≥1.0×10^9/L, Platelets <100×10^9/L, independence from RBC transfusions over the past week, no myeloblasts and <5% myeloblasts in bone marrow. CRi as per AML response criteria is defined as peripheral blood ANC <1.0×10^9/L, no myeloblasts and <5% myeloblasts in bone marrow.

ORR is defined as percentage of participants with complete response(CR), partial response(PR), marrow complete response(mCR) and haematological improvement(HI). CR:normal peripheral counts with persistent granulocyte count ≥1.0×10^9/L, platelet count ≥100×10^9/L and normal bone marrow (BM) with persistent marrow blasts ≤5%; persistent dysplasia was noted. PR:normal peripheral counts with granulocyte count ≥1.0×10^9/L and platelet count ≥100 ×10^9/L and normal BM with marrow blasts >5% but were reduced by 50% or more. mCR:reduction of BM blasts to ≤5% without normalization of peripheral counts. HI is divided as erythroid response(HI-E): hemoglobin increase ≥1.5 g/dL or red blood cells transfusion independence, platelet response (HI-P): absolute increase of platelet count from <20 to >20×10^9/L and by at least 100%,/if more than 20×10^9/L, by an absolute increase of 30×10^9/L, neutrophil response (HI-N): granulocyte increase ≥100%, and by an absolute increase ≥0.5×10^9/L.

Response rate for AML participants was assessed by Modified International Working Group (IWG) 2003 response criteria with complete response (CR), complete response with incomplete platelet recovery (CRp), CR with incomplete blood count recovery(CRi), and partial response (PR). CR: absolute neutrophil count (ANC) >1.0×10^9/L, platelets ≥100×10^9/L, independence from RBC and platelet transfusions, no or <5% myeloblasts in bone marrow(BM). CRp: ANC >1.0×10^9/L, Platelets <100×10^9/L, independence from RBC transfusions, no or <5% myeloblasts in BM. CRi: ANC <1.0×10^9/L, no or <5% myeloblasts in BM. PR: ANC >1.0×10^9/L, Platelets ≥100×10^9/L, no or decrease of ≥50% in myeloblasts to 5-25% in BM.

Response rate for MDS participants was assessed by IWG 2006 Response Criteria with CR, PR, marrow complete response(mCR) and HI. CR: normal peripheral counts with persistent granulocyte count ≥1.0×10^9/L, platelet count ≥100×10^9/L; normal BM with persistent marrow blasts ≤5%; persistent dysplasia. PR: Normal peripheral counts with granulocyte count ≥1.0×10^9/L, platelet count ≥100×10^9/L and normal BM with blasts >5% but reduced by 50% or more. mCR: reduction of BM blasts to ≤5% without normalization of peripheral counts.

Duration of response (in number of days) was calculated from the first time a complete response (CR, CRp, or CRi) was observed to time of relapse defined as the earliest time point whereby BM blasts or peripheral blood blasts become ≥5% and stayed at that level in subsequent visits while participants were still on study. CR:normal peripheral counts with persistent granulocyte count ≥1.0×10^9/L, platelet count ≥100×10^9/L and normal bone marrow (BM) with persistent marrow blasts ≤5%; persistent dysplasia was noted. CRp as per AML response criteria is defined as peripheral blood ANC ≥1.0×10^9/L, Platelets <100×10^9/L, independence from RBC transfusions over the past week, no myeloblasts and <5% myeloblasts in bone marrow. CRi as per AML response criteria is defined as peripheral blood ANC <1.0×10^9/L, no myeloblasts and <5% myeloblasts in bone marrow.

DOR was calculated from first time a response category (CR, PR, mCR, or HI) was achieved until response category was no longer met or the last available time point, whichever occurred first. CR:normal peripheral counts with persistent granulocyte count ≥1.0×10^9/L, platelet count ≥100×10^9/L and normal bone marrow (BM) with persistent marrow blasts ≤5%; persistent dysplasia was noted. PR:normal peripheral counts with granulocyte count ≥1.0×10^9/L and platelet count ≥100 ×10^9/L and normal BM with marrow blasts >5% but were reduced by 50% or more. mCR:reduction of BM blasts to ≤5% without normalization of peripheral counts. HI is divided as erythroid response(HI-E): hemoglobin increase ≥1.5 g/dL or RBC transfusion independence, platelet response (HI-P): absolute increase of platelet count from <20 to >20×10^9/L by at least 100%,/if more than 20×10^9/L, by absolute increase of 30×10^9/L, neutrophil response (HI-N): granulocyte increase ≥100%, by an absolute increase ≥0.5×10^9/L.

Time to response was defined as the number of days from the day a participants received the first dose of guadecitabine (cycle 1 day 1 {C1D1}) to the first day of response. Composite complete response rate (CRc = CR + CRp + CRi), which is an overall complete response assessment including CR, CR with incomplete platelet recovery (CRp) and CR with incomplete blood count recovery (CRi). CRc rate, was defined as the number of participants who achieved a response status of CR, CRp, or CRi divided by the total number of participants included in the efficacy dataset. The CR rate is defined as the number of participants whose best response is CR divided by the total number of participants included in the efficacy dataset.

Time to response was defined as the number of days from the day a participants received the first dose of guadecitabine (C1D1) to the first day of response. CR:normal peripheral counts with persistent granulocyte count ≥1.0×10^9/L, platelet count ≥100×10^9/L and normal bone marrow (BM) with persistent marrow blasts ≤5%; persistent dysplasia was noted. PR:normal peripheral counts with granulocyte count ≥1.0×10^9/L and platelet count ≥100 ×10^9/L and normal BM with marrow blasts >5% but were reduced by 50% or more. mCR:reduction of BM blasts to ≤5% without normalization of peripheral counts. HI is divided as erythroid response(HI-E): hemoglobin increase ≥1.5 g/dL or RBC transfusion independence, platelet response (HI-P): absolute increase of platelet count from <20 to >20×10^9/L by at least 100%,/if more than 20×10^9/L, by absolute increase of 30×10^9/L, neutrophil response (HI-N): granulocyte increase ≥100%, by an absolute increase ≥0.5×10^9/L.

DLT was defined using CTCAE v4.0. Toxicities were considered related to SGI-110 if it cannot be explained by underlying disease, intercurrent illness or concomitant medications. Any related Grade 3 or 4 non-hematologic toxicity except Grade 3 or 4 nausea/vomiting that is controllable by anti-emetics or diarrhea controllable by optimal therapy. Grade 3 laboratory investigations other than serum creatinine, bilirubin, AST or ALT were not considered a DLT unless they are associated with clinical manifestations. Study-drug related Grade 4 thrombocytopenia and Febrile neutropenia that was not present at study entry, and not resolve within 7 days, and is not related to underlying disease. Prolonged myelosuppression or pancytopenia with hypocellular bone marrow and no marrow blasts lasting for 6 weeks or more that is not related to disease progression. Any toxicity that results in treatment delays of > 4 weeks. Data is reported for any AE occurring during Cycle 1 (each cycle = 28 days).

Treatment-emergent AEs are defined as events that first occurred or worsened after the first dose of study drug given on C1D1 until 30 days after the last dose of study treatment or the start of an alternative anti-cancer treatment for MDS/CMML and subsequent AML, whichever occurs first, with the following exceptions: events that occurred after 30 days beyond the last dose of study treatment or the start of an alternative anti-cancer treatment for MDS/CMML and subsequent AML was considered treatment-emergent if the events are both serious and related to the study treatment.

Time to AML or death was defined as the number of days from the date the subject received the first dose of guadecitabine (C1D1) to the date of death or the date of MDS/ chronic myelomonocytic leukemia (CMML) progression to AML, whichever occurred earlier. Time to AML or death was evaluated using the Kaplan-Meier method, with the time censored on the last date of contact if a participant was still alive without progression to AML.

OS was defined as the number of days from the day the participant received the first dose of guadecitabine to the date of death (regardless of cause).

CR is defined absolute neutrophil count (ANC) >1.0×109/L, Platelets ≥100×109/L, independence from RBC and platelet transfusions over the past week, no myeloblasts and <5% myeloblasts in bone marrow. CRp is defined ANC >1.0×10^9/L, Platelets <100×10^9/L, independence from RBC transfusions over the past week, no myeloblasts and <5% myeloblasts in bone marrow. CRi is defined as ANC <1.0×10^9/L, no myeloblasts and <5% myeloblasts in bone marrow. PR is defined as ANC >1.0×10^9/L, Platelets ≥100×10^9/L, no myeloblasts and Decrease of ≥50% in myeloblasts to level of 5% to 25% in bone marrow.

CR is defined ANC >1.0×109/L, Platelets ≥100×109/L, independence from RBC and platelet transfusions over the past week, no myeloblasts and <5% myeloblasts in bone marrow. CRp is defined ANC >1.0×10^9/L, Platelets <100×10^9/L, independence from RBC transfusions over the past week, no myeloblasts and <5% myeloblasts in bone marrow. CRi is defined as ANC <1.0×10^9/L, no myeloblasts and <5% myeloblasts in bone marrow. PR is defined as ANC >1.0×10^9/L, Platelets ≥100×10^9/L, no myeloblasts and Decrease of ≥50% in myeloblasts to level of 5% to 25% in bone marrow.

Transfusion dependence at baseline was defined as any transfusion within 4 weeks of the first study dose (C1D1) with C1D1 transfusion counted, assuming it was always done before dosing. Transfusion independence after treatment was defined as no transfusion within an 8-week or 16-week period between C1D1 and last treatment date + 30 days.

Transfusion dependence at baseline was defined as any transfusion within 4 weeks of the first study dose (C1D1) with C1D1 transfusion counted, assuming it was always done before dosing. Transfusion independence after treatment was defined as no transfusion within an 8-week or 16-week period between C1D1 and last treatment date + 30 days.