MDS, CMML, AML
Conditions
Keywords
SGI-110, DNA Hypomethylating Agent, Intermediate 1, Intermediate 2, CMML or High Risk MDS, AML
Brief summary
Phase 1-2 dose-escalation randomized study in participants with intermediate or high risk myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). The Dose Escalation Segment will evaluate the biological activity, preliminary safety and efficacy of SGI-110 with two dosing schedules in MDS and AML participants while the Dose Expansion Segment will further evaluate safety and efficacy at the biological effective dose (BED) or maximum tolerated dose (MTD) as defined in the Dose Escalation Segment.
Detailed description
Once the biologically effective dose (BED) and maximum tolerated dose (MTD) is determined in the Dose Escalation Segment, the Dose Expansion Segment will randomize participants with MDS, treatment naïve elderly acute myeloid leukemia (AML), and relapsed/refractory AML participants to receive the BED or MTD dose. Relapsed/refractory AML participants may also receive SGI-110 on a daily x 10 schedule based on the total dose per cycle evaluated in the Dose-escalation Segment using the 5-daily regimen.
Interventions
DRUGGuadecitabine
Subcutaneous injection
Sponsors
Astex Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men or women, 18 years of age or older, with a confirmed diagnosis of international prognostic scoring system (IPSS) intermediate-1, intermediate-2 or high-risk MDS including Chronic Myelomonocytic Leukemia (CMML) or AML. * In the Dose Escalation Segment, participants who are refractory, relapsed, or unresponsive to standard treatment. * In the Dose Expansion Segment, hypomethylating agent (HMA) treatment-naïve MDS participants (including CMML), and intermediate-2 or high-risk MDS participant (including CMML) relapsed or refractory to prior HMA treatment are allowed, and treatment-naïve AML participants who is at least 65 years of age will be allowed if they also have at least one of the following criteria * AML secondary to MDS, chemotherapy, or radiation therapy * poor cytogenetics * pre-existing clinically significant dysfunction of the heart or Chronic Obstructive Pulmonary Disease (COPD) * poor performance status, Eastern Cooperative Oncology Group (ECOG), of 2 2. Eastern ECOG performance status of 0 to 2. 3. Adequate organ function. 4. Prior allogeneic stem cell transplant, no evidence of active graft-versus host disease (GVHD) and must be ≥ 2 weeks off immunosuppressive therapy. 5. No major surgery within 4 weeks of first dose of SGI-110. 6. No chemotherapy within 2 weeks of first dose of SGI-110 (minimum of 6 weeks for nitrosoureas and 8 weeks for bone marrow transplantation) with the exception of hydroxyurea which will be allowed during course 1 of treatment. 7. Sign an approved informed consent form for this study.
Exclusion criteria
1. In the Dose Expansion Segment, which includes the 10-day regimen, participants who have received 2 complete full dose cycles or more of a hypomethylating agent (HMA) decitabine or azacitidine (except for intermediate-2 or high-risk MDS participant (including CMML) relapsed or refractory to prior HMA treatment). 2. Acute promyelocytic leukemia (M3 classification). 3. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the participant has been disease free for at least 3 years. 4. Life-threatening illnesses other than AML or MDS, uncontrolled medical conditions or organ system dysfunction which, in the investigator's opinion, could compromise the participant's safety, or put the study outcomes at risk. 5. Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). 6. Hypersensitivity to decitabine, SGI-110, or SGI-110 excipients. 7. With the exception of treatment-naïve elderly AML participants, participants with uncontrolled congestive heart failure (CHF), coronary heart disease (CAD), chronic obstructive pulmonary disease (COPD), or left ventricular ejection fraction (LVEF) of ≤ 50% are excluded, symptomatic or uncontrolled arrhythmias or on continuous corticosteroids.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | Cycle 1 Day 8 | 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. |
| Dose Escalation Phase-Maximum Tolerated Dose (MTD): Number of Participants With Dose Limiting Toxicity (DLT) | From the start of study treatment up to 30 days post treatment (Up to approximately 46 months) | 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). |
| Dose Expansion (DE) Phase- r/r AML, TN AML: Composite Complete Response (CRc) Rate | At end of each Cycle of 28 days (Up to approximately 38 months) | 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. |
| Dose Expansion (DE) Phase- r/r MDS, TN MDS: Overall Response Rate (ORR) | At end of each Cycle of 28 days (Up to approximately 45 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DE Phase- r/r MDS, TN MDS: Duration of Response | At end of each Cycle of 28 days (Up to approximately 45 months) | 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. |
| Dose Escalation r/r AML, TN AML: Time to Response | At end of each Cycle of 28 days (Up to approximately 38 months) | 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. |
| Dose Expansion Phase- r/r MDS, TN MDS: Time to Response | At end of each Cycle of 28 days (Up to approximately 45 months) | 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. |
| Number of Participants With Dose Limiting Toxicities (DLT) Assessed Per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Cycle 1 (each cycle = 28 days) | 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). |
| Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | From first dose of study drug up 30 days post treatment (up to approximately 46 months) | 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. |
| Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | From first dose of study drug up 30 days post treatment (up to approximately 46 months) | — |
| Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Days 1, 5 and 8 | — |
| Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | Days 5 and 8 | — |
| Dose Escalation Phase: Response Rate in AML Participants | At end of each Cycle of 28 days (Up to approximately 23 months) | 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. |
| Dose Escalation and DE Phase- r/r MDS, TN MDS: Time to AML or Death | At end of each Cycle of 28 days (Up to approximately 38 months) | 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. |
| Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival | At end of each Cycle of 28 days (Up to approximately 45 months) | 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). |
| Dose Escalation: Number of Participants Achieving Blood and Platelet Transfusions | Cycle 1, Day 1 through 30 days after the last dose of study drug (up to approximately 46 months) | — |
| DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | At end of each Cycle of 28 days (Up to approximately 45 months) | 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. |
| DE Phase- r/r MDS, TN MDS: Percentage of Participants With CR, PR, mCR and HI | At end of each Cycle of 28 days (Up to approximately 45 months) | 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. |
| DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks | Weeks 8 and 16 | 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. |
| DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks | Weeks 8 and 16 | 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. |
| Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | Days 1, 5 and 8 | — |
| Dose Escalation Phase: Response Rate in MDS Participants | At end of each Cycle of 28 days (Up to approximately 23 months) | 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. |
| Dose Escalation and Dose Expansion Phase- r/r AML, TN AML: Duration of Response | At end of each Cycle of 28 days (Up to approximately 38 months) | 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. |
| Dose Escalation Phase: Hematologic Improvement Rate in MDS | At end of each Cycle of 28 days (Up to approximately 45 months) | — |
Countries
Canada, United States
Participant flow
Pre-assignment details
Total 94 participants with Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndromes (MDS) were enrolled in Dose escalation Phase 1, out of which 93 received treatment; Total 108 participants with relapsed and refractory (r/r) AML were enrolled, and 103 received study treatment; 107 participants with TN AML were enrolled, and 103 participants received study treatment; 105 participants with MDS were enrolled, and 102 received study treatment in Dose expansion (DE) Phase 2.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily Participants received starting dose of guadecitabine 3 mg/m\^2, SC, daily from Days 1-5 of a 28-day cycle. The dose was subsequently increased to 9, 18, 36, 60, 90, 125 mg/m\^2 for subsequent cycles until development of toxicity or disease progression. | 44 |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly Participants received starting dose of guadecitabine 6 mg/m\^2, SC, once weekly on Days 1, 8 and 15of a 28-day cycle. The dose was subsequently increased to 18, 36, 60, 90, 125 mg/m\^2 for subsequent cycles until development of toxicity or disease progression. | 34 |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly Participants received starting dose of guadecitabine 60 mg/m\^2, SC, twice weekly on Days 1, 4, 8, 11, 15 and 18of a 28-day cycle. The dose was subsequently increased to 90 mg/m\^2 for subsequent cycles until development of toxicity or disease progression. | 15 |
| Dose Expansion: r/r AML Guadecitabine 60 mg/m^2 (5-Day) Participants received guadecitabine 60 mg/m\^2, SC, daily,from Days 1-5 of a 28-day cycle in participants with diagnosis of r/r AML. | 24 |
| Dose Expansion: r/r AML Guadecitabine 90 mg/m^2 (5-Day) Participants received guadecitabine 90 mg/m\^2, SC, daily, from Days 1-5of a 28-day cycle in participants with a diagnosis of r/r AML. | 26 |
| Dose Expansion: r/r AML Guadecitabine 60 mg/m^2 (10-Day) Participants received guadecitabine 60 mg/m\^2, SC, daily from Days 1-5 and 8-12of a 28-day cycle in participants with a diagnosis of r/r AML. | 53 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) Participants received guadecitabine 60 mg/m\^2, SC, daily from Days 1-5, SC of a 28-day cycle in participants with a diagnosis of TN AML. | 24 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) Participants received guadecitabine 90 mg/m\^2, SC, daily, from Days 1-5of a 28-day cycle in participants with a diagnosis of TN AML. | 27 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) Participants received guadecitabine 60 mg/m\^2, SC, daily, from Days 1-5 and 8-12of a 28-day cycle in participants with a diagnosis of TN AML. | 52 |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) Participants received guadecitabine 60 mg/m\^2, SC, daily on Days 1-5 of a 28-day cycle in participants with a diagnosis of r/r MDS. | 26 |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) Participants received guadecitabine 90 mg/m\^2, SC, daily on Days 1-5of a 28-day cycle in participants with a diagnosis of r/r MDS. | 27 |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) Participants received guadecitabine 60 mg/m\^2, SC, daily on Days 1-5 of a 28-day cycle in participants with a diagnosis of TN MDS. | 27 |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) Participants received guadecitabine 90 mg/m\^2, SC. daily on Days 1-5 of a 28-day cycle in participants with a diagnosis of TN MDS. | 22 |
| Total | 401 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DE Phase: r/r AML (Week 75-242) | Adverse Event | 0 | 0 | 0 | 0 | 2 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| DE Phase: r/r AML (Week 75-242) | Death | 0 | 0 | 0 | 4 | 3 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| DE Phase: r/r AML (Week 75-242) | HCT | 0 | 0 | 0 | 5 | 3 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| DE Phase: r/r AML (Week 75-242) | Investigator Decision | 0 | 0 | 0 | 0 | 0 | 6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| DE Phase: r/r AML (Week 75-242) | Progressive Disease | 0 | 0 | 0 | 14 | 16 | 24 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| DE Phase: r/r AML (Week 75-242) | Reason not Specified | 0 | 0 | 0 | 1 | 2 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| DE Phase: r/r AML (Week 75-242) | Withdrew Consent | 0 | 0 | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| DE Phase: r/r MDS &TN MDS (Week 78-298) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 3 | 3 |
| DE Phase: r/r MDS &TN MDS (Week 78-298) | BM/Stem Cell Transplant | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 1 | 6 | 4 |
| DE Phase: r/r MDS &TN MDS (Week 78-298) | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 4 | 1 | 2 |
| DE Phase: r/r MDS &TN MDS (Week 78-298) | Investigator Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 6 | 3 | 5 |
| DE Phase: r/r MDS &TN MDS (Week 78-298) | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 7 | 7 | 9 | 2 |
| DE Phase: r/r MDS &TN MDS (Week 78-298) | Reason not Specified | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 2 | 1 |
| DE Phase: r/r MDS &TN MDS (Week 78-298) | Withdrew Consent | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 5 | 3 | 3 |
| DE Phase: TN AML (Week 85-283) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 |
| DE Phase: TN AML (Week 85-283) | Bone marrow (BM)/Stem cell transplant | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 2 | 0 | 0 | 0 | 0 |
| DE Phase: TN AML (Week 85-283) | Death | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 7 | 11 | 0 | 0 | 0 | 0 |
| DE Phase: TN AML (Week 85-283) | Investigator Decision | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 9 | 0 | 0 | 0 | 0 |
| DE Phase: TN AML (Week 85-283) | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 9 | 11 | 17 | 0 | 0 | 0 | 0 |
| DE Phase: TN AML (Week 85-283) | Reason not Specified | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 1 | 6 | 0 | 0 | 0 | 0 |
| DE Phase: TN AML (Week 85-283) | Withdrew Consent | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 3 | 3 | 0 | 0 | 0 | 0 |
| Dose Escalation Phase (Day 0- Week 170) | Adverse Event | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation Phase (Day 0- Week 170) | Death | 5 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation Phase (Day 0- Week 170) | Hematopoietic Cell Transplant (HCT) | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation Phase (Day 0- Week 170) | Investigator Decision | 4 | 1 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation Phase (Day 0- Week 170) | Progressive Disease | 27 | 26 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation Phase (Day 0- Week 170) | Reason not Specified | 3 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation Phase (Day 0- Week 170) | Subject Withdrew Consent | 3 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Expansion: r/r AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Expansion: r/r AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Expansion: r/r AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 78.46 years | 66.22 years | 64.90 years | 71.04 years | 55.83 years | 62.01 years | 58.86 years | 77.83 years | 77.78 years | 71.61 years | 72.05 years | 68.38 years | 71.27 years | 68.94 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 5 Participants | 3 Participants | 5 Participants | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 1 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 42 Participants | 32 Participants | 12 Participants | 19 Participants | 23 Participants | 48 Participants | 22 Participants | 51 Participants | 26 Participants | 25 Participants | 24 Participants | 21 Participants | 372 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 3 Participants | 1 Participants | 4 Participants | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 24 Participants | 39 Participants | 31 Participants | 14 Participants | 18 Participants | 21 Participants | 44 Participants | 23 Participants | 50 Participants | 25 Participants | 25 Participants | 25 Participants | 22 Participants | 361 Participants |
| Sex: Female, Male Female | 11 Participants | 19 Participants | 8 Participants | 3 Participants | 9 Participants | 6 Participants | 26 Participants | 10 Participants | 18 Participants | 10 Participants | 11 Participants | 6 Participants | 8 Participants | 145 Participants |
| Sex: Female, Male Male | 16 Participants | 25 Participants | 26 Participants | 12 Participants | 15 Participants | 20 Participants | 27 Participants | 14 Participants | 34 Participants | 16 Participants | 16 Participants | 21 Participants | 14 Participants | 256 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 44 | 4 / 35 | 0 / 15 | 4 / 25 | 3 / 28 | 10 / 55 | 4 / 24 | 7 / 27 | 11 / 52 | 2 / 26 | 4 / 27 | 1 / 27 | 2 / 22 |
| other Total, other adverse events | 44 / 44 | 34 / 34 | 15 / 15 | 24 / 24 | 26 / 26 | 53 / 53 | 24 / 24 | 27 / 27 | 52 / 52 | 26 / 26 | 27 / 27 | 27 / 27 | 22 / 22 |
| serious Total, serious adverse events | 33 / 44 | 28 / 34 | 8 / 15 | 19 / 24 | 21 / 26 | 44 / 53 | 21 / 24 | 24 / 27 | 45 / 52 | 17 / 26 | 22 / 27 | 17 / 27 | 17 / 22 |
Outcome results
Primary
Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation
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.
Time frame: Cycle 1 Day 22
Population: Pharmacodynamic (PD) analysis set included all participants who provided evaluable blood samples for analysis of at least one PD parameter or biomarker being tested. Overall number analyzed is number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -6.325 percent change | Standard Deviation 7.477 |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -4.777 percent change | Standard Deviation 4.765 |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -16.959 percent change | Standard Deviation 10.112 |
Primary
Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation
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.
Time frame: Cycle 1 Day 15
Population: Pharmacodynamic (PD) analysis set included all participants who provided evaluable blood samples for analysis of at least one PD parameter or biomarker being tested. Overall number analyzed is number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -10.359 percent change | Standard Deviation 9.837 |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -5.312 percent change | Standard Deviation 5.796 |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -17.540 percent change | Standard Deviation 9.207 |
Primary
Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation
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.
Time frame: Cycle 1 Day 8
Population: Pharmacodynamic (PD) analysis set included all participants who provided evaluable blood samples for analysis of at least one PD parameter or biomarker being tested. Overall number analyzed is number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -16.143 percent change | Standard Deviation 12.692 |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -4.362 percent change | Standard Deviation 5.484 |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -10.574 percent change | Standard Deviation 8.444 |
Primary
Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation
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.
Time frame: Cycle 2 Day 1
Population: Pharmacodynamic (PD) analysis set included all participants who provided evaluable blood samples for analysis of at least one PD parameter or biomarker being tested. Overall number analyzed is number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -2.805 percent change | Standard Deviation 4.249 |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -1.860 percent change | Standard Deviation 3.844 |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation | -13.346 percent change | Standard Deviation 6.039 |
Primary
Dose Escalation Phase-Maximum Tolerated Dose (MTD): Number of Participants With Dose Limiting Toxicity (DLT)
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).
Time frame: From the start of study treatment up to 30 days post treatment (Up to approximately 46 months)
Population: Safety data analysis set included all regimen 1, 2A and 2 B participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation Phase-Maximum Tolerated Dose (MTD): Number of Participants With Dose Limiting Toxicity (DLT) | DLT | 2 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation Phase-Maximum Tolerated Dose (MTD): Number of Participants With Dose Limiting Toxicity (DLT) | Adverse Event (AE) | 44 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation Phase-Maximum Tolerated Dose (MTD): Number of Participants With Dose Limiting Toxicity (DLT) | DLT | 0 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation Phase-Maximum Tolerated Dose (MTD): Number of Participants With Dose Limiting Toxicity (DLT) | Adverse Event (AE) | 34 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation Phase-Maximum Tolerated Dose (MTD): Number of Participants With Dose Limiting Toxicity (DLT) | DLT | 0 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation Phase-Maximum Tolerated Dose (MTD): Number of Participants With Dose Limiting Toxicity (DLT) | Adverse Event (AE) | 15 Participants |
Primary
Dose Expansion (DE) Phase- r/r AML, TN AML: Composite Complete Response (CRc) Rate
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.
Time frame: At end of each Cycle of 28 days (Up to approximately 38 months)
Population: Efficacy analysis set included r/r AML and TN AML participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Expansion (DE) Phase- r/r AML, TN AML: Composite Complete Response (CRc) Rate | 12.5 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Expansion (DE) Phase- r/r AML, TN AML: Composite Complete Response (CRc) Rate | 19.2 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Expansion (DE) Phase- r/r AML, TN AML: Composite Complete Response (CRc) Rate | 30.2 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Expansion (DE) Phase- r/r AML, TN AML: Composite Complete Response (CRc) Rate | 54.2 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Expansion (DE) Phase- r/r AML, TN AML: Composite Complete Response (CRc) Rate | 59.3 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Expansion (DE) Phase- r/r AML, TN AML: Composite Complete Response (CRc) Rate | 50.0 percentage of participants |
Primary
Dose Expansion (DE) Phase- r/r MDS, TN MDS: Overall Response Rate (ORR)
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.
Time frame: At end of each Cycle of 28 days (Up to approximately 45 months)
Population: Efficacy analysis set included r/r MDS and TN MDS participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Expansion (DE) Phase- r/r MDS, TN MDS: Overall Response Rate (ORR) | 31 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Expansion (DE) Phase- r/r MDS, TN MDS: Overall Response Rate (ORR) | 56 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Expansion (DE) Phase- r/r MDS, TN MDS: Overall Response Rate (ORR) | 48 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Expansion (DE) Phase- r/r MDS, TN MDS: Overall Response Rate (ORR) | 55 percentage of participants |
Secondary
DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR
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.
Time frame: At end of each Cycle of 28 days (Up to approximately 45 months)
Population: Efficacy analysis set included r/r AML and TN AML participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRi | 4.2 percentage of participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | PR | 0 percentage of participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRp | 0 percentage of participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CR | 8.3 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRi | 11.5 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | PR | 0 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CR | 7.7 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRp | 0 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | PR | 0 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRi | 3.8 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRp | 7.5 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CR | 18.9 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRp | 0 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | PR | 4.2 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRi | 16.7 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CR | 37.5 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRi | 11.1 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | PR | 3.7 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRp | 7.4 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CR | 40.7 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | PR | 1.9 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CR | 32.7 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRi | 7.7 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR | CRp | 9.6 percentage of participants |
Secondary
DE Phase- r/r MDS, TN MDS: Duration of Response
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 frame: At end of each Cycle of 28 days (Up to approximately 45 months)
Population: Efficacy analysis set included participants with MDS who received at least one dose of study drug. Overall number of participants analyzed are the number of participants with response. Number analyzed are the number of participants with data available for analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r MDS, TN MDS: Duration of Response | CR+PR+mCR | 295.0 days |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r MDS, TN MDS: Duration of Response | HI | 202.5 days |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r MDS, TN MDS: Duration of Response | HI | 193.0 days |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r MDS, TN MDS: Duration of Response | CR+PR+mCR | 207.0 days |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r MDS, TN MDS: Duration of Response | CR+PR+mCR | 103.0 days |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r MDS, TN MDS: Duration of Response | HI | 227.0 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r MDS, TN MDS: Duration of Response | CR+PR+mCR | 165.0 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r MDS, TN MDS: Duration of Response | HI | 127.0 days |
Secondary
DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks
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.
Time frame: Weeks 8 and 16
Population: Efficacy analysis set included r/r MDS and TN MDS participants who received at least one dose of study drug. Overall Number of Participants Analyzed are those who were dependent on RBC transfusions at baseline.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks | RBC Independence for Week 8 | 1 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks | RBC Independence for Week 16 | 0 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks | RBC Independence for Week 16 | 3 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks | RBC Independence for Week 8 | 4 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks | RBC Independence for Week 8 | 6 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks | RBC Independence for Week 16 | 5 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks | RBC Independence for Week 8 | 4 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks | RBC Independence for Week 16 | 1 Participants |
Secondary
DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks
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.
Time frame: Weeks 8 and 16
Population: Efficacy analysis set included r/r MDS and TN MDS participants who received at least one dose of study drug. Overall Number of Participants Analyzed are those who were dependent on platelet transfusions at baseline.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks | Platelet Independence for Week 8 | 0 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks | Platelet Independence for Week 16 | 0 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks | Platelet Independence for Week 16 | 2 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks | Platelet Independence for Week 8 | 5 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks | Platelet Independence for Week 8 | 3 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks | Platelet Independence for Week 16 | 2 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks | Platelet Independence for Week 8 | 3 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks | Platelet Independence for Week 16 | 2 Participants |
Secondary
DE Phase- r/r MDS, TN MDS: Percentage of Participants With CR, PR, mCR and HI
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.
Time frame: At end of each Cycle of 28 days (Up to approximately 45 months)
Population: Efficacy analysis set included r/r MDS and TN MDS participants who received at least one dose of study drug. Overall number of participants are the number of participants with data available for analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r MDS, TN MDS: Percentage of Participants With CR, PR, mCR and HI | CR+PR+mCR | 19 percentage of participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | DE Phase- r/r MDS, TN MDS: Percentage of Participants With CR, PR, mCR and HI | HI | 23 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r MDS, TN MDS: Percentage of Participants With CR, PR, mCR and HI | HI | 33 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | DE Phase- r/r MDS, TN MDS: Percentage of Participants With CR, PR, mCR and HI | CR+PR+mCR | 44 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r MDS, TN MDS: Percentage of Participants With CR, PR, mCR and HI | CR+PR+mCR | 26 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | DE Phase- r/r MDS, TN MDS: Percentage of Participants With CR, PR, mCR and HI | HI | 44 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r MDS, TN MDS: Percentage of Participants With CR, PR, mCR and HI | CR+PR+mCR | 50 percentage of participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | DE Phase- r/r MDS, TN MDS: Percentage of Participants With CR, PR, mCR and HI | HI | 41 percentage of participants |
Secondary
Dose Escalation and DE Phase- r/r MDS, TN MDS: Time to AML or Death
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.
Time frame: At end of each Cycle of 28 days (Up to approximately 38 months)
Population: Efficacy analysis set included Regimen 1, 2A, 2B, r/r MDS and TN MDS participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phase- r/r MDS, TN MDS: Time to AML or Death | 244.5 days |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phase- r/r MDS, TN MDS: Time to AML or Death | 275.0 days |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phase- r/r MDS, TN MDS: Time to AML or Death | 373.0 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phase- r/r MDS, TN MDS: Time to AML or Death | 273 days |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phase- r/r MDS, TN MDS: Time to AML or Death | 276 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phase- r/r MDS, TN MDS: Time to AML or Death | 680 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phase- r/r MDS, TN MDS: Time to AML or Death | 542.5 days |
Secondary
Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events
Time frame: From first dose of study drug up 30 days post treatment (up to approximately 46 months)
Population: Safety data set included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 2 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 1 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 6 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 1 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 2 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 1 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 3 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 1 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 2 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 1 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 0 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 1 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 1 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 3 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 1 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 0 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 1 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 1 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 0 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 1 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 0 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 0 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 0 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 0 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 0 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 2 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 2 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 2 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 2 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 2 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 3 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 3 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 3 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 1 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 4 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 6 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 2 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 1 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 1 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 1 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 1 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 2 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 0 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 2 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 2 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 1 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 1 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 2 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 2 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 1 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Potassium Increased | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Increased | 1 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hypoalbuminaemia | 1 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Increased | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Magnesium Increased | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Alkaline Phosphatase Decreased | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Aspartate Aminotransferase Increased | 1 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Hyperbilirubinaemia | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Bilirubin Increased | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Alanine Aminotransferase Increased | 0 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With Abnormal Laboratory Values Reported as Adverse Events | Blood Creatinine Decreased | 0 Participants |
Secondary
Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival
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).
Time frame: At end of each Cycle of 28 days (Up to approximately 45 months)
Population: Efficacy analysis set included participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival | 124 days |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival | 186.5 days |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival | 212.0 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival | 172 days |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival | 214 days |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival | 273 days |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival | 370 days |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival | 771 days |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival | 558 days |
Secondary
Dose Escalation and Dose Expansion Phase- r/r AML, TN AML: Duration of Response
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.
Time frame: At end of each Cycle of 28 days (Up to approximately 38 months)
Population: Efficacy analysis set included regimen 1, 2A and 2B, r/r AML and TN AML participants who received at least one dose of study drug. Data for responders was reported for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and Dose Expansion Phase- r/r AML, TN AML: Duration of Response | 213.0 days |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and Dose Expansion Phase- r/r AML, TN AML: Duration of Response | 300.0 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phase- r/r AML, TN AML: Duration of Response | 816.0 days |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phase- r/r AML, TN AML: Duration of Response | 112.0 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and Dose Expansion Phase- r/r AML, TN AML: Duration of Response | 233.0 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phase- r/r AML, TN AML: Duration of Response | 237.0 days |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phase- r/r AML, TN AML: Duration of Response | 185.5 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and Dose Expansion Phase- r/r AML, TN AML: Duration of Response | 269.5 days |
Secondary
Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs)
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 frame: From first dose of study drug up 30 days post treatment (up to approximately 46 months)
Population: Safety data set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 44 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 34 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 15 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 24 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 26 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 53 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 24 Participants |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 27 Participants |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 52 Participants |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 26 Participants |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 27 Participants |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 27 Participants |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation and Dose Expansion Phases- r/r AML, TN AML, r/r MDS, TN MDS: Number of Participants With At Least One Treatment-Emergent Adverse Events (TEAEs) | 22 Participants |
Secondary
Dose Escalation: Area Under the Curve to Infinity (AUC0-inf)
Time frame: Days 1, 5 and 8
Population: Pharmacokinetic (PK) analysis set included all available plasma concentrations and PK parameters for guadecitabine and decitabine for participants who received study drug. Overall number of participants analyzed are the number of participants available for analysis. Number analyzed are the number of participants with data available for analysis at the given timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 12.1 ng*hr/mL | Geometric Coefficient of Variation 71.5 |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 5 | 26.5 ng*hr/mL | Geometric Coefficient of Variation 5.87 |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 5 | 63.5 ng*hr/mL | Geometric Coefficient of Variation 13.7 |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 45.2 ng*hr/mL | Geometric Coefficient of Variation 23.9 |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 102 ng*hr/mL | Geometric Coefficient of Variation 42.7 |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 5 | 112 ng*hr/mL | Geometric Coefficient of Variation 29.8 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 211 ng*hr/mL | Geometric Coefficient of Variation 55.8 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 5 | 226 ng*hr/mL | Geometric Coefficient of Variation 35 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 5 | 354 ng*hr/mL | Geometric Coefficient of Variation 13.8 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 410 ng*hr/mL | Geometric Coefficient of Variation 25.8 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 5 | 423 ng*hr/mL | Geometric Coefficient of Variation 46 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 528 ng*hr/mL | Geometric Coefficient of Variation 26.8 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 5 | 658 ng*hr/mL | Geometric Coefficient of Variation 26.9 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 648 ng*hr/mL | Geometric Coefficient of Variation 31.3 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 21.4 ng*hr/mL | Geometric Coefficient of Variation 65.4 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 8 | 17.9 ng*hr/mL | Geometric Coefficient of Variation 42.1 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 99.8 ng*hr/mL | Geometric Coefficient of Variation 25.2 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 8 | 58.0 ng*hr/mL | Geometric Coefficient of Variation 15 |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 8 | 227 ng*hr/mL | Geometric Coefficient of Variation 50.5 |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 182 ng*hr/mL | Geometric Coefficient of Variation 19.5 |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 327 ng*hr/mL | Geometric Coefficient of Variation 48.9 |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 8 | 371 ng*hr/mL | Geometric Coefficient of Variation 15.2 |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 331 ng*hr/mL | Geometric Coefficient of Variation 23.1 |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 8 | 383 ng*hr/mL | Geometric Coefficient of Variation 27.4 |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 8 | 675 ng*hr/mL | Geometric Coefficient of Variation 45.1 |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 636 ng*hr/mL | Geometric Coefficient of Variation 40.2 |
| Dose Escalation: Regimen 2B: Twice Weekly - 60 mg/m^2 | Dose Escalation: Area Under the Curve to Infinity (AUC0-inf) | SGI-110: Day 1 | 328 ng*hr/mL | Geometric Coefficient of Variation 38.4 |
Secondary
Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine
Time frame: Days 1, 5 and 8
Population: Pharmacokinetic (PK) analysis set included all available plasma concentrations and PK parameters for guadecitabine and decitabine for participants who received study drug. Number analyzed are the number of participants with data available for analysis at the given timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 5 | 1.67 ng/mL | Geometric Coefficient of Variation 54.7 |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 1.27 ng/mL | Geometric Coefficient of Variation 30.5 |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 5 | 11.1 ng/mL | Geometric Coefficient of Variation 65.8 |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 6.69 ng/mL | Geometric Coefficient of Variation 72.9 |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 19.1 ng/mL | Geometric Coefficient of Variation 43.5 |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 5 | 3.52 ng/mL | Geometric Coefficient of Variation 27.4 |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 5 | 30.7 ng/mL | Geometric Coefficient of Variation 42.5 |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 2.54 ng/mL | Geometric Coefficient of Variation 18.5 |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 8.18 ng/mL | Geometric Coefficient of Variation 56.9 |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 45.7 ng/mL | Geometric Coefficient of Variation 57.9 |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 5 | 10.3 ng/mL | Geometric Coefficient of Variation 65.1 |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 5 | 45.2 ng/mL | Geometric Coefficient of Variation 43.4 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 5 | 16.7 ng/mL | Geometric Coefficient of Variation 37.6 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 13.9 ng/mL | Geometric Coefficient of Variation 60.4 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 106 ng/mL | Geometric Coefficient of Variation 129 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 5 | 72.7 ng/mL | Geometric Coefficient of Variation 41.1 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 23.7 ng/mL | Geometric Coefficient of Variation 79.8 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 121 ng/mL | Geometric Coefficient of Variation 31.9 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 5 | 120 ng/mL | Geometric Coefficient of Variation 31.7 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 5 | 22.7 ng/mL | Geometric Coefficient of Variation 69.9 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 5 | 205 ng/mL | Geometric Coefficient of Variation 34.9 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 42.0 ng/mL | Geometric Coefficient of Variation 40 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 155 ng/mL | Geometric Coefficient of Variation 34.6 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 5 | 53.6 ng/mL | Geometric Coefficient of Variation 37.4 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 5 | 59.1 ng/mL | Geometric Coefficient of Variation 30.5 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 178 ng/mL | Geometric Coefficient of Variation 46.2 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 5 | 173 ng/mL | Geometric Coefficient of Variation 36.7 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 61.5 ng/mL | Geometric Coefficient of Variation 37.4 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 11.7 ng/mL | Geometric Coefficient of Variation 65.7 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 8 | 2.78 ng/mL | Geometric Coefficient of Variation 43.8 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 3.05 ng/mL | Geometric Coefficient of Variation 48.4 |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 8 | 10.7 ng/mL | Geometric Coefficient of Variation 60.7 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 8.20 ng/mL | Geometric Coefficient of Variation 52.7 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 8 | 6.92 ng/mL | Geometric Coefficient of Variation 79.5 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 8 | 18.1 ng/mL | Geometric Coefficient of Variation 99.3 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 37.4 ng/mL | Geometric Coefficient of Variation 73.4 |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 61.9 ng/mL | Geometric Coefficient of Variation 44.5 |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 17.1 ng/mL | Geometric Coefficient of Variation 55.9 |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 8 | 66.3 ng/mL | Geometric Coefficient of Variation 63.8 |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 8 | 12.7 ng/mL | Geometric Coefficient of Variation 41.8 |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 16.7 ng/mL | Geometric Coefficient of Variation 47 |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 8 | 19.0 ng/mL | Geometric Coefficient of Variation 55.8 |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 8 | 107 ng/mL | Geometric Coefficient of Variation 40 |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 101 ng/mL | Geometric Coefficient of Variation 51 |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 8 | 118 ng/mL | Geometric Coefficient of Variation 27.8 |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 30.1 ng/mL | Geometric Coefficient of Variation 41.3 |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 100 ng/mL | Geometric Coefficient of Variation 30.2 |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 8 | 35.0 ng/mL | Geometric Coefficient of Variation 45.4 |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 219 ng/mL | Geometric Coefficient of Variation 36.5 |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 65.9 ng/mL | Geometric Coefficient of Variation 50 |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 8 | 53.2 ng/mL | Geometric Coefficient of Variation 39.5 |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 8 | 187 ng/mL | Geometric Coefficient of Variation 40.9 |
| Dose Escalation: Regimen 2B: Twice Weekly - 60 mg/m^2 | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | Decitabine: Day 1 | 26.1 ng/mL | Geometric Coefficient of Variation 83.2 |
| Dose Escalation: Regimen 2B: Twice Weekly - 60 mg/m^2 | Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine | SGI-110: Day 1 | 106 ng/mL | Geometric Coefficient of Variation 29.9 |
Secondary
Dose Escalation: Minimum Observed Plasma Concentration (Cmin)
Time frame: Days 5 and 8
Population: PK analysis set included all available plasma concentrations and PK parameters for guadecitabine and decitabine for participants who received study drug. Overall number of participants analyzed are the number of participants available for analysis. Number analyzed are the number of participants with data available for analysis at the given timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 5 | NA ng/mL | — |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 5 | NA ng/mL | — |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 5 | NA ng/mL | — |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 5 | NA ng/mL | — |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 5 | NA ng/mL | — |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 5 | NA ng/mL | — |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 5 | NA ng/mL | — |
| Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 8 | NA ng/mL | Geometric Coefficient of Variation 224 |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day) | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 8 | NA ng/mL | — |
| Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 8 | NA ng/mL | — |
| Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 8 | NA ng/mL | Geometric Coefficient of Variation 200 |
| Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day) | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 8 | NA ng/mL | — |
| Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day) | Dose Escalation: Minimum Observed Plasma Concentration (Cmin) | SGI-110: Day 8 | NA ng/mL | — |
Secondary
Dose Escalation: Number of Participants Achieving Blood and Platelet Transfusions
Time frame: Cycle 1, Day 1 through 30 days after the last dose of study drug (up to approximately 46 months)
Population: Efficacy analysis set included all participants who received at least one dose of study drug. Overall number of participants are the number of participants with data available for analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation: Number of Participants Achieving Blood and Platelet Transfusions | (Maintaining/achieving RBC transfusion independence) | 100 percentage of participants |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation: Number of Participants Achieving Blood and Platelet Transfusions | (Maintaining/achieving platelet transfusion independence) | 100 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation: Number of Participants Achieving Blood and Platelet Transfusions | (Maintaining/achieving platelet transfusion independence) | 89 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation: Number of Participants Achieving Blood and Platelet Transfusions | (Maintaining/achieving RBC transfusion independence) | 79 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation: Number of Participants Achieving Blood and Platelet Transfusions | (Maintaining/achieving platelet transfusion independence) | 75 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation: Number of Participants Achieving Blood and Platelet Transfusions | (Maintaining/achieving RBC transfusion independence) | 89 percentage of participants |
Secondary
Dose Escalation Phase: Hematologic Improvement Rate in MDS
Time frame: At end of each Cycle of 28 days (Up to approximately 45 months)
Population: Efficacy analysis set included regimen 1, 2A and 2B participants who received at least one dose of study drug. Overall number of participants analyzed are the number of participants with data available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation Phase: Hematologic Improvement Rate in MDS | 0.0 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation Phase: Hematologic Improvement Rate in MDS | 50.0 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation Phase: Hematologic Improvement Rate in MDS | 25.0 percentage of participants |
Secondary
Dose Escalation Phase: Response Rate in AML Participants
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.
Time frame: At end of each Cycle of 28 days (Up to approximately 23 months)
Population: Efficacy analysis set included regimen 1, 2A and 2B participants who received at least one dose of study drug. Overall number of participants analyzed are the number of participants with AML available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation Phase: Response Rate in AML Participants | 11.4 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation Phase: Response Rate in AML Participants | 7.1 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation Phase: Response Rate in AML Participants | 0.0 percentage of participants |
Secondary
Dose Escalation Phase: Response Rate in MDS Participants
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.
Time frame: At end of each Cycle of 28 days (Up to approximately 23 months)
Population: Efficacy analysis set included regimen 1, 2A and 2B participants who received at least one dose of study drug. Overall number of participants analyzed are the number of participants with MDS available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation Phase: Response Rate in MDS Participants | 22.2 percentage of participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation Phase: Response Rate in MDS Participants | 50.0 percentage of participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Escalation Phase: Response Rate in MDS Participants | 25.0 percentage of participants |
Secondary
Dose Escalation r/r AML, TN AML: Time to Response
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 frame: At end of each Cycle of 28 days (Up to approximately 38 months)
Population: Efficacy analysis set included regimen 1, 2A and 2B, r/r AML and TN AML participants who received at least one dose of study drug. Data is reported for responders in this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Escalation r/r AML, TN AML: Time to Response | 106.0 days |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Escalation r/r AML, TN AML: Time to Response | 55.5 days |
Secondary
Dose Expansion Phase- r/r MDS, TN MDS: Time to Response
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.
Time frame: At end of each Cycle of 28 days (Up to approximately 45 months)
Population: Efficacy analysis set included r/r MDS and TN MDS participants who received at least one dose of study drug. Overall number of participants analysed are the participants with response. Number analyzed is number of participants with response.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Expansion Phase- r/r MDS, TN MDS: Time to Response | CR+PR+mCR | 27.0 days |
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Dose Expansion Phase- r/r MDS, TN MDS: Time to Response | HI | 108.0 days |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Expansion Phase- r/r MDS, TN MDS: Time to Response | HI | 58.0 days |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Dose Expansion Phase- r/r MDS, TN MDS: Time to Response | CR+PR+mCR | 68.0 days |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Expansion Phase- r/r MDS, TN MDS: Time to Response | HI | 64.5 days |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Dose Expansion Phase- r/r MDS, TN MDS: Time to Response | CR+PR+mCR | 196.0 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Expansion Phase- r/r MDS, TN MDS: Time to Response | HI | 49.0 days |
| Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day) | Dose Expansion Phase- r/r MDS, TN MDS: Time to Response | CR+PR+mCR | 133 days |
Secondary
Number of Participants With Dose Limiting Toxicities (DLT) Assessed Per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
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).
Time frame: Cycle 1 (each cycle = 28 days)
Population: Safety analysis set included data from regimen 1, 2A and 2B participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily | Number of Participants With Dose Limiting Toxicities (DLT) Assessed Per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | 2 Participants |
| Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly | Number of Participants With Dose Limiting Toxicities (DLT) Assessed Per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | 0 Participants |
| Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly | Number of Participants With Dose Limiting Toxicities (DLT) Assessed Per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | 0 Participants |