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

Phase 1

Completed

Conditions: MDS
CMML
AML

Interventions: Drug: Guadecitabine

Registration Number: NCT01261312

Lead Sponsor: Astex Pharmaceuticals, Inc.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 414

Inclusion Criteria

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
Eastern ECOG performance status of 0 to 2.
Adequate organ function.
Prior allogeneic stem cell transplant, no evidence of active graft-versus host disease (GVHD) and must be ≥ 2 weeks off immunosuppressive therapy.
No major surgery within 4 weeks of first dose of SGI-110.
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.
Sign an approved informed consent form for this study.

Exclusion Criteria

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).
Acute promyelocytic leukemia (M3 classification).
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.
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.
Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).
Hypersensitivity to decitabine, SGI-110, or SGI-110 excipients.
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily	Guadecitabine	Participants received starting dose of guadecitabine 3 milligrams per meter square (mg/m\^2), subcutaneously (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.
Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly	Guadecitabine	Participants received starting dose of guadecitabine 6 mg/m\^2, SC, once weekly on Days 1, 8 and 15, of 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.
Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly	Guadecitabine	Participants received starting dose of guadecitabine 60 mg/m\^2, SC, twice weekly on Days 1, 4, 8, 11, 15 and 18, of a 28-day cycle. The dose was subsequently increased to 90 mg/m\^2 for subsequent cycles until development of toxicity or disease progression.
Dose Expansion: r/r AML Guadecitabine 60 mg/m^2 (5-Day)	Guadecitabine	Participants received guadecitabine 60 mg/m\^2, SC, daily, from Days 1-5, of a 28-day cycle in participants with diagnosis relapsed/refractory (r/r) AML.
Dose Expansion: r/r AML Guadecitabine 90 mg/m^2 (5-Day)	Guadecitabine	Participants received guadecitabine 90 mg/m\^2, SC, daily, from Days 1-5, of a 28-day cycle in participants with a diagnosis of r/r AML.
Dose Expansion: r/r AML Guadecitabine 60 mg/m^2 (10-Day)	Guadecitabine	Participants received guadecitabine 60 mg/m\^2, SC, daily from Days 1-5 and 8-12, of a 28-day cycle in participants with a diagnosis of r/r AML.
Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day)	Guadecitabine	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 treatment naïve (TN) AML.
Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day)	Guadecitabine	Participants received guadecitabine 90 mg/m\^2, SC, daily, from Days 1-5, of a 28-day cycle in participants with a diagnosis of TN AML.
Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day)	Guadecitabine	Participants received guadecitabine 60 mg/m\^2, SC, daily from Days 1-5 and 8-12, of a 28-day cycle in participants with a diagnosis of TN AML.
Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day)	Guadecitabine	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 Myelodysplastic Syndromes (MDS).
Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day)	Guadecitabine	Participants received guadecitabine 90 mg/m\^2, SC, daily on Days 1-5, of a 28-day cycle in participants with a diagnosis of r/r MDS.
Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day)	Guadecitabine	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.
Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day)	Guadecitabine	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.

Primary Outcome Measures

Name	Time	Method
Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation	Cycle 2 Day 1	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 Outcome Measures

Name	Time	Method
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 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)
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: Area Under the Curve to Infinity (AUC0-inf)	Days 1, 5 and 8
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.

Trial Locations

Locations (16): Florida Cancer Specialists - South
🇺🇸
Fort Myers, Florida, United States
Princess Margaret Hospital
🇨🇦
Toronto, Ontario, Canada
Florida Cancer Specialists - North
🇺🇸
Saint Petersburg, Florida, United States
University of Chicago Cancer Center
🇺🇸
Chicago, Illinois, United States
Sarah Cannon Research Institute
🇺🇸
Nashville, Tennessee, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Cornell University
🇺🇸
New York, New York, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of Southern California
🇺🇸
Los Angeles, California, United States
Yale University
🇺🇸
New Haven, Connecticut, United States
Temple University
🇺🇸
Philadelphia, Pennsylvania, United States
Duke University
🇺🇸
Durham, North Carolina, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
Ohio State University
🇺🇸
Columbus, Ohio, United States
Tennessee Oncology
🇺🇸
Nashville, Tennessee, United States
Mayo Clinic
🇺🇸
Scottsdale, Arizona, United States