A Phase 1-2, Dose Escalation, Multicenter Study of Two Subcutaneous Regimens of SGI-110, a DNA Hypomethylating Agent, in Subjects With Intermediate or High-Risk Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 414
- 试验地点
- 16
- 主要终点
- Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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-
- •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.
排除标准
- •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.
研究组 & 干预措施
Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily
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.
干预措施: Guadecitabine (Drug)
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 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.
干预措施: Guadecitabine (Drug)
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 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.
干预措施: Guadecitabine (Drug)
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 relapsed/refractory (r/r) AML.
干预措施: Guadecitabine (Drug)
Dose Expansion: r/r AML Guadecitabine 90 mg/m^2 (5-Day)
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.
干预措施: Guadecitabine (Drug)
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 8-12, of a 28-day cycle in participants with a diagnosis of r/r AML.
干预措施: Guadecitabine (Drug)
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 treatment naïve (TN) AML.
干预措施: Guadecitabine (Drug)
Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day)
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.
干预措施: Guadecitabine (Drug)
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 8-12, of a 28-day cycle in participants with a diagnosis of TN AML.
干预措施: Guadecitabine (Drug)
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 Myelodysplastic Syndromes (MDS).
干预措施: Guadecitabine (Drug)
Dose Expansion: r/r 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 r/r MDS.
干预措施: Guadecitabine (Drug)
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.
干预措施: Guadecitabine (Drug)
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.
干预措施: Guadecitabine (Drug)
结局指标
主要结局
Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation
时间窗: 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)
时间窗: 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
时间窗: 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)
时间窗: 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.
次要结局
- Dose Escalation Phase: Response Rate in AML Participants(At end of each Cycle of 28 days (Up to approximately 23 months))
- Dose Escalation Phase: Response Rate in MDS Participants(At end of each Cycle of 28 days (Up to approximately 23 months))
- 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))
- 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))
- Dose Escalation r/r AML, TN AML: Time to Response(At end of each Cycle of 28 days (Up to approximately 38 months))
- Dose Expansion Phase- r/r MDS, TN MDS: Time to Response(At end of each Cycle of 28 days (Up to approximately 45 months))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks(Weeks 8 and 16)
- DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks(Weeks 8 and 16)