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

NCT01261312 | Completed Phase 1 Results FDA Drug

• 1 other identifier: SGI-110-01
• Study Type: interventional
• Target: 414
• Locations: 2 countries
• Sites: 16

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.

Conditions

MDS; CMML; AML

Keywords

SGI-110; DNA Hypomethylating Agent; Intermediate 1, Intermediate 2, CMML or High Risk MDS; AML

Outcome Measures

Primary Outcomes (7)

• 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.

  Cycle 1 Day 8

• 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.

  Cycle 1 Day 15

• 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.

  Cycle 1 Day 22

• 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.

  Cycle 2 Day 1

• 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).

  From the start of study treatment up to 30 days post treatment (Up to approximately 46 months)

• 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.

  At end of each Cycle of 28 days (Up to approximately 38 months)

• 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.

  At end of each Cycle of 28 days (Up to approximately 45 months)

Secondary Outcomes (20)

• 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)

Study Arms (13)

Dose Escalation: Regimen 1 - Guadecitabine 3 mg/m^2 Daily

EXPERIMENTAL

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.

Drug: Guadecitabine

Dose Escalation: Regimen 2A - Guadecitabine 6 mg/m^2 Once Weekly

EXPERIMENTAL

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.

Drug: Guadecitabine

Dose Escalation: Regimen 2B - Guadecitabine 60 mg/m^2 Twice Weekly

EXPERIMENTAL

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.

Drug: Guadecitabine

Dose Expansion: r/r AML Guadecitabine 60 mg/m^2 (5-Day)

EXPERIMENTAL

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.

Drug: Guadecitabine

Dose Expansion: r/r AML Guadecitabine 90 mg/m^2 (5-Day)

EXPERIMENTAL

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.

Drug: Guadecitabine

Dose Expansion: r/r AML Guadecitabine 60 mg/m^2 (10-Day)

EXPERIMENTAL

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.

Drug: Guadecitabine

Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day)

EXPERIMENTAL

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.

Drug: Guadecitabine

Dose Expansion: TN AML Guadecitabine 90 mg/m^2 (5-Day)

EXPERIMENTAL

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.

Drug: Guadecitabine

Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (10-Day)

EXPERIMENTAL

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.

Drug: Guadecitabine

Dose Expansion: r/r MDS Guadecitabine 60 mg/m^2 (5-Day)

EXPERIMENTAL

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).

Drug: Guadecitabine

Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day)

EXPERIMENTAL

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.

Drug: Guadecitabine

Dose Expansion: TN MDS Guadecitabine 60 mg/m^2 (5-Day)

EXPERIMENTAL

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.

Drug: Guadecitabine

Dose Expansion: TN MDS Guadecitabine 90 mg/m^2 (5-Day)

EXPERIMENTAL

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.

Drug: Guadecitabine

Interventions

Guadecitabine DRUG

Subcutaneous injection

Also known as: SGI-110

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: TN AML Guadecitabine 60 mg/m^2 (10-Day); Dose Expansion: TN AML Guadecitabine 60 mg/m^2 (5-Day); Dose Expansion: TN AML 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); Dose Expansion: r/r AML Guadecitabine 60 mg/m^2 (10-Day); 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 MDS Guadecitabine 60 mg/m^2 (5-Day); Dose Expansion: r/r MDS Guadecitabine 90 mg/m^2 (5-Day)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Astex Pharmaceuticals, Inc.: lead

Study Sites (16)

Mayo Clinic

Scottsdale, Arizona, 85259, United States

Location

University of Southern California

Los Angeles, California, 90033, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

Florida Cancer Specialists - South

Fort Myers, Florida, 33916, United States

Location

Florida Cancer Specialists - North

St. Petersburg, Florida, 33705, United States

Location

University of Chicago Cancer Center

Chicago, Illinois, 60637, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Cornell University

New York, New York, 10021, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Duke University

Durham, North Carolina, 27705, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Temple University

Philadelphia, Pennsylvania, 19111, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Tennessee Oncology

Nashville, Tennessee, 37203, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

Related Publications (3)

• Chung W, Kelly AD, Kropf P, Fung H, Jelinek J, Su XY, Roboz GJ, Kantarjian HM, Azab M, Issa JJ. Genomic and epigenomic predictors of response to guadecitabine in relapsed/refractory acute myelogenous leukemia. Clin Epigenetics. 2019 Jul 22;11(1):106. doi: 10.1186/s13148-019-0704-3.

  PMID: 31331399 DERIVED

• Garcia-Manero G, Roboz G, Walsh K, Kantarjian H, Ritchie E, Kropf P, O'Connell C, Tibes R, Lunin S, Rosenblat T, Yee K, Stock W, Griffiths E, Mace J, Podoltsev N, Berdeja J, Jabbour E, Issa JJ, Hao Y, Keer HN, Azab M, Savona MR. Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial. Lancet Haematol. 2019 Jun;6(6):e317-e327. doi: 10.1016/S2352-3026(19)30029-8. Epub 2019 May 3.

  PMID: 31060979 DERIVED

• Issa JJ, Roboz G, Rizzieri D, Jabbour E, Stock W, O'Connell C, Yee K, Tibes R, Griffiths EA, Walsh K, Daver N, Chung W, Naim S, Taverna P, Oganesian A, Hao Y, Lowder JN, Azab M, Kantarjian H. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015 Sep;16(9):1099-1110. doi: 10.1016/S1470-2045(15)00038-8. Epub 2015 Aug 19.

  PMID: 26296954 DERIVED

MeSH Terms

Interventions

guadecitabine

Results Point of Contact

• Title: Dr. Harold Keer
• Organization: Astex Pharmaceuticals, Inc.

harold.keer@astx.com

925-560-2913

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 29, 2010
• First Posted: December 16, 2010
• Study Start: January 4, 2011
• Primary Completion: July 22, 2016
• Study Completion: July 22, 2016
• Last Updated: January 23, 2025
• Results First Posted: January 23, 2025

Record last verified: 2024-12

Locations

US (15); CA (1)