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

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)

Phase 1-2 dose escalation randomized study in patients 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 patients 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.

Study Overview

• Status: Completed
• Conditions: AML; MDS; CMML
• Intervention / Treatment: Drug: SGI-110; Drug: SGI-110

Detailed Description

Once the BED and MTD is determined in the Dose Escalation Segment, the Dose Expansion Segment will randomize patients with MDS, treatment naïve elderly AML, and relapsed/refractory AML patients to receive the BED or MTD dose. Relapsed/refractory AML patients 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.

• Study Type: Interventional
• Enrollment (Actual): 401
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Florida
    • Fort Myers, Florida, United States, 33916
      • Florida Cancer Specialists - South
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists - North
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Cancer Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10021
      • Cornell University
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Temple University
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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, patients who are refractory, relapsed, or unresponsive to standard treatment.

   • In the Dose Expansion Segment, hypomethylating agent (HMA) treatment-naïve MDS subjects (including CMML), and intermediate-2 or high-risk MDS subjects (including CMML) relapsed or refractory to prior HMA treatment are allowed, and treatment-naïve AML subjects who are 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, subjects 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 subjects (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 patient 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 patient'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 patients, patients 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Daily Regimen; SGI-110 daily x5 dosing on a 28-day course; SGI-110 daily x10 dosing on a 28-day course	Drug: SGI-110; SGI-110 subcutaneous injection administered on Days 1-5; SGI-110 subcutaneous injection administered on Days 1-5 and 8-12; Drug: SGI-110; SGI-110 administered weekly on Days 1, 8 and 15; SGI-110 administered weekly on Days 1, 4, 8, 11, 15, and 18
Experimental: Weekly Regimen; SGI-110 weekly dosing for three weeks on a 28-day course; SGI-110 twice weekly dosing for three weeks on a 28-day course	Drug: SGI-110; SGI-110 subcutaneous injection administered on Days 1-5; SGI-110 subcutaneous injection administered on Days 1-5 and 8-12; Drug: SGI-110; SGI-110 administered weekly on Days 1, 8 and 15; SGI-110 administered weekly on Days 1, 4, 8, 11, 15, and 18

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Escalation Segment (Safety Lead-in): Determine the optimal BED or MTD and the frequency of drug administration.	Number of patients with adverse events.; Incidence of dose limiting toxicities.; Degree of hypomethylation as measured by LINE-1.	Assessed at the end of Course 1 (4 weeks) for each dose cohort.
Dose Expansion Segment: Assess the activity of SGI-110 as measured by overall remission rate.	Overall survival measured in weeks.	12 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the pharmacokinetic profile of SGI-110 and decitabine.	Cmax, Cmin, AUC and other secondary PK parameters of SGI-110 and decitabine in patients during Course 1.	Assessed at the end of Course 1 (4 weeks) for each cohort.
Remission duration, hematological improvements and transfusion independence rates.	Assess remission duration, hematological improvement and transfusion independence rates as measured by weeks.	12 months
Determine epigenetic modulation in peripheral blood and bone marrow samples.		12 months

Collaborators and Investigators

• Sponsor: Astex Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): January 1, 2019

Study Registration Dates

• First Submitted: November 29, 2010
• First Submitted That Met QC Criteria: December 15, 2010
• First Posted (Estimate): December 16, 2010

Study Record Updates

• Last Update Posted (Actual): April 20, 2021
• Last Update Submitted That Met QC Criteria: April 16, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: AML; DNA Hypomethylating Agent; SGI-110; Intermediate 1, Intermediate 2, CMML or High Risk MDS
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Leukemia; Myelodysplastic Syndromes; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine; Guadecitabine
• Other Study ID Numbers: SGI-110-01