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

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ClinicalTrials.gov Identifier: NCT01261312

Recruitment Status : Completed

First Posted : December 16, 2010

Last Update Posted : April 20, 2021

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Astex Pharmaceuticals, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
MDS CMML AML	Drug: SGI-110	Phase 1 Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	401 participants
Allocation:	Randomized
Intervention Model:	Sequential Assignment
Masking:	None (Open Label)
Primary Purpose:	Other
Official Title:	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)
Study Start Date :	December 2010
Actual Primary Completion Date :	July 2016
Actual Study Completion Date :	January 2019

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Familial acute myeloid leukemia with mutated CEBPA Cytogenetically normal acute myeloid leukemia Core binding factor acute myeloid leukemia

MedlinePlus related topics: Acute Myeloid Leukemia Leukemia Myelodysplastic Syndromes

Genetic and Rare Diseases Information Center resources: Myeloid Leukemia Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia Myelodysplastic Syndromes Acute Graft Versus Host Disease

U.S. FDA Resources

Arms and Interventions

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
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 administered weekly on Days 1, 8 and 15 SGI-110 administered weekly on Days 1, 4, 8, 11, 15, and 18

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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, 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
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, 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).
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 patient 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 patient'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 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.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01261312

Locations

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

Sponsors and Collaborators

Astex Pharmaceuticals, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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Responsible Party:	Astex Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT01261312
Other Study ID Numbers:	SGI-110-01
First Posted:	December 16, 2010 Key Record Dates
Last Update Posted:	April 20, 2021
Last Verified:	April 2021

Keywords provided by Astex Pharmaceuticals, Inc.:


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

Additional relevant MeSH terms:

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Preleukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Myelodysplastic Syndromes Leukemia Neoplasms by Histologic Type Neoplasms Bone Marrow Diseases Hematologic Diseases	Precancerous Conditions Guadecitabine Azacitidine Antineoplastic Agents Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Enzyme Inhibitors

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