Clinical trial NCT01261312: SGI-110 in Participants With Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: MDS
CMML
AML
Keywords: SGI-110
DNA Hypomethylating Agent
Intermediate 1, Intermediate 2, CMML or High Risk MDS
AML
Lead sponsor: Astex Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2010-12-16
Enrollment: 414
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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.

Eligibility criteria: 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, 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
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, 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).
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 participant 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 participant'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 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.

Primary outcomes:
measure: Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation
timeFrame: Cycle 1 Day 8
measure: Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation
timeFrame: Cycle 1 Day 15
measure: Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation
timeFrame: Cycle 1 Day 22
measure: Dose Escalation Phase- Biological Effective Dose (BED): Percent Change From Baseline in DNA Long Interspersed Nucleotide Element-1 (LINE-1) Demethylation
timeFrame: Cycle 2 Day 1
measure: Dose Escalation Phase-Maximum Tolerated Dose (MTD): Number of Participants With Dose Limiting Toxicity (DLT)
timeFrame: From the start of study treatment up to 30 days post treatment (Up to approximately 46 months)
measure: Dose Expansion (DE) Phase- r/r AML, TN AML: Composite Complete Response (CRc) Rate
timeFrame: At end of each Cycle of 28 days (Up to approximately 38 months)
measure: Dose Expansion (DE) Phase- r/r MDS, TN MDS: Overall Response Rate (ORR)
timeFrame: At end of each Cycle of 28 days (Up to approximately 45 months)
Secondary outcomes:
measure: Dose Escalation Phase: Response Rate in AML Participants
timeFrame: At end of each Cycle of 28 days (Up to approximately 23 months)
measure: Dose Escalation Phase: Response Rate in MDS Participants
timeFrame: At end of each Cycle of 28 days (Up to approximately 23 months)
measure: Dose Escalation and Dose Expansion Phase- r/r AML, TN AML: Duration of Response
timeFrame: At end of each Cycle of 28 days (Up to approximately 38 months)
measure: Dose Escalation Phase: Hematologic Improvement Rate in MDS
timeFrame: At end of each Cycle of 28 days (Up to approximately 45 months)
measure: DE Phase- r/r MDS, TN MDS: Duration of Response
timeFrame: At end of each Cycle of 28 days (Up to approximately 45 months)
measure: Dose Escalation r/r AML, TN AML: Time to Response
timeFrame: At end of each Cycle of 28 days (Up to approximately 38 months)
measure: Dose Expansion Phase- r/r MDS, TN MDS: Time to Response
timeFrame: At end of each Cycle of 28 days (Up to approximately 45 months)
measure: Number of Participants With Dose Limiting Toxicities (DLT) Assessed Per Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
timeFrame: Cycle 1 (each cycle = 28 days)
measure: 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)
timeFrame: From first dose of study drug up 30 days post treatment (up to approximately 46 months)
measure: 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
timeFrame: From first dose of study drug up 30 days post treatment (up to approximately 46 months)
measure: Dose Escalation: Maximum Observed Plasma Concentration (Cmax ) of SGI-110 and Decitabine
timeFrame: Days 1, 5 and 8
measure: Dose Escalation: Minimum Observed Plasma Concentration (Cmin)
timeFrame: Days 5 and 8
measure: Dose Escalation: Area Under the Curve to Infinity (AUC0-inf)
timeFrame: Days 1, 5 and 8
measure: Dose Escalation and DE Phase- r/r MDS, TN MDS: Time to AML or Death
timeFrame: At end of each Cycle of 28 days (Up to approximately 38 months)
measure: Dose Escalation and DE Phases- r/r AML, TN AML, r/r MDS, TN MDS: Overall Survival
timeFrame: At end of each Cycle of 28 days (Up to approximately 45 months)
measure: Dose Escalation: Number of Participants Achieving Blood and Platelet Transfusions
timeFrame: Cycle 1, Day 1 through 30 days after the last dose of study drug (up to approximately 46 months)
measure: DE Phase- r/r AML, TN AML: Percentage of Participants With Cr, CRp and PR
timeFrame: At end of each Cycle of 28 days (Up to approximately 45 months)
measure: DE Phase- r/r MDS, TN MDS: Percentage of Participants With CR, PR, mCR and HI
timeFrame: At end of each Cycle of 28 days (Up to approximately 45 months)
measure: DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Blood Transfusion Independence for 8 or 16-weeks
timeFrame: Weeks 8 and 16
measure: DE Phase- r/r MDS, TN MDS: Number of Participants Achieving Platelet Transfusion Independence for 8 or 16-weeks
timeFrame: Weeks 8 and 16
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - South
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists - North
state: Florida
city: Chicago
country: United States
facility: University of Chicago Cancer Center
state: Illinois
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Cornell University
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.