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

Astex Pharmaceuticals

Status and phase

Completed

Phase 2

Phase 1

Conditions

CMML

AML

MDS

Treatments

Drug: Guadecitabine

Study type

Interventional

Funder types

Industry

Identifiers

NCT01261312

SGI-110-01

Details and patient eligibility

About

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.

Full 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.

Enrollment

414 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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, 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.

Exclusion criteria

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.

Trial design

Primary purpose

Other

Allocation

Randomized

Interventional model

Sequential Assignment

Masking

None (Open label)

414 participants in 13 patient groups

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

Experimental group

Description:

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.

Treatment:

Drug: Guadecitabine

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

Experimental group

Description:

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.

Treatment:

Drug: Guadecitabine

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

Experimental group

Description:

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.

Treatment:

Drug: Guadecitabine

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

Experimental group

Description:

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.

Treatment:

Drug: Guadecitabine

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

Experimental group

Description:

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.

Treatment:

Drug: Guadecitabine

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

Experimental group

Description:

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.

Treatment:

Drug: Guadecitabine

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

Experimental group

Description:

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.

Treatment:

Drug: Guadecitabine

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

Experimental group

Description:

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.

Treatment:

Drug: Guadecitabine

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

Experimental group

Description:

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.

Treatment:

Drug: Guadecitabine

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

Experimental group

Description:

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).

Treatment:

Drug: Guadecitabine

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

Experimental group

Description:

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.

Treatment:

Drug: Guadecitabine

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

Experimental group

Description:

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.