Leukemia, Myeloid, Acute
Conditions
Keywords
AML, Acute Myeloid Leukemia, SGI-110, DNA Hypomethylating Agen
Brief summary
To compare efficacy and safety between SGI-110 and Treatment Choice in adults with previously untreated AML who are not considered candidates for intensive remission induction chemotherapy.
Interventions
Investigational medicinal product
DRUGTreatment Choice
Choice of one: cytarabine, decitabine, or azacitidine
Sponsors
Astex Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Cytologically or histologically confirmed diagnosis of AML (except M3 acute promyelocytic leukemia) according to World Health Organization (WHO) classification. Performance status (ECOG) of 0-3. Adults with previously untreated AML except for hydroxyurea or corticosteroids. Prior hydroxyurea or lenalidomide treatment for myelodysplastic syndrome (MDS) is allowed. Not considered candidates for intensive remission induction chemotherapy at time of enrollment based on EITHER: 1. ≥75 years of age OR 2. \<75 years of age with at least 1 of the following: i. Poor performance status (ECOG) score of 2-3. ii. Clinically significant heart or lung comorbidities, as reflected by at least 1 of: 1. Left ventricular ejection fraction (LVEF) ≤50%. 2. Lung diffusing capacity for carbon monoxide (DLCO) ≤65% of expected. 3. Forced expiratory volume in 1 second (FEV1) ≤65% of expected. 4. Chronic stable angina or congestive heart failure controlled with medication. iii. Liver transaminases \>3 × upper limit of normal (ULN). iv. Other contraindication(s) to anthracycline therapy (must be documented). v. Other comorbidity the investigator judges incompatible with intensive remission induction chemotherapy, which must be documented and approved by the study medical monitor before randomization. Creatinine clearance as estimated by the Cockcroft-Gault (C-G) or other medically acceptable formulas ≥30 mL/min.
Exclusion criteria
Candidate for intensive remission induction chemotherapy at the time of enrollment. Candidate for best supportive care only, ie, not a candidate for any active therapy with the TC comparators. Known extramedullary central nervous system (CNS) AML. Second malignancy currently requiring active therapy except breast or prostate cancer stable on or responding to endocrine therapy. Prior treatment with decitabine or azacitidine. Hypersensitivity to decitabine, SGI-110, or SGI-110 excipients. Known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals is allowed. Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol. Refractory congestive heart failure unresponsive to medical treatment; active infection resistant to all antibiotics; or advanced pulmonary disease requiring \>2 liters per minute (LPM) oxygen.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Complete Response (CR) | Up to 38 months (median follow-up of 25.5 months) | Number of participants with a best response of CR assessed based on International Working Group 2003 acute myeloid leukemia (AML) response criteria by a blinded independent pathologist. |
| Overall Survival | At 676 death events (up to 38 months) | Survival time was defined as the number of days from the day the participant was randomly assigned to study treatment to the date of death, regardless of cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 38 months (median follow-up of 25.5 months) | Progression-free survival was defined as the number of days from randomization to the earliest date of investigator's assessment of disease progression, participant receiving an alternative anti-leukemia therapy (including hematopoietic cell transplant), or relapse by peripheral blood (PB) assessment or blinded bone marrow (BM) assessment, whichever occurred first, or death, regardless of cause. |
| Number of Red Blood Cell or Platelet Transfusions | Month 6 | The total number of red blood cells (RBCs) transfused or, separately, the total number of platelets transfused up to the 6-month time point for each participant was counted from the date of randomization to Day 180, the date of last contact, or date of death, whichever occurred earlier. One RBC or platelet transfusion was defined as one unit, and a single bag of RBCs or platelets was considered one unit. |
| Number of Participants With Composite CR (CRc) | Up to 38 months (median follow-up of 25.5 months) | CRc is reported as the number of participants with a best response of CR, complete response with incomplete platelet recovery (CRp), or complete response with incomplete blood count recovery (CRi). |
| Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-VAS | Baseline to Month 6 | EuroQol-Visual Analogue Scale (EQ-VAS) descriptive scores were collected for each participant for a minimum of 6 months, unless the participant died or withdrew consent. A vertical 20-cm scale for EQ-VAS was used where the lowest value of 0 was labeled the worst health you can imagine and the top value of 100 was labeled the best health you can imagine. Mean change in scores from baseline are summarized. |
| Duration of CR | Up to 38 months (median follow-up of 25.5 months) | Duration of CR (in number of days) was calculated from the first time a CR was observed to the time of relapse, defined as the earliest time point whereby BM assessment or PB assessment indicated relapse/disease progression due to reappearance of leukemic blasts in PB or ≥ 5% leukemic blasts in BM. |
| Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-5D-5L | Baseline to Month 6 | EuroQol 5-level 5-dimension (EQ-5D-5L) descriptive scores were collected for each participant for a minimum of 6 months, unless the participant died or withdrew consent. Scores within each dimension for EQ-5D (mobility, self-care, usual activity, pain/discomfort, anxiety/depression) were calculated using counts and proportions. Mean change in scores from baseline are summarized in which an index score of 0 represents the worst health state and 1 represents the best health state. |
| Number of Days Alive and Out of the Hospital | Month 6 | The date of each hospital admission and discharge was collected for each participant for up to 6 months, unless the participant died or withdrew consent prior to that time. Duration of each hospital stay in days was calculated as date of discharge minus date of admission. The Number of Days Alive and Out of the Hospital (NDAOH) was calculated as: NDAOH=180 - total duration of all hospital stays within 180 days from the first treatment - number of death days before Day 180. For subjects who were lost to follow-up within 6 months, the NDAOH was calculated conservatively assuming that the subject would have died the day after the last contact day. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Czechia, Denmark, Finland, France, Germany, Hungary, Italy, Japan, Netherlands, Poland, Romania, Russia, Serbia, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
A total of 949 participants were assessed for inclusion in the study. Of these, 134 participants failed screening assessments and 815 participants were randomized.
Pre-assignment details
For the efficacy analysis (all randomized participants), the total duration was 38 months, with a median follow-up of 766 days (25.5 months), lower quartile follow-up of 671 days (22.4 months), and upper quartile follow-up of 896 days (29.9 months). For safety analysis (all treated participants), total duration was 51 months. Combining participants into a single group as part of the Treatment Choice arm was pre-specified as part of the study design.
Participants by arm
| Arm | Count |
|---|---|
| SGI-110 (Guadecitabine) Guadecitabine 60 mg/m\^2 was administered subcutaneously (SC) daily for 5 days (Days 1-5) in 28-day cycles. | 408 |
| Treatment Choice One of the following treatment regimens was administered: 20 mg cytarabine subcutaneously (SC) BID on Days 1-10 every 28 days; 20 mg/m\^2 decitabine given as a 1-hour intravenous (IV) infusion daily on Days 1-5 every 28 days; or 75 mg/m\^2 azacitidine given IV or SC daily on Days 1-7 every 28 days. | 407 |
| Total | 815 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 336 | 335 |
| Overall Study | Lost to Follow-up | 3 | 5 |
| Overall Study | Withdrawal by Subject | 14 | 27 |
Baseline characteristics
| Characteristic | Treatment Choice | Total | SGI-110 (Guadecitabine) |
|---|---|---|---|
| Age, Continuous | 75.9 years STANDARD_DEVIATION 5.8 | 75.9 years STANDARD_DEVIATION 6 | 75.9 years STANDARD_DEVIATION 6.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 29 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 345 Participants | 710 Participants | 365 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 48 Participants | 76 Participants | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 74 Participants | 145 Participants | 71 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 14 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 35 Participants | 50 Participants | 15 Participants |
| Race (NIH/OMB) White | 291 Participants | 602 Participants | 311 Participants |
| Sex: Female, Male Female | 165 Participants | 342 Participants | 177 Participants |
| Sex: Female, Male Male | 242 Participants | 473 Participants | 231 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 341 / 408 | 344 / 407 |
| other Total, other adverse events | 379 / 401 | 371 / 392 |
| serious Total, serious adverse events | 327 / 401 | 297 / 392 |
Outcome results
Primary
Number of Participants With a Complete Response (CR)
Number of participants with a best response of CR assessed based on International Working Group 2003 acute myeloid leukemia (AML) response criteria by a blinded independent pathologist.
Time frame: Up to 38 months (median follow-up of 25.5 months)
Population: The efficacy analysis set includes all randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SGI-110 (Guadecitabine) | Number of Participants With a Complete Response (CR) | 79 Participants |
| Treatment Choice | Number of Participants With a Complete Response (CR) | 71 Participants |
Comparison: The complete response rate was compared between the treatment groups using a Cochran Mantel-Haenszel (CMH) test at an alpha level of 0.04 stratified to adjust for stratification factors used at randomization: age (\<75 or \>=75), Eastern Cooperative Oncology Group (ECOG) performance status (0-1, 2-3), study center region (North American, Europe, Rest of World), and secondary AML (secondary to MDS or other antecedent hematologic disorder) or poor-risk cytogenetics (Yes, No/Unknown).p-value: 0.48296% CI: [-3.67, 7.5]Cochran-Mantel-Haenszel
Primary
Overall Survival
Survival time was defined as the number of days from the day the participant was randomly assigned to study treatment to the date of death, regardless of cause.
Time frame: At 676 death events (up to 38 months)
Population: The efficacy analysis set includes all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SGI-110 (Guadecitabine) | Overall Survival | 213 days |
| Treatment Choice | Overall Survival | 254 days |
Comparison: Overall survival curves were estimated using Kaplan-Meier method and compared between the treatment groups using a 2-sided stratification log-rank test, stratified by the same factors used at randomization: age (\<75 or \>=75), Eastern Cooperative Oncology Group (ECOG) performance status (0-1, 2-3), study center region (North American, Europe, Rest of World), and secondary AML (secondary to MDS or other antecedent hematologic disorder) or poor-risk cytogenetics (Yes, No/Unknown).p-value: 0.732895% CI: [0.83, 1.14]Stratified log-rank
Secondary
Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-5D-5L
EuroQol 5-level 5-dimension (EQ-5D-5L) descriptive scores were collected for each participant for a minimum of 6 months, unless the participant died or withdrew consent. Scores within each dimension for EQ-5D (mobility, self-care, usual activity, pain/discomfort, anxiety/depression) were calculated using counts and proportions. Mean change in scores from baseline are summarized in which an index score of 0 represents the worst health state and 1 represents the best health state.
Time frame: Baseline to Month 6
Population: The efficacy analysis set includes all randomized participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SGI-110 (Guadecitabine) | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-5D-5L | Baseline | 0.7767 score on a scale | Standard Deviation 0.216 |
| SGI-110 (Guadecitabine) | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-5D-5L | Month 6 | 0.8252 score on a scale | Standard Deviation 0.1825 |
| SGI-110 (Guadecitabine) | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-5D-5L | Change from Baseline | -0.0023 score on a scale | Standard Deviation 0.183 |
| Treatment Choice | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-5D-5L | Baseline | 0.7663 score on a scale | Standard Deviation 0.2291 |
| Treatment Choice | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-5D-5L | Month 6 | 0.8240 score on a scale | Standard Deviation 0.1948 |
| Treatment Choice | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-5D-5L | Change from Baseline | 0.0112 score on a scale | Standard Deviation 0.2325 |
Secondary
Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-VAS
EuroQol-Visual Analogue Scale (EQ-VAS) descriptive scores were collected for each participant for a minimum of 6 months, unless the participant died or withdrew consent. A vertical 20-cm scale for EQ-VAS was used where the lowest value of 0 was labeled the worst health you can imagine and the top value of 100 was labeled the best health you can imagine. Mean change in scores from baseline are summarized.
Time frame: Baseline to Month 6
Population: The efficacy analysis set includes all randomized participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SGI-110 (Guadecitabine) | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-VAS | Month 6 | 72.76 score on a scale | Standard Deviation 18.61 |
| SGI-110 (Guadecitabine) | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-VAS | Baseline | 64.64 score on a scale | Standard Deviation 21.69 |
| SGI-110 (Guadecitabine) | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-VAS | Change from Baseline | 3.28 score on a scale | Standard Deviation 19.35 |
| Treatment Choice | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-VAS | Baseline | 63.58 score on a scale | Standard Deviation 21.05 |
| Treatment Choice | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-VAS | Month 6 | 71.72 score on a scale | Standard Deviation 18.88 |
| Treatment Choice | Change in Health-related Quality of Life (QOL) Scores From Baseline: EQ-VAS | Change from Baseline | 3.67 score on a scale | Standard Deviation 22.16 |
Secondary
Duration of CR
Duration of CR (in number of days) was calculated from the first time a CR was observed to the time of relapse, defined as the earliest time point whereby BM assessment or PB assessment indicated relapse/disease progression due to reappearance of leukemic blasts in PB or ≥ 5% leukemic blasts in BM.
Time frame: Up to 38 months (median follow-up of 25.5 months)
Population: The efficacy analysis set includes all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SGI-110 (Guadecitabine) | Duration of CR | 217 days |
| Treatment Choice | Duration of CR | 231 days |
Secondary
Number of Days Alive and Out of the Hospital
The date of each hospital admission and discharge was collected for each participant for up to 6 months, unless the participant died or withdrew consent prior to that time. Duration of each hospital stay in days was calculated as date of discharge minus date of admission. The Number of Days Alive and Out of the Hospital (NDAOH) was calculated as: NDAOH=180 - total duration of all hospital stays within 180 days from the first treatment - number of death days before Day 180. For subjects who were lost to follow-up within 6 months, the NDAOH was calculated conservatively assuming that the subject would have died the day after the last contact day.
Time frame: Month 6
Population: The efficacy analysis set includes all randomized participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SGI-110 (Guadecitabine) | Number of Days Alive and Out of the Hospital | 98.1 days | Standard Deviation 63.6 |
| Treatment Choice | Number of Days Alive and Out of the Hospital | 105.7 days | Standard Deviation 63.58 |
Secondary
Number of Participants With Composite CR (CRc)
CRc is reported as the number of participants with a best response of CR, complete response with incomplete platelet recovery (CRp), or complete response with incomplete blood count recovery (CRi).
Time frame: Up to 38 months (median follow-up of 25.5 months)
Population: The efficacy analysis set includes all randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SGI-110 (Guadecitabine) | Number of Participants With Composite CR (CRc) | 93 Participants |
| Treatment Choice | Number of Participants With Composite CR (CRc) | 91 Participants |
Secondary
Number of Red Blood Cell or Platelet Transfusions
The total number of red blood cells (RBCs) transfused or, separately, the total number of platelets transfused up to the 6-month time point for each participant was counted from the date of randomization to Day 180, the date of last contact, or date of death, whichever occurred earlier. One RBC or platelet transfusion was defined as one unit, and a single bag of RBCs or platelets was considered one unit.
Time frame: Month 6
Population: The efficacy analysis set includes all randomized participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SGI-110 (Guadecitabine) | Number of Red Blood Cell or Platelet Transfusions | Red Blood Cell Transfusions | 16.2 transfusion units | Standard Deviation 11.84 |
| SGI-110 (Guadecitabine) | Number of Red Blood Cell or Platelet Transfusions | Platelet Transfusions | 12.5 transfusion units | Standard Deviation 18.78 |
| Treatment Choice | Number of Red Blood Cell or Platelet Transfusions | Red Blood Cell Transfusions | 15.6 transfusion units | Standard Deviation 13.02 |
| Treatment Choice | Number of Red Blood Cell or Platelet Transfusions | Platelet Transfusions | 14.4 transfusion units | Standard Deviation 39.1 |
Secondary
Progression-free Survival (PFS)
Progression-free survival was defined as the number of days from randomization to the earliest date of investigator's assessment of disease progression, participant receiving an alternative anti-leukemia therapy (including hematopoietic cell transplant), or relapse by peripheral blood (PB) assessment or blinded bone marrow (BM) assessment, whichever occurred first, or death, regardless of cause.
Time frame: Up to 38 months (median follow-up of 25.5 months)
Population: The efficacy analysis set includes all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SGI-110 (Guadecitabine) | Progression-free Survival (PFS) | 159 days |
| Treatment Choice | Progression-free Survival (PFS) | 166 days |