Acute Myeloid Leukemia
Conditions
Keywords
AML, acute myeloid leukemia, guadecitabine, SGI-110, Phase 3
Brief summary
Multicenter, randomized, open-label, parallel-group study of guadecitabine vs treatment choice (TC). Participants will be randomly assigned in a 1:1 ratio to either guadecitabine or TC. TC options include the 8 high or low intensity, locally available regimens below; or Best supportive Care (BSC) alone: * High intensity (intermediate or high dose cytarabine \[HiDAC\]; mitoxantrone, etoposide, and cytarabine \[MEC\]; or fludarabine, cytarabine, granulocyte colony stimulating factor \[G-CSF\], +/- idarubicin \[FLAG/FLAG-Ida\]). * Low intensity (low dose cytarabine \[LDAC\], decitabine, or azacitidine). * BSC.
Detailed description
This Phase 3, randomized, open-label, parallel-group multicenter study of the efficacy and safety of guadecitabine in adults with previously treated acute myeloid leukemia (AML) will be conducted in approximately 20 countries. There will be a 14-day screening period, a treatment period, a safety follow-up visit, and a long-term follow-up period. The study is expected to last approximately 2 years. Duration of individual participant participation will vary, and participants may continue to receive treatment for as long as they continue to benefit. Approximately 404 participants from approximately 100 study centers will be randomly assigned to either guadecitabine or treatment choice (TC) in a 1:1 ratio (approximately 202 participants per group). TC is as follows: * High intensity: intermediate or high dose cytarabine (HiDAC); mitoxantrone, etoposide, and cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida). * Low intensity: low dose cytarabine (LDAC), decitabine, or azacitidine. * Best Supportive Care (BSC). Guadecitabine will be given subcutaneous (SC) at a dose of 60 microgram per meter square (mg/m\^2) in 28-day cycles. In Cycle 1, guadecitabine will be given for 10 days on Days 1-5 and Days 8-12. Cycle 2 will be either the 5-day regimen (Days 1-5) or 10-day regimen (Days 1-5 and 8-12) based on assessment of disease response and hematologic recovery at the end of Cycle 1. In subsequent cycles, guadecitabine treatment will be for 5 days only (Days 1-5).
Interventions
DRUGguadecitabine
In Cycle 1, guadecitabine will be given for 10 days on Days 1-5 and Days 8-12. In Cycle 2, the guadecitabine dose will be 60 mg/m\^2 for either 10 days (Days 1-5 and 8-12) or 5 days (Days 1-5 only) based on assessment of disease response, and hematological recovery by Day ≥28.
DRUGTreatment Choice (TC)
* High intensity: intermediate or high dose cytarabine (HiDAC); mitoxantrone, etoposide, and cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida). * Low intensity: low dose cytarabine (LDAC), decitabine, or azacitidine. * Best Supportive Care (BSC).
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
1. Adult participants ≥18 years of age who are able to understand study procedures, comply with them, and provide written informed consent before any study-specific procedure. 2. History of cytologically or histologically confirmed diagnosis of AML (except acute promyelocytic leukemia) according to the 2008 World Health Organization (WHO) classification (bone marrow \[BM\] or peripheral blood \[PB\] blast counts ≥20%). 3. Performance status (Eastern Cooperative Oncology Group; ECOG) of 0-2. 4. Participants with AML previously treated with initial induction therapy using a standard intensive chemotherapy regimen, including cytarabine and an anthracycline, and who are refractory to initial induction (primary refractory) or in relapse after such initial induction with or without prior HCT. 5. Participants must have either PB or BM blasts ≥5% at time of randomization. 6. Creatinine clearance or glomerular filtration rate ≥30 mL/min as estimated by the Cockroft-Gault (C-G) or other medically acceptable formulas, such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration). 7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of child-bearing potential and men with female partners of child-bearing potential must agree to practice 2 highly effective contraceptive measures of birth control and must agree not to become pregnant or father a child (a) while receiving treatment of guadecitabine, decitabine, or azacitidine and for at least 3 months after completing treatment and (b) while receiving treatment with high-intensity TC or LDAC and for at least 6 months after completing treatment.
Exclusion criteria
1. Known clinically active central nervous system (CNS) or extramedullary AML, except leukemia cutis. 2. Participants who are in first relapse after initial induction, if they had a response duration of \>12 months from date when first response first documented or if they are good candidates for HCT. 3. BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). 4. Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy. 5. Grade 3 or higher Graft Versus Host Disease (GVHD), or GVHD on either a calcineurin inhibitor or prednisone more than 5 mg/day. 6. Prior treatment with guadecitabine for any indication, or more than 2 cycles of prior decitabine or azacitidine. 7. Hypersensitivity to decitabine, guadecitabine, or any of their excipients. 8. Treated with any investigational therapy within 2 weeks of the first dose of study treatment. 9. Total serum bilirubin \>2.5 × upper limit of normal (ULN; except for participants with Gilbert's Syndrome for whom direct bilirubin is \<2.5 × ULN), or liver cirrhosis, or chronic liver disease Child-Pugh Class B or C. 10. 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. 11. 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 participant to high risk of noncompliance with the protocol. 12. Refractory congestive heart failure unresponsive to medical treatment; active infection resistant to all antibiotics; or non-AML-associated pulmonary disease requiring \>2 liters per minute (LPM) oxygen, or any other condition that puts the participant at an imminent risk of death. 13. Participants with high PB blasts \>50% AND poor ECOG PS of 2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From the date of randomization until the date of death, or approximately 34 months | Overall survival is defined as number of days from day of randomization to date of death, regardless of cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival | From the date of randomization until the date of death, or approximately 38 months | Event-free survival is defined as number of days from randomization to earliest date of treatment discontinuation (for reasons other than initiation of hematopoietic cell transplant \[HCT\]), start of alternative anti-leukemia therapy (except HCT), or death. |
| Long-Term Survival | Up to approximately 38 months | Survival rate at 1 year after randomization; participants were also followed to estimate 2-year survival rate. |
| Number of Days Alive and Out of the Hospital (NDAOH) | 6 months | Number of days participants alive and out of hospital during first 6 months of the study. |
| Transfusion Independence Rate | Baseline up to approximately 38 months | Number of participants without red blood cells (RBC) or platelet transfusion for any 8-week period after treatment divided by total number of participants in efficacy analysis. |
| Complete Response Rate | Baseline to end of treatment, or approximately 38 months | The Complete response (CR) rate based on modified International Working Group (IWG) 2003 AML Response Criteria was calculated as the number of participants with a best response of CR divided by the total number of participants included in the efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is absolute neutrophil count (ANC) ≥1000/μL, platelets ≥100,000/μL, independence from red blood cells (RBC) and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells. |
| Combined Complete Response and Complete Response With Partial Hematologic Recovery Rate | Baseline to end of treatment, or approximately 38 months | The combined CR and CR with partial hematologic recovery rate based on modified International Working Group (IWG) 2003 AML Response Criteria was calculated as number of participants with CR and CR with partial hematologic recovery divided by the total number of participants included in the efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is absolute neutrophil count (ANC) ≥1000/μL, platelets ≥100,000/μL, independence from red blood cells (RBC) and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells. |
| Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Baseline to 6 months | VAS score is obtained using vertical 20-cm visual analogue scale with the top value of 100 labelled as 'the best health you can imagine' and the bottom value of 0 labelled as 'the worst health you can imagine'. |
| Hematopoietic Cell Transplant (HCT) Rate | Baseline to long term follow-up or approximately 38 months | Number of participants who received HCT after randomization divided by total number of participants in efficacy analysis. |
| Duration of Complete Response (CR) + CR With Partial Hematologic Recovery (CRh) | Baseline to end of treatment, or approximately 38 months | The time from first CR or CRh to time of relapse (the date of the earliest of the following 3 events): 1. relapse (defined as the earliest time point whereby BM assessment or PB assessment by the investigator indicate relapse/disease progression due to confirmed reappearance of leukemic blasts in PB or ≥5% leukemic blasts in BM, or clinical progression determined by the investigator), 2. start of alternative therapy (except HCT) or 3. death. |
| Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Baseline to 6 months | Index score is calculated based on 5-level version of the EQ-5D descriptive system using the value set for England. The range of index score is from -0.281 (for the worst health state, score of 5 for all categories) to 1 (for the best health state, score of 1 for all categories). |
| Percentage of Participants With Adverse Events (AEs) | From first dose until 30 days after the last dose of study drug, or approximately 38 months | An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal finding in laboratory tests or other diagnostic procedures), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. |
| All-Cause Mortality | From the first dose until 60 days after the first dose of study drug | All-cause mortality in the first 30 days and first 60 days after the start of treatment divided by the total number of participants receiving at least one dose of study treatment. |
| Composite Complete Response Rate | Baseline to end of treatment, or approximately 38 months | Composite complete response rate based on modified IWG 2003 AML Response Criteria defined as number of participants with best response of CR, CR with incomplete platelet recovery (CRp), or CR with incomplete blood count recovery (CRi) divided by total number of participants in efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is ANC ≥1000/μL, platelets ≥100,000/μL, independence from RBC and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells. CRp is defined as ANC ≥1000/μL, Platelets \<100,000/μL, independence from RBC transfusions over the past week, no leukemic blasts and bone marrow should contain less than 5% blast cells. CRi is defined as ANC \<1000/μL, no leukemic blasts and bone marrow should contain less than 5% blast cells. |
Countries
Belgium, Canada, Denmark, France, Germany, Hungary, Italy, Japan, Poland, South Korea, Spain, Sweden, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 358 participants were assessed for study inclusion. Of these 56 failed screening assessments. A total of 302 participants were randomized (148 guadecitabine, 154 treatment choice \[TC\]). Of the randomized participants, 10 did not receive study drug (3 guadecitabine, 7 TC).
Participants by arm
| Arm | Count |
|---|---|
| Guadecitabine Guadecitabine was administered SC at a dose of 60 mg/m\^2 for 10 days on Days 1-5 and Days 8-12 or on Days 1-10 in the first cycle. Second cycle was 60 mg/m\^2 for either 10 days (Days 1-5 and 8-12 or Days 1-10) or 5 days (Days 1-5 only) based on assessment of disease response, and hematological recovery by end of Cycle 1. For Cycles ≥3, guadecitabine, 60 mg/m\^2 was given for 5 days only (Days 1-5). Each cycle = 28 days. | 148 |
| Treatment Choice (TC) Intermediate or HiDAC, MEC, and FLAG/FLAG-Ida, LDAC, decitabine, azacitidine, or BSC was administered only. High intensity: Intermediate or HiDAC, recommended as 1-1.5 g/m\^2 every 12 hours or up to 6 g/m\^2/day for ≤6 days, maximum 36 g/m\^2 per cycle; MEC: For example: mitoxantrone 6-12 mg/m\^2 IV (recommended 8 mg/m\^2), etoposide 80-200 mg/m\^2 IV (recommended 100 mg/m\^2), and cytarabine 1000 mg/m\^2 IV; each daily for 5 days (Days 1-5); FLAG/FLAG-Ida: For example: fludarabine 25-30 mg/m\^2 IV daily Days 1-5; cytarabine 1-2 g/m\^2 IV daily for up to 5 days (recommended to be given for 4 hours after fludarabine); G-CSF SC daily from Day 6 up to white cell count recovery with or without idarubicin 8 mg/m\^2 IV daily on Days 3 to 5. Low intensity: LDAC 20 mg SC or IV twice daily on Days 1-10; Decitabine 20 mg/m\^2 IV daily on Days 1-5; Azacitidine 75 mg/m\^2 IV or SC daily on Days 1-7. Best supportive care only. | 154 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 117 | 127 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 6 |
Baseline characteristics
| Characteristic | Guadecitabine | Treatment Choice (TC) | Total |
|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 12.2 | 59.8 years STANDARD_DEVIATION 13.1 | 60.8 years STANDARD_DEVIATION 12.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 16 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 113 Participants | 114 Participants | 227 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 17 Participants | 24 Participants | 41 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 30 Participants | 34 Participants | 64 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 6 Participants | 9 Participants |
| Race/Ethnicity, Customized Not Reported | 19 Participants | 24 Participants | 43 Participants |
| Race/Ethnicity, Customized White | 95 Participants | 90 Participants | 185 Participants |
| Sex: Female, Male Female | 62 Participants | 76 Participants | 138 Participants |
| Sex: Female, Male Male | 86 Participants | 78 Participants | 164 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 117 / 148 | 129 / 154 |
| other Total, other adverse events | 138 / 145 | 137 / 147 |
| serious Total, serious adverse events | 113 / 145 | 91 / 147 |
Outcome results
Primary
Overall Survival
Overall survival is defined as number of days from day of randomization to date of death, regardless of cause.
Time frame: From the date of randomization until the date of death, or approximately 34 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Guadecitabine | Overall Survival | 191.0 days |
| Treatment Choice (TC) | Overall Survival | 163.0 days |
p-value: =0.3287Stratified log-rank
Secondary
All-Cause Mortality
All-cause mortality in the first 30 days and first 60 days after the start of treatment divided by the total number of participants receiving at least one dose of study treatment.
Time frame: From the first dose until 60 days after the first dose of study drug
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Guadecitabine | All-Cause Mortality | Within 30 days | 11.7 percentage of participants |
| Guadecitabine | All-Cause Mortality | Within 60 days | 24.8 percentage of participants |
| Treatment Choice (TC) | All-Cause Mortality | Within 30 days | 9.5 percentage of participants |
| Treatment Choice (TC) | All-Cause Mortality | Within 60 days | 20.4 percentage of participants |
Secondary
Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores
Index score is calculated based on 5-level version of the EQ-5D descriptive system using the value set for England. The range of index score is from -0.281 (for the worst health state, score of 5 for all categories) to 1 (for the best health state, score of 1 for all categories).
Time frame: Baseline to 6 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment. Overall number of participants analyzed is the number of participants with data available for analysis in this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Guadecitabine | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 2 Day 1 | -0.027 score on a scale |
| Guadecitabine | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 3 Day 1 | -0.026 score on a scale |
| Guadecitabine | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 4 Day 1 | -0.008 score on a scale |
| Guadecitabine | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 5 Day 1 | -0.022 score on a scale |
| Guadecitabine | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 6 Day 1 | -0.027 score on a scale |
| Guadecitabine | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 7 Day 1 | -0.020 score on a scale |
| Treatment Choice (TC) | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 6 Day 1 | -0.070 score on a scale |
| Treatment Choice (TC) | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 2 Day 1 | -0.034 score on a scale |
| Treatment Choice (TC) | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 5 Day 1 | -0.072 score on a scale |
| Treatment Choice (TC) | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 3 Day 1 | -0.028 score on a scale |
| Treatment Choice (TC) | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 7 Day 1 | -0.022 score on a scale |
| Treatment Choice (TC) | Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores | Cycle 4 Day 1 | -0.061 score on a scale |
Secondary
Change in EQ-5D-5L Visual Analogue Scale (VAS) Score
VAS score is obtained using vertical 20-cm visual analogue scale with the top value of 100 labelled as 'the best health you can imagine' and the bottom value of 0 labelled as 'the worst health you can imagine'.
Time frame: Baseline to 6 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment. Overall number of participants analyzed is the number of participants with data available for analysis in this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Guadecitabine | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 2 Day 1 | -2.80 score on a scale |
| Guadecitabine | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 3 Day 1 | -0.61 score on a scale |
| Guadecitabine | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 4 Day 1 | 1.13 score on a scale |
| Guadecitabine | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 5 Day 1 | 1.28 score on a scale |
| Guadecitabine | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 6 Day 1 | 0.67 score on a scale |
| Guadecitabine | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 7 Day 1 | -0.44 score on a scale |
| Treatment Choice (TC) | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 6 Day 1 | -1.42 score on a scale |
| Treatment Choice (TC) | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 2 Day 1 | -1.86 score on a scale |
| Treatment Choice (TC) | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 5 Day 1 | -2.30 score on a scale |
| Treatment Choice (TC) | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 3 Day 1 | -1.47 score on a scale |
| Treatment Choice (TC) | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 7 Day 1 | -0.77 score on a scale |
| Treatment Choice (TC) | Change in EQ-5D-5L Visual Analogue Scale (VAS) Score | Cycle 4 Day 1 | -2.37 score on a scale |
Secondary
Combined Complete Response and Complete Response With Partial Hematologic Recovery Rate
The combined CR and CR with partial hematologic recovery rate based on modified International Working Group (IWG) 2003 AML Response Criteria was calculated as number of participants with CR and CR with partial hematologic recovery divided by the total number of participants included in the efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is absolute neutrophil count (ANC) ≥1000/μL, platelets ≥100,000/μL, independence from red blood cells (RBC) and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells.
Time frame: Baseline to end of treatment, or approximately 38 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Guadecitabine | Combined Complete Response and Complete Response With Partial Hematologic Recovery Rate | 16.9 percentage of participants |
| Treatment Choice (TC) | Combined Complete Response and Complete Response With Partial Hematologic Recovery Rate | 7.8 percentage of participants |
Secondary
Complete Response Rate
The Complete response (CR) rate based on modified International Working Group (IWG) 2003 AML Response Criteria was calculated as the number of participants with a best response of CR divided by the total number of participants included in the efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is absolute neutrophil count (ANC) ≥1000/μL, platelets ≥100,000/μL, independence from red blood cells (RBC) and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells.
Time frame: Baseline to end of treatment, or approximately 38 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Guadecitabine | Complete Response Rate | 12.8 percentage of participants |
| Treatment Choice (TC) | Complete Response Rate | 7.1 percentage of participants |
Secondary
Composite Complete Response Rate
Composite complete response rate based on modified IWG 2003 AML Response Criteria defined as number of participants with best response of CR, CR with incomplete platelet recovery (CRp), or CR with incomplete blood count recovery (CRi) divided by total number of participants in efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is ANC ≥1000/μL, platelets ≥100,000/μL, independence from RBC and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells. CRp is defined as ANC ≥1000/μL, Platelets \<100,000/μL, independence from RBC transfusions over the past week, no leukemic blasts and bone marrow should contain less than 5% blast cells. CRi is defined as ANC \<1000/μL, no leukemic blasts and bone marrow should contain less than 5% blast cells.
Time frame: Baseline to end of treatment, or approximately 38 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Guadecitabine | Composite Complete Response Rate | 27.0 percentage of participants |
| Treatment Choice (TC) | Composite Complete Response Rate | 14.3 percentage of participants |
Secondary
Duration of Complete Response (CR) + CR With Partial Hematologic Recovery (CRh)
The time from first CR or CRh to time of relapse (the date of the earliest of the following 3 events): 1. relapse (defined as the earliest time point whereby BM assessment or PB assessment by the investigator indicate relapse/disease progression due to confirmed reappearance of leukemic blasts in PB or ≥5% leukemic blasts in BM, or clinical progression determined by the investigator), 2. start of alternative therapy (except HCT) or 3. death.
Time frame: Baseline to end of treatment, or approximately 38 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Guadecitabine | Duration of Complete Response (CR) + CR With Partial Hematologic Recovery (CRh) | 124 days |
| Treatment Choice (TC) | Duration of Complete Response (CR) + CR With Partial Hematologic Recovery (CRh) | 63 days |
Secondary
Event-Free Survival
Event-free survival is defined as number of days from randomization to earliest date of treatment discontinuation (for reasons other than initiation of hematopoietic cell transplant \[HCT\]), start of alternative anti-leukemia therapy (except HCT), or death.
Time frame: From the date of randomization until the date of death, or approximately 38 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Guadecitabine | Event-Free Survival | 90.0 days |
| Treatment Choice (TC) | Event-Free Survival | 71.5 days |
Secondary
Hematopoietic Cell Transplant (HCT) Rate
Number of participants who received HCT after randomization divided by total number of participants in efficacy analysis.
Time frame: Baseline to long term follow-up or approximately 38 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Guadecitabine | Hematopoietic Cell Transplant (HCT) Rate | 17.6 percentage of participants |
| Treatment Choice (TC) | Hematopoietic Cell Transplant (HCT) Rate | 16.2 percentage of participants |
Secondary
Long-Term Survival
Survival rate at 1 year after randomization; participants were also followed to estimate 2-year survival rate.
Time frame: Up to approximately 38 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Guadecitabine | Long-Term Survival | 12-month survival rate | 0.32 proportion |
| Guadecitabine | Long-Term Survival | 24-month survival rate | 0.19 proportion |
| Treatment Choice (TC) | Long-Term Survival | 12-month survival rate | 0.26 proportion |
| Treatment Choice (TC) | Long-Term Survival | 24-month survival rate | 0.10 proportion |
Secondary
Number of Days Alive and Out of the Hospital (NDAOH)
Number of days participants alive and out of hospital during first 6 months of the study.
Time frame: 6 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Guadecitabine | Number of Days Alive and Out of the Hospital (NDAOH) | 73.2 days |
| Treatment Choice (TC) | Number of Days Alive and Out of the Hospital (NDAOH) | 73.9 days |
Secondary
Percentage of Participants With Adverse Events (AEs)
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal finding in laboratory tests or other diagnostic procedures), symptom, or disease temporally associated with the use of a drug, without any judgment about causality.
Time frame: From first dose until 30 days after the last dose of study drug, or approximately 38 months
Population: The safety analysis set included data from all participants randomly assigned to study treatment who received any amount of study treatment or any component of a multi-dose study treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Guadecitabine | Percentage of Participants With Adverse Events (AEs) | 96.6 percentage of participants |
| Treatment Choice (TC) | Percentage of Participants With Adverse Events (AEs) | 97.3 percentage of participants |
Secondary
Transfusion Independence Rate
Number of participants without red blood cells (RBC) or platelet transfusion for any 8-week period after treatment divided by total number of participants in efficacy analysis.
Time frame: Baseline up to approximately 38 months
Population: The efficacy analysis set included data from all participants randomly assigned to study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Guadecitabine | Transfusion Independence Rate | Overall transfusion independence | 20.3 percentage of participants |
| Guadecitabine | Transfusion Independence Rate | Platelet transfusion independence | 23.6 percentage of participants |
| Guadecitabine | Transfusion Independence Rate | RBC transfusion independence | 21.6 percentage of participants |
| Treatment Choice (TC) | Transfusion Independence Rate | Overall transfusion independence | 13.0 percentage of participants |
| Treatment Choice (TC) | Transfusion Independence Rate | Platelet transfusion independence | 21.4 percentage of participants |
| Treatment Choice (TC) | Transfusion Independence Rate | RBC transfusion independence | 14.3 percentage of participants |