Trial Outcomes & Findings for Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs (NCT NCT02907359)

Last Updated: 2024-08-27

Results Overview

OS was defined as the number of days from the day the participant was randomized to the date of death due to any cause. Survival time was censored on the last date the participant is known alive with no event of death. OS time will be estimated using the Kaplan-Meier method.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

417 participants

Primary outcome timeframe

From randomization up to death (up to approximately 38.6 months)

Results posted on

2024-08-27

Participant Flow

Participants took part in the study at 101 investigative sites in the United States, Canada, Spain, Italy, France, Germany, Czech Republic, Denmark, Poland, Belgium, Sweden, United Kingdom, Japan, and South Korea from 13 January 2017 to 30 November 2020.

A total of 417 participants were randomized (277 in Guadecitabine arm group and 140 in Treatment Choice arm group) and 392 received treatment. Of 417 participants, 48 completed the study.

Participant milestones

Participant milestones
Measure	Guadecitabine Participants received Guadecitabine 60 milligrams per square meter (mg/m\^2), subcutaneously (SC), on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice Participants received one of the three treatment choice options: 1. Low dose cytarabine (LDAC) 20 mg/m\^2 SC or intravenous (IV) once daily for 14 days of each 28-day cycles for at least 4 cycles in the absence of disease progression or unacceptable toxicity. Participants who were responding or had stable disease were to continue treatment as per standard and institutional practice. 2. Standard Intensive Chemotherapy (IC) of a 7+3 regimen: Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and an anthracycline (daunorubicin (45-60 mg)/idarubicin (9-12 mg)/mitoxantrone (8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. Best Supportive Care (BSC) as needed during the treatment included, but was not limited to, blood transfusions (Red blood cells \[RBCs\] or platelets), growth factors including erythropoiesis stimulating agents, granulocyte stimulating factors, iron chelating therapy, and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Overall Study STARTED	277	140
Overall Study Safety Analysis Set	270	122
Overall Study COMPLETED	36	12
Overall Study NOT COMPLETED	241	128

Reasons for withdrawal

Reasons for withdrawal
Measure	Guadecitabine Participants received Guadecitabine 60 milligrams per square meter (mg/m\^2), subcutaneously (SC), on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice Participants received one of the three treatment choice options: 1. Low dose cytarabine (LDAC) 20 mg/m\^2 SC or intravenous (IV) once daily for 14 days of each 28-day cycles for at least 4 cycles in the absence of disease progression or unacceptable toxicity. Participants who were responding or had stable disease were to continue treatment as per standard and institutional practice. 2. Standard Intensive Chemotherapy (IC) of a 7+3 regimen: Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and an anthracycline (daunorubicin (45-60 mg)/idarubicin (9-12 mg)/mitoxantrone (8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. Best Supportive Care (BSC) as needed during the treatment included, but was not limited to, blood transfusions (Red blood cells \[RBCs\] or platelets), growth factors including erythropoiesis stimulating agents, granulocyte stimulating factors, iron chelating therapy, and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Overall Study Death	234	117
Overall Study Withdrawal by Subject	6	11
Overall Study Lost to Follow-up	1	0

Baseline Characteristics

Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Guadecitabine n=277 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=140 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.	Total n=417 Participants Total of all reporting groups
Age, Continuous	73.5 years STANDARD_DEVIATION 7 • n=5 Participants	73.7 years STANDARD_DEVIATION 6.1 • n=7 Participants	73.6 years STANDARD_DEVIATION 6.7 • n=5 Participants
Sex: Female, Male Female	83 Participants n=5 Participants	44 Participants n=7 Participants	127 Participants n=5 Participants
Sex: Female, Male Male	194 Participants n=5 Participants	96 Participants n=7 Participants	290 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	24 Participants n=5 Participants	7 Participants n=7 Participants	31 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	225 Participants n=5 Participants	117 Participants n=7 Participants	342 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	28 Participants n=5 Participants	16 Participants n=7 Participants	44 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	64 Participants n=5 Participants	33 Participants n=7 Participants	97 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) White	179 Participants n=5 Participants	86 Participants n=7 Participants	265 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	29 Participants n=5 Participants	16 Participants n=7 Participants	45 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization up to death (up to approximately 38.6 months)

Population: The Efficacy Analysis Set included all participants randomly assigned to the study treatment.

Outcome measures

Outcome measures
Measure	Guadecitabine n=277 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=140 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Overall Survival (OS)	277.0 days Interval 243.0 to 313.0	252.0 days Interval 200.0 to 325.0

SECONDARY outcome

Timeframe: Up to approximately 46.6 months

Population: The Efficacy Analysis Set included all participants randomly assigned to the study treatment.

Transfusion independence rate was calculated as the number of participants with neither RBC nor platelet transfusion for any period of 8 weeks after the initiation of treatment (or cycle 1 day 1 { C1D1} visit date for participants randomized to BSC or randomization date for participants not treated) and up to treatment discontinuation (or 180 days for participants discontinuing the treatment within 6 months), while maintaining haemoglobin (Hgb) ≥8 gram per deciliter (g/dL) and platelets ≥20×10\^9/liter (L) divided by the total number of participants included in the efficacy analysis. RBC or Platelet transfusion independence rate was defined similarly as above. Percentage of participants are rounded off to the single decimal point.

Outcome measures

Outcome measures
Measure	Guadecitabine n=277 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=140 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Percentage of Participants With Transfusion Independence for Any 8 Consecutive Weeks Transfusion Independence Rate (8 weeks)	15.9 percentage of participants	15.7 percentage of participants
Percentage of Participants With Transfusion Independence for Any 8 Consecutive Weeks RBC Transfusion Independence Rate	22.4 percentage of participants	22.0 percentage of participants
Percentage of Participants With Transfusion Independence for Any 8 Consecutive Weeks Platelet Transfusion Independence Rate	32.1 percentage of participants	37.9 percentage of participants

SECONDARY outcome

Timeframe: Up to approximately 46.6 months

Population: The Efficacy Analysis Set included all participants randomly assigned to the study treatment.

mCR was defined as per 2006 Myelodysplastic Syndromes International Council for Harmonisation (MDS IWG) criteria as reduction of bone marrow (BM) blasts to ≤5% and decrease by 50% or more with or without normalization of peripheral counts. Transfusion independence rate was calculated as the number of participants with neither RBC nor platelet transfusion for any period of 8 weeks after the initiation of treatment (or C1D1 visit date for participants randomized to BSC or randomization date for participants not treated) and up to treatment discontinuation (or 180 days for participants discontinuing the treatment within 6 months), while maintaining Hgb ≥8 g/dL and platelets ≥20×10\^9/L divided by the total number of participants included in the efficacy analysis. The percentage of participants who achieved mCR and transfusion independence simultaneously in the same period were calculated for each group. Percentage of participants are rounded off to the single decimal point.

Outcome measures

Outcome measures
Measure	Guadecitabine n=277 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=140 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Percentage of Participants With Marrow Complete Response (mCR) Along With Transfusion Independence Rate	5.8 percentage of participants	2.9 percentage of participants

SECONDARY outcome

Timeframe: From randomization up to 12 months

Population: The Efficacy Analysis Set included all participants randomly assigned to the study treatment.

One year survival rate was defined as the percentage of participants that survived at the end of the first year from randomization. Participants who did not have death in record were censored on the last date known to be alive. Percentage of participants are rounded off to the nearest whole number.

Outcome measures

Outcome measures
Measure	Guadecitabine n=277 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=140 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Survival Rate at 1 Year After Randomization	39 percentage of participants Interval 34.0 to 45.0	39 percentage of participants Interval 30.0 to 47.0

SECONDARY outcome

Timeframe: From randomization up to 46.6 months

Population: The Efficacy Analysis Set included all participants randomly assigned to the study treatment.

Leukemia-free survival was defined as the number of days from randomization to the earliest date when participants have bone marrow (BM) or peripheral blood (PB) blasts ≥20%, conversion to acute myeloid leukemia (AML) or death of any cause. Participants with no events in leukemia-free survival were censored on the last date of BM or PB blasts assessment, whichever is later. Survival time will be estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Guadecitabine n=277 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=140 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Leukemia-free Survival	173.0 days Interval 135.0 to 206.0	181.0 days Interval 125.0 to 213.0

SECONDARY outcome

Timeframe: Up to 6 months

Population: The Efficacy Analysis Set included all participants randomly assigned to the study treatment.

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 NDAOH within first 6 month period was calculated as: NDAOH 6M=180 -total duration of all hospital stays within 180 days from the first treatment -number of death days before Day 180. For participants who were lost to follow-up within 6 months, the NDAOH was calculated conservatively assuming that the participant would have died the day after the last contact day.

Outcome measures

Outcome measures
Measure	Guadecitabine n=277 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=140 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Number of Days Alive and Out of the Hospital (NDAOH)	144.0 days Interval 0.0 to 180.0	149.5 days Interval 0.0 to 180.0

SECONDARY outcome

Timeframe: Up to approximately 46.6 months

Population: The Efficacy Analysis Set included all participants randomly assigned to the study treatment. Participants who had multiple responses of HI (HI-E, HI-N and HI-P) were counted only once while calculating the total HI value in both treatment groups. Percentage of participants are rounded off to the nearest single decimal point.

DR: Complete Response(CR), Partial Response(PR),Marrow Complete Response(mCR), and Hematological Improvement(HI) including HI with Erythroid (HI-E), HI with Neutrophil (HI-N), or HI with Platelet (HI-P) based on IWG 2006 criteria. CR: BM:≤5% myeloblasts, Peripheral blood: Hgb≥11g/dL, Platelets(PLTs)≥100x10\^9/L, Neutrophils≥1.0x10\^9/L, Blasts 0%. PR: All CR criteria if abnormal before treatment except BM blasts decreased ≥50% over pretreatment but still\>5%, Cellularity, morphology not relevant. HI responses:1) HI-E: Hgb increase ≥1.5g/dL, Relevant reduction of RBC units transfusions by absolute ≥4 RBC transfusions/8 week(wk) compared with pretreatment transfusion number previous 8wk. Only RBC transfusions given for Hgb≤9.0g/dL. 2) HI-P: Absolute increase≥30x10\^9/L starting\>20x10\^9/L PLTs; Increase from\<20x10\^9/L to\>20x10\^9/L and by≥100%. 3) HI-N: ≥100% increase, absolute increase\>0.5x10\^9/L.

Outcome measures

Outcome measures
Measure	Guadecitabine n=277 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=140 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Disease Response (DR) Rate Marrow Complete Response (mCR)	17.3 percentage of participants Interval 12.9 to 21.8	8.6 percentage of participants Interval 3.9 to 13.2
Disease Response (DR) Rate Hematological Improvement (HI)	3.2 percentage of participants Interval 1.2 to 5.3	5.7 percentage of participants Interval 1.9 to 9.6
Disease Response (DR) Rate HI with Erythroid (HI-E)	1.1 percentage of participants Interval 0.0 to 2.2	2.1 percentage of participants Interval 0.0 to 4.5
Disease Response (DR) Rate HI with Platelet (HI-P)	1.8 percentage of participants Interval 0.2 to 3.3	2.1 percentage of participants Interval 0.0 to 4.5
Disease Response (DR) Rate Complete Response (CR)	1.4 percentage of participants Interval 0.0 to 2.8	0.7 percentage of participants Interval 0.0 to 2.1
Disease Response (DR) Rate Partial Response (PR)	0 percentage of participants Interval 0.0 to 0.0	0 percentage of participants Interval 0.0 to 0.0
Disease Response (DR) Rate HI with Neutrophil (HI-N)	0.7 percentage of participants Interval 0.0 to 1.7	2.1 percentage of participants Interval 0.0 to 4.5

SECONDARY outcome

Timeframe: Up to approximately 46.6 months

Duration of complete response (in number of days) was calculated from the first time a CR was observed to the date of the earliest of the following three events: 1) relapse/disease progression, 2) start of alternative therapy (except Hematopoietic Cell Transplant \[HCT\]) or 3) death. In the absence of any event, the duration of CR was censored at the last available time point (BM assessment, PB assessment, or safety/long-term follow-up visit) at which an event was not observed. Duration of complete response was analysed using a Kaplan-Meier method for participants who achieved a CR during the study. CR: BM: ≤5% myeloblasts (all cell lines normal maturation), Peripheral blood: Hgb ≥11g/dL, PLTs ≥100x10\^9/L, Neutrophils ≥1.0x10\^9/L, Blasts 0%.

Outcome measures

Outcome measures
Measure	Guadecitabine n=4 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=1 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Duration of Complete Response (CR)	198 days Interval 112.0 to 266.0	406 days The upper and lower limit of 95% confidence interval was not estimable for a single participant.

SECONDARY outcome

Timeframe: From study Day 1 to the earliest date that a response was first documented (up to approximately 46.6 months)

Time to first response was the time(days) from randomization to first date when any response was achieved. Time to CR was the time(days) from randomization to first date when CR was achieved. Time to best response was the time(days) from randomization to first date when participant's best response (CR,PR,mCR or HI) was achieved. CR:BM:≤5% myeloblasts, Peripheral blood:Hgb≥11g/dL,PLTs≥100x10\^9/L,Neutrophils≥1.0x10\^9/L,Blasts 0%. PR: All CR criteria except BM blasts decreased≥50% over pretreatment but still \>5%,Cellularity,morphology not relevant. mCR: Reduction of BM blasts to≤5%; decrease ≥50% with/without normalization of peripheral counts. HI responses:1)HI-E:Hgb increase≥1.5 g/dL, Relevant reduction of RBC units transfusions by absolute≥4 RBC transfusions/8wk compared with pretreatment transfusion number previous 8wk. 2)HI-P:Absolute increase≥30x10\^9/L starting\>20x10\^9/L PLTs; Increase from≤20 to\>20x10\^9/L and by≥100% 3)HI-N:≥100% granulocyte increase, absolute increase\>0.5x10\^9/L.

Outcome measures

Outcome measures
Measure	Guadecitabine n=61 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=21 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Time to First Response, Complete Response (CR) and Best Response Time to First Response (CR, PR, mCR, or HI)	63.0 days Interval 28.0 to 323.0	67.0 days Interval 21.0 to 295.0
Time to First Response, Complete Response (CR) and Best Response Time to CR	91.0 days Interval 56.0 to 106.0	266.0 days Interval 266.0 to 266.0
Time to First Response, Complete Response (CR) and Best Response Time to Best Response (CR, PR, mCR, or HI)	64.0 days Interval 28.0 to 469.0	77.0 days Interval 23.0 to 295.0

SECONDARY outcome

Timeframe: Up to 6 months

Population: The Efficacy Analysis Set included all participants randomly assigned to the study treatment.

The total number of 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. The mean total number of RBC or platelet units transfused per participant is presented.

Outcome measures

Outcome measures
Measure	Guadecitabine n=277 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=140 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Number of Red Blood Cell (RBC) and Platelet Transfusions RBC Transfusions	18.9 units of transfused RBC or platelet Standard Deviation 13.94	15.0 units of transfused RBC or platelet Standard Deviation 13.53
Number of Red Blood Cell (RBC) and Platelet Transfusions Platelet Transfusions	16.8 units of transfused RBC or platelet Standard Deviation 18.64	12.1 units of transfused RBC or platelet Standard Deviation 20.15

SECONDARY outcome

Timeframe: Baseline to Month 6

Population: The Efficacy Analysis Set included all participants randomly assigned to the study treatment. Overall number of participants analyzed are the number of participants with data available for analysis. 'Number Analyzed' indicates the number of participants with data available for analysis at the given timepoint. As pre-specified in the statistical analysis plan (SAP), the analysis included only the data collected for each participant during the first 6 months of study participation.

The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L, first component is a descriptive system five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a second component visual analogue scale (VAS) that measures health state. Each dimension comprises 5 levels with corresponding numeric scores, where 1 indicates no problems, and 5 indicates extreme problems. The health status is converted to an index value using the country-specific weighted scoring algorithm for England. The summary index value for the England ranges from a worst score of -0.281 to a best score of 1. An increase in the EQ-5D-5L total score indicates improvement.

Outcome measures

Outcome measures
Measure	Guadecitabine n=266 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=119 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Change From Baseline in Health-related Quality of Life (QOL) By EuroQol 5-level 5-dimension (EQ-5D-5L) Summary Index Baseline	0.8414 score on a scale Standard Deviation 0.1596	0.8404 score on a scale Standard Deviation 0.1587
Change From Baseline in Health-related Quality of Life (QOL) By EuroQol 5-level 5-dimension (EQ-5D-5L) Summary Index Change from Baseline at Month 6	-0.0386 score on a scale Standard Deviation 0.1466	-0.0149 score on a scale Standard Deviation 0.1266

SECONDARY outcome

Timeframe: Baseline to Month 6

The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. The second component, EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine).

Outcome measures

Outcome measures
Measure	Guadecitabine n=266 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=119 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Change From Baseline in Health-related QOL: EuroQOL Visual Analogue Scale (EQ-VAS) Score Baseline	71.24 score on a scale Standard Deviation 18.33	70.70 score on a scale Standard Deviation 18.32
Change From Baseline in Health-related QOL: EuroQOL Visual Analogue Scale (EQ-VAS) Score Change from Baseline at Month 6	-1.52 score on a scale Standard Deviation 16.39	-2.43 score on a scale Standard Deviation 18.04

SECONDARY outcome

Timeframe: From first dose through end of study (up to approximately 46.6 months)

Population: The Safety Analysis Set included all participants randomly assigned to study treatment who received any amount of study treatment or any component of a multi-dose study treatment regimen.

An AE is defined as any untoward medical occurrence in a clinical investigation participants administered a drug; it does not necessarily have to have a causal relationship with this treatment. An SAE is defined any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalization; results in persistent or significant disability; is congenital anomaly; is suspected transmission of any infectious agent via a medicinal product or is medically important. Treatment emergent AEs which are those with onset date on or after the date of the first dose of study drug on C1D1 until 30 days after the last dose of study treatment, or the start of an alternative anticancer treatment, whichever occurs first.

Outcome measures

Outcome measures
Measure	Guadecitabine n=270 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=122 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAE	216 Participants	65 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAE	268 Participants	113 Participants

SECONDARY outcome

Timeframe: From first dose until 60 days after study treatment initiation

Population: The Safety Analysis Set included all participants randomly assigned to study treatment who received any amount of study treatment or any component of a multi-dose study treatment regimen.

Number of deaths, regardless of cause, within 30 or 60 days from the first study dose divided by the total number of participants included in the Safety Analysis Set. Participants who died within 30 days were also included in the 60-day mortality calculations.

Outcome measures

Outcome measures
Measure	Guadecitabine n=270 Participants Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).	Treatment Choice n=122 Participants Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
30-day and 60-day All-cause Mortality Within 30 Days	16 Participants	6 Participants
30-day and 60-day All-cause Mortality Within 60 days	35 Participants	13 Participants

Adverse Events

Guadecitabine

Serious events: 216 serious events

Other events: 266 other events

Deaths: 237 deaths

Treatment Choice

Serious events: 65 serious events

Other events: 107 other events

Deaths: 122 deaths

Serious adverse events

Other adverse events

Additional Information

Taiho Central

Taiho Oncology, Inc.

Phone: 609-250-7336

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER