Trial Outcomes & Findings for An Efficacy and Safety Study of Luspatercept (ACE-536) for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS) in Japanese Subjects Who Are Not Requiring Red Blood Cell Transfusion (NCT NCT03900715)

NCT ID: NCT03900715

Last Updated: 2024-10-17

Results Overview

Hematologic improvement is defined as the percent of participants meeting HI-E criteria of \>= 1.5 g/dL increase in hemoglobin (Hgb) sustained over any consecutive 56-day period in the absence of red blood cell (RBC) transfusions from Week 1 Day 1 through Week 24. Participants who discontinued from the Treatment Period without achieving HI-E are counted as non-responders.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 21 participants
• Primary outcome timeframe: Week 1 Day 1 through Week 24
• Results posted on: 2024-10-17

Participant Flow

Participant milestones

Measure	Luspatercept Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Overall Study STARTED	21
Overall Study Efficacy Evaluable Population	19
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	21

Reasons for withdrawal

Measure	Luspatercept Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Overall Study Protocol Deviation	1
Overall Study Lack of Efficacy	1
Overall Study Progressive Disease	6
Overall Study Adverse Event	2
Overall Study Other reasons	11

Baseline Characteristics

An Efficacy and Safety Study of Luspatercept (ACE-536) for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS) in Japanese Subjects Who Are Not Requiring Red Blood Cell Transfusion

Baseline characteristics by cohort

Measure	Luspatercept n=21 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Age, Continuous	74.5 Years STANDARD_DEVIATION 8.47 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants
Race/Ethnicity, Customized Asian (Japanese)	21 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	21 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 1 Day 1 through Week 24

Population: Intent-to-Treat Population: All enrolled participants regardless of whether or not the participant received luspatercept.

Hematologic improvement is defined as the percent of participants meeting HI-E criteria of >= 1.5 g/dL increase in hemoglobin (Hgb) sustained over any consecutive 56-day period in the absence of red blood cell (RBC) transfusions from Week 1 Day 1 through Week 24. Participants who discontinued from the Treatment Period without achieving HI-E are counted as non-responders.

Outcome measures

Measure	Luspatercept n=21 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Percentage of Participants Who Achieved Hematologic Improvement in Erythroid Response (HI-E) Per International Working Group (IWG) Through Week 24	47.6 Percentage of participants Interval 25.7 to 70.2

SECONDARY outcome

Timeframe: Week 1 Day 1 through Week 24 and Week 48

Population: Intent-to-Treat Population: All enrolled participants regardless of whether or not the participant received luspatercept.

Modified hematologic improvement is defined as the percent of participants meeting mHI-E criteria of >= 1.5 g/dL mean increase in hemoglobin (Hgb) compared to baseline sustained over any consecutive 56-day period in the absence of red blood cell (RBC) transfusions from Week 1 Day 1 through Week 24 and Week 48 of the Treatment Period. Participants who discontinued from the Treatment Period without achieving mHI-E are counted as non-responders. Baseline Hgb is defined as the mean of the two central laboratory values (one performed within 1 day prior to W1D1 and the other performed 7 to 35 days prior to W1D1).

Outcome measures

Measure	Luspatercept n=21 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Percentage of Participants Who Achieved Modified Hematologic Improvement in Erythroid Response (mHI-E) Per International Working Group (IWG) Week 1 Day 1 through Week 24	57.1 Percentage of participants Interval 34.0 to 78.2
Percentage of Participants Who Achieved Modified Hematologic Improvement in Erythroid Response (mHI-E) Per International Working Group (IWG) Week 1 Day 1 through Week 48	66.7 Percentage of participants Interval 43.0 to 85.4

SECONDARY outcome

Timeframe: Week 1 Day 1 through Week 48

Population: Intent-to-Treat Population: All enrolled participants regardless of whether or not the participant received luspatercept.

Hematologic improvement is defined as the percent of participants meeting HI-E criteria of >= 1.5 g/dL increase in hemoglobin (Hgb) sustained over any consecutive 56-day period in the absence of red blood cell (RBC) transfusions from Week 1 Day 1 through Week 48 of the Treatment Period. Participants who discontinued from the Treatment Period without achieving HI-E are counted as non-responders.

Outcome measures

Measure	Luspatercept n=21 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Percentage of Participants Who Achieved Hematologic Improvement in Erythroid Response (HI-E) Per International Working Group (IWG) Through Week 48	57.1 Percentage of participants Interval 34.0 to 78.2

SECONDARY outcome

Timeframe: Week 1 Day 1 through Week 24 and Week 48

Population: All treated participants who achieve HI-E until week 24 and 48.

Defined as time from Week 1 Day 1 to first onset of achieving ≥ 1.5 g/dL increase in hemoglobin (Hgb) over any consecutive 56-day period in the absence of red blood cell (RBC) transfusions.

Outcome measures

Measure	Luspatercept n=12 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Time to Hematologic Improvement in Erythroid Response (HI-E) Week 1 Day 1 through Week 48	36.5 Days Interval 14.0 to 275.0
Time to Hematologic Improvement in Erythroid Response (HI-E) Week 1 Day 1 through Week 24	26.5 Days Interval 14.0 to 87.0

SECONDARY outcome

Timeframe: Week 1 Day 1 through Week 24 and Week 48

Population: All treated participants who achieve mHI-E until week 24 and 48.

Defined as the time from Week 1 Day 1 to first onset of achieving ≥ 1.5 g/dL mean increase in hemoglobin (Hgb) compared to baseline over any consecutive 56-day period in the absence of red blood cell (RBC) transfusions. Baseline Hgb is defined as the mean of the two central laboratory values (one performed within 1 day prior to W1D1 and the other performed 7 to 35 days prior to W1D1.

Outcome measures

Measure	Luspatercept n=14 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Time to Modified Hematologic Improvement in Erythroid Response (mHI-E) Week 1 Day 1 through Week 24	0.0 Days Interval 0.0 to 8.0
Time to Modified Hematologic Improvement in Erythroid Response (mHI-E) Week 1 Day 1 through Week 48	0.0 Days Interval 0.0 to 210.0

SECONDARY outcome

Timeframe: Week 1 Day 1 through end of treatment period (up to an average of 74 weeks and maximum of 178 weeks)

Population: All treated participants who achieve HI-E

Defined as the maximum duration of achieving ≥ 1.5 g/dL increase in hemoglobin (Hgb) for participants who achieve Hgb increase ≥ 56 days in the absence of red blood cell (RBC) transfusions. Participants who maintain HI-E through the end of the Treatment Period or time of analysis will be censored at the date of treatment discontinuation/time of analysis or death, whichever occurs first.

Outcome measures

Measure	Luspatercept n=13 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Duration of Hematologic Improvement in Erythroid Response (HI-E)	40.0 Weeks Interval 30.1 to 57.9

SECONDARY outcome

Timeframe: Week 1 Day 1 through end of treatment period (up to an average of 74 weeks and maximum of 178 weeks)

Population: All treated participants who achieve mHI-E

Defined as the maximum duration of achieving ≥ 1.5 g/dL increase in hemoglobin for participants who achieve mean hemoglobin (Hgb) increase compared to baseline ≥ 56 days in the absence of red blood cell (RBC) transfusions. Participants who maintain mHI-E through the end of the Treatment Period or time of analysis will be censored at the date of treatment discontinuation/time of analysis or death, whichever occurs first. Baseline Hgb is defined as the mean of the two central laboratory values (one performed within 1 day prior to W1D1 and the other performed 7 to 35 days prior to W1D1.

Outcome measures

Measure	Luspatercept n=14 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Duration of Modified Hematologic Improvement in Erythroid Response (mHI-E)	92.1 Weeks Interval 46.1 to 157.4

SECONDARY outcome

Timeframe: Week 1 Day 1 through Week 24, Week 48, and Week 72

Population: Intent-to-Treat Population: All enrolled participants regardless of whether or not the participant received luspatercept.

Defined as the percentage of participants not being given any red blood cell (RBC) transfusion during the treatment period.

Outcome measures

Measure	Luspatercept n=21 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Red Blood Cell Transfusion Independence (RBC-TI) Week 1 Day 1 through Week 24	81.0 Percentage of participants Interval 58.1 to 94.6
Red Blood Cell Transfusion Independence (RBC-TI) Week 1 Day 1 through Week 48	81.0 Percentage of participants Interval 58.1 to 94.6
Red Blood Cell Transfusion Independence (RBC-TI) Week 1 Day 1 through Week 72	81.0 Percentage of participants Interval 58.1 to 94.6

SECONDARY outcome

Timeframe: From Week 1 Day 1 up to approximately 44 months

Population: Intent-to-Treat Population: All enrolled participants regardless of whether or not the participant received luspatercept.

Number of participants progressing to acute myeloid leukemia (AML). AML progression is defined per WHO classification of ≥ 20% blasts in peripheral blood or bone marrow. Subjects with diagnosis of AML will be considered to have had an event. Subjects who have not progressed to AML at the time of analysis will be censored at the last assessment date which does not indicate progression to AML.

Outcome measures

Measure	Luspatercept n=21 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Progression to Acute Myeloid Leukemia (AML)	0 Participants

SECONDARY outcome

Timeframe: Week 1 Day 1 to first diagnosis of AML (up to approximately 44 months)

Population: All treated participants with AML progression. (No participants had AML progression)

Defined as the time between W1D1 and first diagnosis of AML as per WHO classification of ≥ 20% blasts in peripheral blood or bone marrow. Participants with diagnosis of AML will be considered to have had an event. Participants who have not progressed to AML at the time of analysis will be censored at the last assessment date which does not indicate progression to AML.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 1 Day 1 to to a participants death date or last known alive date (up to approximately 44 months)

Population: Intent-to-Treat Population: All enrolled participants regardless of whether or not the participant received luspatercept.

Overall Survival is defined as time from Week 1 Day 1 to a participants death date or last known alive date. Participants who die, regardless of the cause of death, will be considered to have had an event. Participants who are alive at the time of analysis will be censored at the last assessment date at which the participant was known to be alive. All participants who were lost to follow-up will also be censored at the time of last contact.

Outcome measures

Measure	Luspatercept n=21 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Overall Survival	NA Months Insufficient number of participants with events

SECONDARY outcome

Timeframe: From first dose to 42 days after last dose (up to approximately 42.5 months)

Population: Safety Population: All participants who were enrolled and received at least one dose of luspatercept.

Treatment-emergent adverse events include adverse events that started on or after the first dose until 42 days after the last dose, as well as those SAEs made known to the investigator at any time thereafter that are suspected of being related to study drug. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study.

Grade 3 = Severe Grade 4 = Life-threatening Grade 5 = Death

Outcome measures

Measure	Luspatercept n=21 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Number of Participants With Adverse Events (AEs) Treatment-Emergent Adverse Events (TEAEs)	20 Participants
Number of Participants With Adverse Events (AEs) Suspected Drug Related TEAE	8 Participants
Number of Participants With Adverse Events (AEs) Serious TEAE	6 Participants
Number of Participants With Adverse Events (AEs) Suspected Drug Related Serious TEAE	1 Participants
Number of Participants With Adverse Events (AEs) Grade 3 or 4 TEAE	8 Participants
Number of Participants With Adverse Events (AEs) Suspected Drug Related Grade 3 or 4 TEAE	4 Participants
Number of Participants With Adverse Events (AEs) Grade 5 TEAE	0 Participants
Number of Participants With Adverse Events (AEs) Suspected Drug Related Grade 5 TEAE	0 Participants
Number of Participants With Adverse Events (AEs) TEAE Leading to Dose Interruption	5 Participants
Number of Participants With Adverse Events (AEs) TEAE Leading to Dose Reduction	2 Participants
Number of Participants With Adverse Events (AEs) TEAE Leading to Dose Withdrawn	6 Participants

SECONDARY outcome

Timeframe: W1D1 (pre-dose), W1D3, W2D1, W2D3, W3D1, W4D1, W10D1, W13D1, W16D1, W17D1, W18D1, W19D1, W22D1, 24-Week MDS Disease Assessment, and every 12 weeks from the 24-Week MDS Disease Assessment Visit for up to 1 year from the first dose.

Population: All participants who received at least 1 dose of luspatercept and had sufficient PK samples collected for non-compartmental analysis.

Outcome measures

Measure	Luspatercept n=9 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Maximum Plasma Concentration (Cmax)	5.713 ug/mL Geometric Coefficient of Variation 29.27

SECONDARY outcome

Timeframe: W1D1 (pre-dose), W1D3, W2D1, W2D3, W3D1, W4D1, W10D1, W13D1, W16D1, W17D1, W18D1, W19D1, W22D1, 24-Week MDS Disease Assessment, and every 12 weeks from the 24-Week MDS Disease Assessment Visit for up to 1 year from the first dose.

Population: All participants who received at least 1 dose of luspatercept and had sufficient PK samples collected for non-compartmental analysis.

Outcome measures

Measure	Luspatercept n=9 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Time to Maximum Plasma Concentration (Tmax)	7.921 Day Interval 2.884 to 13.75

SECONDARY outcome

Timeframe: W1D1 (pre-dose), W1D3, W2D1, W2D3 , W3D1, W4D1 (21 days after dose administration)

Population: All participants who received at least 1 dose of luspatercept and had sufficient PK samples collected for non-compartmental analysis.

Outcome measures

Measure	Luspatercept n=9 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Area Under the Concentration-Time Curve (AUC21d)	94.28 Day*ug/mL Geometric Coefficient of Variation 29.31

SECONDARY outcome

Timeframe: W1D1 (must be collected before the first dose), W4D1, W10D1, W16D1, W22D1, 24-Week MDS Disease Assessment Visit and every 12 weeks (± 14 days) from the 24-Week MDS Disease Assessment Visit for up to 1 year from the first dose..

Population: Safety Population: all participants who were enrolled and received at least one dose of luspatercept.

Number of participants under each ADA positive category. A participant is counted as 'Treatment-Emergent' if there is a positive post-baseline sample while the baseline sample is ADA negative, or there is a positive post-baseline sample with a titer >= 4-fold of the baseline titer while the baseline sample is ADA positive. A participant is counted as 'Preexisting' if the baseline sample is ADA positive and the participant is not qualified for 'Treatment-Emergent'. Positive to preexisting ADA is considered baseline sample is positive and all post-baseline samples are negative, or both baseline and post-baseline samples are positive, but all positive post-baseline sample have a titer < 4-fold of the baseline titer.

Outcome measures

Measure	Luspatercept n=21 Participants Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Number of Participants With a Positive Anti-Drug Antibody (ADA) Test Preexisting	0 Participants
Number of Participants With a Positive Anti-Drug Antibody (ADA) Test Treatment-Emergent	0 Participants

Adverse Events

Luspatercept

Serious events: 6 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Measure	Luspatercept n=21 participants at risk Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Infections and infestations Bronchitis	4.8% 1/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Injury, poisoning and procedural complications Alcohol poisoning	4.8% 1/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Injury, poisoning and procedural complications Lumbar vertebral fracture	4.8% 1/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myelodysplastic syndrome	19.0% 4/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	4.8% 1/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).

Other adverse events

Measure	Luspatercept n=21 participants at risk Participants are administered luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W).
Gastrointestinal disorders Constipation	19.0% 4/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Gastrointestinal disorders Stomatitis	9.5% 2/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Gastrointestinal disorders Vomiting	9.5% 2/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
General disorders Injection site pruritus	9.5% 2/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
General disorders Oedema peripheral	14.3% 3/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
General disorders Pyrexia	9.5% 2/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Infections and infestations Conjunctivitis	9.5% 2/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Injury, poisoning and procedural complications Contusion	19.0% 4/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Injury, poisoning and procedural complications Fall	14.3% 3/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Investigations Blood creatinine increased	9.5% 2/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Musculoskeletal and connective tissue disorders Arthralgia	14.3% 3/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Musculoskeletal and connective tissue disorders Back pain	14.3% 3/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).
Vascular disorders Hypertension	9.5% 2/21 • Participants were assessed for all-cause mortality from their first dose until their study completion (up to approximately 44 months). SAEs and other AEs were assessed from first dose to 42 days after last dose (up to approximately 42.5 months).

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Phone: Please email

Email: Clinical.Trials@bms.com

Results disclosure agreements

• Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
• Publication restrictions are in place

Restriction type: OTHER