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All Drugs and Chemicals

Luspatercept

Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks

Placebo

Rodrigo Ito, MD

The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in participants with anemia due to the Revised International Prognostic Scoring System (IPSS-R) very low, low, or intermediate MDS with ring sideroblasts who require red blood cell (RBC) transfusions.

Anemia is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes, an umbrella term used to describe disorders relating to the ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular red blood cell (RBC) transfusions, which can lead to further complications from iron overload. The goal of this study is to assess the safety and efficacy of luspatercept versus placebo in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), have ring sideroblasts present, and require constant RBC transfusions. The design of the study will allow a period of initial randomization of patients into either the luspatercept or placebo arm, followed by a double-blind treatment period, and then an MDS disease assessment visit. For those patients that are determined to be experiencing clinical benefit as judged from the study Investigator by this disease assessment visit, they will be permitted to enter the double-blind Extension Phase of the study. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.

A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Placebo for the Treatment of Anemia Due to the IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes in Subjects With Ring Sideroblasts Who Require Red Blood Cell Transfusions.

RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during the first 24 weeks of study treatment. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 24 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to or on the cut-off date were counted as non-responders.

RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 24 weeks of treatment.

RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 48 weeks of treatment.

RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during Week 1 through Week 48. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 48 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to Week 48 were counted as non-responders.

Mean change in total number of Red Blood Cells (RBC) units transfused over a fixed 16-week period (Week 9-24 or Week 33-48) from the total number of RBC units transfused in the 16 weeks immediately on or prior to first dose of study treatment.

A modified HI-E response was defined as the percentage of participants meeting the modified HI-E per the International Working Group (IWG) sustained over 56-day consecutive period during the Treatment period. For participants with a baseline RBC transfusion burden of ≥ 4 units/8 weeks, a mHI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks; for participants with baseline RBC transfusion burden of \<4 units/8 weeks, mHI-E, was defined as a mean increase in hemoglobin of ≥ 1.5 g/dL for 8 weeks in the absence of RBC transfusions.

A mean hgb increase of ≥ 1.0 g/dL was analyzed as the percentage of participants with a hgb increase ≥ 1.0 g/dL compared with baseline (after applying the 14/3 day rule) that was sustained over any consecutive 56-day (8-week) period in the absence of RBC transfusions during the treatment period. (Week 1 through Week 24 and Week 1 through Week 48).

Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 24. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.

Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 48. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.

The EORTC questionnaire is a validated health-related quality of life (HRQoL) measure applicable to participants with any cancer diagnosis. Version 3.0 of the questionnaire was used in the study.

It is composed of 30 items that address 15 domains, including one global health status, functional domains, and symptom domains. Domain scores are transformed to a 0 to 100 scale, where higher scores on the global quality of life score indicate better function. As such, a positive change from Baseline score indicates an improvement in quality of life.

Percentage of participants who achieved a hematologic improvement in neutrophil response (HI-N) per IWG criteria sustained over any consecutive 56-day (8-week) period, during the treatment period (Week 1 to Week 24 and Week 1 to Week 48) HI-N was defined as at least a 100% increase and an absolute increase \> 0.5 X 10\^9/L.

Percentage of participants who achieved a hematologic improvement platelet response (HI-P) was defined as the percentage of participants meeting the HI-P criteria per the IWG sustained over any consecutive 56-day (8-week) period (Week 1 to Week 24 and Week 1 to Week 48) during the treatment period. HI - P reponse was defined as:

* Absolute increase of ≥ 30 X 10\^9/L in platelets for participants starting with \> 20 X 10\^9/L platelets
* Increase in platelets from \< 20 X 10\^9/L to \> 20 X 10\^9/L and by at least 100%

Mean change from baseline in mean serum ferritin was calculated as the difference of postbaseline mean serum ferritin (averaged over the specified timepoints) and baseline mean serum ferritin.

Mean change from baseline in mean daily dose of ICT averaged over Week 9 to Week 24 or Week 33 to Week 48. For each participant, the mean change in daily dose of ICT was calculated as the difference of postbaseline mean daily dose and baseline mean daily dose.

Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 24

Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 48

Percentage of participants progressing to AML throughout the course of the study

Time to AML progression was defined as the time between randomization date and the first diagnosis of AML as per World Health Organization (WHO) classification of ≥ 20% blasts in peripheral blood or bone marrow. Participants with a diagnosis of AML were considered to have had an event, participants who did not progress to AML at the time of analysis were censored at the last assessment date which did not indicate progression to AML.

Overall Survival was defined as the time from the date of study drug randomization to death due to any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for those who discontinued from the study or were lost to follow-up.

The outcome measure describes the number of participants who experienced different types of Treatment-emergent adverse events (TEAEs).

TEAEs were defined as Adverse Events (AEs) that started on or after the day of the first dose and on or before 42 days after the last dose of IP.

The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.

Apparent total plasma clearance was calculated as Dose/Area Under the Curve to infinity (ꝏ).

Apparent volume of distribution of luspatercept was calculated according to the equation Vz = (CL)/λ.

Terminal phase half-life was calculated according to the following equation: t1/2 = 0.693/λz.

Tmax was defined as the observed time to maximum plasma concentration of luspatercept.

Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration versus time.

Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration at a steady state.

Area under the curve steady state was defined as the area under the plasma concentration-time curve for a steady state. calculated by the linear trapezoidal rule.

Number of participants with positive ADA prior to taking study drug and/or during study. A participant was counted as "treatment-emergent" if there was a positive post-baseline sample while the baseline sample was ADA negative, or there was a positive post-baseline sample with a titer ≥ 4-fold of the baseline titer while the baseline sample was ADA positive. A participant was counted as "preexisting" if the baseline sample was ADA positive and the participant was not qualified for "treatment-emergent."

Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

Celgene

Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle

Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Bristol-Myers Squibb Study Director

Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24

Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24

Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48

Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48

Weeks 9 to 24

Weeks 33 to 48

All treated participants with available measurements at the indicated timepoints

Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period

Week 1 Through Week 24

Week 1 Through Week 48

Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period

Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over Any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions

All treated participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 24 of study treatment

Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24

All treated participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 48 of study treatment

Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48

Cycle 3 Day 1 (C3 D1)

C5 D1

C7 D1

Week 25

Extension Phase C1 D1

Extension Phase C3 D1

Extension Phase C5 D1

Extension Phase C7 D1

Extension Phase C9 D1

Extension Phase C11 D1

Extension Phase C13 D1

Extension Phase C15 D1

Extension Phase C17 D1

Extension Phase C19 D1

Extension Phase C21 D1

Extension Phase C23 D1

Extension Phase C25 D1

Extension Phase C27 D1

Extension Phase C29 D1

Extension Phase C31 D1

Extension Phase C33 D1

Extension Phase C35 D1

Extension Phase C37 D1

Extension Phase C39 D1

Extension Phase C41 D1

Extension Phase C43 D1

Extension Phase C45 D1

Extension Phase C47 D1

Extension Phase C49 D1

Extension Phase C51 D1

Extension Phase C53 D1

Extension Phase C55 D1

Extension Phase C57 D1

Extension Phase C59 D1

End of Treatment

All treated participants who completed the EORTC QLQ-C30 assessment at baseline and at least one post-baseline assessment visit.

Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score

All treated participants with available measurements

Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period

Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period

Weeks 9-24

Weeks 33-48

Change From Baseline in Mean Serum Ferritin

Change From Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)

All participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 24

Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24

All participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 48

Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48

Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML)

All treated participants who progressed to AML

Time to Acute Myeloid Leukemia (AML) Progression

Overall Survival

≥ 1 TEAE

≥ 1 Suspected Related TEAE

≥ 1 Serious TEAE

≥ 1 Suspected Related Serious TEAE

≥ 1 TEAE CTCAE Toxicity Grade (GR) 5

≥ 1 Suspected Related TEAE With CTCAE GR 5

≥ 1 TEAE with CTCAE GR 3 or 4

≥ 1 Suspected Related TEAE With CTCAE GR 3 or 4

≥ 1 TEAE Leading to Dose Interruption

≥ 1 TEAE Leading to Dose Reduction

≥ 1 TEAE Leading to Study Drug Discontinuation

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Pharmacokinetic (PK) population included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)

Pharmacokinetic population included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)

Pharmacokinetic population Included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)

Pre-Existing ADA

Treatment Emergent ADA

Treatment Emergent Neutralizing ADA

Safety population of participants with ADA samples collected.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes	NCT02631070	Myelodysplastic...	Luspatercept Placebo	18 Years -	Celgene
A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes	NCT02631070	Myelodysplastic...	Luspatercept Placebo	18 Years -	Celgene
A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes	NCT02631070	Myelodysplastic...	Luspatercept Placebo	18 Years -	Celgene

Spots Global Cancer Trial Database for require red blood cell transfusions