A Phase 3 study to see the benefit and safety of Luspatercept in comparison with Epoetin Alfa to treat anaemia due to very low, low or intermediate risk Myelodysplastic Syndromes (MDS) in people who have not taken erythropoiesis-stimulating agents (ESA's) before and who require red blood cell transfusions.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Celgene Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

18 Dec 2018 → ongoing

Decision date (initial)

2023-08-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Celgene Corporation

External identifiers

EU CT number

2022-501485-22-00

EudraCT number

2017-003190-34

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Pharmacokinetic, Safety, Pharmacodynamic, Others

To evaluate the efficacy of luspatercept on red blood cell transfusion independence (RBC-TI; for 12 weeks [84 days] with an associated concurrent mean hemoglobin increase ≥ 1.5 g/dL) compared with epoetin alfa for the treatment of anemia due to very low, low, or intermediate risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System -Revised IPSS-R) in erythropoiesis stimulating agent (ESA) naïve subjects who require RBC transfusions.

Secondary objectives 1

1. • To assess the safety and efficacy of luspatercept compared to epoetin alfa • To assess health-related quality of life (HRQoL) and anemia outcome measures (ie, the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire [EORTC QLQ-C30] and the Functional Assessment of Cancer Therapy - Anemia (FACT-An) questionnaire for subjects treated with luspatercept compared to epoetin alfa • To evaluate pharmacokinetics for luspatercept in MDS subjects

Conditions and MedDRA coding

Myelodysplastic syndrome (MDS)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. 1. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF). 2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. 3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. 4. Subject has a documented diagnosis of MDS according to WHO 2016 classification that meets IPSS R classification of very low, low, or intermediate risk disease, and < 5% blasts in bone marrow. 5. Subject has an endogenous serum erythropoietin (sEPO) level of < 500 U/L. 6. Subject requires RBC transfusions, as documented by the following criteria: • A transfusion requirement of 2 to 6 pRBCs units/8 weeks confirmed for a minimum of 8 weeks immediately preceding randomization. Hemoglobin levels at the time of or within 7 days prior to administration of a RBC transfusion must have been ≤ 9.0 g/dL (5.6 mmol/L) with symptoms of anemia (or ≤ 7 g/dL [4.3 mmol/L] in the absence of symptoms) in order for the transfusion to be counted towards meeting eligibility criteria. Red blood cell transfusions administered when Hgb levels were > 9.0 g/dL (or > 7 g/dL in the absence of symptoms) and/or RBC transfusions administered for elective surgery, infections or bleeding events will not qualify as a required transfusion for the purpose of meeting eligibility criteria or stratification. The hemoglobin level after the last RBC transfusion prior to randomization must be < 11.0 g/dL (6.8 mmol/L) (centrally or locally analyzed).
2. 7. Subject has Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2. 8. Females of childbearing potential (FCBP), defined as a sexually mature woman who: 1) has achieved menarche at some point, 2) not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy or amenorrhea due to other medical reasons does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months), must: •Have two negative pregnancy tests as verified by the investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of W1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. •Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented), or agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy. 9. Male subjects must: •Practice true abstinence (which must be reviewed prior to each IP administration or on a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex or non-latex, but not made out of natural [animal] membrane) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks following investigational product discontinuation, even if he has undergone a successful vasectomy.

Exclusion criteria 11

1. 1. Subject with the any of the following prior treatments: •Erythropoiesis-stimulating agents (ESAs) Subjects may be randomized at the investigator's discretion contingent on the fact that the subject received no more than 2 doses of epoetin alfa (prior treatment with darbepoetin not acceptable for entry into the study). The last dose of epoetin alfa must be ≥ 8 weeks from the date of randomization. A blood sample to determine the endogenous sEPO level (central laboratory) for stratification must be taken within 5 days of randomization unless a prior screening sample analyzed by the central laboratory demonstrated an endogenous sEPO level ≤ 500 U/L •Granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), within 8 weeks prior to randomization, unless given for treatment of febrile neutropenia •Disease modifying agents (eg, immune-modulatory drug [IMiDs such as lenalidomide] Except if the subject received ≤ 1 week of treatment with a disease modifying agent ≥ 8 weeks from randomization, at the investigator's discretion. •Hypomethylating agents Subjects may be randomized at the investigator's discretion contingent that the subject received no more than 2 doses of HMA. The last dose must be ≥ 8 weeks from the date of randomization. •Luspatercept (ACE-536) or sotatercept (ACE-011) •Immunosuppressive therapy for MDS •Hematopoietic cell transplant
2. 2. Subject with MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable (MDS-U) according to WHO 2016 classification.
3. 3. Subject with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) according to WHO 2016 classification (ie, Chronic myelomonocytic leukemia (CMML), Atypical chronic myeloid leukemia (aCML), BCR-ABL12, Juvenile myelomonocytic leukemia (JMML), MDS/MPN unclassifiable.
4. 4. Subject with secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.
5. 5. Subject with known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any type of known clinically significant bleeding or sequestration. Subject with drug induced anemia (eg, mycophenolate). •Iron deficiency to be determined by serum ferritin < 100 µg/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron).
6. 6. Subject with known history of diagnosis of AML.
7. 7. Subject receiving any of the following treatment within 8 weeks prior to randomization: •Anticancer cytotoxic chemotherapeutic agent or treatment •Systemic corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS •Iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization •Other RBC hematopoietic growth factors (eg, Interleukin-3) •Androgens, unless to treat hypogonadism •Hydroxyurea •Oral retinoids (except for topical retinoids) •Arsenic trioxide •Interferon and interleukins •Investigational drug or device, or approved therapy for investigational use (if 5 times the half-life of the previous investigational drug exceeds 8 weeks, then the time of exclusion should be extended up to 5 times the half-life of the investigational drug)
8. 8. Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment.
9. 9. Subject with any of the following laboratory abnormalities: •Absolute neutrophil count (ANC) < 500/μL (0.5 x 10^9/L) •Platelet count < 50,000/μL (50 x 10^9/L) •Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (Appendix F) •Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) •Total bilirubin ≥ 2.0 x ULN. Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome.
10. 10. Subject with prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 5 years (see details in the Protocol).
11. 11. Subject has history of active SARS-CoV-2 infection within 4 weeks prior to screening, unless the subject has adequately recovered from COVID symptoms and related complications as per investigator's discretion and following a discussion with the Medical Monitor. Use of a live COVID-19 vaccine is prohibited within 4 weeks prior to randomization. Further exclusion criteria are noted in the Protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of subjects who are RBC transfusion-free for any 12-week period associated with a concurrent mean hemoglobin increase ≥ 1.5 g/dL compared to baseline

Secondary endpoints 8

1. 1. Proportion of subjects who are RBC transfusion-free from Week 1 through Week 24 2. Mean hemoglobin change over the 24-week period of Week 1 through Week 24 compared to baseline 3. Proportion of subjects achieving HI-E over any consecutive 56-day Period
2. 4. Time from first dose to first onset of achieving HI-E 5. Proportion of subjects who are RBC transfusion-free over a consecutive 84-day period 6. Maximum duration of RBC transfusion independence for subjects who achieve RBC-TI ≥ 84 days
3. 7. Time from first dose to first onset of transfusion independence ≥ 84 days 8. Time from first dose to first transfusion on treatment 9. Total number of RBC units transfused on treatment
4. 10. Proportion of subjects who are RBC transfusion-free over a consecutive 56-day period 11. Proportion of subjects who are RBC transfusion-free for a consecutive 24-week period in the first 48 weeks from first dose 12. Evaluation of EORTC QLQ-C30 score and FACT-An
5. 13. Type, frequency, severity of AEs and relationship of AEs to luspatercept/epoetin alfa 14. A Population PK model that describes the PK exposure data of luspatercept and associated variability. Exposure-response relationship for selected endpoints of efficacy and Safety
6. 15. Frequency of antidrug antibodies and effects on efficacy, or safety, or PK 16. Number and percentage of subjects progressing to AML; time to AML Progression 17. Time from date of randomization to death due to any cause
7. 18. Evaluation of biomarkers that may potentially impact luspatercept efficacy, predict response or relapse, help to better understand MOA and/or provide further prognostic classification of MDS subtypes. Molecular markers (eg, SF3B1) include evaluation of MDSassociated gene mutations and their impact on drug efficacy, clinical response or relapse, drug MOA and prognostication of MDS
8. 19. Evaluation of healthcare resource use (eg, hospitalization) associated with investigational product (IP) during study 20. Description of QUALMS-P and Treatment Satisfaction

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Celgene Corp.

Sponsor organisation

Celgene Corp.

Address

Route 206 And Province Line Road

City

Princeton

Postcode

08543-4000

Country

United States

Scientific contact point

Organisation

Celgene Corp.

Contact name

GSM-CT

Public contact point

Organisation

Celgene Corp.

Contact name

GSM-CT

Third parties 10

Locations

14 EU/EEA countries · 60 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 286 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications