| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Myelodysplastic syndrome (MDS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Umbrella term for disorders of the bone marrow, leading to a reduced number of red blood cells. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068361 |
| E.1.2 | Term | MDS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to evaluate the efficacy of luspatercept compared with epoetin alfa for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in ESA naïve subjects who require RBC transfusions. |
|
| E.2.2 | Secondary objectives of the trial |
• 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 population pharmacokinetics and exposure-response relationships for luspatercept in MDS subjects |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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:
• Average transfusion requirement of 2 - 6 units/8 weeks of pRBCs 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 with symptoms of anemia (or ≤ 7 g/dL 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 (centrally or locally analyzed).
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 not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy 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.
•If sexually active, 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.
|
|
| E.4 | Principal exclusion criteria |
1.Subject with the any of the following prior treatments:
•Erythropoiesis-stimulating agents (ESAs)
•Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), 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.Subject with MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable (MDS-U) according to WHO 2016 classification.
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 with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), MDS/MPN unclassifiable.
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.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.Subject with known history of diagnosis of AML.
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.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.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 (via the 4-variable modification of diet in renal disease [MDRD] formula)
•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.Subject with prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:
•Basal or squamous cell carcinoma of the skin
•Carcinoma in situ of the cervix
•Carcinoma in situ of the breast
•Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
11.Subject with major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization.
12.Subject with history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (DVT; including proximal and distal), pulmonary or arterial embolism, arterial thrombosis or other venous thrombosis within 6 months prior to randomization
Note: prior superficial thrombophlebitis is not an exclusion criterion.
Further exclusion criteria are noted in the Protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects who are RBC transfusion free over the first 24 weeks from randomization |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Randomization through week 24 |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of subjects achieving HI-E over any consecutive 56-day period.
2. Proportion of subjects achieving ≥ 1.5 g/dL mean increase in hemoglobin over the first 24 weeks from randomization compared to baseline in the absence of RBC transfusions.
3. Proportion of subjects achieving HI-E over any consecutive 56-day period.
4. Proportion of subjects achieving ≥ 1.5 g/dL mean increase in hemoglobin over any consecutive 24-week period compared to baseline in the absence of RBC transfusions.
5. Time from first dose to first onset of achieving ≥ 1.5 g/dL increase in hemoglobin over any consecutive 56-day period in the absence of RBC transfusions.
6. Maximum duration of achieving ≥ 1.5 g/dL increase in hemoglobin for subjects who achieve mean hemoglobin increase ≥ 56 days in the absence of RBC transfusions.
7. Maximum duration of RBC transfusion independence for subjects who achieve RBC TI ≥ 24 weeks.
8. Proportion of subjects who are RBC transfusion free over a consecutive 84-day period.
9. Maximum duration of RBC transfusion independence for subjects who achieve RBC TI ≥ 84 days.
10. Time from randomization to first onset of transfusion independence ≥ 84 days.
11. Time from randomization to first transfusion on treatment.
12. Total number of RBC units transfused on treatment.
13. Mean change in total pRBC units transfused over a rolling 8-week period.
14. Proportion of subjects who are RBC transfusion independent during Weeks 4-24.
15. Proportion of subjects who are RBC transfusion free for a consecutive 24-week period in the first 48 weeks from Randomization.
16. Evaluation of EORTC QLQ-C30 score and FACT-An.
17. Type, frequency, severity of AEs and relationship of AEs to luspatercept/epoetin alfa.
18. 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.
19. Frequency of antidrug antibodies and effects on efficacy, or safety, or PK.
20. Number and percentage of subjects progressing to AML; time to AML progression.
21. Time from date of randomization to death due to any cause.
22. Evaluation of biomarkers such as TGF-ß superfamily members (eg, GDF11) and other molecules 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 MDS-associated gene mutations and their impact on drug efficacy, clinical response or relapse, disease progression, drug MOA and prognostication of MDS.
23. Evaluation of healthcare resource use (eg, hospitalization) associated with investigational product (IP) during study.
24. Description of QUALMS-P and Treatment Satisfaction. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2, 5, 8, 10, 12, 13: Randomization through week 24
3, 4, 5, 13, 15: Randomization thought week 48
6, 7, 9, 11: Randomization through End of Treatment
14: week 4 through week 24
17: Screening though 42 days post last dose; randomization thorough week 48
18, 19: Randomization through 1-year post first dose
20, 21: randomization though at least 3 year post last dose
22, 23: Baseline through end of treatment
16, 24: Screening through end of treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 111 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Germany |
| Italy |
| Japan |
| Lithuania |
| Netherlands |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Either the date of the last visit of the last subject to complete the post-treatement follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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