| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Lower-risk myelodysplastic syndrome with ring-sideroblastic phenotype (MDS-RS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients whose suffering from low risk blood cancer characterized by decreased red blood cells below normal. |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028534 |
| E.1.2 | Term | Myelodysplastic syndrome NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10050910 |
| E.1.2 | Term | Bone marrow disorder NOS |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 red blood cell transfusion independence (RBC-TI) rate of luspatercept for the treatment of anemia due to International Prognostic Scoring System-Revised (IPSS-R) very low-, low-, or intermediate-risk MDS in subjects with ring sideroblasts (RS) who require RBC transfusions (according to IWG 2018 criteria) |
|
| E.2.2 | Secondary objectives of the trial |
• To determine response rates in MDS-RS failing prior therapy with either lenalidomide (LEN) or hypomethylating agents (HMA) according to IWG 2018 criteria (max. 10 patients)
• To determine RBC-TI and response rates according to IWG 2006 criteria
• To evaluate the effect of luspatercept on: time to RBC-TI, duration of RBC-TI, increase in hemoglobin (Hb), neutrophils and platelets, decrease in serum ferritin and in iron chelation therapy (ICT) use
• To investigate safety and tolerability of the luspatercept dosing regimen applied in this study
• To investigate and compare Quality of Life (QoL) by patient-reported outcome (PRO) and performance outcome (PerfO) measures before and during luspatercept treatment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Principal inclusion criteria
1. Subject is 18 years of age or older at the time of signing the informed consent form (ICF)
2. Subject is able to understand and voluntarily sign the ICF prior to any study-related assessments/procedures being conducted
3. Subject has documented diagnosis of MDS according to WHO classification that meets IPSS-R classification[4] of very low-, low-, or intermediate-risk disease, and the following:
• Ring sideroblasts (RS) ≥ 15% of erythroid precursors in bone marrow or ≥ 5% if SF3B1 mutation is present
• Less than 5% blasts in bone marrow
• Peripheral blood white blood cell (WBC) count < 13,000/μL
4. Subject must be one of the following:
• Refractory to prior ESA treatment: Documentation of non-response or response that was no longer maintained to prior ESA-containing regimen, either as a single agent or in combination (e.g. with
granulocyte colony-stimulating factor [G-CSF]). The ESA regimen must be either:
- Recombinant human erythropoietin ≥ 40,000 IU/week for at least 8 weeks (=doses) or equivalent; or
- Darbepoetin-α ≥ 500 μg q3w for at least 4 doses or equivalent
• Intolerant to prior ESA treatment: Documentation of discontinuation of prior ESA containing regimen, either as a single agent or in combination (e.g. with G-CSF), at any time after introduction due to intolerance or an adverse event (AE)
• ESA ineligible: Low chance of response to ESA based on endogenous serum erythropoietin (EPO) level > 200 U/L for subjects not previously treated with ESAs
• Refractory to- /relapsed after prior HMA treatment1: Treatment failure/relapse after at least six (azacitidine) or four (decitabine) 4-week treatment cycles except for del(5q) MDS
• Refractory to- /relapsed after prior lenalidomide treatment1 except for del(5q) MDS
5. If previously treated with ESAs or G-CSF/granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents must be discontinued ≥ 4 weeks prior to the date of starting treatment with the Investigational medicinal Product (IMP) in this study
6. Required RBC transfusions, as documented by the following criteria:
• Average transfusion requirement of ≥ 2 units/8 weeks of packed RBCs confirmed for a minimum period of 16 weeks immediately preceding start of treatment with IMP
• Hemoglobin (Hb) levels at the time of or within 7 days prior to administration of an RBC transfusion must be ≤ 10.0 g/dL in order for the transfusion to be counted towards meeting eligibility criteria.
RBC transfusions administered when Hb levels are > 10 g/dL and/or RBC transfusions administered for elective surgery do not qualify as a required transfusion for the purpose of meeting eligibility criteria
• No consecutive 56-day period that is RBC transfusion-free during the 16 weeks immediately prior to starting treatment with IMP
7. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2
8. A female of childbearing potential (FCBP) for this study is defined as a sexually mature woman who: (1) has not undergone a hysterectomy or bilateral oophorectomy; or (2) is not naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e. had menses at any time in the preceding 24 consecutive months). An FCBP participating in the study must:
• Have 2 negative pregnancy tests as verified by the investigator prior to starting IMP (unless the screening pregnancy test is done within 72 hours of Cycle 1 Day 1). She must agree to ongoing
pregnancy testing during the course of the study and after end of treatment (EOT).
• If sexually active, agree to use, and be able to comply with, highly effective contraception** without interruption, 5 weeks prior to starting IMP, during treatment with IMP (including dose interruptions), and for 12 weeks after discontinuation of IMP.
** Highly effective contraception is defined in this protocol as the following (information also appears in the ICF): Hormonal contraception (e.g. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation, or a partner with a vasectomy
9. Male subjects must agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g. polyurethane), during sexual contact with a pregnant female or an FCBP while participating in the study, during dose interruptions, and for at least 12 weeks following IMP discontinuation, even if he has undergone a successful vasectomy
10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements |
|
| E.4 | Principal exclusion criteria |
Principal exclusion criteria
1. Prior therapy with disease modifying agents other than HMA or LEN for underlying MDS disease
2. Previously treated with either luspatercept or sotatercept
3. Secondary MDS, i.e. MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases
4. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding
• Iron deficiency to be determined by local laboratory via serum ferritin ≤ 15 μg/L and additional testing if clinically indicated (e.g. calculated transferrin saturation [iron/total iron binding capacity
≤ 20%] or bone marrow aspirate stain for iron)
5. Prior allogeneic or autologous stem cell transplant
6. Known history of diagnosis of acute myeloid leukemia (AML)
7. Use of any of the following within 5 weeks prior to the first dose of the IMP in this study:
• Anticancer cytotoxic chemotherapeutic agent or treatment
• Corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to the first dose of IMP for medical conditions other than MDS
• ICT, except for subjects on a stable or decreasing dose for at least 8 weeks prior to the first dose of IMP
• Other RBC hematopoietic growth factors (e.g. interleukin [IL]-3)
• Investigational drug or device, or approved therapy for investigational use. If the half-life of the previous study drug is known, the use of it within 5 times the half-life prior to the first dose of IMP or within 5 weeks, whichever is longer, is excluded
8. Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment
9. Platelet count < 30,000/μL (30 × 10^9/L)
10. Estimated glomerular filtration rate or creatinine clearance < 40 mL/min
11. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≥ 3.0 × upper limit of normal
(ULN)
12. Total bilirubin ≥ 2.0 × ULN
• Higher levels are acceptable if these can be attributed to active RBC precursor destruction within the bone marrow (i.e. ineffective erythropoiesis) or in the presence of known history of Gilbert
Syndrome
• Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive Coombs test or over 50% indirect bilirubin
13. Prior history of malignancies, other than MDS, unless the subject is free of the disease (including completion of any active or adjuvant treatment for prior malignancy) 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 clinical staging system)
14. Major surgery within 8 weeks prior to the first dose of IMP. Subjects must be completely recovered from any previous surgery prior to the first dose of IMP
15. History of stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months prior to the first dose of IMP
16. Pregnant or breast-feeding females
17. Myocardial infarction, uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator within 6 months prior to the first dose of IMP. Subjects with a known ejection fraction of ˂ 35%, confirmed by a local echocardiography or multigated acquisition scan (MUGA) performed within 6 months prior to the first dose of IMP, are excluded
18. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment), known human immunodeficiency virus (HIV), known evidence of active infectious hepatitis B, and/or known evidence of active hepatitis C
19. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the IMP
20. Subject is in custody by order of an authority or a court of law
21. Participation in another interventional clinical study within the last 3 months prior to signing the ICF or simultaneous participation in other clinical studies
22. Previous assignment to treatment during this study
23. Close affiliation with the investigator (e.g. a close relative) or persons working at the study site
24. Subject is an employee of the sponsor or involved Contract research Organization (CRO)
25. Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the subject’s safety
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| RBC-TI rate according to IWG 2018 modified criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from Week 1 through Week 24 |
|
| E.5.2 | Secondary end point(s) |
• RBC-TI rate according to IWG 2006 criteria from Week 1 through Week 24 and through Week 52
• Median time to RBC-TI (Week 1 through Week 24 and through Week 52)
• Median duration of RBC-TI (Week 1 through Week 24 and through Week 52)
• Change in RBC units transfused over a fixed 16-weeks period (Week 9 through Week 24 and Week 37 through Week 52) compared to the 16-week period prior to screening
• Proportion of subjects achieving mean Hb increase ≥ 1.0 g/dL over ≥ 8 weeks (Week 1 through Week 24 and through Week 52)
• Proportion of subjects achieving modified hematologic improvement - erythroids (mHI-E) per IWG 2006 criteria (Week 1 through Week 24 and through Week 52)
• Proportion of subjects achieving hematologic improvement - neutrophils (HI-N) per IWG 2006 criteria[2] (Week 1 through Week 24 and through Week 52)
• Proportion of subjects achieving hematologic improvement - platelets (HI-P) per IWG 2006 criteria (Week 1 through Week 24 and through Week 52)
• Mean change in serum ferritin from Week 9 through 24 and Week 37 through Week 52 compared to baseline
• Mean change in mean daily dose of ICT from Week 9 through 24 and Week 37 through Week 52 compared to baseline
• Proportion of subjects with progression to AML
• Overall survival (OS)
• Safety measures: type, frequency, severity of adverse events (AEs) and relationship to luspatercept, dose reductions and dose delays
• Mean change in PRO (via EORTC QLQ-C30) and PerfO (via “Timed Up and Go test” [TUG]) from baseline (Week 1) to Week 52 and to End of Treatment (EOT). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| as mentioned above in 5.2 |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| As for this study, the primary outcome will be analyzed after the last patient has completed the study (individual EOS). The end of the study as a whole will be the date when the clean database is available and ready for export for the statistical analyses. However, the primary completion event of the study will be the date of last patient end of study (LPEOS). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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