Brief description of trial (Data source: BASEC)
In dieser Studie soll vornehmlich untersucht werden, ob Patient*innen mit einer durch das MDS verursachten Anämie unter einer Therapie mit Luspatercept einen verminderten Bedarf an regelmässigen Blutransfusionen haben. Dabei soll Luspatercept in einer höheren Dosierung (1.75 mg/kg Körpergewicht) verabreicht werden, als dies bei der in den USA und der EU zugelassenen Anwendung der Fall ist (1.0 mg/kg). Neben einem möglicherweise verbesserten Ansprechen bei erhöhter Dosis, wird auch die Sicherheit von Luspatercept bei zu erwartenden (geringen) Nebenwirkungen weiter untersucht. Ebenso soll untersucht werden, ob die Therapie mit Luspatercept die Lebensqualität und das Wohlbefinden beeinflusst. Die Studie wird sogenannt „einarmig“ geführt, das heisst, dass es in dieser Studie nur eine Behandlungsgruppe gibt. Alle Patient*innen, die einer Teilnahme an der Studie zugestimmt haben und die aufgrund der Eignungskriterien für die Studie infrage kommen, erhalten die gleiche Behandlung. In der Schweiz werden voraussichtlich 12 Patient*innen an der Studie teilnehmen. Die Behandlung erfolgt in Zyklen von 21 Tagen. Das Prüfpräparat wird Ihnen jeweils am 1. Tag jedes Zyklus unter die Haut am Oberarm, Oberschenkel oder Bauch injiziert. Nach einer initialen Behandlung über 9 Zyklen bzw. 27 Wochen, kann die Behandlung je nach Entwicklung Ihrer MDS-Erkrankung ab der Woche 28 für maximal weitere 9 Zyklen bzw. weitere 27 Wochen fortgesetzt werden. Nach der letzten Gabe des Prüfprodukts in Zyklus 18 folgt eine Nachbeobachtungsphase von 16 Wochen. Der genaue Ablauf wird in Kapitel 3 nochmals erklärt. Maximal dauert die Studie für Sie 72 Wochen bzw. etwa 1 Jahr und 5 Monate. Luspatercept ist in der Schweiz nicht zugelassen.
Health conditions investigated(Data source: BASEC)
Myelodysplastisches Syndrom mit sehr niedrigem, niedrigem oder mittlerem Risiko
Health conditions
(Data source: WHO)
Lower-risk myelodysplastic syndrome with ring-sideroblastic phenotype (MDS-RS)
MedDRA version: 21.0Level: LLTClassification code 10028534Term: Myelodysplastic syndrome NOSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: LLTClassification code 10068361Term: MDSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: LLTClassification code 10050910Term: Bone marrow disorder NOSSystem Organ Class: 10005329 - Blood and lymphatic system disorders;Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]
Rare disease
(Data source: BASEC)
No
Intervention investigated (e.g. drug, therapy or campaign)
(Data source: BASEC)
Eine höhere Dosis Luspatercept wird untersucht. Die Dosis beträgt jeweils 1.75 mg/kg Körpergewicht - das ist über der Dosis von 1.0 mg/kg, die standardmässig gemäss der Zulassung in den USA und der EU angewandt wird.
Interventions
(Data source: WHO)
Trade Name: Reblozyl? 25 mg
Product Code: ACE-536
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: LUSPATERCEPT
CAS Number: 1373715-00-4
Current Sponsor code: ACE-536
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Trade Name: Reblozyl? 75 mg
Product Code: ACE-536
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: LUSPATERCEPT
Current Sponsor code: ACE-536
Other descriptive name: 1373715-00-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Criteria for participation in trial
(Data source: BASEC)
1. Der Teilnehmer / die Teilnehmerin ist zum Zeitpunkt der Unterzeichnung der Einwilligungserklärung (ICF) 18 Jahre alt oder älter.
2. Der Teilnehmer / die Teilnehmerin ist in der Lage, das ICF zu verstehen und selbst zu unterschreiben.
3. Der Teilnehmer / die Teilnehmerin hat eine dokumentierte MDS-Diagnose
Exclusion criteria
(Data source: BASEC)
1. Vorherige Therapie mit Ausnahme von Lenalidomid oder hypomethylierenden Wirkstoffen für die MDSErkrankung
2. Vorherige Behandlung mit entweder Luspatercept oder Sotatercept
3. Sekundäres MDS, d. h. MDS-Erkrankung, die sich bekanntermassen als Folge einer chemischen Verletzung entwickelt hat
Inclusion/Exclusion Criteria
(Data source: WHO)
Gender:
Female: yes
Male: yes
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/?L
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-a = 500 ?g 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 ongoin
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 ?g/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/?L (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 with
-
Further information on trial
Date trial registered
Jun 8, 2021
Incorporation of the first participant
Sep 17, 2021
Recruitment status
Authorised-recruitment may be ongoing or finished
Academic title
(Data source: WHO)
A phase IIIb, open-label, single arm study to evaluate the efficacy and safety of luspatercept in patients with lower-risk MDS and ring-sideroblastic phenotype (MDS-RS)
Type of trial
(Data source: WHO)
Interventional clinical trial of medicinal product
Design of the trial
(Data source: WHO)
Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
Phase
(Data source: WHO)
Human pharmacology (Phase I): noTherapeutic exploratory (Phase II): noTherapeutic confirmatory - (Phase III): yesTherapeutic use (Phase IV): no
Primary end point
(Data source: WHO)
Main Objective: 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);Secondary Objective: ? 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;Primary end point(s): RBC-TI rate according to IWG 2018 modified criteria ;Timepoint(s) of evaluation of this end point: from Week 1 through Week 24
Secundary end point
(Data source: WHO)
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).;Timepoint(s) of evaluation of this end point: as mentioned above in 5.2
Contact information
(Data source: WHO)
Celgene International II S?rl.
Trial results
(Data source: WHO)
Results summary
A phase IIIb, open-label, single arm study to evaluate the efficacy and safety of luspatercept in patients with lower-risk MDS and ring-sideroblastic phenotype (MDS-RS)
Link to the results in the primary register
no information available yet
Information on the availability of individual participant data
no information available yet
Trial sites
Trial sites in Switzerland
(Data source: BASEC)
Basel, Bellinzona, Bern
Countries
(Data source: WHO)
Austria, Germany, Spain, Switzerland
Contact for further information on the trial
Details of contact in Switzerland
(Data source: BASEC)
Dr. med. et phil. nat. Nicola Andina
+41 31 66 4 11 60
nicola.andina@insel.ch
Contact for general information
(Data source: WHO)
Martin Puttrich
Freiberger Str. 33
GWT-TUD GmbH
004935125933193
martin.puttrich@g-wt.de
Contact for scientific information
(Data source: WHO)
Martin Puttrich
Freiberger Str. 33
GWT-TUD GmbH
004935125933193
martin.puttrich@g-wt.de
Authorisation by the ethics committee (Data source: BASEC)
Name of the authorising ethics committee (for multicentre studies only the lead committee)
Kantonale
Ethikkommission Bern
Date of authorisation by the ethics committee
16.12.2022
Further trial identification numbers
Trial identification number of the ethics committee (BASEC-ID)
(Data source: BASEC)
2022-00877
Secondary ID (Data source: WHO)
LUSPLUS
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