| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Myelfibrosis (MF)
MF- associated cytopenias |
Myelfibrosis (MF)
MF- associated cytopenias |
|
| E.1.1.1 | Medical condition in easily understood language |
| MF is a chronic myeloproliferative malignancy characterized by clonal proliferation of myeloid cells and megakaryocytic hyperplasia/dysplasia resulting in bone marrow fibrosis and osteosclerosis. |
| MF is a chronic myeloproliferative malignancy characterized by clonal proliferation of myeloid cells and megakaryocytic hyperplasia/dysplasia resulting in bone marrow fibrosis and osteosclerosis. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028537 |
| E.1.2 | Term | Myelofibrosis |
| 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 | 10002272 |
| E.1.2 | Term | Anemia |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 | 10074690 |
| E.1.2 | Term | Post essential thrombocythemia myelofibrosis |
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10074691 |
| E.1.2 | Term | Post polycythaemia vera myelofibrosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Part 1 Dose Escalation:
•To evaluate the safety and tolerability of ascending doses of KER-050 monotherapy in participants with primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (post-ET MF), and post-polycythemia vera myelofibrosis (post-PV MF) who have anemia, and to determine the dose that will be evaluated in Part 2 of the study
•To evaluate the safety and tolerability of ascending doses of KER-050 in combination with ruxolitinib in participants with PMF, post-ET MF, and post-PV MF who have anemia, and to determine the dose that will be evaluated in Part 2 of the study
Part 2 Dose Expansion:
•To evaluate the safety and tolerability of the dose(s) selected in Part 1
|
Parte 1 - Incremento della dose:
• Valutare la sicurezza e la tollerabilità di dosi crescenti di KER-050 in monoterapia in partecipanti con mielofibrosi primaria (MFP), mielofibrosi post-trombocitemia essenziale (MF post-TE) e mielofibrosi post-policitemia vera (MF post-PV) che presentano anemia e determinare la dose che sarà valutata nella Parte 2 dello studio
• Valutare la sicurezza e la tollerabilità di dosi crescenti di KER-050 in combinazione con ruxolitinib in partecipanti con MFP, MF post-TE e MF post-PV che presentano anemia e determinare la dose che sarà valutata nella Parte 2 dello studio.
Parte 2 - Espansione della dose:
• Valutare la sicurezza e la tollerabilità della/e dose/i selezionata/e nella Parte 1 |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the PK of KER-050 administered with or without ruxolitinib in participants with PMF/post-ET MF/post-PV MF
•To evaluate the PD effects related to erythropoiesis of KER-050 administered with or without ruxolitinib in participants with PMF/post-ET MF/post-PV MF
•To evaluate the effect on anemia of KER-050 administered with or without ruxolitinib in participants with PMF/post-ET MF/post-PV MF
•To evaluate the effect on MF disease manifestations and symptoms of KER-050 administered with or without ruxolitinib in participants with PMF/post-ET MF/post-PV MF
•To evaluate the effect of KER-050 administered with or without ruxolitinib on progression to acute myeloid leukemia (AML) or accelerated MF
Additional exploratory objective can be found in the Protocol.
|
• Valutare la farmacocinetica (PK) di KER-050 somministrato con o senza ruxolitinib in partecipanti con MFP/MF post-TE/MF post-PV
• Valutare gli effetti farmacodinamici (PD) relativi all’eritropoiesi di KER-050 somministrato con o senza ruxolitinib in partecipanti con MFP/MF post-TE/MF post-PV
• Valutare l’effetto sull’anemia di KER-050 somministrato con o senza ruxolitinib in partecipanti con MFP/MF post-TE/MF post-PV
• Valutare l’effetto di KER-050 sulle manifestazioni e i sintomi della malattia quando somministrato con o senza ruxolitinib in partecipanti con MFP/MF post-TE/MF post-PV
• Valutare l’effetto di KER-050 somministrato con o senza ruxolitinib sulla progressione in leucemia mieloide acuta (LMA) o mielofibrosi (MF) accelerata
Ulteriori obiettivi esplorativi possono essere trovati nel Protocollo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female >=18 years of age, at the time of signing informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance score <=2.
• Life expectancy >=12 months per Investigator assessment
• Diagnosis of PMF, post-PV MF, or post-ET MF according to the 2017 World
Health Organization criteria.
Arm-specific criteria:
Arm 1A :
• Previously treated with JAK inhibitor(s) and per the Investigator discontinued due to relapse, refractory, intolerance, or no longer met the benefit/risk ratio to continue on JAK inhibitor(s) treatment or ineligibility for JAK inhibitor(s) treatment.
• Anemia, defined as hemoglobin <=10 g/dL during screening, or receiving
RBC transfusions
Arm 2A:
• Previously treated with JAK inhibitor(s)
• Anemia, defined as hemoglobin <=10 g/dL during screening, or receiving
RBC transfusions
Arm-specific criteria for 1B and 2B:
• Has been receiving ruxolitinib for >=8 weeks prior to C1D1 and on a stable
dose for >=4 weeks prior to C1D1.
• Anemia, defined as hemoglobin <=10 g/dL during screening, or receiving
RBC transfusions |
Soggetti ambosesso di età >=18 anni al momento della firma del consenso informato.
• Punteggio dello stato prestazionale secondo l’Eastern Cooperative Oncology Group (ECOG) <=2.
• Aspettativa di vita >=12 mesi secondo la valutazione dello sperimentatore.
• Diagnosi di MFP, MF post-PV o MF post-TE secondo i criteri dell’Organizzazione Mondiale della Sanità 2017.
Criteri specifici per il braccio:
1. Braccio 1A
• Precedente trattamento con uno o più inibitori di JAK che, a giudizio dello sperimentatore, è stato interrotto per ricaduta, refrattarietà, intolleranza, non ha più soddisfatto il rapporto rischio/beneficio per continuare ad assumere l’inibitori JAK o per inammissibilità al trattamento con inibitori JAK.
• Anemia, definita come livelli di emoglobina <=10 g/dl durante lo screening o ricezione di trasfusioni di RBC
2. Braccio 2A
• Previo trattamento con uno o più inibitori di JAK
• Anemia, definita come livelli di emoglobina <=10 g/dl durante lo screening, o ricezione di trasfusioni di RBC
3. Braccio 1B e 2B
• Trattamento con ruxolitinib =8 settimane prima del C1G1 e assunzione di una dose stabile da >=4 settimane prima del C1G1.
• Anemia, definita come livelli di emoglobina <=10 g/dl durante lo screening, o ricezione di trasfusioni di RBC |
|
| E.4 | Principal exclusion criteria |
• Presence of the following cardiac conditions:
a. New York Heart Association Class 3 or 4 heart failure
b. QTcF >500 msec on the screening or C1D1 electrocardiogram (ECG)
c. Uncontrolled clinically significant arrhythmia (participants with rate controlled atrial fibrillation are not excluded)
d. Acute myocardial infarction or unstable angina pectoris <=6 months prior to C1D1
• History of stroke, deep venous thrombosis, or arterial embolism within 6 months prior to C1D1.
• Any malignancy other than PMF, post-ET MF, or post-PV MF that has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy, or surgery, within 1 year prior to C1D1. In-situ cancers, squamous cell, and basal cell carcinomas which have been fully excised, and monoclonal gammopathy of unclear significance are allowed at the discretion of the Investigator.
• History of solid organ or hematological transplantation.
• Presence of uncontrolled hypertension, defined as systolic blood pressure
>=150 mm Hg or diastolic blood pressure >=100 mm Hg despite adequate treatment.
• Diagnosis of hemolytic anemia, active bleeding, hemoglobinopathies, or congenital disorders as a cause of the participant’s anemia.
• CTCAE Grade >=2 bleeding events within the 3 months prior to C1D1.
• Bone marrow blast percentage >=2%. Participants with blast % between 2-5% are allowed if at least 2 bone marrows >6 months apart demonstrate stability of blast percentage, these participants must be reviewed with the Medical Monitor prior to study entry.
• Prior treatment with luspatercept, sotatercept, or other commercially available or investigational TGF-ß inhibitors (all Arms)
• Treatment within 28 days prior to C1D1 with:
a. Erythropoiesis stimulating agent (ESA)
b. Granulocyte colony-stimulating factor (G-CSF)
c. Granulocyte-macrophage colony-stimulating factor (GM-CSF)
d. Thrombopoietin agonists (TPO)
e. Immunomodulator imide drugs (IMiDs; e.g., thalidomide,
pomalidomide, lenalidomide)
f. Interferon
• Newly initiated iron chelation therapy within the 8 weeks prior to C1D1.
• Treatment with another investigational drug or device or approved therapy for investigational use given for treatment of MF or anemia in MF <=28 days prior to C1D1, or if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, or whichever is longer.
• Treatment with strong cytochrome P450 (CYP)3A4 inhibitors within 2 weeks prior to C1D1 (for Arms 1B and 2B)
• Estimated glomerular filtration rate (eGFR) <40 mL/min/1.73 m2 (as determined by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) |
• Presenza delle seguenti condizioni cardiache:
a) Insufficienza cardiaca di classe 3 o 4 secondo la New York Heart Association
b) QTcF >500 msec allo screening o all’elettrocardiogramma (ECG) del C1G1
c) Aritmia clinicamente significativa non controllata (i partecipanti con fibrillazione atriale con controllo della frequenza non sono esclusi)
d) Infarto miocardico acuto o angina pectoris instabile <=6 mesi prima del C1G1
• Anamnesi di ictus, trombosi venosa profonda o embolia arteriosa nei 6 mesi precedenti il C1G1.
• Qualsiasi tumore maligno diverso da MFP, MF post-ET o MF post-PV che non sia stato in remissione e/o abbia richiesto una terapia sistemica, tra cui radioterapia, chemioterapia, terapia ormonale o intervento chirurgico, entro 1 anno prima del C1G1. A discrezione dello sperimentatore sono consentiti carcinomi in situ, carcinomi a cellule squamose e basali che siano stati completamente asportati e gammopatia monoclonale di significato non chiaro.
• Anamnesi di trapianto di organo solido o trapianto ematologico
• Presenza di ipertensione non controllata, definita come pressione sanguigna sistolica >=150 mmHg o pressione sanguigna diastolica >=100 mmHg nonostante un trattamento adeguato.
• Diagnosi di anemia emolitica, sanguinamento attivo, emoglobinopatie o disturbi congeniti come causa dell’anemia del partecipante.
• Eventi di sanguinamento di grado CTCAE >=2 nei 3 mesi precedenti il C1G1.
• Percentuale di blasti nel midollo osseo >=2%. I partecipanti con percentuale di blasti tra il 2 e 5% sono ammessi se almeno 2 campioni di midollo osseo prelevati a distanza di >6 mesi dimostrano stabilità nella percentuale di blasti; questi partecipanti devono essere esaminati con il monitor medico prima dell’ingresso nello studio.
• Precedente trattamento con luspatercept, sotatercept o altri inibitori del fattore di crescita trasformante (TGF)-ß disponibili in commercio o sperimentali (tutti i bracci)
• Trattamento nei 28 giorni precedenti il C1G1 con:
a) Agente stimolante l’eritropoiesi (ESA)
b) Fattore stimolante le colonie granulocitarie (G-CSF)
c) Fattore stimolante le colonie granulocitarie-macrofagiche (MG-CSF)
d) Agonisti della trombopoietina (TPO)
e) Farmaci immidici immunomodulatori (IMiD; ad es. talidomide, pomalidomide, lenalidomide)
f) Interferone
g) Idrossiurea
• Terapia ferro-chelante iniziata recentemente entro 8 settimane precedenti il C1G1.
• Trattamento con un altro farmaco o dispositivo sperimentale o terapia approvata per uso sperimentale somministrato per il trattamento della MF o dell’anemia nella MF <=28 giorni prima del C1G1 o, se è nota l’emivita del prodotto precedente, entro 5 volte l’emivita prima del C1G1 o a seconda di quale sia il periodo più lungo.
• Trattamento con forti inibitori del citocromo P450 (CYP)3A4 nelle 2 settimane precedenti il C1G1 (per i Bracci 1B e 2B)
• Velocità di filtrazione glomerulare stimata (eGFR) <40 ml/min/1,73 m2 (determinata in base all’equazione della Collaborazione per l’epidemiologia della malattia renale cronica [CKD-EPI]) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| •Safety and tolerability as determined by the incidence of AEs, including severe AEs and SAEs |
| • Sicurezza e tollerabilità determinate dall’incidenza di eventi avversi (EA), compresi EA gravi ed EA seri (SAE) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of participants with mean hemoglobin increase >=1.5 g/dL or >=2.0 g/dL from baseline over a period of >=12 consecutive weeks within the first 24 weeks of study in subgroup of transfusion-independent participants
2. Proportion of participants with decrease in number of RBC transfusions from baseline over a period of >=12
consecutive weeks within the first 24 weeks of study in subgroup of participants with anemia requiring RBC
transfusions
[Time Frame: Week 24]
3. Evaluate PK
• Plasma concentrations of KER-050
• AUClast
• Accumulation rate (Rac) and assessment of steady-state as possible
[Time Frame: 52 Weeks] |
1. Percentuale di partecipanti con aumento medio dei livelli di emoglobina >=1,5 g/dl oppure >=2,0 rispetto al basale in un periodo >=12 settimane consecutive entro le prime 24 settimane dello studio nel sottogruppo di partecipanti trasfusione-indipendenti.
2. Percentuale di partecipanti con riduzione del numero di trasfusioni di RBC rispetto al basale in un periodo >=12 settimane consecutive durante il periodo entro le prime 24 settimane di studio nel sottogruppo di partecipanti con anemia che richiedono trasfusioni di RBC
3. PK evaluation:
• Concentrazioni plasmatiche di KER-050
• AUClast
• Tasso di accumulo (Rac) e valutazione dello stato stazionario se possibile |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints indicated above. |
1 e 2: 24 settimane;
3: 52 settimane |
|
| 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 | No |
| 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 |
| Tolerability |
| Tollerabilità |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| KER-050 (senza AIC) in combinazione con ruxolitinib (con AIC) |
| KER-050 (unauthorized IMP) in combination with ruxolitinib (authorized IMP) |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 | Information not present in EudraCT |
| 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 |
| Brazil |
| France |
| Italy |
| Spain |
| United Kingdom |
|
| 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
|
| The EOS is defined as the last participant completing the last visit or last procedure shown in the Schedule of Assessments in the protocol. |
| L'EOS è definito come l'ultimo partecipante che ha completato l'ultima visita o ultima procedura indicata nel Calendario delle Valutazioni del protocollo. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 23 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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