| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Myelfibrosis (MF)
MF- associated cytopenias |
Mielofibrosis (MF)
Citopenias asociadas a mielofibrosis |
|
| 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: neoplasia mieloproliferativa crónica caracterizada por proliferación clonal de células mieloides e hiperplasia/displasia megacariocítica que produce fibrosis de médula ósea y osteoesclerosis |
|
| 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 de aumento gradual de la dosis:
• Evaluar la seguridad y tolerabilidad de dosis ascendentes de KER‐050 en monoterapia en participantes con mielofibrosis primaria (MFP), mielofibrosis post-trombocitemia esencial (MF post-TE) y mielofibrosis post-policitemia vera (MF post-PV) que tienen anemia, y determinar la dosis que se evaluará en la parte 2 del estudio
• Evaluar la seguridad y tolerabilidad de dosis ascendentes de KER-050 en combinación con ruxolitinib en participantes con MFP, MF post-TE y MF post-PV que tienen anemia, y determinar la dosis que se evaluará en la parte 2 del estudio
Parte 2 de expansión de la dosis:
• Evaluar la seguridad y tolerabilidad de la(s) dosis seleccionada(s) en la 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 |
• Evaluar la farmacocinética (FC) de KER-050 administrado con o sin ruxolitinib en participantes con MFP/MF post-TE/MF post-PV
• Evaluar los efectos farmacodinámicos (FD) relacionados con la eritropoyesis de KER-050 administrado con o sin ruxolitinib en participantes con MFP/MF post-TE/FM post-PV
• Evaluar el efecto sobre la anemia de KER-050 administrado con o sin ruxolitinib en participantes con MFP/MF post-TE/MF post-PV
• Evaluar el efecto de sobre las manifestaciones y los síntomas de la enfermedad de MF de KER-050 administrado con o sin ruxolitinib en participantes con MFP/MF post-TE/MF post-PV
• Evaluar el efecto de KER-050 administrado con o sin ruxolitinib sobre la progresión a leucemia mieloide aguda (LMA) o mielofibrosis (MF) acelerada |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female > or = 18 years of age, at the time of signing informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance score < or =2.
• Life expectancy > or =12 months per Investigator assessment
• Diagnosis of PMF, post-PV MF, or post-ET MF according to the 2017 WorldHealth 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 < or =10 g/dL during screening, or receiving RBC transfusions
Arm 2A:
• Previously treated with JAK inhibitor(s)
• Anemia, defined as hemoglobin < or =10 g/dL during screening, or receiving RBC transfusions
Arm-specific criteria for 1B and 2B:
• Has been receiving ruxolitinib for > or = 8 weeks prior to C1D1 and on a stable dose for > or = 4 weeks prior to C1D1.
• Anemia, defined as hemoglobin < or = 10 g/dL during screening, or receiving RBC transfusions |
- Hombre o mujer > o = 18 años de edad, en el momento de firmar el consentimiento informado.
- Puntuación del Eastern Cooperative Oncology Group (ECOG) < o =2.
- Esperanza de vida > o =12 meses según la evaluación del investigador
- Diagnóstico de PMF, MF post-PV o MF post-ET según los criterios de la Organización Mundial de la Salud de 2017.
Criterios específicos de cada brazo:
Brazo 1A :
- Tratados previamente con inhibidor(es) de JAK y por el Investigador suspendidos debido a recaída, refractariedad, intolerancia, o que ya no cumplían la relación beneficio/riesgo para continuar con el tratamiento con inhibidor(es) de JAK o inelegibilidad para el tratamiento con inhibidor(es) de JAK.
- Anemia, definida como hemoglobina < o =10 g/dL durante el cribado, o recibir transfusiones de glóbulos rojos
Brazo 2A:
- Tratamiento previo con inhibidor(es) de JAK
- Anemia, definida como hemoglobina < o =10 g/dL durante el cribado, o recepción de transfusiones de glóbulos rojos
Criterios específicos para los brazos 1B y 2B:
- Ha estado recibiendo ruxolitinib durante > o = 8 semanas antes del C1D1 y con una dosis estable durante > o = 4 semanas antes del C1D1.
- Anemia, definida como hemoglobina < o = 10 g/dL durante el cribado, o recibir transfusiones de glóbulos rojos |
|
| 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 > or = 150 mm Hg or diastolic blood pressure > or =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 > or =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-β 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 < or =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) |
- Presencia de las siguientes condiciones cardíacas:
a. Insuficiencia cardíaca de clase 3 o 4 de la New York Heart Association
b. QTcF >500 mseg en el electrocardiograma (ECG) de cribado o C1D1
c. Arritmia clínicamente significativa no controlada (no se excluyen los participantes con fibrilación auricular de frecuencia controlada)
d. Infarto agudo de miocardio o angina de pecho inestable <6 meses antes del C1D1
- Antecedentes de ictus, trombosis venosa profunda o embolia arterial en los 6 meses anteriores al C1D1.
- Cualquier tumor maligno que no sea PMF, MF post-ET o MF post-PV que no haya estado en remisión y/o que haya requerido terapia sistémica, incluyendo radiación, quimioterapia, terapia hormonal o cirugía, dentro de 1 año antes de C1D1. Los cánceres in situ, los carcinomas de células escamosas y de células basales que hayan sido completamente extirpados, y la gammapatía monoclonal de significado incierto se permiten a discreción del investigador.
- Antecedentes de trasplante de órganos sólidos o hematológicos.
- Presencia de hipertensión no controlada, definida como presión arterial sistólica > o = 150 mm Hg o presión arterial diastólica > o = 100 mm Hg a pesar del tratamiento adecuado.
- Diagnóstico de anemia hemolítica, hemorragia activa, hemoglobinopatías o trastornos congénitos como causa de la anemia del participante.
- Eventos hemorrágicos de grado CTCAE > o =2 en los 3 meses anteriores al C1D1.
- Porcentaje de blastos en la médula ósea >2%. Los participantes con un porcentaje de blastos entre el 2 y el 5% están permitidos si al menos 2 médulas óseas con un intervalo de 6 meses demuestran la estabilidad del porcentaje de blastos; estos participantes deben ser revisados por el monitor médico antes de entrar en el estudio.
- Tratamiento previo con luspatercept, sotatercept u otros inhibidores del TGF-β disponibles en el mercado o en investigación (todos los brazos)
- Tratamiento dentro de los 28 días anteriores al C1D1 con:
a. Agente estimulante de la eritropoyesis (AEE)
b. Factor estimulante de colonias de granulocitos (G-CSF)
c. Factor estimulante de colonias de granulocitos y macrófagos (GM-CSF)
d. Agonistas de la trombopoyetina (TPO)
e. Fármacos inmunomoduladores de imidas (IMiDs; por ejemplo, talidomida, pomalidomida, lenalidomida)
f. Interferón
- Terapia de quelación de hierro recién iniciada en las 8 semanas anteriores al C1D1.
- Tratamiento con otro fármaco o dispositivo en investigación o terapia aprobada para uso en investigación administrada para el tratamiento de la MF o la anemia en la MF < o =28 días antes del C1D1, o si se conoce la vida media del producto anterior, dentro de 5 veces la vida media antes del C1D1, o lo que sea más largo.
- Tratamiento con inhibidores potentes del citocromo P450 (CYP)3A4 en las 2 semanas anteriores al C1D1 (para los brazos 1B y 2B)
- Tasa de filtración glomerular estimada (TFGe) <40 ml/min/1,73 m2 (según la ecuación de la Chronic Kidney Disease Epidemiology Collaboration [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 |
| • Seguridad y tolerabilidad determinadas por la incidencia de acontecimientos adversos (AA), incluidos AA intensos y AA graves (AAG) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
•Proportion of participants with mean hemoglobin increase > or = 1.5 g/dL or > 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
• 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]
Evaluate PK
• Plasma concentrations of KER-050
• AUClast
• Accumulation rate (Rac) and assessment of steady-state as possible
[Time Frame: 52 Weeks] |
-Proporción de participantes con un aumento medio de hemoglobina > o = 1,5 g/dL o > o = 2,0 g/dL desde el inicio del estudio durante un periodo de >12 semanas consecutivas dentro de las primeras 24 semanas del estudio en el subgrupo de participantes independientes de las transfusiones
- Proporción de participantes con una disminución en el número de transfusiones de glóbulos rojos desde el inicio durante un período de >12 semanas consecutivas dentro de las primeras 24 semanas del estudio en el subgrupo de participantes con anemia que requiere transfusiones de glóbulos rojos
[Tiempo: Semana 24]
Evaluar la PK
- Concentraciones plasmáticas de KER-050
- AUClast
- Tasa de acumulación (Rac) y evaluación del estado estacionario como sea posible
[Periodo de tiempo: 52 semanas] |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints indicated above. |
| Momentos indicados arriba. |
|
| 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 |
|
| 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 (medicamento no autorizado) en combinación con ruxolitinib (medicamento autorizado) |
| 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 | 5 |
| 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 | 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 |
| 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. |
| El fin del ensayo se define como el último participante que completa la última visita o el último procedimiento indicado en el calendario de evaluaciones del protocolo. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| 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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