| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High risk haematological malignancies |
| Neoplasias hematológicas de alto riesgo |
|
| E.1.1.1 | Medical condition in easily understood language |
| cancer affecting blood, bone marrow, lymph nodes |
| cáncer que afecta a la sangre, la médula ósea, los ganglios linfáticos |
|
| 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 | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000845 |
| E.1.2 | Term | Acute lymphoblastic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025316 |
| E.1.2 | Term | Lymphoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009015 |
| E.1.2 | Term | Chronic myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028534 |
| E.1.2 | Term | Myelodysplastic syndrome NOS |
| E.1.2 | System Organ Class | 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 |
Assess the cumulative incidence of patients with NiCord-derived neutrophil engraftment at 42 days following transplantation
Assess the incidence of secondary graft failure at 180 days following transplantation of NiCord |
Evaluar la incidencia acumulada de pacientes con un injerto de neutrófilos derivado de NiCord® 42 días después del trasplante
Evaluar la incidencia de rechazo de un injerto secundario 180 días después del trasplante de NiCord |
|
| E.2.2 | Secondary objectives of the trial |
Time from infusion to neutrophil engraftment
Time from infusion to platelet engraftment
Incidence of platelet engraftment at 100 days
Proportion of non-relapse mortality at 100 days
Incidence of acute GvHD grade II-IV and III-IV at 100 days
Incidence of chronic GvHD (limited or extensive) at 180 days and 1 year
Incidence of secondary graft failure at 1 year following transplantation of NiCord®
Overall survival at 180 days and 1 year
Safety and tolerability of NiCord® transplantation |
Tiempo desde la perfusión hasta el injerto de neutrófilos
Tiempo desde la perfusión hasta el injerto de plaquetas
Incidencia del injerto de plaquetas a los 100 días
Proporción de mortalidad sin recidiva a los 100 días
Incidencia de EICH aguda de grado II-IV y III-IV a los 100 días
Incidencia de EICH crónica (limitada o extensiva) 180 días y 1 año después
Incidencia de rechazo de un injerto secundario un año después del trasplante de NiCord®
Supervivencia global 180 días y 1 año después
Seguridad y tolerabilidad del trasplante de NiCord® |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patients must be 12-65 years of age
2.Patients with one of the following hematologic malignancies:
Acute lymphoblastic leukemia(ALL)at one of the following stages:
a.High risk first complete morphologic remission (CR1), defined as one or more of the following:
-The presence of t(4;11), t(9;22), t(1;19) or MLL rearrangements t(11q23)
-Extreme leukocytosis (WBC>30,000/µl for B-ALL or >100,000/µl for T-ALL)
-Longer than 4 weeks to achieve complete remission after induction therapy
b.Second or subsequent remission
Acute myelogenous leukemia(AML)at one of the following stages:
a.First complete morphologic remission (CR1) that is NOT considered as favorable-risk:
Favorable risk is defined as having one of the following:
-t(8,21) without cKIT mutation
-inv(16) without cKIT mutation or t(16;16)
-Normal karyotype with mutated NPM1 and no FLT-3 Internal Tandem Duplication
-Normal karyotype with double mutated CEBPA
-APL in first or second molecular remission at end of consolidation
b.Second or subsequent remission
Chronic myelogenous leukemia(CML)at one of the following phases:
a.Chronic phase with one or more of the following characteristics:
-Failure to achieve a primary hematologic or cytogenetic response to either nilotinib or dasatinib (following European LeukemiaNet timelines)
-Intolerance to/failure of two tyrosine kinase inhibitors (TKI)
-Any T3151 mutation
b.Accelerated phase with one or more of the following characteristics:
-Newly diagnosed patients who do not achieve an optimal response to TKIs
-TKI-treated patients who progress from chronic phase
c.Blast crisis (myeloid or lymphoid) with disease control
Myelodysplastic Syndrome (MDS) with International Prognostic Scoring System (IPSS) risk category of INT-1 or greater and <5% myeloblasts in the bone marrow on morphologic analysis. MDS patients categorized as INT-1 on primary presentation must have life threatening neutropenia or thrombocytopenia.
Lymphoma fulfilling one of the following criteria:
a.Chemotherapy-sensitive (complete or partial response) lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are INELIGIBLE for an autologous transplant.
b.Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least two prior therapies (excluding single agent Rituxan).
3.Patients must have a partially HLA-matched CBU: the unit must be HLA-matched at 4-6/6 HLA class I (HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high resolution) loci with the patient. The CBU must have a pre-cryopreserved, total CD34+ cell dose of greater than or equal to 10x10^6 as well as a pre-cryopreserved total nucleated cell dose of greater than or equal to 1.8x10^9 and greater than or equal to 1.8x10^7 TNC/kg. The CBU will have undergone volume reduction (both plasma and red blood cell depletion) prior to cryopreservation.
4.Patients must have an additional partially HLA-matched CBU, or two CBUs, reserved as a backup in case of batch failure. The backup CBU/s must be HLA-matched at 4-6/6 HLA class I (HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high resolution) loci with the patient, and must have a pre-cryopreserved, total nucleated cell dose of at least 2x10^7 per kilogram, in case of one CBU, or 3x10^7 per kilogram, in case of two CBUs.
5.Patients must have a related, haplo-identical family member who is suitable for bone marrow or peripheral blood stem cell donation and has agreed to do so in the event of graft failure.
6.Subjects' Performance score greater than or equal to 70% by Karnofsky/Lansky
7.Patient has sufficient physiologic reserves including:
-Cardiac:Left ventricular ejection fraction (LVEF) of >40% by echocardiogram, radionuclide scan or cardiac MRI
-Pulmonary function tests demonstrating FVC and FEV1 of >50% of predicted for age and DLCO >50% of predicted
-Renal: Creatinine clearance test (by Cockcroft-Gault equation) ?60 mL/min
-Hepatic: Serum Bilirubin < 2.0 mg/dl; Hepatic transaminases (ALT and AST) < 3 x upper limit of normal range
8.Females of childbearing potential, defined as any female who has experienced menarche and is not postmenopausal or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy), agree to use an appropriate method of contraception from at least 7 days prior to myeloablative therapy until completion of follow-up procedures. An appropriate method of contraception is defined as one that results in a low failure rate (i.e., less than 1 percent per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner.
9.Patient (or legal guardian) signs the written informed consent after being aware of the nature of the patient's disease and willingly consents to the treatment program after being informed of alternative treatments, potential risks, benefits, and discomforts. |
1.Los pacientes deben tener entre 12y65años de edad
2.Pacientes con una de las siguientes neoplasias hematológicas malignas:Leucemia linfoblástica aguda en una de las fases siguientes:a.Primera remisión morfológica completa de alto riesgo(CR1),definida como uno o varios de los siguientes:-Presencia de t(4;11),t(9;22),t(1;19)o reordenamientos de M/L t(11q23).-Leucocitosis extrema(LEUC>30 000/JlparaLLA-Bo>100 000/Jl para LLA-T).-Más de 4semanas en conseguir la remisión completa después de la terapia de inducción.b.Segunda remisión o posterior
Leucemia mielógena aguda en una de las fases siguientes:a.Primera remisión morfológica completa(CR1)que NOse considere como riesgo favorable:
Riesgo favorable se define como tener uno de los siguientes:-t(8,21)sin mutación cKIT,-inv(16)sin mutación cKIT o t(16;16),-cariotipo normal conNPM1 mutado y sin duplicación en tándem interna deFLT-3,-cariotipo normal con doble mutaciónCEBPA,-APLen primera o segunda remisión molecular al final de la consolidación.b.Segunda remisión o posterior
Leucemia mielógena crónica en una de las fases siguientes:a.Fase crónica con una o varias de las siguientes características:-Imposibilidad de conseguir una respuesta hematológica o citogenética principal a nilotinib o dasatinib-Intolerancia/fracaso de los dos inhibidores de laTKI-Cualquier mutaciónT3151.b.Fase acelerada con una o varias de las siguientes características:- cientes con un diagnóstico reciente que no alcanzan una respuesta óptima a losTKI-Pacientes tratados conTKI que evolucionen desde una fase crónica.c.Crisis de blastos(mieloides o linfoides)con control de la enfermedad
Síndrome mielodisplásico con una categoría de riesgo en el IPSSdeINT-1 o superior y<5%de mieloblastos en la médula ósea según el análisis morfológico.Los pacientes conSMDclasificados comoINT-1 según la presentación principal deben tener trombocitopenia o neutropenia potencialmente mortal
Linfoma que cumpla uno de los criterios siguientes:a.Linfomas sensibles a la quimioterapia que no hayan dado resultado con al menos una pauta previa de quimioterapia multiagente y NO SEAN ELEGIBLES para un trasplante autólogo.b.Linfoma de zona marginal de células B o linfoma folicular que haya progresado después de al menos dos tratamientos previos (excepto el fármaco único Rituxan)
3.Pacientes que tengan una USC parcialmente compatible con HLA:la unidad debe ser compatible con los loci del HLA4-6/6de claseI(HLA-AyHLA-B,baja resolución)y de claseII(HLA-DRB1,alta resolución)del paciente.LaUSCdebe tener una dosis de célulasCD34+ totales previamente crioconservadas de mayor o igual a 10x10^6,así como una dosis de células nucleadas totales previamente crioconservadas de mayor o igual a 1,8x10^9 y mayor o igual a 1,8x10^7CNT/kg. La USC se habrá sometido a una reducción del volumen antes de la crioconservación.
4.Los pacientes deben tener unaUSCadicional parcialmente compatible conHLAo dosUSC,como reserva en caso de rechazo del lote.LasUSCde reserva deben ser compatibles con los loci delHLA4-6/6de claseI(HLA-AyHLA-B,baja resolución)y de claseII(HLA-DRB1, lta resolución)del paciente y deben tener una dosis de células nucleadas totales previamente crioconservadas de al menos2x10^7por kilogramo, en caso de una USC,o 3x10^7por kilogramo,en caso de dos USC
5.Los pacientes deben tener un familiar haploidéntico que sea apto para una donación de células madre de sangre periférica o médula ósea y que haya aceptado realizar la donación en caso de rechazo de injerto
6.Índice de Karnofsky/Lansky del sujeto mayor o igual a 70%
7.Pacientes con reservas fisiológicas suficientes como:-Cardíaca:FEVI>40%mediante ecocardiografía,tomografía computarizada oRMcardíaca-Pruebas de función pulmonar que demuestren unaFVCyFEV1>50%de lo pronosticado para la edad yDLCO>50%de lo pronosticado-Renal:Prueba de aclaramiento de creatinina mayor o igual a60ml/min-Hepática:Bilirrubina sérica<2,0mg/dl;transaminasas hepáticas(ALTyAST)<3xlímite superior normal
8.Las mujeres en edad fértil definidas como cualquier mujer que haya experimentado menarquia y no sea postmenopáusica ni haya sido esterilizada permanentemente(p.ej,oclusión tubárica,histerectomía,salpingectomía bilateral),aceptan utilizar un método anticonceptivo adecuado desde al menos 7días antes de comenzar el tratamiento mieloablativo hasta la finalización de los procedimientos de seguimiento.Un método anticonceptivo adecuado se define como aquel que conlleva una baja tasa de fracaso(es decir, menos de 1por cien al año)cuando se utiliza de forma sistemática y correcta,como implantes,inyectables,anticonceptivos orales combinados,algunos DIU,abstinencia sexual o pareja a quien se le haya realizado una vasectomía
9.El paciente(o tutor legal)firme el consentimiento informado por escrito después de conocer la naturaleza de la enfermedad del paciente y acepte voluntariamente el programa de tratamiento una vez informado de los tratamientos alternativos,riesgos potenciales,beneficios y molestias |
|
| E.4 | Principal exclusion criteria |
1. NK cell lymphoma, Burkitt's lymphoma
2. CLL/SLL diagnosis
3. MDS or CML with "marked" or "3+" fibrosis
4. Less than 21 days have elapsed since initiation of the patient's last chemotherapy regimen and the initiation of the stem cell transplant preparative regimen (intrathecal agents, hydroxyurea, tyrosine kinase inhibitors, hypomethylating agents and rituximab, not considered chemotherapy)
5. Persistent clinically significant toxicities from prior chemotherapy that, in the investigator's opinion, make the patient unsuitable for transplant
6. Evidence of anti-HLA antibodies to the selected NiCord® CBU (MFI>3000)
7. Evidence of HIV infection or HIV positive serology
8. Evidence of active Hepatitis B, Hepatitis C or EBV as determined by serology or PCR
9. Pregnancy (beta HCG +) or lactation
10. Active malignancy other than that for which the UCB transplant is being performed within 12 months of enrollment. Fully resected cutaneous squamous cell or basal cell carcinoma or cervical carcinoma in situ within 12 months of enrollment will be permitted.
11. Evidence of uncontrolled bacterial, fungal or viral infections or severe concomitant diseases, which in the judgment of the Principal Investigator indicate that the patient could not tolerate transplantation
12. Patients with signs and symptoms of active central nervous system (CNS) disease, including CNS leukemia or lymphoma
13. Patients with an 8/8 allele level HLA-matched and readily available related or unrelated donor, e.g. patients who have haploidentical related donors will not be excluded
14. Prior allogeneic hematopoietic stem cell transplant
15. Allergy to bovine, gentamicin, or to any other product which may interfere with the treatment
16. Psychiatric illness and/or social situations that would limit compliance with study requirements
17. Enrolled in another clinical trial or received an investigational treatment during the last 30 days, unless approved by Sponsor |
1. Linfoma de células NK, linfoma de Burkitt.
2. Diagnóstico de LLC / LLCP.
3. SMD o LMC con fibrosis "marcada" o "3+".
4. Que hayan transcurrido menos de 21 días desde el inicio de la última pauta de quimioterapia del paciente y el inicio de la pauta de preparación del trasplante de células madre (fármacos intratecales, hidroxiurea, inhibidores de la tirosina quinasa, agentes de hipometilación y rituximab no se consideran quimioterapia).
5. Toxicidades persistentes clínicamente significativas previas a la quimioterapia que, en opinión del investigador, hagan que el sujeto no sea apto para el trasplante.
6. Presencia de anticuerpos anti-HLA a la USC de NiCord® seleccionada (IFM > 3000).
7. Infección por el VIH o serología positiva del VIH.
8. Hepatitis B , hepatitis C o VEB activas determinadas por serología o PCR.
9. Embarazo (beta HCG +) o lactancia.
10. Neoplasia maligna activa, salvo la neoplasia que causa el trasplante de SCU, durante los 12 meses siguientes a la inclusión. Estarán permitidos el carcinoma de células escamosas de la piel completamente resecado, carcinoma de células basales o carcinoma de cuello uterino in situ durante los 12 meses siguientes a la inclusión.
11. Infecciones bacterianas, fúngicas o víricas no controladas o enfermedades concomitantes graves que, según el criterio del investigador principal, indiquen que el paciente no podría tolerar un trasplante.
12. Pacientes con signos y síntomas de una enfermedad activa del sistema nervioso central (SNC), incluida la leucemia o el linfoma del SNC.
13. Pacientes con un nivel de alelos 8/8 compatible con HLA y donantes emparentados o no que estén disponibles. Por ejemplo, los pacientes que tengan un familiar donante haploidéntico no serán excluidos.
14. Pacientes que hayan recibido un trasplante alogénico de células madre hematopoyéticas con anterioridad.
15. Alergia a la gentamicina bovina o cualquier otro producto que pueda interferir en el tratamiento.
16. Enfermedad psiquiátrica y/o situaciones sociales que puedan limitar el cumplimiento de los requisitos del estudio.
17. Pacientes que hayan participado en otro ensayo clínico o que hayan recibido un tratamiento en investigación durante los últimos 30 días, salvo que lo apruebe el promotor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. cumulative incidence of patients with NiCord®-derived neutrophil engraftment at 42 days following transplantation
2. incidence of secondary graft failure at 180 days following transplantation of NiCord® |
1. incidencia acumulada de pacientes con un injerto de neutrófilos derivado de NiCord® 42 días después del trasplante
2. incidencia de rechazo de un injerto secundario 180 días después del trasplante de NiCord® |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. day 42 and 2. day 180 |
| 1. día 42 y 2. día 180 |
|
| E.5.2 | Secondary end point(s) |
1. Time to Neutrophil engraftment
2. Time to Platelet engraftment
3. Incidence of platelet engraftment at 100 days
4. Non-relapse mortality at 100 days
5. Acute GvHD grade II-IV and III-IV at 100 days
6. Chronic GvHD (limited or extensive) at 180 days and 1 year
7. Incidence of secondary graft failure at 1 year following transplantation of NiCord®
8. Overall survival at 180 days and 1 year
9.Safety and tolerability of NiCord® transplantation
Exploratory endpoints:
1. Immune Reconstitution |
1. Tiempo de injerto de neutrófilos
2. Tiempo de injerto de plaquetas
3. Incidencia del injerto de plaquetas a los 100 días.
4. Mortalidad sin recidiva a los 100 días
5. EICH aguda de grado II-IV y III-IV a los 100 días
6. EICH crónica (limitada o extensiva) 180 días y 1 año después
7. Incidencia de rechazo de un injerto secundario un año después del trasplante de NiCord®
8. Supervivencia global 180 días y 1 año después
9.Seguridad y tolerabilidad del trasplante de NiCord®
Variables exploratorias:
1. Reconstitución inmune |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 1. Not relevant; 2. Not relevant; 3. 100 days; 4. 100 days; 5. 100 days; 6. 180 days and 1 year; 7. 1 year; 8. 180 days and 1 year; 1. 70, 100, 180 and 365 days;9.1 year |
| 1 No relevante; 2 No relevante; 3. 100 días; 4. 100 días; 5. 100 días; 6. 180 días y 1 año; 7. 1 año; 8. 180 días y 1 año; 1. 70, 100, 180 y 365 días; 9.1 año |
|
| 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 | 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | 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.8.3 |
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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 | 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
|
| LSLV |
| sujeto último visita última |
|
| 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 | 5 |
| 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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