E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with a hematologic malignancy (AML, ALL, or MDS) who are eligible for a haploidentical HSCT |
Pacientes con neoplasia maligna hematológica (LMA, LLA o SMD) elegibles para trasplante haploidéntico de células madre hematopoyéticas. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with blood cancer who are eligible for a stem cell transplantation from a related haploidentical donor |
Pacientes con cáncer en la sangre que sean elegibles para un trasplante de células madre de un donante emparentado haploidéntico. |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10059044 |
E.1.2 | Term | Allogeneic peripheral hematopoietic stem cell transplant |
E.1.2 | System Organ Class | 100000022080 |
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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 | 10000845 |
E.1.2 | Term | Acute lymphoblastic leukemia |
E.1.2 | System Organ Class | 100000012958 |
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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 | 10027703 |
E.1.2 | Term | Mismatched donor bone marrow transplantation therapy |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 | 10000880 |
E.1.2 | Term | Acute myeloid leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 objective of this study is to compare safety and efficacy of a haploidentical T cell depleted HSCT and adjunctive treatment with ATIR101 versus a haploidentical T cell replete HSCT with post-transplant administration of high dose cyclophosphamide (PTCy) in patients with a hematologic malignancy. An additional objective of the study is to compare the effect of the two treatments on quality of life. |
El objetivo principal de este estudio es comparar la seguridad y eficacia de un trasplante de células madre hematopoyéticas haploidéntico privado de células T y tratamiento adyuvante con ATIR101 frente a un trasplante de células madre hematopoyéticas haploidéntico repuesto de células T con administración postrasplante de una dosis alta de ciclofosfamida (CiPT) en pacientes con neoplasia maligna hematológica. Un objetivo adicional del estudio es comparar el efecto de los dos tratamientos en la calidad de vida. |
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E.2.2 | Secondary objectives of the trial |
Not applicable |
No aplicable |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Any of the following hematologic malignancies: - Acute myeloid leukemia (AML) in first cytomorphological remission with Disease Risk Index (DRI) intermediate or above, or in second or higher cytomorphological remission - Acute lymphoblastic leukemia (ALL) in first or higher remission - Myelodysplastic syndrome (MDS): transfusion-dependent (requiring at least one transfusion per month), or intermediate or higher IPSS-R risk group 2. Clinical justification of allogeneic stem cell transplantation where a suitable HLA matched sibling or unrelated donor is unavailable in a timely manner. An unrelated donor search is not required for a patient to be eligible if the clinical situation dictates an urgent transplantation. Clinical urgency is defined as 6-8 weeks from referral to transplant center or low likelihood of finding a matched unrelated donor 3. Availability of a related haploidentical donor with ≥ 4/8 but < 8/8, or ≥ 5/10 but < 10/10 matches at the HLA-A, -B, -C, -DRB1, and/or -DQB1 loci, as determined by high resolution HLA-typing 4. Karnofsky Performance Status (KPS) ≥ 70% 5. Male or female, age ≥ 18 years and ≤ 70 years Patients aged ≥ 65 years must have a Sorror score ≤ 3 6. Availability of a donor aged ≥ 16 years and ≤ 75 years who is eligible according to local requirements and regulations 7. For females of childbearing potential who are sexually active and males who have sexual contact with a female of childbearing potential: use of reliable methods of contraception during study participation 8. Given written informed consent (patient and donor) |
1. Cualquiera de las siguientes neoplasias malignas hematológicas : - Leucemia mieloide aguda (LMA) en primera remisión citomorfológica con Índice de Riesgo de la Enfermedad (IRE) intermedio o superior, o en remisión citomorfológica segunda o mayor. - Leucemia linfoblástica aguda (LLA) en primera remisión o mayor. - Síndrome mielodisplásico (SMD) : Dependiente de transfusión (que requiera al menos una transfusión al mes), o perteneciente al grupo de riesgo IPSS-R intermedio o mayor. 2. Justificación clínica para un trasplante alogénico de células madre cuando no se dispone de un donante HLA compatible ni familiar ni no emparentado en un tiempo razonable. No se requiere búsqueda de donante no emparentado para que el paciente sea elegible si la situación clínica obliga a un transplante urgente. Se define urgencia clínica al periodo de 6-8 semanas desde que el paciente es referido al centro de trasplante o a la baja probabilidad de encontrar un donante no emparentado compatible. 3. Disponibilidad de un donante haploidéntico con ≥ 4/8 pero < 8/8, o ≥ 5/10 pero < 10/10 compatibilidades en los loci HLA-A, -B, -C, -DRB1, y/o - DQB1, determinado mediante tipaje-HLA de alta resolución. 4. Estado Funcional de Karnofsky (KPS) ≥ 70%. 5. Hombre o mujer de edad ≥ 18 años y ≤ 70. Los pacientes de edad ≥ 65 años deben tener puntuación Sorror ≤ 3. 6. Disponibilidad de un donante de edad ≥ 16 años y ≤ 75 que sea elegible de acuerdo a los requisitos y normativa local. 7. Para las mujeres en edad fértil que sean sexualmente activas y los hombres que tengan contacto sexual con una mujer fértil : uso de métodos anticonceptivos fiables durante la participación en el estudio. 8. Consentimiento informado firmado por escrito (paciente y donante). |
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E.4 | Principal exclusion criteria |
1. Availability of a suitable fully matched related or unrelated donor in a donor search 2. Prior allogeneic hematopoietic stem cell transplantation 3. Diffusing capacity for carbon monoxide (DLCO) < 50% predicted 4. Left ventricular ejection fraction < 50% (evaluated by echocardiogram or MUGA) 5. AST and/or ALT > 2.5 × ULN (CTCAE grade 2) 6. Bilirubin > 1.5 × ULN (CTCAE grade 2) 7. Creatinine clearance < 50 ml/min (calculated or measured) 8. Positive pregnancy test or breastfeeding of patient or donor (women of childbearing age only) 9. Estimated probability of surviving less than 3 months 10. Known allergy to any of the components of ATIR101 (e.g., dimethyl sulfoxide) 11. Known hypersensitivity to cyclophosphamide or any of its metabolites 12. Known presence of HLA antibodies against the non-shared donor haplotype 13. Positive HIV test 14. Positive CMV test of the patient and negative CMV test of the donor 15. Positive viral test of the donor for HIV-1, HIV-2, HBV, HCV, Treponema pallidum, HTLV 1 (if tested), HTLV-2 (if tested), WNV (if tested), or Zika virus (if tested) 16. Any other condition that, in the opinion of the investigator, makes the patient or donor ineligible for the study |
1. Disponibilidad de un donante completamente compatible emparentado o no en una búsqueda de donantes. 2. Trasplante alogénico de células madre hematopoyéticas previo. 3. Capacidad de difusión de monóxido de carbono prevista de <50%. 4. Fracción de eyección ventricular iquierda <50% (evaluada mediante ecocardiograma o MUGA). 5. AST y/o ALT >2.5 x LSN (límite superior normal) (CTCAE grado 2). 6. Bilirrubina > 1.5 x LSN (CTCAE grado 2). 7. Aclaramiento de creatinina > 50 ml/min (calculado o medido). 8. Prueba de embarazo positiva o paciente o donante que esté dando el pecho (solo mujeres en edad fértil). 9. Probabilidad estimada de supervivencia menor de 3 meses. 10. Alergia conocida a alguno de los componentes de ATIR101 (por ejemplo dimetil sulfóxido). 11. Hipersensibilidad conocida a la ciclofosfamida o alguno de sus metabolitos. 12. Presencia conocida de anticuerpos HLA frente al haplotipo no compartido con el donante. 13. Prueba positiva frente a VIH. 14. Prueba positiva de CMV para el paciente y negativa para el donante. 15. Test positivo para el donante para VIH-1, VIH-2, VHB, VHC, Treponema pallidum, VLTH-1 (si testado), VLTH-2 (si testado), VNO (si testado), o virus Zika (si testado). 16. Cualquier otra condición que, en opinión del investigador, haga al paciente o al donante inelegible para el estudio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the study is GVHD-free, relapse-free survival (GRFS). GRFS is defined as time from randomization until grade III/IV acute graft-versus-host disease (GVHD), chronic GVHD requiring systemic immunosuppressive treatment, disease relapse, or death, whichever occurs first. This endpoint captures both safety and efficacy. |
El criterio de valoración principal del estudio es la supervivencia sin EICH y sin recidiva (SSER). La SSER se define como el tiempo desde la aleatorización hasta la enfermedad del injerto contra el huésped (EICH) aguda de grado III/IV, la EICH crónica que requiere tratamiento inmunosupresor sistémico, la recidiva de la enfermedad o la muerte (lo que ocurra primero). Este criterio de valoración contempla tanto la seguridad como la eficacia. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the study (no fixed timepoint) |
A lo largo de todo el estudio (no hay un momento fijo). |
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E.5.2 | Secondary end point(s) |
• Overall survival (safety and efficacy), defined as the time from randomization until death from any cause • Progression-free survival (efficacy), defined as the time from randomization until relapse, disease progression, or death, whichever occurs first • Relapse-related mortality (efficacy), defined as the time from randomization to death due to disease relapse or disease progression • Transplant-related mortality (safety and efficacy), defined as the time from randomization to death due to causes other than disease relapse or disease progression |
• Supervivencia global (SG) (seguridad y eficacia), definida como desde el momento de la aleatorización hasta la muerte por cualquier causa. • Supervivencia sin progresión (SLP) (eficacia), definida como desde el momento de la aleatorización hasta la recaída, progresión de la enfermedad o la muerte, lo que ocurra primero. • Mortalidad relacionada con la recidiva (MRR) (eficacia), definida como desde el momento de la aleatorización hasta la muerte causada por recaída o progresión de la enfermedad. • Mortalidad relacionada con el trasplante (MRT) (seguridad y eficacia), definida como desde el momento de la aleatorizacion hasta la muerte debido a causas distintas de la recaída o progresión de la enfermedad.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the study (no fixed timepoint) |
A lo largo de todo el estudio (no hay un momento fijo). |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Belgium |
Canada |
Croatia |
France |
Germany |
Italy |
Netherlands |
Portugal |
Spain |
Sweden |
United Kingdom |
United States |
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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
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The end of the study is defined as the date at which the last data point from the last patient is received. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |