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    Summary
    EudraCT Number:2020-004583-26
    Sponsor's Protocol Code Number:LV2020-001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-08-05
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2020-004583-26
    A.3Full title of the trial
    A Phase 1 and 2a open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of LAVA-051 in patients with relapsed or refractory CD1d-positive chronic lymphocytic leukemia, multiple
    myeloma or acute myeloid leukemia
    Estudio sin enmascaramiento de fase 1 y 2a para evaluar la seguridad, la tolerabilidad, la farmacocinética, la farmacodinámica, la inmunogenicidad y la actividad antitumoral de LAVA-051 en pacientes con leucemia linfocítica crónica, mieloma múltiple o leucemia mieloide aguda con CD1d positivo recidivantes o refractarios.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A dose escalation trial to assess the safety and tolerability of multiple doses of the LAVA-051 antibody in patients with chronic lymphocytic leukemia, multiple myeloma or acute myeloid leukemia
    Ensayo para evaluar la seguridad y la tolerabilidad del nuevo fármaco en investigación LAVA-051 en pacientes con leucemia linfocítica crónica, mieloma múltiple o leucemia mieloide aguda que no responde o que reaparece.
    A.3.2Name or abbreviated title of the trial where available
    LAVA
    A.4.1Sponsor's protocol code numberLV2020-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLAVA Therapeutics B.V.
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLAVA Therapeutics B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCATO SMS
    B.5.2Functional name of contact pointRuth Cohen
    B.5.3 Address:
    B.5.3.1Street AddressStationsplein NO 438
    B.5.3.2Town/ citySchiphol
    B.5.3.3Post code1117 CL
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31204350 580
    B.5.5Fax number+31204350 589
    B.5.6E-mailSSUReg@cato-sms.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLAVA-051
    D.3.2Product code LAVA-051
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNA
    D.3.9.1CAS number NA
    D.3.9.2Current sponsor codeLAVA-051
    D.3.9.3Other descriptive nameLAVA-051
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    CD1d-positive relapsed/refractory chronic lymphocytic leukemia (CLL), multiple myeloma (MM), or acute myeloid leukemia (AML)
    Leucemia linfocítica crónica (CLL), mieloma múltiple (MM) o leucemia mieloide aguda (AML) positiva para CD1d recidivante / refractaria
    E.1.1.1Medical condition in easily understood language
    Patients with chronic lymphocytic leukemia, multiple myeloma or acute myeloid leukemia
    Pacientes con leucemia linfocítica crónica, mieloma múltiple o leucemia mieloide aguda
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part 1 Dose Escalation
    • To investigate the safety and tolerability of LAVA-051 in patients with relapsed/refractory CLL, MM, or AML with positive tumor cell expression for CD1d.
    • To determine the recommended Phase 2a dose (RP2D) of LAVA-051 in patients with relapsed/refractory CLL, MM or AML with positive tumor cell expression for CD1d.
    Part 2 Proof of Concept (PoC)
    • To evaluate the antitumor activity of LAVA-051 at the respective RP2D in separate cohorts with relapsed/refractory CLL, MM or AML with positive tumor cell expression for CD1d.
    • To investigate the safety and tolerability of LAVA-051 in these respective expansion cohorts.
    Parte 1 Escalada de la dosis
    • Investigar la seguridad y tolerabilidad de LAVA-051 en pacientes con LCC, MM o LMA recidiva/refractaria con expresión celular tumoral positiva para CD1d.
    • Determinar la RP2D de LAVA-051 en pacientes con LCC, MM o LMA recidiva/refractaria con expresión celular tumoral positiva para CD1d.
    Parte 2 PdC
    • Evaluar la actividad antitumoral de LAVA-051 en la RP2D respectiva en cohortes separadas con LCC, MM o LMA recidiva/refractaria con expresión celular tumoral positiva para CD1d.
    • Investigar la seguridad y tolerabilidad de LAVA-051 en estas cohortes de expansión respectivas.
    E.2.2Secondary objectives of the trial
    Part 1 Dose Escalation
    • To explore the antitumor activity of LAVA-051.
    Part 1 Dose Escalation and Part 2 PoC
    • To evaluate the pharmacokinetics of LAVA-051.
    • To evaluate the pharmacodynamics of LAVA-051.
    • To evaluate the immunogenicity of LAVA-051.
    Parte 1 Escalada de la dosis
    • Explorar la actividad antitumoral de LAVA-051.
    Parte 1 Escalada de la dosis y Parte 2 PdC
    • Evaluar la farmacocinética de LAVA-051.
    • Evaluar la farmacodinámica de LAVA-051.
    • Evaluar la inmunogenicidad de LAVA-051.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient must be 18 years of age inclusive or above, at the time of signing the informed consent
    2. Confirmed tumor cell CD1d positivity/expression
    3. Patients with documented diagnosis of CLL, MM, or AML who have failed to respond to or who have relapsed after prior therapy and are not amenable to standard treatments or for whom no standard treatments are available. Patients may have undergone prior cell therapy
    3.1. CLL/ Small Lymphocytic Lymphoma (SLL) patients:
    3.1.1. Proven disease by the presence of CD5+CD19+CD23+ clonal B cells in blood, bone marrow and/or lymph nodes.
    3.1.2. Patients should meet criteria for requiring therapy (the most recent iwCLL guidelines (39)) and must have measurable disease (measurable lesion > 1.5 cm diameter in at least one dimension) and/or lymphocytosis
    3.1.3. Patients must have failed at least one line of targeted therapy (ibrutinib or venetoclax or similar) and not be amenable to- or for whom no further standard treatment is available
    3.1.4. Patients with Richter’s transformation can be included in Part 1 of the trial but not in Part 2 of the trial
    3.2. MM patients:
    3.2.1. Documented diagnosis of MM and measurable disease (see Appendix 6, Section 13.6.2; measurable disease is defined as serum monoclonal paraprotein (M-protein) ≥ 5 g/L or urine M-protein ≥ 200 mg/24 hours or abnormal free light chain (FLC) ratio with involved FLC > 100 mg/L or proven plasmacytoma by biopsy*)
    3.2.2. Documented progression or refractory multiple myeloma as per the IMWG uniform response criteria (see Appendix 6, Section 13.6.3) following ≥3 prior regimens that include at least one immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody in any order.
    * If plasmacytoma is the only measurable parameter, the patient is not allowed to be included in the trial, because of difficult response evaluation.
    3.3. AML patients:
    3.3.1. Patients with relapsed/refractory AML (defined using World Health Organization [WHO] 2016 criteria, WHO classification definition of ≥ 20% blasts) of any type with the exception of acute promyelocytic leukemia (APL; AML M3). [Patients with a myelomonocytic or monocytic lineage (M4, M5) are most likely to be positive for the CD1d expression].
    3.3.2. Patients with relapsed/refractory AML (defined using either recurrence of disease after a CR, or failure to achieve CR with initial therapy) after at least one prior AML therapy.
    4. Males or non-pregnant, non-breastfeeding females who are:
    a. Surgically sterile (hysterectomy, bilateral oophorectomy or bilateral salpingectomy, vasectomy).
    b. Female of childbearing potential with a negative pregnancy test prior to first dosing and compliant with a highly effective contraceptive regimen (i.e., pregnancy rate of <1% per year: oral contraceptives, intrauterine device (IUD), intrauterine hormone-releasing systems; refer to Appendix 4, Section 13.4 for more details) from signing of the informed consent form (ICF) through 90 days after the last IMP administration. Abstinence is not considered an adequate contraceptive regimen.
    c. Female, postmenopausal defined as continuous amenorrhea for at least 12 consecutive months without an alternative medical cause and a serum follicle-stimulating hormone (FSH) measurement of > 40 IU/L).
    d. Male, compliant with an effective contraceptive regimen (i.e., use of male condom with female partner and assuring use of an additional highly effective contraceptive method with a failure rate of <1% per year when having sexual intercourse with a woman of childbearing potential who is not currently pregnant following from signing of the ICF through 90 days after the last IMP administration; refer to Appendix 4, Section 13.4 for more details) from signing of the ICF through 90 days after the last IMP administration). Abstinence is not considered an adequate contraceptive regimen.
    e. Male, refraining from donating sperm following from signing of the ICF through 90 days after the last IMP administration.
    5. Predicted life-expectancy of ≥ 3 months
    6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
    7. Adequate renal function (estimated glomerular filtration rate [eGFR] per local laboratory > 40 mL/min/1.73m2), hepatic function [(total bilirubin ≤ 2 times upper limit of normal (ULN), unless in patients with known Gilbert’s syndrome who must have total bilirubin ≤ 3 times ULN; AST and ALT ≤ 3.0 times ULN] and hematological function (neutrophils ≥ 1 x109/L; platelet count ≥ 75x109/L, unless due to bone marrow tumor infiltration, in which case it must be ≥ 50x109/L)
    8. Capable of giving signed and dated informed consent prior to initiation of any trial-related procedure that is not considered Standard of Care which includes compliance with the requirements and restrictions listed in the ICF and in the protocol
    Los pacientes son elegibles para ser incluidos en el ensayo solo si se aplican todos los criterios siguientes (tanto para la Parte 1 como para la Parte 2 del ensayo):
    El paciente debe tener 18 años o más, inclusive, en el momento de firmar el consentimiento informado.
    Confirmación de positividad/expresión de células tumorales CD1d. Nota: se hará un cribado en los pacientes para detectar CD1d.
    Pacientes con diagnóstico documentado de LCC, MM o LMA que no han respondido o que han recaído después de terapia previa y no son susceptibles a tratamientos estándar o para los que no hay tratamientos estándar disponibles. Los pacientes pueden haberse sometido a terapia celular previa.
    Pacientes con LCC/linfoma linfocítico de células pequeñas:
    Enfermedad comprobada por la presencia de células B clonales CD5+CD19+CD23+ en sangre, médula ósea y/o ganglios linfáticos. Los pacientes con la transformación de Richter se pueden incluir en la Parte 1 del ensayo, pero no en la Parte 2.
    Los pacientes deben cumplir los criterios para requerir terapia y deben tener enfermedad mensurable y/o linfocitosis.
    Los pacientes deben haber rechazado al menos una línea de terapia dirigida y no ser susceptibles de recibir o no disponer de otro tratamiento estándar.

    Pacientes con MM:
    Diagnóstico documentado de MM y enfermedad mensurable. Si el único parámetro mensurable es el plasmocitoma, no se permite incluir al paciente en el ensayo, debido a la difícil evaluación de la respuesta.
    Progresión documentada o MM refractaria según los criterios de respuesta uniformes del IMWG siguiendo 3 planes previos que incluyen al menos un fármaco inmunomodulador, un inhibidor de proteasoma y un anticuerpo monoclonal anti-CD38 en cualquier orden.

    Pacientes con LMA:
    Pacientes con LMA recidiva/refractaria de cualquier tipo, con excepción de la leucemia promielocítica aguda. [Los pacientes con un linaje mielomonocítico o monocítico tienen más probabilidades de ser positivos para la expresión de CD1d].
    Pacientes con LMA recidiva/refractaria (definida usando la recurrencia de la enfermedad después de una remisión completa , o la incapacidad de alcanzar la RC con terapia inicial) después de al menos una terapia previa de LMA.
    Hombres o mujeres no embarazadas, no lactantes que sean:
    Quirúrgicamente estériles (histerectomía, ooforectomía bilateral o salpingectomía bilateral, vasectomía)
    Mujer con potencial reproductivo con una prueba de embarazo negativa antes de la primera dosis y que cumple con un régimen anticonceptivo altamente eficaz (es decir, tasa de embarazo del 1 % por año: anticonceptivos orales, dispositivo intrauterino, sistemas de liberación hormonal intrauterinos) desde la firma del formulario de consentimiento informado hasta 90 días después de la última administración del medicamento en investigación. La abstinencia no se considera un régimen anticonceptivo adecuado.
    Mujer, postmenopáusica definido como amenorrea continua durante al menos 12 meses consecutivos sin una causa médica alternativa y una medición de hormona foliculoestimulante sérica (FSH) de > 40 UI/L).
    Hombre, que cumple con un régimen anticonceptivo eficaz (es decir, uso de preservativo masculino con la pareja femenina y garantía del uso de un método anticonceptivo adicional altamente eficaz con una tasa de fracaso del 1 % al año al tener relaciones sexuales con una mujer con potencial de procreación que no está embarazada después de firmar el FCI hasta 90 días después de la última administración del medicamento en investigación) desde la firma del FCI hasta 90 días después de la última administración del medicamento en investigación). La abstinencia no se considera un régimen anticonceptivo adecuado.
    Hombre, absteniéndose de donar esperma después de firmar el FCI durante 90 días después de la última administración del medicamento en investigación.
    5. Esperanza de vida prevista de ≥ 3 meses.
    6. Estado funcional del Grupo Oncológico Cooperativo del Este (ECOG) de 0 o 1.
    7. Función renal adecuada (tasa estimada de filtración glomerular [TFGe] por laboratorio local> 40 mL/min/1,73m2), función hepática [(bilirrubina total ≤ 2 veces el límite superior de lo normal (ULN), excepto en pacientes con síndrome de Gilbert conocido que debe tener bilirrubina total ≤ 3 veces ULN; aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) ≤ 3,0 veces ULN] y función hematológica (neutrófilos 1 x109/L; recuento de plaquetas 75x109/L, a menos que se deba a una infiltración tumoral en la médula ósea, en cuyo caso debe ser ≥50x109/L)
    8. Capaz de dar consentimiento informado firmado y fechado antes de iniciar cualquier procedimiento relacionado con el ensayo que no se considere atención médica estándar que incluya el cumplimiento de los requisitos y restricciones enumerados en el FCI y en el protocolo.
    E.4Principal exclusion criteria
    1. Prior allogeneic bone marrow transplant as long as the patient still has active acute or chronic graft versus host disease requiring >10 mg prednisone or equivalent corticosteroids.
    2. Concomitant malignancies except carcinoma in situ, basal or squamous cell skin carcinoma. Patients who had no evidence of disease from another primary cancer for 2 or more years are allowed to participate in the trial. Localized non-metastatic prostate cancer, not requiring systemic treatment, and for which no local treatment is planned, is allowed.
    3. Uncontrolled or severe intercurrent medical condition.
    4. Known uncontrolled central nervous system involvement.
    5. Patient has any active-, uncontrolled-, or suspected infection.
    6. A significant history of renal, neurologic, psychiatric, pulmonary, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in the opinion of the investigator would adversely affect his/her participating in this trial.
    7. Unstable cardiovascular function defined as: (a) symptomatic ischemia, or (b) uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic agents are excluded; 1st degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block (left anterior fascicular block /right bundle branch block) will not be excluded), or (c) congestive heart failure New York Heart Association Class ≥ 3, or (d) myocardial infarction within 3 months.
    8. Previous treatment with radiotherapy, immunotherapy, or chemotherapy in the 2 weeks prior to initial IMP administration.
    9. Previous treatment with biological therapy or with an investigational product in the 4 weeks prior to initial IMP administration.
    10. Previous treatment with an aminobisphosphonate IV (e.g., ibandronate, pamidronate, zoledronate etc) within 4 weeks prior to initial IMP.
    11. Previous treatment of any systemic immunosuppressant within 2 weeks prior to initial IMP administration, with the exception of systemic corticosteroid use up to oral dose of 10 mg prednisolone daily (or equivalent for other steroids).
    12. Previous treatment with live or live attenuated vaccines within 2 weeks prior to initial IMP administration. Other (new) types of vaccines need to be evaluated as to their mode of action.
    13. Known non-CLL/MM/AML related pre-existing clinically relevant immunodeficiency disorders.
    14. Positive serological testing for Human Immunodeficiency Virus (HIV) antibody, hepatitis B surface antigen [HBsAg] and hepatitis B core antibody (anti-HBc) negative, and hepatitis C virus antibody. Patients who are positive for anti-HBc or hepatitis C antibody may be included if they have a negative PCR within 6 weeks prior to initial IMP administration. Those who are PCR positive will be excluded.
    15. Known allergies, hypersensitivity, or intolerance to the excipients of the IMP.
    16. Major surgery within 4 weeks of initial IMP administration or planned surgery during the time the patient is expected to participate in the trial.
    17. Known ongoing drug and alcohol abuse in the opinion of the investigator.
    Se excluye a los pacientes del ensayo si se aplica alguno de los siguientes criterios:
    1. Trasplante de médula ósea alogénico previo siempre y cuando el paciente aún tenga enfermedad aguda o crónica activa de injerto frente a enfermedad huésped que requiera >10 mg de prednisona o corticosteroides equivalentes.
    2. Neoplasias malignas concomitantes, excepto carcinoma de piel in situ, basal o de células escamosas. A los pacientes que no tuviesen evidencia de enfermedad de otro cáncer primario durante 2 años o más se les permite participar en el ensayo. Se permite el cáncer de próstata no metastásico localizado, que no requiere tratamiento sistémico y para el que no está previsto tratamiento local.
    3. Condición médica intercurrente grave o no controlada.
    4. Conocida afectación incontrolada del sistema nervioso central.
    5. El paciente tiene cualquier infección activa, incontrolada o sospechosa.
    6. Antecedentes significativos de enfermedad renal, neurológica, psiquiátrica, pulmonar, endocrinológica, metabólica, inmunológica, cardiovascular o hepática que, en opinión del investigador, afectaría de modo adverso a su participación en este ensayo.
    7. Función cardiovascular inestable definida como: (a) isquemia sintomática, o (b) anomalías de conducción clínicamente significativas no controladas (es decir, se excluye la taquicardia ventricular con agentes antiarrítmicos; no se excluirá el bloqueo auriculoventricular de primer grado o el bloqueo fascicular anterior izquierdo/bloqueo de rama derecha asintomático (bloqueo fascicular anterior izquierdo/bloqueo de rama derecha)), o (c) insuficiencia cardíaca congestiva Clase de la Asociación Cardíaca de Nueva York ≥ 3, o (d) infarto de miocardio en un plazo de 3 meses.
    8. Tratamiento previo con radioterapia, inmunoterapia o quimioterapia en las 2 semanas previas a la administración inicial de medicamento en investigación.
    9. Tratamiento previo con terapia biológica o con un producto en investigación en las 4 semanas previas a la administración inicial del medicamento en investigación.
    10. Tratamiento previo con un aminobisfosfonato IV (por ejemplo, ibandronato, pamidronato, zoledronato, etc.) dentro de las 4 semanas previas al medicamento en investigación inicial.
    11. Tratamiento previo de cualquier inmunosupresor sistémico dentro de las 2 semanas previas a la administración inicial del medicamento en investigación, con la excepción del uso de corticosteroides sistémicos hasta la dosis oral de 10 mg de prednisolona diaria (o equivalente para otros esteroides).
    12. Tratamiento previo con vacunas vivas o vivas atenuadas en las 2 semanas previas a la administración inicial del medicamento en investigación.Es necesario evaluar otros tipos (nuevos) de vacunas en cuanto a su modo de acción.
    13. Trastornos de inmunodeficiencia preexistentes clínicamente relevantes conocidos no relacionados con LCC/MM/LMA.
    14. Pruebas serológicas positivas para anticuerpos del virus de inmunodeficiencia humana (VIH), antígeno superficial de la hepatitis B [HBsAg] y anticuerpo central de la hepatitis B (anti-HBc) negativas, y anticuerpo del virus de la hepatitis C. Los pacientes que son positivos para anticuerpos anti-HBc o hepatitis C pueden ser incluidos si tienen una PCR negativa dentro de 6 semanas antes de la administración inicial del medicamento en investigación. Aquellos que tengan PCR positiva serán excluidos.
    15. Alergias conocidas, hipersensibilidad o intolerancia a los excipientes del medicamento en investigación.
    16. Cirugía mayor dentro de las 4 semanas de la administración inicial del medicamento en investigación o cirugía planificada durante el tiempo que se espera que el paciente participe en el ensayo.
    17. Abuso continuado de drogas y alcohol conocido en opinión del investigador
    E.5 End points
    E.5.1Primary end point(s)
    Part 1 Dose Escalation
    • Frequency and severity of Adverse Events using the Common Terminology Criteria and grading for Adverse Events (CTCAE version 5.0) and American Society for Transplantation and Cellular Therapy (ASTCT) grading for CRS.
    • Frequency and type of dose-limiting toxicity (DLT).
    Part 2 PoC
    • Antitumor Response:
    o For CLL patients: Response according to the most recent International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guideline (Appendix 6, Section 13.6.1).
    o For MM patients: Response according to the most recent International Myeloma Working Group (IMWG) criteria (Appendix 6, Section 13.6.3).
    o For AML patients: Response according to the most recent European LeukemiaNet (ELN) criteria (Appendix 6, Section 13.6.4).
    • Frequency and severity, including CTCAE and ASTCT grading, of AEs.
    Parte 1 Escalada de la dosis
    • Frecuencia y gravedad de los AA utilizando la versión 5.0 de CTCAE y la clasificación ASTCT para SLC.
    • Frecuencia y tipo de TLD.
    Parte 2 PdC
    • Respuesta antitumoral:
    o Para los pacientes con LCC: Respuesta según la guía más reciente del Taller Internacional sobre Leucemia Linfocítica Crónica (iwLCC).
    o Para los pacientes con MM: Respuesta según los criterios más recientes del Grupo Internacional de Trabajo sobre el Mieloma (IMWG).
    o Para los pacientes con LMA: Respuesta según los criterios más recientes de la European LeukemiaNet (ELN).
    • Frecuencia y gravedad, incluidas la clasificación CTCAE y ASTCT de los AA.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1 AEs are monitored continuously from ICF signature until the FU visit. DLT is defined as an AE and is occurring during Cycle 1 (28 days). Part 2 Anti-tumor response will take place: 1) CLL: screening, Peripheral blood at predose of C1-6D1, CT-scan of neck/chest/abdomen in the C3-4th wk, Peripheral Blood MRD at predose of C4D1, BM biopsy in case of suspected remission based on CT analysis and blood evaluation and EoT. 2) MM: screening, Blood/24-h urine at predose of C1-6D1, BM biopsy in C3-4th wk and for confirmation of CR or at disease progression, CT-scan as clinically indicated to document progression and in the C3-4th wk, PE at predose of C1-6D1, and EoT. 3) AML: screening, Peripheral blood at predose of C1-6D1, BM biopsy in the C3-4th wk, MRD of C4D1 and EoT
    Parte 1 AEs se controlan continuamente desde firma de ICF hasta la visita a la UF DLT se define como un EA ocurre durante el ciclo 1 Parte 2 respuesta antitumoral tendrá lugar CLL detección sangre periférica en predosis de C1-6D1 tomografía computarizada del cuello tórax abdomen en semana C3-4a ERM de sangre periférica predosis de C4D1 BM biopsia caso de sospecha de remisión basada análisis de TC evaluación de sangre EoT MM detección sangre orina de 24 h antes de dosis de C1-6D1 biopsia de MO en semana C3-4 para confirmación de RC o en progresión de enfermedad tomografía computarizada según esté clínicamente indicado para documentar progresión en C3- 4ª semana PE en predosis de C1-6D1 EoT AML detecció sangre periférica en predosis de C1-6D1 biopsia de MO en semana C3-4 ERM de C4D1 y EoT
    E.5.2Secondary end point(s)
    Part 1 Dose Escalation
    • For CLL patients: Response according to the most recent iwCLL guideline
    • For MM patients: Response according to the most recent IMWG criteria
    • For AML patients: Response according to the most recent most recent ELN criteria criteria
    Part 1 Dose Escalation and Part 2 PoC
    • Pharmacokinetic parameters.
    • Pharmacodynamic markers (binding of LAVA-051 to Vγ9Vδ2-T cells and CD1d positive tumor cells, frequency and activation status of Vγ9Vδ2-T cells and iNKT cells, induction of activation of Vγ9Vδ2-T cells ex vivo and general immune monitoring) and serum cytokines (IL-1β, IL-2, IL-6, IL-8, TNF-α, IFN-γ) and CD1d and CD277 expression on tumor cells.
    • Presence or development of anti-LAVA-051 antibodies.
    Parte 1 Escalada de la dosis
    • Para los pacientes con LCC: Respuesta según las directrices más recientes de iwLCC.
    • Para los pacientes con MM: Respuesta según los criterios más recientes de IMWG.
    • Para los pacientes con LMA: Respuesta según los criterios más recientes de ELN.
    Parte 1 Escalada de la dosis y Parte 2 PdC
    • Parámetros farmacocinéticos.
    • Marcadores farmacodinámicos.
    • Presencia o desarrollo de anticuerpos anti LAVA-051.
    E.5.2.1Timepoint(s) of evaluation of this end point
    PK collection: SCR, C1D1 at predose, C1D1 1h after SoI, EoI, 15min after EoI, 30min after EoI, 1h, 1,5h, 2h, 3h, 4h, 6h, 8h and 12h after EoI, 24h, 36h, 48h, 72h and 96h after SoI; C1D2-D4-D6 at predose and EoI; C1D3 predose, EoI, 24h and 48h after SOI; C2D1 predose, EoI, 1h, 2h and 4h after EoI, 24h and 48h after SoI; C3-6D1 predose and EoI; EoT
    PD collection: SCR, C1D1 predose, 2h after EoI, 24h, 48h, 72h and 96h after SoI; C1D2-D4-D6 predose; C1D3 predose, 24h and 48h after SoI; C2D1 predose, 24h and 48h after SoI; C3-6D1 predose; EoT
    Lava antibodies collection: SCR, C1D1, C1D4, C2-6D1 and EoT.
    Recolección de PK: SCR, C1D1 en la predosis, C1D1 1h después de la EoI, EoI, 15min después de la EoI, 30min después de la EoI, 1h, 1,5h, 2h, 3h, 4h, 6h, 8h y 12h después de la EoI, 24h, 36h, 48h, 72 y 96 horas después de SoI; C1D2-D4-D6 en predosis y EoI; Predosificación de C1D3, EoI, 24 y 48 horas después de SOI; Predosificación de C2D1, EoI, 1h, 2h y 4h después de EoI, 24h y 48h después de SoI; Predosis de C3-6D1 y EoI; EoT
    Recolección de DP: SCR, predosis de C1D1, 2h después de la EoI, 24h, 48h, 72h y 96h después de la SoI; Predosis de C1D2-D4-D6; Predosificación de C1D3, 24 y 48 horas después de SoI; Predosificación de C2D1, 24 y 48 horas después de SoI; Predosis de C3-6D1; EoT
    Colección de anticuerpos de lava: SCR, C1D1, C1D4, C2-6D1 y EoT.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability, immunogenicity, antitumor activity
    Tolerabilidad, inmunogenicidad, actividad antitumoral
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Estudio de aumento de dosis y expansión de cohortes
    Dose escalation and cohort expansion study
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other 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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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 trial completion is defined as LPLV. For patients still on treatment beyond their maximum planned treatment duration follow up in the trial will end at the date of database lock of Part 2.
    La finalización de la prueba se define como LPLV. Para los pacientes que aún reciben tratamiento más allá de la duración máxima de tratamiento planificada, el seguimiento del ensayo finalizará en la fecha de bloqueo de la base de datos de la Parte 2.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 52
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state17
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 82
    F.4.2.2In the whole clinical trial 102
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the request of the treating physician and in consultation with the sponsor, continued access to IMP might be offered beyond the planned treatment duration of 24 weeks for individual patients with ongoing disease control provided that there is availability of IMP allocated to this trial
    A petición del médico tratante y en consulta con el patrocinador, se puede ofrecer acceso continuo a IMP más allá de la duración planificada del tratamiento de 24 semanas para pacientes individuales con control continuo de la enfermedad, siempre que haya disponibilidad de IMP asignado a este ensayo.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-12-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-09-06
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