Estudio en fase I/II, abierto, de escalada de dosis y expansión de la dosis de enzomenib (DSP-5336) en pacientes con leucemia aguda y otras neoplasias malignas hematológicas seleccionadas, con y sin reordenamiento del gen de la leucemia de linaje mixto (MLL) o mutación en el gen de la nucleofosmina 1 (NPM1)
ESTADO CLÍNICO
Reclutando
FASE/S DEL ENSAYO
Fase I-II
PATOLOGÍA
Leucemia mieloide aguda, Linfoma, Leucemia
CENTRO INVESTIGADOR
MD Anderson Cancer Center Madrid
INVESTIGADOR PRINCIPAL
Adolfo de la Fuente Burguera
FECHA DE APERTURA
Septiembre, 2023
FECHA DE CIERRE
,
CRITERIOS DE INCLUSIÓN
Para los pacientes de la fase I: Participantes con un diagnóstico confirmado de LMA, LLA o leucemia aguda de linaje ambiguo recidivante o resistente, cuya enfermedad haya progresado después de tratamientos estándar disponibles que son activos frente a la LMA, LLA o leucemia aguda de linaje ambiguo. Los participantes deben tener una fusión de KMT2A (MLL) o mutación de NPM1 documentada, incluidos aquellos con alteraciones genómicas de FLT3 y/o mutaciones de IDH1/2 coexistentes. A los participantes que sean candidatos para un trasplante de células madre se les debe haber ofrecido esta opción terapéutica. ¿¿Para todos los pacientes: ¿Tener una esperanza de vida estimada de ¿3 meses, según la evaluación del investigador.¿ Para todos los pacientes: Las mujeres con capacidad de concebir deben presentar un resultado negativo en una prueba de embarazo en orina o suero. Para todos los pacientes: Deben comprometerse a utilizar un método anticonceptivo muy eficaz o 2 métodos anticonceptivos aceptables (cada miembro de la pareja un método) o a usar medidas de prevención del embarazo (es decir, practicar la abstinencia sexual, cuando esta forme parte del estilo de vida habitual y preferido del paciente) durante el estudio y durante 6 meses (tanto hombres como mujeres) después de la última dosis del fármaco del estudio, si se trata de pacientes de sexo masculino o femenino con capacidad de concebir. Para todos los pacientes: Tener muestras de médula ósea adecuadas para el análisis genómico (p. ej., reordenamientos de MLL o mutaciones de NPM1) de las alteraciones genéticas de la LMA o LLA. Nota: Si una muestra de médula ósea es insuficiente, se debe proporcionar una muestra de tejido alternativo adecuado (p. ej., sangre periférica). Para los pacientes de la fase II: Participantes con un diagnóstico confirmado de LMA o LLA recidivante o resistente de acuerdo con la clasificación de la OMS de 2022, determinado mediante revisión anatomopatológica en el centro de tratamiento, con una proporción de blastocitos ¿5 % en la evaluación morfológica de la médula ósea. Los pacientes no deben haber estado expuestos previamente a un inhibidor de la menina Los pacientes deben haber recibido tratamientos de referencia clínicamente aplicables con beneficio de supervivencia confirmado. Para los pacientes de la fase II: Tener una fusión de KMT2A (MLL) o una mutación de NPM1 documentada evaluada en el momento de la recidiva o inmediatamente antes de la determinación de la resistencia. ¿¿Para todos los pacientes: ¿Tener ¿18 años.¿ En los países y centros donde esté permitido, se podrá inscribir a pacientes con leucemia aguda de ¿12 años de edad que pesen ¿40 kg, para que reciban DSP-5336 en monoterapia. Para todos los pacientes: Tener un estado funcional según el Grupo Oncológico Cooperativo de la Costa Este de EE. UU. (ECOG) ¿2. Para todos los pacientes: Para la administración de DSP-5336 en monoterapia, el recuento de leucocitos (LEU) debe ser inferior a 30 000/¿l en el momento de la inscripción y antes de iniciar el tratamiento del estudio. (Se permitirá la administración de hidroxicarbamida y corticoesteroides con fines de citorreducción antes de la inscripción y durante el tratamiento del estudio). ¿ ¿¿Para todos los pacientes: ¿Cualquier toxicidad relacionada con el tratamiento anterior se debe haber resuelto a grado ¿1 antes de la inscripción, con la excepción de la alopecia o la neuropatía de grado ¿2. ¿¿Para todos los pacientes: ¿Tener una función renal y hepática adecuada en la selección, según lo determinado por: a. Nivel de aclaramiento de creatinina (AcCr) ¿50 ml/min, evaluado mediante la fórmula de Cockcroft-Gault ¿b. Bilirrubina total ¿1,5 veces el límite superior de la normalidad (LSN) (o ¿2,0 veces el LSN para pacientes con síndrome de Gilbert conocido) ¿c. Aspartato aminotransferasa (AST) ¿3,0 veces el LSN ¿d. Alanina aminotransferasa (ALT) ¿3,0¿veces el¿LSN ¿¿Para todos los pacientes: ¿Estar dispuesto a asistir a las visitas del estudio según lo requerido por el protocolo.
CRITERIOS DE EXCLUSIÓN
Have a histologic diagnosis of acute promyelocytic leukemia
Have a cognitive, psychologic, or psychosocial impediment that would impair the ability of the patient to receive therapy according to the protocol, or adversely affect the ability of the patient to comply with the informed consent/assent process, protocol, or protocol-required visits and procedures
Have a history of Grade 2 drug-induced interstitial lung disease or Grade 2 non-infectious pneumonitis within 6 months of starting study treatment.
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336.
Receive concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5. Other antifungals that are used as standard of care to prevent or treat infections are permitted Note: If a patient is on one of the excluded azole class antifungals and can be switched to a permitted azole 7 or more days prior to study, that patient could be allowed on study (Arm B).
Have a known detectable viral load for human immunodeficiency virus or hepatitis C, or evidence of a hepatitis B surface antigen, all being indicative of active infection.
In the opinion of the treating investigator, have any concurrent conditions that could pose an undue medical hazard or interfere with interpretation of study results; these conditions include, but are not limited to: clinically significant non-healing or healing wounds; concurrent congestive heart failure (New York Heart Association Functional Classification Class III or IV; see Section 21.7); concurrent unstable angina; concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation); recent (within the prior 6 months) myocardial infarction; acute coronary syndrome within the previous 6 months; significant pulmonary disease (shortness of breath at rest or on mild exertion), eg, due to concurrent severe obstructive pulmonary disease, concurrent hypertension not controlled with concomitant medication, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 6 months.
Have a history of Torsades de Pointes
Have abnormal ECGs at screening that are clinically significant, such as QTc >480 with QTc corrected according to Fridericias formula [QTcF]).
Are pregnant or breastfeeding or planning to become pregnant Note: Patients who are breastfeeding may be enrolled if they interrupt breastfeeding prior to the first dose of any study drugs and do not feed the baby with breast milk expressed after receiving the first dose of any study drugs. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug. .
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336.
Received a donor lymphocyte infusion within 28 days prior to the first dose of DSP 5336, or receiving immunosuppressive therapy post-HSCT at the time of Screening, or with clinically active GVHD or GVHD requiring active medical intervention other than the use of topical steroids for ongoing cutaneous GVHD.
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336
Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336
Had major surgery within 28 days prior to the first dose of DSP-5336
Have active central nervous system leukemia (prophylactic intrathecal chemotherapy is allowed).
Have any history or complication of interstitial lung disease (for sites in Japan only) and, for clinical sites operating under the European Medicines Agencies, a history of Grade 2 drug-induced interstitial lung disease or Grade 2 non-infectious pneumonitis within 6 months of starting study treatment
Have a known intolerance or hypersensitivity reaction to components of any of the investigational medicinal products
Have a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336 .
Received systemic calcineurin inhibitors within 42 weeks prior to the first dose of DSP 5336.
Have an active and uncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy
Have known severe dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally, including the inability to swallow oral medication
Have a cognitive, psychologic, or psychosocial impediment that would impair the ability of the patient to receive therapy according to the protocol, or adversely affect the ability of the patient to comply with the informed consent/assent process, protocol, or protocol-required visits and procedures
Have a history of Grade 2 drug-induced interstitial lung disease or Grade 2 non-infectious pneumonitis within 6 months of starting study treatment.
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336.
Receive concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5. Other antifungals that are used as standard of care to prevent or treat infections are permitted Note: If a patient is on one of the excluded azole class antifungals and can be switched to a permitted azole 7 or more days prior to study, that patient could be allowed on study (Arm B).
Have a known detectable viral load for human immunodeficiency virus or hepatitis C, or evidence of a hepatitis B surface antigen, all being indicative of active infection.
In the opinion of the treating investigator, have any concurrent conditions that could pose an undue medical hazard or interfere with interpretation of study results; these conditions include, but are not limited to: clinically significant non-healing or healing wounds; concurrent congestive heart failure (New York Heart Association Functional Classification Class III or IV; see Section 21.7); concurrent unstable angina; concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation); recent (within the prior 6 months) myocardial infarction; acute coronary syndrome within the previous 6 months; significant pulmonary disease (shortness of breath at rest or on mild exertion), eg, due to concurrent severe obstructive pulmonary disease, concurrent hypertension not controlled with concomitant medication, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 6 months.
Have a history of Torsades de Pointes
Have abnormal ECGs at screening that are clinically significant, such as QTc >480 with QTc corrected according to Fridericias formula [QTcF]).
Are pregnant or breastfeeding or planning to become pregnant Note: Patients who are breastfeeding may be enrolled if they interrupt breastfeeding prior to the first dose of any study drugs and do not feed the baby with breast milk expressed after receiving the first dose of any study drugs. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug. .
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336.
Received a donor lymphocyte infusion within 28 days prior to the first dose of DSP 5336, or receiving immunosuppressive therapy post-HSCT at the time of Screening, or with clinically active GVHD or GVHD requiring active medical intervention other than the use of topical steroids for ongoing cutaneous GVHD.
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336
Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336
Had major surgery within 28 days prior to the first dose of DSP-5336
Have active central nervous system leukemia (prophylactic intrathecal chemotherapy is allowed).
Have any history or complication of interstitial lung disease (for sites in Japan only) and, for clinical sites operating under the European Medicines Agencies, a history of Grade 2 drug-induced interstitial lung disease or Grade 2 non-infectious pneumonitis within 6 months of starting study treatment
Have a known intolerance or hypersensitivity reaction to components of any of the investigational medicinal products
Have a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336 .
Received systemic calcineurin inhibitors within 42 weeks prior to the first dose of DSP 5336.
Have an active and uncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy
Have known severe dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally, including the inability to swallow oral medication
DESCRIPCIÓN
Fase I: Evaluar la seguridad y tolerabilidad de DSP-5336 en monoterapia en pacientes con LMA, LLA o leucemia aguda de linaje ambiguo recidivante o resistente. Determinar la dosis recomendada para la fase II (DRF2) de DSP-5336 basándose en la menor dosis de DSP-5336 que ejerza el máximo efecto biológico y clínico o la dosis máxima tolerable (DMT), la que sea inferior. Fase II: Evaluar la actividad clínica de DSP-5336 en monoterapia en pacientes con leucemia aguda recidivante/resistente al tratamiento con reordenación en MLL o en pacientes con LMA recidivante/resistente al tratamiento con mutación en NPM1
PALABRAS CLAVE
leucemia, leukemia, npm1
