Combinación intratecal de anticuerpo biespecífico PD-1/CTLA-4 y pemetrexed para metástasis leptomeníngeas.
Un estudio clínico de fase I/II de una combinación intratecal de anticuerpo biespecífico PD-1/CTLA-4 y pemetrexed para metástasis leptomeníngeas de tumores sólidos.
Leptomeningeal metastasis, characterized by tumor cells infiltrating and proliferating in the subarachnoid space, represents a distinct pattern of central nervous system involvement and is a fatal complication of malignant tumors. This phase I/II study is to evaluate the recommended dose, safety, feasibility, and therapeutic response of intrathecal Programmed Death-1 (PD-1)/Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) bispecific antibodies combined with pemetrexed in patients with leptomeningeal metastasis.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
Leptomeningeal metastasis is a severe complication of advanced cancer, traditionally managed with intrathecal chemotherapy. Recently, immunotherapy has emerged as a promising treatment for solid tumors. The preliminary results from our previous study on PD-1 combined with pemetrexed intrathecal administration showed safety and feasibility for leptomeningeal metastasis from solid tumors with potential activity. Currently, a clinical trial in Switzerland is evaluating the efficacy of dual immunotherapy (PD-1 plus CTLA-4 inhibitors) administered intrathecally for leptomeningeal metastasis. Cadonilimab, the world's first PD-1/CTLA-4 bispecific antibody, has shown favorable safety and efficacy in clinical practice, further supporting its potential in this setting. The primary objectives are to determine the recommended dose of intrathecal cadonilimab in combination with pemetrexed and to assess safety based on the incidence of treatment-related adverse events. Clinical response rate, disease control rate, and overall survival are also evaluated. Patients undergo cerebrospinal fluid and blood specimen collection to evaluate potential clinical, molecular, and/or immune predictors of treatment efficacy and safety.
Tipo de estudio
Inscripción (Estimado)
Fase
- Fase 2
- Fase 1
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Guozi Yang, PhD, MD
- Número de teléfono: +8615804302755
- Correo electrónico: 2023621057@gzhmu.edu.cn
Copia de seguridad de contactos de estudio
- Nombre: Zhenyu Pan, PhD, MD
- Número de teléfono: +8617702171708
- Correo electrónico: dr-zypan@163.com
Ubicaciones de estudio
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Beijing, Porcelana, 101100
- Reclutamiento
- Beijing Chest Hospital, Capital Medical University
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Contacto:
- Zhenyu Pan, Ph.D.
- Número de teléfono: +8615804302753
- Correo electrónico: dr-zypan@163.com
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Investigador principal:
- Zhenyu Pan
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Shanghai, Porcelana
- Activo, no reclutando
- Jinshan Hospital, Fudan University
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Guangdong
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Huizhou, Guangdong, Porcelana, 516000
- Reclutamiento
- The Affiliated Huizhou Hospital, Guangzhou Medical University
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Contacto:
- Zhenyu Pan, PhD, MD
- Número de teléfono: +8618718178286
- Correo electrónico: dr-zypan@163.com
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Contacto:
- Guozi Yang, PhD, MD
- Número de teléfono: +8615804302755
- Correo electrónico: 2023621057@gzhmu.edu.cn
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
- Histologically or cytologically confirmed diagnosis of solid tumors; Cerebrospinal fluid cytopathology is positive.
- Male or female aged between 21 and 75 years; Normal liver and kidney function; WBC≥4000/mm3, Plt≥100000/mm3.
- No history of severe nervous system disease; No severe dyscrasia.
Exclusion Criteria:
- Any evidence of nervous system failure, including severe encephalopathy, grade 3 or 4 leukoencephalopathy on imaging, and Glasgow Coma Score less than 11.
- Any evidence of extensive and lethal progressive systemic diseases without effective treatment.
- A history of HIV or AIDS, acute or chronic hepatitis B or C infection, previous anti-PD1 therapy-induced pneumonitis, or have ongoing >Grade 2 adverse events of such therapy; or ongoing autoimmune disease that required systemic treatment in the past 2 years.
- The first month to treatment, as well as during induction and consolidation therapy, new drugs effective against leptomeningeal metastases were used, excluding those previously administered. These primarily included small molecule targeted therapies, such as EGFR-TKI/ALK-TKI drugs like Osimertinib and Lorlatinib.
- Patients with poor compliance or other reasons that were unsuitable for this study.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: N / A
- Modelo Intervencionista: Asignación de un solo grupo
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: PD-1/CTLA-4 Bispecific Antibody with Pemetrexed
This study is a prospective, single-arm, Phase I/II clinical trial. The primary objective is to determine the recommended Phase II dose (RP2D) for the intrathecal combination of PD-1/CTLA-4 bispecific antibody with pemetrexed and and safety based on the incidence of treatment-related adverse events. Clinical response rate (CRR), disease control rate (DCR) and overall survival (OS) are also evaluated. Patients will have cerebrospinal fluid (CSF) and blood specimen collection for the evaluation of predictors (clinical, molecular, and/or immune) of the efficacy and safety of this regimen. |
Intrathecal injection of PD-1/CTLA-4 bispecific antibody was administered every two weeks for six weeks during the induction phase, followed by monthly injections during the maintenance phase, until recurrence or death. Pemetrexed was administrated by intrathecal injection, first as induction therapy, twice per week for 2 weeks, followed by consolidation therapy, once per week for 4 weeks, then maintenance therapy, once per month until the patient's death, leptomeningeal metastasis progresses, or intolerable severe adverse events occurred. |
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Recommended Phase II Dose (RP2D)
Periodo de tiempo: Dose limiting toxicity was assessed during the first 6 weeks after the first intrathecal administration.
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The recommended phase II dose. The dose limiting toxicity was defined as ≥ grade 3 neurological toxicities (e.g., meningitis) or other grade 4 toxicity. |
Dose limiting toxicity was assessed during the first 6 weeks after the first intrathecal administration.
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Incidence of treatment-related adverse events
Periodo de tiempo: From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months
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The incidence of treatment-related adverse events were measured for determining tolerability and safety. Adverse events (AEs) are evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE). Events of grade 3-5 are defined as moderate and severe adverse events |
From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months
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Otras medidas de resultado
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Clinical response rate
Periodo de tiempo: Time Frame: From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months
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The response assessment in neuro-oncology criteria (RANO) proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study. |
Time Frame: From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months
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Disease control rate (DCR)
Periodo de tiempo: From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months.
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Disease control rate was defined as proportion of patients achieving clinical response or stable disease. Clinical response and stable disease were determined based on the RANO proposal evaluation criteria which have been established and published on Neuro Oncol. |
From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months.
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Overall survival(OS)
Periodo de tiempo: From the enrollment of this study until date of death from any cause, whichever came first, or the last follow-up (at least 6 months)
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Overall survival was recorded since the date of patient enrollment. All patients were followed up until death or the end of the study. |
From the enrollment of this study until date of death from any cause, whichever came first, or the last follow-up (at least 6 months)
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Colaboradores e Investigadores
Patrocinador
Colaboradores
Investigadores
- Investigador principal: Zhenyu Pan, PhD, MD, Jinshan Hospital Fudan University
Publicaciones y enlaces útiles
Publicaciones Generales
- Pan Z, Yang G, Cui J, Li W, Li Y, Gao P, Jiang T, Sun Y, Dong L, Song Y, Zhao G. A Pilot Phase 1 Study of Intrathecal Pemetrexed for Refractory Leptomeningeal Metastases From Non-small-cell Lung Cancer. Front Oncol. 2019 Aug 30;9:838. doi: 10.3389/fonc.2019.00838. eCollection 2019.
- Glitza Oliva IC, Ferguson SD, Bassett R Jr, Foster AP, John I, Hennegan TD, Rohlfs M, Richard J, Iqbal M, Dett T, Lacey C, Jackson N, Rodgers T, Phillips S, Duncan S, Haydu L, Lin R, Amaria RN, Wong MK, Diab A, Yee C, Patel SP, McQuade JL, Fischer GM, McCutcheon IE, O'Brien BJ, Tummala S, Debnam M, Guha-Thakurta N, Wargo JA, Carapeto FCL, Hudgens CW, Huse JT, Tetzlaff MT, Burton EM, Tawbi HA, Davies MA. Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results. Nat Med. 2023 Apr;29(4):898-905. doi: 10.1038/s41591-022-02170-x. Epub 2023 Mar 30.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades del Sistema Nervioso
- Neoplasias por sitio
- Neoplasias
- Neoplasias del Sistema Nervioso
- Neoplasias meníngeas
- Neoplasias del Sistema Nervioso Central
- Carcinomatosis meníngea
- Aminoácidos, péptidos y proteínas
- Compuestos heterocíclicos
- Compuestos heterocíclicos, 2 anillos
- Compuestos heterocíclicos, anillo fusionado
- Guanina
- Hipoxantino
- Purinones
- Purinas
- Glutamatos
- Aminoácidos, ácido
- Aminoácidos
- Aminoácidos, dicarboxílico
- Pemetrexed
Otros números de identificación del estudio
- IMPACT
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Información sobre medicamentos y dispositivos, documentos del estudio
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