Hepatic Artery Infusion of Carfilzomib in Participants With Liver Metastatic Disease Previously Treated With Hepatic Artery Infusion Pump Therapy
Phase I Study Evaluating Hepatic Artery Infusion of Carfilzomib in Participants With Liver Metastatic Disease Previously Treated With Hepatic Artery Infusion Pump Therapy
Background:
Cancers that begin in the colon, adrenal glands, or bile ducts may spread to the liver. These liver tumors are often treated using a hepatic artery infusion (HAI) pump. The HAI pump is installed in the artery that goes to the liver; drugs are administered directly to the liver through this pump. But these tumors often return after treatment. Carfilzomib (CFZ) is a drug approved to treat another kind of cancer. Researchers want to find out if this drug may be helpful when administered through the HAI pump directly to the liver for people with colon, adrenal glands, or bile duct cancer that has spread to the liver.
Objective:
To test the safety of carfilzomib (CFZ) delivered via a hepatic artery infusion (HAI) pump directly to the liver in people with cancer in their liver.
Eligibility:
People aged 18 years or older with cancers of the colon, adrenal glands, or bile ducts that spread to the liver and persist after treatment. They must have a functioning hepatic artery infusion (HAI) pump in place from previous treatment of HAI pump therapy.
Design:
Participants will be screened. They will have a physical exam, blood tests, imaging scans, and a test of their heart function. They will also have a test to show how the blood flows through their liver: A radioactive substance will be injected into a vein, and a special camera will take pictures of the blood flow for up to 1 hour.
Participants will receive the study drug for about 6 months. They will visit the clinic once a week. Their HAI pump will be filled with the drug at each visit; the drug will slowly drain from the pump into the liver. Blood tests and imaging scans will be repeated during the study.
Participants will have follow-up visits 1 and 3 months after their last dose of study drug.
An optional liver biopsy (tissue sample) for research purposes may be done before the study drug is given, and again (optional) within 28 days after first receiving the study drug. Individuals may participate in the study even if they do not agree to have the biopsies done.
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Descripción general del estudio
Estado
Estado
Condiciones
Condiciones
Intervención / Tratamiento
Intervención / Tratamiento
Descripción detallada
Background:
- Targeting protein homeostasis with proteasome inhibitors has demonstrated excellent efficacy across multiple pre-clinical cancer models, although translation to patients with solid tumors has consistently failed to yield meaningful responses secondary to new protein synthesis rebound associated with intermittent dosing.
- Implantable pumps for outpatient continuous infusion were developed and culminated in a commercialized product in 1980, though the only drug used to date is floxuridine.
- Carfilzomib (CFZ), a second-generation irreversible 20S core particle proteasome inhibitor, can be delivered by the hepatic artery infusion pump to diminish extra-hepatic systemic clearance and feasibly direct a larger percentage of the total dose to the desired tissues at continuous concentrations.
Objective:
-To establish the safety of hepatic artery infusion (HAI) of carfilzomib (CFZ) in participants with liver metastatic disease who were previously treated with HAI pump therapy
Eligibility:
- Participants with colorectal cancer (CRC), intrahepatic cholangiocarcinoma (ICC), or adrenocortical carcinoma (ACC) with liver metastatic disease not amenable to resection
- Participants must have been treated with HAI floxuridine and already have a surgically inserted HAI pump in place
- Age >= 18 years
- Adequate organ function
Design:
- Open-label, single-center, non-randomized Phase I study
- Treatment with HAI infusion of CFZ will be delivered in cycles of 28 days for up to 6 cycles.
Tipo de estudio
Tipo de estudio
Inscripción (Estimado)
Inscripción
Fase
Fase
- Fase 1
Contactos y Ubicaciones
Estudio Contacto
Estudio Contacto
- Nombre: Kathleen M Smith, R.N.
- Número de teléfono: (240) 858-3531
- Correo electrónico: kathleen.smith3@nih.gov
Copia de seguridad de contactos de estudio
- Nombre: Jonathan M Hernandez, M.D.
- Número de teléfono: (240) 760-6072
- Correo electrónico: jonathan.hernandez@nih.gov
Ubicaciones de estudio
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Maryland
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Bethesda, Maryland, Estados Unidos, 20892
- National Institutes of Health Clinical Center
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Contacto:
- National Cancer Institute Referral Office
- Número de teléfono: 888-624-1937
- Correo electrónico: ncimo_referrals@mail.nih.gov
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Criterios de participación
Criterio de elegibilidad
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
- INCLUSION CRITERIA:
- Participants must have a histologically or cytologically confirmed by pathology report diagnosis of colorectal cancer (CRC), intrahepatic cholangiocarcinoma (ICC), or adrenocortical carcinoma (ACC).
- Participants must have measurable liver-dominant metastatic disease. Note: liver-dominant metastatic disease is defined as >=75% of metastatic disease present in the liver as assessed by the principal investigator.
- Extrahepatic disease should be treated with anticancer therapy, if applicable, and should be stable by RECIST criteria for at least 6 weeks prior to study treatment initiation.
- Participants must have previously undergone hepatic artery infusion pump therapy and have a functioning hepatic artery infusion pump in place.
- Participants must have progressed on, been intolerant of, or have residual disease after HAI floxuridine and appropriate current standard-of-care treatment.
- Age >= 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status <= 2.
- Participants must have an adequate organ and marrow function as defined below:
Leukocytes > 3,000/mcL
Hemoglobin >= 9 mg/dL
Absolute neutrophil count > 1,500/mcL
Platelets > 100,000/mcL
Total bilirubin < 2 X institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) < 2.5 X institutional (ULN)
Alanine aminotransferase (ALT) < 2.5 X institutional (ULN)
Creatinine <2 X institutional (ULN)
- Participants positive for human immunodeficiency virus (HIV) 1/2 antibody must have a negative HIV viral load.
- Participants positive for Hepatitis C (HCV) antibody must have a negative HCV viral load.
- Participants positive for Hepatitis B (HBV) core antibody (HBcAb) must have a negative HBV viral load. Note: Participants positive for Hepatitis B surface antigen (HBsAg) are excluded.
- Women of childbearing potential (WOCBP) must agree to use effective contraception (barrier, hormonal, intrauterine device, abstinence, surgical sterilization) at the study entry and up to 6 months after the last dose of the study drug. A participant may request a male partner to use an effective form of contraception to fulfill this requirement (e.g., condom/barrier).
Men must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 3 months after the last dose of the study drug. A participant may request a female partner to use an effective form of contraception to fulfill this requirement (e.g., intrauterine device, hormonal contraceptives). Men must not freeze or donate sperm within the same period.
- Women who are breastfeeding or plan to breastfeed must agree to discontinue/postpone breastfeeding from study treatment initiation through 2 weeks after the last dose of the study drug.
- Ability of participant to understand and the willingness to sign a written informed consent document.
EXCLUSION CRITERIA:
- Participants with liver metastases amenable to resection.
- Participants who received floxuridine within 6 weeks prior to the study treatment initiation.
- Participants who received any anticancer therapy within 2 weeks prior to the study treatment initiation.
- Participants who received any investigational agents within 4 weeks prior to the study treatment initiation.
- Participants with incontrovertible radiographic evidence of disease progression per the RECIST definition outside of the liver within 3 months prior to the study treatment initiation. Note: Pulmonary lesions less than 1 cm are allowed.
- Prior radiation to the liver (Yttrium-90 [Y-90] or External Beam Radiation Therapy [EBRT]).
- History of allergic reactions attributed to compounds of similar chemical composition to CFZ.
- Positive serum or urine Beta-human chorionic gonadotropin (Beta-HCG) pregnancy test performed at screening.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, evaluated by medical history, electrocardiogram (EKG), physical exam, and laboratory testing, or social situations that would unacceptably increase risk for the participant or impair the ability to evaluate the endpoints of the study or that would limit compliance with study requirements.
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)
Número de brazos
Armas e Intervenciones
Grupo de participantes/brazoGrupo de participantes/brazo |
Intervención / TratamientoIntervención / Tratamiento |
|---|---|
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Experimental: 1/Phase I
Participants with liver metastatic disease will receive continuous administration of carfilzomib via Hepatic Artery Infusion Pump (HAIP) |
Variable doses, continuously administered via Hepatic Artery Infusion Pump (HAIP) for up to 6 cycles |
¿Qué mide el estudio?
Medidas de resultado primarias
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Establish the safety of hepatic artery infusion (HAI) of carfilzomib (CFZ) in participants with liver metastatic disease who were previously treated with HAI pump therapy
Periodo de tiempo: DLT assessment will occur during Cycle 1 (28 days total).Assessment of adverse events will occur from the first study intervention through 28 days after the last study intervention or initiation of a new anti-cancer treatment whichever comes first
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The safety of the study therapy will be evaluated by the maximum dosage at which no more than 1 of 6 participants experience DLT during DLT period (Cycle 1) and by reporting the grade and type of toxicity at each dose level |
DLT assessment will occur during Cycle 1 (28 days total).Assessment of adverse events will occur from the first study intervention through 28 days after the last study intervention or initiation of a new anti-cancer treatment whichever comes first
|
Medidas de resultado secundarias
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Establish the Overall Response Rate (ORR), defined as complete response (CR) + partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST)
Periodo de tiempo: Assessed based on imaging studies prior to starting cycles 1, 3 and 5, Day 28 Safety visit, and 3-month Follow Up visit
|
The proportion of participants with partial response or complete response along with a 95% confidence interval (analyzed in a combined fashion, regardless of dose level). |
Assessed based on imaging studies prior to starting cycles 1, 3 and 5, Day 28 Safety visit, and 3-month Follow Up visit
|
Colaboradores e Investigadores
Patrocinador
Patrocinador
Investigadores
Investigadores
- Investigador principal: Jonathan M Hernandez, M.D., National Cancer Institute (NCI)
Publicaciones y enlaces útiles
Publicaciones Generales
- Larrain CM, Victory JH, Desai PP, Friedman LR, Stepp H, Ashe R, Remmert K, Sinha S, Smith EC, Russell N, Pu T, Eade AV, Burke JF, Ho J, Yaffe MB, Kleiner DE, Schmidt K, Figg WD, Hernandez JM. A rebrand for proteasome inhibition in solid tumors via continuous hepatic artery infusion. JCI Insight. 2025 Nov 4;10(24):e199200. doi: 10.1172/jci.insight.199200. eCollection 2025 Dec 22.
- Jun Y, Xu J, Kim H, Park JE, Jeong YS, Min JS, Yoon N, Choi JY, Yoo J, Bae SK, Chung SJ, Yeo Y, Lee W. Carfilzomib Delivery by Quinic Acid-Conjugated Nanoparticles: Discrepancy Between Tumoral Drug Accumulation and Anticancer Efficacy in a Murine 4T1 Orthotopic Breast Cancer Model. J Pharm Sci. 2020 Apr;109(4):1615-1622. doi: 10.1016/j.xphs.2020.01.008. Epub 2020 Jan 13.
- Zeng TM, Jiang TY, Yang G, Cheng Z, Lou C, Wei W, Tao CJ, Hu S, Wang H, Cui XW, Tan YX, Dong LW, Wang HY, Yuan ZG. Bortezomib in previously treated phosphatase and tension homology-deficient patients with advanced intrahepatic cholangiocarcinoma: An open-label, prospective and single-centre phase II trial. Clin Transl Med. 2024 May;14(5):e1675. doi: 10.1002/ctm2.1675.
- Tilk S, Frydman J, Curtis C, Petrov DA. Cancers adapt to their mutational load by buffering protein misfolding stress. Elife. 2024 Nov 25;12:RP87301. doi: 10.7554/eLife.87301.
Enlaces Útiles
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Estimado)
Inicio del estudio
Finalización primaria (Estimado)
Finalización primaria
Finalización del estudio (Estimado)
Finalización del estudio
Fechas de registro del estudio
Enviado por primera vez
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Publicado por primera vez
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización publicada
Última actualización enviada que cumplió con los criterios de control de calidad
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades del sistema endocrino
- Procesos Patológicos
- Neoplasias por sitio
- Enfermedades intestinales
- Neoplasias por tipo histológico
- Neoplasias Gastrointestinales
- Neoplasias del Sistema Digestivo
- Enfermedades del Sistema Digestivo
- Enfermedades Gastrointestinales
- Neoplasias Intestinales
- Enfermedades Rectales
- Neoplasias de glándulas endocrinas
- Neoplasias Glandulares y Epiteliales
- Adenocarcinoma
- Enfermedades del Colon
- Procesos Neoplásicos
- Carcinoma
- Neoplasias de las glándulas suprarrenales
- Enfermedades de la corteza suprarrenal
- Enfermedades de las glándulas suprarrenales
- Condiciones Patológicas, Signos y Síntomas
- Neoplasias
- Neoplasias colorrectales
- Metástasis de neoplasias
- Colangiocarcinoma
- Carcinoma adrenocortical
- Neoplasias de la corteza suprarrenal
- carfilzomib
Otros números de identificación del estudio
Otros números de identificación del estudio
- 10002574
- 002574-C
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Descripción del plan IPD
This study will comply with the NIH Data Management and Sharing (DMS) Policy, which applies to all new and ongoing NIH-funded research in the IRP, as of January 25, 2023, that is associated with a ZIA, with a clinical protocol that undergoes scientific review.
Marco de tiempo para compartir IPD
Data will be made available as soon as possible or at the time of associated publication. Data not published in a manuscript will be shared via public source once the data set completes QC.
Criterios de acceso compartido de IPD
Clinical data will be made available upon request and with the permission of the study PI.
Tipo de información de apoyo para compartir IPD
- PROTOCOLO DE ESTUDIO
- SAVIA
- CIF
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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