- ICH GCP
- Registro de ensayos clínicos de EE. UU.
- Ensayo clínico NCT01236573
Cell Therapy for Metastatic Melanoma Using CD8 Enriched Tumor Infiltrating Lymphocytes
Phase I/II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Tumor Infiltrating Lymphocytes Genetically Engineered to Express IL-12
Background:
- One experimental treatment for certain types of cancer is cell therapy, which involves collecting lymphocytes (white blood cells) from a tumor, growing them in the laboratory in large numbers, and then modifying the cells with a gene (interleukin-12 (IL-12)) that stimulates the immune system to attack and destroy the cancer cells. Because this treatment is experimental, researchers are interested in determining the side effects and overall effectiveness of cell therapy using white blood cells modified with IL-12 as a treatment for aggressive cancer.
Objectives:
- To determine the safety and effectiveness of cell therapy using IL-12 modified tumor white blood cells to treat metastatic melanoma.
Eligibility:
- Individuals greater than or equal to 18 years of age and less than or equal to age 66 who have been diagnosed with metastatic melanoma.
Design:
- Participants will be screened with a medical history, physical examination, blood and urine tests, and imaging studies.
- Cells for treatment will be collected during tumor biopsy or surgery.
- Prior to the start of cell therapy, participants will have imaging procedures, heart and lung function tests, and blood and urine tests, as well as leukapheresis to collect additional white blood cells.
- For 5 days before the cell infusion, participants will be admitted for inpatient chemotherapy with cyclophosphamide and fludarabine to suppress the immune system in preparation for the cell therapy.
- Participants will receive the modified white blood cells as an infusion 1 to 4 days after the last dose of chemotherapy. The day after the infusion, participants will receive filgrastim to stimulate blood cell growth.
- Participants will remain as inpatients for at least 5 to 10 days to recover from the treatment, and will be followed regularly after the treatment to study side effects and general effectiveness.
- Participants who initially respond to treatment but have a relapse may have one additional treatment using the same procedure.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
Background:
- Interleukin-12 (IL-12) is an important immunostimulatory cytokine. We have constructed a retroviral vector that contains an inducible single chain IL-12 driven by an nuclear factor of activated T-cells (NFAT) responsive promoter which can be used to mediate transfer of this gene into anti-tumor lymphocytes. This construct enables the secretion of IL-12 following stimulation of the T cell receptor.
- Transduction of the IL-12 gene into mouse anti-tumor lymphocytes results in a profound increase in the ability of these lymphocytes to mediate tumor regression following administration to tumor bearing mice. These cells have a profound advantage in inducing anti-tumor responses because very few cells are needed and there is no requirement for the concomitant administration of interleukin-2 (IL-2) as is the case for conventional cell transfer immunotherapies.
- Based on these murine studies we have now constructed a similar retrovirus that contains an inducible human single chain IL-12 driven by an NFAT responsive promoter. This retrovirus can be used to transduce tumor infiltrating lymphocytes (TIL) suitable for the therapy of patients with metastatic melanoma.
Objectives:
Primary objectives:
- To evaluate the safety of the administration of IL-12 engineered TIL in patients receiving a non-myeloablative conditioning regimen.
- Determine if the administration of IL-12 engineered TIL to patients following a non-myeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer.
Secondary objective:
-Determine the in vivo survival of IL-12 gene-engineered cells.
Eligibility:
Patients who are 18 years of age or older must have:
- metastatic melanoma;
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
Design:
- TIL will be resected from metastatic deposits and grown in IL-2 using standard techniques.
- Prior to approval of amendment A, after about 2 weeks TIL will undergo cluster of differentiation 8 (CD8) enrichment on a Miltenyi column and then undergo a rapid expansion by exposure to Muromoanb-CD3) OKT-3 an IL-2 in the presence irradiated feeder cells. Four to five days later, transduction is initiated by addition of retroviral vector supernatant containing the IL-12 gene.
With approval of amendment A, TIL will not undergo CD8 enrichment. Starting with cohort 5, after initial growth, TIL undergo a rapid expansion by exposure to OKT-3 and IL-2 in the presence irradiated feeder cells. Four to five days later, transduction is initiated by addition of retroviral vector supernatant containing the IL-12 gene.
- Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL. Cohorts of 3 patients each will receive increasing cell doses.
- Patients will undergo complete evaluation of tumor with physical examination, computed tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has stable disease (SD) or tumor shrinkage, repeat complete evaluations will be performed every 1-3 months. After the first year, patients continuing to respond will continue to be followed with this evaluation every 3-4 months until off study criteria are met.
- The study will be conducted using a Phase I/II optimal design. The protocol will proceed in a phase 1 dose escalation design.
- Prior to approval of amendment A, the protocol enrolled 1 patient in each of the first 3 dose cohorts. Cohort 4 proceeded in a phase 1 dose escalation design, with of n=3. Should a single patient experience a dose limiting toxicity due to the cell transfer at a particular dose level, additional patients would be treated at that dose to confirm that no greater than 1/6 patients have a dose-limiting toxicity (DLT) prior to proceeding to the next higher level. If a level with 2 or more DLTs in 3-6 patients has been identified, three additional patients will be accrued at the next- lowest dose, for a total of 6, in order to further characterize the safety of the maximum tolerated dose.
- With approval of amendment A, no additional patients will be enrolled in cohort 4, and the protocol will enroll 1 patient in cohort 5 with a dose of 1 X 10^7 bulk young TIL cells. Cohorts 6-12 will proceeded in a phase 1 dose escalation design, with an n=3. Should a single patient experience a dose limiting toxicity due to the cell transfer at a particular dose level, additional patients would be treated at that dose to confirm that no greater than 1/6 patients have a DLT prior to proceeding to the next higher level. If a level with 2 or more DLTs in 3-6 patients has been identified, three additional patients will be accrued at the next-lowest dose, for a total of 6, in order to further characterize the safety of the maximum tolerated dose prior to starting the pahse II portion. If a dose limiting toxicity occurs in the cohort 4, that cohort will be expanded to 6 patients. If 2 DLTs are encountered in this cohort, the study will be terminated.
- Once the maximum tolerated dose (MTD) has been determined, the study then would proceed to the phase II portion using a phase II optimal design where initially 21 evaluable patients will be enrolled. If 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled.
- The objective will be to determine if the combination of lymphocyte depleting chemotherapy, and IL-12 gene engineered lymphocytes is associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% partial response (PR) + complete response (CR) rate (p1=0.20).
Tipo de estudio
Inscripción (Actual)
Fase
- Fase 2
- Fase 1
Contactos y Ubicaciones
Ubicaciones de estudio
-
-
Maryland
-
Bethesda, Maryland, Estados Unidos, 20892
- National Institutes of Health Clinical Center, 9000 Rockville Pike
-
-
Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
- INCLUSION CRITERIA:
- Metastatic melanoma with evaluable disease.
- Greater than or equal to 18 years of age and less than or equal to age 66.
- Willing to sign a durable power of attorney
- Able to understand and sign the Informed Consent Document
- Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1
- Life expectancy of greater than three months
- Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after the cells are no longer detected in the blood.
Serology:
- Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
- Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative.
- Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
Hematology:
- Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim.
- White blood cell (WBC) (> 3000/mm^3).
- Platelet count greater than 100,000/mm^3.
- Hemoglobin greater than 8.0 g/dl.
Chemistry:
- Serum alanine transaminase (ALT)/aspartate transaminase (AST) less or equal to 2.5 times the upper limit of normal.
- Serum creatinine less than or equal to 1.6 mg/dl.
- Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilberts Syndrome who must have a total bilirubin less than 3.0 mg/dl.
- More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
EXCLUSION CRITERIA:
- Previous treatment with interleukin-12 (IL-12).
- Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
- Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
- Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
- Concurrent systemic steroid therapy.
- History of severe immediate hypersensitivity reaction to any of the agents used in this study.
- In patients > 60 years old and/or history of coronary revasularization or ischemic symptoms, documented left ventricular ejection fraction (LVEF) of less than or equal to 45%.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: No aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
---|---|
Experimental: Group 1 - CD8 + TIL expressing IL-12 1x10^6
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of interleukin-12 (IL-12) gene-transduced tumor infiltrating lymphocytes (TIL).
|
Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.
On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
|
Experimental: Group 2 - CD8 + TIL expressing IL-12 3x10^6
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
|
Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.
On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
|
Experimental: Group 3 - CD8 + TIL expressing IL-12 1x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
|
Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.
On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
|
Experimental: Group 4- CD8+TIL expressing IL-12 3x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
|
Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.
On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
|
Experimental: Group 5 - Bulk TIL expressing IL-12 1x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
|
Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.
On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
|
Experimental: Group 6 - Bulk TIL expressing IL-12 3x10^7
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
|
Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.
On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
|
Experimental: Group 7- Bulk TIL expressing IL-12 1x10^8
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
|
Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.
On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
|
Experimental: Group 8 - Bulk TIL expressing IL-12 3x10^8
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
|
Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.
On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
|
Experimental: Group 9 - Bulk TIL expressing IL-12 1x10^9
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
|
Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.
On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
|
Experimental: Group 10- Bulk TIL expressing IL12 3x10^9
Phase 1. Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
|
Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.
On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
|
Experimental: Group 11 - Bulk TIL expressing MTD 1x10^9 (Phase 2)
Maximum tolerated dose (MTD).
Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of IL-12 gene-transduced TIL.
|
Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml dextrose 5% in water (D5W) over 1 hr.
On day 0 (one to four days after the last dose of fludarabine), cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes.
|
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
---|---|---|
Maximum Tolerated Dose (MTD)
Periodo de tiempo: 4 years
|
The MTD was determined by evaluating dose limiting toxicities (DLT) of participants that received increasing doses of intravenous infusion of IL-12 gene transduced tumor infiltrating lymphocytes (TIL) (i.e., 1x10^6, 3x10^6, 3x10^7, 1x10^7, 3x10^7, 1x10^8, 3x10^8, 1x10^9, and 3x10^9) in cohorts 1-10.
Maximum tolerated cell dose is the highest dose at which </= 1 of 6 patients experienced a DLT (i.e.
grade 2 or greater allergic reaction)).
|
4 years
|
Response (Complete Response (CR) + Partial Response (PR)) to Therapy
Periodo de tiempo: 4 years
|
Response was determined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0.
Complete response (CR) is disappearance of all target lesions.
Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline um LD.
Progressive disease (PD) is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions.
|
4 years
|
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
---|---|---|
Number of Participants With Adverse Events
Periodo de tiempo: 49 months and 20 days
|
Here is the number of participants with adverse events.
For a detailed list of adverse events, see the adverse event module.
|
49 months and 20 days
|
Colaboradores e Investigadores
Patrocinador
Colaboradores
Publicaciones y enlaces útiles
Publicaciones Generales
- Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43.
- Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer. 2007 Feb 1;109(3):455-64. doi: 10.1002/cncr.22427.
- Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. doi: 10.1200/JCO.1999.17.7.2105.
- Zhang L, Morgan RA, Beane JD, Zheng Z, Dudley ME, Kassim SH, Nahvi AV, Ngo LT, Sherry RM, Phan GQ, Hughes MS, Kammula US, Feldman SA, Toomey MA, Kerkar SP, Restifo NP, Yang JC, Rosenberg SA. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin Cancer Res. 2015 May 15;21(10):2278-88. doi: 10.1158/1078-0432.CCR-14-2085. Epub 2015 Feb 18.
- Kerkar SP, Goldszmid RS, Muranski P, Chinnasamy D, Yu Z, Reger RN, Leonardi AJ, Morgan RA, Wang E, Marincola FM, Trinchieri G, Rosenberg SA, Restifo NP. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J Clin Invest. 2011 Dec;121(12):4746-57. doi: 10.1172/JCI58814. Epub 2011 Nov 7.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio
Finalización primaria (Actual)
Finalización del estudio (Actual)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimar)
Actualizaciones de registros de estudio
Última actualización publicada (Estimar)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Términos MeSH relevantes adicionales
- Neoplasias por tipo histológico
- Neoplasias
- Tumores neuroectodérmicos
- Neoplasias De Células Germinales Y Embrionarias
- Neoplasias De Tejido Nervioso
- Tumores neuroendocrinos
- Nevos y Melanomas
- Melanoma
- Efectos fisiológicos de las drogas
- Mecanismos moleculares de acción farmacológica
- Agentes antirreumáticos
- Agentes antineoplásicos
- Agentes inmunosupresores
- Factores inmunológicos
- Agentes antineoplásicos, alquilantes
- Agentes alquilantes
- Agonistas mieloablativos
- Ciclofosfamida
- Fludarabina
Otros números de identificación del estudio
- 110011
- 11-C-0011
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .
Ensayos clínicos sobre Cáncer de piel
-
Abramson Cancer Center of the University of PennsylvaniaTerminadoPaciente con cancerEstados Unidos
-
Peking Union Medical College HospitalTerminadoEncuesta | Estado nutricional | Paciente con cancerPorcelana
-
Ankara Medipol UniversityReclutamientoCuidados personales | Inmunoterapia | Manejo de síntomas | Paciente con cancerPavo
-
Northwestern UniversityGenzyme, a Sanofi CompanyRetiradoCANCER DE PROSTATAEstados Unidos
-
Fundacao ChampalimaudTerminado
-
University College London HospitalsTerminado
-
GenSpera, Inc.RetiradoCancer de prostata.Estados Unidos
-
University of Colorado, DenverColorado State UniversityRetiradoRealidad virtual | Diagnóstico por imagen | Educación del paciente | Paciente con cancerEstados Unidos
-
Dana-Farber Cancer InstituteTerminadoCancer de RIÑON | Cancer de prostata | Cáncer genitourinarioEstados Unidos
-
Rabin Medical CenterReclutamiento