ES2521679T3 - Terapia específica usando ligandos de integrinas para el tratamiento del cáncer - Google Patents

Terapia específica usando ligandos de integrinas para el tratamiento del cáncer Download PDF

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ES2521679T3
ES2521679T3 ES10015608.2T ES10015608T ES2521679T3 ES 2521679 T3 ES2521679 T3 ES 2521679T3 ES 10015608 T ES10015608 T ES 10015608T ES 2521679 T3 ES2521679 T3 ES 2521679T3
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hours
emd
sick
cancer treatment
specific therapy
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Inventor
Simon Dr. Goodman
Martin Andreas Dr. Picard
Johannes Dr. Nippgen
Andreas Dr. Harstrick
Ulrike Dr. Grimm
Matthias Dr. Grell
Roger Dr. Stupp
Michael Prof. Dr. Weller
Tom Dr. Mikkelsen
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Merck Patent GmbH
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Merck Patent GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Uso de al menos un ligando específico de integrinas, que comprende ciclo-(Arg-Gly-Asp-DPhe-NMeVal), los solvatos y/o sales farmacéuticamente aceptables del mismo, para la fabricación de un medicamento para el tratamiento del cáncer, en donde el medicamento se usa en combinación con radiación de haz externo, en donde al menos el ligando de integrinas específico ciclo-(Arg-Gly-Asp-DPhe-NMeVal), los solvatos y/o sales farmacéuticamente aceptables del mismo se administra de 1 a 10 horas (h) antes de la aplicación de la radiación de haz externo.

Description

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E10015608
28-10-2014
Ratas NIH rnu desnudas se anestesiaron, se inmovilizaron y se les inyectó intracerebralmente 1 mm retroorbitalmente, 3 mm a la derecha del bregma y a una profundidad de 2,5 mm con 5 × 105 células de glioblastoma humano U251 suspendidas en 10 µl de medio de cultivo, usando una jeringa de Hamilton N.º 2701 conectada a una aguja de calibre 26, esencialmente como se ha descrito previamente (Engebraaten y col., 1999). 5 Después de 14 días, se administra Cilengitide (4 mg/kg) como bolo intraperitoneal en PBS, a diversos tiempos (8, 4, 2 y 1 h) antes de un tratamiento único con haz dorso-ventral colimado y único de rayos X de 6 MV, de modo que el 95-100% de la dosis del eje central de 25 Gy incida sobre el volumen del tumor (Kim y col., 1999). Cada uno de los 7 días posteriores, los animales también recibieron un bolo i.p. de Cilengitide idéntico. Los animales se mantuvieron con libre acceso a agua y comida hasta que estuvieron moribundos o se obtuvieron muestras para el análisis de los
10 tejidos (en los grupos t-4 y t-8 h, en los que los animales estaban sanos 230 días después de la inyección del tumor). Se calculó y representó la curva de supervivencia de Kaplan-Meier (figura 1) a partir de los datos sin procesar (tabla 1). Todos los animales del grupo de monoterapia RT murieron antes de los 120 días.
Lista de referencias:
Engebraaten, O., Hjortland, G.O., Hirschberg, H. y Fodstad, O. (1999). Growth of precultured human glioma 15 specimens in nude rat brain. J. Neurosurg. 90, 125-132.
Kim, J.H., Khil, M.S., Kolozsvary, A., Gutierrez, J.A. y Brown, S.L. (1999). Fractionated radiosurgery for 9L gliosarcoma in the rat brain. Int. J. Radiat. Oncol. Biol. Phys. 45, 1035-1040.
Los resultados se proporcionan a continuación en la tabla 1 y en la figura 1:
Tabla 1
400.000 células U251n iny.
Estudio de supervivencia de EMD
Grupo
Tiempo preirradiación N.º animal Trat. Fecha de inyección Fecha de radiación Fecha de terminación Días post implante
89
8 horas G89-1 Rt 03.03.2005 17.03.2005 (Enfer.) 7/6/2005 96
89
8 horas G89-2 Rt 03.03.2005 17.03.2005 (Enfer.) 17/6/2005 106
89
8 horas G89-3 Rt + EMD 03.03.2005 17.03.2005 (Sano) 15/11/2005 257
89
8 horas G89-4 Rt + EMD 03.03 2005 17.03.2005 (Sano) 15/11/2005 257
89
8 horas G89-5 Rt + EMD 03.03.2005 17.03.2005 (Vivo) 15/12/2005 287
89
8 horas G89-6 Rt + EMD 03.03.2005 17.03.2005 (Vivo) 15/12/2005 287
90
4 horas G90-1 Rt 05.04.2005 19.04.2005 (Enfer.) 20/7/2005 106
90
4 horas G90-2 Rt 05.04.2005 19.04.2005 (Enfer.) 29/7/2005 115
90
4 horas G90-3 Rt + EMD 05.04.2005 19.04.2005 (Sano) 29/11/2005 238
90
4 horas G90-4 Rt + EMD 05.04.2005 19.04.2005 (Sano) 29/11/2005 238
90
4 horas G90-5 Rt + EMD 05.04.2005 19.04.2005 (Vivo) 15/12/2005 254
90
4 horas G90-6 Rt + EMD 05.04.2005 19.04.2005 (Vivo) 15/12/2005 254
47
E10015608
28-10-2014
(continuación)
400.000 células U251n iny.
Estudio de supervivencia de EMD
Grupo
Tiempo preirradiación N.º animal Trat. Fecha de inyección Fecha de radiación Fecha de terminación Días post implante
91
2 horas G91-1 Rt 12.04.2005 26.04.2005 (Enfer.) 26/7/2005 105
91
2 horas G91-2 Rt 12.04.2005 26.04.2005 (Enfer.) 12/8/2005 122
91
2 horas G91-3 Rt + EMD 12.04.2005 26.04.2005 (Enfer.) 10/8/2005 120
91
2 horas G91-4 Rt + EMD 12.04.2005 26.04.2005 (Enfer.) 6/9/2005 147
91
2 horas G91-5 Rt + EMD 12.04.2005 26.04.2005 (Enfer.) 21/9/2005 162
91
2 horas G91-6 Rt + EMD 12.04.2005 26.04.2005 (Enfer.) 25/10/2005 196
92
1 hora G92-1 Rt 12.05.2005 26.05.2005 (Enfer.) 26/8/2005 106
92
1 hora G92-2 Rt 12.05.2005 26.05.2005 (Enfer.) 1/9/2005 112
92
1 hora G92-3 Rt + EMD 12.05.2005 26.05.2005 (Enfer.) 1/09/2005 112
92
1 hora G92-4 Rt + EMD 12.05.2005 26.05.2005 (Enfer.) 2/9/2005 113
92
1 hora G92-5 Rt + EMD 12.05.2005 26.05.2005 (Enfer.) 19/9/2005 130
92
1 hora G92-6 Rt + EMD 12.05.2005 26.05.2005 (Enfer.) 30/9/2005 141
Enfer. = moribundo y retirado del estudio Sano = indica que se tomó una muestra de tejido en la fecha mostrada, pero seguía vivo en ese punto temporal. Vivo = sobrevive en el punto temporal mostrado.
Tiempo preirradiación = cuando se administra Cilengitide a 4 mg/kg. Rt = radioterapia 25 Gy 5 EMD = bolo de 4 mg/kg de Cilengitide Convención de fecha americana en la columna de fecha de finalización y convención europea en la columna de fecha de radiación.
Ejemplo 2: Ensayo clínico en fase IIa de terapia con el agente único Cilengitide (= ciclo-(Arg-Gly-Asp-DPhe-NMeVal)) en pacientes con glioblastoma recurrente
10 Antecedentes: El presente estudio en fase IIa se diseñó para evaluar la seguridad, toxicidad y actividad clínica del pentapéptido RGD cíclico Cilengitide (= ciclo-(Arg-Gly-Asp-DPhe-NMeVal)), un inhibidor de las integrinas αvβ3y αvβ5, como agente único a dosis de 500 y 2000 mg en pacientes (pcs) con glioblastoma recurrente (GBM).
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Claims (1)

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ES10015608.2T 2006-01-18 2007-01-18 Terapia específica usando ligandos de integrinas para el tratamiento del cáncer Active ES2521679T3 (es)

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EP06001044 2006-01-18
EP06000988 2006-01-18
EP06000988 2006-01-18
EP06001044 2006-01-18
EP06006003 2006-01-20
EP06006003 2006-01-20
EP06015883 2006-07-31
EP06015883 2006-07-31

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JP (2) JP2009523813A (es)
KR (1) KR20080089489A (es)
AU (1) AU2007207465B2 (es)
BR (1) BRPI0706540A2 (es)
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EA (2) EA201200560A1 (es)
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