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Specific therapy and medicament using integrin ligands for treating cancer

一种整联蛋白、配体的技术，应用在药物组合、肽/蛋白质成分、含有效成分的医用配制品等方向，能够解决效力降低等问题

Inactive Publication Date: 2009-11-25
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many physiological barriers and pharmacokinetic parameters contribute to its reduced potency

Method used

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  • Specific therapy and medicament using integrin ligands for treating cancer
  • Specific therapy and medicament using integrin ligands for treating cancer
  • Specific therapy and medicament using integrin ligands for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0910] Example 1: Radiation therapy of a rat orthotopic glioblastoma model, cilengitide (=cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)) schedule experiment

[0911] NIH rnu nude rats were anesthetized, restrained, and 5x10E5 U251 human glioblastoma suspended in 10 ul of medium was placed 1 mm retroorbitally and 3 mm to the right of the anterior blotch using a #2701 Hamilton syringe fitted with a 26 gauge needle , 2.5 mm deep intracerebral injections were performed essentially as previously published (Engebraaten et al., 1999). Fourteen days later, at various times (8 h, 8 h, 4h, 2h, 1h) Cilengitide (4 mg / kg) in PBS was administered as an intraperitoneal bolus. Animals also received the same intraperitoneal bolus of cilengitide each day for the next 7 days. Animals were maintained on an unrestricted diet until they were moribund, or for sampling for tissue analysis (in the t-4 and t-8 groups, the animals were still healthy 230 days after tumor injection). Kaplan-Meier survival curves we...

Embodiment 2

[0925] Example 2: Phase IIa trial of cilengitide ((=cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)) single agent therapy in recurrent glioblastoma patients

[0926] Background: This phase IIa study was designed to evaluate integrin alpha as a single agent v beta 3 and alpha v beta 5 The inhibitor of the cyclic RGD pentapeptide cilengitide ((=cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)) at 500 and 2000 mg doses in patients with recurrent glioblastoma (GBM) Safety, toxicity and clinical activity in (pts).

[0927] Methods: In this multicentre, open-label, randomized, uncontrolled study, patients with GBM and predictable disease (relapsed after prior treatment with temozolomide and radiation therapy) were randomized to receive twice-weekly intravenous doses of Cilengitide 500mg or 2000mg until progression. Histopathological diagnosis and magnetic resonance (MRI) imaging were used for independent blinded review. The primary endpoint was progression-free survival (PFS) at 6 months (mths). Secondary ...

Embodiment 3

[0930] Example 3: Use of Cilengitide (= Cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)) and Temozolomide and Simultaneously in Patients with Newly Diagnosed Glioblastoma (GBM) Radiation therapy followed by a phase I / IIa trial of maintenance temozolomide and cilengitide

[0931] Objective: To evaluate the combination of inhibitors of integrins avβ3 and avβ5 in combination with the cyclic RGD pentapeptide-cilengitide (=cyclic-(Arg-Gly-Asp-(Arg-Gly-Asp- DPhe-NMe-Val),) safety, toxicity and efficacy.

[0932] Patients and methods: 52 patients (PS 0-1: 92%, 2: 8%; age Median age 57) (Stupp et al NEJM 2005). In addition, cilengitide injections (500 mg twice weekly intravenously) were initiated one week prior to TMZ / RT and administered throughout chemotherapy or until progression. The primary endpoint was progression-free survival at 6 months (target: 65%). Patients then underwent MRI every 2 months. Looking at histopathological diagnosis and MRI imaging alone, the methylation status of the M...

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Abstract

The invention relates to a combination therapy for the treatment of tumors and tumor metastases comprising administration of integrin ligands, preferably integrin antagonists, together with co-therapeutic agents or therapy forms that have synergistic efficacy when administered consecutively with said ligands, such as chemotherapeutic agents and or radiation therapy. The therapy results in a synergistic potential increase of the inhibition effect of each individual therapeutic on tumor cell proliferation, yielding more effective treatment than found by administering an individual component alone, concurrently or not in the dosage regime of the present invention.

Description

field of invention [0001] The present invention relates to a specific therapeutic modality for the treatment of cancer, especially tumors and tumor metastases, comprising the administration of an integrin ligand with a cancer co-therapeutic agent or other cancer co-therapeutic therapy modality, when in combination with said integrin ligand The cancer co-therapy modalities are administered with additive or synergistic efficacy, such as chemotherapeutics, immunotherapy, including antibodies, radioimmunoconjugates and immunocytokines and or radiation therapy. More specifically, the present invention relates to the use of at least one specific integrin ligand for the manufacture of a medicament for the treatment of cancer, wherein said medicament to be used is combined with a) one or more alkylating chemotherapeutic agents, and optionally b) one or more other chemotherapeutic agents than said at least one specific integrin ligand and one or more alkylating chemotherapeutic agents....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/08A61P35/00
CPCA61K45/06A61P35/00A61P35/02A61P35/04A61P43/00A61K33/243
Inventor S·克吕格尔S·戈德曼A·哈斯特里克M·A·皮卡德J·尼普根U·格里姆R·施图普M·韦勒
Owner MERCK PATENT GMBH
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