Specific therapy using integrin ligands for treating cancer

An integrin and ligand technology, which can be used in peptide/protein components, medical preparations containing active ingredients, and pharmaceutical formulations, and can solve problems such as reducing efficacy

Inactive Publication Date: 2009-02-18
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Many physiological barriers and pharmacokinetic p

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0448]Example 1: Radiation Therapy, Cilengitide (= Cyclo-(Arg-Gly-Asp-DPhe-Nme-Val)) Sequence Experiment in a Rat Orthotopic Glioblastoma Model

[0449] NlH rnu nude rats were anesthetized, bound, and injected 5x10E5 U251 human glioblastoma cells suspended in 10ul of cell culture medium 1mm behind the orbit, 3mm and 2.5mm deep from the right side of the anterior blemish, wherein Injections were performed essentially as previously published (Engebraaten et al., 1999) using a #2701 Hamilton syringe fitted with a 26 gauge needle. After 14 days, before monotherapy with a single, collimated, dorsal-ventral 6MV x-ray beam so that 95-100% of the central axis dose of 25Gy hits the tumor volume (Kim et al., 1999) At time (8h, 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 under conditions of food and water ad libitum until ...

Embodiment 2

[0463] Example 2: Phase IIa trial of cilengitide ((=cyclo-(Arg-Gly-Asp-DPhe-NMe-Val)) mono-agent therapy in patients with recurrent glioblastoma

[0464] Background: This phase IIa study was designed to evaluate the cyclic RGD pentapeptide, cilengitide ((=cyclo-(Arg-Gly-Asp-DPhe-NMe-Val), inhibitor of integrins avβ3 and avβ5) as a single Safety, toxicity and clinical activity of the active agent at doses of 500 mg and 2000 mg in patients (pts) with relapsed glioblastoma (GBM).

[0465] METHODS: In this multicentre, open-label, randomized and uncontrolled study, pts with recurrent GBM and detectable disease following previous treatment with temozolomide and radiation therapy were randomized to receive a dose of 500 mg Or cilengitide 2000 mg intraperitoneally twice a week until disease progression. Independent blinded examinations were performed for histopathological diagnosis and MRI imaging. The primary endpoint was progression-free survival (PFS) at 6 months (mths). Second...

Embodiment 3

[0468] 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

[0469] Objective: To evaluate the combination of cyclic RGD pentapeptide-cilengitide (=cyclo-(Arg-Gly-Asp-DPhe-NMe-Val), integrin, in addition to standard temozolomide (TMZ) and radiation therapy (RT). Inhibitors of proteins avβ3 and avβ5) safety, toxicity and efficacy.

[0470] Patients and methods: 52 patients (PS 0-1: 92%, 2: 8%; median age 57 years) after biopsy (n=9 / 17%) or tumor resection (n=43 / 83%) Standard TMZ / RT therapy (Stupp et al NEJM 2005). Additionally cilengitide (500 mg iv, twice / week) was started one week prior to TMZ / RT and was administered throughout the duration of chemotherapy or until progression. The primary endpoint was progression-free survival at 6 months (target: 65%). Patients were followed up...

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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

technical field [0001] The present invention relates to specific therapeutic modalities for the treatment of tumors and metastases comprising co-administration, preferably in a timed manner, of an integrin ligand and a cancer co-therapeutic agent or other form of cancer co-therapeutics, the cancer co-therapeutic agent or other forms of cancer co-therapy, such as chemotherapeutics, immunotherapeutics (including antibodies) that have an additive or synergistic effect when administered in combination with said integrin ligand , radioimmunoconjugates and immunocytokine and / or radiation therapy. This treatment will result in a synergistic potential potentiation of the respective inhibitory effects of each of the treatments on tumor cell and tumor endothelial cell proliferation, resulting in a greater increase in the individual components than when the individual components are administered alone, together or in other treatment regimens than the present invention. effective treatme...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K38/08A61K31/4188A61K41/00A61P35/00
Inventor S·戈德曼M·A·皮卡德T·米克尔森J·尼普根U·格里姆R·施图普M·韦勒A·哈斯特里克M·格雷尔
Owner MERCK PATENT GMBH
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