# US 2013/0156768 A1 · Combination of anti-ctla4 antibody with braf inhibitors for the synergistic treatment of proliferative diseases

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- Number: US 2013/0156768 A1
- Document ID: US20130156768A1
- Status: Published application
- Kind: A1
- Application number: 13/818,714
- Filed: 2011-08-25
- Published: 2013-06-20
- Earliest claimed: 2010-08-26
- Assignees: Bristol-Myers Squibb Company
- Inventors: Maria Jure-Kunkel; Jon Marc Wigginton; Ashok Kumar Gupta
- Web page: https://patentgrep.com/patent/US20130156768A1

## CPC

- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Compositions and methods are disclosed which are useful of the treatment and prevention of proliferative disorders.

## Claims

### Claim 1

A method for the treatment of proliferative diseases, including cancer, which comprises administration to a mammal in need thereof a synergistically, therapeutically effective amount of an anti-CTLA-4 agent with methyl {5-[2-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate.

### Claim 2 (depends on 1)

The method according to claim 1, wherein said administration comprises the sequential administration of (i) one or more cycles of methyl {5-[2-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate; followed by the administration of (ii) one or more cycles of said anti-CTLA-4 agent or a combination comprising said methyl {5-[2-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate and said anti-CTLA-4 agent.

### Claim 3 (depends on 1, 2)

The method according to claim 1 or claim 2 wherein the anti-CTLA-4 agent(s) is selected from the group consisting of ipilimumab and tremelimumab.

### Claim 4 (depends on 1, 2)

The method according to claim 1 or claim 2, wherein said method is for the treatment of cancerous solid tumors.

### Claim 5 (depends on 1, 2)

The method according to claim 1 or claim 2, wherein said method is for the treatment of refractory tumors.

### Claim 6 (depends on 1, 2)

The method according to claim 1 or claim 2, wherein the anti-CTLA-4 agent is selected from the group consisting of an anti-CTLA-4 antibody, an anti-CTLA-4 adnectin, an anti-CTLA-4 RNAi, single chain anti-CTLA-4 antibody fragments, domain anti-CTLA-4 antibody fragments, and an anti-CTLA-4 antisense molecule.

### Claim 7

A method for the treatment of proliferative diseases, including cancer, which comprises administration to a mammal in need thereof a synergistically, therapeutically effective amount of an anti-CTLA-4 agent with PLX-4032.

### Claim 8 (depends on 7)

The method according to claim 7, wherein said administration comprises the sequential administration of (i) one or more cycles of a BRAF inhibitor; followed by the administration of (ii) one or more cycles of said anti-CTLA-4 agent or a combination comprising said BRAF inhibitor and said anti-CTLA-4 agent.

### Claim 9 (depends on 7, 8)

The method according to claim 7 or claim 8 wherein the anti-CTLA-4 agent(s) is selected from the group consisting of ipilimumab and tremelimumab.

### Claim 10 (depends on 7, 8)

The method according to claim 7 or claim 8, wherein said method is for the treatment of cancerous solid tumors.

### Claim 11 (depends on 7, 8)

The method according to claim 7 or claim 8, wherein said method is for the treatment of refractory tumors.

### Claim 12 (depends on 7, 8)

The method according to claim 7 or claim 8, wherein the anti-CTLA-4 agent is selected from the group consisting of an anti-CTLA-4 antibody, an anti-CTLA-4 adnectin, an anti-CTLA-4 RNAi, single chain anti-CTLA-4 antibody fragments, domain anti-CTLA-4 antibody fragments, and an anti-CTLA-4 antisense molecule.

### Claim 13 (depends on 7, 8)

The method according to claim 7 or claim 8 wherein the BRAF inhibitor is selected from the group consisting of methyl {5-[2-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate; a V600E BRAF inhibitor, and PLX-4032.