# US 10,946,000 B2 · Method for treating cancer with combination therapy

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- Number: US 10,946,000 B2
- Document ID: US10946000B2
- Status: Granted
- Kind: B2
- Application number: 16/573,325
- Filed: 2019-09-17
- Published: 2020-04-16
- Granted: 2021-03-16
- Earliest claimed: 2015-10-06
- Assignees: RedHill Biopharma Ltd.
- Applicants: RedHill Biopharma Ltd.
- Inventors: Reza Fathi; Dror Ben-Asher; Danielle Abramson
- Web page: https://patentgrep.com/patent/US10946000B2

## CPC

- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/438: The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are methods for treating cancer in a patient by administering at least one antibiotic selected from the group consisting of clofazimine, rifabutin and clarithromycin, in combination with an aryladamantane compound. In an embodiment, the aryladamantane compound is [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide], or a pharmaceutically acceptable salt thereof.

## Claims

### Claim 1

A method for treating a solid tumor cancer comprising:
administering to a patient with a solid tumor cancer:
(i) a first pharmaceutical composition comprising a therapeutically effective amount of a first compound, wherein the first compound is 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridine-4-ylmethyl)-amide or a pharmaceutical acceptable salt thereof; and
(ii) a second pharmaceutical composition comprising a therapeutically effective amount of a second compound, wherein the second compound is N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4-ethoxycarbonylpiperazide, a stereoisomer, a racemic mixture, a metabolite, a salt, crystal, or any combination thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the second compound is present as a sulfate or a hydrogen sulfate salt.

### Claim 3 (depends on 1)

The method of claim 1, wherein the second compound is selected from the group consisting of:
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)phenylalanine-4 ethoxycarbonylpiperazide,
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(D)phenylalanine-4-ethoxycarbonylpiperazide, and
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(D,L)phenylalanine-4-ethoxycarbonylpiperazide,
or a physiologically compatible salt thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the second compound is N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)phenylalanine-4-ethoxycarbonylpiperazide hydrogen sulfate.

### Claim 5 (depends on 1)

The method of claim 1, wherein the second compound is a crystalline form of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)phenylalanine-4-ethoxycarbonylpiperazide or a physiologically compatible salt thereof.

### Claim 6 (depends on 1)

The method of claim 1, wherein the first compound and the second compound are administered concurrently.

### Claim 7 (depends on 1)

The method of claim 1, wherein the first compound and the second compound are administered sequentially.

### Claim 8 (depends on 1)

The method of claim 1, wherein the first compound and the second compound are simultaneously and sequentially.

### Claim 9 (depends on 1)

The method of claim 1 further comprising administering at least one antineoplastic agent.

### Claim 10 (depends on 9)

The method of claim 9, wherein the at least one antineoplastic agent is selected from one of gemcitabine, capecitabine, alone or in combination.

### Claim 11 (depends on 1)

The method of claim 1 further comprising administering at least one immunomodulator.

### Claim 12 (depends on 1)

The method of claim 1 further comprising administering at least one immune checkpoint inhibitor.

### Claim 13 (depends on 1)

The method of claim 1 further comprising administering at least one matrix metalloproteinase inhibitor.

### Claim 14 (depends on 1)

The method of claim 1, wherein the first pharmaceutical composition comprising the first compound is in the form of a capsule.

### Claim 15 (depends on 1)

The method of claim 1, wherein the second pharmaceutical composition comprising the second compound is in the form of a capsule.

### Claim 16 (depends on 1)

The method of claim 1, wherein the solid tumor cancer is a carcinoma.

### Claim 17 (depends on 1)

The method of claim 1, wherein the solid tumor cancer is a metastatic solid tumor cancer.

### Claim 18 (depends on 1)

The method of claim 1, wherein the patient is a human patient.

### Claim 19 (depends on 1)

The method of claim 1, wherein the first pharmaceutical composition and the second pharmaceutical composition are administered orally.