# US 2023/0053364 A1 · Treatment of adrenocortical carcinoma with selective glucocorticoid receptor modulators (sgrms) and antibody checkpoint inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2023/0053364 A1
- Document ID: US20230053364A1
- Status: Published application
- Kind: A1
- Application number: 17/792,675
- Filed: 2021-01-26
- Published: 2023-02-23
- Earliest claimed: 2020-01-29
- Assignees: Corcept Therapeutics, Inc.
- Applicants: Corcept Therapeutics Incorporated
- Inventors: Andrew Greenstein; Andreas Grauer; Stacie Shepherd
- Web page: https://patentgrep.com/patent/US20230053364A1

## CPC

- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 33/243: Platinum; Compounds thereof
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 5/38: of the suprarenal hormones
- A61P 35/00: Antineoplastic agents
- A61K 2039/505: {comprising antibodies}
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Methods and compositions for treating a subject suffering from adrenocortical carcinoma and having excess cortisol are disclosed. The methods provide therapeutic benefits including reduction of ACC tumor load, restoration of T-cell and natural killer (NK) cell signaling pathways, increase in T-cell and NK cell infiltration into the ACC tumor, reduction of neutrophil infiltration into the ACC tumor in the patient, and other therapeutic benefits. The methods include administration of a glucocorticoid receptor modulator (GRM) (which may be a selective glucocorticoid receptor modulator (SGRM)) and an antibody checkpoint inhibitor. In embodiments, the GRM (e.g., a SGRM) is orally administered. The GRM may be a nonsteroidal compound comprising: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure.

## Claims

### Claim 1

A method of treating a subject suffering from adrenocortical carcinoma tumor and having cortisol excess, the method comprising:
Identifying a patient suffering from a) an adrenocortical tumor and b) suffering from glucocorticoid excess;
administering a combination treatment comprising administration of 1) a selective glucocorticoid receptor modulator (SGRM), and 2) an antibody checkpoint inhibitor to said identified patient;
thereby achieving a better treatment outcome from said identified patient than would be achieved by treatment with an antibody checkpoint inhibitor alone, wherein said treatment outcome is selected from a) reduction in ACC tumor load, b) restoration of T-cell and natural killer (NK) cell signaling pathways, c) increased T-cell and NK cell infiltration into the ACC tumor, and d) reduced neutrophil infiltration into the ACC tumor in the patient.

### Claim 2 (depends on 1)

The method of claim 1, wherein the antibody checkpoint inhibitor is selected from an antibody effective against PD-1, an antibody effective against CTLA-4, an antibody effective against PD-L1, and an antibody effective against PD-L2.

### Claim 3

(canceled)

### Claim 4

(canceled)

### Claim 5

(canceled)

### Claim 6

(canceled)

### Claim 7 (depends on 1)

The method of claim 1, wherein the method further comprises administering a chemotherapeutic agent selected from the group consisting of taxanes, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducing agents, antimetabolites, mitotic inhibitors and combinations thereof.

### Claim 8 (depends on 7)

The method of claim 7, wherein the chemotherapeutic agent is a taxane.

### Claim 9 (depends on 8)

The method of claim 8, wherein the chemotherapeutic agent is selected from the group consisting of nab-paclitaxel, 5-fluorouracil (5-FU), gemcitabine, cisplatin and capecitabine.

### Claim 10 (depends on 1)

The method of claim 1, wherein the SGRM is a heteroaryl-ketone fused azadecalin compound having the formula:
wherein
R1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R1a;
each R1a is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, CN, N-oxide, C3-8 cycloalkyl, and C3-8 heterocycloalkyl;
ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S;
each R2 is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl-C1-6 alkoxy, CN, OH, NR2aR2b, C(O)R2a, C(O)OR2a, C(O)NR2aR2b, SR2a, S(O)R2a, S(O)2R2a, C3-8 cycloalkyl, and C3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R2c groups;
alternatively, two R2 groups linked to the same carbon are combined to form an oxo group (═O);
alternatively, two R2 groups are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R2d groups;
R2a and R2b are each independently selected from the group consisting of hydrogen and C1-6 alkyl;
each R2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, CN, and NR2aR2b;
each R2d is independently selected from the group consisting of hydrogen and C1-6 alkyl, or two R2d groups attached to the same ring atom are combined to form (═O);
R3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R3a groups;
each R3a is independently selected from the group consisting of hydrogen, halogen, and C1-6 haloalkyl; and
subscript n is an integer from 0 to 3;
or salts and isomers thereof.

### Claim 11 (depends on 10)

The method of claim 10, wherein the compound comprising a heteroaryl-ketone fused azadecalin is relacorilant, having the formula:

### Claim 12 (depends on 11)

The method of claim 11, wherein the checkpoint inhibitor is an antibody checkpoint inhibitor.

### Claim 13 (depends on 12)

The method of claim 12, wherein the antibody checkpoint inhibitor is selected from an antibody effective against PD-1, an antibody effective against CTLA-4, an antibody effective against PD-L1, and an antibody effective against PDL-2.

### Claim 14

(canceled)

### Claim 15

(canceled)

### Claim 16 (depends on 1)

The method of claim 1, wherein the SGRM is a fused azadecalin compound having the formula:
wherein L1 and L2 are members independently selected from a bond and unsubstituted alkylene; R1 is a member selected from unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl, —OR1A, NR1CR1D, —C(O)NR1CR1D, and —C(O)OR1A, wherein R1A is a member selected from hydrogen, unsubstituted alkyl, and unsubstituted heteroalkyl; R1C and R1D are members independently selected from unsubstituted alkyl and unsubstituted heteroalkyl, and are optionally joined to form an unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring nitrogen. R2 has the formula:
wherein R2G is a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF3; J is phenyl; t is an integer from 0 to 5; X is —S(O2)—; and R5 is phenyl optionally substituted with 1-5 R5A groups, wherein R5A is a member selected from hydrogen, halogen, —OR5A1, S(O2)NR5A2R5A3, —CN, and unsubstituted alkyl, and R5A1 is a member selected from hydrogen and unsubstituted alkyl, and R5A2 and R5A3 are members independently selected from hydrogen and unsubstituted alkyl, or salts and isomers thereof.

### Claim 17 (depends on 16)

The method of claim 16, wherein the fused azadecalin compound is (R)-(4a-ethoxymethyl-1-(4-fluorophenyl)-6-(4-trifluoromethyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H,1,2,6-triaza-cyclopenta[b]naphthalene, also known as CORT108297, which has the formula:

### Claim 18

(canceled)

### Claim 19 (depends on 17)

The method of claim 17, wherein the SGRM is CORT108297 and the checkpoint inhibitor is an antibody checkpoint inhibitor selected from an antibody effective against PD-1, an antibody effective against CTLA-4, an antibody effective against PD-L1, and an antibody effective against PDL-2.

### Claim 20

(canceled)

### Claim 21

(canceled)

### Claim 22 (depends on 1)

The method of claim 1, wherein the SGRM is an octahydro fused azadecalin compound having the formula:
wherein R1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, optionally substituted with 1-4 groups each independently selected from R1a; each R1a is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, N-oxide, and C3-8 cycloalkyl; ring J is selected from the group consisting of an aryl ring and a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; each R2 is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl-C1-6 alkoxy, CN, OH, NR2aR2b, C(O)R2a, C(O)OR2a, C(O)NR2aR2b, SR2a, S(O)R2a, S(O)2R2a, C3-8 cycloalkyl, and C3-8 heterocycloalkyl having from 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S; alternatively, the two R2 groups on adjacent ring atoms are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is optionally substituted with 1-3 R2′ groups; R2a, R2b, and R2c are each independently selected from the group consisting of hydrogen and C1-6 alkyl; each R3a is independently halogen; and subscript n is an integer from 0 to 3, or salts and isomers thereof.

### Claim 23 (depends on 22)

The method of claim 22, wherein the octahydro fused azadecalin SGRM is ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, also known as CORT125281, which has the following structure:

### Claim 24 (depends on 23)

The method of claim 23, wherein the checkpoint inhibitor is an antibody effective checkpoint inhibitor.

### Claim 25 (depends on 24)

The method of claim 24, wherein the antibody checkpoint inhibitor is selected from an antibody effective against PD-1 an antibody effective against CTLA-4, an antibody effective against PD-L1, and an antibody effective against PDL-2.

### Claim 26

(canceled)

### Claim 27

(canceled)

### Claim 28

A pharmaceutical composition for treating adrenocortical carcinoma comprising a selective glucocorticoid receptor modulator (SGRM) compound selected from a heteroaryl ketone fused azadecalin SGRM, a fused azadecalin SGRM, and an octahydro fused azadecalin SGRM and an antibody checkpoint inhibitor effective against PD-1, CTLA-4, PDL-1 or PDL-2.

### Claim 29

(canceled)

### Claim 30 (depends on 28)

The pharmaceutical composition of claim 28, wherein the SGRM is and the checkpoint inhibitor is an antibody checkpoint inhibitor selected from an antibody effective against PD-1, an antibody effective against CTL-4, an antibody effective against PD-L1, and an antibody effective against PDL-2.

### Claim 31 (depends on 29)

The pharmaceutical composition of claim 29, wherein the SGRM is CORT125281 and the checkpoint inhibitor is an antibody checkpoint inhibitor selected from an antibody effective against PD-1, an antibody effective against CTLA-4, an antibody effective against PD-L1, and an antibody effective against PDL-2.

### Claim 32

(canceled)

### Claim 33

(canceled)

### Claim 34

(canceled)

### Claim 35 (depends on 1)

The method of claim 1, wherein the SGRM is the compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo P,4-g]isoquinolin-4a-yl) (pyridin-2-yl)methanone (termed “CORT113176”), which has the following structure: