Concomitant administration of glucocorticoid receptor modulator relacorilant and paclitaxel, a dual substrate of CYP2C8 and CYP3A4

Patent metadata

Field	Value
Publication number	US-12589094-B2
Application number	US-202418590002-A
Country	US
Kind code	B2
Filing date	Feb 28, 2024
Priority date	May 27, 2020
Publication date	Mar 31, 2026
Grant date	Mar 31, 2026

Abstract

Many drugs useful in treating cancer are metabolized by CYP2C8 enzymes, by CYP3A4 enzymes, or both. The effects of concomitant administration of relacorilant and paclitaxel, a drug used to treat cancer that is a substrate for both CYP2C8 and CYP3A4, are disclosed herein.
Relacorilant potently inhibited CYP2C8 and CYP3A4 in in vitro tests, indicating that co-administration of relacorilant and paclitaxel would increase paclitaxel plasma exposure more than 5-fold in vivo, requiring significant reductions in paclitaxel doses when co-administering paclitaxel with relacorilant.
Surprisingly, paclitaxel plasma exposure increased only by about 80% instead of the expected more than 5-fold increase expected with concomitant relacorilant and paclitaxel administration. Applicant discloses safe methods of co-administering relacorilant and paclitaxel by reducing the dose of paclitaxel to about half the paclitaxel dose used when paclitaxel is administered alone. Relacorilant and such reduced doses of paclitaxel may be co-administered to treat cancer, e.g., ovarian or pancreatic cancer.

First claim

The invention claimed is:

1 . A method of treating cancer according to a 28-day cycle of intermittent paclitaxel and relacorilant administration, wherein said 28-day cycle begins on day0, wherein said cancer comprises a solid tumor, comprising the following administrations to a patient in need of treatment for said cancer: a) administering an effective oral dose of relacorilant of between about 75 milligrams (mg) to about 200 mg on day 0, day 7, and day 14 of said 28-day cycle of intermittent paclitaxel and relacorilant administration; and then, b) administering, on day 1, day 8, and day 15 of said 28-day cycle of intermittent paclitaxel and relacorilant administration, an effective oral dose of relacorilant of between about 75 mg to about 200 mg and an effective dose of paclitaxel that is reduced by about 20% to about 35% from the paclitaxel single agent dose of about 100 mg/m 2 to about 125 mg/m 2 , wherein said single agent dose is the paclitaxel dose to be administered when paclitaxel is administered without other pharmaceutical agents; and then, c) administering, on day 2, day 9 and day 16 of said 28-day cycle of intermittent paclitaxel and relacorilant administration an effective oral dose of relacorilant of between about 75 mg to about 200 mg, wherein steps a), and b), and c) are intermittent administration steps in which paclitaxel administration is performed on days 1, 8, and 15 of said 28-day cycle, and in which relacorilant administration is performed on the day before, the day of, and the day after said paclitaxel administration, effective to provide the patient with an effective level of relacorilant and an effective level of paclitaxel at the same time, whereby the cancer comprising a solid tumor is treated according to a 28-day cycle of intermittent paclitaxel and relacorilant administration.

2 . The method of claim 1 , wherein said effective dose of paclitaxel is reduced from said single agent dose of paclitaxel by an amount selected from about 20%, about 25%, about 30%, and about 35%, when co-administered with relacorilant.

3 . The method of claim 1 , wherein said effective dose of paclitaxel is reduced from said single agent dose of paclitaxel to an effective dose of paclitaxel selected from about 72 mg/m 2 , about 75 mg/m 2 , about 80 mg/m 2 , about 83 mg/m 2 , about 88 mg/m 2 , about 94 mg/m 2 , and about 96 mg/m 2 of paclitaxel.

4 . The method of claim 1 , wherein paclitaxel is in the form of nab-paclitaxel.

5 . The method of claim 1 , wherein said effective oral dose of relacorilant is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and 200 mg of relacorilant.

6 . The method of claim 1 , wherein said cancer is selected from ovarian cancer, pancreatic cancer, prostate cancer, esophageal cancer, and melanoma.

7 . The method of claim 1 , wherein paclitaxel is in the form of nab-paclitaxel, and wherein the dose of nab-paclitaxel is selected from about 60 mg/m 2 , about 72 mg/m 2 , about 75 mg/m 2 , about 80 mg/m 2 , and about 83 mg/m 2 of nab-paclitaxel administered by intravenous infusion on days 1, 8 and 15 of said 28-day cycle.

8 . A method of treating cancer according to a 28-day cycle of intermittent paclitaxel and relacorilant administration, wherein said 28-day cycle begins on day0, wherein said cancer comprises a solid tumor, comprising the following administrations to a patient in need of treatment for said cancer: a) administering an effective oral dose of relacorilant of between about 75 milligrams (mg) to about 200 mg on day 0, day 7, and day 14 of said 28-day cycle of intermittent paclitaxel and relacorilant administration; and then, b) administering an effective oral dose of relacorilant of between 75 mg to about 200 mg and an effective dose of paclitaxel of between about 60 mg/m 2 to about 95 mg/m 2 , on day 1, day 8, and day 15 of said 28-day cycle of intermittent paclitaxel and relacorilant administration, and then c) administering an effective oral dose of relacorilant of between about 75 mg to about 200 mg on day 2, day 9 and day 16 of said 28-day cycle of intermittent paclitaxel and relacorilant administration, wherein steps a), and b), and c) are intermittent administration steps in which paclitaxel administration is performed on days 1, 8, and 15 of said 28-day cycle, and in which relacorilant administration is performed on the day before, the day of, and the day after said paclitaxel administration, at times effective to provide the patient with an effective level of relacorilant and an effective level of paclitaxel at the same time, whereby the cancer comprising a solid tumor is treated according to a 28-day cycle of intermittent paclitaxel and relacorilant administration.

9 . The method of claim 8 , wherein said paclitaxel is in the form of nab-paclitaxel.

10 . The method of claim 8 , wherein said effective dose of paclitaxel is selected from about 60 mg/m 2 , about 65 mg/m 2 , about 70 mg/m 2 , about 75 mg/m 2 , about 80 mg/m 2 , about 85 mg/m 2 , about 90 mg/m 2 , and about 95 mg/m 2 of paclitaxel.

11 . The method of claim 8 , wherein said effective oral dose of relacorilant is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and 200 mg of relacorilant.

12 . The method of claim 8 , wherein said cancer is selected from ovarian cancer, pancreatic cancer, prostate cancer, esophageal cancer, and melanoma.

13 . The method of claim 8 , wherein paclitaxel is in the form of nab-paclitaxel, wherein the dose of nab-paclitaxel is selected from about 60 mg/m 2 , about 72 mg/m 2 , about 75 mg/m 2 , about 80 mg/m 2 , and about 83 mg/m 2 of nab-paclitaxel administered by intravenous infusion on days 1, 8 and 15 of said 28-day cycle.

Assignees

• Corcept Therapeutics Inc

Inventors

• Hunt Hazel
• Custodio Joseph

Classifications

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K31/4745 Primary

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K31/4725 Primary

  containing further heterocyclic rings · CPC title