Granted Patent B2

US 12,226,409 · App. 17/407,742 · Granted Feb 18, 2025

Inventor: Toshiyuki Tamai (Tokyo, JP)

Assignee: Eisai R&D Management Co., Ltd.

A61K31/47A61K9/48A61P35/00

Abstract

Claims (68)

1. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg,

wherein the human subject develops an occurrence of a first Grade 3 nonhematologic toxicity during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the first Grade 3 nonhematologic toxicity until the first Grade 3 nonhematologic toxicity is resolved to Grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg, wherein the human subject develops an occurrence of a second Grade 3 nonhematologic toxicity during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second Grade 3 nonhematologic toxicity until the second Grade 3 nonhematologic toxicity is resolved to Grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg every other day if the body weight of the human subject is less than 60 kg, wherein the human subject develops an occurrence of a third Grade 3 nonhematologic toxicity during treatment with the third dosage regimen; and

(c) terminating administration of the third dosage regimen after the occurrence of the third Grade 3 nonhematologic toxicity until the third Grade 3 nonhematologic toxicity is resolved to Grade 0-1 or baseline, and, if the body weight of the human subject is equal to or more than 60 kg, administering to the human subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day.

2. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg,

wherein the human subject develops an occurrence of a first persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the first persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity until the first persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity is resolved to Grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg, wherein the human subject develops an occurrence of a second persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity until the second persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity is resolved to Grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg every other day if the body weight of the human subject is less than 60 kg, wherein the human subject develops an occurrence of a third persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity during treatment with the third dosage regimen; and

(c) terminating administration of the third dosage regimen after the occurrence of the third persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity until the third persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity is resolved to Grade 0-1 or baseline, and, if the body weight of the human subject is equal to or more than 60 kg, administering to the human subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day.

3. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg,

wherein the human subject develops an occurrence of a first persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the first persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality until the first persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg, wherein the human subject develops an occurrence of a second persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality until the second persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg every other day if the body weight of the human subject is less than 60 kg, wherein the human subject develops an occurrence of a third persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality during treatment with the third dosage regimen; and

(c) terminating administration of the third dosage regimen after the occurrence of the third persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality until the third persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, and, if the body weight of the human subject is equal to or more than 60 kg, administering to the human subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day.

4. The method of claim 1 , wherein the human subject develops an occurrence of a Grade 4 nonhematologic toxicity excluding non-life-threatening Grade 4 laboratory abnormality during treatment with the first, second, third or fourth dosage regimen, and the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 nonhematologic toxicity excluding the non-life-threatening Grade 4 laboratory abnormality.

5. The method of claim 1 , wherein medical management of each of the first, second, and third persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicities or non-life-threatening Grade 4 laboratory abnormality is initiated prior to terminating administration of the dosage regimen administered at the time of onset of the Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality.

6. The method of claim 1 , wherein the first persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality is the same as the second and/or third persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality.

7. The method of claim 1 , wherein the Grade 3 nonhematologic toxicity is selected from the group consisting of Grade 3 hypertension, Grade 3 diarrhea, Grade 3 arthralgia, Grade 3 myalgia, Grade 3 decreased appetite, Grade 3 fatigue, Grade 3 decreased weight, Grade 3 dysphonia, Grade 3 nausea, Grade 3 abdominal pain, Grade 3 QT/QTc interval prolongation, Grade 3 hypothyroidism, Grade 3 vomiting, Grade 3 constipation, Grade 3 rash, and Grade 3 palmar-plantar erythrodysesthesia.

8. The method of claim 2 , wherein the Grade 2 or Grade 3 nonhematologic toxicity is selected from the group consisting of Grade 3 hypertension, Grade 2 hypertension, Grade 3 diarrhea, Grade 2 diarrhea, Grade 3 decreased appetite, Grade 2 decreased appetite, Grade 3 arthralgia, Grade 2 arthralgia, Grade 3 myalgia, Grade 2 myalgia, Grade 3 fatigue, Grade 2 fatigue, Grade 3 decreased weight, Grade 2 decreased weight, Grade 2 alopecia, Grade 3 dysphonia, Grade 2 dysphonia, Grade 3 nausea, Grade 2 nausea, Grade 3 abdominal pain, Grade 2 abdominal pain, Grade 3 QT/QTc interval prolongation, Grade 2 QT/QTc interval prolongation, Grade 3 hypothyroidism, Grade 2 hypothyroidism, Grade 3 vomiting, Grade 2 vomiting, Grade 3 constipation, Grade 2 constipation, Grade 3 rash, Grade 2 rash, Grade 3 palmar-plantar erythrodysesthesia, and Grade 2 palmar-plantar erythrodysesthesia.

9. The method of claim 3 , wherein the Grade 4 laboratory abnormality is selected from the group consisting of Grade 4 increase in aspartate aminotransferase, Grade 4 increase in alanine aminotransferase, Grade 4 increase in alkaline phosphatase, Grade 4 hypokalemia, Grade 4 hyponatremia, Grade 4 hypoglycemia, Grade 4 increase in blood bilirubin, and Grade 4 increase in gamma glutamyl transferase.

10. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma:

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg, and wherein the human subject developed an occurrence of a Grade 3 nonhematologic toxicity during treatment with the prior dosage regimen;

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg every other day if the body weight of the human subject is less than 60 kg, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg, and wherein the human subject developed an occurrence of a Grade 3 nonhematologic toxicity during treatment with the prior dosage regimen; or

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day, wherein the body weight of the human subject is equal to or more than 60 kg, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject developed an occurrence of a Grade 3 nonhematologic toxicity during treatment with the prior dosage regimen.

11. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma:

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg, and wherein the human subject developed an occurrence of a persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity during treatment with the prior dosage regimen;

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg every other day if the body weight of the human subject is less than 60 kg, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg, and wherein the human subject developed an occurrence of a persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity during treatment with the prior dosage regimen; or

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day, wherein the body weight of the human subject is equal to or more than 60 kg, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject developed an occurrence of a persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity during treatment with the prior dosage regimen.

12. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma:

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg, and wherein the human subject developed an occurrence of a persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality during treatment with the prior dosage regimen;

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg every other day if the body weight of the human subject is less than 60 kg, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg, and wherein the human subject developed an occurrence of a persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality during treatment with the prior dosage regimen; or

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day, wherein the body weight of the human subject is equal to or more than 60 kg, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject developed an occurrence of a persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality during treatment with the prior dosage regimen.

13. The method of claim 10 , wherein the Grade 3 nonhematologic toxicity is selected from the group consisting of Grade 3 hypertension, Grade 3 diarrhea, Grade 3 arthralgia, Grade 3 myalgia, Grade 3 decreased appetite, Grade 3 fatigue, Grade 3 decreased weight, Grade 3 dysphonia, Grade 3 nausea, Grade 3 abdominal pain, Grade 3 QT/QTc interval prolongation, Grade 3 hypothyroidism, Grade 3 vomiting, Grade 3 constipation, Grade 3 rash, and Grade 3 palmar-plantar erythrodysesthesia.

14. The method of claim 11 , wherein the Grade 2 or Grade 3 nonhematologic toxicity is selected from the group consisting of Grade 3 hypertension, Grade 2 hypertension, Grade 3 diarrhea, Grade 2 diarrhea, Grade 3 decreased appetite, Grade 2 decreased appetite, Grade 3 arthralgia, Grade 2 arthralgia, Grade 3 myalgia, Grade 2 myalgia, Grade 3 fatigue, Grade 2 fatigue, Grade 3 decreased weight, Grade 2 decreased weight, Grade 2 alopecia, Grade 3 dysphonia, Grade 2 dysphonia, Grade 3 nausea, Grade 2 nausea, Grade 3 abdominal pain, Grade 2 abdominal pain, Grade 3 QT/QTc interval prolongation, Grade 2 QT/QTc interval prolongation, Grade 3 hypothyroidism, Grade 2 hypothyroidism, Grade 3 vomiting, Grade 2 vomiting, Grade 3 constipation, Grade 2 constipation, Grade 3 rash, Grade 2 rash, Grade 3 palmar-plantar erythrodysesthesia, and Grade 2 palmar-plantar erythrodysesthesia.

15. The method of claim 12 , wherein the Grade 4 laboratory abnormality is selected from the group consisting of Grade 4 increase in aspartate aminotransferase, Grade 4 increase in alanine aminotransferase, Grade 4 increase in alkaline phosphatase, Grade 4 hypokalemia, Grade 4 hyponatremia, Grade 4 hypoglycemia, Grade 4 increase in blood bilirubin, and Grade 4 increase in gamma glutamyl transferase.

16. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg,

(I) wherein the human subject develops an occurrence of a first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality until the first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg, wherein the human subject develops an occurrence of a second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality until the second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg every other day if the body weight of the human subject is less than 60 kg, wherein the human subject develops an occurrence of a third persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality during treatment with the third dosage regimen; and

(c) terminating administration of the third dosage regimen after the occurrence of the third persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality until the third persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, and, if the body weight of the human subject is equal to or more than 60 kg, administering to the human subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day; or

(II) wherein the human subject develops an occurrence of a Grade 4 adverse reaction excluding Grade 4 laboratory abnormality during treatment with the first, second, third, or fourth dosage regimen, and the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality;

provided that Grade 3 hypertension, Grade 4 hypertension, Grade 3 cardiac dysfunction, Grade 4 cardiac dysfunction, any grade arterial thromboembolic event, Grade 3 hepatotoxicity, Grade 4 hepatotoxicity, 2 g or greater proteinuria in 24 hours, Grade 3 renal failure or impairment, Grade 4 renal failure or impairment, any Grade gastrointestinal perforation, Grade 3 fistula, Grade 4 fistula, a greater than 500 ms QT/QTc interval prolongation, a greater than 60 ms increase from baseline QT/QTc interval prolongation, and any Grade reversible posterior leukoencephalopathy syndrome are excluded from the persistent and intolerable Grade 2, Grade 3, or Grade 4 adverse reaction or Grade 4 laboratory abnormality.

17. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg,

(I) wherein the human subject develops an occurrence of a first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the occurrence of the first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality until the first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg; or

(II) wherein the human subject develops an occurrence of a Grade 4 adverse reaction excluding Grade 4 laboratory abnormality during treatment with the first dosage regimen, and the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality;

provided that Grade 3 hypertension, Grade 4 hypertension, Grade 3 cardiac dysfunction, Grade 4 cardiac dysfunction, any grade arterial thromboembolic event, Grade 3 hepatotoxicity, Grade 4 hepatotoxicity, 2 g or greater proteinuria in 24 hours, Grade 3 renal failure or impairment, Grade 4 renal failure or impairment, any Grade gastrointestinal perforation, Grade 3 fistula, Grade 4 fistula, a greater than 500 ms QT/QTc interval prolongation, a greater than 60 ms increase from baseline QT/QTc interval prolongation, and any Grade reversible posterior leukoencephalopathy syndrome are excluded from the persistent and intolerable Grade 2, Grade 3 or Grade 4 adverse reaction or Grade 4 laboratory abnormality.

18. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg,

(I) wherein the human subject develops an occurrence of a first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality until the first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg, wherein the human subject develops an occurrence of a second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality until the second persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 4 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg every other day if the body weight of the human subject is less than 60 kg, wherein the human subject develops an occurrence of a third persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality during treatment with the third dosage regimen; and

(c) terminating administration of the third dosage regimen after the occurrence of the third persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality until the third persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, and, if the body weight of the human subject is equal to or more than 60 kg, administering to the human subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day; or

(II) wherein the human subject develops an occurrence of a Grade 4 adverse reaction excluding Grade 4 laboratory abnormality during treatment with the first, second, third, or fourth dosage regimen, and the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality;

provided that hypertension, cardiac dysfunction, arterial thromboembolic event, hepatotoxicity, proteinuria, renal failure or impairment, gastrointestinal perforation, fistula, QT/QTc interval prolongation, and reversible posterior leukoencephalopathy syndrome are excluded from the persistent and intolerable Grade 2, Grade 3, or Grade 4 adverse reaction or Grade 4 laboratory abnormality.

19. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg,

(I) wherein the human subject develops an occurrence of a first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the occurrence of the first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality until the first persistent and intolerable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved to Grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg; or

(II) wherein the human subject develops an occurrence of a Grade 4 adverse reaction excluding Grade 4 laboratory abnormality during treatment with the first dosage regimen, and the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality;

provided that hypertension, cardiac dysfunction, arterial thromboembolic event, hepatotoxicity, proteinuria, renal failure or impairment, gastrointestinal perforation, fistula, QT/QTc interval prolongation, and reversible posterior leukoencephalopathy syndrome are excluded from the persistent and intolerable Grade 2, Grade 3, or Grade 4 adverse reaction or Grade 4 laboratory abnormality.

20. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg,

wherein the human subject develops an occurrence of a Grade 3 hypertension during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the occurrence of the Grade 3 hypertension until the Grade 3 hypertension is controlled at less than or equal to Grade 2, and administering to the human subject the second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg.

21. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg,

wherein the human subject develops an occurrence of a 2 g or greater proteinuria in 24 hours during treatment with the first dosage regimen, and the method further comprises terminating administration of the dosage regimen after the occurrence of the 2 g or greater proteinuria in 24 hours until the proteinuria is less than or equal to 2 g of proteinuria in 24 hours and, administering to the human subject the second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg,

provided that the human subject develops an occurrence of a nephrotic syndrome during treatment with the first dosage regimen, and the method further comprises terminating administration of the dosage regimen after the occurrence of the nephrotic syndrome.

22. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 12 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 8 mg/day if the body weight of the human subject is less than 60 kg,

wherein the human subject develops an occurrence of a greater than 500 ms QT/QTc interval prolongation or a greater than 60 ms increase from baseline QT/QTc interval prolongation during treatment with the first dosage regimen, and the method further comprises terminating administration of the dosage regimen after the occurrence of the greater than 500 ms QT/QTc interval prolongation or a greater than 60 ms increase from baseline QT/QTc interval prolongation until the QT/QTc interval prolongation improves to less than or equal to 480 ms or baseline and, administering to the human subject the second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of (i) 8 mg/day if the body weight of the human subject is equal to or more than 60 kg or (ii) 4 mg/day if the body weight of the human subject is less than 60 kg.

23. The method of claim 1 , wherein lenvatinib or the pharmaceutically acceptable salt thereof is formulated as a capsule.

24. The method of claim 1 , wherein lenvatinib or the pharmaceutically acceptable salt thereof is administered to the human subject orally.

25. The method of claim 1 , wherein lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate.

Assignments (1)

Continuity (3)

References Cited (400)