WO2018212202A1 - Treatment of hepatocellular carcinoma - Google Patents

Treatment of hepatocellular carcinoma Download PDF

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Publication number
WO2018212202A1
WO2018212202A1 PCT/JP2018/018810 JP2018018810W WO2018212202A1 WO 2018212202 A1 WO2018212202 A1 WO 2018212202A1 JP 2018018810 W JP2018018810 W JP 2018018810W WO 2018212202 A1 WO2018212202 A1 WO 2018212202A1
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grade
human subject
dosage regimen
occurrence
day
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PCT/JP2018/018810
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English (en)
French (fr)
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Toshiyuki Tamai
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Eisai R&D Management Co Ltd
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Eisai R&D Management Co Ltd
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Priority to BR112019023064A priority Critical patent/BR112019023064A2/pt
Priority to US16/609,895 priority patent/US20200197384A1/en
Priority to CA3061888A priority patent/CA3061888A1/en
Priority to JP2019559868A priority patent/JP2020519576A/ja
Priority to SG11201910100P priority patent/SG11201910100PA/en
Priority to CN201880028701.2A priority patent/CN110831597A/zh
Priority to MX2019013014A priority patent/MX2019013014A/es
Priority to KR1020197032983A priority patent/KR20200013644A/ko
Application filed by Eisai R&D Management Co Ltd filed Critical Eisai R&D Management Co Ltd
Priority to RU2019134940A priority patent/RU2019134940A/ru
Priority to EP18801285.0A priority patent/EP3624800A4/en
Priority to AU2018269996A priority patent/AU2018269996A1/en
Publication of WO2018212202A1 publication Critical patent/WO2018212202A1/en
Anticipated expiration legal-status Critical
Priority to US17/407,742 priority patent/US12226409B2/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application relates generally to methods of treating hepatocellular carcinoma.
  • Hepatocellular carcinoma is the second leading cause of cancer death worldwide and is responsible for nearly 745,000 deaths each year. It usually occurs in a background of chronic liver disease, particularly in cirrhosis, which limits the feasibility of surgical resection.
  • Sorafenib an oral multikinase inhibitor, extends overall survival when used as a first-line treatment for HCC, demonstrating a median improvement of 2.8 months compared with placebo (10.7 months vs. 7.9 months; hazard ratio [HR]: 0.69; P ⁇ 0.001) despite a low response rate of 2% (Llovet, N Engl. J Med., 359:378-390, 2008).
  • This disclosure relates, in part, to methods of treating a subject with a HCC (e.g., advanced HCC, unresectable HCC (uHCC), or advanced uHCC) with lenvatinib or a pharmaceutically acceptable salt thereof.
  • a HCC e.g., advanced HCC, unresectable HCC (uHCC), or advanced uHCC
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered as a first-line single agent to patients with unresectable HCC.
  • the dosage of lenvatinib or a pharmaceutically acceptable salt thereof is modified upon the occurrence of one or more adverse events in the treated subject.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma a dosage regimen of lenvatinib or a pharmaceutically acceptable salt thereof that is: (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.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered orally.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered once daily.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered orally, once daily.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen of lenvatinib or a pharmaceutically acceptable salt thereof that is 8 mg/day.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered orally.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered once daily.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered orally, once daily.
  • a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a specified dose means that lenvatinib or a pharmaceutically acceptable salt thereof is present in the dosage regimen at the specified dose.
  • a dosage regimen can contain additional components, lenvatinib or a pharmaceutically acceptable salt thereof is present only at the specific dose listed.
  • the dose of lenvatinib or a pharmaceutically acceptable salt thereof e.g., 12 mg, 8 mg, or 4 mg
  • the disclosure provides a method of treating unresectable hepatocellular carcinoma that comprises 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.
  • the human subject develops an occurrence of a first Grade 3 nonhematologic toxicity during treatment with the first dosage regimen.
  • the method further comprises 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.
  • the human subject develops an occurrence of a second Grade 3 nonhematologic toxicity during treatment with the second dosage regimen.
  • the method further comprises 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.
  • the human subject develops an occurrence of a third Grade 3 nonhematologic toxicity during treatment with the third dosage regimen.
  • the method further comprises 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.
  • the disclosure provides a method of treating unresectable hepatocellular carcinoma that comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • the method further comprises 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 4 mg/day.
  • the human subject develops an occurrence of a second Grade 3 nonhematologic toxicity during treatment with the second dosage regimen.
  • the method further comprises 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 4 mg every other day.
  • the human subject develops an occurrence of a third Grade 3 nonhematologic toxicity during treatment with the third dosage regimen.
  • the method further comprises terminating administration of the third dosage regimen after the occurrence of the third Grade 3 nonhematologic toxicity.
  • the disclosure provides a method of treating unresectable hepatocellular carcinoma that comprises 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.
  • 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.
  • 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 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.
  • 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.
  • the method further comprises 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.
  • 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.
  • the method further comprises 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.
  • the disclosure provides a method of treating unresectable hepatocellular carcinoma that comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • 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.
  • 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 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 4 mg/day.
  • 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.
  • the method further comprises 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 4 mg every other day.
  • 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.
  • the method further comprises terminating administration of the third dosage regimen after the occurrence of the third persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity.
  • the disclosure provides a method of treating unresectable hepatocellular carcinoma that comprises 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.
  • 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.
  • 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 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.
  • 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.
  • the method further comprises 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.
  • 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.
  • the method further comprises 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.
  • the disclosure provides a method of treating unresectable hepatocellular carcinoma that comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • 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.
  • 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 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 4 mg/day.
  • 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.
  • the method further comprises 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 4 mg every other day.
  • 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.
  • the method further comprises 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.
  • the human subject does not develop an occurrence of a second persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life threatening Grade 4 laboratory abnormality.
  • the method further comprises continuing administration of the second dosage regimen to the human subject (i.e., not lowering the dose being given in the second dosage regimen).
  • the human subject does not develop an occurrence of a third persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life threatening Grade 4 laboratory abnormality.
  • the method further comprises continuing administration of the third dosage regimen to the human subject (i.e., not lowering the dose being given in the third dosage regimen).
  • the human subject develops an occurrence of a Grade 4 nonhematologic toxicity excluding a non-life-threatening Grade 4 laboratory abnormality during treatment with the above dosage regimens.
  • the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 nonhematologic toxicity excluding non-life-threatening Grade 4 laboratory abnormality.
  • the disclosure provides a method of treating unresectable hepatocellular carcinoma that comprises 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.
  • the human subject develops an occurrence of a first Grade 3 hematologic toxicity or proteinuria during treatment with the first dosage regimen.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first Grade 3 hematologic toxicity or proteinuria until the first Grade 3 hematologic toxicity or proteinuria is resolved to Grade 0-2 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) 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.
  • the human subject develops an occurrence of a second Grade 3 hematologic toxicity or proteinuria during treatment with the second dosage regimen.
  • the method further comprises terminating administration of the second dosage regimen after the occurrence of the second Grade 3 hematologic toxicity or proteinuria until the second Grade 3 hematologic toxicity or proteinuria is resolved to Grade 0-2 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) 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.
  • the human subject develops an occurrence of a third Grade 3 hematologic toxicity or proteinuria during treatment with the third dosage regimen.
  • the method further comprises terminating administration of the third dosage regimen after the occurrence of the third Grade 3 hematologic toxicity or proteinuria until the third Grade 3 hematologic toxicity or proteinuria is resolved to Grade 0-2 or baseline, and administering to the human subject a fourth 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.
  • the human subject develops an occurrence of a fourth Grade 3 hematologic toxicity or proteinuria during treatment with the fourth dosage regimen.
  • the method further comprises terminating administration of the fourth dosage regimen after the occurrence of the fourth Grade 3 hematologic toxicity or proteinuria until the fourth Grade 3 hematologic toxicity or proteinuria is resolved to Grade 0-2 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 fifth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day.
  • the disclosure provides a method of treating unresectable hepatocellular carcinoma that comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • the human subject develops an occurrence of a first Grade 3 hematologic toxicity or proteinuria during treatment with the first dosage regimen.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first Grade 3 hematologic toxicity or proteinuria until the first Grade 3 hematologic toxicity or proteinuria is resolved to Grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • the human subject develops an occurrence of a second Grade 3 hematologic toxicity or proteinuria during treatment with the second dosage regimen.
  • the method further comprises terminating administration of the second dosage regimen after the occurrence of the second Grade 3 hematologic toxicity or proteinuria until the second Grade 3 hematologic toxicity or proteinuria is resolved to Grade 0-2 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day.
  • the human subject develops an occurrence of a third Grade 3 hematologic toxicity or proteinuria during treatment with the third dosage regimen.
  • the method further comprises terminating administration of the third dosage regimen after the occurrence of the third Grade 3 hematologic toxicity or proteinuria until the third Grade 3 hematologic toxicity or proteinuria is resolved to Grade 0-2 or baseline, and 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.
  • the human subject develops an occurrence of a fourth Grade 3 hematologic toxicity or proteinuria during treatment with the fourth dosage regimen.
  • the method further comprises terminating administration of the fourth dosage regimen after the occurrence of the fourth Grade 3 hematologic toxicity or proteinuria.
  • the method further comprises continuing administration of the second dosage regimen to the human subject (i.e., not lowering the dose being given in the second dosage regimen).
  • the method further comprises continuing administration of the third dosage regimen to the human subject (i.e., not lowering the dose being given in the third dosage regimen).
  • the method further comprises continuing administration of the fourth dosage regimen to the human subject (i.e., not lowering the dose being given in the fourth dosage regimen).
  • the disclosure provides 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 comprises 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.
  • a first dosage regimen comprises 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.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first Grade 4 hematologic toxicity until the first Grade 4 hematologic toxicity is resolved to Grade 0-2 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.
  • the human subject develops an occurrence of a second Grade 4 hematologic toxicity during treatment with the second dosage regimen.
  • the method further comprises terminating administration of the second dosage regimen after the occurrence of the second Grade 4 hematologic toxicity until the second Grade 4 hematologic toxicity is resolved to Grade 0-2 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.
  • the human subject develops an occurrence of a third Grade 4 hematologic toxicity during treatment with the third dosage regimen.
  • the method further comprises terminating administration of the third dosage regimen after the occurrence of the third Grade 4 hematologic toxicity until the third Grade 4 hematologic toxicity is resolved to Grade 0-2 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.
  • the disclosure provides a method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprises lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • a first dosage regimen comprises lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • the human subject develops an occurrence of a first Grade 4 hematologic toxicity during treatment with the first dosage regimen.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first Grade 4 hematologic toxicity until the first Grade 4 hematologic toxicity is resolved to Grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day.
  • the human subject develops an occurrence of a second Grade 4 hematologic toxicity during treatment with the second dosage regimen.
  • the method further comprises terminating administration of the second dosage regimen after the occurrence of the second Grade 4 hematologic toxicity until the second Grade 4 hematologic toxicity is resolved to Grade 0-2 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day.
  • the human subject develops an occurrence of a third Grade 4 hematologic toxicity during treatment with the third dosage regimen.
  • the method further comprises terminating administration of the third dosage regimen after the occurrence of the third Grade 4 hematologic toxicity.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first Grade 3 hematologic toxicity or proteinuria excluding non-clinically relevant laboratory abnormality until the first Grade 3 hematologic toxicity or proteinuria excluding non-clinically relevant laboratory abnormality is resolved to Grade 0-2 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) 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.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first Grade 4 hematologic toxicity until the first Grade 4 hematologic toxicity is resolved to Grade 0-2 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.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first persistent and intolerable Grade 2 nonhematologic toxicity, and with or without interruption of the fist dosage regimen until the first persistent and intolerable Grade 2 nonhematologic toxicity is resolved to Grade 0-1 or baseline, 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.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first Grade 3 nonhematologic toxicity excluding non-clinically relevant laboratory abnormality until the first Grade 3 nonhematologic toxicity excluding non-clinically relevant 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.
  • the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 nonhematologic toxicity excluding nonlife-threatening laboratory abnormality.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first Grade 3 hematologic toxicity or proteinuria excluding non-clinically relevant laboratory abnormality until the first Grade 3 hematologic toxicity or proteinuria excluding non-clinically relevant laboratory abnormality is resolved to Grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first Grade 4 hematologic toxicity until the first Grade 4 hematologic toxicity is resolved to Grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first persistent and intolerable Grade 2 nonhematologic toxicity, and with or without interruption of the fist dosage regimen until the first persistent and intolerable Grade 2 nonhematologic toxicity is resolved to Grade 0-1 or baseline, administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day.
  • the method further comprises terminating administration of the first dosage regimen after the occurrence of the first Grade 3 nonhematologic toxicity excluding non-clinically relevant laboratory abnormality until the first Grade 3 nonhematologic toxicity excluding non-clinically relevant 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 4 mg/day.
  • the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 nonhematologic toxicity excluding nonlife-threatening laboratory abnormality.
  • the method further comprises continuing administration of the second dosage regimen to the human subject (i.e., not lowering the dose being given in the second dosage regimen).
  • the method further comprises continuing administration of the third dosage regimen to the human subject (i.e., not lowering the dose being given in the third dosage regimen).
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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.
  • the method comprises 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) 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.
  • the method comprises 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 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject developed an occurrence of a Grade 3 nonhematologic toxicity during treatment with the prior dosage regimen.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day, 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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.
  • the method comprises 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) 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.
  • the method comprises 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 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 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.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day, 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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
  • the method comprises 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) 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.
  • the method comprises 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 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 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.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day, 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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) 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 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 hematologic toxicity or proteinuria during treatment with the prior dosage regimen.
  • the method comprises 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 hematologic toxicity or proteinuria during treatment with the prior dosage regimen.
  • the method comprises 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) 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 hematologic toxicity or proteinuria during treatment with the prior dosage regimen.
  • the method comprises 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 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 hematologic toxicity or proteinuria during treatment with the prior dosage regimen.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject developed an occurrence of a Grade 3 hematologic toxicity or proteinuria during treatment with the prior dosage regimen.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject developed an occurrence of a Grade 3 hematologic toxicity or proteinuria during treatment with the prior dosage regimen.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day, 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 hematologic toxicity or proteinuria during treatment with the prior dosage regimen.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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 4 hematologic toxicity during treatment with the prior dosage regimen.
  • the method comprises 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) 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 4 hematologic toxicity during treatment with the prior dosage regimen.
  • the method comprises 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 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 4 hematologic toxicity during treatment with the prior dosage regimen.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a prior dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject developed an occurrence of a Grade 4 hematologic toxicity during treatment with the prior dosage regimen.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day, 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 4 hematologic toxicity during treatment with the prior dosage regimen.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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.
  • 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.
  • 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, 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.
  • the method further comprises 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.
  • the method further comprises 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.
  • the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality.
  • 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • 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.
  • 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 4 mg/day, 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.
  • the method further comprises 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 4 mg every other day, 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.
  • the method further comprises 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.
  • the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality.
  • 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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.
  • 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.
  • the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • 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 4 mg/day.
  • the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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.
  • 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.
  • 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, 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.
  • the method further comprises 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.
  • the method further comprises 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.
  • the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality.
  • 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • 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.
  • 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 4 mg/day, 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.
  • the method further comprises 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 4 mg every other day, 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.
  • the method further comprises 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.
  • the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality.
  • 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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.
  • 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.
  • the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality.
  • 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • 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 4 mg/day.
  • the method further comprises terminating administration of the dosage regimen after the occurrence of the Grade 4 adverse reaction excluding Grade 4 laboratory abnormality.
  • 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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.
  • 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • 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 4 mg/day.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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.
  • 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.
  • 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • 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 4 mg/day.
  • 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises 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.
  • 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.
  • the disclosure features a method of treating unresectable hepatocellular carcinoma.
  • the method comprises administering to a human subject that has an unresectable hepatocellular carcinoma and moderate hepatic impairment classified in Child-Pugh class B under Child-Pugh Classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • 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 4 mg/day if the body weight of the human subject is less than 60 kg.
  • median overall survival is 13.6 months.
  • median overall survival with 95% confidence interval is between 12.1 and 14.9 months.
  • hazard ratio of overall survival compared with sorafenib at a dosage of 400 mg twice daily is 0.92.
  • hazard ratio of overall survival compared with sorafenib at a dosage of 400 mg twice daily with 95% confidence interval is between 0.79 and 1.06.
  • Fig. 1 Kaplan-Meier Plot of Overall Survival
  • median progression-free survival is 7.4 months.
  • median progression-free survival with 95% confidence interval is between 6.9 to 8.8 months.
  • hazard ratio of progression-free survival compared with sorafenib at a dosage of 400 mg twice daily is 0.66.
  • hazard ratio of progression-free survival compared with sorafenib at a dosage of 400 mg twice daily with 95% confidence interval is between 0.57 and 0.77.
  • progression-free survival is shown in Fig. 2 (Kaplan-Meier Plot of Progression-Free Survival).
  • median time to progression is 8.9 months.
  • median time to progression with 95% confidence interval is between 7.4 to 9.2 months.
  • hazard ratio of time to progression compared with sorafenib at a dosage of 400 mg twice daily is 0.63.
  • hazard ratio of time to progression compared with sorafenib at a dosage of 400 mg twice daily with 95% confidence interval is between 0.53 and 0.73.
  • time to progression is shown in Fig. 6 (Kaplan-Meier Plot of Time to Progression).
  • the objective response rate is 24.1%.
  • the odds ratio of objective response rate compared with sorafenib at a dosage of 400 mg twice daily is 3.13.
  • the odds ratio of objective response rate compared with sorafenib at a dosage of 400 mg twice daily with 95% confidence interval is between 2.15 to 4.56.
  • the method comprises achieving the results shown in Table 2 or Table 10 (Efficacy Results in HCC).
  • the method comprises achieving the results shown in Fig. 15 (Quality of Life).
  • the human subject consists essentially of the subject with mild hepatic impairment classified in Child-Pugh class A under Child-Pugh Classification.
  • the human subject is categorized to stage B or stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system.
  • BCLC Barcelona Clinic Liver Cancer
  • 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.
  • medical management of each of the first, second, third, and fourth Grade 3 hematologic toxicities or proteinuria is initiated prior to terminating administration of the dosage regimen administered at the time of onset of the Grade 3 hematologic toxicities or proteinuria.
  • medical management of each of the first, second, and third Grade 4 hematologic toxicities is initiated prior to terminating administration of the dosage regimen administered at the time of onset of the Grade 4 hematologic toxicities.
  • 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.
  • the first Grade 3 hematologic toxicity or proteinuria is the same as the second and/or third Grade 3 hematologic toxicity or proteinuria.
  • the first Grade 4 hematologic toxicity is the same as the second and/or third Grade 4 hematologic toxicity.
  • the Grade 3 nonhematologic toxicity is selected from the group consisting of Grade 3 hypertension, Grade 3 diarrhea, Grade 3 decreased appetite, Grade 3 fatigue, Grade 3 arthralgia, Grade 3 myalgia, 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.
  • 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 fatigue, Grade 2 fatigue, Grade 3 arthralgia, Grade 2 arthralgia, Grade 3 myalgia, Grade 2 myalgia, 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.
  • 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.
  • the Grade 3 hematologic toxicity or proteinuria is selected from the group consisting of Grade 3 proteinuria, Grade 3 thrombopenia (thrombocytopenia), Grade 3 anemia, Grade 3 decrease in white blood cell count, Grade 3 neutropenia, and Grade 3 lymphocytopenia.
  • the Grade 4 hematologic toxicity is selected from the group consisting of Grade 4 thrombopenia (thrombocytopenia), Grade 4 anemia, Grade 4 decrease in white blood cell count, Grade 4 neutropenia, and Grade 4 lymphocytopenia.
  • lenvatinib or the pharmaceutically acceptable salt thereof is formulated as a capsule.
  • lenvatinib or the pharmaceutically acceptable salt thereof is administered to the human subject orally.
  • lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate.
  • hepatocellular carcinoma e.g., unresectable hepatocellular carcinoma
  • Fig. 1 depicts Kaplan-Meier estimates of overall survival by treatment group.
  • CI denotes confidence interval, and HR hazard ratio.
  • Fig. 2 shows progression-free survival by modified Response Evaluation Criteria in Solid Tumors (mRECIST).
  • CI denotes confidence interval, and HR hazard ratio.
  • Fig. 3 provides a subgroup analyses of overall survival indicating associated hazard ratio and 95% confidence interval.
  • AFP denotes alpha-fetoprotein, BCLC Barcelona Clinic Liver Cancer, CI confidence interval, and HR hazard ratio.
  • Fig. 4 provides subgroup analyses of progression-free survival indicating the associated hazard ratio and 95% confidence interval.
  • AFP denotes alpha-fetoprotein, BCLC Barcelona Clinic Liver Cancer, CI confidence interval, and HR hazard ratio.
  • Fig. 5 provides a schematic representation of the enrollment, randomization, and treatment of the 954 patients in the phase 3 trial.
  • Fig. 6 is a graph providing a Kaplan-Meier Estimate of time to progression.
  • CI denotes confidence interval, and HR hazard ratio.
  • Fig. 7 provides Forest plots indicating hazard ratios for time to progression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio.
  • Fig. 8 provides Forest plots indicating hazard ratios for time to progression in the subgroup analyses.
  • Fig. 9 provides Forest plots indicating hazard ratios for time to progression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio.
  • Fig. 10 provides Forest plots indicating hazard ratios for time to progression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio.
  • Fig. 11 depicts waterfall graphs of percentage change in summed diameter of target lesions. The percentage change in lesion size is shown from baseline to nadir. Fig.
  • Fig. 12 provides Forest plots indicating hazard ratios for time to progression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio.
  • Fig. 13 provides Forest plots indicating hazard ratios for time to progression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio.
  • Fig. 14 provides Forest plots indicating hazard ratios for time to progression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio.
  • Fig. 13 provides Forest plots indicating hazard ratios for time to progression in the subgroup analyses. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio.
  • Fig. 13 provides Forest plots indicating hazard ratio
  • This disclosure provides methods of treating a human subject that has a hepatocellular carcinoma (e.g., advanced HCC, unresectable HCC, or unresectable advanced HCC).
  • the method comprises administering to the subject a starting dose of lenvatinib or a pharmaceutically acceptable salt thereof.
  • the starting dose is determined based on the body weight of the subject: 12 mg/day if the body weight of the human subject is equal to or more than 60 kg, and 8 mg/day if the body weight of the human subject is less than 60 kg.
  • the human subject has moderate hepatic impairment classified in Child-Pugh class B under the Child-Pugh Classification, then the starting dose can be 8 mg/day regardless of the body weight of the subject.
  • the disclosure provides modifications of the treatment regimen as well as adjusted dosing regimens (reduced doses of lenvatinib or a pharmaceutically acceptable salt thereof). These dose modifications enable the subject to continue treatment with lenvatinib or a pharmaceutically acceptable salt thereof. If the subject does not develop an adverse reaction as a result of administration of a particular dose of lenvatinib or a pharmaceutically acceptable salt thereof, the subject can be maintained on the same dosage regimen.
  • liver cancer is the sixth most common cancer worldwide with approximately 782,000 new cases worldwide in 2012. A total of 83% of the world’s cases occur in less-developed regions and more than 50% occur in China alone; however, the incidence of liver cancer has been rising in a number of low-rate areas such as Australia, the United Kingdom, and the United States. In all populations, males have higher rates of liver cancer than do females. Liver cancer is the third most common cause of cancer death worldwide, accounting for an estimated 746,000 cancer deaths annually.
  • Hepatocellular carcinoma accounts for 85% to 90% of primary cancer of the liver and occurs predominantly in patients with underlying chronic liver disease, in particular cirrhosis.
  • Major causes of cirrhosis include hepatitis B virus (HBV), hepatitis C virus (HCV), and alcoholic liver disease.
  • Hepatitis B is the most frequent underlying cause of HCC, with an estimated 300 million people with chronic infection worldwide.
  • Chronic HBV carriers have a 5- to 15-fold increased risk of developing HCC compared with the general population.
  • Chronic HCV infection is also a major risk factor for HCC. The risk of HCC was 17-fold higher in HCV-infected patients compared with HCV-negative controls.
  • BCLC Barcelona Clinic Liver Cancer
  • the BCLC system categorizes HCC based on characteristics of the tumor, liver function, performance status, and cancer-related symptoms.
  • BCLC stage groupings include: Very early stage. The tumor is smaller than 2 cm. There is no increased pressure in the portal vein. Bilirubin levels are normal. Surgery is usually recommended. Early stage. The tumor is smaller than 5 cm. Liver function varies.
  • portal vein pressure and normal bilirubin levels There may be no increased pressure in the portal vein, increased portal vein pressure and normal bilirubin levels, or increased portal vein pressure and increased bilirubin levels.
  • People with early-stage disease may be candidates for a liver transplant, surgery, or radiofrequency ablation (RFA).
  • RFA radiofrequency ablation
  • the tumor may be large or there may be multiple tumors. Doctors usually recommend regional therapies, such as transarterial chemoembolization. Advanced stage. The tumor has invaded the portal vein or spread to other parts of the body, such as the lungs and bones. Targeted therapy is generally recommended.
  • HCC HCC-based guidelines for the diagnosis and treatment of HCC have been established and adopted (El-Serag, et al., Ann. Intern. Med., 139(10):817-23, 2003; Llovet, et al., Lancet, 362(9399):1907-17, 2003).
  • Recent technological advances for patients with early-stage HCC include surgical resection, localized treatments such as radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), cryotherapy and transarterial chemoembolization (TACE). Treatment options for HCC are determined by stage of the disease. For very early stage HCC, surgical resection is the treatment of choice in patients without cirrhosis.
  • RFA radiofrequency ablation
  • PEI percutaneous ethanol injection
  • TACE transarterial chemoembolization
  • orthotopic liver transplantation is the treatment option associated with the lowest risk of tumor recurrence.
  • RFA is likely the best alternative treatment, although PEI and cryoablation are also routinely performed.
  • Other locoregional treatment options for HCC include transarterial TACE, which has been shown to improve survival among patients with preserved liver function and unresectable HCC whose disease is either too large or too multifocal for percutaneous ablation techniques, as well as radioembolization, which has been used as palliative treatment in intermediate-stage HCC.
  • TACE transarterial TACE
  • radioembolization which has been used as palliative treatment in intermediate-stage HCC.
  • recurrence due to residual tumor cells is a clinical characteristic of HCC and ultimately leads to an advanced stage where surgery, RFA, and TACE are no longer appropriate.
  • This disclosure provides methods of treating unresectable HCC using lenvatinib or a pharmaceutically acceptable salt thereof.
  • Lenvatinib A number of kinase inhibitors have been developed as antitumor agents. For example, a group of compounds having inhibitory activity against receptor tyrosine kinases, such as vascular endothelial growth factor receptor (VEGFR), are known to inhibit angiogenesis and are regarded as a new class of antitumor agents.
  • Lenvatinib is a multi-target receptor tyrosine kinase inhibitor that inhibits the kinase activities of VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4).
  • Lenvatinib inhibits other receptor tyrosine kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, FGFR2, FGFR3, and FGFR4; rearranged during transfection receptor (RET), KIT, and platelet-derived growth factor receptor alpha (PDGFR ⁇ ).
  • FGF fibroblast growth factor
  • RET transfection receptor
  • KIT KIT
  • PDGFR ⁇ platelet-derived growth factor receptor alpha
  • Lenvatinib also exhibits antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2 ⁇ (FRS2 ⁇ ) phosphorylation.
  • salts include, but are not limited to, inorganic acid addition salt such as hydrochloric acid salt, sulfuric acid salt, carbonic acid salt, bicarbonate salt, hydrobromic acid salt, and hydriodic acid salt; organic carboxylic acid addition salt such as acetic acid salt, maleic acid salt, lactic acid salt, tartaric acid salt, and trifluoroacetic acid salt; organic sulfonic acid addition salt such as methanesulfonic acid salt, hydroxymethanesulfonic acid salt, hydroxyethanesulfonic acid salt, benzenesulfonic acid salt, toluenesulfonic acid salt, and taurine salt; amine addition salt such as trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N,N’-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylmethyl)
  • the pharmaceutically acceptable salt is a methanesulfonic acid salt (“mesylate”).
  • methanesulfonic acid salt form i.e., the mesylate
  • the chemical name of lenvatinib mesylate is 4-[3-chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate and it chemical structure is provided below:
  • Lenvatinib mesylate is also referred to as LENVIMA (registered trademark) .
  • Lenvatinib mesylate is a white to pale reddish yellow powder. It is slightly soluble in water and practically insoluble in ethanol (dehydrated).
  • the dissociation constant (pKa value) of lenvatinib mesylate is 5.05 at 25°C.
  • the partition coefficient (log P value) is 3.30.
  • lenvatinib was shown to be noninferior to sorafenib in overall survival (median 13.6 months with lenvatinib vs. 12.3 months with sorafenib; hazard ratio [HR]: 0.92; 95% confidence interval [CI], 0.79 to 1.06).
  • Lenvatinib prolonged progression-free survival (median 7.3 vs. 3.6 months; HR: 0.64; 95% CI, 0.55 to 0.75; P ⁇ 0.001) versus sorafenib.
  • lenvatinib improved progression-free survival, time to progression, and objective response rate versus sorafenib.
  • lenvatinib can be used for the treatment of HCC.
  • Lenvatinib or a pharmaceutically acceptable salt thereof may be administered orally to a human subject in need thereof (e.g., a human subject having advanced HCC, uHCC, or advanced uHCC) by any means that the health care provider deems useful.
  • the lenvatinib compound can be in the form of, e.g., a tablet, capsule, suspension, or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient(s) may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered to the human subject as a capsule.
  • the capsule can contain, lenvatinib or a pharmaceutically acceptable salt thereof (e.g., lenvatinib mesylate) equivalent to 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, or 12 mg of lenvatinib.
  • the capsule contains lenvatinib mesylate equivalent to 4 mg lenvatinib.
  • the capsule contains lenvatinib mesylate equivalent to 8 mg lenvatinib.
  • the capsule contains lenvatinib mesylate equivalent to 12 mg lenvatinib.
  • these capsules also contain one or more of the following inactive ingredients: calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropyl cellulose (type H), and talc.
  • the shell of these capsules is a hypromellose shell and can contain one or more of: titanium dioxide, ferric oxide yellow, and ferric oxide red.
  • the printing ink used on the capsule may contain one or more of: shellac, black iron oxide, potassium hydroxide, and propylene glycol.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered to the human subject at a dose of 12 mg once daily. This dose can be administered, e.g., as three 4 mg capsules orally once daily. In other embodiments, lenvatinib or a pharmaceutically acceptable salt thereof (e.g., lenvatinib mesylate) is administered to the human subject at a dose of 8 mg once daily. This dose can be administered, e.g., as two 4 mg capsules orally once daily.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered to the human subject at a dose of 4 mg once daily. This dose can be administered, e.g., as one 4 mg capsule orally once daily. In some embodiments, lenvatinib or a pharmaceutically acceptable salt thereof (e.g., lenvatinib mesylate) is administered to the human subject at a dose of 4 mg every other day. This dose can be administered, e.g., as one 4 mg capsule orally once every other day.
  • lenvatinib or a pharmaceutically acceptable salt thereof one time each day at about the same time, with or without food.
  • the patient may use a cup to measure about one tablespoon of water or apple juice into a glass and place the drug capsules into the liquid without breaking or crushing them.
  • the capsules should be left in the liquid for at least 10 minutes and the contents then stirred for at least 3 minutes. The patient can then drink this mixture. After drinking, the patient should rinse the glass with a small amount of additional water or apple juice and swallow the liquid.
  • lenvatinib or the pharmaceutically acceptable salt thereof is administered to a subject that has a HCC (e.g., advanced HCC or unresectable HCC) once daily for at least 7 weeks, at least 14 weeks, at least 28 weeks, at least 56 weeks, at least 84 weeks, at least 112 weeks, at least 140 weeks, at least 168 weeks, or at least 196 weeks.
  • HCC e.g., advanced HCC or unresectable HCC
  • a major problem in treating a subject with a new therapy is the development of a treatment-emergent adverse event(s) (TEAE).
  • TEAE treatment-emergent adverse event
  • a treatment-emergent adverse event is as any adverse event not present in the subject prior to the initiation of the treatment, or any adverse event already present that worsens in either intensity or frequency following exposure to the treatment.
  • the adverse event is a persistent and intolerable adverse event.
  • An Adverse Event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.
  • An AE is a term that is a unique representation of a specific event used for medical documentation and scientific analyses.
  • An AE can be graded. The CTCAE grade refers to the severity of the AE.
  • the CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this guideline: Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL).
  • Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
  • Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL).
  • Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.
  • Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
  • Grade 4 Life-threatening consequences; urgent intervention indicated.
  • Grade 5 Death related to AE.
  • the adverse event associated with therapy with lenvatinib or a pharmaceutically acceptable salt thereof is a persistent and intolerable AE.
  • the persistent and intolerable AE is a Grade 2 AE.
  • the persistent and intolerable AE is a Grade 3 AE.
  • the adverse event associated with the therapy using lenvatinib or a pharmaceutically acceptable salt thereof is a Grade 4 AE.
  • the persistent and intolerable AE is a Grade 4 laboratory abnormality.
  • the Grade 2 or Grade 3 AE is a nonhematological toxicity. In other cases, the Grade 3 or Grade 4 AE is a hematological toxicity. In yet other cases, the Grade 3 AE is proteinuria.
  • the most common adverse reactions observed in lenvatinib-treated HCC subjects were, in order of decreasing frequency, hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, and decreased weight.
  • Fatigue is a disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities and is graded as follows: Grade 1: Fatigue relieved by rest. Grade 2: Fatigue not relieved by rest or limiting instrumental activities of daily living (ADL). Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. Grade 3: Fatigue not relieved by rest, limiting self-care ADL. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. Grade 4: Grade is not available. Grade 5: Grade is not available.
  • Decreased appetite is a disorder characterized by a loss of appetite, and is graded as follows: Grade 1: Loss of appetite without alteration in eating habits Grade 2: Oral intake altered without significant weight loss or malnutrition; oral nutritional supplements indicated Grade 3: Associated with significant weight loss or malnutrition (e.g., inadequate oral caloric and/or fluid intake); tube feeding or TPN indicated Grade 4: Life-threatening consequences; urgent intervention indicated Grade 5: Death
  • Arthralgia is a disorder characterized by a sensation of marked discomfort in a joint, and is graded as follows: Grade 1: Mild pain Grade 2: Moderate pain; limiting instrumental ADL Grade 3: Severe pain; limiting self care ADL Grade 4: Not available Grade 5: Not available
  • Myalgia is a disorder characterized by marked discomfort sensation originating from a muscle or group of muscles, and is graded as follows: Grade 1: Mild pain Grade 2: Moderate pain; limiting instrumental ADL Grade 3: Severe pain; limiting self care ADL Grade 4: Not available Grade 5: Not available
  • Hepatic encephalopathy comprises hepatobiliary disorders, and is graded as follows: Grade 1: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self care ADL Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death
  • Hepatic failure is a disorder characterized by the inability of the liver to metabolize chemicals in the body. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic dehydrogenase, and alkaline phosphatase. Hepatic failure is graded as follows: Grade 1: Not available Grade 2: Not available Grade 3: Asterixis or mild encephalopathy or limiting self-care ADL Grade 4: Moderate to severe encephalopathy or coma or life-threatening consequences Grade 5: Death
  • Grade 1 Asymptomatic or clinical or diagnostic observations only or intervention not indicated
  • Grade 2 Symptomatic or medical intervention indicated
  • Grade 3 Severe symptoms or invasive intervention indicated
  • Grade 4 Life-threatening consequences or urgent operative intervention indicated
  • Grade 5 Death
  • Palmar-plantar erythrodysesthesia syndrome is a disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet, and is graded as follows:.
  • Grade 1 Minimal skin changes or dermatitis (e.g., erythema, edema, or hyperkeratosis) without pain
  • Grade 2 Skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting instrumental
  • Grade 3 Severe skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting self-care
  • ADL Grade 4 Not Available Grade 5: Not Available
  • Hyperbilirubinemia (“Blood bilirubin increased”) is a finding based on laboratory test results that indicate an abnormally high level of bilirubin in the blood. Excess bilirubin is associated with jaundice. Grade 1: > 1.0 ULN - 1.5 x ULN (upper limit of the normal range (ULN)). Grade 2: >1.5 ULN - 3.0 x ULN Grade 3: >3.0 ULN - 10.0 x ULN Grade 4: >10.0 x ULN Grade 5: Not Available
  • This disclosure provides dose modifications for therapy comprising lenvatinib or a pharmaceutically acceptable salt thereof upon the occurrence of a treatment-emergent adverse event(s) during the course of treatment.
  • a subject who has a baseline body weight of 60 kg or greater and who has a HCC is administered a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 12 mg/day.
  • a subject who has a baseline body weight of less than 60 kg and who has a HCC is administered a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day.
  • a subject who has HCC and has moderate hepatic impairment classified in Child-Pugh class B under the Child-Pugh Classification then the subject is administered a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose 8 mg/day regardless of the body weight of the subject.
  • Non-Hematologic Toxicity the subject may develop a Grade 1 or tolerable Grade 2 adverse reaction (e.g., nonhematological toxicity) after being administered the first dosage regimen.
  • treatment of the subject can continue without any changes to the first dosage regimen.
  • the first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 12 mg/day or 8 mg/day, if the human subject does not develop an intolerable Grade 2 or Grade 3 adverse reaction or non-life-threatening Grade 4 laboratory abnormality (e.g., nonhematological toxicity)
  • the dosage regimen can be maintained without any changes to the first dosage regimen.
  • the subject develops an intolerable Grade 2 or Grade 3 adverse reaction or non-life-threatening Grade 4 laboratory abnormality (e.g., non-hematologic toxicity) during the period of treatment with the first dosage regimen that is related to lenvatinib toxicity.
  • the subject develops a Grade 2 or Grade 3 non-hematologic toxicity or non-life-threatening Grade 4 laboratory abnormality within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks after the administration of the first dosage regimen.
  • the subject develops an intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality within 12 weeks after the administration of the first dosage regimen. In another embodiment, the subject develops an intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality within 16 weeks after the administration of the first dosage regimen.
  • the intolerable Grade 2 or Grade 3 non-hematologic toxicity is Grade 3 hypertension, Grade 2 hypertension, Grade 3 fatigue, Grade 2 fatigue, Grade 3 palmar-plantar erythrodysesthesia, Grade 2 palmar-plantar erythrodysesthesia, Grade 3 diarrhea, Grade 2 diarrhea, Grade 3 decreased appetite, Grade 2 decreased appetite, Grade 3 fatigue, Grade 2 fatigue, Grade 3 arthralgia, Grade 2 arthralgia, Grade 3 myalgia, Grade 2 myalgia, 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 (Electrocardiogram QT corrected interval prolonged), 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, and
  • the persistent and intolerable Grade 2 or Grade 3 non-hematologic toxicity is Grade 3 hypertension, Grade 2 hypertension, Grade 3 fatigue, Grade 2 fatigue, 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 decreased weight, or Grade 2 decreased weight.
  • Grade 2 toxicities can be determined to be tolerable or intolerable by both the subject and healthcare provider.
  • the Grade 4 laboratory abnormality is 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, or Grade 4 increase in gamma glutamyl transferase.
  • the healthcare provider can determine whether the Grade 4 laboratory abnormality is life-threatening or not.
  • the healthcare provider can terminate the first dosage regimen and administer to the subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day (if the patient has a baseline body weight of greater than or equal to 60 kg) or 4 mg/day (if the patient has a baseline body weight of less than 60 kg).
  • the second dosage regimen is administered after interruption of the first dosage regimen and after the nonhematologic toxicity observed after the first dosage regimen is resolved to Grade 0-1 or baseline.
  • the first dosage regimen is terminated only after commencement of medical management of the intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality.
  • the intolerable Grade 2 or Grade 3 adverse reaction is hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, or decreased weight.
  • the subject is provided antihypertensive therapy and treatment with lenvatinib or a pharmaceutically acceptable salt thereof is resumed at a lower dose (e.g., 8 or 4 mg/day) when hypertension is controlled at less than or equal to Grade 1; however, therapy with lenvatinib or a pharmaceutically acceptable salt thereof is discontinued for life-threatening hypertension.
  • a lower dose e.g. 8 or 4 mg/day
  • a subject may develop an adverse reaction (e.g., nonhematologic toxicity).
  • the subject develops an intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after the administration of the second dosage regimen.
  • the nonhematologic toxicity after the second dosage regimen may be the same as, or different from, the nonhematologic toxicity after the first dosage regimen.
  • the nonhematologic toxicity after the second dosage regimen may be an intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality.
  • the nonhematologic toxicity is hypertension. In some instances, the nonhematologic toxicity is fatigue. In some instances, the nonhematologic toxicity is arthralgia. In some instances, the nonhematologic toxicity is myalgia. In some instances, the nonhematologic toxicity is diarrhea. In some instances, the nonhematologic toxicity is decreased appetite. In some instances, the nonhematologic toxicity is decreased weight.
  • the healthcare provider can terminate the second dosage regimen and administer to the subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day (if the patient has a baseline body weight of greater than or equal to 60 kg) or 4 mg every other day (if the patient has a baseline body weight of less than 60 kg).
  • the third dosage regimen is administered after interruption of the second dosage regimen and after the nonhematologic toxicity observed after the second dosage regimen is resolved to Grade 0-1 or baseline.
  • the second dosage regimen is terminated only after commencement of medical management of the intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality.
  • the intolerable Grade 2 or Grade 3 nonhematologic toxicity is hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, or decreased weight.
  • the subject is provided antihypertensive therapy and treatment with lenvatinib or a pharmaceutically acceptable salt thereof is resumed at a lower dose (e.g., 4 mg every other day) when hypertension is controlled at less than or equal to Grade 1; however, therapy with lenvatinib or a pharmaceutically acceptable salt thereof is discontinued for life-threatening hypertension.
  • a lower dose e.g. 4 mg every other day
  • a subject may develop an adverse reaction (e.g., nonhematologic toxicity).
  • the subject develops an intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after the administration of the third dosage regimen.
  • the nonhematologic toxicity after the third dosage regimen may be the same as, or different from, the nonhematologic toxicity after the second dosage regimen.
  • the nonhematologic toxicity after the third dosage regimen may be an intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality.
  • the nonhematologic toxicity is hypertension. In some instances, the nonhematologic toxicity is fatigue. In some instances, the nonhematologic toxicity is arthralgia. In some instances, the nonhematologic toxicity is myalgia. In some instances, the nonhematologic toxicity is diarrhea. In some instances, the nonhematologic toxicity is decreased appetite. In some instances, the nonhematologic toxicity is decreased weight.
  • the healthcare provider can terminate the third dosage regimen and administer to the subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day (if the patient has a baseline body weight of greater than or equal to 60 kg).
  • lenvatinib therapy may be discontinued.
  • the fourth dosage regimen is administered after interruption of the third dosage regimen and after the nonhematologic toxicity observed after the third dosage regimen is resolved to Grade 0-1 or baseline.
  • the third dosage regimen is terminated only after commencement of medical management of the intolerable Grade 2 or Grade 3 nonhematologic toxicity or non-life-threatening Grade 4 laboratory abnormality.
  • the persistent and intolerable Grade 2 or Grade 3 nonhematologic toxicity is hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, or decreased weight.
  • the subject is provided antihypertensive therapy and treatment with lenvatinib or a pharmaceutically acceptable salt thereof is resumed at a lower dose when hypertension is controlled at less than or equal to Grade 1; however, therapy with lenvatinib or a pharmaceutically acceptable salt thereof is discontinued for life-threatening hypertension.
  • the healthcare provider can terminate administration of the dosage regimen after the occurrence of the Grade 4 nonhematologic toxicity excluding non-life-threatening Grade 4 laboratory abnormality.
  • a Grade 3 laboratory abnormality that is not clinically relevant based on a judgment of healthcare provider is excluded from a Grade 3 nonhematologic toxicity.
  • a Grade 3 proteinuria is excluded from a Grade 3 nonhematologic toxicity to those dosage regimens.
  • the subject may develop a Grade 1 or Grade 2 hematologic toxicity or Grade 1 or Grade 2 proteinuria during the period of treatment with the first dosage regimen (i.e., lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 12 mg/day (if the patient has a baseline body weight of greater than or equal to 60 kg) or 8 mg/day (if the patient has a baseline body weight of less than 60 kg)) that is related to lenvatinib toxicity.
  • the subject can continue with treatment with the first dosage regimen.
  • the subject may develop a Grade 3 adverse reaction (e.g., hematologic toxicity or proteinuria) during the period of treatment with the first dosage regimen that is related to lenvatinib toxicity.
  • a Grade 3 hematologic toxicity or Grade 3 proteinuria within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks after the administration of the first dosage regimen.
  • the subject develops a Grade 3 hematologic toxicity or Grade 3 proteinuria within 12 weeks after the administration of the first dosage regimen.
  • the subject develops a Grade 3 hematologic toxicity or Grade 3 proteinuria within 16 weeks after the administration of the first dosage regimen.
  • the Grade 3 hematologic toxicity is Grade 3 thrombopenia (thrombocytopenia; platelet count decreased), Grade 3 anemia (hemoglobin decreased), Grade 3 decrease in white blood cell count (leukocyte count decreased; white blood cell decreased), Grade 3 neutropenia (neutrophil count decreased), or Grade 3 lymphocytopenia (lymphocyte count decreased).
  • the healthcare provider can terminate the first dosage regimen and administer to the subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 12 mg/day (if the patient has a baseline body weight of greater than or equal to 60 kg) or 8 mg/day (if the patient has a baseline body weight of less than 60 kg).
  • the second dosage regimen is administered after interruption of the first dosage regimen and after the nonhematologic toxicity observed after the first dosage regimen is resolved to Grade 0-2 or baseline.
  • the first dosage regimen is terminated only after commencement of medical management of the Grade 3 hematologic toxicity.
  • the Grade 3 hematologic toxicity is Grade 3 thrombopenia (thrombocytopenia), Grade 3 anemia, Grade 3 decrease in white blood cell count, Grade 3 neutropenia, or Grade 3 lymphocytopenia.
  • a subject may develop a Grade 3 hematologic toxicity or Grade 3 proteinuria.
  • the subject develops a Grade 3 hematologic toxicity or Grade 3 proteinuria within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after the administration of the second dosage regimen.
  • the Grade 3 hematologic toxicity or Grade 3 proteinuria after the second dosage regimen may be the same as, or different from, the Grade 3 hematologic toxicity or Grade 3 proteinuria after the first dosage regimen.
  • the hematologic toxicity or proteinuria after the second dosage regimen may be a Grade 3 hematologic toxicity or Grade 3 proteinuria.
  • the healthcare provider can terminate the second dosage regimen and administer to the subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day (if the patient has a baseline body weight of greater than or equal to 60 kg) or 4 mg/day (if the patient has a baseline body weight of less than 60 kg).
  • the third dosage regimen is administered after interruption of the second dosage regimen and after the Grade 3 hematologic toxicity or Grade 3 proteinuria observed after the second dosage regimen is resolved to Grade 0-2 or baseline. In some instances, the second dosage regimen is terminated only after commencement of medical management of the Grade 3 hematologic toxicity or Grade 3 proteinuria.
  • a subject may develop a Grade 3 hematologic toxicity or Grade 3 proteinuria.
  • the subject develops a Grade 3 hematologic toxicity or Grade 3 proteinuria within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after the administration of the third dosage regimen.
  • the Grade 3 hematologic toxicity or Grade 3 proteinuria after the third dosage regimen may be the same as, or different from, the Grade 3 hematologic toxicity or Grade 3 proteinuria after the second dosage regimen.
  • the Grade 3 hematologic toxicity or Grade 3 proteinuria after the third dosage regimen may be a Grade 3 hematologic toxicity or Grade 3 proteinuria.
  • the healthcare provider can terminate the third dosage regimen and administer to the subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day (if the patient has a baseline body weight of greater than or equal to 60 kg) or 4 mg every other day (if the patient has a baseline body weight of less than 60 kg).
  • the fourth dosage regimen is administered after interruption of the third dosage regimen and after the Grade 3 hematologic toxicity or Grade 3 proteinuria observed after the third dosage regimen is resolved to Grade 0-2 or baseline.
  • the third dosage regimen is terminated only after commencement of medical management of the Grade 3 hematologic toxicity or Grade 3 proteinuria.
  • a subject may develop a Grade 3 hematologic toxicity or Grade 3 proteinuria.
  • the subject develops a Grade 3 hematologic toxicity or Grade 3 proteinuria within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after the administration of the third dosage regimen.
  • the Grade 3 hematologic toxicity or Grade 3 proteinuria after the third dosage regimen may be the same as, or different from, the Grade 3 hematologic toxicity or Grade 3 proteinuria after the second dosage regimen.
  • the Grade 3 hematologic toxicity or Grade 3 proteinuria after the third dosage regimen may be a Grade 3 hematologic toxicity or Grade 3 proteinuria.
  • the healthcare provider can terminate the fourth dosage regimen and administer to the subject a fifth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day (if the patient has a baseline body weight of greater than or equal to 60 kg).
  • lenvatinib treatment may be discontinued.
  • the fifth dosage regimen is administered after interruption of the fourth dosage regimen and after the Grade 3 hematologic toxicity or Grade 3 proteinuria observed after the third dosage regimen is resolved to Grade 0-2 or baseline.
  • the fourth dosage regimen is terminated only after commencement of medical management of the Grade 3 hematologic toxicity or Grade 3 proteinuria.
  • a Grade 3 laboratory abnormality that is not clinically relevant based on a judgment of healthcare provider is excluded from a Grade 3 hematologic toxicity.
  • the subject may develop a Grade 4 hematologic toxicity during the period of treatment with the first dosage regimen (i.e., lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 12 mg/day (if the patient has a baseline body weight of greater than or equal to 60 kg) or 8 mg/day (if the patient has a baseline body weight of less than 60 kg)) that is related to lenvatinib toxicity.
  • the first dosage regimen i.e., lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 12 mg/day (if the patient has a baseline body weight of greater than or equal to 60 kg) or 8 mg/day (if the patient has a baseline body weight of less than 60 kg)
  • the subject develops the Grade 4 hematologic toxicity within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks after the administration of the first dosage regimen.
  • the subject develops Grade 4 hematologic toxicity within 12 weeks after the administration of the first dosage regimen.
  • the subject develops the Grade 4 hematologic toxicity within 16 weeks after the administration of the first dosage regimen.
  • the Grade 4 hematologic toxicity is Grade 4 thrombopenia (thrombocytopenia; platelet count decreased), Grade 4 anemia, Grade 4 decrease in white blood cell count, Grade 4 neutropenia, or Grade 4 lymphocytopenia.
  • the healthcare provider can terminate the first dosage regimen and administer to the subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day (if the patient has a baseline body weight of greater than or equal to 60 kg) or 4 mg/day (if the patient has a baseline body weight of less than 60 kg).
  • the second dosage regimen is administered after interruption of the first dosage regimen and after the Grade 4 hematologic toxicity observed after the first dosage regimen is resolved to Grade 0-2 or baseline.
  • the first dosage regimen is terminated only after commencement of medical management of the Grade 4 hematologic toxicity.
  • the Grade 4 hematologic toxicity is Grade 4 thrombopenia (thrombocytopenia), Grade 4 anemia, Grade 4 decrease in white blood cell count, Grade 4 neutropenia, or Grade 4 lymphocytopenia.
  • a subject may develop a Grade 4 hematologic toxicity.
  • the subject develops a Grade 4 hematologic toxicity within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after the administration of the second dosage regimen.
  • the Grade 4 hematologic toxicity after the second dosage regimen may be the same as, or different from, the Grade 4 hematologic toxicity after the first dosage regimen.
  • the hematologic toxicity after the second dosage regimen may be a persistent and intolerable Grade 4 hematologic toxicity.
  • the healthcare provider can terminate the second dosage regimen and administer to the subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day (if the patient has a baseline body weight of greater than or equal to 60 kg) or 4 mg every other day (if the patient has a baseline body weight of less than 60 kg).
  • the third dosage regimen is administered after interruption of the second dosage regimen and after the Grade 4 hematologic toxicity observed after the second dosage regimen is resolved to Grade 0-2 or baseline. In some instances, the second dosage regimen is terminated only after commencement of medical management of the Grade 4 hematologic toxicity.
  • a subject may develop a Grade 4 hematologic toxicity.
  • the subject develops a Grade 4 hematologic toxicity within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after the administration of the third dosage regimen.
  • the Grade 4 hematologic toxicity after the third dosage regimen may be the same as, or different from, the Grade 4 hematologic toxicity after the second dosage regimen.
  • the Grade 4 hematologic toxicity after the third dosage regimen may be a persistent and intolerable Grade 4 hematologic toxicity.
  • the healthcare provider can terminate the third dosage regimen and administer to the subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg every other day (if the patient has a baseline body weight of greater than or equal to 60 kg). If the patient has a baseline body weight of less than 60 kg, lenvatinib therapy can, in some embodiments, be discontinued.
  • the fourth dosage regimen is administered after interruption of the third dosage regimen and after the Grade 4 hematologic toxicity observed after the third dosage regimen is resolved to Grade 0-2 or baseline. In some instances, the third dosage regimen is terminated only after commencement of medical management of the Grade 4 hematologic toxicity.
  • the dose modifications discussed above can be helpful in permitting a subject who develops an adverse reaction to the lenvatinib therapy (e.g., a nonhematologic toxicity, a hematologic toxicity, proteinuria, or a laboratory abnormality) to continue with and benefit from the lenvatinib therapy.
  • an adverse reaction to the lenvatinib therapy e.g., a nonhematologic toxicity, a hematologic toxicity, proteinuria, or a laboratory abnormality
  • Table II lists exemplary dose reductions for LENVIMA due to adverse reactions after administration of a first dosage regimen discussed above.
  • Endpoints and Assessments The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to progression, objective response rate, and quality of life as measurements including use of EORTC QLQ-C30 (Cocks, J, Clin. Oncol., 29:89-96, 2011, Giesinger, J., Clin. Epidemiol., 69:79-88, 2016) and HCC-specific EORTC QLQ-HCC18 (Chie, Hepatology, 55(4):1122-9, 2012) health questionnaires.
  • Tumors were evaluated in accordance with mRECIST (Lencioni R., Semin Liver Dis., 30(1):52-60, 2010); RECIST 1.1 was applied for nonhepatic lesions (Eisenhauer, Eur J Cancer, 45(2):228-47, 2009).
  • the liver was examined with computed tomography or magnetic resonance imaging was performed using a triphasic scanning technique. Assessments were performed every 8 weeks until disease progression. Quality of life questionnaires were administered at baseline, on day 1 of each subsequent treatment cycle, and at the off-treatment visit.
  • the primary endpoint of overall survival was first tested for noninferiority then for superiority.
  • the required number of events for the primary analysis was 700 deaths, based on the full analysis set.
  • the HR and its 95% confidence interval (CI) were estimated from a Cox proportional hazard model with treatment group as a factor and with the analysis stratified according to the same factors applied for randomization.
  • the noninferiority margin was set at 1.08 based on previous phase 3 trials of sorafenib (Llovet NEJM 2008, Cheng Lancet Oncol 2009).
  • Lenvatinib demonstrated a statistically significant improvement compared to sorafenib in all secondary efficacy endpoints as determined by tumor assessment based on mRECIST.
  • Median progression-free survival for lenvatinib was 7.4 months (95% CI, 6.9 to 8.8 months) compared with 3.7 months (95% CI, 3.6 to 4.6 months) with sorafenib (HR: 0.66; 95% CI, 0.57 to 0.77; P ⁇ 0.001) ( Figure 2).
  • progression-free survival in each of the prespecified subgroups was longer with lenvatinib compared with sorafenib ( Figure 4).
  • the median time to progression was 8.9 months (95% CI, 7.4 to 9.2 months) for patients in the lenvatinib group compared with 3.7 months (95% CI, 3.6 to 5.4 months) for patients in the sorafenib group (HR: 0.63; 95% CI, 0.53 to 0.73; P ⁇ 0.001) (Table 2 and Figure 6).
  • Safety and Side-effect Profile Median duration of study treatment for patients in the lenvatinib group was longer than for patients in the sorafenib group (5.7 vs. 3.7 months).
  • Treatment-emergent adverse events occurred in 98.7% of patients who received lenvatinib and 99.4% of patients who received sorafenib. Adjusted by patient-years, the adverse event rate was 18.9 in the lenvatinib group and 19.7 in the sorafenib group.
  • Treatment-emergent adverse events of grade 3 or higher occurred in 75.0% of patients who received lenvatinib and 66.5% of patients who received sorafenib (adverse event rate: 3.2 vs. 3.3).
  • the most common treatment-emergent adverse events among patients who received lenvatinib were hypertension (8 mg per day, 43.0%; 12 mg per day, 41.8%), diarrhea (35.1%; 40.3%), decreased appetite (33.1%; 34.5%), and decreased weight (28.5%; 32.0%).
  • the most common treatment-emergent adverse events were palmar-plantar erythrodysesthesia (52.4%), diarrhea (46.3%), hypertension (30.3%), and decreased appetite (26.7%) (Table 5).
  • the median duration of lenvatinib treatment was 1.5 times longer than that of sorafenib, which may have contributed to the higher incidence of adverse events. When adjusted for treatment duration, almost all episodes were comparable for the lenvatinib and sorafenib arms.
  • the dosages of lenvatinib for HCC (8 or 12 mg per day based on body weight) are lower than the lenvatinib dosage for radioiodine-refractory differentiated thyroid cancer (24 mg per day).
  • Example 2 Dose Interruption and Dose Reduction for Lenvatinib Toxicity Lenvatinib capsules were taken orally, once daily (QD) in continuous 28-day cycles. The dose of lenvatinib was based on the subject’s baseline body weight (BW) as shown below.
  • Lenvatinib toxicity was managed by treatment interruption, dose reduction, and/or treatment discontinuation. Dose adjustment for management of lenvatinib toxicity (with the exception of hypertension) was done in accordance with Table 6.
  • Hypertension is a recognized side effect of treatment with drugs inhibiting vascular endothelial growth factor (VEGF) signaling.
  • VEGF vascular endothelial growth factor
  • Early detection and effective management of hypertension were important to minimize the need for lenvatinib dose interruptions and reductions.
  • One BP assessment was defined as the mean value of 3 measurements at least 5 minutes apart.
  • treatment modification may have been necessary if hypertension persisted.
  • appropriate therapy e.g., angiotensin-converting enzyme inhibitor or angiotensin-II receptor antagonist was preferred.
  • the 24-hour urine collection was not required in the following situations: Persistence of the same severity of proteinuria by urine dipstick at the same study dose level when a 24-hour urine collection has already been collected at that dose level) Subsequent occurrences of 2+, 3+, or 4+ proteinuria by urine dipstick when the subject was off study drug
  • liver function tests e.g., alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels
  • ALT alanine transaminase
  • AST aspartate transaminase
  • bilirubin levels e.g., alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels
  • thromboembolic Events Subjects were advised to pay attention to the symptoms suggestive of venous thromboembolic events, which included acute onset of dyspnea, chest pain, cough, hemoptysis, tachypnea, tachycardia, cyanosis, and deep vein thrombosis signs including lower extremity swelling, redness, and warmth to touch or tenderness. If any of these signs or symptoms appeared, subjects were instructed to report such signs and symptoms promptly to the treating physician. If a thromboembolic event was confirmed, instructions contained in Table 6 were followed. If a subject experienced life-threatening (Grade 4) thromboembolic reactions, including pulmonary embolism, the study drug was discontinued.
  • Gram 4 life-threatening
  • PRES posterior reversible encephalopathy syndrome
  • MRI magnetic resonance imaging
  • a TEAE occurred in all but 6 and 3 subjects in the lenvatinib and sorafenib arms, respectively.
  • the most frequently reported TEAEs (>30% of subjects) were hypertension, diarrhea, decreased appetite, and weight decreased for lenvatinib and palmar-plantar erythrodysaesthesia (PPE) syndrome, diarrhea, and hypertension for sorafenib.
  • Adverse events that occurred in > 10% more subjects in the lenvatinib arm than in the sorafenib arm were: hypertension (42.2% vs 30.3%), proteinuria (24.6% vs 11.4%), dysphonia (23.7% vs 12.0%), and hypothyroidism (16.4% vs 1.7%).
  • AEs are consistent with the known safety profile of lenvatinib in other cancer indications.
  • TEAEs that led to dose modification in a higher percentage of subjects in the lenvatinib arm (total incidence >2% to ⁇ 5% but [approximately] >2 times the rate) than in the sorafenib arm were hepatic encephalopathy (4.2% vs 0.6%), weight decreased (4.2% vs 0.8%), pyrexia (2.5% vs 1.1%), vomiting (2.5% vs 1.3%), neutrophil count decreased (2.3% vs 1.1%), and ascites (2.1% vs 1.1%).
  • Example 4 Efficacy Results in Hepatocellular Carcinoma Clinical Study
  • the efficacy of LENVIMA was evaluated in a randomized, open-label, multicenter, international study (REFLECT; NCT0761266) conducted in patients with previously untreated unresectable hepatocellular carcinoma (HCC).
  • the study enrolled adults with Child-Pugh A and Barcelona Clinic Liver Cancer (BCLC) Stage C or B HCC who were ineligible for local liver-directed therapy; had an ECOG PS of 0 or 1; had received no prior systemic therapy for HCC; and had at least one measurable target lesion according to modified RECIST for HCC.
  • Efficacy results are summarized in Table 10.
  • Example 5 Drug Interaction Studies: Effect of Lenvatinib on Other Drugs Clinical Studies with Substrates of CYP3A4 or CYP2C8: There is no projected significant drug-drug interaction risk between lenvatinib and midazolam (a CYP3A4 substrate) or repaglinide (a CYP2C8 substrate).
  • Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Lenvatinib does not inhibit CYP2A6 and CYP2E1. Lenvatinib induces CYP3A, but it does not induce CYP1A1, CYP1A2, CYP2B6, and CYP2C9.
  • Lenvatinib inhibits UGT1A1, UGT1A4, and UGT1A9 in vitro, but likely only inhibits UGT1A1 in vivo in the gastrointestinal tract based on the expression of the enzyme in tissues. Lenvatinib does not inhibit UGT1A6, UGT2B7 or aldehyde oxidase. Lenvatinib does not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7.
  • Lenvatinib does not have the potential to inhibit MATE1, MATE2-K, OCT1, OCT2, OAT1, OAT3, BSEP, OATP1B1, or OATP1B3 in vivo.

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