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Treatment of hepatocellular carcinoma

Inactive Publication Date: 2020-06-25
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

The technical effects of the patent text are not specified in detail, but it mentions a new invention that has specific features and advantages. These features and advantages are explained in detail in the claims portion of the text.

Problems solved by technology

It usually occurs in a background of chronic liver disease, particularly in cirrhosis, which limits the feasibility of surgical resection.
Therefore, unresectable HCC represents a highly unmet medical need.

Method used

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  • Treatment of hepatocellular carcinoma
  • Treatment of hepatocellular carcinoma
  • Treatment of hepatocellular carcinoma

Examples

Experimental program
Comparison scheme
Effect test

example 1

b for Unresectable Hepatocellular Carcinoma

[0257]This Example describes the open-label phase 3 noninferiority study using lenvatinib in unresectable HCC. In this study 478 patients were randomized to lenvatinib (body weight >=60 kg: 12 mg / day; <60 kg: 8 mg / day) and 476 to sorafenib 400 mg twice daily. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to progression, objective response rate, safety, and quality of life.

[0258]Materials & Methods

[0259]Study Eligibility

[0260]Patients who were eligible for enrollment had unresectable HCC with diagnosis confirmed histologically or cytologically or with diagnosis confirmed clinically in accordance with the American Association for the Study of Liver Diseases criteria. Included patients also had >=1 measureable target lesion, based on modified Response Evaluation Criteria in Solid Tumors (Lencioni 2010); Barcelona Clinic Liver Cancer stage B or C categorization (Bruix Hepatology 2011); C...

example 2

rruption and Dose Reduction for Lenvatinib Toxicity

[0289]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 (13W) as shown below.

TABLE 10DrugBaselineOral DoseNumber DispensedNameBWStrengthFormand FrequencyLenvatinib≥60 kg12 mgcapsule3 × 4-mg capsules,once daily at thesame time each day 8 mgcapsule2 × 4-mg capsules,once daily at thesame time each day

[0290]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.

TABLE 6Lenvatinib Dose Reductions and Interruption InstructionsDose reductions occurred in succession based on the previous doselevel (12, 8, and 4 mg / day, and 4 mg every other day [QOD]). Anydose reduction below 4 mg QOD was discussed with the sponsor.Once the dose was reduced, it was not increased...

example 3

vents that Required Dose Reduction or Interruption of Study Drug

[0324]A summary of TEAEs occurring in >=10% of subjects in the lenvatinib or sorafenib treatment arm, in decreasing order of frequency in the total lenvatinib arm, is presented in Table 7.

TABLE 7Treatment-emergent Adverse Events Occurring in at Least 10%of Subjects in Either Treatment Arm, by Preferred TermLenvatinib8 mg a12 mg aTotalSorafenib(N = 151)(N = 325)(N = 476)(N = 475)Preferred Termn (%)n (%)n (%)n (%)Subjects with Any TEAEs151 (100.0)319 (98.2) 470 (98.7) 472 (99.4) Hypertension65 (43.0)136 (41.8) 201 (42.2) 144 (30.3) Diarrhea53 (35.1)131 (40.3) 184 (38.7) 220 (46.3) Decreased appetite50 (33.1)112 (34.5) 162 (34.0) 127 (26.7) Weight decreased43 (28.5)104 (32.0) 147 (30.9) 106 (22.3) Fatigue42 (27.8)99 (30.5)141 (29.6) 119 (25.1) Palmar-plantar erythrodysesthesia35 (23.2)93 (28.6)128 (26.9) 249 (52.4) syndromeProteinuria37 (24.5)80 (24.6)117 (24.6) 54 (11.4)Dysphonia28 (18.5)85 (26.2)113 (23.7) 57 (12.0)Nause...

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Abstract

This disclosure provides methods for treating a hepatocellular carcinoma (e.g., unresectable HCC) with lenvatinib or a pharmaceutically acceptable salt thereof. Also encompassed by the disclosure are dosage regimens described herein of lenvatinib or a pharmaceutically acceptable salt thereof for use in treating hepatocellular carcinoma (e.g., unresectable hepatocellular carcinoma) according to any of the methods described herein. Particularly useful dosages and dose modifications upon the occurrence of an adverse event or events are also disclosed.

Description

TECHNICAL FIELD[0001]The present application relates generally to methods of treating hepatocellular carcinoma.BACKGROUND ART[0002]Hepatocellular carcinoma (HCC) 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).[0003]Drug development in HCC in the past 10 years is marked by four failed phase 3 trials (of sunitinib, brivanib, linifanib, and erlotinib plus sorafenib) that did not demonstrate noninferiority (Cheng, J. Clin. Oncol., 31:4067-4075, 2013; Johnson, I. Clin...

Claims

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Application Information

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IPC IPC(8): A61K31/47A61P35/00A61K9/48
CPCA61P35/00A61K31/47A61K9/48
Inventor TAMAI, TOSHIYUKI
Owner EISIA R&D MANAGEMENT CO LTD