KR20180129795A - Treatment of Renal Cell Carcinoma with Renatidib and Everolimus - Google Patents

Abstract

Methods and compositions are provided for treating renal cell carcinoma using a combination of renavitinib or its pharmaceutically acceptable salt and everolimus. Particularly useful doses and capacity control during adverse events are also provided.

Description

Treatment of Renal Cell Carcinoma with Renatidib and Everolimus

The present application relates generally to methods of treating renal cell carcinoma.

Kidney cancer constitutes approximately 3% of all cancers worldwide, and is among the 10 most common cancers in both males and females. Taken together, the lifetime risk for developing kidney cancer is about 1.6%, where the risk is higher in males than females. The American Cancer Society estimates that in 2016, approximately 62,700 new cases of kidney cancer diagnosed in the United States (39,650 men and 23,050 women) will be diagnosed with approximately 14,240 deaths (9,240 men and 5,000 women) .

Renal cell carcinoma (RCC) accounts for more than 90% of all kidney malignancies in adults. RCC occurs from the epithelium of the renal tubule; Specifically, it is derived from the renal cortex from the proximal renal tubular epithelium. RCC has a male-to-female dominance ratio of 1.6: 1 and is most common among people aged 40-70. The incidence of RCC is greater in people of Northern European ancestry and North America than people of Asian or African descent.

As approximately 40% of patients with RCC die from disease progression, the cancer is one of the most lethal malignancies. Therefore, new treatment options for the cancer are highly needed.

This disclosure is based, in part, on a method of treating a subject with RCC using a combination of renatriptib or a pharmaceutically acceptable salt thereof with rivulimumus, wherein at the onset of one or more adverse events in the subject , A combination therapy, or a combination thereof.

In a first aspect, the present disclosure features a method of treating RCC. The method comprises administering to a human subject having an RCC a first dose regimen comprising (i) 18 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus . In certain embodiments, after or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or occurrence beyond the Grade 4 laboratory develops in the human subject. The method comprises terminating the administration of the first dose regimen after occurrence of a first persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event and administering to the human subject a dose of 14 mg / And a second administration regimen comprising a pharmaceutically acceptable salt. In another embodiment, after or after treatment with the first dose regimen, the adverse reaction does not develop in the human subject, or the occurrence of Class 1 or acceptable Class 2 adverse reactions develops. In such an embodiment, the method further comprises continuing administration of the first administration regimen to the human subject (i. E., Not lowering the dose of the first administration regimen).

As used throughout this disclosure, a regimen of administration comprising a specified dose of lenbatinib or a pharmaceutically acceptable salt thereof is intended to encompass administration of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, . Although such dosing regimens may contain additional ingredients, lenbactinib or a pharmaceutically acceptable salt thereof exists only in the specific dosages listed. Similarly, as used throughout this application, a dosage regimen comprising the indicated dose of everolimus means that the everolimus is present in the dosage regimen at the stated doses. Although such dosing regimens may contain additional ingredients, everolimus exists only in the specific dosages listed. (E.g., 18 mg, 14 mg, 10 mg, 8 mg, or 6 mg) of levetabiem or a pharmaceutically acceptable salt thereof as used throughout 5 mg or 2.5 mg) refers to the free form dose of lenbactinib or everolimus, respectively.

In a second aspect, the disclosure provides a method of treating a human subject having an RCC comprising (i) 18 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus The method comprising administering a first administration regimen comprising administering to the subject a first administration regimen. During or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun develops in the human subject. The method then terminates the administration of the first dose regimen after occurrence of a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory event and provides the human subject with a dose of 14 mg / Lt; RTI ID = 0.0 > pharmaceutically < / RTI > acceptable salt thereof. In certain embodiments, after or after treatment with the second dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun occurs in the human subject. The method is to terminate the administration of the second dose regimen after the second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory event, and administering to the human subject a dose of 10 mg / day of lenbactinib or its pharmaceutical Or a pharmaceutically acceptable salt thereof. In another embodiment, after or after treatment with the second dose regimen, the adverse reaction does not develop in the human subject, or the occurrence of Class 1 or acceptable Class 2 adverse reactions develops. In such an embodiment, the method further comprises continuing administration of the second administration regimen to the human subject (i.e., not lowering the dose provided in the second administration regimen).

In a third aspect, the disclosure provides a method of treating a human subject having an RCC comprising (i) 18 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus The method comprising administering a first dose regimen. After or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method comprises terminating the administration of the first dose regimen after occurrence of a first persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event and administering to the human subject a dose of 14 mg / And a second administration regimen comprising a pharmaceutically acceptable salt. After or after treatment with the second dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method is to terminate the administration of the second dose regimen after the second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory event, and administering to the human subject a dose of 10 mg / day of lenbactinib or its pharmaceutical Or a pharmaceutically acceptable salt thereof. In certain embodiments, after or after treatment with the third dose regimen, a third persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory overrun in the human subject occurs during treatment with the third dose regimen Developed. The method is terminated after the third persistent and unacceptable Grade 2 or Grade 3 adverse event or grade 4 laboratory event and administration of the third dose regimen is completed and the human subject is administered with a dose of 8 mg / And a fourth administration regimen comprising a pharmaceutically acceptable salt. In another embodiment, after or after treatment with the third dose regimen, the adverse reaction does not develop in the human subject, or the occurrence of Class 1 or acceptable Class 2 adverse reactions develops. In such an embodiment, the method further comprises continuing administration of the third administration regimen to the human subject (i. E., Not lowering the dose provided in the third administration regimen).

In a fourth aspect, the present disclosure provides a method of treating a human subject having an RCC comprising (i) 18 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of ivolorimus The method comprising administering a first dose regimen. After or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method comprises terminating the administration of the first dose regimen after occurrence of a first persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event and administering to the human subject a dose of 14 mg / And a second administration regimen comprising a pharmaceutically acceptable salt. After or after treatment with the second dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method is to terminate the administration of the second dose regimen after the second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory event, and administering to the human subject a dose of 10 mg / day of lenbactinib or its pharmaceutical Or a pharmaceutically acceptable salt thereof. After or during treatment with the third dose regimen, a third persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory over time in the human subject develops during treatment with the third dose regimen. The method is terminated after the third persistent and unacceptable Grade 2 or Grade 3 adverse event or grade 4 laboratory event and administration of the third dose regimen is completed and the human subject is administered with a dose of 8 mg / And a fourth administration regimen comprising a pharmaceutically acceptable salt. In certain embodiments, a fourth persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory abnormality in a human subject after the treatment with or in the course of the fourth administration regimen develops during treatment with the fourth administration regimen do. The method further comprises stopping the administration of the fourth administration regimen to the human subject. In another embodiment, after or after treatment with the fourth dose regimen, the adverse reaction does not develop in the human subject, or the occurrence of Class 1 or acceptable Class 2 adverse reactions develops. The method further comprises continuing the administration of the fourth administration regimen to the human subject (i.e., not lowering the dose provided in the fourth administration regimen).

The following embodiments apply to all of the above aspects. In certain embodiments, the second dose regimen, the third dose regimen and the fourth dose regimen are not disclosed, respectively, until the resolution of the adverse reaction or toxicity associated with administration of everolimus.

In another embodiment, the second dose regimen, the third dose regimen and the fourth dose regimen each comprise 5 mg / day of everolimus.

In some embodiments, the second dose regimen, the third dose regimen and the fourth dose regimen each comprise a 5 mg dose of Everolimus.

In some embodiments, the second dose regimen comprises 5 mg / day dose of enverolimus, the third dose regimen comprises 5 mg / day dose of enverolimus, the fourth dose regimen is eneloylmus Or does not contain or contains 5 mg of everolimus.

In some embodiments, the second dose regimen comprises everolimus at a dose of 5 mg / day, the third dose regimen comprises everolimus at a 5 mg dose, and the fourth dose regimen includes everolimus Or 5 mg daily dose of Everolimus.

In another embodiment, the second dose regimen, the third dose regimen and the fourth dose regimen each comprise 2.5 mg / day of everolimus.

In some embodiments, the second dose regimen, the third dose regimen and the fourth dose regimen each comprise a 2.5 mg dose of Everolimus.

In some embodiments, the second dose regimen does not include everolimus. In some embodiments, the third dose regimen does not include everolimus. In some embodiments, the fourth dose regimen does not include everolimus. In another embodiment, the second dose regimen and the third dose regimen do not include everolimus. In another embodiment, the second dose regimen and the fourth dose regimen do not include everolimus. In certain embodiments, the third dose regimen and the fourth dose regimen do not include everolimus. In another embodiment, each of the second dose regimen, the third dose regimen and the fourth dose regimen does not include everolimus.

In a fifth aspect, the disclosure provides a method of treating RCC. (I) a dose of 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) a dose of 2.5 mg / day of Evelolimus to a human subject having renal cell carcinoma and severe renal or severe liver disorders ≪ / RTI > During or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction in the human subject or the occurrence of more than Grade 4 laboratory develops. The method comprises terminating the administration of the first dose regimen after the first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory event, and administering to the human subject a dose of 10 mg / day of Lenvatib, Comprising administering a second dosage regimen comprising a therapeutically acceptable salt.

In a sixth aspect, the present disclosure features a method of treating RCC. (I) a dose of 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) a dose of 2.5 mg / day of Evelolimus to a human subject having renal cell carcinoma and severe renal or severe liver disorders ≪ / RTI > During or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction in the human subject or the occurrence of more than Grade 4 laboratory develops. The method comprises terminating the administration of the first dose regimen after the first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory event, and administering to the human subject a dose of 10 mg / day of Lenvatib, Comprising administering a second dosage regimen comprising a therapeutically acceptable salt. During or after treatment with the second dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction in the human subject or the occurrence of a Grade 4 or higher lab develops. The method is to terminate the administration of the second dose regimen after a second persistent and unacceptable Grade 2 or Grade 3 adverse event or grade 4 laboratory event, and administering to a human subject a dose of 8 mg / day of Lenvatib, Or a pharmaceutically acceptable salt thereof.

In a seventh aspect, the present disclosure provides a method of treating RCC. (I) a dose of 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) a dose of 2.5 mg / day of Evelolimus to a human subject having renal cell carcinoma and severe renal or severe liver disorders ≪ / RTI > During or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction in the human subject or the occurrence of more than Grade 4 laboratory develops. The method comprises terminating the administration of the first dose regimen after the first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory event, and administering to the human subject a dose of 10 mg / day of Lenvatib, Comprising administering a second dosage regimen comprising a therapeutically acceptable salt. During or after treatment with the second dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction in the human subject or the occurrence of a Grade 4 or higher lab develops. The method is to terminate the administration of the second dose regimen after a second persistent and unacceptable Grade 2 or Grade 3 adverse event or grade 4 laboratory event, and administering to a human subject a dose of 8 mg / day of Lenvatib, Or a pharmaceutically acceptable salt thereof. During or after treatment with the third dose regimen, a third persistent and unacceptable Grade 2 or Grade 3 adverse reaction in the human subject or the occurrence of a Grade 4 or higher lab develops. The method is to terminate the administration of the third dose regimen after the third persistent and unacceptable Grade 2 or Grade 3 adverse event or grade 4 laboratory event, and administering to the human subject a dose of 6 mg / day of Lenvatib, And a fourth administration regimen comprising a pharmaceutically acceptable salt.

The following embodiments apply to all the fifth, sixth and seventh aspects.

In one embodiment, the human subject has severe renal impairment and has a creatinine clearance [CLcr] of less than 30 mL / min as calculated by the Cockroft-Gault equation.

In another embodiment, the human subject has severe liver disorders and has liver disease classified as Child-Pugh class C.

In certain embodiments, the second dose regimen, the third dose regimen and the fourth dose regimen are not disclosed, respectively, until the resolution of the adverse reaction or toxicity associated with administration of everolimus.

In some embodiments, the second dose regimen comprises Everel Rimus at a dose of 2.5 mg / day. In another embodiment, the third dose regimen comprises Everel Rimus at a dose of 2.5 mg / day. In another embodiment, the fourth dose regimen comprises Everel Rimus at a dose of 2.5 mg / day. In certain embodiments, the second dose regimen and the third dose regimen comprise Everel Rimus at a dose of 2.5 mg / day. In some embodiments, the second dose regimen and the fourth dose regimen comprise Everel Rimus at a dose of 2.5 mg / day. In another embodiment, the third dose regimen and the fourth dose regimen comprise Everel Rimus at a dose of 2.5 mg / day. In some embodiments, the second dose regimen, the third dose regimen and the fourth dose regimen each comprise 2.5 mg / day of everolimus.

In some embodiments, the second dose regimen comprises a 2.5 mg dose of Everolimus. In another embodiment, the third dosage regimen comprises a 2.5 mg dose of Everolimus. In another embodiment, the fourth dose regimen comprises a 2.5 mg dose of Everolimus. In certain embodiments, the second dose regimen and the third dose regimen comprise a 2.5 mg dose of Everolimus. In some embodiments, the second dose regimen and the fourth dose regimen comprise a 2.5 mg dose of everolimus. In another embodiment, the third dose regimen and the fourth dose regimen comprise a 2.5 mg dose of everolimus. In some embodiments, the second dose regimen, the third dose regimen and the fourth dose regimen each comprise a 2.5 mg dose of Everolimus.

In some embodiments, the second dose regimen does not include everolimus. In some embodiments, the third dose regimen does not include everolimus. In some embodiments, the fourth dose regimen does not include everolimus. In another embodiment, the second dose regimen and the third dose regimen do not include everolimus. In another embodiment, the second dose regimen and the fourth dose regimen do not include everolimus. In certain embodiments, the third dose regimen and the fourth dose regimen do not include everolimus. In another embodiment, each of the second dose regimen, the third dose regimen and the fourth dose regimen does not include everolimus.

In an eighth aspect, the present disclosure features a method of treating RCC. The method comprises administering to a human subject having an RCC a first dose regimen comprising (i) 18 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus . After or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method is to terminate the administration of the first dose regimen after a first persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory event, and administering to the human subject (i) a dose of 14 mg / day of Lenvatibin Or a pharmaceutically acceptable salt thereof; And optionally (ii) a second dose regimen comprising 5 mg / day, 5 mg / day, 2.5 mg / day, or 2.5 mg daily dose of everolimus.

In a ninth aspect, the disclosure provides a method of treating a human subject having RCC comprising (i) 18 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus The method comprising administering a first administration regimen comprising administering to the subject a first administration regimen. During or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun develops in the human subject. Thereafter, the method terminates the administration of the first dose regimen after occurrence of a first persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event, and administers to the human subject (i) a dose of 14 mg / day Lt; / RTI > or a pharmaceutically acceptable salt thereof; And (ii) optionally, a second dose regimen comprising 5 mg / day, 5 mg / day, 2.5 mg / day, or 2.5 mg daily dose of everolimus. After or after treatment with the second dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method is to terminate the administration of the second dose regimen after the second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory event, and administering to the human subject (i) a dose of 10 mg / Or a pharmaceutically acceptable salt thereof and optionally (ii) a third dose regimen comprising 5 mg / day, 5 mg / day, 2.5 mg / day, or 2.5 mg daily dose of everolimus .

In a tenth aspect, the disclosure provides a method of treating a human subject having an RCC comprising (i) 18 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus The method comprising administering a first dose regimen. After or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method is to terminate the administration of the first dose regimen after a first persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory event, and administering to the human subject (i) a dose of 14 mg / day of Lenvatibin Or a pharmaceutically acceptable salt thereof, and optionally (ii) 5 mg / day, 5 mg every other day, 2.5 mg / day, or 2.5 mg daily dose of everolimus . After or after treatment with the second dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method is to terminate the administration of the second dose regimen after the second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory event, and administering to the human subject (i) a dose of 10 mg / Or a pharmaceutically acceptable salt thereof and optionally (ii) a third dose regimen comprising 5 mg / day, 5 mg / day, 2.5 mg / day, or 2.5 mg daily dose of everolimus . After or during treatment with the third dose regimen, a third persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory over time in the human subject develops during treatment with the third dose regimen. The method is terminated after the third persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory event, administration of the third dose regimen and administration of (i) a dose of 8 mg / day of Lenvatibin Or a pharmaceutically acceptable salt thereof, and optionally (ii) 5 mg / day, 5 mg every other day, 2.5 mg / day, or 2.5 mg daily dose of everolimus .

In an eleventh aspect, the disclosure provides a method of treating a human subject having RCC comprising (i) 18 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus The method comprising administering a first dose regimen. After or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method is to terminate the administration of the first dose regimen after a first persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory event, and administering to the human subject (i) a dose of 14 mg / day of Lenvatibin Or a pharmaceutically acceptable salt thereof, and (ii) a second dose regimen comprising 5 mg / day or 5 mg daily dose of everolimus. After or after treatment with the second dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method is to terminate the administration of the second dose regimen after the second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory event, and administering to the human subject (i) a dose of 10 mg / Or a pharmaceutically acceptable salt thereof and (ii) a third dose regimen comprising 5 mg / day or 5 mg daily dose of everolimus. After or during treatment with the third dose regimen, a third persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory over time in the human subject develops during treatment with the third dose regimen. The method is terminated after the third persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory event, administration of the third dose regimen and administration of (i) a dose of 8 mg / day of Lenvatibin Or a pharmaceutically acceptable salt thereof, and (ii) a fourth dose regimen comprising 5 mg / day or 5 mg daily dose of everolimus.

In a twelfth aspect, the present disclosure features a method of treating RCC. The method comprises administering to a human subject having an RCC a first administration regimen comprising (i) 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus . In certain embodiments, after or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or occurrence beyond the Grade 4 laboratory develops in the human subject. The method comprises terminating the administration of the first dose regimen after the first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory event, and administering to the human subject a dose of 10 mg / day of Lenvatib, And a second administration regimen comprising a pharmaceutically acceptable salt. In another embodiment, after or after treatment with the first dose regimen, the adverse reaction does not develop in the human subject, or the occurrence of Class 1 or acceptable Class 2 adverse reactions develops. In such an embodiment, the method further comprises continuing administration of the first administration regimen to the human subject (i. E., Not lowering the dose of the first administration regimen).

In a thirteenth aspect, the disclosure provides a method of treating a human subject having an RCC comprising (i) a dose of 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus The method comprising administering a first administration regimen comprising administering to the subject a first administration regimen. During or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun develops in the human subject. The method then terminates the administration of the first dose regimen after occurrence of a first persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory event and provides the human subject with a 10 mg / Lt; RTI ID = 0.0 > pharmaceutically < / RTI > acceptable salt thereof. In certain embodiments, after or after treatment with the second dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun occurs in the human subject. The method is to terminate the administration of the second dose regimen after a second persistent and unacceptable Grade 2 or Grade 3 adverse event or grade 4 laboratory event, and administering to a human subject a dose of 8 mg / day of Lenvatib, Or a pharmaceutically acceptable salt thereof. In another embodiment, after or after treatment with the second dose regimen, the adverse reaction does not develop in the human subject, or the occurrence of Class 1 or acceptable Class 2 adverse reactions develops. In such an embodiment, the method further comprises continuing administration of the second administration regimen to the human subject (i.e., not lowering the dose provided in the second administration regimen).

In a fourteenth aspect, the present disclosure provides a method of treating a human subject having RCC comprising (i) a dose of 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus The method comprising administering a first dose regimen. After or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method comprises terminating the administration of the first dose regimen after the first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory event, and administering to the human subject a dose of 10 mg / day of Lenvatib, And a second administration regimen comprising a pharmaceutically acceptable salt. After or after treatment with the second dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method is to terminate the administration of the second dose regimen after a second persistent and unacceptable Grade 2 or Grade 3 adverse event or grade 4 laboratory event, and administering to a human subject a dose of 8 mg / day of Lenvatib, Or a pharmaceutically acceptable salt thereof. In certain embodiments, after or after treatment with the third dose regimen, a third persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory overrun in the human subject occurs during treatment with the third dose regimen Developed. The method is terminated after the third persistent and unacceptable Grade 2 or Grade 3 adverse event or grade 4 laboratory event and administration of the third dose regimen is stopped and the human subject is administered with 4 mg / And a fourth administration regimen comprising a pharmaceutically acceptable salt. In another embodiment, after or after treatment with the third dose regimen, the adverse reaction does not develop in the human subject, or the occurrence of Class 1 or acceptable Class 2 adverse reactions develops. In such an embodiment, the method further comprises continuing administration of the third administration regimen to the human subject (i. E., Not lowering the dose provided in the third administration regimen).

In a fifteenth aspect, the disclosure provides a method of treating a human subject with RCC comprising administering to a human subject having (i) 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus The method comprising administering a first dose regimen. After or after treatment with the first dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method comprises terminating the administration of the first dose regimen after the first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory event, and administering to the human subject a dose of 10 mg / day of Lenvatib, And a second administration regimen comprising a pharmaceutically acceptable salt. After or after treatment with the second dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. The method is to terminate the administration of the second dose regimen after a second persistent and unacceptable Grade 2 or Grade 3 adverse event or grade 4 laboratory event, and administering to a human subject a dose of 8 mg / day of Lenvatib, Or a pharmaceutically acceptable salt thereof. After or during treatment with the third dose regimen, a third persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory over time in the human subject develops during treatment with the third dose regimen. The method is terminated after the third persistent and unacceptable Grade 2 or Grade 3 adverse event or grade 4 laboratory event and administration of the third dose regimen is stopped and the human subject is administered with 4 mg / And a fourth administration regimen comprising a pharmaceutically acceptable salt. In certain embodiments, a fourth persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory abnormality in a human subject after the treatment with or in the course of the fourth administration regimen develops during treatment with the fourth administration regimen do. In such an embodiment, the method further comprises stopping administration of the fourth administration regimen to a human subject. In another embodiment, after or after treatment with the fourth dose regimen, the adverse reaction does not develop in the human subject, or the occurrence of Class 1 or acceptable Class 2 adverse reactions develops. In such an embodiment, the method further comprises continuing administration of the fourth administration regimen to the human subject (i.e., not lowering the dose provided in the fourth administration regimen).

The following embodiments apply to the twelfth, thirteenth, fourteenth, and fifteenth aspects.

In one embodiment, the second administration regimen is initiated until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 2, Class 0-1, or baseline, I never do that. In one embodiment, the third dose regimen is initiated until a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved with Grade 2, Grade 0-1, or baseline acceptable I never do that. In one embodiment, the fourth dose regimen is initiated until a third persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory overrun is resolved with Class 2, Class 0-1, or baseline, I never do that. In another embodiment, until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 2, Class 0-1, or Baseline, a second dose regimen Not initiated; The third dose regimen is not initiated until a second persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory abnormality is resolved with Class 2, Class 0-1, or baseline acceptable. In another embodiment, until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 2, Class 0-1, or Baseline, a second dose regimen Not initiated; Does not initiate a third dose regimen until a second persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory override is resolved with Class 2, Class 0-1, or baseline acceptable; The fourth dose regimen is not initiated until a third persistent and unacceptable Class 2 or Class 3 adverse event or class 4 laboratory abnormality is resolved with a Class 2, Class 0-1, or baseline acceptable.

In some embodiments, the first, second and third persistent and unacceptable Grade 2 or Grade 3 adverse reactions or Grade 4 laboratory abnormalities, prior to termination of administration of the dosing regimen administered at the time of adverse reaction or onset of the laboratory, Each medical care management is started.

In certain embodiments, prior to commencing administration of a dose regimen that occurs after an adverse reaction or laboratory anomaly is resolved with Class 2, Class 0-1, or baseline, the first, second, and third persistent and not allowed Not a Class 2 or Class 3 adverse reaction or a Class 4 laboratory initiates each medical care.

In some embodiments, a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is a second and / or third persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 It is the same as the lab.

In certain embodiments, the first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormalities are secondary and / or third persistent and unacceptable Class 2 or Class 3 adverse reactions or Class 4 It is different from the laboratory ideal.

In some embodiments, the Grade 2 or Grade 3 adverse reaction is selected from the group consisting of grade 3 hypertension, grade 2 hypertension, grade 3 cardiac dysfunction, grade 2 cardiac dysfunction, grade 3 arterial thromboembolic event, grade 2 arterial thromboembolic event, Grade 3 diarrhea, grade 2 diarrhea, grade 3 gastrointestinal perforation or fistula, grade 2 gastrointestinal perforation or fistula, grade 3 vomiting, grade 2 vomiting, grade 2 proteinuria, grade 2 proteinuria, grade 3 renal failure or renal disease, grade 2 renal failure or renal disease, Grade 3 reduced appetite, grade 2 reduced appetite, grade 3 fatigue, grade 2 fatigue, grade 3 nausea, grade 2 nausea, grade 3 cough, grade 2 cough, grade 3 reduced weight, grade 2 reduced weight, grade 3 Grade 3 anemia, grade 2 anemia, grade 3 acute renal failure, grade 2 acute renal failure, grade 3 QT / QTc interval extension, grade 2 QT / QTc interval extension, grade 3 hypertension, Grade 3 reversible postprandial encephalopathy It is selected from Syndrome (RPLS), RPLS Class 2, Class 3 hemorrhagic events, Grade 2 bleeding events, Class 3 hyperthyroidism, and Level 2 the group consisting of hyperthyroidism. In some cases, a Class 2 or Class 3 adverse reaction is selected from the group consisting of a grade 3 diarrhea, a grade 2 diarrhea, a grade 3 vomit, a grade 2 vomit, a grade 3 nausea, a grade 2 nausea, a grade 3 proteinuria, do.

In certain embodiments, the Grade 4 laboratory abnormalities include, but are not limited to, Grade 4 aspartate aminotransferase increase, Grade 4 alanine aminotransferase increase, Grade 4 alkaline phosphatase increase, Grade 4 hyperkalemia, Grade 4 hypokalemia, Grade 4 hyperglycemia, grade 4 hyperglycemia, grade 4 hyperlipidemia, grade 4 cholesterol increase, grade 4 lipase increase, grade 4 hemoglobin decrease, grade 4 platelet count decrease, and grade 4 lymphocyte count decrease ≪ / RTI > In some cases, the Grade 4 laboratory abnormalities are selected from the group consisting of Grade 4 Lipase Increase, Grade 4 hyperglyceridemia, Grade 4 cholesterol increase, Grade 4 hypophosphatemia, Grade 4 hyponatremia, and Grade 4 hypokalemia.

In certain embodiments, the second dose regimen, the third dose regimen and the fourth dose regimen are not disclosed, respectively, until the resolution of the adverse reaction or toxicity associated with administration of everolimus.

In another embodiment, the second dose regimen, the third dose regimen and the fourth dose regimen each comprise 5 mg / day of everolimus.

In some embodiments, the second dose regimen, the third dose regimen and the fourth dose regimen each comprise a 5 mg dose of Everolimus.

In some embodiments, the second dose regimen comprises 5 mg / day dose of enverolimus, the third dose regimen comprises 5 mg / day dose of enverolimus, the fourth dose regimen is eneloylmus Or does not contain or contains 5 mg of everolimus.

In some embodiments, the second dose regimen comprises everolimus at a dose of 5 mg / day, the third dose regimen comprises everolimus at a 5 mg dose, and the fourth dose regimen includes everolimus Or 5 mg daily dose of Everolimus.

In some embodiments, the second dose regimen does not include everolimus. In some embodiments, the third dose regimen does not include everolimus. In some embodiments, the fourth dose regimen does not include everolimus. In another embodiment, the second dose regimen and the third dose regimen do not include everolimus. In another embodiment, the second dose regimen and the fourth dose regimen do not include everolimus. In certain embodiments, the third dose regimen and the fourth dose regimen do not include everolimus. In another embodiment, each of the second dose regimen, the third dose regimen and the fourth dose regimen does not include everolimus.

In a sixteenth aspect, the present disclosure provides a method of treating renal cell carcinoma in a human subject in need of treatment of renal cell carcinoma. The method comprises administering to a human subject having renal cell carcinoma (i) a therapeutically effective amount of a therapeutically effective amount of a compound selected from the group consisting of lenbatinib or a pharmaceutically acceptable salt thereof at a dose of 14 mg / day, and (ii) 1 dose regimen, wherein during treatment with the first dose regimen, no Class 2 or Class 3 adverse reactions or grade 4 laboratory abnormalities that are not allowed in human subjects are developed. The method comprises terminating the administration of the first dose regimen and administering to the human subject (i) a dose of 18 mg / day of lenbatinib or a pharmaceutically acceptable salt thereof and (ii) a dose of 5 mg / Lt; RTI ID = 0.0 > Ralimumus < / RTI >

In some embodiments of this aspect, during treatment with the second dose regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun occurs in the human subject. The method is to terminate the administration of the second dose regimen after the first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory event, and administering to the human subject a dose of 14 mg / day of lenbactinib or its pharmaceutical Or a pharmaceutically acceptable salt thereof. In some cases, during treatment with a third dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory overrun in the human subject develops. In this case, the administration of the third administration regimen is terminated and a fourth administration regimen is administered to the human subject comprising lambtatinib or a pharmaceutically acceptable salt thereof at a dose of 10 mg / day. In other cases, no adverse reaction develops in the human subject, or a Class 1 or acceptable Class 2 adverse reaction develops. In this case, the administration of the third administration regimen to the human subject can be continued.

In some embodiments of the sixteenth aspect, during treatment with the second administration regimen, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or a Grade 4 laboratory or higher event develops in the human subject. The method is to terminate the administration of the second dose regimen after the first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory event, and administering to the human subject a dose of 14 mg / day of lenbactinib or its pharmaceutical Or a pharmaceutically acceptable salt thereof. During treatment with the third dose regimen, a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or grade 4 laboratory or higher event develops in the human subject, terminating the administration of the third dose regimen, A fourth dose regimen is administered comprising 10 mg / day dose of Lenvatibine or a pharmaceutically acceptable salt thereof. In certain instances, during treatment with the fourth dose regimen, a third persistent and unacceptable grade 2 or grade 3 adverse event or grade 4 laboratory or higher event develops in the human subject, the administration of the fourth dose regimen is terminated , A fifth dose regimen is administered to a human subject comprising a dose of 8 mg / day of Lenvatibin or a pharmaceutically acceptable salt thereof. In other cases, no adverse reaction develops in the human subject, or a Class 1 or acceptable Class 2 adverse reaction develops. In this case, administration of the fourth administration regimen to the human subject can be continued.

In certain embodiments of this aspect, the period of treatment with the first dose regimen comprises 28 days.

In certain embodiments of this aspect, the treatment period for the first dose regimen is 28 days. The following embodiments apply to all of the above aspects described above.

In one embodiment, the second administration regimen is initiated until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 2, Class 0-1, or baseline, I never do that. In one embodiment, the third dose regimen is initiated until a second persistent and unacceptable Grade 2 or Grade 3 adverse reaction or Grade 4 laboratory abnormality is resolved with Grade 2, Grade 0-1, or baseline acceptable I never do that. In one embodiment, the fourth dose regimen is initiated until a third persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory overrun is resolved with Class 2, Class 0-1, or baseline, I never do that. In another embodiment, until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 2, Class 0-1, or Baseline, a second dose regimen Not initiated; The third dose regimen is not initiated until a second persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory abnormality is resolved with Class 2, Class 0-1, or baseline acceptable. In another embodiment, until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 2, Class 0-1, or Baseline, a second dose regimen Not initiated; Does not initiate a third dose regimen until a second persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory override is resolved with Class 2, Class 0-1, or baseline acceptable; The fourth dose regimen is not initiated until a third persistent and unacceptable Class 2 or Class 3 adverse event or class 4 laboratory abnormality is resolved with a Class 2, Class 0-1, or baseline acceptable.

In one embodiment, the second dose regimen is not initiated until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 0-1 or Class 2 acceptable. In one embodiment, the third dose regimen is not initiated until a second persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 0-1 or Class 2 acceptable. In one embodiment, the fourth dose regimen is not initiated until a third persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 0-1 or Class 2 acceptable. In another embodiment, until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 0-1 or Class 2 acceptable, a second dose regimen may not be initiated ; A second sustained and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is not initiated until the Class 0-1 or Class 2 permit is resolved. In another embodiment, until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 0-1 or Class 2 acceptable, a second dose regimen may not be initiated ; Does not initiate a third dose regimen until a second persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 0-1 or Class 2 acceptable; A third continuing and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is not initiated until the Class 0-1 or Class 2 permit is resolved.

In some embodiments, the first, second and third persistent and unacceptable Grade 2 or Grade 3 adverse reactions or Grade 4 laboratory abnormalities, prior to termination of administration of the dosing regimen administered at the time of adverse reaction or onset of the laboratory, Each medical care management is started.

In certain embodiments, prior to commencing administration of a dose regimen that occurs after an adverse reaction or laboratory anomaly is resolved with Class 2, Class 0-1, or baseline, the first, second, and third persistent and not allowed Not a Class 2 or Class 3 adverse reaction or a Class 4 laboratory initiates each medical care.

In certain embodiments, first, second and third persistent and unacceptable Grade 2 or Grade 3 adverse reactions or medical care of each of the Grade 4 laboratories or more may result in adverse reactions or laboratory abnormalities being classified as Grade 0-1 or acceptable Is initiated prior to commencement of administration of the dosage regimen that occurs after resolution to Grade 2.

In some embodiments, a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is a second and / or third persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 It is the same as the lab.

In certain embodiments, the first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormalities are secondary and / or third persistent and unacceptable Class 2 or Class 3 adverse reactions or Class 4 It is different from the laboratory ideal.

In some embodiments, the Grade 2 or Grade 3 adverse reaction is selected from the group consisting of grade 3 hypertension, grade 2 hypertension, grade 3 cardiac dysfunction, grade 2 cardiac dysfunction, grade 3 arterial thromboembolic event, grade 2 arterial thromboembolic event, Grade 3 diarrhea, grade 2 diarrhea, grade 3 gastrointestinal perforation or fistula, grade 2 gastrointestinal perforation or fistula, grade 3 vomiting, grade 2 vomiting, grade 2 proteinuria, grade 2 proteinuria, grade 3 renal failure or renal disease, grade 2 renal failure or renal disease, Grade 3 reduced appetite, grade 2 reduced appetite, grade 3 fatigue, grade 2 fatigue, grade 3 nausea, grade 2 nausea, grade 3 cough, grade 2 cough, grade 3 reduced weight, grade 2 reduced weight, grade 3 Grade 3 anemia, grade 2 anemia, grade 3 acute renal failure, grade 2 acute renal failure, grade 3 QT / QTc interval extension, grade 2 QT / QTc interval extension, grade 3 hypertension, Grade 3 reversible postprandial encephalopathy It is selected from Syndrome (RPLS), RPLS Class 2, Class 3 hemorrhagic events, Grade 2 bleeding events, Class 3 hyperthyroidism, and Level 2 the group consisting of hyperthyroidism. In some cases, a Class 2 or Class 3 adverse reaction is selected from the group consisting of a grade 3 diarrhea, a grade 2 diarrhea, a grade 3 vomit, a grade 2 vomit, a grade 3 nausea, a grade 2 nausea, a grade 3 proteinuria, do.

In certain embodiments, the Grade 4 laboratory abnormalities include, but are not limited to, Grade 4 aspartate aminotransferase increase, Grade 4 alanine aminotransferase increase, Grade 4 alkaline phosphatase increase, Grade 4 hyperkalemia, Grade 4 hypokalemia, Grade 4 hyperglycemia, grade 4 hyperglycemia, grade 4 hyperlipidemia, grade 4 cholesterol increase, grade 4 lipase increase, grade 4 hemoglobin decrease, grade 4 platelet count decrease, and grade 4 lymphocyte count decrease ≪ / RTI > In some cases, the Grade 4 laboratory abnormalities are selected from the group consisting of Grade 4 Lipase Increase, Grade 4 hyperglyceridemia, Grade 4 cholesterol increase, Grade 4 hypophosphatemia, Grade 4 hyponatremia, and Grade 4 hypokalemia.

In certain embodiments, the second dose regimen, the third dose regimen and the fourth dose regimen are not disclosed, respectively, until the resolution of the adverse reaction or toxicity associated with administration of everolimus.

In some embodiments, the second dose regimen does not include everolimus. In some embodiments, the third dose regimen does not include everolimus. In some embodiments, the fourth dose regimen does not include everolimus. In another embodiment, the second dose regimen and the third dose regimen do not include everolimus. In another embodiment, the second dose regimen and the fourth dose regimen do not include everolimus. In certain embodiments, the third dose regimen and the fourth dose regimen do not include everolimus. In another embodiment, each of the second dose regimen, the third dose regimen and the fourth dose regimen does not include everolimus.

In certain embodiments, the rennatibin or a pharmaceutically acceptable salt thereof is formulated as a capsule.

In some embodiments, everolimus is formulated as a tablet.

In certain embodiments, lenbatinib, or a pharmaceutically acceptable salt thereof, and everolimus are administered orally to a human subject.

In some embodiments, human subjects have received prior vascular endothelial growth factor (VEGF) -targeted therapy.

In some embodiments, lenbatinib or a pharmaceutically acceptable salt thereof and everolimus are administered once a day.

In certain embodiments, the administration of Lenvatib or a pharmaceutically acceptable salt thereof and everolimus is administered once daily for at least 28 weeks, at least 56 weeks, at least 84 weeks, at least 112 weeks, at least 140 weeks, or at least 168 weeks do.

In some embodiments, the renal cell carcinoma is an unresectable advanced renal cell carcinoma.

In another embodiment, the renal cell carcinoma is metastatic renal cell carcinoma.

In another embodiment, the renal cell carcinoma is advanced renal cell carcinoma (e. G., Advanced renal cell carcinoma following prior anti-angiogenic therapy). In certain embodiments, the prior anti-angiogenic therapy is VEGF-targeted therapy.

In some embodiments, the rennatibin or a pharmaceutically acceptable salt thereof is lanbatitin mesylate.

In certain embodiments, the human subject has a poor MSKCC risk score.

Unless defined otherwise, all technical scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present application, including justice, shall prevail. The materials, methods and examples are illustrative only and not intended to be limiting.

Other features and advantages of the present invention will become apparent from the following detailed description and claims.

Figure 1 is a Kaplan-Meier plot of progression-free survival comparing three study divisions. Sector A = Renbima ^{(registered trademark)} 18 mg + Everolimus 5 mg (top line in the figure); Category B = Renimbas ^{(registered trademark)} 24 mg (median line in the figure); And section C = everolimus 10 mg (bottom line in the figure). Risk ratios are based on a layered Cox regression model that includes hemoglobin as the factor and the corrected serum calcium as a factor. The Efron method was used to calibrate the bundled events. The median survival time is based on the Kaplan-Meier method, and the 95% confidence interval is based on the Greenwood equation using log-log transformations.
Figure 2 is a Kaplan-Meier plot of overall survival comparing three study divisions. Sector A = Renbima ^{(registered trademark)} 18 mg + Everolimus 5 mg (top line in the figure); Category B = Renimbas ^{(registered trademark)} 24 mg (median line in the figure); And section C = everolimus 10 mg (bottom line in the figure). Risk ratios are based on a layered Cox regression model that includes hemoglobin as the factor and the corrected serum calcium as a factor. The Efron method was used to calibrate the bundled events. The median survival time is based on the Kaplan-Meier method and the 95% confidence interval is based on the Greenwood equation using log-log transformations.
Figure 3 is a Kaplan-Meier plot of overall survival comparing three study divisions. Sector A = Renbima ^{(registered trademark)} 18 mg + Everolimus 5 mg (top line in the figure); Category B = Renimbas ^{(registered trademark)} 24 mg (median line in the figure); And section C = everolimus 10 mg (bottom line in the figure). Risk ratios are based on a layered Cox regression model that includes hemoglobin as the factor and the corrected serum calcium as a factor. The Efron method was used to calibrate the bundled events. The median survival time is based on the Kaplan-Meier method and the 95% confidence interval is based on the Greenwood equation using log-log transformations. The data cutoff date was July 31, 2015.

The present application provides a method of treating a human subject having a renal cell carcinoma (e.g., a progressive RCC, an unresectable advanced RCC, or a metastatic RCC). The method comprises administering to the subject a therapeutically effective amount of a medicament selected from the group consisting of everolimus (5 mg) and lenbactinib or a pharmaceutically acceptable salt thereof (18 mg or 14 mg as a starting dose (or 14 mg or 10 mg if the subject has severe renal or hepatic impairment Starting dose)). In the event that one or more adverse events develop as a result of treatment with lenbatinib or a pharmaceutically acceptable salt thereof and / or everolimus in a subject, the present application is not limited to a modification of the therapeutic regimen, Reduced capacity of one or both of nip and everolimus). If the adverse reaction does not evolve as a result of administration of a starting dose of 14 mg of lenbactinib or a pharmaceutically acceptable salt thereof in combination with 5 mg of everolimus in the subject, the subject may be administered a high dose therapy (e.g., 5 mg 18 mg < RTI ID = 0.0 > of lenbactinib < / RTI > or a pharmaceutically acceptable salt thereof in combination with everolimus).

Renal cell carcinoma

Kidney cancer accounts for about 2.5% of the total human cancer burden, and approximately 338,000 new cases were diagnosed in 2012. These occur in all world regions and dominate in developed countries. There are several types of renal cancer, of which renal cell carcinoma (RCC) is the most common (> 90%). RCC occurs in cells of the proximal renal tubular epithelium of the renal tubule and is often asymptomatic and is incidentally detected in imaging studies when human beings are examined for other diseases. Although hematuria, pain and lateral abdominal mass are the three typical signs of presentation, all of these symptoms are absent in a large percentage of patients, and instead of chronic fatigue, weight loss, abdominal pain, abdominal mass, anorexia, anemia, hypercalcemia , Sleep disturbances, and recurrent fever. These cancers are clearly predominant in males, and males are two-thirds of cases. Due to disease progression, approximately 40% of patients with RCC die.

According to the World Health Organization classification in 2004, there were no significant differences between the two groups in terms of clear cell RCC, multilocular clear cell RCC, papillary RCC, and hypoxic RCC, Bellini collecting duct carcinoma, renal medullary carcinoma, Xp11 avascular carcinoma, Several histological RCC subtypes have been recognized, including associated carcinomas, mucinous tubular and pustular carcinomas, papillary adenomas, tumor cell tumors, and undifferentiated renal cell carcinomas. In 2013, the Classification Working Group of the International Society of Urological Pathology (ISUP) Consensus Conference on Renal Neoplasms, a new well-characterized 5 There are two types of RCC: tubulointerstitial RCC, MiT family potential RCC (especially t (6; 11) RCC), and hereditary leiomyomatosis RCC syndrome-associated RCC The In addition, ISUP also has three additional types considered as new neoplasia: thyroid cancer-like follicular RCC; Succinate dehydrogenase B deficiency-associated RCC; And ALK dislocation RCC. Of the many histologic RCC subtypes, clear cell RCC, papillary RCC and hypochromic RCC are the most frequent histologic subtypes and account for more than 90% of all RCCs.

RCC staging is important to determine the best way to treat the disease. RCC can be staged using a TNM staging system that individually classifies tumor size and extent (T), lymph node involvement (N), and metastasis (M). Also, using the 1997 revision of AJCC described below, an entire armamental alternative to Stages I-IV may be used.

Stage I: limited to tumors less than 7 cm in diameter (approximately 2 3/4 inches), and kidneys. No lymph node involvement or transfer to the distal organ.

Stage II: tumors larger than 7 cm, but still limited to the kidneys. No lymph node involvement or transfer to the distal organ.

Stage III (any of the following): (1) A tumor of any size with adjacent lymph node metastasis but no metastasis to the distal organ. Tumors of this stage may or may not be accompanied by proliferation into the adipose tissue around the kidney and may or may not be accompanied by proliferation into the large vena cava extending from the kidney to the heart. (2) a tumor that diffuses into the adipose tissue around the kidney and / or spreads from the kidney to the heart into the vena cava, but is not accompanied by spread to any lymph nodes or other organs.

Stage IV (any of the following): (1) adipose tissue around the kidney and fascia ligament - a tumor with direct diffusion across similar tissues. (2) Invasion of more than one lymph node near the kidney. (3) invasion of any lymph node not near the kidney. (4) Remote metastases such as in the lungs, bone or brain.

In certain embodiments, the RCC is a progressive RCC (e.g., advanced renal cell carcinoma following a prior anti-angiogenic therapy). In certain cases, the pre-existing anti-angiogenic regimen is VEGF-targeted therapy. In another embodiment, the RCC is an unresectable progressive RCC. In another embodiment, the RCC is a metastatic RCC.

Treatment of RCC may involve surgery (partial nephrectomy or nephrectomy) to remove some or all of the kidneys. Surgery is most useful when the cancer is present only in the kidney. In the case of metastatic disease, surgical treatment may be an option that depends on the stage of growth of the tumor and the extent to which the disease has spread. Surgery is not a good option for the patient, and percutaneous resection therapies such as radiofrequency ablation and freezing resection may be used. Another approach to the treatment of RCC is to use immunotherapy to activate the immune system of the patient to attack the cancer. An additional approach is to use targeting therapies that target known growth factors as promoting tumor growth and spread. These therapies include, but are not limited to, nobilulam, axitinib, sunitinib, bevacizumab, sorafenib, pazopanib, interferon-alpha, temsirolimus, carbozanthin, everolimus, and lenbactinib.

The present disclosure provides methods for treating various types of RCCs (e. G., Those mentioned above) using a combination of everolimus and lenbactinib or a pharmaceutically acceptable salt thereof.

Lenbatinip

A number of kinase inhibitors have been developed as antitumor agents. For example, a group of compounds having an inhibitory activity on receptor tyrosine kinases, such as vascular endothelial growth factor receptor (VEGFR), is known to inhibit angiogenesis and is considered a new class of antineoplastic agents. Renatinate is a multi-target receptor tyrosine kinase inhibitor that inhibits the kinase activity of VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4). Lentinib contains fibroblast growth factor (FGF) receptors FGFR1, FGFR2, FGFR3 and FGFR4; In addition to its normal cellular function, including the rearranged receptor (RET), KIT, and platelet-derived growth factor receptor alpha (PDGFRα) during transfection, it also inhibits other receptor tyrosine kinases involved in pathogenic angiogenesis, tumor growth, and cancer progression .

Refers to 4- (3-chloro-4 (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide. This compound is disclosed in Example 368 (see column 270) of U.S. Patent No. 7,253,286. U.S. Patent No. 7,253,286 is incorporated herein by reference in its entirety. The term " pharmaceutically acceptable salt "is not particularly limited to the type of salt. Examples of such salts include inorganic acid addition salts such as hydrochloride, sulfate, carbonate, bicarbonate, hydrobromide, and iodine hydrobromide; Organic carboxylic acid addition salts such as acetate, maleate, lactate, tartrate, and trifluoroacetate; Organic sulfonic acid addition salts such as methanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate, benzenesulfonate, toluenesulfonate, and taurine salts; Amine addition salts such as trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanol Amine salts, triethanolamine salts, tris (hydroxymethylamino) methane salts, and phenethylbenzylamine salts; And amino acid addition salts such as arginine salts, lysine salts, serine salts, glycine salts, aspartic acid salts, and glutamic acid salts. In one embodiment, the pharmaceutically acceptable salt is a methanesulfonate salt ("mesylate"). The methanesulfonate salt form (i.e., mesylate) of Lenvatib is disclosed in U.S. Patent No. 7,612,208, the disclosure of which is incorporated herein by reference in its entirety. The chemical name of the renatintib mesylate is 4- [3-chloro-4- (N'-cyclopropylureido) phenoxy] -7-methoxyquinoline-6-carboxamide methanesulfonate, Are provided below.

Lentinib mesylate is also referred to as LENBIMA ^(R) .

Lentinib mesylate is a white to red light yellow powder. It is poorly soluble and substantially insoluble (dehydrated) in ethanol. The dissociation constant (pKa value) of the lanthabine mesylate is 5.05 at 25 占 폚. The partition coefficient (log P value) is 3.30.

Iverolimus

Everolimus is an inhibitor of the mammalian rapamycin target (mTOR), serine-threonine kinase, downstream of the PI3K / AKT pathway. The mTOR pathway is abnormally regulated in several human cancers. Iverolimus binds to the intracellular protein FKBP-12, leading to the formation of inhibitory complexes with mTOR complex 1 (mTORC1) and consequent inhibition of mTOR kinase activity. Everolimus may reduce the activity of the S6 ribosomal protein kinase (S6K1) and the eukaryotic initiation factor 4E-binding protein (4E-BP1), which are downstream effectors of mTOR following protein synthesis. S6K1 is a substrate for mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor, which leads to ligand-dependent activation of the receptor. In addition, everolimus can inhibit the expression of hypoxia-inducible factors (e.g., HIF-1) and reduce the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis and glucose uptake in vitro and / or in vivo studies.

The chemical name of everolimus is (1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-dihydroxy- (1 R) -2 - [(1S, 3R, 4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl] -1- methylethyl} -19,30-dimethoxy- , 21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo [30.3.1.04,9] hexatriaconta-16,24,26,28- 3,10,14,20-pentanone.

The structural formula of Everolimus is as follows.

Iverolimus is marketed under the trade name AFINITOR ^(R) . The ampicillin ^(R) tablets are supplied for oral administration and contain 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus. The tablet also contains, as an inert ingredient, anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate and magnesium stearate.

Everolimus is indicated for the treatment of adults with progressive RCC, especially after failure of treatment with sunitinib or sorafenib.

Combination therapy for the treatment of RCC

This disclosure, in part, provides a combination therapy for the treatment of human subjects with RCC. In certain cases, the human subject has a progressive RCC after one type of prior anti-angiogenic therapy. In certain embodiments, the subject to whom the combination therapy is to be administered is administered at least one of the preceding VEGF-targeting treatments (e.g., sutitinib, pazopanib, tibosanip, acacitnib, sorafenib or bevacizumab) received. In other words, combination therapy can be used as a second-line therapy. In certain cases, the best response to at least one preceding VEGF-targeting therapy was a complete response. In certain cases, the best response to at least one preceding VEGF-targeting therapy was a partial response. In certain cases, the best response to at least one preceding VEGF-targeting therapy was a stable disease. In certain cases, the best response to at least one preceding VEGF-targeting therapy was a progressive disease. In certain instances, the subject has received at least one of at least one preceding VEGF-targeting treatment, and a preceding checkpoint inhibitor therapy, a prior interferon therapy, or a prior radiation therapy. In certain embodiments, the subject had progression of RCC after one prior VEGF-targeting treatment. In some cases, the subject had RCC progression within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after stopping the preceding VEGF-targeting treatment. In one embodiment, the subject had RCC progression within 9 months of stopping the preceding VEGF-targeting treatment.

Combination therapy involves administering to a human subject having RCC a combination of levetirimus and levetabim or a pharmaceutically acceptable salt thereof. In certain embodiments, the RCC is a progressive RCC (e.g., advanced renal cell carcinoma following a prior anti-angiogenic therapy). In certain cases, the pre-existing anti-angiogenic regimen is VEGF-targeted therapy. In another embodiment, the RCC is an unresectable progressive RCC. In another embodiment, the RCC is a metastatic RCC. In certain embodiments, the RCC in a human subject has one type of transition. In some embodiments, the RCC in a human subject has two types of transitions. In some embodiments, the RCC in a human subject has three or more transitions. In certain instances, the site of metastasis / metastasis is bone, liver, lung, or lymph node. In certain embodiments, the subject is in the favorable moderate Sloan Kettering Cancer Center (MSKCC) risk group. In certain embodiments, the subject is in the moderate MSKCC risk group. In some embodiments, the subject is in a poor MSKCC risk group. In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of zero. In another embodiment, the subject has an ECOG performance state of one. In certain embodiments, the subject has undergone a prior renalectomy.

As shown in Example 1, which describes the results of a two-phase human clinical trial, the combination of Renbma ^(R) and Everolimus is statistically significant compared to Everolimus alone or Renbima ^(R) alone Indicating clinically significant improvement in progression-free survival (PFS). In addition, after treatment with a combination of Renbma ^(R) and Everolimus, overall survival was longer.

administration

Combination therapy of Everolimus and Lentinib or its pharmaceutically acceptable salts may be administered to a human subject in need thereof by any means that the healthcare provider considers useful. For example, each of these compounds may be administered orally, rectally, nasally, topically (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous), or by inhalation, And the like. Each compound may be administered in the same manner or via a different method. Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

For oral administration, the compounds may be in the form of, for example, tablets, capsules, suspensions or liquids. The pharmaceutical compositions are preferably prepared in the form of dosage units containing a certain amount of the active ingredient. Examples of such dosage units include conventional additives such as lactose, mannitol, corn starch or potato starch; Binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatin; Disintegrants such as corn starch, potato starch or sodium carboxymethyl-cellulose; Capsules, tablets, powders, granules or suspensions together with a lubricant such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition, for example, saline, dextrose or water may be employed as suitable pharmaceutically acceptable carriers.

In one embodiment, the rebin'tinib mesylate is administered to a human subject as a capsule. The capsules may contain, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, , 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg of lenbactinib mesylate. In certain cases, the capsules contain lambatty nim mesylate equivalent to 4 mg of lenbactinib. In certain cases, the capsules contain lenbactin mesylate equivalent to 10 mg of lenbactinib. In some embodiments, these capsules also contain one or more of the following inactive ingredients: calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose (type H) and talc. In some embodiments, the shell of these capsules is a hypromellose shell and may contain at least one of titanium dioxide, ferric oxide ferricyanide, and ferric oxide ferric red. The printing ink used in the capsules may contain at least one of shellac, black iron oxide, potassium hydroxide and propylene glycol.

In certain embodiments, the renatintin mesylate is administered to a human subject at a dose of 18 mg once daily. Such doses may be administered orally once a day, for example, as one 10 mg capsule and two 4 mg capsules. In another embodiment, the renatintin mesylate is administered to a human subject at a dose of 14 mg once daily. Such doses may be administered orally once a day, for example, as one 10 mg capsule and one 4 mg capsule. In some embodiments, the lenbatinib mesylate is administered to a human subject at a dose of 10 mg once daily. Such a dose may be administered orally once a day, for example, as one 10 mg capsule. In some embodiments, the lenbatinib mesylate is administered to a human subject at a dose of 8 mg once daily. Such a dose may be administered orally once a day, for example as two 4 mg capsules. In some embodiments, the renatintin mesylate is administered to a human subject at a dose of 6 mg once daily. In some embodiments, the renatintin mesylate is administered to a human subject at a dose of 4 mg once daily. Such a dose may be administered orally once a day, for example as one 4 mg capsule.

In one embodiment, everolimus is administered to a human subject as a tablet. Tablets may contain, for example, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg or 10 mg of everolimus have. In certain cases, the ravelolimus tablets also contain an inert ingredient (s). For example, the everolimus tablet may contain, as an inert ingredient, at least one of anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate. In one embodiment, everolimus is administered to a human subject as an oral suspension. Oral suspensions may be prepared by dissolving the everolimus tablets in a liquid (e.g., water). The Everolimus tablet for oral suspension also contains an inert ingredient (s). For example, everolimus tablets for oral suspensions may contain as inert ingredients butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose May also contain more than one species.

In certain embodiments, everolimus is administered to human subjects at a dose of 5 mg once daily. Such doses may be, for example, once per day orally as one 5 mg tablet, or once daily as two 2.5 mg tablets; Or as an oral suspension of 5 mg tablet. In some embodiments, everolimus is administered to a human subject at a dose of 5 mg every other day. In some embodiments, everolimus is administered to a human subject at a dose of 2.5 mg once daily. In some embodiments, everolimus is administered to a human subject at a dose of 2.5 mg once a day. In certain cases, in the case of Grade 3 toxicity, Iverolimus is discontinued.

In some embodiments, the rennatibin or a pharmaceutically acceptable salt thereof (e.g., lenbatinib mesylate) is administered as a capsule, and the everolimus is administered as a tablet. In one embodiment, lenbatinib or a pharmaceutically acceptable salt thereof (e.g., lenbatinib mesylate) is administered at a dose of 18 mg once daily, and everolimus is administered at a dose of 5 mg once daily Co-administered. In another embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 18 mg once daily, and the enverolimus is co-administered at a dose of 5 mg once a day. In one embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 18 mg once daily, and the everolimus is co-administered at a dose of 2.5 mg once daily. In another embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 18 mg once daily, and the everolimus is co-administered at a dose of 2.5 mg once a day. In a different embodiment, lenbatinib or a pharmaceutically acceptable salt thereof (e.g., lenbatinib mesylate) is administered at a dose of 14 mg once daily, and everolimus is administered at a dose of 5 mg once daily Co-administered. In another embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 14 mg once daily, and the everolimus is coadministered at a dose of 5 mg once a day. In another embodiment, lenbatinib or a pharmaceutically acceptable salt thereof is administered at a dose of 14 mg once daily, and the everolimus is co-administered at a dose of 2.5 mg once daily. In another embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 14 mg once daily, and the everolimus is co-administered at a dose of 2.5 mg once a day. In a different embodiment, lenbatinib or a pharmaceutically acceptable salt thereof (e. G., Lenbatinib mesylate) is administered at a dose of 10 mg once daily, and everolimus is administered at a dose of 5 mg once daily Co-administered. In another embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg once daily, and the everolimus is co-administered at a dose of 5 mg once a day. In another embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg once daily, and the everolimus is coadministered at a dose of 2.5 mg once daily. In another embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg once daily, and the everolimus is co-administered at a dose of 2.5 mg once a day. In a different embodiment, lenbatinib or a pharmaceutically acceptable salt thereof (e. G., Lenbatinib mesylate) is administered at a dose of 8 mg once daily, and everolimus is administered at a dose of 5 mg once daily Co-administered. In one embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 8 mg once daily, and the everolimus is co-administered at a dose of 5 mg once a day. In another embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 8 mg once daily, and the everolimus is coadministered at a dose of 2.5 mg once daily. In another embodiment, lenbatinib or a pharmaceutically acceptable salt thereof is administered at a dose of 8 mg once daily, and the everolimus is co-administered at a dose of 2.5 mg once a day. In a different embodiment, lenbatinib or a pharmaceutically acceptable salt thereof (e. G., Lenbatinib mesylate) is administered at a dose of 6 mg once daily, and everolimus is administered at a dose of 5 mg once daily Co-administered. In one embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 6 mg once daily, and the everolimus is co-administered at a dose of 5 mg once a day. In another embodiment, lenbatinib or a pharmaceutically acceptable salt thereof is administered at a dose of 6 mg once daily, and the everolimus is co-administered at a dose of 2.5 mg once daily. In another embodiment, the rennatibin or a pharmaceutically acceptable salt thereof is administered at a dose of 6 mg once daily, and the everolimus is co-administered at a dose of 2.5 mg once a day.

It is recommended that the subject take either lenbitalip or its pharmaceutically acceptable salt and everolimus at approximately the same time once daily, with or without food. In certain embodiments, the subject should not ingest a CYP3A4 inhibitor and / or a Pgp inhibitor. In certain embodiments, the subject should not take herbal supplements and / or eat grapefruit and / or drink grapefruit juice.

In cases where the patient can not swallow the whole Lenbetype nipple capsule, the patient can put about 1 teaspoon of water or apple juice into the glass using a cup and place the drug capsule in the liquid without rupturing or breaking . Capsules should be left in the liquid for at least 10 minutes and then the contents should be stirred for at least 3 minutes. The patient can then drink the mixture. After drinking, the patient should rinse the glass with a small amount of additional water or apple juice and swallow the liquid.

In certain embodiments, lenbatinib or a pharmaceutically acceptable salt thereof and agaverolimus are administered to a subject having an RCC 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, 140 weeks, at least 168 weeks, or at least 196 weeks.

Treatment methods to control, reduce or prevent harmful events

A major problem in treating subjects with new therapies is the development of therapeutic-expressive adverse event (s) (TEAE). Therapeutic-Expressive Therapeutic-Expressive Adverse Events are any adverse events that do not exist in the subject prior to initiation of treatment, or any existing adverse events that are exacerbated in intensity or frequency after exposure to treatment. In certain embodiments, the adverse event is a persistent and unacceptable adverse event.

(CTCAE, publication date: May 28, 2009; v4.03: June 14, 2010), which is hereby incorporated by reference in its entirety, It is a descriptive term that can be used in event reporting. The CTCAE provides a rating (severity) scale for each hazard event term. An adverse event (AE) is any adverse and unintended symptom (including abnormal laboratory findings), a symptom or a disease that is temporarily associated with the use of a medical treatment or procedure that may or may not be considered to be related to a medical treatment or procedure . AE is a unique term for a particular event used in medical documentation and scientific analysis. AE can be graded. The CTCAE grade refers to the severity of AE. The CTCAE represents Grades 1 to 5 with a unique clinical description of severity for each AE based on these guidelines:

Grade 1: Hardness; Asymptomatic or mild symptoms; Only clinical or diagnostic observations; No intervention is indicated.

Grade 2: Moderate; Minimal, local or noninvasive intervention indicated; Limited age - appropriate Activities of Daily Living (ADL). ["Sudanese ADL" refers to food preparation, grocery or clothing shopping, telephone use, money management, etc.]

Class 3: Severe or medically significant but not immediate life-threatening; Hospitalization or extension of hospitalization ordered; disability; Limited self - management ADL. ["Self-administered ADL" refers to bathing, wearing and dislodging, self-feeding, toilet use, medicinal use, and bed-and-

Grade 4: Life-threatening consequences; Urgent intervention is indicated.

Class 5: AE related deaths.

Not all grades are appropriate for all AEs. Therefore, some AEs are listed in CTCAE with fewer than five options for grading.

Combination therapies with renatintib or a pharmaceutically acceptable salt thereof may lead to a treatment-expressing adverse event (see Example 2). In certain embodiments, the adverse event associated with therapy with a combination of lenbatinib or a pharmaceutically acceptable salt thereof and everolimus is a persistent and unacceptable AE. In certain cases, AEs that are persistent and not allowed are Class 2 AEs. In other cases, AEs that are persistent and not allowed are Class 3 AEs. In certain embodiments, the adverse event associated with the combination therapy of lenbatinib or its pharmaceutical acceptable salt and everolimus is a grade 4 AE. In other cases, persistent and unacceptable AEs are more than Class 4 laboratories. The most common adverse reactions observed in the Renbima ^(R) + Everolimus-treated subjects were diarrhea, decreased appetite, fatigue, vomiting, nausea, hypertension, cough, and reduced body weight in order of decreasing frequency .

Diarrhea is a disorder characterized by frequent and diluted intestinal motility, and is graded as follows:

Grade 1: increase of stool <4 times per day compared to baseline; Increased hardness of bowel excretion compared to baseline

Grade 2: an increase of 4 to 6 stools per day compared to baseline; Moderate increase in intestinal excretion compared to baseline

Grade 3: increase of> = 7 stools per day compared to baseline; incontinence; Admission is indicated; Significant increase in bowel excretion compared to baseline; Limited self-management ADL

Grade 4: Life-threatening consequences; Urgent intervention ordered

Grade 5: Death

Fatigue is a disorder characterized by a state of systemic weakness that has apparent disability to summarize enough energy to achieve daily activity and is graded as follows:

Grade 1: Fatigue relaxed by rest

Grade 2: fatigue is not relieved by rest; Restrictive instrumental ADL

Grade 3: Fatigue not relieved by rest, limited self-management ADL

Grade 4: Not Available

Grade 5: Not Available

Vomiting is a disorder characterized by the reflex action of the above contents through the mouth and is graded as follows:

Grade 1: 1 - 2 episodes within 24 hours (every 5 minutes)

Grade 2: 3-5 episodes within 24 hours (every 5 minutes)

Grade 3: within 24 hours > = 6 episodes (every 5 minutes); Tube feeding, TPN or hospitalization ordered

Grade 4: Life-threatening consequences; Urgent intervention ordered

Grade 5: Death

Nausea is a disorder characterized by zone sensation and / or vomiting impulse and is graded as follows:

Grade 1: loss of appetite with no change in eating habits

Grade 2: reduced oral intake without significant weight loss, dehydration or malnutrition

Grade 3: Inappropriate oral calorie or fluid intake; Tube feeding, TPN, or hospitalization ordered

Grade 4: Not Available

Grade 5: Not Available

Hypertension is a pathological increase in blood pressure; 140 and a repetitive rise in blood pressure above 90 mm Hg relative to 140, and is graded as follows:

Grade 1: Total hypertension (systolic BP 120 - 139 mm Hg or diastolic BP 80 - 89 mm Hg)

Grade 2: Stage 1 Hypertension (systolic BP 140 - 159 mm Hg or diastolic BP 90 - 99 mm Hg); Medical intervention directed; Recurrence or persistence (> = 24 hours); > 20 mm Hg (dilator) or> 140/90 mm Hg for WNL previously; Monotherapy directed to the child: recurrent or persistent (> = 24 hours) BP> ULN; Monotherapy directed

Grade 3: Stage 2 Hypertension (systolic BP> = 160 mm Hg or expander BP> = 100 mm Hg); Medical intervention directed; More than one drug or stronger therapy than previously used is indicated to the child: Same as adult

Grade 4: life-threatening consequences (eg, malignant hypertension, temporary or permanent neurological deficit, hypertensive manifestation); Urgent intervention directed to child: Same as adult

Grade 5: Death

Cough is a disorder characterized by spasmodic and often repetitive condylar constriction of the thoracic cavity, which causes explosive release of air from the lungs and usually accompanies a unique sound, and is graded as follows:

Class 1: mild symptoms; Non-prescription intervention indicated

Class 2: Severity Symptoms, medical intervention indicated; Restrictive instrumental ADL

Grade 3: Severe symptoms; Limited self-management ADL

Grade 4: Not Available

Grade 5: Not Available

Reduced appetite is a disorder characterized by appetite loss and is graded as follows:

Grade 1: loss of appetite with no change in eating habits

Grade 2: Altered oral intake without significant weight loss or malnutrition; Oral nutritional supplements indicated

Grade 3: associated with significant weight loss or malnutrition (e. G., Inappropriate oral calorie and / or liquid ingestion); Tube feeding or TPN indicated

Grade 4: Life-threatening consequences; Urgent intervention ordered

Grade 5: Death

Reduced weight is a finding characterized by a decrease in overall body weight, below the baseline growth curve for children, and is graded as follows:

Grade 1: weight loss from 5 to < 10% from the baseline; Intervention not indicated

Class 2: 10 - <20% from the baseline; Nutritional support directed

Grade 3:> = 20% from baseline; Tube feeding or TPN indicated

Grade 4: Not Available

Grade 5: Not Available

The most common serious adverse reactions in the Renimbas ^(R) + Everolimus-treated group were anemia, dehydration, acute renal failure, diarrhea, and thrombocytopenia.

Anemia is a disorder characterized by a decrease in the amount of hemoglobin in 100 ml of blood. Symptoms and symptoms of anemia may include pale skin and mucous membranes, shortness of breath, palpitations of the heart, soft systolic noise, burning, and fatigue and are graded as follows:

Class 1: Hemoglobin (Hgb) <LLN -10.0 g / dL; <LLN - 6.2 mmol / L; <LLN - 100 g / L

Class 2: Hgb < 10.0 - 8.0 g / dL; <6.2 -4.9 mmol / L; <100 - 80g / L

Grade 3: Hgb < 8.0 g / dL; &Lt; 4.9 mmol / L; &Lt; 80 g / L; Transfusion ordered

Grade 4: Life-threatening consequences; Urgent intervention ordered

Grade 5: Death

Dehydration is a disorder characterized by excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or perspiration and is graded as follows:

Grade 1: indicated increased oral fluid; Dry mucosa; Degraded skin pressure

Grade 2: <IV liquid is directed at <24 hours

Class 3: IV Liquid or Hospitalized Indicated

Grade 4: Life-threatening consequences; Urgent intervention ordered

Grade 5: Death

Acute renal failure is a disorder characterized by acute loss of renal function and is traditionally associated with pre-renal (low blood flow into the kidney), renal (kidney damage) and postrenal causes (ureters or bladder outlet obstruction ), And is graded as follows:

Grade 1: increased creatinine level> 0.3 mg / dL; Creatinine 1.5-2.0 x higher than baseline

Class 2: 2-3 x higher creatinine than baseline

Grade 3:> 3 x baseline or> 4.0 mg / dL creatinine; Hospitalization ordered

Grade 4: Life-threatening consequences; Urgent intervention ordered

Grade 5: Death

Thrombocytopenia is a finding based on laboratory tests that show a decrease in platelet count in blood samples and is graded as follows:

Class 1: <LLN - 75,000 pcs / mm ³ ; <LLN - 75.0 x 10 ⁹ / L

Grade 2: < 75,000 - 50,000 pieces / mm ³ ; &Lt; 75.0 - 50.0 x 10 ⁹ pieces / L

Grade 3: < 50,000 - 25,000 pieces / mm ³ ; <50.0 - 25.0 x 10 ⁹ / L

Grade 4: < 25,000 pieces / mm ³ ; <25.0 x 10 ⁹ pieces / L

Grade 5: Not Available

The present disclosure provides for dose control of lenbatinib or its pharmaceutically acceptable salts and / or everolimus upon occurrence of a therapeutic-expressing adverse event (s) during a combination therapy process. In certain embodiments, a subject with an RCC is administered a first dose regimen comprising 18 mg / day of a dose of Lenvatibin or a pharmaceutically acceptable salt thereof, and 5 mg / day of everolimus. In another embodiment, a subject with RCC is administered a first dose regimen comprising 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof, and 5 mg / day of everolimus. In some cases, after administration of the first administration regimen, a Class 1 or acceptable Class 2 adverse reaction may develop in the subject. In such a case, the treatment of the subject may continue with the first dose regimen without any change. An unacceptable level in a human subject after or in the course of treatment with a first dose regimen comprising 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof, and 5 mg / day of everolimus, 2 or grade 3 adverse events or grade 4 laboratory abnormalities are not developed, the regimen may be up-titrated (e.g., a dose of 18 mg / day of lenbitalipine or a pharmaceutically acceptable salt thereof, and 5 mg / day with everolimus).

In some embodiments, persistent and unacceptable Class 2 or Class 3 adverse reactions may develop in the subject during the course of treatment with the first dose regimen associated with a compound of one or both of the combination regimens. In certain cases, the first dose regimen may be administered at 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 14 or 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks, a persistent and unacceptable Class 2 or Class 3 adverse reaction develops in the subject. In one embodiment, persistent and unacceptable Class 2 or Class 3 adverse reactions develop in the subject within 12 weeks of administration of the first dose regimen. In another embodiment, persistent and unacceptable Class 2 or Class 3 adverse reactions develop in the subject within 16 weeks of administration of the first dose regimen. In certain cases, AE is diarrhea. In other cases, AE is vomiting. In other cases, AE is nausea. In another case, AE is proteinuria. In other cases, AE is a reduced appetite. In some cases, AE is fatigue. In some cases, AE is hypertension. In some cases, AE is a cough. In other cases, AE is a reduced body weight. In certain instances, a Class 2 or Class 3 adverse reaction may be classified as Category 3 hypertension, Class 2 hypertension, Class 3 cardiac dysfunction, Class 2 cardiac dysfunction, Class 3 arterial thromboembolic events, Class 2 arterial thromboembolic events, 3 proteinuria, grade 2 proteinuria, grade 3 renal failure or renal disease, grade 2 renal failure or renal disease, grade 3 diarrhea, grade 2 diarrhea, grade 3 gastrointestinal perforation or fistula, grade 2 gastrointestinal perforation or fistula, grade 3 vomiting, grade 2 vomiting, 3 reduced appetite, grade 2 reduced appetite, grade 3 fatigue, grade 2 fatigue, grade 3 nausea, grade 2 nausea, grade 3 cough, grade 2 cough, grade 3 reduced weight, grade 2 reduced weight, grade 3 dehydration Grade 3 depletion, grade 3 thrombocytopenia, grade 2 thrombocytopenia grade 3 anemia grade 2 anemia grade 3 acute renal failure grade 2 acute renal failure grade 3 proteinuria grade 2 proteinuria grade 3 QT / 2 QT / QTc interval extension, grade 3 (RPLS), grade 2 RPLS, grade 3 hemorrhagic event, grade 2 hemorrhagic event, grade 3 hyperthyroidism, or grade 2 hyperthyroidism. In some instances, adverse events may be classified as Category 4 laboratory abnormalities (eg, increased lipase, hypertriglyceridemia, hypophosphatemia, hypercholesterolemia, hyponatremia, hypokalemia, hyperkalemia, hypocalcemia, hyperglycemia, Fructose aminotransferase, increased alanine aminotransferase, or increased alkaline phosphatase). In certain instances, Class 4 laboratory abnormalities include, but are not limited to, elevated grade 4 aspartate aminotransferase, increased grade 4 alanine aminotransferase, increased grade 4 alkaline phosphatase, grade 4 hyperkalemia, grade 4 hypokalemia, grade 4 hyponatremia , Grade 4 hypercalcemia, grade 4 hypophosphatemia, grade 4 hyperglycemia, grade 4 hypertriglyceridemia, grade 4 hypercholesterolemia, grade 4 lipase increase, grade 4 hemoglobin decrease, grade 4 platelet count decrease, or grade 4 lymphocyte count decrease . In certain cases, a Class 4 AE is developed at the object. In some cases, Class 4 AE is renal failure or renal failure. In some cases, Class 4 AE is hepatotoxicity.

After administration of the first dose regimen (i.e., 18 mg / day of lenbactinib or its pharmaceutically acceptable salt, and 5 mg / day dose of everolimus), a sustained and unacceptable grade 2 or grade In the event of an adverse reaction or a Grade 4 laboratory or better, the healthcare provider terminates the first dose regimen and administers a second dose of the subject to a 14 mg / day dose of Lenvatibin or a pharmaceutically acceptable salt thereof Therapy can be given. Similarly, if the first administration regimen comprises 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof, then the healthcare provider terminates the first dose regimen and administers 10 mg / Day &lt; / RTI &gt; dose of lenbactinib or a pharmaceutically acceptable salt thereof. If the health care provider considers the adverse reaction to the combination therapy of the first dose regimen not to be associated with the administration of rivulimumus, the second dose regimen may be a 5 mg / day dose of everolimus (i.e., 14 mg / day Dose of lenbactinib or a pharmaceutically acceptable salt thereof, and 5 mg / day of everolimus). However, if the health care provider considers the adverse reaction to the combination regimen of the first administration regimen Lenbethidin + everolimus combination presumably or possibly possibly related to administration of ravelromus, It is possible to reduce the dose of everolimus administered with renatintib or a pharmaceutically acceptable salt thereof. For example, if the healthcare provider considers the adverse reaction to the combination regimen of the first administration regimen Lenbethib + everolimus combination presumably or possibly possibly associated with administration of evelormim, RTI ID = 0.0 &gt; mg / day &lt; / RTI &gt; of lenbactinib or a pharmaceutically acceptable salt thereof, and 5 mg of everolimus; 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof, and 2.5 mg / day of everolimus; Or 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof, and a 2.5 mg dose of everolimus. In certain cases, the second dose regimen may be administered after the first dose regimen has been discontinued and after the adverse reactions observed after the first dose regimen have been resolved to a grade 0-1 or baseline (or grade 0-1 or acceptable grade 2) . In certain cases, the second dose regimen is administered after the first dose regimen has stopped, and after the adverse reactions observed after the first dose regimen have been resolved to a Grade 2 or lower. In some cases, the first dose regimen is terminated only after the onset of medical care of a Class 2 or Class 3 adverse reaction or Class 4 laboratory that is not persistent and unacceptable. In a specific embodiment, persistent and unacceptable Class 2 or Class 3 adverse reactions are diarrhea, vomiting, nausea, or proteinuria. Persistent and unacceptable Grade 2 or Grade 3 adverse reactions are proteinuria, in one embodiment, &gt; = 2 grams of proteinuria / 24 hours, therapy with lenbatinib or a pharmaceutically acceptable salt thereof is suspended And resumes treatment with lower doses (e.g., 14 mg / day) of treatment with lenbatinib or a pharmaceutically acceptable salt thereof if the proteinuria is &lt; 2 gm / 24 hours; When a nephrotic syndrome develops in a subject, treatment with renativinib or a pharmaceutically acceptable salt thereof is discontinued. If the persistent and unacceptable Grade 3 adverse reaction is hypertension, in one embodiment, an antihypertensive regimen is provided to the subject, and when hypertension is controlled to a Grade 2 or lower, (E.g., 14 mg / day) of treatment; In the case of life-threatening hypertension, treatment with lenbactinib or a pharmaceutically acceptable salt thereof is discontinued. Persistent and Unacceptable Grade 3 In cases where the adverse reaction is a cardiac dysfunction or bleeding, in one embodiment, until improvement to grade 0 or 1 or baseline (or grade 0-1 or acceptable grade 2) Or a pharmaceutically acceptable salt thereof, and then administering a lower dose (e.g., 14 mg / day) of Lenvatib or a pharmaceutically acceptable salt thereof to the subject; If the cardiac dysfunction or bleeding is severe and / or persistent, therapy with lenbactinib or a pharmaceutically acceptable salt thereof is discontinued. If the adverse reaction is an arterial thrombotic event, therapy with lenbactinib or a pharmaceutically acceptable salt thereof is discontinued. In one embodiment, when a grade 3 or grade 4 kidney failure / renal or hepatotoxicity is developed in a subject, the administration of the term &quot; Treatment with bartinib or a pharmaceutically acceptable salt thereof is withheld and resumes at a lower dose (e. G., 14 mg / day); If renal / renal or hepatic toxicity is severe (e.g., hepatic failure) and / or persistence, treatment with lenbactinib or a pharmaceutically acceptable salt thereof is discontinued. If the adverse reaction is gastrointestinal perforation or life-threatening fistula formation, treatment with lenbactinib or a pharmaceutically acceptable salt thereof is discontinued. If the adverse reaction is a QT interval prolongation of grade 3 or greater, cease therapy with lenbatinib or a pharmaceutically acceptable salt thereof and discontinue therapy with QT extension to grade 0 or 1 or baseline (or grade 0-1 or acceptable grade 2 ), The therapy can be resumed at a lower dose (for example, 14 mg / day). If the adverse reaction is RPLS, cease therapy with renatinate or a pharmaceutically acceptable salt thereof until the adverse reaction is completely resolved; Upon resolution, therapy with lenbactinib or a pharmaceutically acceptable salt thereof may be resumed at a lower dose (e.g., 14 mg / day) or stopped if the neurological symptoms are severe and / or persistent can do.

In some cases, even after administration of the second dose regimen, an adverse reaction may develop in the subject. In certain instances, 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 administration of the second administration regimen, Persistent and unacceptable Class 2 or Class 3 adverse events develop. The adverse reaction after the second administration regimen may be the same as or different from the adverse reaction after the first administration regimen. The adverse reaction following the second dose regimen may be a persistent and unacceptable Class 2 or Class 3 adverse reaction. In certain cases, AE is diarrhea. In other cases, AE is vomiting. In other cases, AE is nausea. In another case, AE is proteinuria. In other cases, AE is a reduced appetite. In some cases, AE is fatigue. In some cases, AE is hypertension. In some cases, AE is a cough. In other cases, AE is a reduced body weight. In some embodiments, the adverse event is associated with an elevated level of risk for a patient with a Grade 4 laboratory or higher (eg, increased lipase, hypertriglyceridemia, hypophosphatemia, hypercholesterolemia, hyponatremia, hypokalemia, hyperkalemia, hypocalcemia, Aspartate aminotransferase, increased alanine aminotransferase, or increased alkaline phosphatase). In certain cases, a Class 4 AE is developed at the object. In some cases, Class 4 AE is renal failure or renal failure. In some cases, Class 4 AE is hepatotoxicity. After administration of a second dose regimen (e.g., lambatinate or a pharmaceutically acceptable salt thereof at a dose of 14 mg / day and everolimus at a dose of 5 mg / day), a sustained and unacceptable grade 2 or grade In the event of an adverse reaction or a Grade 4 laboratory abnormality develops, the healthcare provider terminates the second dose regimen and administers to the subject a third dose comprising lambatinate or a pharmaceutically acceptable salt thereof at a dose of 10 mg / Therapy can be given. Similarly, if the second administration regimen comprises a 10 mg / day dose of lenbactinib or a pharmaceutically acceptable salt thereof, then the healthcare provider terminates the second administration regimen and administers to the subject 8 mg / Day &lt; / RTI &gt; dose of lenbactinib or a pharmaceutically acceptable salt thereof. If the healthcare provider considers the adverse reaction to the second dose regimen not to be associated with the administration of rivulimumus, the third dose regimen is a 5 mg / day dose of everolimus (i.e., 10 mg / Baptinib or a pharmaceutically acceptable salt thereof, and 5 mg / day of everolimus). However, if the health care provider considers the adverse reaction to the combination regimen of the second administration regimen to be combined with the treatment regimen of the second administration regimen presumably or possibly possibly related to the administration of everrorimus, Can reduce the dose of rivulimumus administered with nip or a pharmaceutically acceptable salt thereof. For example, if the health care provider considers the adverse reaction to the second dose regimen to be presumably or possibly possibly related to the administration of rivulimumus, the third dose regimen may be, for example, a 10 mg / Nip or a pharmaceutically acceptable salt thereof, and 5 mg every other dose of Everolimus; A dose of 10 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof, and 2.5 mg / day of everolimus; Or 10 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof, and a 2.5 mg dose of everolimus. In certain cases, the third dose regimen may be administered after the end of the second dose regimen and after the adverse reactions observed after the second dose regimen are resolved to a grade 0-1 or baseline (or grade 0-1 or acceptable grade 2) . In some cases, the second dose regimen is terminated only after the initiation of medical care beyond the duration and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory. In a specific embodiment, persistent and unacceptable Class 2 or Class 3 adverse reactions are diarrhea, vomiting, nausea, or proteinuria.

In certain embodiments, even after administration of the third dose regimen, an adverse reaction may develop in the subject. In certain instances, 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 administration of the third administration regimen, Persistent and unacceptable Class 2 or Class 3 adverse events develop. The adverse reaction after the third administration regimen may be the same as or different from the adverse reaction after the second and / or first administration regimen. The adverse reaction following the third dose regimen may be a persistent and unacceptable Class 2 or Class 3 adverse reaction. In certain cases, AE is diarrhea. In other cases, AE is vomiting. In other cases, AE is nausea. In another case, AE is proteinuria. In other cases, AE is a reduced appetite. In some cases, AE is fatigue. In some cases, AE is hypertension. In some cases, AE is a cough. In other cases, AE is a reduced body weight. In some embodiments, the adverse event is associated with an elevated level of risk for a patient with a Grade 4 laboratory or higher (eg, increased lipase, hypertriglyceridemia, hypophosphatemia, hypercholesterolemia, hyponatremia, hypokalemia, hyperkalemia, hypocalcemia, Aspartate aminotransferase, increased alanine aminotransferase, or increased alkaline phosphatase). In certain cases, a Class 4 AE is developed at the object. In some cases, Class 4 AE is renal failure or renal failure. In some cases, Class 4 AE is hepatotoxicity. After administration of a third dose regimen (e.g., lenbatiship or a pharmaceutically acceptable salt thereof at a dose of 10 mg / day, and everolimus at a dose of 5 mg / day), a sustained and unacceptable grade 2 Or a Class 3 adverse event or a Class 4 laboratory event develops, the healthcare provider terminates the third dose regimen and administers to the subject a dose of 8 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof 4 dose regimen may be administered. Similarly, if the third administration regimen comprises an 8 mg / day dose of lenbactinib or a pharmaceutically acceptable salt thereof, then the healthcare provider terminates the third administration regimen and administers to the subject 4 mg / Day &lt; / RTI &gt; dose of lenbactinib or a &lt; RTI ID = 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable salt thereof. If the healthcare provider considers the adverse reaction to the third dose regimen not to be associated with the administration of rivulimumus, the fourth dose regimen is a 5 mg / day dose of everolimus (i.e., 8 mg / Baptinib or a pharmaceutically acceptable salt thereof, and 5 mg / day of everolimus). However, if the healthcare provider considers that the adverse reaction to the combination therapy of Lenvatib + plus Iverolimus is presumably or possibly possibly associated with administration of Everolimus, the healthcare provider may be required to administer 8 mg / day It is possible to reduce the dose of everolimus administered with renatintib or a pharmaceutically acceptable salt thereof. For example, if the health care provider considers the adverse reaction to the third dose regimen to be presumably or possibly possibly related to administration of rivulimumus, the fourth dose regimen may be, for example, a dose of 8 mg / Nip or a pharmaceutically acceptable salt thereof, and 5 mg every other dose of Everolimus; 8 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof, and 2.5 mg / day of everolimus; Or 8 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof, and a 2.5 mg dose of everolimus. In certain cases, the fourth dose regimen may be administered after the third dose regimen is stopped, and after the adverse reactions observed after the third dose regimen are resolved to a grade 0-1 or baseline (or grade 0-1 or acceptable grade 2) . In some cases, the third dose regimen is terminated only after the onset of medical care beyond the duration and admission of Class 2 or Class 3 adverse reactions or Class 4 laboratories. In a specific embodiment, persistent and unacceptable Class 2 or Class 3 adverse reactions are diarrhea, vomiting, nausea, or proteinuria.

In some cases, a subject with RCC may have severe renal impairment (creatinine clearance [CLcr] less than 30 mL / min calculated by the Cockcroft-Wheaton equation) or severe liver failure (child-per C). For such a subject, the first dose regimen may include 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof, and 2.5 mg / day of everolimus. When the adverse reaction develops in the subject during the course of treatment with the first administration regimen, the administration of the first administration regimen may be terminated and a low dose administration regimen may be administered. For example, a second dose comprising a 10 mg / day dose of lenbatinib or a pharmaceutically acceptable salt thereof (and optionally an everolimus at 2.5 mg / day or an everolimus at 2.5 mg / day) Therapy can be given. When the adverse reaction develops in the subject during the course of treatment with the second administration regimen, the administration of the second administration regimen may be terminated and a low dose administration regimen may be administered. For example, a third dose comprising a dose of 8 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof (and optionally, everolimus in 2.5 mg / day or everolimus in 2.5 mg dose) Therapy may be administered. When the adverse reaction develops in the subject during the course of treatment with the third administration regimen, administration of the third administration regimen may be terminated and a low dose regimen administered. For example, a fourth dose comprising a 6 mg / day dose of lenbactinib or a pharmaceutically acceptable salt thereof (and optionally an everolimus in a dose of 2.5 mg / day or everolimus in a 2.5 mg dose) Therapy can be given.

In a particular embodiment for treating a subject having RCC and also suffering from a severe renal or hepatic impairment, the first dose regimen comprises a 10 mg / day dose of Lenvatibin or a pharmaceutically acceptable salt thereof, and 2.5 mg / day Dose of Everolimus. When the adverse reaction develops in the subject during the course of treatment with the first administration regimen, the administration of the first administration regimen may be terminated and a low dose administration regimen may be administered. For example, a second dose comprising a dose of 8 mg / day of lenbitalinib or a pharmaceutically acceptable salt thereof (and optionally, everolimus in 2.5 mg / day or everolimus in 2.5 mg dose) Therapy can be given. When the adverse reaction develops in the subject during the course of treatment with the second administration regimen, the administration of the second administration regimen may be terminated and a low dose administration regimen may be administered. For example, a third dose comprising a 6 mg / day dose of lenbatinib or a pharmaceutically acceptable salt thereof (and optionally, everolimus in 2.5 mg / day or everolimus in 2.5 mg dose) Therapy can be given. When the adverse reaction develops in the subject during the course of treatment with the third administration regimen, administration of the third administration regimen may be terminated and a low dose regimen administered. For example, a fourth dose comprising 5 mg / day of a dose of 5 mg / day of lenbatinib or a pharmaceutically acceptable salt thereof (and optionally 2.5 mg / day of everolimus or 2.5 mg of everolimus) Therapy can be given. In certain cases, if grade 3 toxicity is observed, administration of Everolimus may be terminated.

The following is an embodiment of the present invention. They should not be construed as limiting the scope of the invention in any way.

Example

Example 1: Determination of Safety and Efficacy of Renatinate Treatment

Manifold, randomized, open-label testing is performed to determine the safety and efficacy of lenbactinib administered alone or in combination with rivulibridase in subjects with unresectable advanced or metastatic renal cell carcinoma (RCC) Respectively. The test consisted of a 1b-phase capacity setting and a 2-phase section. A total of 153 patients with unresectable advanced or metastatic RCCs were enrolled after one prior VEGF-targeting treatment in the two-phase portion. Particularly, patients were treated with histologic confirmation of dominant clear cell RCC, radiographic evidence of disease progression according to response criteria of solid tumors version 1.1 (RECIST), one prior VEGF-targeting therapy, and 0 or 1 Eastern cooperative oncology group (ECOG) performance status.

Random three portions to the patient: (i) alkylene Bima ^(R) (the mesylate salt of the alkylene BATIE nip) 18 mg + everolimus mousse 5 mg, (ii) alkylene Bima ^(R) 24 mg, or (iii ) Of 10 mg of everolimus was assigned using a 1: 1: 1 ratio. Patients were randomly assigned to receive serum calorimetry (> = 10 mg / dL) and hemoglobin (11 g / dL versus <13 g / dL for men and <11.5 g / dL for women) &Lt; 10 mg / dL).

The primary efficacy outcome measures based on investigator-assessed tumor response were: survivor survival of the Iverolimus segment versus the Iverolimus segment versus the Renome ^{( TM)} plus Iverolimus segment; (PFS). Other efficacy outcome measures included investigator-rated overall survival (OS) and objective response rate (ORR).

Of the 153 randomly assigned patients, 73% were male, the median age was 61, 36% were over 65, and 97% were white. Metastasis was present in 95% of patients, and 5% had progressive disease unresectable. All patients had 0 (55%) or 1 (45%) Eastern Cooperative Oncology Group (ECOG) performance status (PS) baseline in a similar distribution across the three treatment sectors. 39% of the patients in the Renbrema ^(registered) + Everolmus section, 44% in the Renbma ^(registered) sector and 38% in the Everolimus section had a poor risk of observing the Memorial Sloan Kettering Cancer Center (MSKCC) . The median time from diagnosis to the first dose was 32 months in the Renbre ^(R) + Everolimus-Therapeutic category, 33 months in the Ren Barmo ^(R) category and 26 months in the Everolimus category.

Tumor evaluation was assessed according to RECIST. The Renimbas ^{(registered trademark)} + everolimus sector showed statistically significant and clinically significant improvements in PFS compared to the everolimus sector (see Table 1 and Figure 1). The Renimbas sector also showed an improvement in PFS compared to the Everolmus sector (see Table 1 and Figure 1). Overall survival was longer in the Renvima + everolimus sector; Updated OS analysis also tended to be retained via cutoff (see Table 1 and Figures 2 and 3).

The therapeutic effect of Renbre ^(TM) + Everolimus on PFS and overall response rate (ORR) was also supported by a retrospective, independent, blinded study of the scan. The Renimbas ^{(registered trademark)} + everolimus sector showed statistically significant and clinically significant improvement in PFS (hazard ratio [HR] = 0.50, [95% CI: 0.26, 0.79 ], P = 0.003). The results for ORR were consistent with the results of an investigator with 35.3% with one complete response and 17 partial responses in the Renimbas ^(R) + Everolimus section; The Renbre ^(TM) + Everolimus category was advantageous, with no objective response in the Everolimus category (P value <0.0001).

Example 2: Adverse reaction in a test to examine renatinate treatment for RCC

To set forth the safety data, patients with unresectable advanced or metastatic renal cell carcinoma (RCC), alkylene Bima ^(R) 18 mg + everolimus mousse 5 mg (n = 51), alkylene Bima ^(R) 24 mg (1: 1: 1), once daily for 10 days (n = 52) or everolimus 10 mg (n = 50) The median duration of treatment was 7.6 months for Renimbas ^(registered) + Everolimus, 7.4 months for Renimbas ^(registered) , and 4.1 months for Everolimus. Of the 51 patients treated with Renimbas ^(R) + Everolimus in this study, the median age was 61 years, 69% were male, and 98% were white.

In this test, Len Bima ^(TM) + everolimus mousse - the most common adverse reactions (greater than 30%) observed in the treatment group, in order of frequency is decreased, diarrhea, decreased appetite, fatigue, vomiting, nausea, hypertension, , Cough, and decreased body weight. The most common serious adverse reactions (at least 5%) were anemia (4%), dehydration in 4 (8%), acute renal failure in 3 (6%), diarrhea in 3 (6%), and thrombocytopenia in 3 6%).

Adverse reactions were reported in 88% of patients receiving Renimbas ^(R) + Everolimus, 79% of patients receiving Renimbas ^(R) , and 54% of patients receiving Everolimus Or disruption. Of the 44 Renimbima ^(R) + Everolimus combination therapy patients who were reduced or discontinued due to adverse events, most (31) were not completely stopped due to the harmful incident. In the case of adverse reaction, alkylene Bima ^(R) + everolimus mousse-stops in the treatment of patients of 13 patients (26%) treatment groups, alkylene Bima ^(R) - the treatment of patients 16 patients (31%) in treatment group And 6 patients (12%) were discontinued in the ravelolimus-treated group. Alkylene Bima ^(R) + everolimus mousse - The most common adverse events that may have caused the capacity is decreased in the treatment group (at least 5%), diarrhea and 12 (24%), 4 vomiting (8%), three nausea (6 ), And proteinuria (3%, 6%). Table 2 shows the percentage of patients who experienced an adverse reaction at a frequency of at least 10% at the time of testing.

In the following, some of the above mentioned harmful events will be addressed together with suggestions on them.

High blood pressure

Carried out in the test described in Example 1, the blood pressure is alkylene Bima ^(R) + everolimus mousse-treatment in 43% of cases (incidence of Grade 3 or Grade 4 Hypertension 14% was), alkylene Bima ^(R) - group Reported that 48% of patients (grade 3 or grade 4 hypertension incidence was 17%) and 10% of patients (grade 3 or grade 4 hypertension incidence was 2%) in the Iverolimus-treated group.

Given these findings, it would be beneficial to control blood pressure before treating the patient with Renimbas &lt; ^(R) &^gt; + everolimus. The patient &apos; s blood pressure should be monitored at least once a month during treatment with Renimbas &lt; ^(R) &^gt; + everolimus, then every two weeks for the first two months, and then at least monthly thereafter. In the case of grade 3 hypertension despite optimal antihypertensive therapy, renbma ^(R) is reserved; If hypertension is controlled below grade 2, it would be advisable to resume at reduced doses. Furthermore, in the case of life-threatening hypertension, Renimbas ^(TM) should be discontinued. In addition, discontinuation or daily dosing of everolimus should be considered until the toxicity is resolved.

The healthcare provider should receive regular blood pressure monitoring and advise his / her healthcare provider to contact his health care provider if his blood pressure rises, to patients who have undergone treatment with Renbma ^{(registered trademark)} + Everolimus.

Heart failure

Example 1 In the test described in a reduced ejection fraction and cardiac failure is alkylene Bima ^(R) + everolimus mousse-in 4% of patients treated group (2% grade 3), butylene Bima ^(R) - the treatment of the patient 8% (2% grade 3), and 4% (2% grade 3) of patients in the Iverolimus-treated group.

Given these findings, it would be beneficial to monitor the patient for clinical signs or symptoms of cardiac dysfunction. Also, in the case of the development of a Class 3 cardiac dysfunction, it would be advisable to suspend Renbima ^(R) until the improvement to Class 0 or 1 or baseline. Then, it can be resumed in accordance with the severity and duration of cardiac dysfunction, alkylene Bima ^(R) a reduced capacity or stop. In the case of Grade 4 cardiac dysfunction, Lenvima ^(TM) should be discontinued. In addition, discontinuation or daily dosing of everolimus should be considered until the toxicity is resolved.

Health care providers Rennes Bima ^(TM) + patients have undergone treatment with everolimus mousse, Rennes Bima ^{(registered trademark),} the heart can lead to failure, and any clinical symptoms such as shortness of breath or ankle of cardiac dysfunction If you experience swelling, you should immediately contact your healthcare provider.

Arterial thrombotic event

In the tests described above, no arterial thromboembolic events were observed in the Renimbas ^(R) + Everolimus-treated group. Rennes Bima ^(TM) - The group of 8% (8% grade 3 and higher) in patients and everolimus mousse - was reported to have treatment in 6% (4% grade 3 and higher) in patients with arterial thromboembolic events.

After an arterial thrombotic event, Lenvima ^(TM) should be discontinued.

The healthcare provider should advise patients who have undergone treatment with Renbma ^(R) + Everolimus to receive immediate medical care for newly developed chest pain or acute nervous system symptoms consistent with myocardial infarction or stroke.

Hepatotoxicity

In the above described RCC test, alkylene Bima ^(R) + everolimus mousse-group in 4% of patients, alkylene Bima ^(R) in the treatment group 4% of patients, and everolimus mousse-in treatment group 2% of the patients , A grade 3 or greater alanine aminotransferase increase (ALT). 4% of the patients in the Renbima ^(R) + Everolimus-treated group and 4% of the patients in the Ren-Bm ^(R) -treated group experienced a grade 3 or greater ascitate aminotransferase increase (AST) No patients in the everolimus-treated group experienced the above.

Before the start of the alkylene Bima ^(R) liver function during treatment, then every two weeks for the first two months, and then it is recommended to monitor at least a month. If liver damage of grade 3 or higher occurs, renbima ^(TM) should be suspended until a resolution of 0 to 1 or baseline. Then, it can be in accordance with the severity and duration of hepatotoxicity, resume from the alkylene Bima ^(R) a reduced capacity or stop. In the case of hepatic insufficiency, Renbima ^(TM) should be discontinued.

The healthcare provider should be advised to undergo laboratory testing to monitor liver function and to report any new symptoms indicative of hepatotoxicity or liver failure, to patients who have undergone treatment with Renbre ^(TM) + Everolimus .

Proteinuria

In the RCC test, proteinuria was found in 31% (19% ⁾ of patients in the Renvima ^(R) + Everolimus-treated group versus 24% (4% Were grade 3 or higher), and 14% (2% were grade 3 or higher) of patients in the Iverolimus-treated group.

It is proposed that the healthcare provider periodically monitor for proteinuria before initiation and throughout treatment. If 2+ more urine dipstick proteinuria is detected, the healthcare provider must obtain a 24-hour urine protein. > = 2 for proteinuria / 24 gram, alkylene Bima ^(R) is to be held, and for proteinuria of <2 gm / 24 hours, can be resumed in the treatment is reduced capacity to alkylene Bima ^(R) have. In the case of nephrotic syndrome, Renimbas ^(TM) should be discontinued.

The healthcare provider should advise patients undergoing renal ^(R) + ivolorimus treatment to undergo periodic laboratory testing to monitor kidney function and urinary proteins.

Kidney failure and diarrhea / diarrhea

Case of renal impairment is alkylene Bima ^(R) + everolimus mousse ^{(registered trademark)} in 18% Bima alkylene group - 15% in the treatment group, and everolimus mousse-treatment was reported in 12%. The incidence of grade 3 or more kidney failure or renal impairment was 8% in the WRENBIMA ^(R) + Ebelorimus-treated group, 6% in the LENBIA ^(TM) -treated group, and 2% in the Evelorimus-treated group. Class 3 or more diarrhea alkylene Bima ^(R) + everolimus mousse-treatment in 22% of patients, alkylene Bima ^(R) in the treatment groups 12% of patients, and everolimus mousse - the treatment reported in 2% of patients .

The primary risk factors for severe renal impairment in Renimbas ^(TM) -treated patients were dehydration / hypovolaemia due to diarrhea and vomiting. In the case of a Class 1 incident, active management of diarrhea and any other gastrointestinal symptoms should be initiated.

It is recommended that the healthcare provider suspend the Renimbas ^(TM) until a resolution of Class 0 or 1 or Baseline at the time of development of Class 3 or 4 renal failure / renal impairment. Then, it can be in accordance with the severity and duration of renal insufficiency, in the resume alkylene Bima ^(R) a reduced capacity or stop.

The healthcare provider should advise patients undergoing renal ^(R) + ivolorimus treatment to undergo periodic laboratory testing to monitor kidney function and urinary proteins.

Gastrointestinal perforation and fistula formation

In RCC test, the case of gastrointestinal perforation or fistula is alkylene Bima ^(R) + everolimus mousse-group in 2% of patients, alkylene Bima ^(R) in the treatment groups is reported in 6%, everolimus mousse-in treatment group No patients were reported.

In patients with gastrointestinal perforation or life-threatening fistulae, it is recommended that the healthcare provider discontinue the Renimbas ^(TM) .

A health care provider may wish to provide a patient who has undergone treatment with Renbma ^(R) + Evelylimus, for which Renbima ^(R) may increase the risk of gastrointestinal perforation or fistulae and, in the case of severe abdominal pain, .

QT interval extension

In the above described test, QT / QTc interval prolongation is alkylene Bima ^(R) + everolimus mousse-was reported in 6% of patients in both treatment groups-alkylene group and Bima ^(R). No case of grade 3 or higher was reported in any of these groups. No reports of QT / QTc interval extension occurred in the everolimus-treated group.

Considering the above findings, it is believed that the healthcare provider may be able to provide an electrocardiogram (ECG) in patients with congenital long QT syndrome, congestive heart failure, patients with unstable bradycardia, or patients taking medications known to prolong QT intervals, including class Ia and III antiarrhythmics Is recommended. In addition, it is recommended that healthcare providers monitor and correct for electrolyte abnormalities in all patients. At the development of a QT interval extension of grade 3 or higher, Renimbas ^(R) must be suspended. When the QT prolongation that are fixed on a scale of 0 or 1, or reference line, alkylene Bima ^(R) administration is to be resumed at a reduced capacity.

Hypocalcemia

In the RCC study, 6% of the patients were reported in the Renbma ^(R) + Everolimus-treated group, none of the patients were reported in the Ren-V ^(R) -treated group, and 2 of the patients in the Everolimus- % Experienced grade 3 or higher hypocalcemia.

Therefore, it is recommended that the patient be monitored at least monthly for blood calcium levels and to replace calcium when needed during renbima ^(TM) treatment. If necessary, depending on the severity of hypocalcemia, the presence of ECG changes and persistence, the administration of Renimbas ^(TM) may be discontinued or adjusted.

Reversible postprandial encephalopathy syndrome

In RCC test, experienced alkylene Bima ^(R) + everolimus or sirolimus alkylene Bima ^(R) after the first 103 patients who received reversibility of administering a protein alone encephalopathy syndrome (RPLS).

It is prudent to confirm the diagnosis of RPLS using MRI and to withhold RPLS treatment to Renimbas ^(R) until the RPLS is completely resolved. At the time of resolution, the severity and persistence of the neurological symptoms Accordingly, the administration of Renimbas &lt; ^(R) &gt; may be resumed or discontinued at reduced doses.

Hemorrhagic event

In the RCC trial, hemorrhagic events occurred in 33% of patients (8% were in grade 3 or higher) in the Renvima ^(R) + Everolimus-treated group, where the most frequently reported hemorrhagic events were non-bleeding (18 % Grade 1). Discontinuation of treatment due to hemorrhagic events occurred in 4% of patients in the Renvima ^(R) + Everolimus-treated group. Rennes Bima ^(TM) in the treatment group, hemorrhagic events was 29% of patients (2% grade 3 or been a) occurred in, the hemorrhagic events most frequently reported here were epistaxis (8% Tier 1 million). Interruptions due to hemorrhagic events occurred in 2% of patients in the Renimbas ^(TM) -treated group. There was one case of fatal cerebral hemorrhage in the Renbma ^(R) + Everolimus-treated group, and one case of fatal intracranial hemorrhage in the Ren-B ^(R) -treated group. In the everolimus-treated group, haemorrhagic events occurred in 28% of patients (2% were in grade 3 or higher), where the most frequently reported hemorrhagic events were nonhemorrhagic (20% grade 1, and 4% grade 2 ). There was no interruption due to hemorrhagic events in the Iverolimus-treated group.

The health care provider should consider retaining Lenbima ^(R) until the resolution of the class 0 to 1 for the development of grade 3 bleeding. Depending on the severity and persistence of bleeding, treatment with Renimbas ^(TM) should be resumed or discontinued at reduced doses. In patients experiencing grade 4 bleeding, treatment with Renimbas ^(TM) should be discontinued.

Health care providers Rennes Bima ^(TM) + everolimus in patients undergone treatment with sirolimus, Len Bima ^{(registered trademark)} is may increase the risk of bleeding, bleeding or a health care provider if symptoms of severe bleeding Should be contacted.

Thyroid stimulating hormone inhibition disorder / thyroid dysfunction

In RCC test, hypothyroidism is alkylene Bima ^(R) + everolimus mousse-treatment in 24% of patients, alkylene Bima ^(R) in the treatment of 37%, and everolimus mousse of patients in the treatment group 2, the patient %. All hypothyroidism events in the Renimbas ^(R) + Everolimus-treated group were of grade 1 or 2.

Seventy-five percent of patients in the Renimbas ^(R) + Everolimus-treated group received no exogenous thyroid replacement, of which 71% had normal baseline TSH levels. In patients with normal TSH at the patient baseline, elevations in TSH levels were observed in 63% of patients treated with Renbre ^(TM) + Everolimus compared to patients not receiving Evelrorimus alone Respectively.

Thyroid function should be monitored periodically before initiation of treatment with Renimbarma, and throughout the treatment. Hypothyroidism should be treated according to standard medical practices to maintain normal thyroid status.

Embryotoxicity

Alkylene Bima ^(R), upon basis of the data from its mechanism of action, and animal reproduction studies, can lead to damage to the fetus when administered to pregnant women. In animal reproductive studies, oral administration of lenbatinize at doses below the human recommended dose during the course of organogenesis has resulted in embryotoxicity, fetal toxicity, and teratogenicity in rats and rabbits.

Therefore, health care providers should advise pregnant women of the potential risks to the fetus. In addition, in the case of women with reproductive capacity, the healthcare provider should advise the patient to use effective contraception during treatment with Renimbas ^{(TM) and} for at least two weeks after completion of therapy.

The healthcare provider should advise patients who have undergone treatment with Renbre ^(R) + Evelorimus to inform their healthcare provider of known or suspected pregnancies.

Table 3 provides a summary of the laboratory overrides observed in the patient in the RCC test described in Example 1.

Cross-reference to related application

This application claims priority to U.S. Provisional Application No. 62 / 322,916, both filed on April 15, 2016, and Japanese Patent Application No. JP2016-081787, both of which are incorporated herein by reference in their entirety .

Other embodiments

While the invention has been described in conjunction with the detailed description thereof, the description is intended to be illustrative, and is not intended to limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims (69)

A human subject with renal cell carcinoma is administered a first dose regimen comprising (i) 18 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus &Lt; RTI ID = 0.0 &gt; a &lt; / RTI &gt; renal cell carcinoma,
Wherein during the treatment with the first administration regimen a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction in the human subject or a development over a Grade 4 laboratory develops,
The method comprises:
(a) terminating the administration of the first dose regimen after a first persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event, and administering to a human subject a dose of 14 mg / day of Lenvatib or Administering a second dosing regimen comprising a pharmaceutically acceptable salt wherein during the course of treatment with the second dosing regimen a second persistent and unacceptable Class 2 or Class 3 adverse reaction in a human subject, Lt; / RTI &gt;
(b) terminating the administration of the second dose regimen after a second persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event, and administering to the human subject a dose of 10 mg / day of Lenvatib or Administering a third dose regimen comprising a pharmaceutically acceptable salt wherein during the course of treatment with the third dose regimen a third persistent and unacceptable Class 2 or Class 3 adverse reaction or grade 4 laboratory event occurs in a human subject Lt; / RTI &gt;
(c) After the third persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event, the administration of the third dose regimen is terminated and the human subject is dosed with 8 mg / Administering a fourth dose regimen comprising a pharmaceutically acceptable salt
. &Lt; / RTI &gt;
Methods for treating renal cell carcinoma. The method according to claim 1,
Do not initiate a second dose regimen until a first persistent and unacceptable Class 2 or Class 3 adverse event or class 4 laboratory abnormality is resolved to a Class 0-1 or baseline;
A second persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory failure until a Class III or higher baseline resolves the third dose regimen;
A third persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory failure is not initiated with the fourth dose regimen until the class 0-1 or baseline is resolved.
Way. The method of claim 1, wherein, prior to terminating administration of the dosing regimen administered at the time of the adverse reaction or outbreak of the laboratory, the first, second and third persistent and unacceptable Class 2 or Class 3 adverse reactions or Class 4 laboratory Or more of the medical care. 3. A method according to claim 2, characterized in that the first, second and third persistent and unacceptable class 2 or class 3 HAZARDOUS RESPONSE or Grade 4 A laboratory is commencing each medical care. 5. The method of any one of claims 1 to 4, wherein the first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormalities is the second and / or third persistent and non- 2 or grade 3 adverse reaction or grade 4 laboratory. 5. The method of any one of claims 1 to 4, wherein the first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormalities is the second and / or third persistent and non- 2 or grade 3 adverse reaction or grade 4 laboratory abnormalities. 7. The method of any one of claims 1 to 6 wherein the Class 2 or Class 3 adverse reaction is selected from the group consisting of grade 3 hypertension, grade 2 hypertension, grade 3 heart failure, grade 2 heart failure, grade 3 arterial thromboembolic event Grade 2 arterial thromboembolic events, grade 3 proteinuria, grade 2 proteinuria, grade 3 renal failure or renal impairment, grade 2 renal failure or renal impairment, grade 3 diarrhea, grade 2 diarrhea, grade 3 gastrointestinal perforation or fistulae, grade 2 gastrointestinal perforation or fistula Grade 3 Vomiting, Grade 2 Vomiting, Grade 3 Reduced Appetite, Grade 2 Reduced Appetite, Grade 3 Fatigue, Grade 2 Fatigue, Grade 3 Nausea, Grade 2 Nausea, Grade 3 Cough, Grade 2 Cough, Grade 3 Reduced Weight , Grade 2 reduced weight, grade 3 dehydration, grade 2 dehydration, grade 3 thrombocytopenia, grade 2 thrombocytopenia, grade 3 anemia, grade 2 anemia, grade 3 acute renal failure, grade 2 acute renal failure, grade 3 QT / QTc interval extension , Grade 2 QT / QTc interval extension, grade 3 Immunity after white matter encephalopathy syndrome (RPLS), RPLS Class 2, Class 3 hemorrhagic events, Grade 2 bleeding events, Class 3 hyperthyroidism, and Level 2 the method selected from the group consisting of hyperthyroidism. 8. The method of claim 7, wherein the Class 2 or Class 3 adverse reaction is grade 3 diarrhea, grade 2 diarrhea, grade 3 vomiting, grade 2 vomiting, grade 3 nausea, grade 2 nausea, grade 3 proteinuria, &Lt; / RTI &gt; 9. A method according to any one of claims 1 to 8, wherein the Grade 4 laboratory or higher is selected from the group consisting of Grade 4 aspartate aminotransferase increase, Grade 4 alanine aminotransferase increase, Grade 4 alkaline phosphatase increase, Grade 4 hyperkalemia, Grade 4 hypoglycemia, Grade 4 hyponatremia, Grade 4 hypocalcemia, Grade 4 hypoglycemia, Grade 4 hyperglycemia, Grade 4 hypertriglyceridemia, Grade 4 cholesterol increase, Grade 4 lipase increase, Grade 4 hemoglobin decrease, Grade 4 platelet A decrease in the number of cells, a decrease in counts, and a decrease in grade 4 lymphocyte counts. 10. The method according to any one of claims 1 to 9, wherein the administration of the second administration regimen, the third administration regimen and the fourth administration regimen are not started until the adverse reaction or toxicity associated with administration of everolimus is resolved / RTI &gt; 11. The method according to any one of claims 1 to 10, wherein the second dose regimen, the third dose regimen and the fourth dose regimen each comprise 5 mg / day of everolimus. 11. The method according to any one of claims 1 to 10, wherein each of the second administration regimen, the third administration regimen and the fourth administration regimen each comprise 5 mg of everolimus. 13. The method of any one of claims 1 to 12, wherein the rennatibin or a pharmaceutically acceptable salt thereof is formulated as a capsule. 14. The method of any one of claims 1 to 13, wherein everolimus is formulated as a tablet. 15. The method according to any one of claims 1 to 14, wherein lenvatinib or a pharmaceutically acceptable salt thereof and everolimus are orally administered to a human subject. 16. The method according to any one of claims 1 to 15, wherein the human subject has received a prior vascular endothelial growth factor (VEGF) -targeting therapy. 17. The method according to any one of claims 1 to 16, wherein the administration of Lenvatib or a pharmaceutically acceptable salt thereof and everolimus is administered once a day. 17. The use according to any one of claims 1 to 16, wherein the at least 28 weeks, at least 56 weeks, at least 84 weeks, at least 112 weeks, at least 140 weeks, Lt; RTI ID = 0.0 &gt; 168 &lt; / RTI &gt; weeks. 19. The method according to any one of claims 1 to 18, wherein the renal cell carcinoma is a nonresectable advanced renal cell carcinoma. 19. The method according to any one of claims 1 to 18, wherein the renal cell carcinoma is metastatic renal cell carcinoma. 19. The method according to any one of claims 1 to 18, wherein the renal cell carcinoma is advanced renal cell carcinoma. 22. The method according to any one of claims 1 to 21, wherein the renatotinib or a pharmaceutically acceptable salt thereof is lenvatibm mesylate. 23. The method of any one of claims 1 to 22, wherein the human subject has a poor MSKCC risk score. (I) a dose of 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 2.5 mg / day of ivolorimus in a human subject with renal cell carcinoma and severe renal or severe liver disorders A method of treating a renal cell carcinoma, comprising administering a first administration regimen,
Wherein during the treatment with the first administration regimen a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction in the human subject or a development over a Grade 4 laboratory develops,
The method comprises:
(a) terminating the administration of the first dose regimen after a first persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event, and administering to a human subject a dose of 10 mg / day of Lenvatib or Administering a second dosing regimen comprising a pharmaceutically acceptable salt wherein during the course of treatment with the second dosing regimen a second persistent and unacceptable Class 2 or Class 3 adverse reaction in a human subject, Lt; / RTI &gt;
(b) terminating the administration of the second dose regimen after a second persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event, and administering to a human subject a dose of 8 mg / day of Lenvatib or Administering a third dose regimen comprising a pharmaceutically acceptable salt wherein during the course of treatment with the third dose regimen a third persistent and unacceptable Class 2 or Class 3 adverse reaction or grade 4 laboratory event occurs in a human subject Lt; / RTI &gt;
(c) After the third persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event, the administration of the third dose regimen was terminated and human subjects were dosed with 6 mg / Administering a fourth dose regimen comprising a pharmaceutically acceptable salt
. &Lt; / RTI &gt;
Methods for treating renal cell carcinoma. 25. The method of claim 24, wherein the human subject has a significant renal impairment and has a creatinine clearance [CLcr] of less than 30 mL / min calculated by the Cockroft-Gault equation. 25. The method of claim 24, wherein the human subject has a severe liver disorder and has liver disease classified as Child-Pugh class C. 27. The method according to any one of claims 24 to 26, wherein the second dose regimen, the third dose regimen and the fourth dose regimen each comprise 2.5 mg / day of everolimus. 27. The method according to any one of claims 24 to 26, wherein each of the second, third and fourth dosing regimens comprises a 2.5 mg dose of everolimus. A human subject with renal cell carcinoma is administered a first dose regimen comprising (i) 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus &Lt; RTI ID = 0.0 &gt; a &lt; / RTI &gt; renal cell carcinoma,
Wherein during the treatment with the first administration regimen a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction in the human subject or a development over a Grade 4 laboratory develops,
The method comprises:
(a) terminating the administration of the first dose regimen after a first persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event, and administering to a human subject a dose of 10 mg / day of Lenvatib or Administering a second dosing regimen comprising a pharmaceutically acceptable salt wherein during the course of treatment with the second dosing regimen a second persistent and unacceptable Class 2 or Class 3 adverse reaction in a human subject, Lt; / RTI &gt;
(b) terminating the administration of the second dose regimen after a second persistent and unacceptable Class 2 or Class 3 adverse event or Class 4 laboratory event, and administering to a human subject a dose of 8 mg / day of Lenvatib or Administering a third dose regimen comprising a pharmaceutically acceptable salt wherein during the course of treatment with the third dose regimen a third persistent and unacceptable Class 2 or Class 3 adverse reaction or grade 4 laboratory event occurs in a human subject Lt; / RTI &gt;
(c) after the third persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory event, the administration of the third dose regimen was terminated and human subjects received a 4 mg / day dose of Lenvatib or Administering a fourth dose regimen comprising a pharmaceutically acceptable salt
. &Lt; / RTI &gt;
Methods for treating renal cell carcinoma. 30. The method of claim 29,
Do not initiate a second dose regimen until a first persistent and unacceptable Class 2 or Class 3 adverse event or class 4 laboratory abnormality is resolved to a Class 0-1 or baseline;
A second persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory failure until a Class III or higher baseline resolves the third dose regimen;
A third persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory failure is not initiated with the fourth dose regimen until the class 0-1 or baseline is resolved.
Way. 30. The method of claim 29,
Do not initiate a second dose regimen until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 0-1 or Class 2 acceptable;
Does not initiate a third dose regimen until a second persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 0-1 or Class 2 acceptable;
A third persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory failure is not initiated with the fourth dose regimen until the class 0-1 or acceptable Class 2 has been resolved.
Way. 29. The method of claim 29, wherein the first, second, and third persistent and unacceptable Grade 2 or Grade 3 adverse reactions or Grade 4 laboratories are administered prior to terminating administration of the dosing regimen administered at the time of adverse reaction Or more of the medical care. 31. The method of claim 30, wherein, prior to commencing administration of the dosing regimen following adverse reaction or laboratory anomaly after class 0-1 or baseline resolution, the first, second and third persistent and unacceptable class 2 or class 3 HAZARDOUS RESPONSE or Grade 4 A laboratory is commencing each medical care. 34. A method according to any one of claims 29 to 33, wherein a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory error is identified as a second and / or third persistent and non- 2 or grade 3 adverse reaction or grade 4 laboratory. 34. A method according to any one of claims 29 to 33, wherein a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory error is identified as a second and / or third persistent and non- 2 or grade 3 adverse reaction or grade 4 laboratory abnormalities. 37. The method of any one of claims 29 to 35 wherein the Class 2 or Class 3 adverse reaction is selected from the group consisting of grade 3 hypertension, grade 2 hypertension, grade 3 heart failure, grade 2 heart failure, grade 3 arterial thrombosis Grade 2 arterial thromboembolic events, grade 3 proteinuria, grade 2 proteinuria, grade 3 renal failure or renal impairment, grade 2 renal failure or renal impairment, grade 3 diarrhea, grade 2 diarrhea, grade 3 gastrointestinal perforation or fistulae, grade 2 gastrointestinal perforation or fistula Grade 3 Vomiting, Grade 2 Vomiting, Grade 3 Reduced Appetite, Grade 2 Reduced Appetite, Grade 3 Fatigue, Grade 2 Fatigue, Grade 3 Nausea, Grade 2 Nausea, Grade 3 Cough, Grade 2 Cough, Grade 3 Reduced Weight , Grade 2 reduced weight, grade 3 dehydration, grade 2 dehydration, grade 3 thrombocytopenia, grade 2 thrombocytopenia, grade 3 anemia, grade 2 anemia, grade 3 acute renal failure, grade 2 acute renal failure, grade 3 QT / QTc interval extension , Grade 2 QT / QTc interval extension, grade 3 Wherein the method is selected from the group consisting of Reversible Posterior Encephalopathy Syndrome (RPLS), Class 2 RPLS, Class 3 Hemorrhagic Event, Class 2 Hemorrhagic Event, Class 3 Hyperthyroidism, and Class 2 Hyperthyroidism. 37. The method of claim 36, wherein the Class 2 or Class 3 adverse reaction comprises grade 3 diarrhea, grade 2 diarrhea, grade 3 vomiting, grade 2 vomiting, grade 3 nausea, grade 2 nausea, grade 3 proteinuria, &Lt; / RTI &gt; 37. The use according to any one of claims 29 to 37, wherein at least grade 4 laboratory abnormalities are selected from the group consisting of grade 4 aspartate aminotransferase increase, grade 4 alanine aminotransferase increase, grade 4 alkaline phosphatase increase, grade 4 hyperkalemia, Grade 4 hypoglycemia, Grade 4 hyponatremia, Grade 4 hypocalcemia, Grade 4 hypoglycemia, Grade 4 hyperglycemia, Grade 4 hypertriglyceridemia, Grade 4 cholesterol increase, Grade 4 lipase increase, Grade 4 hemoglobin decrease, Grade 4 platelet A decrease in the number of cells, a decrease in counts, and a decrease in grade 4 lymphocyte counts. 39. The method according to any one of claims 29 to 38, wherein the administration of the second administration regimen, the third administration regimen and the fourth administration regimen are not started until the adverse reaction or toxicity associated with administration of everolimus is resolved / RTI &gt; 40. The method according to any one of claims 29 to 39, wherein the second dose regimen, the third dose regimen and the fourth dose regimen each comprise 5 mg / day of everolimus. 40. The method according to any one of claims 29 to 39, wherein each of the second administration regimen, the third administration regimen and the fourth administration regimen each comprise 5 mg daily dose of everolimus. 41. A method according to any one of claims 29 to 39, wherein the second administration regimen comprises everolimus at a dose of 5 mg / day, the third administration regimen comprises everolimus at a dose of 5 mg, 4 dosing regimen does not include everolimus or comprises 5 mg immediate dose of everolimus. A human subject with renal cell carcinoma is administered a first dose regimen comprising (i) 14 mg / day of lenbactinib or a pharmaceutically acceptable salt thereof and (ii) 5 mg / day of everolimus , Wherein during the course of treatment with the first dose regimen, no Class 2 or Class 3 adverse reaction or grade 4 laboratory abnormalities unacceptable in the human subject develop;
After the period of treatment, the administration of the first dose regimen is terminated and a human subject is administered with (i) a dose of 18 mg / day of Lenvatibin or a pharmaceutically acceptable salt thereof and (ii) a dose of 5 mg / day of Everolimus And a second administration regimen comprising
Gt; a &lt; / RTI &gt; renal cell carcinoma. 44. The method of claim 43, wherein, during treatment with a second dose regimen in a human subject, a first persistent and unacceptable Grade 2 or Grade 3 adverse reaction or occurrence of Grade 4 or greater develops,
The method comprises:
(a) terminating the administration of the second dose regimen after the first persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory event, and administering to the human subject a dose of 14 mg / day of Lenvatib or Administering a third dose regimen comprising a pharmaceutically acceptable salt wherein during the course of treatment with the third dose regimen a second persistent and unacceptable Class 2 or Class 3 adverse reaction in a human subject, Lt; / RTI &gt;
(b) terminating the administration of the third dose regimen after the second persistent and unacceptable Grade 2 or Grade 3 adverse event or grade 4 laboratory event, and administering to the human subject a dose of 10 mg / day of Lenvatib or Administering a fourth dosing regimen comprising a pharmaceutically acceptable salt wherein during the course of treatment with the fourth dosing regimen a third persistent and unacceptable Class 2 or Class 3 adverse reaction in a human subject, Lt; / RTI &gt;
(c) terminating the administration of the fourth dose regimen after a third persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory event, and administering a human subject with a dose of 8 mg / day of Lenbatimib or Administration of a fifth administration regimen comprising a pharmaceutically acceptable salt
Lt; RTI ID = 0.0 &gt;
Way. 45. The method of claim 44,
Do not initiate a third dose regimen until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to a Class 0-1 or baseline;
The second continuing and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory failure until the Class 0-1 or baseline is resolved;
A third persistent and unacceptable Class 2 or Class 3 adverse event or grade 4 laboratory failure is not initiated with the fifth dose regimen until the class 0-1 or baseline is resolved.
Way. 45. The method of claim 44,
Do not initiate a third dose regimen until a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 0-1 or Class 2 acceptable;
Do not initiate a fourth dose regimen until a second persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory abnormality is resolved to Class 0-1 or Class 2 acceptable;
A third persistent and unacceptable Class 2 or Class 3 adverse reaction or grade 4 laboratory failure is not initiated with the fifth dose regimen until the Class 0-1 or Class 2 acceptable level is resolved.
Way. 45. The method of claim 44, wherein the first, second, and third persistent and unacceptable Grade 2 or Grade 3 adverse reactions or Grade 4 laboratories prior to termination of administration of the dosing regimen administered at the time of adverse reaction Or more of the medical care. 46. The method of claim 45, wherein the first, second, and third persistent and unacceptable Grade 2 or Grade 3, 3 HAZARDOUS RESPONSE or Grade 4 A laboratory is commencing each medical care. 48. A method according to any one of claims 44 to 48, wherein a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory error is identified as a second and / or third persistent and non- 2 or grade 3 adverse reaction or grade 4 laboratory. 48. A method according to any one of claims 44 to 48, wherein a first persistent and unacceptable Class 2 or Class 3 adverse reaction or Class 4 laboratory error is identified as a second and / or third persistent and non- 2 or grade 3 adverse reaction or grade 4 laboratory abnormalities. 50. The method of any one of claims 44 to 50 wherein the Class 2 or Class 3 adverse reaction is selected from the group consisting of grade 3 hypertension, grade 2 hypertension, grade 3 cardiac dysfunction, grade 2 cardiac dysfunction, grade 3 arterial thromboembolic events Grade 2 arterial thromboembolic events, grade 3 proteinuria, grade 2 proteinuria, grade 3 renal failure or renal impairment, grade 2 renal failure or renal impairment, grade 3 diarrhea, grade 2 diarrhea, grade 3 gastrointestinal perforation or fistulae, grade 2 gastric perforation or fistula Grade 3 Vomiting, Grade 2 Vomiting, Grade 3 Reduced Appetite, Grade 2 Reduced Appetite, Grade 3 Fatigue, Grade 2 Fatigue, Grade 3 Nausea, Grade 2 Nausea, Grade 3 Cough, Grade 2 Cough, Grade 3 Reduced Weight , Grade 2 reduced weight, grade 3 dehydration, grade 2 dehydration, grade 3 thrombocytopenia, grade 2 thrombocytopenia, grade 3 anemia, grade 2 anemia, grade 3 acute renal failure, grade 2 acute renal failure, grade 3 QT / QTc interval extension , Grade 2 QT / QTc interval extension, grade 3 Wherein the method is selected from the group consisting of Reversible Posterior Encephalopathy Syndrome (RPLS), Class 2 RPLS, Class 3 Hemorrhagic Event, Class 2 Hemorrhagic Event, Class 3 Hyperthyroidism, and Class 2 Hyperthyroidism. 51. The method of claim 51, wherein the Class 2 or Class 3 adverse reaction is grade 3 diarrhea, grade 2 diarrhea, grade 3 vomiting, grade 2 vomiting, grade 3 nausea, grade 2 nausea, grade 3 proteinuria, &Lt; / RTI &gt; 52. The method of any one of claims 44 to 52, wherein the Grade 4 laboratory or greater is selected from the group consisting of a Grade 4 aspartate aminotransferase increase, a Grade 4 alanine aminotransferase increase, a Grade 4 alkaline phosphatase increase, Grade 4 hypoglycemia, Grade 4 hyponatremia, Grade 4 hypocalcemia, Grade 4 hypoglycemia, Grade 4 hyperglycemia, Grade 4 hypertriglyceridemia, Grade 4 cholesterol increase, Grade 4 lipase increase, Grade 4 hemoglobin decrease, Grade 4 platelet A decrease in the number of cells, a decrease in counts, and a decrease in grade 4 lymphocyte counts. 54. The method according to any one of claims 44 to 53, which does not disclose each of the second, third and fourth administration regimens until the resolution of the adverse reaction or toxicity associated with administration of everolimus / RTI &gt; 54. The method of any one of claims 44 to 54, wherein each of the second, third and fourth dosing regimens comprises everolimus at a dosage of 5 mg / day. 54. The method of any one of claims 44 to 54, wherein the second dose regimen, the third dose regimen and the fourth dose regimen each comprise a 5 mg dose of everolimus. 55. A method according to any one of claims 44 to 54, wherein the second administration regimen comprises everolimus at a dose of 5 mg / day, the third administration regimen comprises everolimus at a dose of 5 mg, 4 dosing regimen does not include everolimus or comprises 5 mg immediate dose of everolimus. 57. The method of any one of claims 43 to 57, wherein the treatment period to the first administration regimen comprises 28 days. 62. The method of any one of claims 29 to 58, wherein the rennatibin or a pharmaceutically acceptable salt thereof is formulated as a capsule. 60. The method according to any one of claims 29 to 59, wherein everolimus is formulated as a tablet. 60. A method according to any one of claims 29 to 60 wherein lenbatinib or a pharmaceutically acceptable salt thereof and everolimus are orally administered to a human subject. 62. The method of any one of claims 29-61, wherein the human subject has been subjected to a prior vascular endothelial growth factor (VEGF) -targeting therapy. 62. The method of any one of claims 29-62, wherein the administration of Lenvatib or a pharmaceutically acceptable salt thereof and everolimus is administered once a day. 62. The use according to any one of claims 29 to 62 wherein at least 28 weeks, at least 56 weeks, at least 84 weeks, at least 112 weeks, at least 140 weeks, Lt; RTI ID = 0.0 &gt; 168 &lt; / RTI &gt; weeks. 65. The method according to any one of claims 29 to 64, wherein the renal cell carcinoma is a nonresectable advanced renal cell carcinoma. 65. The method according to any one of claims 29-64, wherein the renal cell carcinoma is metastatic renal cell carcinoma. 64. The method according to any one of claims 29 to 64, wherein the renal cell carcinoma is advanced renal cell carcinoma. 67. The method of any one of claims 29-67, wherein the rennatibin or a pharmaceutically acceptable salt thereof is lenvatibm mesylate. 69. The method of any one of claims 29-68, wherein the human subject has a poor MSKCC risk score.

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