US2023045783A9PendingUtilityA9
Method of Treating Renal Cell Carcinoma Using N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate
Est. expiryApr 15, 2036(~9.8 yrs left)· nominal 20-yr term from priority
Inventors:Dana T. AftabGisela SchwabColin HesselChristian ScheffoldSteven LacyDale MilesAlan ArroyoMark Dean
A61K 31/16A61P 35/00A61K 9/2009A61K 9/2054A61K 31/47A61K 9/2018A61K 9/2866A61K 9/20
69
PatentIndex Score
0
Cited by
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References
0
Claims
Abstract
The present disclosure relates to a method of treating advanced renal cell carcinoma (RCC) in human patients who have received prior anti-angiogenic therapy using CABOMETYX, a kinase inhibitor.
Claims
exact text as granted — not AI-modified1 . A method of treating advanced renal cell carcinoma with or without bone metastases in a human patient who has received prior anti-angiogenic therapy, comprising administering to the patient an amount of cabozantinib or a pharmaceutically acceptable salt thereof, wherein progression-free survival (PFS) and one or both of overall survival (OS) and objective response rate (ORR) are extended as compared to patients who have received prior anti-angiogenic therapy, wherein the prior anti-angiogenic therapy is selected from the group consisting of axitinib, pazopanib, sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab, interleukins, interferon-α, peginterferon, nivolumab, AMP-514, and atezolizumab.
2 . The method of claim 1 , wherein the cabozantinib is administered as cabozantinib (S)-malate.
3 . The method of any of claims 1 - 2 , cabozantinib (S)-malate is administered in an amount sufficient to achieve a median time to peak plasma concentration (Tmax) of from approximately 2 to 5 hours post-dose; and a Cmax of 200 to 500 ng/mL.
4 . The method of any of claims 1 - 3 , wherein the prior antiangiogenic therapy is selected from the group consisting of axitinib, pazopanib, sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab, nivolumab, AMP-514, and atezolizumab.
5 . The method of any of claims 1 - 4 , wherein the prior anti-angiogenic therapy is everolimus.
6 . The method of any of claims 1 - 5 , wherein cabozantinib (S)-malate is administered as a tablet comprising cabozantinib (S)-malate, microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide magenisum stearate, and film coating comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
7 . The method of any of claims 1 - 6 , wherein the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately:
30-32 percent by weight of cabozantinib, (S)-malate salt; 38-40 percent by weight of microcrystalline cellulose; 18-22 percent by weight of lactose; 2-4 percent by weight of hydroxypropyl cellulose; 4-8 percent by weight of croscarmellose sodium; 0.2-0.6 percent by weight of colloidal silicon dioxide; 0.5-1 percent by weight of magnesium stearate; and further comprising: a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
8 . The method of any of claims 1 - 7 , wherein the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately (% w/w):
31-32 percent by weight of cabozantinib, (S)-malate salt; 39-40 percent by weight of microcrystalline cellulose; 19-20 percent by weight of lactose; 2.5-3.5 percent by weight of hydroxypropyl cellulose; 5.5-6.5 percent by weight of croscarmellose sodium; 0.25-0.35 percent by weight of colloidal silicon dioxide; 0.7-0.8 percent by weight of magnesium stearate; and further comprising: 3.9-4.1 percent by weight of a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
9 . The method of any of claims 1 - 8 , wherein cabozantinib (S)-malate is administered as a tablet formulation containing 20, 40, or 60 mg of cabozantinib.
10 . The method of any of claims 1 - 9 , wherein cabozantinib (S)-malate is administered as a tablet formulation selected from the group consisting of:
Theoretical Quantity (mg/unit dose)
20-mg
40-mg
60-mg
Ingredient
Tablet*
Tablet*
Tablet*
Cabozantinib (S)-malate
25.34
50.69
76.03
Microcrystalline Cellulose,
31.08
62.16
93.24
PH-102
Lactose Anhydrous, 60M
15.54
31.07
46.61
Hydroxypropyl Cellulose, EXF
2.400
4.800
7.200
Croscarmellose Sodium
4.800
9.600
14.40
Colloidal Silicon Dioxide
0.2400
0.4800
0.7200
Magnesium Stearate
0.6000
1.200
1.800
(Non-Bovine)
Opadry ® Yellow (03K92254)
3.200
6.400
9.600
Total tablet weight
83.20
166.4
249.6
*Free Base Equivalent (FBE)
11 . The method of any of claims 1 - 10 , wherein the cabozantinib (S)-malate is administered once daily.
12 . The method of any of claims 1 - 11 , wherein the amount of cabozantinib that is administered once daily is 60 mg.
13 . The method of any of claims 1 - 12 , wherein the amount of cabozantinib (S)-malate is sufficient to achieve a median time to peak plasma concentration (Tmax) from 3.2 to 3.8 hours post-dose; and a mean Cmax of 310 to 350 ng/mL.
14 . The method of any of claims 1 - 13 , wherein the overall survival of the patient is extended as compared to patients taking everolimus.
15 . The method of any of claims 1 - 14 , wherein the objective response rate of the patient is extended as compared to patients taking everolimus.
16 . The method of any of claims 1 - 15 , wherein both the overall survival and the objective response rate of the patient is extended as compared to patients taking everolimus.
17 . The method of any of claims 1 - 15 wherein an amount of cabozantinib (S)-malate is sufficient to achieve one, two, three, four, five, six, seven, or eight effects selected from the group consisting of:
a median time to peak plasma concentration (Tmax) from 2 to 5 hours post-dose;
a Cmax of 200 to 500 ng/mL;
an AUC 0-24 of 2500 to 5200 ng*h/mL;
an AUC 0-t of 18,000 to 42,000 ng*h/mL;
an AUC 0-∞ of 19,000 to 45,000 ng*h/mL;
an oral volume distribution (Vz/F) of 100 to 600 L;
a terminal half-life of 90 to 135 h; and
a clearance at steady state (CL/F) of 0.7 to 3.9 L/h;
wherein the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately (% w/w):
31-32 percent by weight of cabozantinib, (S)-malate salt;
39-40 percent by weight of microcrystalline cellulose;
19-20 percent by weight of lactose;
2.5-3.5 percent by weight of hydroxypropyl cellulose;
5.5-6.5 percent by weight of croscarmellose sodium;
0.25-0.35 percent by weight of colloidal silicon dioxide;
0.7-0.8 percent by weight of magnesium stearate; and further comprising:
3.9-4.1 percent by weight of a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
18 . The method of 17, wherein cabozantinib (S)-malate is administered as a tablet formulation containing 20, 40, or 60 mg of cabozantinib.
19 . The method of any of claims 1 - 18 , wherein the cabozantinib (S)-malate is administered in an amount sufficient to achieve one, two, three, four, five, six, seven, or eight effects selected from the group consisting of:
a median time to peak plasma concentration (Tmax) from 2 to 5 hours post-dose; a Cmax of 200 to 500 ng/mL; an AUC 0-24 of 2500 to 5200 ng*h/mL; an AUC 0-t of 18,000 to 42,000 ng*h/mL; an AUC 0-∞ of 19,000 to 45,000 ng*h/mL; an oral volume distribution (Vz/F) of 100 to 600 L; a terminal half-life of 90 to 135 h; and a clearance at steady state (CL/F) of 0.7 to 3.9 L/h
20 . The method of any of claims 1 - 19 , wherein the cabozantinib (S)-malate is administered in an amount sufficient to achieve one, two, three, four, five, six, seven, or eight effects selected from the group consisting of:
a median time to peak plasma concentration (Tmax) from 2.5 to 4.5 hours post-dose; a Cmax of 250 to 450 ng/mL; an AUC 0-24 of 3000 to 4700 ng*h/mL; an AUC 0-t of 23,000 to 37,000 ng*h/mL; an AUC 0-∞ of 24,000 to 40,000 ng*h/mL; an oral volume distribution (Vz/F) of 150 to 550 L; a terminal half-life of 100 to 125 h; and a clearance at steady state (CL/F) of 1.2 to 3.2 L/h.
21 . The method of any of claims 1 - 20 , wherein the cabozantinib (S)-malate is administered in an amount sufficient to achieve one, two, three, four, five, six, seven, or eight effects selected from the group consisting of:
a median time to peak plasma concentration (Tmax) from 3 to 4 hours post-dose; a Cmax of 300 to 400 ng/mL; an AUC 0-24 of 3500 to 4200 ng*h/mL; an AUC 0-t of 28,000 to 32,000 ng*h/mL; an AUC 0-∞ of 29,000 to 35,000 ng*h/mL; an oral volume distribution (Vz/F) of 200 to 500 L; a terminal half-life of 110 to 115 h; and a clearance at steady state (CL/F) of 1.2 to 3.2
22 . The method of any of claims 1 - 21 , wherein the cabozantinib (S)-malate is administered in an amount sufficient to achieve one, two, three, four, five, six, seven, or eight effects selected from the group consisting of:
a median time to peak plasma concentration (Tmax) from 3.2 to 3.8 hours post-dose; a Cmax of 310 to 350 ng/mL; an AUC 0-24 of 3700 to 4000 ng*h/mL; an AUC 0-1 of 29,000 to 30,000 ng*h/mL; an AUC 0-∞ of 30,000 to 33,000 ng*h/mL; an oral volume distribution (Vz/F) of 300 to 400 L; a terminal half-life of 110 to 114 h; and a clearance at steady state (CL/F) of 2 to 3.
23 . A method of treating advanced renal cell carcinoma in human patients who have received prior anti-angiogenic therapy, comprising administering to the patient cabozantinib or a pharmaceutically acceptable salt thereof, wherein the overall survival of the patients are extended as compared to the median overall survival of patients who have received prior anti-angiogenic therapy, wherein the prior anti-angiogenic therapy is selected from the group consisting of axitinib, pazopanib, sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab, interleukins, interferon-α, peginterferon, nivolumab, AMP-514, and atezolizumab.
24 . The method of claim 23 , wherein the cabozanitinib is administered as cabozantinib (S)-malate.
25 . The method of any of claims 23 - 24 , wherein the overall survival is extended for patients taking cabozantinib (S)-malate as compared to patients who have received axitinib, pazopanib, sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab, nivolumab, AMP-514, and atezolizumab as the prior anti-angiogenic therapy.
26 . The method of any of claims 23 - 25 , wherein the overall survival is extended for patients taking cabozantinib (S)-malate as compared to patients who have received prior anti-angiogenic therapy.
27 . The method of any of claims 23 - 26 , wherein the patients are selected from the group consisting of patients with favorable, intermediate, and poor prognoses on the Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group, patients with bone metastases, patients with visceral metastases, and patients with visceral and bone metastases.
28 . The method of any of claims 23 - 27 , wherein one or both of progression-free survival (PFS) and objective response rate are also extended over patients who have received prior anti-angiogenic therapy.
29 . The method of any of claims 23 - 28 wherein the cabozantinib (S)-malate is administered in an amount sufficient to achieve to achieve a median time to peak plasma concentration (Tmax) from 3.2 to 3.8 hours post-dose; and a mean Cmax of 310 to 350 ng/mL; wherein: the overall survival of the patient is extended as compared to a the median overall survival of patients taking who have received prior anti-angiogenic therapy; and wherein one or both of progression-free survival (PFS) and objective response rate are also extended over patients taking who have received prior anti-angiogenic therapy.
30 . The method of any of claims 23 - 29 , wherein the prior antiangiogenic therapy is selected from the group consisting of axitinib, pazopanib, sorafenib, sunitinib, and everolimus.
31 . The method of any of claims 23 - 30 , wherein the prior anti-angiogenic therapy is everolimus.
32 . The method of any of claims 23 - 31 , wherein cabozantinib (S)-malate is administered as a tablet comprising cabozantinib (S)-malate, microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide magenisum stearate, and film coating comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
33 . The method of any of claims 23 - 32 , wherein the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately:
30-32 percent by weight of cabozantinib, (S)-malate salt; 38-40 percent by weight of microcrystalline cellulose; 18-22 percent by weight of lactose; 2-4 percent by weight of hydroxypropyl cellulose; 4-8 percent by weight of croscarmellose sodium; 0.2-0.6 percent by weight of colloidal silicon dioxide; 0.5-1 percent by weight of magnesium stearate; and further comprising: a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
34 . The method of any of claims 23 - 33 , wherein the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately (% w/w):
31-32 percent by weight of cabozantinib, (S)-malate salt; 39-40 percent by weight of microcrystalline cellulose; 19-20 percent by weight of lactose; 2.5-3.5 percent by weight of hydroxypropyl cellulose; 5.5-6.5 percent by weight of croscarmellose sodium; 0.25-0.35 percent by weight of colloidal silicon dioxide; 0.7-0.8 percent by weight of magnesium stearate; and further comprising: 3.9-4.1 percent by weight of a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
35 . The method of any of claims 23 - 34 , wherein cabozantinib (S)-malate is administered as a tablet formulation containing 20, 40, or 60 mg of cabozantinib.
36 . The method of any of claims 23 - 35 , wherein cabozantinib (S)-malate is administered as a tablet formulation selected from the group consisting of:
Theoretical Quantity (mg/unit dose)
20-mg
40-mg
60-mg
Ingredient
Tablet*
Tablet*
Tablet*
Cabozantinib (S)-malate
25.34
50.69
76.03
Microcrystalline Cellulose,
31.08
62.16
93.24
PH-102
Lactose Anhydrous, 60M
15.54
31.07
46.61
Hydroxypropyl Cellulose, EXF
2.400
4.800
7.200
Croscarmellose Sodium
4.800
9.600
14.40
Colloidal Silicon Dioxide
0.2400
0.4800
0.7200
Magnesium Stearate
0.6000
1.200
1.800
(Non-Bovine)
Opadry ® Yellow (03K92254)
3.200
6.400
9.600
Total tablet weight
83.20
166.4
249.6
*Free Base Equivalent (FBE)
37 . The method of any of claims 23 - 36 , wherein the cabozantinib (S)-malate is administered once daily.
38 . The method of any of claims 23 - 37 , wherein the amount of cabozantinib that is administered once daily is 60 mg.
39 . The method of any of claims 23 - 38 , wherein the amount of cabozantinib (S)-malate is sufficient to achieve a median time to peak plasma concentration (Tmax) of from 3.2 to 3.8 hours post-dose and a mean Cmax of 310 to 350 ng/mL.
40 . The method of any of claims 23 - 39 , wherein the overall survival of the patient are extended as compared to the median overall survival of patients taking everolimus; and wherein the progression-free survival of the patient is extended over patients taking everolimus.
41 . The method of any of claims 23 - 40 , wherein the overall survival of patients is extended as compared to the median overall survival of patients taking everolimus; and wherein the objective response rate is extended over patients taking everolimus.
42 . The method of any of claims 23 - 41 , wherein the overall survival of patients is extended as compared to everolimus and both of progression-free survival (PFS) and objective response rate are also extended as compared to patients taking everolimus.
43 . A method of treating renal cell carcinoma in a human patient who has received prior anti-angiogenic therapy, comprising administering to the patient an amount of cabozantinib (S)-malate sufficient to achieve one, two, three, four, five, six, seven, or eight effects selected from the group consisting of:
a median time to peak plasma concentration (Tmax) from 2 to 5 hours post-dose; a Cmax of 200 to 500 ng/mL; an AUC 0-24 of 2500 to 5200 ng*h/mL; an AUC 0-t of 18,000 to 42,000 ng*h/mL; an AUC 0-∞ of 19,000 to 45,000 ng*h/mL; an oral volume distribution (Vz/F) of 100 to 600 L; a terminal half-life of 90 to 135 h; and a clearance at steady state (CL/F) of 0.7 to 3.9 L/h; wherein:
the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately (% w/w):
31-32 percent by weight of cabozantinib, (S)-malate salt;
39-40 percent by weight of microcrystalline cellulose;
19-20 percent by weight of lactose;
2.5-3.5 percent by weight of hydroxypropyl cellulose;
5.5-6.5 percent by weight of croscarmellose sodium;
0.25-0.35 percent by weight of colloidal silicon dioxide;
0.7-0.8 percent by weight of magnesium stearate; and further comprising:
3.9-4.1 percent by weight of a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
44 . The method of 43, wherein cabozantinib (S)-malate is administered as a tablet formulation containing 20, 40, or 60 mg of cabozantinib.
45 . The method of any of claims 43 - 44 , wherein cabozantinib (S)-malate is administered as a tablet formulation selected from the group consisting of:
Theoretical Quantity (mg/unit dose)
20-mg
40-mg
60-mg
Ingredient
Tablet*
Tablet*
Tablet*
Cabozantinib (S)-malate
25.34
50.69
76.03
Microcrystalline Cellulose,
31.08
62.16
93.24
PH-102
Lactose Anhydrous, 60M
15.54
31.07
46.61
Hydroxypropyl Cellulose, EXF
2.400
4.800
7.200
Croscarmellose Sodium
4.800
9.600
14.40
Colloidal Silicon Dioxide
0.2400
0.4800
0.7200
Magnesium Stearate
0.6000
1.200
1.800
(Non-Bovine)
Opadry ® Yellow (03K92254)
3.200
6.400
9.600
Total tablet weight
83.20
166.4
249.6
*Free Base Equivalent (FBE)
46 . The method of any of claims 43 - 45 , wherein the cabozantinib (S)-malate is administered in an amount sufficient to achieve one, two, three, four, five, six, seven, or eight effects selected from the group consisting of:
a median time to peak plasma concentration (Tmax) from 2 to 5 hours post-dose; a Cmax of 200 to 500 ng/mL; an AUC 0-24 of 2500 to 5200 ng*h/mL; an AUC 0-t of 18,000 to 42,000 ng*h/mL; an AUC 0-∞ of 19,000 to 45,000 ng*h/mL; an oral volume distribution (Vz/F) of 100 to 600 L; a terminal half-life of 90 to 135 h; and a clearance at steady state (CL/F) of 0.7 to 3.9 L/h
47 . The method of any of claims 43 - 46 , wherein the cabozantinib (S)-malate is administered in an amount sufficient to achieve one, two, three, four, five, six, seven, or eight effects selected from the group consisting of:
a median time to peak plasma concentration (Tmax) from 2.5 to 4.5 hours post-dose; a Cmax of 250 to 450 ng/mL; an AUC 0-24 of 3000 to 4700 ng*h/mL; an AUC 0-t of 23,000 to 37,000 ng*h/mL; an AUC 0-∞ of 24,000 to 40,000 ng*h/mL; an oral volume distribution (Vz/F) of 150 to 550 L; a terminal half-life of 100 to 125 h; and a clearance at steady state (CL/F) of 1.2 to 3.2 L/h.
48 . The method of any of claims 43 - 47 , wherein the cabozantinib (S)-malate is administered in an amount sufficient to achieve one, two, three, four, five, six, seven, or eight effects selected from the group consisting of:
a median time to peak plasma concentration (Tmax) from 3 to 4 hours post-dose; a Cmax of 300 to 400 ng/mL; an AUC 0-24 of 3500 to 4200 ng*h/mL; an AUC 0-t of 28,000 to 32,000 ng*h/mL; an AUC 0-∞ of 29,000 to 35,000 ng*h/mL; an oral volume distribution (Vz/F) of 200 to 500 L; a terminal half-life of 110 to 115 h; and a clearance at steady state (CL/F) of 1.2 to 3.2
49 . The method of any of claims 43 - 48 , wherein the cabozantinib (S)-malate is administered in an amount sufficient to achieve one, two, three, four, five, six, seven, or eight effects selected from the group consisting of:
a median time to peak plasma concentration (Tmax) from 3.2 to 3.8 hours post-dose; a Cmax of 310 to 350 ng/mL; an AUC 0-24 of 3700 to 4000 ng*h/mL; an AUC 0-t of 29,000 to 30,000 ng*h/mL; an AUC 0-∞ of 30,000 to 33,000 ng*h/mL; an oral volume distribution (Vz/F) of 300 to 400 L; a terminal half-life of 110 to 114 h; and a clearance at steady state (CL/F) of 2 to 3.
50 . The method of any of claims 43 - 49 , wherein the overall survival of the patient is extended as compared to the median overall survival of patients taking everolimus; and wherein the progression-free survival of the patient is extended over patients taking everolimus.
51 . The method of any of claims 43 - 50 , wherein the overall survival of the patient is extended as compared to the median overall survival of patients taking everolimus; and wherein the objective response rate is extended over patients taking everolimus.
52 . The method of any of claims 43 - 51 , wherein the overall survival of the patient is extended as compared to a the median overall survival of patients taking everolimus; and wherein progression-free survival (PFS) and objective response rate are also extended over patients taking everolimus.
54 . A method of treating advanced renal cell carcinoma in patients in need of such treatment who has received prior antiangiogenic therapy selected from the group consisting of sunitinib therapy, pazopanib therapy, and anti-PD-1/PD-L1 immune checkpoint inhibitor therapy, comprising administering cabozantinib
or a pharmaceutically acceptable salt thereof.
55 . The method of claim 54 , wherein cabozantinib is administered as cabozantinib S-malate salt.
56 . The method of any of claims 54 - 55 , wherein the median progression free survival is at least 9.1 months when the prior antiangiogenic therapy is sunitinib therapy only and at least 7.4 months when the prior antiangiogenic therapy is pazopanib only.
57 . The method of any of claims 54 - 56 , wherein the median overall survival is at least 21.4 months when the prior antiangiogenic therapy was sunitinib only and at least 22.0 months when the prior antiangiogenic therapy was pazopanib only.
58 . The method of any of claims 54 - 57 , wherein the median progression free survival is at least 9.1 months when the prior antiangiogenic therapy is sunitinib therapy only and at least 7.4 months when the prior antiangiogenic therapy was pazopanib only and the median overall survival is at least 21.4 months when the prior antiangiogenic therapy was sunitinib only and at least 22.0 months when the prior antiangiogenic therapy was pazopanib only.
59 . A method of optimizing the treatment of a renal carcinoma patient with a tyrosine kinase inhibitor (TKI) comprising the step of quantifying the patient's response to one or more dosing regimens of said TKI inhibitor with a model employing Equation 1:
dY
dt
=
k
grow
·
Y
-
(
k
dmax
+
k
dmax
tol
·
e
-
k
tol
·
t
)
·
Cavg
(
EC
50
+
Cavg
)
·
Y
Equation
1
where:
dY/dt is the change in tumor diameter per unit time
k grow is the first-order growth rate constant
k dmax is the maximum non-attenuating drug induced tumor decay rate
k dmax_tol is the maximum loss in the decay rate due to resistance
k tol is the rate constant which governs the rate of attenuation
EC 50 is the cabozantinib concentration yielding one-half of the current tumor decay rate
Cavg is the individual predicted daily average cabozantinib concentration.
60 . The method of 59, wherein the target of the TKI is selected from the group consisting of VEGF receptors, MET, and AXL.
61 . The method of any of claims 59 - 60 , wherein the TKI inhibitor is cabozantinib.
62 . A method of adjusting the dosing level of a composition comprising a tyrosine kinase (TKI) inhibitor for administration to a patient, the method comprising:
measuring plasma clearance (CL/F) and apparent volume of distribution of the central compartment (V c /F) from a patient; utilizing the measured plasma clearance (CL/F) and apparent volume of distribution of the central compartment (V c /F) to calculate the responsiveness of the patient to the administered composition comprising said TKI inhibitor; and comparing the calculated responsiveness to a predetermined responsiveness to compositions comprising said TKI inhibitor.
63 . The method of 62, wherein the TKI inhibitor is cabozantinb.
64 . A method for treating renal cell carcinoma, comprising administering as a starting dose 60 mg of cabozantinib free base equivalent thereof to a patient in need of such treatment, wherein progression free survival is extended, tumor growth is reduced, and overall response rate is extended as compared to 40 mg or 20 mg starting doses or cabozantinib free base equivalent.
65 . The method of claim 64 , wherein cabozantinib is administered as cabozantinib S-malate salt.
66 . A method of treating renal cell carcinoma in a human patient, wherein the method comprises administering cabozantinib or a pharmaceutically acceptable salt thereof daily in an amount of 60 mg of cabozantinib free base equivalent.
67 . The method of claim 66 , wherein the renal cell carcinoma is advanced renal cell carcinoma.
68 . The method of any of claims 66 - 67 , wherein the patient is an adult patient.
69 . The method of any of claims 66 - 68 , wherein said amount is administered to the patient once daily.
70 . The method of any of claims 66 - 69 , wherein the cabozantinib is administered as cabozantinib (S)-malate.
71 . The method of any of claims 66 - 70 , wherein cabozantinib (S)-malate is administered as a tablet comprising cabozantinib (S)-malate, microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide magenisum
stearate, and film coating comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
72 . The method of any of claims 66 - 71 , wherein the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately:
30-32 percent by weight of cabozantinib, (S)-malate salt; 38-40 percent by weight of microcrystalline cellulose; 18-22 percent by weight of lactose; 2-4 percent by weight of hydroxypropyl cellulose; 4-8 percent by weight of croscarmellose sodium; 0.2-0.6 percent by weight of colloidal silicon dioxide; 0.5-1 percent by weight of magnesium stearate; and further comprising: a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
73 . The method of any of claims 66 - 72 , wherein the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately (% w/w):
31-32 percent by weight of cabozantinib, (S)-malate salt; 39-40 percent by weight of microcrystalline cellulose; 19-20 percent by weight of lactose; 2.5-3.5 percent by weight of hydroxypropyl cellulose; 5.5-6.5 percent by weight of croscarmellose sodium; 0.25-0.35 percent by weight of colloidal silicon dioxide; 0.7-0.8 percent by weight of magnesium stearate; and further comprising: 3.9-4.1 percent by weight of a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
74 . The method of any of claims 66 - 73 , wherein the starting dose of 60 mg cabozantinib free base equivalent can be reduced to 40 or 20 mg cabozantinib free base equivalent to minimize adverse side effects.
75 . The method of any of claims 66 - 74 , wherein cabozantinib (S)-malate is administered as a tablet formulation selected from the group consisting of:
Theoretical Quantity (mg/unit dose)
20-mg
40-mg
60-mg
Ingredient
Tablet*
Tablet*
Tablet*
Cabozantinib (S)-malate
25.34
50.69
76.03
Microcrystalline Cellulose,
31.08
62.16
93.24
PH-102
Lactose Anhydrous, 60M
15.54
31.07
46.61
Hydroxypropyl Cellulose, EXF
2.400
4.800
7.200
Croscarmellose Sodium
4.800
9.600
14.40
Colloidal Silicon Dioxide
0.2400
0.4800
0.7200
Magnesium Stearate
0.6000
1.200
1.800
(Non-Bovine)
Opadry ® Yellow (03K92254)
3.200
6.400
9.600
Total tablet weight
83.20
166.4
249.6
*Free Base Equivalent (FBE)
76 . The method of any of claims 66 - 75 , wherein the patient has received prior anti-angiogenic therapy.
77 . The method of claims 66 - 76 , wherein the prior anti-angiogenic therapy is selected axitinib, pazopanib, sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab, interleukins, interferon-α, peginterferon, nivolumab, AMP-514, and atezolizumab.
78 . The method of claims 66 - 77 , wherein the prior anti-angiogenic therapy is everolimus therapy.
79 . A method of treating renal cell carcinoma in a human patient, wherein the method comprises administering cabozantinib or a pharmaceutically acceptable salt thereof daily in an amount of 40 mg of cabozantinib free base equivalent.
80 . The method of claim 79 , wherein the renal cell carcinoma is advanced renal cell carcinoma.
81 . The method of any of claims 79 - 80 , wherein the patient is an adult patient.
82 . The method of any of claims 79 - 81 , wherein said amount is administered to the patient once daily.
83 . The method of any of claims 79 - 82 , wherein the cabozantinib is administered as cabozantinib (S)-malate.
84 . The method of any of claims 79 - 83 , wherein cabozantinib (S)-malate is administered as a tablet comprising cabozantinib (S)-malate, microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide magenisum stearate, and film coating comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
85 . The method of any of claims 79 - 84 , wherein the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately:
30-32 percent by weight of cabozantinib, (S)-malate salt; 38-40 percent by weight of microcrystalline cellulose; 18-22 percent by weight of lactose; 2-4 percent by weight of hydroxypropyl cellulose; 4-8 percent by weight of croscarmellose sodium; 0.2-0.6 percent by weight of colloidal silicon dioxide; 0.5-1 percent by weight of magnesium stearate; and further comprising: a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
86 . The method of any of claims 79 - 85 , wherein the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately (% w/w):
31-32 percent by weight of cabozantinib, (S)-malate salt; 39-40 percent by weight of microcrystalline cellulose; 19-20 percent by weight of lactose; 2.5-3.5 percent by weight of hydroxypropyl cellulose; 5.5-6.5 percent by weight of croscarmellose sodium; 0.25-0.35 percent by weight of colloidal silicon dioxide; 0.7-0.8 percent by weight of magnesium stearate; and further comprising: 3.9-4.1 percent by weight of a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
87 . The method of any of claims 79 - 86 , wherein cabozantinib (S)-malate is administered as a tablet formulation selected from the group consisting of:
Theoretical Quantity (mg/unit dose)
20-mg
40-mg
60-mg
Ingredient
Tablet*
Tablet*
Tablet*
Cabozantinib (S)-malate
25.34
50.69
76.03
Microcrystalline Cellulose,
31.08
62.16
93.24
PH-102
Lactose Anhydrous, 60M
15.54
31.07
46.61
Hydroxypropyl Cellulose, EXF
2.400
4.800
7.200
Croscarmellose Sodium
4.800
9.600
14.40
Colloidal Silicon Dioxide
0.2400
0.4800
0.7200
Magnesium Stearate
0.6000
1.200
1.800
(Non-Bovine)
Opadry ® Yellow (03K92254)
3.200
6.400
9.600
Total tablet weight
83.20
166.4
249.6
*Free Base Equivalent (FBE)
88 . The method of any of claims 79 - 87 , wherein the patient has received prior anti-angiogenic therapy.
89 . The method of claims 79 - 88 , wherein the prior anti-angiogenic therapy is selected axitinib, pazopanib, sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab, interleukins, interferon-α, peginterferon, nivolumab, AMP-514, and atezolizumab.
90 . The method of claims 79 - 89 , wherein the prior anti-angiogenic therapy is everolimus therapy.
91 . A method of treating renal cell carcinoma in a human patient, wherein the method comprises administering cabozantinib or a pharmaceutically acceptable salt thereof daily in an amount of 20 mg of cabozantinib free base equivalent.
92 . The method of claim 91 , wherein the renal cell carcinoma is advanced renal cell carcinoma.
93 . The method of any of claims 91 - 92 , wherein the patient is an adult patient.
94 . The method of any of claims 91 - 93 , wherein said amount is administered to the patient once daily.
95 . The method of any of claims 91 - 94 , wherein the cabozantinib is administered as cabozantinib (S)-malate.
96 . The method of any of claims 91 - 95 , wherein cabozantinib (S)-malate is administered as a tablet comprising cabozantinib (S)-malate, microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide magenisum stearate, and film coating comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
97 . The method of any of claims 91 - 96 , wherein the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately:
30-32 percent by weight of cabozantinib, (S)-malate salt; 38-40 percent by weight of microcrystalline cellulose; 18-22 percent by weight of lactose; 2-4 percent by weight of hydroxypropyl cellulose; 4-8 percent by weight of croscarmellose sodium; 0.2-0.6 percent by weight of colloidal silicon dioxide; 0.5-1 percent by weight of magnesium stearate; and further comprising: a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
98 . The method of any of claims 91 - 97 , wherein the cabozantinib (S)-malate is administered as a tablet formulation comprising approximately (% w/w):
31-32 percent by weight of cabozantinib, (S)-malate salt; 39-40 percent by weight of microcrystalline cellulose; 19-20 percent by weight of lactose; 2.5-3.5 percent by weight of hydroxypropyl cellulose; 5.5-6.5 percent by weight of croscarmellose sodium; 0.25-0.35 percent by weight of colloidal silicon dioxide; 0.7-0.8 percent by weight of magnesium stearate; and further comprising: 3.9-4.1 percent by weight of a film coating material comprising hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
99 . The method of any of claims 91 - 98 , wherein cabozantinib (S)-malate is administered as a tablet formulation selected from the group consisting of:
Theoretical Quantity (mg/unit dose)
20-mg
40-mg
60-mg
Ingredient
Tablet*
Tablet*
Tablet*
Cabozantinib (S)-malate
25.34
50.69
76.03
Microcrystalline Cellulose,
31.08
62.16
93.24
PH-102
Lactose Anhydrous, 60M
15.54
31.07
46.61
Hydroxypropyl Cellulose, EXF
2.400
4.800
7.200
Croscarmellose Sodium
4.800
9.600
14.40
Colloidal Silicon Dioxide
0.2400
0.4800
0.7200
Magnesium Stearate
0.6000
1.200
1.800
(Non-Bovine)
Opadry ® Yellow (03K92254)
3.200
6.400
9.600
Total tablet weight
83.20
166.4
249.6
*Free Base Equivalent (FBE)
100 . The method of any of claims 91 - 99 , wherein the patient has received prior anti-angiogenic therapy.
101 . The method of claims 91 - 100 , wherein the prior anti-angiogenic therapy is selected axitinib, pazopanib, sorafenib, sunitinib, everolimus, temsirolimus, bevacizumab, interleukins, interferon-α, peginterferon, nivolumab, AMP-514, and atezolizumab.
102 . The method of claims 91 - 101 , wherein the prior anti-angiogenic therapy is everolimus therapy.Cited by (0)
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