Combinations for the treatment of cancer
The present invention relates to combinations comprising a checkpoint inhibitor and a c-Met inhibitor, Compound 1. The invention also relates to crystalline forms of the free base of Compound 1, as well as crystalline forms of salts of Compound 1, in combination with a checkpoint inhibitor. The invention further relates to methods of treating cancer by administering Compound 1 as a single agent or a combination described herein.
1 . A method for treating colorectal cancer in a subject, the method comprising administering to the subject in need of such treatment a dosage of from 5 mg to 100 mg of Compound 1:
or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound 1 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient,
in combination with a therapeutically effective amount of a checkpoint inhibitor or a pharmaceutical composition comprising the checkpoint inhibitor, wherein the checkpoint inhibitor is atezolizumab.
2 . The method of claim 1 , wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered orally once per day (qd) or twice per day (bid).
3 . The method of claim 2 , wherein the dosage of Compound 1 or a pharmaceutically acceptable salt thereof is from 5 mg to 80 mg.
4 . The method of claim 3 , wherein the dosage of Compound 1 or a pharmaceutically acceptable salt thereof, is selected from 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg.
5 . The method of claim 1 , wherein atezolizumab is administered intravenously (IV) to the subject.
6 . The method of claim 1 , wherein atezolizumab is administered once every two weeks, once every three weeks, or once every four weeks for the duration of the treatment period.
7 . The method of claim 6 , wherein atezolizumab is administered in an amount from 800 mg to 1700 mg.
8 . The method of claim 1 , wherein a dosage of atezolizumab is 840 mg administered once every two weeks, 1200 mg administered once every three weeks, or 1680 mg administered once every four weeks.
9 . The method of claim 8 , wherein atezolizumab is administered to a subject in an IV unit dosage form, wherein the dosage form comprises 840 mg, 1200 mg, or 1680 mg of atezolizumab, water, glacial acetic acid, L-histidine, polysorbate 20, and sucrose.
10 . The method of claim 1 , wherein Compound 1 is administered as a pharmaceutical composition comprising:
a. 25 to 35 percent by weight of Compound 1 or a pharmaceutically acceptable salt thereof;
b. 37 to 43 percent by weight of microcrystalline cellulose;
c. 18 to 22 percent by weight of anhydrous lactose;
d. 2 to 6 percent by weight of hydroxypropyl cellulose;
e. 5 to 7 percent by weight of croscarmellose sodium;
f. 0.2 to 0.4 percent by weight of colloidal silicon dioxide;
g. 0.5 to 3.5 percent by weight magnesium stearate; and optionally
h. a film coating.
11 . The method of claim 1 , wherein Compound 1 is administered as a pharmaceutical composition comprising:
a. 25 to 35 percent by weight of Compound 1 or a pharmaceutically acceptable salt thereof;
b. 35 to 40 percent by weight of microcrystalline cellulose;
c. 16 to 22 percent by weight of anhydrous lactose;
d. 3 to 7 percent by weight of hydroxypropyl cellulose;
e. 3 to 7 percent by weight of croscarmellose sodium
f. 0.1 to 0.5 percent by weight of colloidal silicon dioxide;
g. 0.5 to 3.5 percent by weight stearic acid; and optionally
h. a film coating.
12 . The method of claim 1 , wherein the colorectal cancer is a solid tumor that is inoperable, locally advanced, metastatic, or recurrent.
13 . The method of claim 12 , wherein the solid tumor is an unresectable or metastatic solid tumor for which no life-prolonging therapies exist, or for which available therapies are intolerable or no longer effective.
14 . The method of claim 1 , wherein the colorectal cancer is right-sided colorectal cancer (RCRC) or left-sided colorectal cancer (LCRC).
15 . The method of claim 1 , wherein the subject has received a prior anticancer therapy.
16 . The method of claim 15 , wherein the prior anticancer therapy is chemotherapy, platinum-based combination therapy, PD-1 immune checkpoint inhibitor monotherapy, PD-1 immune checkpoint inhibitor combination therapy, PD-L1 immune checkpoint inhibitor monotherapy, PD-L1 immune checkpoint inhibitor combination therapy, CTLA-4 checkpoint inhibitor therapy or a combination thereof.
17 . The method of claim 1 , wherein the method further comprises assessing treatment with said combination therapy by determining one or more of: inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors, delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), increased overall response rate, increased Overall Survival (OS) or increased Duration of Response (DOR), changes in tumor markers from baseline.
18 . The method of claim 15 , wherein the prior anticancer therapy comprises a fluoropyrimidine in combination with oxaliplatin or irinotecan.