Methods of treatment of cancer comprising CDC7 inhibitors
Herein disclosed are methods of treatment administering SRA141 as a monotherapy or in a combination therapy useful for inhibiting the growth of tumors such as those in patients with cancer.
1 . A method of treating a cancer, the method comprising:
administering to a human subject with the cancer a therapeutically effective amount of a compound of formula (I-D) or a pharmaceutically acceptable salt thereof:
wherein the therapeutically effective amount is 100, 160, or 200 mg/day, and half of the therapeutically effective amount is administered twice a day (BID), and wherein the cancer is acute myeloid leukemia, bladder cancer, colon cancer, cecum cancer, renal cancer, head-and-neck cancer, melanoma, gastric cancer, colorectal cancer, hematologic cancer, breast cancer, or cervical cancer.
2 . The method of claim 1 , wherein the subject is identified as having one or more of the inclusion criteria disclosed in the table below:
Laboratory Test
Value required
Hemoglobin
≥90 g/L
Absolute neutrophil count
≥1.5 × 10 9 /L
Platelet count
≥120 × 10 9 /L
Bilirubin
≤1.5 × upper limit of normal (ULN)
unless due to Gilbert's syndrome in
which case up to 3 × ULN is
permissible
Alanine aminotransferase
≤2.5 × ULN
(ALT), aspartate
For the Expansion stage,
aminotransferase (AST)
up to 5 × ULN is permissible
and alkaline
if the increase is due to tumor.
phosphatase (ALP)
Serum creatinine
≤1.5 × ULN
or
or
Calculated creatinine
≥60 mL/min using
clearance
Cockcroft-Gault formula.
3 . The method of claim 1 , wherein the subject has not previously had Cdc7 inhibitor therapy.
4 . The method of claim 1 , wherein either
(i) the compound is administered for at least 5 consecutive days; or
(ii) the compound is administered following a dosing schedule selected from the group consisting of: 5 days of dosing followed by 2 days of non-dosing each week; 1 week of daily dosing followed by 1, 2, or 3 weeks of non-dosing; 2 or 3 weeks of daily dosing followed by 1, or 2 weeks of non-dosing; and dosing on days 2 and 3 of a weekly cycle.
5 . The method of claim 1 ,
wherein the hematologic cancer is selected from the group consisting of: acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic eosinophilic leukemia, and diffuse large B-cell lymphoma (DLBCL).
6 . The method of claim 5 , wherein the cancer is diffuse large B-cell lymphoma (DLBCL).
7 . The method of claim 1 , wherein the cancer is not categorized as having a high microsatellite instability (MSI-H) status, or wherein the cancer is categorized as having a microsatellite stability stable (MSS) status.
8 . The method of claim 1 , wherein a tumor associated with the cancer comprises a phenotype selected from the group consisting of: chromosome instability (CIN), a spindle checkpoint assembly defect, a mitosis defect, a G1/S checkpoint defect, and combinations thereof.
9 . The method of claim 1 ,
wherein a tumor associated with the cancer comprises a Wnt signaling pathway mutation; wherein the Wnt signaling pathway mutation is selected from the group consisting of: an Adenomatous polyposis coli (APC) gene mutation, a FAT1 mutation, a FAT4 mutation, and combinations thereof.
10 . The method of claim 1 , wherein the method results in at least one of:
a plasma C max greater than 600 ng/mL of the compound in the subject after administration;
an AUC last greater than 5800 ng-h/mL of the compound in the subject after administration; and
an intra-tumoral concentration of greater than 500 ng/mL of the compound in the subject after administration.
11 . The method of claim 1 ,
wherein the method results in growth inhibition of a tumor or lesion associated with the cancer; wherein the tumor or lesion growth is inhibited by at least 10% relative to an untreated tumor.
12 . The method of claim 1 , wherein the method results in a regression of a tumor associated with the cancer.
13 . The method of claim 1 , wherein the method further comprises administering to the subject a second therapeutically effective amount of one or more additional treatments, wherein the additional treatments are selected from the group consisting of trametinib, rapamycin, bexarotene, tretinoin, ABT-199, copanlisib, BMB673, KU-60019, barasertib, CF1-402257, erlotinib, gemcitabine, and radiation.
14 . The method of claim 13 , wherein the compound and the one or more additional treatments in combination demonstrate synergistic effects.
15 . The method of claim 1 , wherein the compound is administered orally.
16 . The method of claim 1 , wherein the hematologic cancer is AML.
17 . The method of claim 1 , wherein the subject is administered a bis-hydrochloride salt of the compound of formula (I-D).
18 . The method of claim 1 , wherein the therapeutically effective amount of the compound is 100 mg/day, and half of the therapeutically effective amount is administered twice a day (BID).
19 . The method of claim 1 , wherein the therapeutically effective amount of the compound is 160 mg/day, and half of the therapeutically effective amount is administered twice a day (BID).
20 . The method of claim 1 , wherein the therapeutically effective amount of the compound is 200 mg/day, and half of the therapeutically effective amount is administered twice a day (BID).