WO2023141087A1

WO2023141087A1 - Combination therapy with a mutant idh inhibitor

Info

Publication number: WO2023141087A1
Application number: PCT/US2023/010916
Authority: WO
Inventors: Xiaojian XU
Original assignee: Eli Lilly And Company
Priority date: 2022-01-19
Filing date: 2023-01-17
Publication date: 2023-07-27
Also published as: TW202345848A

Abstract

The present invention relates to combination therapy with (a) a mutant IDH inhibitor, or a pharmaceutically acceptable salt thereof, (b) a deoxyadenosine analog, or a pharmaceutically acceptable salt thereof, (c) a platinum agent, and (d) an immune checkpoint inhibitor, for the treatment of a solid tumor cancer. The present invention also relates to combination therapy with (a) a mutant IDH inhibitor, or a pharmaceutically acceptable salt thereof, and (b) an immune checkpoint inhibitor, for the treatment of a solid tumor cancer.

Description

COMBINATION THERAPY WITH A MUTANT IDH INHIBITOR

The present invention relates to combination therapy with a mutant isocitrate dehydrogenase (IDH) inhibitor, or a pharmaceutically acceptable salt thereof, a deoxyadenosine analog, or a pharmaceutically acceptable salt thereof, a platinum agent, and an immune checkpoint inhibitor for the treatment of a solid tumor cancer.

The present invention also relates to combination therapy with a mutant isocitrate dehydrogenase (IDH) inhibitor, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor for the treatment of a solid tumor cancer.

IDH1 is an enzyme that catalyzes the conversion of isocitrate to a-ketoglutarate (2-oxoglutarate), and reduces nicotinamide adenine dinucleotide phosphate (NADP⁺) to NADPH (Megias-Vericat J, et a!.. Blood Lymph. Cancer: Targets and Therapy 2019: 9: 19-32).

Mutations in IDH1, e.g., at IDH1 amino acid residue R132, contribute to tumorigenesis in several types of cancer, including solid tumors (Badur MG, et al., Cell Reports 2018: 25: 1680). IDH1 mutations can result in high levels of 2-hydroxyglutarate (2-HG), which inhibits cellular differentiation, and inhibitors of mutant IDH1 can reduce 2-HG levels, which promotes cellular differentiation (Molenaar RJ, el al., Oncogene 2018,' 37: 1949-1960). Mutations in IDH2, e.g., at IDH2 amino acid residues R140 and R172, also contribute to tumorigenesis (Kotredes KP, et al., Oncotarget 2019,' 10: 2675- 2692).

Certain mutant IDH1/IDH2 inhibitors are disclosed in WO 2018/111707 Al, including a compound defined herein as “Compound A,” which is a covalent inhibitor of mutant IDH1 that modifies a single cysteine (Cys269) in an allosteric binding pocket, rapidly inactivates the enzyme, and selectively inhibits 2-HG production, without affecting alpha-ketoglutarate a-KG levels (WO 2018/111707 Al). Compound A also inhibits 2-HG production in IDH2 mutant cells. Compound A is currently in phase 1 studies for advanced hematologic malignancies (NCT04603001) and advanced solid tumors (NCT04521686).

Effective therapies for the treatment of solid tumor cancer, including cholangiocarcinoma, remain elusive.

In addition, so called “secondary” IDH1 mutations, as defined herein, may contribute to relapse after treatment with a mutant IDH1 inhibitor. For example, post- ivosidenib treatment secondary IDH1 mutations have been reported, including: R119P, G131A, D279N, S280F, G289D or H315D (Choe S, et a!., “Molecular mechanisms mediating relapse following ivosidenib monotherapy in subjects with IDH1 -mutant relapsed or refractory acute myeloid leukemia,” 61^st Am. Soc. Hematol. (ASH) Annual Meeting poster, Dec. 7-10, 2019, Orlando, FL, USA).

Thus, there exists a need for alternative treatments for solid tumor cancers, such as novel combination therapies.

The present invention provides a method of treating a solid tumor cancer, comprising administering to a subject having an IDH mutation a therapeutically effective amount of

(a) a compound of Formula I:

wherein:

R¹ is -CH₂CH(CH₃)2, -CH2CH3, -CH2CH2OCH3, or -CH₂-cyclopropyl;

R² is -CH₃ or -CH2CH3; and

X is N or CH; or a pharmaceutically acceptable salt thereof; (b) a deoxyadenosine analog, or a pharmaceutically acceptable salt thereof; (c) a platinum agent; and (d) an immune checkpoint inhibitor.

The present invention also provides a method of treating a solid tumor cancer, comprising administering to a subject having an IDH mutation a therapeutically effective amount of a compound of Formula I:

wherein:

R¹ is -CH₂CH(CH₃)2, -CH2CH3, -CH2CH2OCH3, or -CH₂-cyclopropyl;

R² is -CH₃ or -CH2CH3; and

X is N or CH; or a pharmaceutically acceptable salt thereof; and an immune checkpoint inhibitor.

The present invention also provides a compound of Formula I:

wherein:

R¹ is -CH₂CH(CH₃)2, -CH2CH3, -CH2CH2OCH3, or -CH₂-cyclopropyl;

R² is -CH₃ or -CH2CH3; and

X is N or CH; or a pharmaceutically acceptable salt thereof; for use in simultaneous, separate or sequential combination with gemcitabine, or a pharmaceutically acceptable salt thereof, cisplatin, and an immune checkpoint inhibitor, in the treatment of a solid tumor cancer in a subject having an IDH mutation. In one embodiment, the present invention provides the compound of Formula I or a pharmaceutically acceptable salt thereof for use in simultaneous combination with gemcitabine, or a pharmaceutically acceptable salt thereof, cisplatin, and an immune checkpoint inhibitor, in the treatment of a solid tumor cancer in a subject having an IDH mutation. In one embodiment, the present invention provides the compound of Formula I or a pharmaceutically acceptable salt thereof for use in separate combination with gemcitabine, or a pharmaceutically acceptable salt thereof, cisplatin, and an immune checkpoint inhibitor, in the treatment of a solid tumor cancer in a subject having an IDH mutation. In one embodiment, the present invention provides the compound of Formula I or a pharmaceutically acceptable salt thereof for use in sequential combination with gemcitabine, or a pharmaceutically acceptable salt thereof, cisplatin, and an immune checkpoint inhibitor, in the treatment of a solid tumor cancer in a subject having an IDH mutation.

The present invention also provides a compound of Formula I:

wherein:

R¹ is -CH₂CH(CH₃)2, -CH2CH3, -CH2CH2OCH3, or -CH₂-cyclopropyl;

R² is -CH₃ or -CH2CH3; and

X is N or CH; or a pharmaceutically acceptable salt thereof; for use in simultaneous, separate or sequential combination with an immune checkpoint inhibitor, in the treatment of a solid tumor cancer in a subject having an IDH mutation. In one embodiment, the present invention provides the compound of Formula I or a pharmaceutically acceptable salt thereof for use in simultaneous combination with an immune checkpoint inhibitor, in the treatment of a solid tumor cancer in a subject having an IDH mutation. In one embodiment, the present invention provides the compound of Formula I or a pharmaceutically acceptable salt thereof for use in separate combination with an immune checkpoint inhibitor, in the treatment of a solid tumor cancer in a subject having an IDH mutation. In one embodiment, the present invention provides the compound of Formula I or a pharmaceutically acceptable salt thereof for use in sequential combination with an immune checkpoint inhibitor, in the treatment of a solid tumor cancer in a subject having an IDH mutation.

In one embodiment, the IDH mutation is an IDH1 mutation or an IDH2 mutation. In another embodiment, the IDH mutation is an IDH1 mutation. In another embodiment, the IDH1 mutation is an IDH1 R132 mutation. In another embodiment, the IDH1 mutation is R132H. In another embodiment, the IDH1 mutation is R132C, R132G, R132L, or R132S. In another embodiment, the IDH1 R132 mutation is R132H. In another embodiment, the IDH1 mutation is R132C. In another embodiment, the IDH1 mutation is R132G. In another embodiment, the IDH1 mutation is R132L. In another embodiment, the IDH1 mutation is R132S.

In another embodiment, the IDH mutation is an IDH2 mutation. In another embodiment, the IDH2 mutation is an IDH2 R140 mutation or an IDH2 R172 mutation. In another embodiment, the IDH2 mutation is an R140 mutation. In another embodiment, the R140 mutation is R140Q, R140L, or R140W. In another embodiment, the IDH2 mutation is an R172 mutation. In another embodiment, the R172 mutation is R172K, R172M, R172G, R172S or R172W.

In another embodiment of the methods of the invention, the subject’s solid tumor cancer has progressed after treatment with an IDH inhibitor compound other than the compound of Formula I. In another embodiment, the subject is intolerant to, or is resistant to, an IDH inhibitor other than the compound of Formula I. In another embodiment, the IDH inhibitor other than the compound of Formula I is ivosidenib or enasidenib. In another embodiment, the IDH inhibitor other than the compound of Formula I is ivosidenib. In another embodiment, the IDH inhibitor other than the compound of Formula I is enasidenib.

In one embodiment, X is N, or a pharmaceutically acceptable salt thereof. In another embodiment, X is N, R¹ is -CH2-cyclopropyl, and R² is -CH2CH3, or a pharmaceutically acceptable salt thereof. In another embodiment, X is N, R¹ is -CH2- cyclopropyl, and R² is -CH2CH3.

In another embodiment, the compound of Formula I is:

7-[[(lS)-l-[4-[(lR)-2-cyclopropyl-l-(4-prop-2-enoylpiperazin-l- yl)ethyl]phenyl]ethyl]amino]-l-ethyl-4H-pyrimido[4,5-d][l,3]oxazin-2-one;

7-[[(l S)- 1 - [4- [( 1 S)-2-cyclopropy 1-1 -(4-prop-2-enoylpiperazin- 1 - yl)ethyl]phenyl]ethyl]amino]-l-ethyl-4H-pyrimido[4,5-d][l,3]oxazin-2-one; or

1 -Ethy 1 -7- [ [( 1 S)- 1 - [4 - [ 1 -(4-prop-2-enoylpiperazin- 1 - yl)propyl]phenyl]ethyl]amino]-4H-pyrimido[4,5-d][l,3]oxazin-2-one; or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I is 7-[[(lS)-l-[4-[(lS)-2- cyclopropyl-l-(4-prop-2-enoylpiperazin-l-yl)ethyl]phenyl]ethyl]amino]-l-ethyl-4H- pyrimido[4,5-d][l,3]oxazin-2-one or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof.

In another embodiment, the compound of Formula I is:

Compound A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of Formula I is Compound A.

In another embodiment, the compound of Formula I is a pharmaceutically acceptable salt of Compound A. In another embodiment, the compound of Formula I is a a digentisic acid salt of Compound A, which can be represented as:

In another embodiment, the deoxyadenosine analog is cytarabine or gemcitabine, or a pharmaceutically acceptable salt thereof. In another embodiment, the deoxyadenosine analog is gemcitabine, or a pharmaceutically acceptable salt thereof. In another embodiment, the deoxyadenosine analog is gemcitabine.

In another embodiment, the platinum agent is cisplatin, carboplatin or oxaliplatin. In another embodiment, the platinum agent is cisplatin.

In another embodiment, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor. In another embodiment, the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (CP-675,206). In another embodiment, the PD- 1 inhibitor is pembrolizumab (Keytruda®), nivolumab (Opdivo®), sintilimab, cemiplimab (Libtayo®), or tislelizumab. In another embodiment, the PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®) or durvalumab (Imfinzi™). In another embodiment, the PD-L1 inhibitor is durvalumab (Imfinzi™). In another embodiment, the compound of Formula I is:

or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof, the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab.

In another embodiment, the compound of Formula I is:

or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof, and the immune checkpoint inhibitor is durvalumab. In another embodiment, the solid tumor cancer is cholangiocarcinoma, the compound of Formula I is

or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof, the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab. In another embodiment, the cholangiocarcinoma is advanced cholangiocarcinoma.

In another embodiment, the solid tumor cancer is cholangiocarcinoma, the compound of Formula I is

or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof, and the immune checkpoint inhibitor is durvalumab. In another embodiment, the cholangiocarcinoma is advanced cholangiocarcinoma.

In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg to about 800 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg to about 300 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 150 mg to about 300 mg once a day.

In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg or 300 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 50 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 75 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 100 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 125 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 150 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 175 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 200 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 250 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 300 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 400 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 600 mg once a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 800 mg once a day.

In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg once a day on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg or 300 mg once a day on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 50 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 75 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 100 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 125 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 150 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 175 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 200 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 250 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 300 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 400 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 600 mg on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 800 mg on each of days 1-21 of a 21 day cycle.

In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg to about 800 mg twice a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg to about 300 mg twice a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 150 mg to about 300 mg twice a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 200 mg to about 300 mg twice a day.

In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg twice a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg or 300 mg twice a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 150 mg twice a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 200 mg twice a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 250 mg twice a day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 300 mg twice a day.

In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg twice a day on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg or 300 mg twice a day on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 150 mg twice a day on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 200 mg twice a day on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 250 mg twice a day on each of days 1-21 of a 21 day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 300 mg twice a day on each of days 1-21 of a 21 day cycle.

In another embodiment, gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of a 21 day cycle. In another embodiment, cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of a 21 day cycle.

In another embodiment, durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of a 21 day cycle.

In another embodiment, gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of a 21 day cycle, cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of the 21 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of a 21 day cycle.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered on each of days 1-21 of a 21 day cycle, gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of the 21 day cycle, cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of the 21 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 21 day cycle.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered on each of days 1-28 of a 28 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 28 day cycle.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg once a day on each of days 1-21 of a 21 day cycle, gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of the 21 day cycle, cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of the 21 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 21 day cycle.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg once a day on each of days 1-28 of a 28 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 28 day cycle.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg or 300 mg once a day on each of days 1-21 of a 21 day cycle, gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of the 21 day cycle, cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of the 21 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 21 day cycle.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg or 300 mg once a day on each of days 1-28 of a 28 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 28 day cycle.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg twice a day on each of days 1-21 of a 21 day cycle, gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of the 21 day cycle, cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of the 21 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 21 day cycle. In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 150 mg twice a day on each of days 1-21 of a 21 day cycle, gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of the 21 day cycle, cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of the 21 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 21 day cycle. In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 200 mg twice a day on each of days 1-21 of a 21 day cycle, gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of the 21 day cycle, cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of the 21 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 21 day cycle. In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 250 mg twice a day on each of days 1-21 of a 21 day cycle, gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of the 21 day cycle, cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of the 21 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 21 day cycle. In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 300 mg twice a day on each of days 1-21 of a 21 day cycle, gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of the 21 day cycle, cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of the 21 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 21 day cycle.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg twice a day on each of days 1-28 of a 28 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 28 day cycle. In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 150 mg twice a day on each of days 1-28 of a 28 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 28 day cycle. In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 200 mg twice a day on each of days 1-28 of a 28 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 28 day cycle. In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 250 mg twice a day on each of days 1-28 of a 28 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 28 day cycle. In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 300 mg twice a day on each of days 1-28 of a 28 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 28 day cycle.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg or 300 mg twice a day on each of days 1-21 of a 21 day cycle, gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of the 21 day cycle, cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of the 21 day cycle, and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of the 21 day cycle.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered in an induction phase comprised of one or more cycles, preferably one or more 21 day cycles, more preferably, 6, 7, or 8, 21 day cycles, followed by administration of the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) and durvalumab in a maintenance phase comprised of one or more cycles, preferably one or more 28 day cycles.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered on each of days 1-21 of each 21 day cycle in an induction phase, followed by administration on each of days 1-28 of each 28 day cycle in a maintenance phase; gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of each 21 day cycle in the induction phase, followed by administration at a dose of about 1500 mg on day 1 of each 28 day cycle in the maintenance phase.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered on each of days 1-21 of each 21 day cycle in an induction phase comprised of 6, 7, or 8 cycles, followed by administration on each of days 1-28 of each 28 day cycle in a maintenance phase; gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of each 21 day cycle in the induction phase, followed by administration at a dose of about 1500 mg on day 1 of each 28 day cycle in the maintenance phase. Preferably, the maintenance phase continues until unacceptable toxicity or disease progression.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg once a day on each of days 1-21 of each 21 day cycle in an induction phase, followed by administration at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg once a day on each of days 1-28 of each 28 day cycle in a maintenance phase; gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of each 21 day cycle in the induction phase, followed by administration at a dose of about 1500 mg on day 1 of each 28 day cycle in the maintenance phase. Preferably, the maintenance phase continues until unacceptable toxicity or disease progression.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg once a day on each of days 1-21 of each 21 day cycle in an induction phase comprised of 6, 7, or 8 cycles, followed by administration at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg once a day on each of days 1- 28 of each 28 day cycle in a maintenance phase; gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of each 21 day cycle in the induction phase, followed by administration at a dose of about 1500 mg on day 1 of each 28 day cycle in the maintenance phase. Preferably, the maintenance phase continues until unacceptable toxicity or disease progression.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg twice a day on each of days 1-21 of each 21 day cycle in an induction phase, followed by administration at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg twice a day on each of days 1-28 of each 28 day cycle in a maintenance phase; gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of each 21 day cycle in the induction phase, followed by administration at a dose of about 1500 mg on day 1 of each 28 day cycle in the maintenance phase. Preferably, the maintenance phase continues until unacceptable toxicity or disease progression.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg or 300 mg twice a day on each of days 1-21 of each 21 day cycle in an induction phase comprised of 6, 7, or 8 cycles, followed by administration at a dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg or 300 mg twice a day on each of days 1-28 of each 28 day cycle in a maintenance phase; gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of each 21 day cycle in the induction phase followed by administration at a dose of about 1500 mg on day 1 of each 28 day cycle in the maintenance phase. Preferably, the maintenance phase continues until unacceptable toxicity or disease progression.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 150 mg twice a day on each of days 1-21 of each 21 day cycle in an induction phase, followed by administration at a dose of about 150 mg twice a day on each of days 1-28 of each 28 day cycle in a maintenance phase; gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of each 21 day cycle in the induction phase, followed by administration at a dose of about 1500 mg on day 1 of each 28 day cycle in the maintenance phase. Preferably, the maintenance phase continues until unacceptable toxicity or disease progression.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 200 mg twice a day on each of days 1-21 of each 21 day cycle in an induction phase, followed by administration at a dose of about 200 mg twice a day on each of days 1-28 of each 28 day cycle in a maintenance phase; gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of each 21 day cycle in the induction phase, followed by administration at a dose of about 1500 mg on day 1 of each 28 day cycle in the maintenance phase. Preferably, the maintenance phase continues until unacceptable toxicity or disease progression.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 250 mg twice a day on each of days 1-21 of each 21 day cycle in an induction phase, followed by administration at a dose of about 250 mg twice a day on each of days 1-28 of each 28 day cycle in a maintenance phase; gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of each 21 day cycle in the induction phase, followed by administration at a dose of about 1500 mg on day 1 of each 28 day cycle in the maintenance phase. Preferably, the maintenance phase continues until unacceptable toxicity or disease progression.

In another embodiment, a compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof) is administered at a dose of about 300 mg twice a day on each of days 1-21 of each 21 day cycle in an induction phase, followed by administration at a dose of about 300 mg twice a day on each of days 1-28 of each 28 day cycle in a maintenance phase; gemcitabine is administered to the subject at a dose of about 1000 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; cisplatin is administered to the subject at a dose of about 25 mg/m² on each of days 1 and 8 of each 21 day cycle in the induction phase; and durvalumab is administered to the subject at a dose of about 1500 mg on day 1 of each 21 day cycle in the induction phase, followed by administration at a dose of about 1500 mg on day 1 of each 28 day cycle in the maintenance phase. Preferably, the maintenance phase continues until unacceptable toxicity or disease progression.

In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: the compound of Formula I, gemcitabine, cisplatin, and durvalumab. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: the compound of Formula I, cisplatin, gemcitabine, and durvalumab. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: the compound of Formula I, cisplatin, gemcitabine, and durvalumab. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: the compound of Formula I, cisplatin, durvalumab, and gemcitabine. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: the compound of Formula I, durvalumab, gemcitabine, and cisplatin. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: the compound of Formula I, durvalumab, cisplatin, and gemcitabine. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: gemcitabine, the compound of Formula I, cisplatin, and durvalumab. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: gemcitabine, the compound of Formula I, durvalumab, and cisplatin. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: gemcitabine, cisplatin, the compound of Formula I, and durvalumab. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: gemcitabine, cisplatin, durvalumab, and the compound of Formula I. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: gemcitabine, durvalumab, the compound of Formula I, and cisplatin. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: gemcitabine, durvalumab, cisplatin, and the compound of Formula I. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: cisplatin, the compound of Formula I, gemcitabine, and durvalumab. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: cisplatin, the compound of Formula I, durvalumab, and gemcitabine. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: cisplatin, gemcitabine, the compound of Formula I, and durvalumab. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: cisplatin, gemcitabine, durvalumab, and the compound of Formula I. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: cisplatin, durvalumab, the compound of Formula I, and gemcitabine. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: cisplatin, durvalumab, gemcitabine, and the compound of Formula I. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: durvalumab, the compound of Formula I, gemcitabine, and cisplatin. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: durvalumab, the compound of Formula I, cisplatin, and gemcitabine. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: durvalumab, gemcitabine, the compound of Formula I, and cisplatin. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: durvalumab, gemcitabine, cisplatin, and the compound of Formula I. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: durvalumab, cisplatin, the compound of Formula I, and gemcitabine. In another embodiment, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, they are administered in the following order: durvalumab, cisplatin, gemcitabine, and the compound of Formula I.

Preferably, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), gemcitabine, cisplatin, and durvalumab are administered on the same day, the compound of Formula I dose (or first dose if greater than once per day) is to be administered thirty minutes prior to cisplatin, gemcitabine, and durvalumab administration. Preferably, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably a digentisic acid salt thereof), and durvalumab are administered on the same day, the compound of Formula I dose (or first dose if greater than once per day) is to be administered thirty minutes prior to durvalumab administration.

In another embodiment, an anti emetic agent is administered to the subject prior to administration of gemcitabine and/or cisplatin.

In another embodiment, the subject is identified as having an IDH mutation. In another embodiment, the subject is identified as having one or more IDH1 mutations or one or more IDH2 mutations. In another embodiment, the subject is identified as one or more IDH1 mutations and one or more IDH2 mutations.

In another embodiment, the subject is identified as having an IDH mutation in solid tumor tissue. In another embodiment, the subject is identified as having an IDH1 mutation in solid tumor tissue cells. In another embodiment, the subject is identified as having an IDH1 mutation in peripheral blood. In another embodiment, the subject is identified as having an IDH2 mutation in solid tumor tissue cells. In another embodiment, the subject is identified as having an IDH2 mutation in peripheral blood.

In another embodiment, the subject is identified as having an IDH1 R132, IDH2 R140, or IDH2 R172 mutation, and has previously treated unresectable/metastatic cholangiocarcinoma. In another embodiment of the method of the invention, the solid tumor cancer is cholangiocarcinoma, head & neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder carcinoma, colorectal cancer, or lung cancer. In another embodiment, the lung cancer is non-small cell lung cancer. In another embodiment, the lung cancer is nonsmall cell lung cancer, and a KRas G12C inhibitor and or an EGFR inhibitor is also administered. In another embodiment, the solid tumor cancer is cholangiocarcinoma. In another embodiment, the cholangiocarcimona is advanced cholangiocarcinoma. In another embodiment, radiation therapy is also administered to the subject.

The present invention also provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a solid tumor cancer in a subject, wherein the medicament is administered in simultaneous, separate or sequential combination with gemcitabine, or a pharmaceutically acceptable salt thereof, cisplatin, and durvalumab.

In one embodiment, the solid tumor cancer is frontline cancer. In another embodiment, solid tumor cancer is relapsed cancer. In another embodiment, the solid tumor cancer is refractory solid tumor cancer. In another embodiment, the solid tumor cancer is advanced solid tumor cancer. In another embodiment, the advanced solid tumor cancer is advanced cholangiocarcinoma.

In another embodiment, the subject has advanced solid tumor cancer, and has not received prior therapy for advanced solid tumor cancer. In another embodiment, the subject has advanced cholangiocarcinoma, and has not received prior therapy for advanced cholangiocarcinoma.

In another embodiment, the subject has one or more secondary IDH1 mutations. In another embodiment, the subject is identified as having one or more secondary IDH1 mutations. In another embodiment, the subject has one or more secondary IDH2 mutations. In another embodiment, the subject is identified as having one or more secondary IDH2 mutations.

As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings: The term “solid tumor tissue” refers to tissue that is not hematologic tissue (hematologic tissue is blood, bone marrow, or lymphatic tissue). Non-limiting examples of solid tissue are cholangial tissue, pancreatic tissue, head tissue, neck tissue, hepatic tissue, skin tissue, astrocytomal tissue, oligodendroglial tissue, glial tissue, brain tissue, bladder tissue, colorectal tissue, and lung tissue.

The term “frontline solid tumor cancer” means that the solid tumor cancer subject has never been treated for the solid tumor cancer being treated.

The term “refractory solid tumor cancer” refers to cancer that has been treated, but the solid tumor cancer subject did not respond to treatment.

The term “relapsed solid tumor cancer” means that the solid tumor cancer subject responded to treatment for a period of time, but that the solid tumor cancer has reoccurred.

The term “advanced solid tumor cancer” refers to solid tumor cancer that has spread to lymph nodes or to other tissues outside of the solid tumor cancer’s point of origin.

The term “cancer subject” means a subject who has been diagnosed with cancer.

The term “solid tumor subject” means a subject who has been diagnosed with a solid tumor cancer. In one embodiment, the solid tumor cancer is cholangiocarcinoma.

The term “IDH1 R132 mutation” refers to an IDH1 mutation at amino acid residue 132 in a subject’s IDH1 enzyme, as determined, e.g., in the subject’s nucleic acid (e.g., DNA).

The term “IDH2 R140 mutation” refers to an IDH2 mutation at amino acid residue 140 in a subject’s IDH2 enzyme, as determined, e.g., in the subject’s nucleic acid (e.g., DNA).

The term “IDH2 R172 mutation” refers to an IDH2 mutation at amino acid residue 172 in a subject’s IDH2 enzyme, as determined, e.g., in the subject’s nucleic acid (e.g., DNA).

The term “mutant IDH1 inhibitor” refers to a compound that inhibits the enzyme activity of and/or the production of 2-HG by a mutant IDH1 enzyme. Methods for assaying mutant IDH1 and IDH2 enzyme activity are known to those of ordinary skill in the art, e.g, in WO 2018/111707 Al. The term “secondary IDH1 mutation” refers to an IDH1 mutation that occurs in the IDH1 enzyme in a subject after treatment with a mutant IDH1 inhibitor other than a compound of Formula I herein. In one embodiment, the one or more secondary IDH1 mutations is one or more ofR119P, G131A, D279N, S280F, G289D or H315D in IDH1. However, other secondary IDH1 mutations may be reported in the future. As used herein, a “secondary IDH1 mutation” is not an “IDH1 R132 mutation,” an “IDH2 R140 mutation,” or an “IDH2 R172 mutation.”

The term “identified as having an IDH1 R132 mutation” means that nucleic acid (e.g., DNA) from the subject’s tissue or cells (e.g., circulating tumor cells) has been analyzed to determine if a subject has an IDH1 R132 mutation. In one embodiment, the subject’s blood cells, bone marrow cells, or blood cells and bone marrow has been analyzed for an IDH1 R132 mutation. In another embodiment, the subject’s solid tissue has been analyzed for an IDH1 R132 mutation.

The term “identified as having an IDH2 R140 mutation” means that nucleic acid (e.g., DNA) from the subject’s tissue or cells has been analyzed to determine if a subject has an IDH2 R140 mutation. In one embodiment, the subject’s blood cells, bone marrow cells, or blood cells and bone marrow has been analyzed for an IDH2 R140 mutation. In another embodiment, the subject’s solid tissue has been analyzed for an IDH2 R140 mutation.

The term “identified as having an IDH2 R172 mutation” means that nucleic acid (e.g., DNA) from the subject’s tissue or cells has been analyzed to determine if a subject has an IDH2 R172 mutation. In one embodiment, the subject’s blood cells, bone marrow cells, or blood cells and bone marrow has been analyzed for an IDH2 R172 mutation. In another embodiment, the subject’s solid tissue has been analyzed for an IDH2 R172 mutation.

In one embodiment, the party who identifies the subject as having an IDH mutation (e.g., one or more of an IDH1 R132 mutation, IDH2 R140 mutation or IDH2 R172 mutation) is different than the party that administers a compound of formula I, or a pharmaceutically acceptable salt thereof, a deoxyadenosine analog, or a pharmaceutically acceptable salt thereof, a platinum agent, and an immune checkpoint inhibitor. In another embodiment, the party who identifies the subject as having an IDH mutation (e.g., one or more of an IDH1 R132 mutation, IDH2 R140 mutation or IDH2 R172 mutation) is the same as the party that administers a compound of formula I, or a pharmaceutically acceptable salt thereof, a deoxyadenosine analog, or a pharmaceutically acceptable salt thereof, a platinum agent, and an immune checkpoint inhibitor.

In one embodiment, the party who identifies the subject as having an IDH mutation (e.g., one or more of an IDH1 R132 mutation, IDH2 R140 mutation or IDH2 R172 mutation) is different than the party that administers a compound of formula I, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor. In another embodiment, the party who identifies the subject as having an IDH mutation (e.g., one or more of an IDH1 R132 mutation, IDH2 R140 mutation or IDH2 R172 mutation) is the same as the party that administers a compound of formula I, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor.

Analytical methods for identifying IDH mutations are known to those of ordinary skill in the art (Clark, O., et al., Clin. Cancer. Res. 2016,' 22: 1837-42), including, but not limited to, karyotyping (Guller JL, et al., J. Mol. Diagn. 2010,' 12: 3-16), fluorescence in situ hybridization (Yeung DT, et al., Pathology 2011,' 43: 566-579), Sanger sequencing (Lutha, R et al, Haematologica 2014,' 99: 465-473), metabolic profiling (Miyata S, et al., Scientific Reports 2019,' 9: 9787), polymerase chain reaction (Ziai, JM and AJ Siddon, Am. J. Clin. Pathol 2015,' 144: 539-554), and next-generation sequencing (e.g., whole transcriptome sequencing) (Lutha, R et al., Haematologica 2014,' 99: 465-473; Wang H- Y, et al. , J. Exp. Clin. Cancer Res. 2016,' 35: 86.

The term “about” means + 5% of the numerical value recited.

The terms "treatment," "treat," "treating," and the like, are meant to include slowing, stopping, or reversing the progression of cancer. These terms also include alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the cancer is not actually eliminated and even if progression of the cancer is not itself slowed, stopped or reversed.

"Therapeutically effective amount" means the amount of a compound, or pharmaceutically acceptable salt thereof, administered to the subject that will elicit the biological or medical response of or desired therapeutic effect on a subject. A therapeutically effective amount can be readily determined by the attending clinician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for a subject, a number of factors are considered by the attending clinician, including, but not limited to: size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

A "pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans.

The compounds administered according to the invention can optionally be formulated as pharmaceutical compositions administered by any route which makes the compound bioavailable. In an embodiment, such compositions are formulated for oral administration. Such pharmaceutical compositions and processes for preparing same are well known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy (D.B. Troy, Editor, 21st Edition, Lippincott, Williams & Wilkins, 2006).

"Pharmaceutically acceptable salts" or “a pharmaceutically acceptable salt” refers to the relatively non-toxic, inorganic and organic salt or salts of the compound of the present invention (S.M. Berge, et a!.. “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, Vol 66, No. 1, January 1977).

It will be understood by one of ordinary skill in the art that compounds administered according to the invention are capable of forming salts. The compounds react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Such pharmaceutically acceptable acid addition salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2008).

It is to be understood compounds of Formula I may be administered as the non-salt free base form, or a pharmaceutically acceptable salt thereof; however unless indicated otherwise, administered amounts of compounds of Formula I, or a pharmaceutically acceptable salt thereof, are expressed herein based on weight of the non-salt free base form of the compounds of Formula I.

The term “gentisic acid” refers to 2,5-dihydroxybenzoic acid, which can be represented by the structure:

Various aspects of the invention are set forth in the following numbered clauses.

Clause 1. A method of treating a solid tumor cancer, comprising administering to a subject having an IDH mutation a therapeutically effective amount of

(a) a compound of Formula I:

wherein:

R¹ is -CH₂CH(CH₃)2, -CH2CH3, -CH2CH2OCH3, or -CH2-cyclopropyl;

R² is -CH₃ or -CH2CH3; and

X is N or CH, or a pharmaceutically acceptable salt thereof;

(b) a deoxyadenosine analog, or a pharmaceutically acceptable salt thereof;

(c) a platinum agent; and

(d) an immune checkpoint inhibitor.

Clause 2. The method of clause 1, wherein the IDH mutation is an IDH1 mutation or an IDH2 mutation.

Clause 3. The method of clause 2, wherein the IDH mutation is an IDH1 mutation. Clause 4. The method of clause 3, wherein the IDH1 mutation is an IDH1 R132 mutation.

Clause 5. The method of clause 2, wherein the IDH mutation is an IDH2 mutation.

Clause 6. The method of clause 5, wherein the IDH2 mutation is an IDH2 R140 or IDH2 R172 mutation.

Clause 7. The method of any one of clauses 1 to 6, wherein X is N, or a pharmaceutically acceptable salt thereof.

Clause 8. The method of any one of clauses 1 to 7, wherein X is N, R¹ is -CFb- cyclopropyl, and R² is -CH2CH3, or a pharmaceutically acceptable salt thereof.

Clause 9. The method of any one of clauses 1 to 6, wherein the compound of Formula I is:

7- [[( 1 S)- 1 - [4- [( 1 S)-2-cyclopropy 1-1 -(4-prop-2-enoylpiperazin- 1 - yl)ethyl]phenyl]ethyl]amino]-l-ethyl-4H-pyrimido[4,5-d][l,3]oxazin-2-one; or

1 -Ethy 1 -7- [ [( 1 S)- 1 - [4 - [ 1 -(4-prop-2-enoylpiperazin- 1 -yl)propyl] phenyl]ethyl]amino]-4H-pyrimido[4,5-d][l,3]oxazin-2-one; or a pharmaceutically acceptable salt thereof.

Clause 10. The method of any one of clauses 1 to 6, wherein the compound of

Formula I is

or a pharmaceutically acceptable salt thereof (preferably a digentisic acid salt thereof).

Clause 11. The method of clause 10, wherein the compound of Formula I is

Clause 12. The method of any one of clauses 1 to 6, wherein the compound of Formula I or pharmaceutically acceptable salt thereof is a digentisic acid salt of

Clause 13. The method of any one of clauses 1 to 12, wherein the deoxyadenosine analog is cytarabine or gemcitabine, or a pharmaceutically acceptable salt thereof.

Clause 14. The method of clause 13, wherein the deoxyadenosine analog is gemcitabine, or a pharmaceutically acceptable salt thereof.

Clause 15. The method of clause 14, wherein the deoxyadenosine analog is gemcitabine.

Clause 16. The method of any one of clauses 1 to 15, wherein the platinum agent is cisplatin, carboplatin or oxaliplatin.

Clause 17. The method of clause 16, wherein the platinum agent is cisplatin.

Clause 18. The method of any one of clauses 1 to 17, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.

Clause 19. The method of clause 18, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

Clause 20. The method of clause 19, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.

Clause 21. The method of clause 18, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

Clause 22. The method of clause 21, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplimab, or tislelizumab. Clause 23. The method of clause 18, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

Clause 24. The method of clause 23, wherein the PD-L1 inhibitor is atezolizumab, avelumab or durvalumab.

Clause 25. The method of clause 23, wherein the PD-L1 inhibitor is durvalumab.

Clause 26. The method of any one of clauses 1 to 12, wherein the deoxyadenosine analog is gemcitabine, and the platinum agent is cisplatin.

Clause 27. The method of any one of clauses 1 to 12, wherein the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab.

Clause 28. The method of any one of clauses 1 to 6, wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof (preferably a digentisic acid salt thereof), the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab.

Clause 29. The method of any one of clauses 1 to 28, wherein the solid tumor cancer is cholangiocarcinoma, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder carcinoma, colorectal cancer, or lung cancer.

Clause 30. The method of clause 29, wherein the solid tumor cancer is cholangiocarcinoma.

Clause 31. The method of clause 30, wherein the cholangiocarcinoma is advanced cholangiocarcinoma.

Clause 32. A compound of Formula I:

wherein:

R¹ is -CH₂CH(CH₃)2, -CH2CH3, -CH2CH2OCH3, or -CH₂-cyclopropyl;

R² is -CH₃ or -CH2CH3; and

X is N or CH, or a pharmaceutically acceptable salt thereof; for use in simultaneous, separate or sequential combination with a deoxyadenosine analog, or a pharmaceutically acceptable salt thereof, a platinum agent, and an immune checkpoint inhibitor, in the treatment of a solid tumor cancer in a subject having an IDH mutation.

Clause 33. The compound for use of clause 32, wherein the IDH mutation is an IDH1 mutation or an IDH2 mutation.

Clause 34. The compound for use of clause 33, wherein the IDH mutation is an IDH1 mutation.

Clause 35. The compound for use of clause 34, wherein the IDH1 mutation is an IDH1 R132 mutation.

Clause 36. The compound for use of clause 33, wherein the IDH mutation is an IDH2 mutation.

Clause 37. The compound for use of clause 36, wherein the IDH2 mutation is an IDH2 R140 or IDH2 R172 mutation.

Clause 38. The compound for use of any one of clauses 32 to 37, wherein X is N, or a pharmaceutically acceptable salt thereof.

Clause 39. The compound for use of any one of clauses 32 to 38, wherein R¹ is - CH2-cyclopropyl, or a pharmaceutically acceptable salt thereof.

Clause 40. The compound for use of any one of clauses 32 to 39, wherein R² is - CH2CH3, or a pharmaceutically acceptable salt thereof.

Clause 41. The compound for use of any one of clauses 32 to 37, wherein the compound is: 7-[[(lS)-l-[4-[(lR)-2-cyclopropyl-l-(4-prop-2-enoylpiperazin-l- yl)ethyl]phenyl]ethyl]amino]-l-ethyl-4H-pyrimido[4,5-d][l,3]oxazin-2-one;

Clause 42. The compound for use of any one of clauses 32 to 37, wherein the compound is

Clause 43. The compound for use of any one of clauses 32 to 37, wherein the compound is

Clause 44. The compound for use of any one of clauses 32 to 37, wherein the compound of Formula I or pharmaceutically acceptable salt thereof is a digentisic acid salt of

Clause 45. The compound for use of any one of clauses 32 to 44, wherein the deoxyadenosine analog is cytarabine or gemcitabine, or a pharmaceutically acceptable salt thereof.

Clause 46. The compound for use of clause 45, wherein the deoxyadenosine analog is gemcitabine, or a pharmaceutically acceptable salt thereof.

Clause 47. The compound for use of clause 46, wherein the deoxyadenosine analog is gemcitabine.

Clause 48. The compound for use of any one of clauses 32 to 47, wherein the platinum agent is cisplatin, carboplatin or oxaliplatin.

Clause 49. The compound for use of clause 48, wherein the platinum agent is cisplatin.

Clause 50. The compound for use of any one of clauses 32 to 49, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.

Clause 51. The compound for use of clause 50, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

Clause 52. The compound for use of clause 51, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.

Clause 53. The compound for use of clause 50, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

Clause 54. The compound for use of clause 53, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplimab, or tislelizumab.

Clause 55. The compound for use of clause 50, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

Clause 56. The compound for use of clause 55, wherein the PD-L1 inhibitor is atezolizumab, avelumab or durvalumab. Clause 57. The compound for use of clause 55, wherein the PD-L1 inhibitor is durvalumab.

Clause 58. The compound for use of any one of clauses 32 to 37, wherein the compound of Formula I is

Clause 59. The compound for use of any one of clauses 32 to 58, wherein the solid tumor cancer is cholangiocarcinoma, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder carcinoma, colorectal cancer, or lung cancer.

Clause 60. The compound for use of clause 59, wherein the solid tumor cancer is cholangiocarcinoma.

Clause 61. The compound for use of clause 60, wherein the solid tumor cancer is advanced cholangiocarcinoma.

Clause 62. The compound for use of any one of clauses 32 to 37, wherein the solid tumor cancer is cholangiocarcinoma, the compound of Formula I is

or a pharmaceutically acceptable salt thereof (preferably a digentisic acid salt thereof), the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab. Clause 63. The compound for use of clause 62, wherein the solid tumor cancer is advanced cholangiocarcinoma.

Clause 64. A method of treating a solid tumor cancer, comprising administering to a subject having an IDH mutation a therapeutically effective amount of a compound of Formula I:

wherein:

R¹ is -CH₂CH(CH₃)2, -CH2CH3, -CH2CH2OCH3, or -CH₂-cyclopropyl;

R² is -CH₃ or -CH2CH3; and

X is N or CH, or a pharmaceutically acceptable salt thereof; and an immune checkpoint inhibitor.

Clause 65. The method of clause 64, wherein the IDH mutation is an IDH1 mutation or an IDH2 mutation.

Clause 66. The method of clause 65, wherein the IDH mutation is an IDH1 mutation.

Clause 67. The method of clause 66, wherein the IDH1 mutation is an IDH1 R132 mutation.

Clause 68. The method of clause 65, wherein the IDH mutation is an IDH2 mutation.

Clause 69. The method of clause 68, wherein the IDH2 mutation is an IDH2 R140 or IDH2 R172 mutation.

Clause 70. The method of any one of clauses 64 to 69, wherein X is N, or a pharmaceutically acceptable salt thereof.

Clause 71. The method of any one of clauses 64 to 70, wherein X is N, R¹ is - CH2-cyclopropyl, and R² is -CH2CH3, or a pharmaceutically acceptable salt thereof. Clause 72. The method of any one of clauses 64 to 69, wherein the compound of Formula I is:

7-[[(lS)-l-[4-[(lR)-2-cyclopropyl-l-(4-prop-2-enoylpiperazin-l- yl)ethyl]phenyl]ethyl]amino]-l-ethyl-4H-pyrimido[4,5-d][l,3]oxazin-2-one; 7-[[(l S)- 1 - [4- [( 1 S)-2-cyclopropy 1-1 -(4-prop-2-enoylpiperazin- 1 - yl)ethyl]phenyl]ethyl]amino]-l-ethyl-4H-pyrimido[4,5-d][l,3]oxazin-2-one; or

1 -Ethy 1 -7- [ [( 1 S)- 1 - [4 - [ 1 -(4-prop-2-enoylpiperazin- 1 -yl)propyl] phenyl]ethyl]amino]-4H-pyrimido[4,5-d][l,3]oxazin-2-one; or a pharmaceutically acceptable salt thereof. Clause 73. The method of any one of clauses 64 to 69, wherein the compound of

Formula I is

or a pharmaceutically acceptable salt thereof (preferably a digentisic acid salt thereof). Clause 74. The method of clause 73, wherein the compound of Formula I is

Clause 75. The method of any one of clauses 64 to 69, wherein the compound of Formula I or pharmaceutically acceptable salt thereof is a digentisic acid salt of

Clause 76. The method of any one of clauses 64 to 75, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.

Clause 77. The method of clause 76, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

Clause 78. The method of clause 77, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.

Clause 79. The method of clause 76, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

Clause 80. The method of clause 79, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplimab, or tislelizumab.

Clause 81. The method of clause 76, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

Clause 82. The method of clause 81, wherein the PD-L1 inhibitor is atezolizumab, avelumab or durvalumab.

Clause 83. The method of clause 81, wherein the PD-L1 inhibitor is durvalumab.

Clause 84. The method of any one of clauses 64 to 69, wherein the compound of

Formula I is:

or a pharmaceutically acceptable salt thereof (preferably a digentisic acid salt thereof), and the immune checkpoint inhibitor is durvalumab.

Clause 85. The method of any one of clauses 64 to 84, wherein the solid tumor cancer is cholangiocarcinoma, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder carcinoma, colorectal cancer, or lung cancer.

Clause 86. The method of clause 85, wherein the solid tumor cancer is cholangiocarcinoma. Clause 87. The method of clause 86, wherein the cholangiocarcinoma is advanced cholangiocarcinoma.

Clause 88. A compound of Formula I:

wherein:

R¹ is -CH₂CH(CH₃)2, -CH2CH3, -CH2CH2OCH3, or -CH₂-cyclopropyl;

R² is -CH₃ or -CH2CH3; and

X is N or CH, or a pharmaceutically acceptable salt thereof; for use in simultaneous, separate or sequential combination with an immune checkpoint inhibitor, in the treatment of a solid tumor cancer in a subject having an IDH mutation.

Clause 89. The compound for use of clause 88, wherein the IDH mutation is an IDH1 mutation or an IDH2 mutation.

Clause 90. The compound for use of clause 89, wherein the IDH mutation is an IDH1 mutation.

Clause 91. The compound for use of clause 90, wherein the IDH1 mutation is an IDH1 R132 mutation.

Clause 92. The compound for use of clause 89, wherein the IDH mutation is an IDH2 mutation.

Clause 93. The compound for use of clause 92 wherein the IDH2 mutation is an IDH2 R140 or IDH2 R172 mutation.

Clause 94. The compound for use of any one of clauses 88 to 93, wherein X is N, or a pharmaceutically acceptable salt thereof.

Clause 95. The compound for use of any one of clauses 88 to 94, wherein R¹ is - CH2-cyclopropyl, or a pharmaceutically acceptable salt thereof.

Clause 96. The compound for use of any one of clauses 88 to 95, wherein R² is - CH2CH3, or a pharmaceutically acceptable salt thereof. Clause 97. The compound for use of any one of clauses 88 to 93, wherein the compound is:

Clause 98. The compound for use of any one of clauses 88 to 93, wherein the compound is

Clause 99. The compound for use of any one of clauses 88 to 93, wherein the compound is

Clause 100. The compound for use of any one of clauses 88 to 93, wherein the compound of Formula I or pharmaceutically acceptable salt thereof is a digentisic acid salt of

Clause 101. The compound for use of any one of clauses 88 to 100, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.

Clause 102. The compound for use of clause 101, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

Clause 103. The compound for use of clause 102, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.

Clause 104. The compound for use of clause 101, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

Clause 105. The compound for use of clause 104, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplimab, or tislelizumab.

Clause 106. The compound for use of clause 101, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

Clause 107. The compound for use of clause 106, wherein the PD-L1 inhibitor is atezolizumab, avelumab or durvalumab.

Clause 108. The compound for use of clause 106, wherein the PD-L1 inhibitor is durvalumab.

Clause 109. The compound for use of any one of clauses 88 to 93, wherein the compound of Formula I is

or a pharmaceutically acceptable salt thereof (preferably a digentisic acid salt thereof), and the immune checkpoint inhibitor is durvalumab. Clause 110. The compound for use of any one of clauses 88 to 109, wherein the solid tumor cancer is cholangiocarcinoma, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder carcinoma, colorectal cancer, or lung cancer.

Clause 111. The compound for use of clause 110, wherein the solid tumor cancer is cholangiocarcinoma.

Clause 112. The compound for use of clause 111, wherein the solid tumor cancer is advanced cholangiocarcinoma.

Clause 113. The compound for use of any one of clauses 88 to 93, wherein the solid tumor cancer is cholangiocarcinoma, the compound of Formula I is

Clause 114. The compound for use of clause 113, wherein the solid tumor cancer is advanced cholangiocarcinoma.

Example 1

In vivo tumor growth inhibition in IDH1 mutant cholangiocarcinoma PDX tumor model

Compounds and Formulation. For in vivo studies, each test article is prepared at an appropriate concentration with vehicle. Compound A is formulated in Acacia vehicle (water, 10% Acacia, 0.05% Antifoam [Dow Coming 1510-US]) with 1.1 molar equivalents HC1. Compound A is prepared fresh at the appropriate concentration with vehicle every 7 days and stored at 4°C between doses. Stock Cisplatin injection solution (Teva Pharmaceuticals, NDC#00703-5747-l 1) is stored at room temperature. On the day of administration, the appropriate concentration is prepared by dilution in 0.9% sterile saline. Gemcitabine is prepared fresh weekly in 0.9% sterile saline. In Vivo Tumor Growth Inhibition Study in IDH1 Mutant (R132C) Intrahepatic Cholangiocarcinoma PDX Tumor Model. Tumor fragments are harvested from host animals and subcutaneously implanted into 6-12 week old immune-deficient female mice. Mice are fed ad libitum on normal chow. The study is initiated at a mean tumor volume of approximately 125 - 250 mm³. Each test article is prepared as described above at the appropriate concentration with vehicle to give animals the doses tested in this study at a dosing volume of 10 pL/gram body weight. Mice are administered Compound A (30 mg/kg, PO, QD) on day 0 by oral gavage and are treated for the duration of the study (day 31). On day 5 of Compound A dosing and Q7D x 3 thereafter, prepare gemcitabine and cisplatin in appropriate vehicle. Dose gemcitabine (40 mg/kg) and cisplatin (1.5 mg/kg) by intraperitoneal administration. Tumor growth and body weight are monitored over time to evaluate efficacy and signs of toxicity. Bidimensional measurements of tumors are performed twice a week and tumor volumes are calculated based on the following formula: (Tumor Volume) = [(L) x (W²) x 0.52] where L is mid-axis length and W is mid-axis width. Mean tumor volumes on day 31 are shown in Table 1.

Compound A, cisplatin plus gemcitabine, and the triple combination of Compound A with cisplatin and gemcitabine are found to have delta T/C % values as provided in Table 1 below. These results indicate that the combination of Compound A with cisplatin and gemcitabine results in a statistically significant additive benefit to tumor growth inhibition in a mutant IDH1 (R132C) cholangiocarcinoma patient-derived xenograft model. The addition of Compound A to the cisplatin-gemcitabine regimen demonstrates no evidence of antagonism or overt toxicity, as compared to the cisplatingemcitabine treatment alone.

Table 1. In vivo tumor growth inhibition in IDH1 mutant cholangiocarcinoma PDX tumor model implanted in mice

Analysis for Tumor Volume is based on Random Measures ANOVA, Log 10 Volume and Spatial Power covariance structure vs. vehicle. Mean tumor volumes (± SEM) are calculated from the anti-log of the least squares means predicted by the Random Measures ANOVA model on log tumor volume.

Delta T/C % is calculated when the endpoint tumor volume in a treated group is at or above baseline tumor volume. The formula is 100 * (T - T₀)/(C - C_o), where T and C are endpoint tumor volumes (day 31) in the treated or control group, respectively. T_o and C_o are baseline (randomization) tumor volumes in those groups (day -1).

* : Significant (p < 0.05)

NA : Not Applicable

Example 2

Compounds and Formulation. For in vivo studies, each test article is prepared at an appropriate concentration with vehicle. Compound A is formulated in Acacia vehicle (water, 10% Acacia, 0.05% Antifoam [Dow Coming 1510-US]) with 1.1 molar equivalents HC1. Compound A is prepared fresh at the appropriate concentrations with vehicle every 7 days and stored at 4°C between doses. Cisplatin is prepared at 1 mg/ml in 0.9% injectable saline and stored at 4°C. Gemcitabine is prepared at 20 mg/ml in 0.9% injectable saline and stored at -80°C. On the day of administration for both cisplatin and gemcitabine, the appropriate concentration is prepared fresh by dilution in 0.9% injectable saline.

In Vivo Tumor Growth Inhibition Study in IDH1 Mutant (R132C) Intrahepatic Cholangiocarcinoma PDX Tumor Model. Tumor fragments are harvested from host animals and subcutaneously implanted into 6-8 week old female Balb/c nude mice. Mice are fed ad libitum on normal chow. The study is initiated at a mean tumor volume of approximately 146 mm³. Each test article is prepared as described above at the appropriate concentration with vehicle to give animals the doses tested in this study at a dosing volume of 10 pL/gram body weight. Mice are administered Compound A (PO, QD) on day 1 by oral gavage and are treated at the indicated doses (10 mg/kg or 30 mg/kg) for the duration of the study (90 days). On day 5 of Compound A dosing and Q7D x 12 thereafter, prepare gemcitabine and cisplatin in appropriate vehicle. Dose gemcitabine (30 mg/kg) and cisplatin (1.5 mg/kg) by intraperitoneal administration.

Tumor growth and body weight are monitored over time to evaluate efficacy and signs of toxicity. Bidimensional measurements of tumors are performed twice a week and tumor volumes are calculated based on the following formula: (Tumor Volume) = [(L) x (W²) x 0.5] where L is mid-axis length and W is mid-axis width. Mean tumor volumes on day 90 are shown in Table 2.

Compound A, cisplatin plus gemcitabine, and the triple combination of Compound A with cisplatin and gemcitabine are found to have delta T/C % values as provided in Table 2 below. These results indicate that Compound A single agent treatment and in combination with cisplatin and gemcitabine result in statistically significant tumor growth inhibition in a mutant IDH1 (R132C) cholangiocarcinoma patient-derived xenograft model. The addition of Compound A to the cisplatin- gemcitabine regimen demonstrates no evidence of antagonism or overt toxicity, as compared to the cisplatin-gemcitabine treatment alone.

Table 2. In vivo tumor growth inhibition in IDH1 mutant cholangiocarcinoma PDX tumor model implanted in mice

Delta T/C % is calculated when the endpoint tumor volume in a treated group is at or above baseline tumor volume. The formula is 100 * (T - T₀)/(C - C_o), where T and C are endpoint tumor volumes (day 90) in the treated or control group, respectively. T_o and C_o are baseline (randomization) tumor volumes in those groups (day 0).

* : Significant (p < 0.05)

NA : Not Applicable

Example 3

A Phase 1 Study of Compound A Administered to Patients with Advanced Solid Tumors with IDH1 or IDH2 Mutations

The primary objective of a Phase 1 dose escalation is to determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of Compound A (or a digentisic acid salt thereof) monotherapy when administered to patients with isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2) mutant advanced solid tumors.

The primary objective of a Phase 1 dose expansion is to assess the preliminary anti-tumor activity of Compound A (or a digentisic acid salt thereof), when administered alone, in combination with cisplatin plus gemcitabine, or in combination with cisplatin, gemcitabine, and durvalumab by determining objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO), as appropriate based on tumor type.

The secondary objectives are (a) to assess the safety and tolerability of Compound A (or a digentisic acid salt thereof) when administered alone, in combination with cisplatin plus gemcitabine, or in combination with cisplatin, gemcitabine, and durvalumab; (b) to assess the preliminary anti-tumor activity of Compound A (or a digentisic acid salt thereof) monotherapy, in combination with cisplatin plus gemcitabine, or in combination with cisplatin, gemcitabine, and durvalumab based on (i) duration of response (DOR), (ii) time to response (TTR), (iii) progression-free survival (PFS), (iv) disease control rate (DCR), (v) overall survival (OS), (v) changes in serum tumor marker CA 19-9 in patients with cholangiocarcinoma; (c) to characterize the pharmacokinetics (PK) properties of Compound A (or a digentisic acid salt thereof) when administered alone, in combination with cisplatin plus gemcitabine, or in combination with cisplatin, gemcitabine, and durvalumab; and (vi) to characterize the pharmacodynamic properties of Compound A (or a digentisic acid salt thereof) as expressed by change in 2- hydroxyglutarate (2-HG) oncometabolite levels in plasma.

Table 3 lists the Compound A monotherapy doses and cycle lengths that are used to determine MTD and R2PD.

Table 3. Compound A monotherapy (28 day cycle length)

Abbreviation: BID = twice daily; DL = dose level; PK = pharmacokinetics; QD = daily; SRC = safety review committee. ^a lower or intermediate dose levels or dose levels above the currently planned maximum dose of 200 mg BID as well as alternative dosing schedules may be considered by safety review committee upon review of safety, PK and pharmacodynamics; data from previous cohort.

The first dose level was completed using a dose of 25 mg QD of Compound A.

Following review of available PK/PD and safety data, the dosing plan was modified to 50 mg QD as the dose and regimen for DL 2, 100 mg QD for DL 3, 200 mg QD for DL 4, and 400 mg QD for DL 5. An additional dose level was selected for investigation: 600 mg QD for DL 6.

After the MTD or R2PD of Compound A (or a digentisic acid salt thereof) have been determined, a cohort of subjects are evaluated with Compound A (or a digentisic acid salt thereof) in combination with cisplatin, gemcitabine, and durvalumab in patients with IDH1 R132, IDH2 R140, or IDH2 R172 mutant advanced cholangiocarcinoma and measurable disease who have not received prior therapy for advanced disease (Table 4). For safety lead-in, up to 6 patients are enrolled and treated at the RP2D or selected dose(s) and schedule(s) of Compound A (or a digentisic acid salt thereof) in combination with cisplatin, gemcitabine, and durvalumab. Safety lead-in patients complete a 21-day DLT evaluation period before additional patients are enrolled into the cohort. If no more than 1 DLT is observed in the first 6 patients, continued enrollment can be allowed to the cohort. If 2 or more DLTs are observed in the first 6 patients, the Compound A (or a digentisic acid salt thereof) dose can be reduced by 1 level or more, and enrollment continues to the cohort. Selected dose(s) and schedule(s) may be tested prior to identifying the monotherapy MTD or RP2D. In this case, the starting dose of Compound A (or a digentisic acid salt thereof) in combination with cisplatin, gemcitabine, and durvalumab will not exceed the highest dose determined by the SRC to be safe when administered as monotherapy. Subsequently, if alternate doses or administration schedules of Compound A (or a digentisic acid salt thereof) are evaluated, an additional 3-6 patients can be similarly enrolled to a safety lead-in as described above. Once safety of the combination has been confirmed, enrollment continues to a total of approximately 10 patients (including any safety lead-in patients treated at the final expansion dose). If multiple doses are evaluated in the cohort, additional patients can be enrolled such that approximately 20 total patients are treated at the Compound A (or a digentisic acid salt thereof) RP2D in combination with cisplatin, gemcitabine, and durvalumab.

Patients enrolled to the dose expansion cohort receive Compound A (or a digentisic acid salt thereof) in combination with cisplatin, gemcitabine, and durvalumab and have an Induction Phase of treatment with a cycle length of 21 days and a Maintenance Phase of treatment with a cycle length of 28 days. Treatment with Compound A (or a digentisic acid salt thereof) in combination with cisplatin, gemcitabine, and durvalumab during the Induction Phase is for a total of 6 to 8 cycles of cisplatin and gemcitabine, with discretionary treatment beyond 8 cycles if in the patient’s best interest. Treatment with durvalumab and Compound A (or a digentisic acid salt thereof) are to continue during the Maintenance Phase until progressive disease (PD), unacceptable toxicity, or other reason for treatment discontinuation. Table 4. Compound A (or a digentisic acid salt thereof) combination with cisplatin, gemcitabine, and durvalumab (Cycle length is 21 days for Induction Phase and 28 days for Maintenance Phase)

Abbreviations: C = cycle; D = day; DL = dose level; n = cycle number; RP2Dm = recommended Phase 2 dose monotherapy; SRC = Safety Review Committee. a Planned for a total of 6 to 8 cycles, with discretionary treatment beyond 8 cycles if in the patient’s best interest. b Treatment with durvalumab is planned for once every 21 days during the induction phase and once every 28 days during the maintenance phase. Treatment with durvalumab may continue until unacceptable toxicity or disease progression.

* Cohort (Compound A or digentisic acid salt in combination with cisplatin, gemcitabine, and durvalumab) may begin prior to identifying the monotherapy MTD or RP2D.

Example 4

The purpose of this study is to assess the safety and tolerability of treatment with Compound A (or a digentisic acid salt thereof) in combination with durvalumab in patients with previously treated unresectable/metastatic cholangiocarcinoma harboring IDH1 R132, IDH2 R140, or IDH2 R172 mutations. In addition, this study will evaluate the impact of durvalumab on the pharmacokinetics (PK) and pharmacodynamics of Compound A (or a digentisic acid salt thereof). 3 to 6 patients will be enrolled and treated at the RP2D or selected dose(s) and schedule(s) of Compound A (or a digentisic acid salt thereof) in combination with durvalumab. Safety lead-in patients will complete a 28-day DLT evaluation period before additional patients can be enrolled into the cohort. If 1 DLT is observed in the first 3 patients, an additional 3 patients will be enrolled. If no more than 1 DLT is observed in the first 3 to 6 patients, continued enrollment may be allowed to the cohort. If 2 or more DLTs are observed in the first 3 to 6 patients, the Compound A (or a digentisic acid salt thereof) dose may be reduced by 1 level or more, and enrollment will continue to the cohort. Selected dose(s) and schedule(s) may be tested prior to identifying the monotherapy MTD/RP2D. In this case, the starting dose of Compound A (or a digentisic acid salt thereof) in combination with durvalumab will not exceed the highest dose determined to be safe when administered as monotherapy. Subsequently, if alternate doses or administration schedules of Compound A (or a digentisic acid salt thereof) are evaluated, an additional 3 to 6 patients will be similarly enrolled to a safety lead-in as described above.

Once safety of the combination has been confirmed, enrollment will continue to a total of approximately 10 patients (including any safety lead-in patients treated at the final expansion dose). If multiple doses are evaluated in the cohort, additional patients may be enrolled such that approximately 20 total patients are treated at the RP2D in combination with durvalumab.

For patients assigned to take combination treatment with durvalumab, on days of durvalumab administration, Compound A dose (or first dose if Compound A is dosed more than once a day) is to be administered 30 minutes prior to durvalumab. Durvalumab will be administered 1500 mg IV every 28 days on Day 1 of each 28-day treatment cycle. Treatment with durvalumab may continue until disease progression or unacceptable toxicity (based on the discretion of the treating Investigator). Suggested administration is using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose through an IV administration set using a 0.2 to 1.2 pM in-line filter. Suggested infusion time is 1 hour. Record the start and stop time of the infusion. Table 5. Compound A (or a digentisic acid salt thereof) combination with durvalumab (Cycle length is 28 days)

Abbreviations: C = cycle; D = day; DL = dose level; n = cycle number; RP2Dm = recommended Phase 2 dose monotherapy; SRC = Safety Review Committee.

Claims

I CLAIM:

1. A method of treating a solid tumor cancer, comprising administering to a subject having an IDH mutation a therapeutically effective amount of

(a) a compound of Formula I:

wherein:

R¹ is -CH₂CH(CH₃)2, -CH2CH3, -CH2CH2OCH3, or -CFL-cyclopropyl;

R² is -CH₃ or -CH2CH3; and

X is N or CH, or a pharmaceutically acceptable salt thereof;

(b) a deoxyadenosine analog, or a pharmaceutically acceptable salt thereof;

(c) a platinum agent; and

(d) an immune checkpoint inhibitor.

2. The method of claim 1, wherein the IDH mutation is an IDH1 mutation or an IDH2 mutation.

3. The method of claim 2, wherein the IDH mutation is an IDH1 mutation.

4. The method of claim 3, wherein the IDH1 mutation is an IDH1 R132 mutation.

5. The method of claim 2, wherein the IDH mutation is an IDH2 mutation.

6. The method of claim 5, wherein the IDH2 mutation is an IDH2 R140 or

IDH2 R172 mutation.

7. The method of any one of claims 1 to 6, wherein X is N, or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1 to 7 wherein X is N, R¹ is -CFb- cyclopropyl, and R² is -CH2CH3, or a pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1 to 6, wherein the compound of Formula I is:

7-[[(lS)-l-[4-[(lR)-2-cyclopropyl-l-(4-prop-2-enoylpiperazin-l- yl)ethyl]phenyl]ethyl]amino]-l-ethyl-4H-pyrimido[4,5-d][l,3]oxazin-2- one;

7- [[( 1 S)- 1 - [4- [( 1 S)-2-cyclopropy 1-1 -(4-prop-2-enoylpiperazin- 1 - yl)ethyl]phenyl]ethyl]amino]-l-ethyl-4H-pyrimido[4,5-d][l,3]oxazin-2- one; or

10. The method of any one of claims 1 to 6, wherein the compound of

Formula I is

11. The method of claim 10, wherein the compound of Formula I is

12. The method of any one of claims 1 to 6, wherein the compound of

Formula I or pharmaceutically acceptable salt thereof is a digentisic acid salt of

13. The method of any one of claims 1 to 12, wherein the deoxyadenosine analog is cytarabine or gemcitabine, or a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein the deoxyadenosine analog is gemcitabine, or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein the deoxyadenosine analog is gemcitabine.

16. The method of any one of claims 1 to 15, wherein the platinum agent is cisplatin, carboplatin or oxaliplatin.

17. The method of claim 16, wherein the platinum agent is cisplatin.

18. The method of any one of claims 1 to 17, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor.

19. The method of claim 18, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

20. The method of claim 19, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.

21. The method of claim 18, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

22. The method of claim 21, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplimab, or tislelizumab.

23. The method of claim 18, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

24. The method of claim 23, wherein the PD-L1 inhibitor is atezolizumab, avelumab or durvalumab.

25. The method of claim 23, wherein the PD-L1 inhibitor is durvalumab.

26. The method of any one of claims 1 to 12, wherein the deoxyadenosine analog is gemcitabine, and the platinum agent is cisplatin.

27. The method of any one of claims 1 to 12, wherein the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab.

28. The method of any one of claims 1 to 6, wherein the compound of Formula I is:

29. The method of any one of claims 1 to 28, wherein the solid tumor cancer is cholangiocarcinoma, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder carcinoma, colorectal cancer, or lung cancer.

30. The method of claim 29, wherein the solid tumor cancer is cholangiocarcinoma.

31. The method of claim 30, wherein the cholangiocarcinoma is advanced cholangiocarcinoma.

32. A compound of Formula I:

wherein:

R¹ is -CH₂CH(CH₃)2, -CH2CH3, -CH2CH2OCH3, or -CH2-cyclopropyl;

R² is -CH₃ or -CH2CH3; and

33. The compound for use of claim 32, wherein the IDH mutation is an IDH1 mutation or an IDH2 mutation.

34. The compound for use of claim 33, wherein the IDH mutation is an IDH1 mutation.

35. The compound for use of claim 34, wherein the IDH1 mutation is an IDH1 R132 mutation.

36. The compound for use of claim 33, wherein the IDH mutation is an IDH2 mutation.

37. The compound for use of claim 36, wherein the IDH2 mutation is an IDH2 R140 or IDH2 R172 mutation.

38. The compound for use of any one of claims 32 to 37, wherein X is N, or a pharmaceutically acceptable salt thereof.

39. The compound for use of any one of claims 32 to 38, wherein R¹ is -CH2- cyclopropyl, or a pharmaceutically acceptable salt thereof.

40. The compound for use of any one of claims 32 to 39, wherein R² is - CH2CH3, or a pharmaceutically acceptable salt thereof. The compound for use of any one of claims 32 to 37, wherein the compound is:

1 -Ethy 1 -7- [ [( 1 S)- 1 - [4 - [ 1 -(4-prop-2-enoylpiperazin- 1 -yl)propyl] phenyl]ethyl]amino]-4H-pyrimido[4,5-d][l,3]oxazin-2-one; or a pharmaceutically acceptable salt thereof. The compound for use of any one of claims 32 to 37, wherein the compound is

or a pharmaceutically acceptable salt thereof (preferably a digentisic acid salt thereof). The compound for use of any one of claims 32 to 37, wherein the compound is

The compound for use of any one of claims 32 to 37, wherein the compound of Formula I or pharmaceutically acceptable salt thereof is a digentisic acid salt of

45. The compound for use of any one of claims 32 to 44, wherein the deoxyadenosine analog is cytarabine or gemcitabine, or a pharmaceutically acceptable salt thereof.

46. The compound for use of claim 45, wherein the deoxyadenosine analog is gemcitabine, or a pharmaceutically acceptable salt thereof.

47. The compound for use of claim 46, wherein the deoxyadenosine analog is gemcitabine.

48. The compound for use of any one of claims 32 to 47, wherein the platinum agent is cisplatin, carboplatin or oxaliplatin.

49. The compound for use of claim 48, wherein the platinum agent is cisplatin.

50. The compound for use of any one of claims 32 to 49, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.

51. The compound for use of claim 50, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

52. The compound for use of claim 51, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.

53. The compound for use of claim 50, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

54. The compound for use of claim 53, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplimab, or tislelizumab.

55. The compound for use of claim 50, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

56. The compound for use of claim 55, wherein the PD-L1 inhibitor is atezolizumab, avelumab or durvalumab. The compound for use of claim 55, wherein the PD-L1 inhibitor is durvalumab. The compound for use of any one of claims 32 to 37, wherein the compound of Formula I is

or a pharmaceutically acceptable salt thereof (preferably a digentisic acid salt thereof), the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab. The compound for use of any one of claims 32 to 58, wherein the solid tumor cancer is cholangiocarcinoma, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendroglioma, glioma, glioblastoma, bladder carcinoma, colorectal cancer, or lung cancer. The compound for use of claim 59, wherein the solid tumor cancer is cholangiocarcinoma. The compound for use of claim 60, wherein the solid tumor cancer is advanced cholangiocarcinoma. The compound for use of any one of claims 32 to 37, wherein the solid tumor cancer is cholangiocarcinoma, the compound of Formula I is

63. The compound for use of claim 62, wherein the solid tumor cancer is advanced cholangiocarcinoma.