TW202345848A - Combination therapy with a mutant idh inhibitor - Google Patents

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 using mutant IDH inhibitors

The present invention relates to the use of mutant isocitrate dehydrogenase (IDH) inhibitors, or pharmaceutically acceptable salts thereof, deoxyadenosine analogs, or pharmaceutically acceptable salts thereof, platinum agents, and immune checkpoint inhibition Combination therapy for the treatment of solid tumor cancers.

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

IDH1 is an enzyme that catalyzes the conversion of isocitrate to α-ketoglutarate (2-oxyglutarate) and the reduction of nicotinamide adenine dinucleotide phosphate (NADP ⁺ ) to NADPH (Megias-Vericat J et al. Blood Lymph. Cancer: Targets and Therapy 2019 ; 9: 19-32).

Mutations in IDH1 (eg, at IDH1 amino acid residue R132) drive tumor formation in several types of cancer, including solid tumors (Badur MG et al., Cell Reports 2018 ; 25: 1680). IDH1 mutations can lead to high levels of 2-hydroxyglutarate (2-HG), which inhibits cell differentiation, and inhibitors of mutated IDH1 can reduce 2-HG levels, which promote cell differentiation (Molenaar RJ et al., Oncogene 2018 ; 37: 1949-1960). Mutations in IDH2, such as at IDH2 amino acid residues R140 and R172, also promote tumor formation (Kotredes KP et al., Oncotarget 2019 ; 10: 2675-2692).

Certain mutant IDH1/IDH2 inhibitors are disclosed in WO 2018/111707 A1, which include compounds defined herein as "Compound A", which are covalent inhibitors of mutant IDH1 and modify the monomers in the allele binding pocket. Cysteine (Cys269) quickly inactivates the enzyme and selectively inhibits 2-HG production without affecting α-ketoglutarate a-KG content (WO 2018/111707 A1). Compound A also inhibits 2-HG production in IDH2 mutant cells. Compound A is currently in Phase 1 studies in advanced hematological malignancies (NCT04603001) and advanced solid tumors (NCT04521686). Compound A

Effective therapies for the treatment of solid tumor cancers, including biliary tract cancer, remain elusive.

Additionally, so-called "secondary" IDH1 mutations, as defined herein, can lead to relapse after treatment with mutant IDH1 inhibitors. For example, secondary IDH1 mutations have been reported after ivosidenib treatment, including: R119P, G131A, D279N, S280F, G289D or H315D (Choe S et al., “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).

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

The present invention provides methods of treating solid tumor cancers, comprising administering to an individual with an IDH mutation a therapeutically effective amount of a compound of formula I (a): Where: R ¹ is -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ -cyclopropyl; R ² is -CH ₃ or -CH ₂ CH ₃ ; And

The present invention also provides methods of treating solid tumor cancers, comprising administering to an individual with an IDH mutation a therapeutically effective amount of a compound of Formula I: Where: R ¹ is -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ -cyclopropyl; R ² is -CH ₃ or -CH ₂ CH ₃ ; And X is N or CH; or a pharmaceutically acceptable salt thereof; and an immune checkpoint inhibitor.

The present invention also provides compounds of formula I: Where: R ¹ is -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ -cyclopropyl; R ² is -CH ₃ or -CH ₂ CH ₃ ; And For the treatment of solid tumor cancers in individuals with IDH mutations. In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for simultaneous combination with gemcitabine, or a pharmaceutically acceptable salt thereof, cisplatin and an immune checkpoint inhibitor for treatment. Solid tumor cancer in individuals with IDH mutations. In one embodiment, the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in combination alone with gemcitabine, or a pharmaceutically acceptable salt thereof, cisplatin, and an immune checkpoint inhibitor for treatment. Solid tumor cancer in individuals with IDH mutations. In one embodiment, the invention provides a 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, for Treatment of solid tumor cancers in individuals with IDH mutations.

The present invention also provides compounds of formula I: Where: R ¹ is -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ -cyclopropyl; R ² is -CH ₃ or -CH ₂ CH ₃ ; And In one embodiment, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous combination with an immune checkpoint inhibitor for the treatment of solid tumor cancer in individuals with IDH mutations. In one embodiment, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use alone in combination with an immune checkpoint inhibitor for the treatment of solid tumor cancer in individuals with IDH mutations. In one embodiment, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in sequential combination with an immune checkpoint inhibitor for the treatment of solid tumor cancer in individuals with IDH mutations.

This application claims the rights under 35 U.S.C. §119(e) in U.S. Provisional Application Series No. 63/300,861, filed on January 19, 2022, and U.S. Provisional Application Series No. 63/390,980, filed on July 21, 2022; The disclosures thereof are incorporated herein by reference.

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 example, 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 example, the IDH1 mutation is R132C. In another example, the IDH1 mutation is R132G. In another example, the IDH1 mutant line is R132L. In another example, 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 present invention, the subject's solid tumor cancer progresses after treatment with an IDH inhibitor compound other than a compound of Formula I. In another embodiment, the subject is intolerant or resistant to IDH inhibitor compounds other than compounds 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 a compound of Formula I is ivonib. In another embodiment, the IDH inhibitor other than a compound of Formula I is enasanib.

In one embodiment, X is N, or a pharmaceutically acceptable salt thereof. In another embodiment, X is N, R ¹ is -CH ₂ -cyclopropyl, and R ² is -CH ₂ CH ₃ , or a pharmaceutically acceptable salt thereof. In another embodiment, X is N, R ¹ is -CH ₂ -cyclopropyl, and R ² is -CH ₂ CH ₃ .

In another embodiment, the compound of formula I is: 7-[[(1S)-1-[4-[(1R)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]Ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or 1-ethyl-7-[[(1S)-1-[4-[1-(4-prop-2-enylhexahydropyrazin-1-yl)propyl]phenyl]ethyl]amine base]-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of formula I is 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyridine) Azin-1-yl)ethyl]phenyl]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one or its pharmaceutical An acceptable salt is the digentisate salt.

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 the digentisate salt of compound A, which can be expressed 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 some embodiments, 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, cetamip 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 its pharmaceutically acceptable salt, preferably its digentisate, the deoxyadenosine analogue is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab.

In another embodiment, the compound of formula I is: Or its pharmaceutically acceptable salt, preferably its digentisate, and the immune checkpoint inhibitor is durvalumab.

In another embodiment, the solid tumor cancer is biliary tract cancer and the compound of Formula I is Or its pharmaceutically acceptable salt, preferably its digentisate, the deoxyadenosine analogue is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab. In another embodiment, the biliary tract cancer is advanced biliary tract cancer.

In another embodiment, the solid tumor cancer is biliary tract cancer and the compound of Formula I is Or its pharmaceutically acceptable salt, preferably its digentisate, and the immune checkpoint inhibitor is durvalumab. In another embodiment, the biliary tract cancer is advanced biliary tract cancer.

In another embodiment, the compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 25 mg to about 800 mg. In another embodiment, the compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 25 mg to about 300 mg. In another embodiment, the compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 150 mg to about 300 mg.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, or 800 mg are administered once daily. In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg are administered once daily. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 25 mg. In another embodiment, a compound of Formula I (eg Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 50 mg. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 75 mg. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 100 mg. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 125 mg. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 150 mg. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 175 mg. In another embodiment, a compound of Formula I (eg Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 200 mg. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 250 mg. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 300 mg. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 400 mg. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 600 mg. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered once daily at a dose of about 800 mg.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, or 800 mg are administered once daily on each of days 1 through 21 of a 21-day cycle. In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg are administered once daily on each of days 1 through 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 its digentisate salt) is administered at a dose of about 25 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 50 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 75 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 100 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 125 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 150 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 175 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 200 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 250 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 300 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 400 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 600 mg on days 1 to 21 of a 21-day cycle. Commit every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 800 mg on days 1 to 21 of a 21-day cycle. Commit every day.

In another embodiment, the compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered twice daily at a dose of about 25 mg to about 800 mg. In another embodiment, the compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered twice daily at a dose of about 25 mg to about 300 mg. In another embodiment, the compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered twice daily at a dose of about 150 mg to about 300 mg. In another embodiment, the compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered twice daily at a dose of about 200 mg to about 300 mg.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, or 800 mg are administered twice daily. In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg are administered twice daily. In another embodiment, a compound of Formula I (eg Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 150 mg twice daily. In another embodiment, a compound of Formula I (eg Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 200 mg twice daily. In another embodiment, a compound of Formula I (eg Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 250 mg twice daily. In another embodiment, a compound of Formula I (eg, Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 300 mg twice daily.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, or 800 mg are administered twice daily on each of days 1 through 21 of a 21-day cycle. In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg are administered twice daily on each of days 1 through 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 its digentisate salt) is administered at a dose of about 150 mg on days 1 to 21 of a 21-day cycle. Give twice a day every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 200 mg on days 1 to 21 of a 21-day cycle. Give twice a day every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 250 mg on days 1 to 21 of a 21-day cycle. Give twice a day every day. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 300 mg on days 1 to 21 of a 21-day cycle. Give twice a day every day.

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

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

In another embodiment, gemcitabine is administered to the subject at a dose of about 1000 mg/ ^m on each of days 1 and 8 of a 21-day cycle, and cisplatin is administered at a dose of about 25 mg/ ^m The subject was administered on each of Days 1 and 8 of the 21-day cycle, and durvalumab was administered to the subject on Day 1 of the 21-day cycle at a dose of approximately 1500 mg.

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

In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered on each of days 1 to 28 of a 28-day cycle, and Durvalumab is administered to subjects at a dose of approximately 1500 mg on Day 1 of a 28-day cycle.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, or 800 mg were administered once daily on each of days 1 through 21 of a 21-day cycle, with gemcitabine administered at approximately 1000 mg/ A dose of ^m2 was administered to the subject on each of days 1 and 8 of a 21-day cycle, and cisplatin was administered at a dose of approximately 25 mg/ ^m2 on each of days 1 and 8 of a 21-day cycle. The subjects were administered on one day, and durvalumab was administered to the subject on day 1 of a 21-day cycle at a dose of approximately 1500 mg.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, or 800 mg are administered once daily on each of days 1 through 28 of a 28-day cycle, and durvalumab is A dose of approximately 1500 mg is administered to the subject on Day 1 of a 28-day cycle.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg was administered once daily on each of days 1 to 21 of a 21-day cycle, and gemcitabine was administered at a dose of approximately 1000 mg/ ^m2 on each of the 21-day cycles. Cisplatin was administered to the subject at a ^dose of approximately 25 mg/m on each of Days 1 and 8 of a 21-day cycle, and Deva Lumumab is administered to subjects at a dose of approximately 1500 mg on Day 1 of a 21-day cycle.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg were administered once daily on each of days 1 to 28 of a 28-day cycle, and durvalumab was administered at a dose of approximately 1500 mg on day 28 The first day of the cycle is given to the individual.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, or 800 mg were administered twice daily on each of days 1 through 21 of a 21-day cycle, with gemcitabine administered at approximately 1000 mg / ^m2 was administered to the subject on each of days 1 and 8 of a 21-day cycle, and cisplatin was administered at a dose of approximately 25 mg/ ^m2 on days 1 and 8 of a 21-day cycle. Each day was administered to the subject, and durvalumab was administered to the subject on Day 1 of a 21-day cycle at a dose of approximately 1500 mg. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 150 mg on days 1 to 21 of a 21-day cycle. Gemcitabine was administered to subjects ^twice daily on days 1 and 8 of a 21-day cycle, with gemcitabine at a dose of approximately 1000 mg/m and cisplatin at a dose of approximately 25 mg/ ^m Doses were administered to subjects on each of Days 1 and 8 of a 21-day cycle, and durvalumab was administered to subjects on Day 1 of a 21-day cycle at a dose of approximately 1500 mg. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 200 mg on days 1 to 21 of a 21-day cycle. Gemcitabine was administered to subjects twice daily on days ¹ and 8 of a 21-day cycle, with gemcitabine at a dose of approximately 1000 mg/m and cisplatin at a dose of approximately 25 mg/ ^m Doses were administered to subjects on each of Days 1 and 8 of a 21-day cycle, and durvalumab was administered to subjects on Day 1 of a 21-day cycle at a dose of approximately 1500 mg. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 250 mg on days 1 to 21 of a 21-day cycle. Gemcitabine was administered to subjects twice daily on days ¹ and 8 of a 21-day cycle, with gemcitabine at a dose of approximately 1000 mg/m and cisplatin at a dose of approximately 25 mg/ ^m Doses were administered to subjects on each of Days 1 and 8 of a 21-day cycle, and durvalumab was administered to subjects on Day 1 of a 21-day cycle at a dose of approximately 1500 mg. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 300 mg on days 1 to 21 of a 21-day cycle. Gemcitabine was administered to subjects twice daily on days ¹ and 8 of a 21-day cycle, with gemcitabine at a dose of approximately 1000 mg/m and cisplatin at a dose of approximately 25 mg/ ^m Doses were administered to subjects on each of Days 1 and 8 of a 21-day cycle, and durvalumab was administered to subjects on Day 1 of a 21-day cycle at a dose of approximately 1500 mg.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, or 800 mg are administered twice daily on each of days 1 through 28 of a 28-day cycle with durvalumab A dose of approximately 1500 mg is administered to the subject on Day 1 of a 28-day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 150 mg on days 1 to 28 of a 28-day cycle. Each day was administered twice daily, and durvalumab was administered to subjects at a dose of approximately 1500 mg on Day 1 of a 28-day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 200 mg on days 1 to 28 of a 28-day cycle. Each day was administered twice daily, and durvalumab was administered to subjects at a dose of approximately 1500 mg on Day 1 of a 28-day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 250 mg on days 1 to 28 of a 28-day cycle. Each day was administered twice daily, and durvalumab was administered to subjects at a dose of approximately 1500 mg on Day 1 of a 28-day cycle. In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 300 mg on days 1 to 28 of a 28-day cycle. Each day was administered twice daily, and durvalumab was administered to subjects at a dose of approximately 1500 mg on Day 1 of a 28-day cycle.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg were administered twice daily on each of days 1 to 21 of the 21-day cycle, and gemcitabine was administered at a dose of approximately 1000 mg/ ^m2 during the 21-day cycle Cisplatin was administered to the subject at a dose of approximately 25 mg/m ² on each of days 1 and 8 of the 21-day cycle, and Valumab is administered to subjects at a dose of approximately 1500 mg on Day 1 of a 21-day cycle.

In another embodiment, the compound of formula I (for example, compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt), gemcitabine, cisplatin and durvalumab comprise one or more period, preferably one or more 21-day periods, preferably 6, 7 or 8 21-day periods, followed by a maintenance period consisting of one or more periods, preferably one or more 28-day periods. Administer a compound of Formula I (eg Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) and durvalumab.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered during the induction phase on each day from 1 to 21 of each 21-day cycle. administered on one day and then on days 1 to 28 of each 28-day cycle during the maintenance phase; gemcitabine was administered at a dose of approximately 1000 mg/ ^m2 on days 1 to 28 of each 21-day cycle during the induction phase. Administered to subjects on Days 1 and 8; ^cisplatin was administered at a dose of approximately 25 mg/m during the induction phase on Days 1 and 8 of each 21-day cycle to the subject; and durvalumab is administered to the subject at a dose of approximately 1500 mg on day 1 of each 21-day cycle during the induction phase, and subsequently at a dose of approximately 1500 mg on day 1 of each 28-day cycle during the maintenance phase Invest on day 1 of the cycle.

In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered every 21 days in an induction phase comprising 6, 7, or 8 cycles. Gemcitabine was administered at a dose of approximately 1000 mg/ ^m during induction The mid-term is administered to individuals on days 1 and 8 of each 21-day cycle; cisplatin is administered to individuals during the induction phase at a dose of approximately 25 mg/ ^m2 on days 1 and 8 of each 21-day cycle. Subjects were administered on each of Day 8; and durvalumab was administered to subjects at a dose of approximately 1500 mg on Day 1 of each 21-day cycle during the induction phase, followed by approximately 1500 mg on Day 1 of each 21-day cycle. Doses are administered on Day 1 of each 28-day cycle during the maintenance phase. Preferably, the maintenance period is continued until unacceptable toxicity or disease progression.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, or 800 mg are administered once daily on each of days 1 through 21 of each 21-day cycle during the induction phase and thereafter At a dose of approximately 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 every 28 days during the maintenance phase Administered once daily on each of days 1 to 28 of the cycle; ^gemcitabine was administered at a dose of approximately 1000 mg/m during the induction phase on each of days 1 and 8 of each 21-day cycle to the subject; cisplatin was administered to the subject at a dose of approximately 25 mg/ ^m on each of Days 1 and 8 of each 21-day cycle during the induction phase; and durvalumab was administered to the subject at a dose of approximately A dose of 1500 mg is administered to the subject on day 1 of each 21-day cycle during the induction phase, followed by a dose of approximately 1500 mg on day 1 of each 28-day cycle during the maintenance phase. Preferably, the maintenance period is continued until unacceptable toxicity or disease progression.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, or 800 mg on days 1 to 21 of each 21-day cycle during an induction phase consisting of 6, 7, or 8 cycles Administer once daily on each day, followed by doses of approximately 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. Doses were administered once daily during the maintenance phase on days 1 to 28 of each 28-day cycle; gemcitabine was administered at a dose of approximately 1000 mg/ ^m during the induction phase on days 1 and 2 of each 21-day cycle. Administered to subjects on each of Day 8; Cisplatin at a dose of approximately 25 mg/ ^m2 was administered to subjects on Days 1 and 8 of each 21-day cycle during the induction phase; And durvalumab was administered to the subject at a dose of approximately 1500 mg on day 1 of each 21-day cycle during the induction phase, and subsequently at a dose of approximately 1500 mg on day 1 of each 28-day cycle during the maintenance phase. Vote in 1 day. Preferably, the maintenance period is continued until unacceptable toxicity or disease progression.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg, or 800 mg are administered twice daily during the induction phase on each of days 1 through 21 of each 21-day cycle, Subsequently administered at doses of approximately 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 at each dose during the maintenance phase. twice daily on days 1 to 28 of a 28-day cycle; gemcitabine was administered at a dose of approximately 1000 mg/ ^m2 during the induction phase on days 1 and 8 of each 21-day cycle is administered to the subject; cisplatin is administered to the subject during the induction phase at a dose of approximately 25 mg/ ^m on each of Days 1 and 8 of each 21-day cycle; and durvalumab is Subjects are administered at a dose of approximately 1500 mg on day 1 of each 21-day cycle during the induction phase, and subsequently at a dose of approximately 1500 mg on day 1 of each 28-day cycle during the maintenance phase. Preferably, the maintenance period is continued until unacceptable toxicity or disease progression.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, Doses of 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg were administered twice daily on each of days 1 through 21 of each 21-day cycle during an induction phase consisting of 6, 7, or 8 cycles, followed by doses of approximately 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, or 300 mg on days 1 through 28 of each 28-day cycle during the maintenance phase. Gemcitabine was administered twice daily on each day; ^gemcitabine was administered to subjects at a dose of approximately 1000 mg/m during the induction phase on days 1 and 8 of each 21-day cycle; cisplatin was administered at A dose of approximately 25 mg/ ^m was administered to subjects during the induction phase on each of Days 1 and 8 of each 21-day cycle; and durvalumab was administered at a dose of approximately 1500 mg during the induction phase Subjects are administered on Day 1 of each 21-day cycle and subsequently on Day 1 of each 28-day cycle during the maintenance phase at a dose of approximately 1500 mg. Preferably, the maintenance period is continued until unacceptable toxicity or disease progression.

In another embodiment, the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 150 mg on the first day of each 21-day cycle during the induction phase. Gemcitabine was administered twice daily on days 1 through 21, followed by a dose of approximately 150 mg twice daily during the maintenance phase on days 1 through 28 of each 28-day cycle; gemcitabine was administered at approximately A dose of 1000 mg/ ^m2 was administered to subjects during the induction phase on days 1 and 8 of each 21-day cycle; cisplatin was administered at a dose of approximately 25 mg/ ^m2 on each day during the induction phase. is administered to the subject on each of Days 1 and 8 of a 21-day cycle; and durvalumab is administered during the induction phase at a dose of approximately 1500 mg on Day 1 of each 21-day cycle to subjects, followed by administration at a dose of approximately 1500 mg on Day 1 of each 28-day cycle during the maintenance phase. Preferably, the maintenance period is continued until unacceptable toxicity or disease progression.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate) is administered at a dose of about 200 mg on the first day of each 21-day cycle during the induction phase. Gemcitabine was administered twice daily on days 1 through 21, followed by a dose of approximately 200 mg twice daily during the maintenance phase on days 1 through 28 of each 28-day cycle; gemcitabine was administered at approximately A dose of 1000 mg/ ^m2 was administered to subjects during the induction phase on days 1 and 8 of each 21-day cycle; cisplatin was administered at a dose of approximately 25 mg/ ^m2 on each day during the induction phase. is administered to the subject on each of Days 1 and 8 of a 21-day cycle; and durvalumab is administered during the induction phase at a dose of approximately 1500 mg on Day 1 of each 21-day cycle to subjects, followed by administration at a dose of approximately 1500 mg on Day 1 of each 28-day cycle during the maintenance phase. Preferably, the maintenance period is continued until unacceptable toxicity or disease progression.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) is administered at a dose of about 250 mg on the first day of each 21-day cycle during the induction phase. Gemcitabine was administered twice daily on days 1 through 21, followed by a dose of approximately 250 mg twice daily during the maintenance phase on days 1 through 28 of each 28-day cycle; gemcitabine was administered at approximately A dose of 1000 mg/ ^m2 was administered to subjects during the induction phase on days 1 and 8 of each 21-day cycle; cisplatin was administered at a dose of approximately 25 mg/ ^m2 on each day during the induction phase. is administered to the subject on each of Days 1 and 8 of a 21-day cycle; and durvalumab is administered during the induction phase at a dose of approximately 1500 mg on Day 1 of each 21-day cycle to subjects, followed by administration at a dose of approximately 1500 mg on Day 1 of each 28-day cycle during the maintenance phase. Preferably, the maintenance period is continued until unacceptable toxicity or disease progression.

In another embodiment, the compound of formula I (such as compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate) is administered at a dose of about 300 mg on the first day of each 21-day cycle during the induction phase. Gemcitabine was administered twice daily on days 1 through 21, followed by a dose of approximately 300 mg twice daily during the maintenance phase on days 1 through 28 of each 28-day cycle; gemcitabine was administered at approximately A dose of 1000 mg/ ^m2 was administered to subjects during the induction phase on days 1 and 8 of each 21-day cycle; cisplatin was administered at a dose of approximately 25 mg/ ^m2 on each day during the induction phase. is administered to the subject on each of Days 1 and 8 of a 21-day cycle; and durvalumab is administered during the induction phase at a dose of approximately 1500 mg on Day 1 of each 21-day cycle to subjects, followed by administration at a dose of approximately 1500 mg on Day 1 of each 28-day cycle during the maintenance phase. Preferably, the maintenance period is continued 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which is administered in the following order: 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which is administered in the following order: 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which is administered in the following order: 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which is administered in the following order: 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which is administered in the following order: 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which is administered in the following order: 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: gemcitabine, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: gemcitabine, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: gemcitabine, cisplatin, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: gemcitabine, durvalumab, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: cisplatin, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: cisplatin, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: cisplatin, gemcitabine, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: cisplatin, durvalumab, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: durvalumab, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: durvalumab, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: durvalumab, gemcitabine, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was administered in the following order: durvalumab, cisplatin, 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 its digentisate salt), gemcitabine, cisplatin, and durvalumab are administered on the same day , which was 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 its digentisate salt), gemcitabine, cisplatin and durvalumab are administered on the same day, Formula I The compound dose (or the first dose if more than once daily) is administered 30 minutes before the administration of cisplatin, gemcitabine, and durvalumab. Preferably, when the compound of Formula I (e.g., Compound A or a pharmaceutically acceptable salt thereof, preferably its digentisate salt) and durvalumab are administered on the same day, the dose of the compound of Formula I (or if more than once daily, the first dose) is administered 30 minutes before durvalumab.

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

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

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

In another example, an individual is identified as having an IDH1 R132, IDH2 R140, or IDH2 R172 mutation and has previously treated unresectable/metastatic biliary tract cancer.

In another embodiment of the method of the invention, the solid tumor cancer is biliary tract cancer, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendritic glioblastoma, glial tumor, glioblastoma, bladder, colorectal, or lung cancer. In one embodiment, the lung cancer is non-small cell lung cancer. In another embodiment, the lung cancer is non-small cell lung cancer and a KRas G12C inhibitor or an EGFR inhibitor is also administered. In another embodiment, the solid tumor cancer is biliary tract cancer. In another embodiment, the biliary tract cancer is advanced biliary tract cancer. 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 treating solid tumor cancer in an individual, wherein the medicament is combined with gemcitabine, or a pharmaceutically acceptable salt thereof, cisplatin and Durvalumab was administered simultaneously, separately, or in sequential combination.

In one embodiment, the solid tumor cancer is a frontline cancer. In another embodiment, the solid tumor cancer is a recurrent cancer. In another embodiment, the solid tumor cancer is a refractory solid tumor cancer. In another embodiment, the solid tumor cancer is an advanced solid tumor cancer. In another embodiment, the advanced solid tumor cancer is advanced biliary tract cancer.

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

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

Unless otherwise indicated, the following terms, as used above and throughout the description of the present invention, shall be understood to have the following meanings:

The term "solid tumor tissue" refers to tissue that is not blood tissue (blood tissue is blood, bone marrow, or lymphoid tissue). Non-limiting examples of solid tissues are biliary tract tissue, pancreatic tissue, head tissue, neck tissue, liver tissue, skin tissue, astrocytoma tissue, oligodendritic glial tissue, glial tissue, brain tissue, Bladder tissue, colorectal tissue and lung tissue.

The term "first-line solid tumor cancer" means a solid tumor cancer individual who has never received treatment for the solid tumor cancer being treated.

The term "refractory solid tumor cancer" refers to a cancer that has been treated but in which the individual solid tumor cancer does not respond to treatment.

The term "recurrent solid tumor cancer" means that an individual with solid tumor cancer responds to treatment for a period of time, but the solid tumor cancer relapses.

The term "advanced solid tumor cancer" refers to solid tumor cancer that has spread to lymph nodes or other tissues beyond the point of origin of the solid tumor cancer.

The term "cancer subject" means an individual diagnosed with cancer.

The term "solid tumor subject" means an individual diagnosed with solid tumor cancer. In one embodiment, the solid tumor cancer is biliary tract cancer.

The term "IDH1 R132 mutation" refers to an IDH1 mutation at amino acid residue 132 in the IDH1 enzyme of an individual, as determined, for example, in a nucleic acid (eg, DNA) of the individual.

The term "IDH2 R140 mutation" refers to an IDH2 mutation at amino acid residue 140 in the IDH2 enzyme of an individual, as determined, for example, in a nucleic acid (eg, DNA) of the individual.

The term "IDH2 R172 mutation" refers to an IDH2 mutation at amino acid residue 172 in the IDH2 enzyme of an individual, as determined, for example, in a nucleic acid (eg, DNA) of the individual.

The term "mutated IDH1 inhibitor" refers to compounds that inhibit the enzymatic activity of the mutant IDH1 enzyme and/or the production of 2-HG. Methods for analyzing the enzymatic activity of mutant IDH1 and IDH2 are known to those skilled in the art, for example in WO 2018/111707 A1.

The term "secondary IDH1 mutation" refers to an IDH1 mutation that arises in an individual's IDH1 enzyme following treatment with a mutant IDH1 inhibitor other than a compound of Formula I herein. In one embodiment, the one or more secondary IDH1 mutations are one or more of R119P, G131A, D279N, S280F, G289D, or H315D of IDH1. However, other secondary IDH1 mutations could be reported in the future. As used herein, "secondary IDH1 mutation" is not "IDH1 R132 mutation," "IDH2 R140 mutation," or "IDH2 R172 mutation."

The term "identified as having the IDH1 R132 mutation" means analyzing nucleic acid (eg, DNA) from tissue or cells (eg, circulating tumor cells) of an individual to determine whether the individual has the IDH1 R132 mutation. In one embodiment, an individual's blood cells, bone marrow cells, or blood cells and bone marrow are analyzed for IDH1 R132 mutations. In another embodiment, solid tissue of an individual is analyzed for IDH1 R132 mutations.

The term "identified as having the IDH2 R140 mutation" means analyzing nucleic acid (eg, DNA) from tissue or cells of an individual to determine whether the individual has the IDH2 R140 mutation. In one embodiment, an individual's blood cells, bone marrow cells, or blood cells and bone marrow are analyzed for IDH2 R140 mutations. In another embodiment, solid tissue of an individual is analyzed for IDH2 R140 mutations.

The term "identified as having the IDH2 R172 mutation" means analyzing nucleic acid (eg, DNA) from tissue or cells of an individual to determine whether the individual has the IDH2 R172 mutation. In one embodiment, an individual's blood cells, bone marrow cells, or blood cells and bone marrow are analyzed for the IDH2 R172 mutation. In another embodiment, solid tissue of an individual is analyzed for IDH2 R172 mutations.

In one embodiment, identifying an individual as having an IDH mutation (e.g., one or more of the IDH1 R132 mutation, the IDH2 R140 mutation, or the IDH2 R172 mutation) is a different group than administering a compound of Formula I, or a pharmaceutically acceptable salt thereof , deoxyadenosine analogues, or pharmaceutically acceptable salts thereof, platinum agents and immune checkpoint inhibitor groups. In another embodiment, a population of individuals with IDH mutations (e.g., one or more of the IDH1 R132 mutation, the IDH2 R140 mutation, or the IDH2 R172 mutation) is identified and administered a compound of Formula I, or a pharmaceutically acceptable salt thereof , deoxyadenosine analogs, or pharmaceutically acceptable salts thereof, platinum agents, and immune checkpoint inhibitors are the same group.

In one embodiment, identifying an individual as having an IDH mutation (e.g., one or more of the IDH1 R132 mutation, the IDH2 R140 mutation, or the IDH2 R172 mutation) is a different group than administering a compound of Formula I, or a pharmaceutically acceptable salt thereof and immune checkpoint inhibitor groups. In another embodiment, a population of individuals with IDH mutations (e.g., one or more of the IDH1 R132 mutation, the IDH2 R140 mutation, or the IDH2 R172 mutation) is identified and administered a compound of Formula I, or a pharmaceutically acceptable salt thereof The same group as immune checkpoint inhibitors.

Analytical methods for identifying IDH mutations are known to those skilled in the art (Clark, O. et al., Clin. Cancer. Res. 2016 ; 22: 1837-42) and include (but are 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 methods (such as whole-transcriptome sequencing) (Lutha, R et al., Haematologica 2014 ; 99: 465-473; Wang HY et al., J . Exp. Clin. Cancer Res. 2016 ; 35: 86).

The term "approximately" means ±5% of the stated value.

The terms "treatment, treat, treating" and the like are intended to include slowing, stopping or reversing the progression of cancer. The terms also include alleviation, amelioration, attenuation, elimination or alleviation of one or more symptoms of a disease or condition, even if the cancer is not actually eliminated and even if the progression of the cancer itself is not slowed, stopped or reversed.

"Therapeutically effective amount" means an amount of a compound, or a pharmaceutically acceptable salt thereof, administered to an individual that will elicit a biological or medical response in the individual or a desired therapeutic effect in the individual. As one skilled in the art, the attending physician can readily determine a therapeutically effective amount by using known techniques and by observing results obtained under similar conditions. In determining the effective amount for an individual, the attending physician considers a number of factors, including (but not limited to): size, age and general health; the specific disease or condition involved; the extent or involvement or severity of the disease or condition; Responses of individual individuals; specific compounds administered; modes of administration; bioavailability properties of formulations administered; dosage regimen selected; use of concomitant medications; and other relevant circumstances.

"Pharmaceutically acceptable carriers, diluents or excipients" are media recognized in the industry for use in delivering bioactive agents to mammals, such as humans.

Compounds administered according to the present invention may be formulated as pharmaceutical compositions for administration by any route that renders the compound bioavailable. In embodiments, the compositions are formulated for oral administration. Such pharmaceutical compositions and their preparation processes are well known in the industry. (See, for example, Remington: The Science and Practice of Pharmacy (ed. D.B. Troy, 21st ed., Lippincott, Williams & Wilkins, 2006).

"Pharmaceutically acceptable salts, a pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic salts of the compounds of the invention (SM Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences , Vol. 66 , Issue 1, January 1977).

Those skilled in the art will understand that compounds administered in accordance with the present 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 methods for their preparation are well known in the art. See, for example, P. Stahl et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2008).

It should be understood that the compound of Formula I may be administered as a non-salt free base form or a pharmaceutically acceptable salt thereof; however, unless otherwise stated, the amount of administration of the compound of Formula I or a pharmaceutically acceptable salt thereof is determined herein. is expressed based on the weight of the non-salt free base form of the compound of formula I.

The term "gentisic acid" refers to 2,5-dihydroxybenzoic acid, which can be represented by the following structure: .

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

Clause 1. A method of treating solid tumor cancer, comprising administering to an individual having an IDH mutation a therapeutically effective amount of a compound of Formula I (a): Where: R ¹ is -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ -cyclopropyl; R ² is -CH ₃ or -CH ₂ CH ₃ ; And X is N or CH, or a pharmaceutically acceptable salt thereof; (b) deoxyadenosine analogues or a pharmaceutically acceptable salt thereof; (c) platinum agent; and (d) 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. A method according to 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, R ¹ is -CH ₂ -cyclopropyl, and R ² is -CH ₂ CH ₃ , or a pharmaceutically acceptable salt thereof.

Clause 9. A method according to any one of clauses 1 to 6, wherein the compound of formula I is: 7-[[(1S)-1-[4-[(1R)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]Ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or 1-ethyl-7-[[(1S)-1-[4-[1-(4-prop-2-enylhexahydropyrazin-1-yl)propyl]phenyl]ethyl]amine base]-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or its pharmaceutically acceptable salt.

Clause 10. A method according to any one of clauses 1 to 6, wherein the compound of formula I is Or its pharmaceutically acceptable salt (preferably, its digentisate).

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

Clause 12. A method according to any one of clauses 1 to 6, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is the following digentisate salt .

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, cimepilimab 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. A method according to any one of clauses 1 to 6, wherein the compound of formula I is: or a pharmaceutically acceptable salt thereof (preferably, its digentisate), the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab anti.

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

Clause 30. The method of Clause 29, wherein the solid tumor cancer is biliary tract cancer.

Clause 31. The method of Clause 30, wherein the biliary tract cancer is advanced biliary tract cancer.

Article 32. A compound of formula I: Where: R ¹ is -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ -cyclopropyl; R ² is -CH ₃ or -CH ₂ CH ₃ ; And Combination for the treatment of solid tumor cancer in individuals with IDH mutations.

Clause 33. A compound as used in Clause 32, wherein the IDH mutation is an IDH1 mutation or an IDH2 mutation.

Clause 34. A compound as used in Clause 33, wherein the IDH mutation is an IDH1 mutation.

Clause 35. A compound as used in Clause 34, wherein the IDH1 mutation is an IDH1 R132 mutation.

Clause 36. A compound as used in Clause 33, wherein the IDH mutation is an IDH2 mutation.

Clause 37. A compound as used in Clause 36, wherein the IDH2 mutation is an IDH2 R140 or IDH2 R172 mutation.

Clause 38. Compounds as used in any of clauses 32 to 37, wherein X is N, or a pharmaceutically acceptable salt thereof.

Clause 39. A compound as used in any of clauses 32 to 38, wherein ^R1 is _-CH2 -cyclopropyl, or a pharmaceutically acceptable salt thereof.

Clause 40. A compound as used in any of clauses 32 to 39, wherein ^R2 is _-CH2CH3 , or _a pharmaceutically acceptable salt thereof.

Clause 41. A compound as used in any of clauses 32 to 37, wherein the compound is: 7-[[(1S)-1-[4-[(1R)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]Ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or 1-ethyl-7-[[(1S)-1-[4-[1-(4-prop-2-enylhexahydropyrazin-1-yl)propyl]phenyl]ethyl]amine base]-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or its pharmaceutically acceptable salt.

Clause 42. A compound as used in any of clauses 32 to 37, wherein the compound is Or its pharmaceutically acceptable salt (preferably, its digentisate).

Clause 43. A compound as used in any of clauses 32 to 37, wherein the compound is .

Clause 44. Compounds as used in any of clauses 32 to 37, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is the following digentisate salt .

Clause 45. A compound as used in any of clauses 32 to 44, wherein the deoxyadenosine analog is cytarabine or gemcitabine, or a pharmaceutically acceptable salt thereof.

Clause 46. A compound as used in clause 45, wherein the deoxyadenosine analog is gemcitabine, or a pharmaceutically acceptable salt thereof.

Clause 47. A compound for use as in Clause 46, wherein the deoxyadenosine analog is gemcitabine.

Clause 48. A compound as used in any of clauses 32 to 47, wherein the platinum agent is cisplatin, carboplatin or oxaliplatin.

Clause 49. A compound as used in Clause 48, wherein the platinum agent is cisplatin.

Clause 50. A compound as used in any 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. A compound as used in Clause 50, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

Clause 52. A compound as used in Clause 51, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.

Clause 53. A compound as used in Clause 50, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

Clause 54. A compound as used in Clause 53, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cimepilimab or tislelizumab.

Clause 55. A compound as used in Clause 50, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

Clause 56. A compound as used in Clause 55, wherein the PD-L1 inhibitor is atezolizumab, avelumab or durvalumab.

Clause 57. A compound as used in Clause 55, wherein the PD-L1 inhibitor is durvalumab.

Clause 58. Compounds as used in any of clauses 32 to 37, wherein the compound of formula I is or a pharmaceutically acceptable salt thereof (preferably, its digentisate), the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab anti.

Clause 59. Compounds as used in any of Clauses 32 to 58, wherein the solid tumor cancer is biliary tract cancer, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendrite Glioblastoma, glioma, glioblastoma, bladder, colorectal, or lung cancer.

Clause 60. A compound as used in Clause 59, wherein the solid tumor cancer is biliary tract cancer.

Clause 61. A compound as used in Clause 60, wherein the solid tumor cancer is advanced biliary tract cancer.

Clause 62. A compound as used in any of clauses 32 to 37, wherein the solid tumor cancer is biliary tract cancer and the compound of formula I is or a pharmaceutically acceptable salt thereof (preferably, its digentisate), the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab anti.

Clause 63. A compound as used in Clause 62, wherein the solid tumor cancer is advanced biliary tract cancer.

Clause 64. A method of treating solid tumor cancer, comprising administering to an individual having an IDH mutation a therapeutically effective amount of a compound of Formula I: Where: R ¹ is -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ -cyclopropyl; R ² is -CH ₃ or -CH ₂ CH ₃ ; 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. A method as in 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. A method according to any of clauses 64 to 69, wherein the compound of formula I is: 7-[[(1S)-1-[4-[(1R)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]Ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or 1-ethyl-7-[[(1S)-1-[4-[1-(4-prop-2-enylhexahydropyrazin-1-yl)propyl]phenyl]ethyl]amine base]-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or its pharmaceutically acceptable salt.

Clause 73. A method according to any one of clauses 64 to 69, wherein the compound of formula I is Or its pharmaceutically acceptable salt (preferably, its digentisate).

Clause 74. The method of clause 73, wherein the compound of formula I is .

Clause 75. A method according to any one of clauses 64 to 69, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is the following digentisate salt .

Clause 76. The method of any 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, cimepilimab 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. A method according to any of clauses 64 to 69, wherein the compound of formula I is: or a pharmaceutically acceptable salt thereof (preferably, its digentisate salt), 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 biliary tract cancer, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendritic nerve glioblastoma, glioma, glioblastoma, bladder, colorectal, or lung cancer.

Clause 86. The method of Clause 85, wherein the solid tumor cancer is biliary tract cancer.

Clause 87. The method of Clause 86, wherein the biliary tract cancer is advanced biliary tract cancer.

Clause 88. A compound of formula I, Where: R ¹ is -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ -cyclopropyl; R ² is -CH ₃ or -CH ₂ CH ₃ ; And X is N or CH, or a pharmaceutically acceptable salt thereof; it is used in combination with an immune checkpoint inhibitor simultaneously, alone, or sequentially for the treatment of solid tumor cancer in individuals with IDH mutations.

Clause 89. A compound as used in Clause 88, wherein the IDH mutation is an IDH1 mutation or an IDH2 mutation.

Clause 90. A compound as used in Clause 89, wherein the IDH mutation is an IDH1 mutation.

Clause 91. A compound as used in Clause 90, wherein the IDH1 mutation is an IDH1 R132 mutation.

Clause 92. A compound as used in Clause 89, wherein the IDH mutation is an IDH2 mutation.

Clause 93. A compound as used in Clause 92, wherein the IDH2 mutation is an IDH2 R140 or IDH2 R172 mutation.

Clause 94. Compounds as used in any of clauses 88 to 93, wherein X is N, or a pharmaceutically acceptable salt thereof.

Clause 95. A compound as used in any of clauses 88 to 94, wherein ^R1 is _-CH2 -cyclopropyl, or a pharmaceutically acceptable salt thereof.

Clause 96. A compound as used in any of clauses 88 to 95, wherein ^R2 is _-CH2CH3 , or _a pharmaceutically acceptable salt thereof.

Clause 97. A compound as used in any of clauses 88 to 93, wherein the compound is: 7-[[(1S)-1-[4-[(1R)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]Ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or 1-ethyl-7-[[(1S)-1-[4-[1-(4-prop-2-enylhexahydropyrazin-1-yl)propyl]phenyl]ethyl]amine base]-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or its pharmaceutically acceptable salt.

Clause 98. A compound as used in any of clauses 88 to 93, wherein the compound is Or its pharmaceutically acceptable salt (preferably, its digentisate).

Clause 99. A compound as used in any of clauses 88 to 93, wherein the compound is .

Clause 100. Compounds as used in any of clauses 88 to 93, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is the following digentisate salt .

Clause 101. A compound as used in any 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. A compound as used in Clause 101, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

Clause 103. A compound as used in Clause 102, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.

Clause 104. A compound as used in Clause 101, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

Clause 105. A compound as used in Clause 104, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cimepilimab or tislelizumab.

Clause 106. A compound as used in Clause 101, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

Clause 107. A compound as used in Clause 106, wherein the PD-L1 inhibitor is atezolizumab, avelumab or durvalumab.

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

Clause 109. Compounds as used in any of clauses 88 to 93, wherein the compound of formula I is or a pharmaceutically acceptable salt thereof (preferably, its digentisate salt), and the immune checkpoint inhibitor is durvalumab.

Clause 110. Compounds as used in any of clauses 88 to 109, wherein the solid tumor cancer is biliary tract cancer, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendrite Glioblastoma, glioma, glioblastoma, bladder, colorectal, or lung cancer.

Clause 111. A compound as used in Clause 110, wherein the solid tumor cancer is biliary tract cancer.

Clause 112. A compound as used in Clause 111, wherein the solid tumor cancer is advanced biliary tract cancer.

Clause 113. A compound as used in any of clauses 88 to 93, wherein the solid tumor cancer is biliary tract cancer and the compound of formula I is or a pharmaceutically acceptable salt thereof (preferably, its digentisate salt), and the immune checkpoint inhibitor is durvalumab.

Clause 114. A compound as used in Clause 113, wherein the solid tumor cancer is advanced biliary tract cancer.

Example 1 In vivo tumor growth inhibitory compounds and formulations in the IDH1 mutated biliary tract cancer PDX tumor model. For in vivo studies, each test article was prepared using vehicle at appropriate concentrations. Compound A was formulated in a gum arabic vehicle (water, 10% gum arabic, 0.05% antifoam agent [Dow Corning 1510-US]) with 1.1 molar equivalents of HCl. Compound A was prepared fresh every 7 days using vehicle at the appropriate concentration and stored at 4°C between doses. Storage Cisplatin Injection (Teva Pharmaceuticals, NDC #00703-5747-11) is stored at room temperature. On the day of administration, prepare the appropriate concentration by diluting in 0.9% sterile saline. Gemcitabine was prepared fresh weekly in 0.9% sterile saline.

In vivo tumor growth inhibition study in the IDH1 mutated (R132C) intrahepatic biliary tract cancer PDX tumor model. Tumor fragments were harvested from host animals and implanted subcutaneously into 6-12 week old immunodeficient female mice. Mice were allowed to eat normal chow ad libitum. The study was initiated with an average tumor volume of approximately 125-250 ^mm3 . Each test strain was prepared as described above using vehicle at the appropriate concentration to be administered at a dose volume of 10 µL/gram of body weight to the animals tested in this study. Mice were administered Compound A (30 mg/kg, PO, QD) via orogastric gavage on Day 0 and 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 the appropriate vehicle. Gemcitabine (40 mg/kg) and cisplatin (1.5 mg/kg) were administered by intraperitoneal administration. Tumor growth and body weight were monitored over time to assess efficacy and signs of toxicity. Two-dimensional measurements of tumors were performed twice weekly, and tumor volume was calculated based on the following formula: (tumor volume) = [(L) x (W ² ) x 0.52], where L is the axial length and W is the axial width. The average tumor volume on day 31 is shown in Table 1.

Compound A, cisplatin plus gemcitabine, and the triple combination of Compound A with cisplatin and gemcitabine were 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 produced a statistically significant additive benefit in tumor growth inhibition in a patient-derived xenograft model of mutant IDH1 (R132C) biliary tract cancer. The addition of Compound A to the cisplatin-gemcitabine regimen demonstrated no evidence of antagonism or significant toxicity compared with cisplatin-gemcitabine treatment alone. Table 1. In vivo tumor growth inhibition in the PDX tumor model of IDH1 mutant biliary cancer implanted in mice group N Mean ± SEM δ T/C % p value medium 10 1103 ± 119 NA NA Compound A (30 mg/kg, QD x 32, PO; Days 0-31) 10 1007 ± 127 89.6 .617 Cisplatin (1.5 mg/kg) + gemcitabine (40 mg/kg) (Q7D x 4, IP; Days 5, 12, 19, 26) 10 907 ± 85 78.0 .282 Compound A (30 mg/kg, QD x 32, PO; Days 0-31) + Cisplatin (1.5 mg/kg) + Gemcitabine (40 mg/kg) (Q7D x 4, IP: Days 5, 12, 19 , 26 days) 10 629 ± 84 48.2 .002* Analysis of tumor volume was based on random measures ANOVA, Log 10 volume, and spatial power covariance structure versus vehicle. Mean tumor volume (± SEM) was calculated from the inverse log of the least square mean predicted by a random measures ANOVA model on the logarithm of tumor volume. δ T/C % was calculated when the endpoint tumor volume in the treatment group was at or above the baseline tumor volume. The formula is 100 * (T – T _o )/(C – C _o ), where T and C are the endpoint tumor volumes (day 31) in the treatment or control group, respectively. T _o and C _o are the baseline (randomization) tumor volumes (day -1) in these groups. *: Significant (p < 0.05) NA: Not applicable

Example 2 In vivo tumor growth inhibitory compounds and formulations in the IDH1 mutated biliary tract cancer PDX tumor model. For in vivo studies, each test article was prepared using vehicle at appropriate concentrations. Compound A was formulated in a gum arabic vehicle (water, 10% gum arabic, 0.05% antifoam agent [Dow Corning 1510-US]) with 1.1 molar equivalents of HCl. Compound A was prepared fresh every 7 days using vehicle at the appropriate concentration and stored at 4°C between doses. Cisplatin series are 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 of cisplatin and gemcitabine, appropriate concentrations were prepared fresh by diluting in 0.9% injectable saline.

In vivo tumor growth inhibition study in the IDH1 mutated (R132C) intrahepatic biliary cancer PDX tumor model. Tumor fragments were harvested from host animals and implanted subcutaneously into 6-8 week old female Balb/c nude mice. Mice were allowed to eat normal chow ad libitum. The study began with a mean tumor volume of approximately 146 ^mm3 . Each test strain was prepared as described above using vehicle at the appropriate concentration to be administered at a dose volume of 10 µL/gram of body weight to the animals tested in this study. Mice were administered Compound A (PO, QD) via orogastric gavage on Day 1 and treated at the indicated doses (10 mg/kg or 30 mg/kg) for the duration of the study (Day 90). On Day 5 of Compound A dosing and Q7D x 12 thereafter, prepare gemcitabine and cisplatin in the appropriate vehicle. Gemcitabine (30 mg/kg) and cisplatin (1.5 mg/kg) were administered by intraperitoneal administration. Tumor growth and body weight were monitored over time to assess efficacy and signs of toxicity. Two-dimensional measurements of tumors were performed twice weekly, and tumor volume was calculated based on the following formula: (tumor volume) = [(L) x (W ² ) x 0.5], where L is the midaxial length and W is the midaxial width. The average tumor volume at day 90 is shown in Table 2.

Compound A, cisplatin plus gemcitabine, and the triple combination of Compound A with cisplatin and gemcitabine were found to have delta T/C % values, as provided in Table 2 below. These results indicate that Compound A single agent treatment and combination with cisplatin and gemcitabine resulted in statistically significant tumor growth inhibition in a patient-derived xenograft model of mutant IDH1 (R132C) biliary tract cancer. The addition of Compound A to the cisplatin-gemcitabine regimen demonstrated no evidence of antagonism or significant toxicity compared with cisplatin-gemcitabine treatment alone. Table 2. In vivo tumor growth inhibition in the PDX tumor model of IDH1 mutant biliary tract cancer implanted in mice group N Mean ± SEM δ T/C % p value medium 10 939 ± 184 NA NA Compound A (10 mg/kg, PO, QD x 90) 10 399 ± 122 32.8 .015* Compound A (30 mg/kg, PO, QD x 90) 10 326 ± 102 23.7 .003* Cisplatin (1.5 mg/kg) + gemcitabine (30 mg/kg) (IP, Q7D x 13, started on day 5) 10 305 ± 74 21.0 .002* Compound A (10 mg/kg, PO, QD x 90) + Cisplatin (1.5 mg/kg) + Gemcitabine (30 mg/kg) (IP, Q7D x 13, starting on Day 5) 10 219 ± 44 10.4 <.001* Compound A (30 mg/kg, PO, QD x 90) + Cisplatin (1.5 mg/kg) + Gemcitabine (30 mg/kg) (IP, Q7D x 13, starting on Day 5) 10 195 ± 49 7.3 <.001* Analysis of tumor volume was based on random measures ANOVA, Log 10 volume, and spatial power covariance structure versus vehicle. Mean tumor volume (± SEM) was calculated from the inverse log of the least square mean predicted by a random measures ANOVA model on the logarithm of tumor volume. δ T/C % was calculated when the endpoint tumor volume in the treatment group was at or above the baseline tumor volume. The formula is 100*(TT _o )/(CC _o ), where T and C are the endpoint tumor volume (day 90) in the treatment or control group, respectively. T _o and C _o are the baseline (randomization) tumor volumes (day 0) in these groups. *: Significant (p < 0.05) NA: Not applicable

Example 3 Phase 1 Study of Compound A Administered to Patients with Advanced Solid Tumors Having IDH1 or IDH2 Mutations The primary objective of Phase 1 dose escalation was to determine when administered to patients with isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2) mutated advanced solid tumors, the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of Compound A (or its digentisate) monotherapy.

The primary goal of Phase 1 dose expansion is to determine objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or Response Evaluation in Neuro-Oncology (RANO), as appropriate, based on tumor type. Preliminary antitumor activity of Compound A (or its digentisate salt) when administered alone, in combination with cisplatin plus gemcitabine, or in combination with cisplatin, gemcitabine, and durvalumab.

Secondary objectives are (a) to evaluate the safety and tolerability of Compound A (or its digentisate salt) when administered alone, in combination with cisplatin plus gemcitabine, or in combination with cisplatin, gemcitabine, and durvalumab (b) 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 biliary tract cancer, evaluating Compound A (or its digentisate) monotherapy, versus cisplatin plus gemcitabine Preliminary anti-tumor activity in combination or with cisplatin, gemcitabine and durvalumab; (c) Characterization of Compound A (or its digentisate) alone, in combination with cisplatin plus gemcitabine or with cisplatin and gemcitabine and pharmacokinetic (PK) properties of durvalumab when administered in combination; and (vi) characterize the pharmacodynamic properties of Compound A (or its digentisate), such as by 2-hydroxypentanol in plasma. Expressed by changes in the content of diacid (2-HG) tumor metabolites.

Table 3 lists Compound A monotherapy doses and cycle lengths used to determine MTD and R2PD. Table 3. Compound A monotherapy (28-day cycle length) dose level Recommended ^dosea DL-1 10 mg QD DL 1 (starting dose) 25 mg QD DL 2 25 mg BID DL 3 50 mg BID DL 4 100 mg BID DL 5 200 mg BID Abbreviations: BID = twice daily; DL = dose level; PK = pharmacokinetics; QD = once daily; SRC = Safety Review Committee. ^aThe Safety Review Committee may consider lower or intermediate dose levels or dose levels above the currently planned maximum dose of 200 mg BID as well as alternative dosing schedules after review of safety, PK, and pharmacodynamics; data from previous studies in this category group.

The first dose level was accomplished using a dose of 25 mg QD of Compound A. After review of available PK/PD and safety data, the dosing schedule was modified to 50 mg QD as the dose and schedule for DL 2, 100 mg QD for DL 3, 200 mg QD for DL 4, and 400 mg QD For DL 5. Additional dose levels were selected for study: 600 mg QD for DL 6.

After determining the MTD or R2PD of Compound A (or its digentisate), in patients with IDH1 R132, IDH2 R140, or IDH2 R172 mutated advanced biliary tract cancer and measurable disease who have not received prior therapy for advanced disease. A cohort of individuals were evaluated using the combination of Compound A (or its digentisate) with cisplatin, gemcitabine, and durvalumab (Table 4). For safety lead-in, up to 6 patients were enrolled and treated with Compound A (or its digentisate salt) at RP2D or at selected doses and schedules in combination with cisplatin, gemcitabine, and durvalumab. Safety induction patients completed the 21-day DLT evaluation period, and additional patients were then enrolled into the cohort. If no more than 1 DLT is observed in the first 6 patients, continued enrollment into the cohort will be allowed. If 2 or more DLTs are observed in the first 6 patients, the Compound A (or its digentisate) dose may be reduced by 1 order of magnitude or more and enrollment in the cohort continues. Selected doses and schedules can be tested before identifying monotherapy MTD or RP2D. In this case, the starting dose of Compound A (or its digentisate salt) in combination with cisplatin, gemcitabine and durvalumab will not exceed the highest dose determined to be safe by the SRC when administered as monotherapy. Subsequently, if alternative doses or administration schedules of Compound A (or its digentisate salt) are evaluated, an additional 3-6 patients may be similarly enrolled into the safety profile described above. Once the safety of the combination is confirmed, enrollment will continue for a total of approximately 10 patients (including any safety-introduced patients treated with final expansion doses). If multiple doses are evaluated in a cohort, additional patients may be enrolled, resulting in a total of approximately 20 patients treated with Compound A (or its digentisate) RP2D in combination with cisplatin, gemcitabine, and durvalumab .

Patients enrolled in the dose expansion cohort received Compound A (or its digentisate salt) in combination with cisplatin, gemcitabine, and durvalumab with a treatment induction period of 21 days and a cycle length of 28 days The treatment maintenance period. During the induction phase, treatment with Compound A (or its digentisate) in combination with cisplatin, gemcitabine, and durvalumab was a total of 6 to 8 cycles of cisplatin and gemcitabine, with the patient's For maximum benefit, treatment may exceed 8 cycles at the discretion. During the maintenance phase, treatment with durvalumab and Compound A (or its digentisate) will continue until disease progression (PD), unacceptable toxicity, or other reasons leading to treatment discontinuation. Table 4. Combinations of Compound A (or its digentisate salt) with cisplatin, gemcitabine and durvalumab (cycle length 21 days for induction phase and 28 days for maintenance phase) Study drug administration dose level Recommended dosage Induction phase dose cycle; number of days Maintenance dose cycle; number of days Compound A (or its digentisate salt) (oral) DL-1 ≤ starting dose-1 magnitude C1-n ^a ; D1-D21 C1-n ^a ; D1-D28 DL 1 (starting dose) RP2Dm or selected dose/schedule determined by SRC* C1-n ^a ; D1-D21 C1-n ^a ; D1-D28 Cisplatin (intravenous) fixed dose 25mg/ ^m2 C1-n ^a ; D1 and D8 Gemcitabine (intravenous) fixed dose 1000mg/ ^m2 C1-n ^a ; D1 and D8 Durvalumab (intravenous) fixed dose 1,500 mg C1-n ^b ;D1 C1-n ^b ;D1 Abbreviations: C = cycle; D = day; DL = dose level; n = number of cycles; RP2Dm = recommended phase 2 dose monotherapy; SRC = Safety Review Committee. ^aA total of 6 to 8 cycles is planned. If it is in the best interest of the patient, treatment for more than 8 cycles may be considered. ^bTreatment with durvalumab was scheduled every 21 days during the induction phase and every 28 days during the maintenance phase. Treatment with durvalumab can be continued until unacceptable toxicity or disease progression occurs. * Cohorts (compound A or digentisate in combination with cisplatin, gemcitabine and durvalumab) can be initiated prior to identification of monotherapy MTD or RP2D.

Example 4 Phase 1 Study of Administration of Compound A to Patients with Advanced Solid Tumors with IDH1 or IDH2 Mutations The purpose of this study was to evaluate the combination therapy of Compound A (or its digentisate) and durvalumab Safety and tolerability in patients with previously treated unresectable/metastatic biliary cancer harboring IDH1 R132, IDH2 R140 or IDH2 R172 mutations. Additionally, this study will evaluate the pharmacokinetics (PK) and pharmacodynamics of durvalumab on Compound A (or its digentisate). Three to six patients will be enrolled and treated with Compound A (or its digentisate salt) in RP2D or in combination with durvalumab at a selected dose and schedule. Safety induction patients will complete the 28-day DLT evaluation period before additional patients are 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 in the cohort will be allowed. If 2 or more DLTs are observed in the first 3 to 6 patients, the Compound A (or its digentisate) dose may be reduced by 1 order of magnitude or more and continued enrollment in the cohort. Selected doses and schedules can be tested before identifying monotherapy for MTD/RP2D. In this case, the starting dose of Compound A (or its digentisate salt) in combination with durvalumab will not exceed the highest dose determined to be safe when administered as monotherapy. Subsequently, if alternative doses or administration schedules of Compound A (or its digentisate salt) are evaluated, an additional 3-6 patients will be similarly enrolled into the safety profile described above.

Once the safety of the combination is confirmed, enrollment will continue for a total of approximately 10 patients (including any safety-introduced patients treated with final expansion doses). If multiple doses are evaluated in a cohort, additional patients may be enrolled, resulting in a total of approximately 20 patients treated with Compound A (or its digentisate) RP2D in combination with durvalumab.

For patients assigned to receive treatment in combination with durvalumab, on the day durvalumab is administered, the Compound A dose (or first dose, if Compound A is administered more than once a day) is Administer durvalumab 30 minutes before administration. Durvalumab will be administered 1500 mg IV every 28 days on Day 1 of each 28-day treatment cycle. Treatment with durvalumab may be continued until disease progression or unacceptable toxicity occurs (based on the discretion of the treating investigator). It is recommended that administration be performed using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose using an IV administration setting using a 0.2 to 1.2 μM in-line filter. The recommended infusion time is 1 hour. Record the start and stop times of the infusion. Table 5. Combination of Compound A (or its digentisate) and durvalumab (cycle length 28 days) Study drug administration dose level Recommended dosage Dosage cycle; number of days Compound A (or its digentisate salt) (oral) DL-1 ≤ starting dose-1 magnitude C1-n; D1 - D28 DL 1 (starting dose) RP2Dm or selected dose/schedule determined by SRC* C1-n; D1 - D28 Durvalumab (intravenous) fixed dose 1,500 mg C1-n;D1 Abbreviations: C = cycle; D = day; DL = dose level; n = number of cycles; RP2Dm = recommended phase 2 dose monotherapy; SRC = Safety Review Committee.

Claims (31)

The use of a compound of formula I or a pharmaceutically acceptable salt thereof, Where: R ¹ is -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ -cyclopropyl; R ² is -CH ₃ or -CH ₂ CH ₃ ; And Point inhibitor combination. Such as the use of claim 1, wherein the IDH mutation is an IDH1 mutation or an IDH2 mutation. Such as the use of claim 2, wherein the IDH mutation is an IDH1 mutation. Such as the use of claim 3, wherein the IDH1 mutation is an IDH1 R132 mutation. Such as the use of claim 2, wherein the IDH mutation is an IDH2 mutation. Such as the use of claim 5, wherein the IDH2 mutation is IDH2 R140 or IDH2 R172 mutation. The use of any one of claims 1 to 6, wherein X is N, or a pharmaceutically acceptable salt thereof. The use of any one of claims 1 to 6, wherein X is N, R ¹ is -CH ₂ -cyclopropyl, and R ² is -CH ₂ CH ₃ , or a pharmaceutically acceptable salt thereof. The use of any one of claims 1 to 6, wherein the compound of formula I is: 7-[[(1S)-1-[4-[(1R)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]Ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; 7-[[(1S)-1-[4-[(1S)-2-cyclopropyl-1-(4-prop-2-enylhexahydropyrazin-1-yl)ethyl]phenyl ]ethyl]amino]-1-ethyl-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or 1-ethyl-7-[[(1S)-1-[4-[1-(4-prop-2-enylhexahydropyrazin-1-yl)propyl]phenyl]ethyl]amine base]-4H-pyrimido[4,5-d][1,3]oxazin-2-one; or its pharmaceutically acceptable salt. The use of any one of claims 1 to 6, wherein the compound of formula I is or its pharmaceutically acceptable salt. The use of any one of claims 1 to 6, wherein the compound of formula I is . The use of any one of claims 1 to 6, wherein the compound of formula I or its pharmaceutically acceptable salt is the following digentisate . The use of any one of claims 1 to 6, wherein the deoxyadenosine analog is cytarabine (cytarabine) or gemcitabine (gemcitabine), or a pharmaceutically acceptable salt thereof. Such as the use of claim 13, wherein the deoxyadenosine analog is gemcitabine, or a pharmaceutically acceptable salt thereof. The use of claim 14, wherein the deoxyadenosine analog is gemcitabine. Such as the use of any one of claims 1 to 6, wherein the platinum agent is cisplatin (cisplatin), carboplatin (carboplatin) or oxaliplatin (oxaliplatin). Such as the use of claim 16, wherein the platinum agent is cisplatin. The use of any one of claims 1 to 6, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor. Such as the use of claim 18, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor. Such as the use of claim 19, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab. The use of claim 18, wherein the immune checkpoint inhibitor is a PD-1 inhibitor. Such as the use of claim 21, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplimab Or tislelizumab. The use of claim 18, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor. Such as the use of claim 23, wherein the PD-L1 inhibitor is atezolizumab, avelumab or durvalumab. Such as the use of claim 23, wherein the PD-L1 inhibitor is durvalumab. The use of any one of claims 1 to 6, wherein the deoxyadenosine analog is gemcitabine, and the platinum agent is cisplatin. The use of any one of claims 1 to 6, wherein the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab. The use of any one of claims 1 to 6, wherein the compound of formula I is: or a pharmaceutically acceptable salt thereof, the deoxyadenosine analog is gemcitabine, the platinum agent is cisplatin, and the immune checkpoint inhibitor is durvalumab. Such as the use of claim 28, wherein the solid tumor cancer is biliary tract cancer, head and neck cancer, chondrosarcoma, hepatocellular carcinoma, melanoma, pancreatic cancer, astrocytoma, oligodendritic glial cell tumor, glioma, Glioblastoma, bladder, colorectal or lung cancer. Such as the use of claim 29, wherein the solid tumor cancer is biliary tract cancer. Such as the use of claim 30, wherein the biliary tract cancer is advanced biliary tract cancer.