Combination therapy for treating cancer

Abstract

The present disclosure generally relates to therapeutic combinations and to corresponding methods of treatment, pharmaceutical compositions, and kits.

Description

Background Art

[0001] Although many advances have been made in cancer treatment, patients still need new and effective therapies. Summary of the Invention

[0002] AZD5305 (5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide) is a small molecule drug that acts by selectively inhibiting and trapping PARP1 at the sites of DNA single-strand breaks (SSBs). This prevents DNA repair and, during DNA replication, when the DNA replication machinery collides with the PARP1-DNA non-covalent complex, leads to the generation of more harmful DNA double-strand breaks (DSBs). In cells where the precise DNA repair pathway is effective, such as in cells with intact homologous recombination repair (HRR), the DSBs are precisely repaired. In contrast, in cells with defective repair pathways, such as those with deleterious mutations in the BRCA genes, AZD5305 treatment leads to the selective accumulation of genomic instability and ultimately selectively kills cancer cells while sparing normal cells.

[0003] Platinum chemotherapeutic agents are drugs used to treat cancer and are often present in first-line treatment settings. Examples of platinum chemotherapeutic agents include cisplatin, oxaliplatin, and carboplatin.

[0004] In some embodiments, a method of treating cancer in a human subject in need thereof is disclosed, the method comprising administering to the human subject a first amount of AZD5305 or a pharmaceutically acceptable salt thereof, and a second amount of a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof; wherein the first amount and the second amount together constitute a therapeutically effective amount.

[0005] In some embodiments, the cancer is ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer (such as gastric cancer and colorectal cancer), or lung cancer.

[0006] In some embodiments, the cancer is a homologous recombination defective (HRD) cancer. For example, it can be determined whether the cancer is HRD-positive by Myriad Genetics HRD or HRD Plus assay.

[0007] In certain embodiments, the cancer cell comprises an HRD gene mutation selected from: BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L gene mutations. In certain embodiments, the cancer cell comprises BRCA1, BRCA2, and / or ATM gene mutations. In certain embodiments, the cancer cell comprises BRCA1 and / or BRCA2 gene mutations. For example, in certain embodiments, the cancer cell comprises a tBRCA gene mutation.

[0008] In certain embodiments of the methods disclosed herein, the cancer comprises a homologous recombination deficiency (HRD)-positive status defined by a deleterious or suspected deleterious BRCA mutation and / or genomic instability.

[0009] In certain embodiments of the methods disclosed herein, the cancer is ovarian cancer or breast cancer. In certain embodiments of the methods disclosed herein, the cancer is ovarian cancer. In certain embodiments, the cancer is advanced epithelial ovarian cancer. In certain embodiments, the cancer is high-grade serous ovarian cancer. In certain embodiments, the cancer is high-grade endometrioid ovarian cancer. In certain embodiments, the cancer is epithelial ovarian cancer that comprises a gBRCA1 or gBRCA2 mutation. In certain embodiments of the methods disclosed herein, the cancer is fallopian tube cancer. In certain embodiments of the methods disclosed herein, the cancer is primary peritoneal cancer.

[0010] In certain embodiments, the cancer is ovarian cancer (such as advanced epithelial ovarian cancer), fallopian tube cancer, or primary peritoneal cancer.

[0011] In certain embodiments, the cancer is ovarian cancer (such as advanced epithelial ovarian cancer), fallopian tube cancer, or primary peritoneal cancer, and the cancer comprises a homologous recombination deficiency (HRD)-positive status defined by a deleterious or suspected deleterious BRCA mutation and / or genomic instability.

[0012] In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is triple-negative breast cancer.

[0013] In some embodiments, the cancer is platinum-resistant.

[0014] In some embodiments, a kit is disclosed, the kit comprising a first pharmaceutical composition comprising AZD5305 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof, and instructions for use. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1Shows the body weight changes of mice in the PDX model (HBCx-9) treated with AZD5305 monotherapy, carboplatin monotherapy, and combination therapy.

[0016] Figure 2 Shows the anti-tumor activity of the combination of AZD5305 and carboplatin in the PDX model (HBCx-9).

[0017] Figure 3 Shows the anti-tumor activity of the combination of AZD5305 and carboplatin in the PDX model (HBCx-9). Individual animal data are shown.

[0018] Figure 4 Shows the X-ray powder diffraction of form A of AZD5305.

[0019] Figure 5 Shows the body weight changes of mice in the xenograft model (SUM149PT) treated with AZD5305 monotherapy, carboplatin monotherapy, and combination therapy.

[0020] Figure 6 Shows the anti-tumor activity of the combination of AZD5305 and carboplatin in the xenograft model (SUM149PT).

[0021] Figure 7 Shows the body weight changes of mice in the PDX model (HBCx-9) treated with AZD5305 monotherapy, carboplatin monotherapy, and combination therapy.

[0022] Figure 8 Shows the anti-tumor activity of the combination of AZD5305 and carboplatin in the PDX model (HBCx-9).

[0023] Figure 9 Shows the anti-tumor activity of the combination of AZD5305 and carboplatin after treatment cessation in the PDX model (HBCx-9) treated with AZD5305 monotherapy, carboplatin monotherapy, and combination therapy. Detailed Description

[0024] In some embodiments, methods for treating cancer by combination therapy of AZD5305 and a platinum chemotherapeutic agent are disclosed. In some embodiments, the method comprises administering to a subject in need a first amount of AZD5305 or a pharmaceutically acceptable salt thereof, and a second amount of a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together constitute a therapeutically effective amount. In some embodiments, the platinum chemotherapeutic agent comprises any one of carboplatin, cisplatin, and oxaliplatin. In some embodiments, the platinum chemotherapeutic agent comprises carboplatin. In one embodiment, the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof is administered first, and then AZD5305 or a pharmaceutically acceptable salt thereof is administered. In one embodiment, AZD5305 or a pharmaceutically acceptable salt thereof is administered first, and then the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof is administered.

[0025] The term "AZD5305" refers to the following compound: having the chemical name 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, and having the structure shown below:

[0026]

[0027] The preparation of AZD5305 is disclosed herein (see Example 1). In some embodiments, the free base of AZD5305 is administered to the subject. In some embodiments, a pharmaceutically acceptable salt of AZD5305 is administered to the subject. In some embodiments, crystalline AZD5305 is administered to the subject. In some embodiments, polymorph A AZD5305 is administered to the subject.

[0028] The term "platinum-containing chemotherapeutic agent" includes drugs containing the metal platinum, such as cisplatin, carboplatin, and oxaliplatin.

[0029] In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof, and the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are administered separately, sequentially, or simultaneously. In one embodiment, the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof is administered first, and then AZD5305 or a pharmaceutically acceptable salt thereof is administered. In one embodiment, AZD5305 or a pharmaceutically acceptable salt thereof is administered first, and then the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof is administered.

[0030] In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof, and the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are administered separately, sequentially, or simultaneously in a treatment cycle.

[0031] As used herein, "cycle", "treatment cycle", or "dosing schedule" refers to a period of time for a combination treatment that is repeated on a regular schedule. For example, treatment can be administered for one week, two weeks, or three weeks, where AZD5305 and a platinum chemotherapeutic agent are administered in a coordinated manner. In some embodiments, the treatment cycle is from about 1 week to about 3 months. In some embodiments, the treatment cycle is from about 5 days to about 1 month. In some embodiments, the treatment cycle is from about 1 week to about 3 weeks. In some embodiments, the treatment cycle is about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or about 3 months.

[0032] In some embodiments, during one or more treatment cycles (e.g., a course of treatment), AZD5305 or a pharmaceutically acceptable salt thereof, and a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are administered to a human subject. A "course of treatment" includes multiple treatment cycles that can be repeated on a regular schedule or adjusted to a tapered schedule based on the monitored disease progression of the patient. For example, at the start of a course of treatment (e.g., when the patient is first diagnosed), the patient's treatment cycles can have longer treatment periods and / or shorter rest periods, and as the cancer remits, the rest periods are extended, thereby increasing the length of a treatment cycle. Throughout the course of treatment, one of ordinary skill in the art can determine and adjust the treatment and rest time periods in a treatment cycle, the number of treatment cycles, and the length of the course of treatment based on the patient's disease progression, treatment tolerance, and prognosis. In some embodiments, the method includes 1 to 10 treatment cycles. In some embodiments, the method includes 2 to 8 treatment cycles.

[0033] In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof is in capsule form. In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof is in tablet form.

[0034] The terms "treat", "treating", and "treatment" include reducing or inhibiting the activity of an enzyme or protein associated with PARP or cancer in a subject, ameliorating one or more symptoms of cancer in a subject, or slowing or delaying the progression of cancer in a subject. The terms "treat" and "treating" also include reducing or inhibiting the growth of a tumor or the proliferation of cancer cells in a subject.

[0035] The term "inhibit", "inhibition", or "inhibiting" includes a decrease in the baseline activity of a biological activity or process.

[0036] The term "cancer" includes, but is not limited to, diseases caused by the uncontrolled division of abnormal cells in a part of the body. In some embodiments, cancer includes cancers susceptible to treatment with a PARP inhibitor (such as AZD5305). In some embodiments, the cancer is ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer. In some embodiments, the cancer is a blood cancer, a gastrointestinal cancer (such as gastric cancer and colorectal cancer), or a lung cancer. In some embodiments, the cancer is a recurrent or refractory cancer. In some embodiments, the cancer is a platinum-resistant cancer.

[0037] The term "pharmaceutical composition" includes: a composition comprising an active ingredient and a pharmaceutically acceptable excipient, carrier, or diluent, wherein the active ingredient is AZD5305 or a pharmaceutically acceptable salt thereof, or a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0038] In this specification, unless otherwise indicated, the term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, salts, and / or dosage forms that are suitable, within the scope of reasonable medical judgment, for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications (commensurate with a reasonable benefit / risk ratio).

[0039] The term "pharmaceutically acceptable excipient, carrier, or diluent" includes compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of reasonable medical judgment as determined by those skilled in the art, for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications. In some embodiments, the pharmaceutical composition is a solid dosage form, such as a capsule, tablet, granule, powder, sachet, etc. In some embodiments, the pharmaceutical composition is in the form of a sterile injectable solution in one or more aqueous or non-aqueous non-toxic parenterally acceptable buffer systems, diluents, solubilizers, co-solvents, or carriers. The sterile injectable preparation may also be a sterile injectable aqueous or oily suspension or suspension in a non-aqueous diluent, carrier, or co-solvent, which may be formulated according to known procedures using one or more suitable dispersing or wetting agents and suspending agents. The pharmaceutical composition may be a solution for intravenous bolus / infusion, or a lyophilized system (alone or with excipients) reconstituted with a buffer system with or without other excipients. The lyophilized lyophilized material may be prepared from a non-aqueous solvent or an aqueous solvent. The dosage form may also be a concentrate further diluted for subsequent infusion.

[0040] The term "subject" includes warm-blooded mammals such as primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, e.g., a human. In some embodiments, the subject has cancer, such as ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer. In some embodiments, the subject has cancer, such as blood cancer, gastrointestinal cancer (e.g., gastric cancer and colorectal cancer), or lung cancer. In some embodiments, the subject has ovarian cancer or breast cancer. In some embodiments, the subject has recurrent or refractory ovarian cancer. In some embodiments, the subject has recurrent or refractory breast cancer. In some embodiments, the subject has cancer and is treatment-naive (e.g., has never received treatment for cancer). In some embodiments, the subject has cancer and is platinum-resistant. Platinum-resistant disease is defined as progression within 6 months after the last administered platinum-based regimen. Platinum-refractory disease is defined as at least a lack of partial response during a platinum-containing regimen. Platinum-based regimens include drugs containing the metal platinum, such as cisplatin and carboplatin.

[0041] The term "therapeutically effective amount" includes an amount of AZD5305 and / or an amount of a platinum chemotherapeutic agent, such an amount that together will cause a biological or medical response in the subject, e.g., a decrease or inhibition of PARP or cancer-related enzyme or protein activity; improvement of cancer symptoms; or slowing or delaying of the progression of cancer. In some embodiments, the term "therapeutically effective amount" includes an amount of AZD5305 and a platinum chemotherapeutic agent together that is effective to at least partially alleviate, inhibit, and / or improve cancer or inhibit PARP, and / or reduce or inhibit the growth of a tumor or the proliferation of cancerous cells in the subject. In some embodiments, the term "therapeutically effective amount" includes an amount of AZD5305 and a platinum chemotherapeutic agent together that is effective to at least partially reduce or inhibit the growth of a tumor or the proliferation of cancerous cells in the subject.

[0042] In some embodiments, a kit is disclosed that comprises: a first pharmaceutical composition comprising AZD5305 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and a second pharmaceutical composition comprising carboplatin or a pharmaceutically acceptable salt; and instructions for using the first and second pharmaceutical compositions in combination. In some embodiments, the first pharmaceutical composition comprises a first amount of AZD5305 or a pharmaceutically acceptable salt thereof, and the second pharmaceutical composition comprises a second amount of a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof; wherein the first amount and the second amount together constitute a therapeutically effective amount.

[0043] Examples

[0044] The combination therapies disclosed herein will now be further explained by reference to the following non-limiting examples.

[0045] Example 1

[0046] Preparation of AZD5305

[0047] General experimental conditions

[0048] Unless otherwise stated, the data were acquired at 27 °C using a Bruker 300 MHz, 400 MHz, or 500 MHz spectrometer. 1 H NMR spectra; chemical shifts are expressed in parts per million (ppm, delta units) and are referenced to the residual unit concentration of the solvent. 1 H isotopologues (CHCl3: 7.24 ppm; CHDCl2: 5.32 ppm; CD3S(=O)CD2H: 2.49 ppm). Coupling constants are given in Hertz (Hz). Splitting patterns describe the apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and brs (broad peak). LC-MS was performed using a Waters UPLC equipped with a Waters SQD mass spectrometer or a Shimadzu LC-20AD LC-20XR LC-30AD equipped with a Shimadzu 2020 mass spectrometer. Unless otherwise stated, the reported molecular ions correspond to [M+H]+; for molecules with multiple isotopic patterns (Br, Cl, etc.), unless otherwise stated, the reported values ​​are those obtained for the lowest isotopic mass.

[0049] Flash chromatography was performed using the following: TM SP1 TM Purification system, from ISCO Rf or on Gilson from Thermo Fisher, using normal phase silica FLASH+ TM (40M, 25M or 12M) or SNAP TM KP-Sil cartridges (340, 100, 50 or 10), flash columns from Agela, silica gel-CS columns, straight phase flash chromatography using C18-flash columns, or standard flash chromatography. Generally, all solvents used are commercially available and are of analytical grade. Anhydrous solvents are routinely used for the reactions. The phase separator used in these examples is Phase separation column. The intermediates and examples named below were named using ACD / Name 12.01 from Advanced Chemistry Development, Inc. (ACD / Laboratories). Starting materials were obtained from commercial sources or prepared by literature routes.

[0050] XRPD analysis was performed using a Bruker D8 diffractometer, which is commercially available from Bruker AXS Inc TM )(Madison, Wisconsin). The XRPD spectrum was obtained by mounting a sample of the material to be analyzed (about 10 mg) on a single-crystal silicon wafer holder (e.g., a Bruker silicon zero-background X-ray diffraction sample holder) and spreading the sample into a thin layer by means of a microscope slide. The sample was rotated at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays having a wavelength of 1.5406 angstroms (i.e., about 1.54 Å) generated by a copper long-fine-focus tube operating at 40 kV and 40 mA. The sample was exposed for 1 second at each 0.02° 2-θ increment (continuous scan mode) in the 2-θ range from 5° to 40° in θ-θ mode. The running time of the D8 was 15 min.

[0051] The XRPD 2-θ values can vary within a reasonable range, e.g., within a range of ±0.2°, and the XRPD intensities may vary when measuring substantially the same crystal form for various reasons, including, for example, preferred orientation. The principles of XRPD are described in publications such as Giacovazzo, C. et al. (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R.L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; and Klug, H.P. and Alexander, L.E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York.

[0052] The following abbreviations are used: aq = aqueous; CH2Cl2 = dichloromethane; DCM = dichloromethane; DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DIPEA = N,N-diisopropylethylamine; DMSO = dimethyl sulfoxide; DMSO-d6 = deuterated dimethyl sulfoxide; ESI = electrospray ionization; MeCN or CH3CN = acetonitrile; NMR = nuclear magnetic resonance; Pd / C = palladium on carbon; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; HCl = hydrochloric acid; HBr = hydrobromic acid; Cs2CO3 = cesium carbonate; MgSO4 = magnesium sulfate; NaHCO3 = sodium bicarbonate; SOCl2 = thionyl chloride; NH4Cl = ammonium chloride; Na2SO4 = sodium sulfate; H2 = hydrogen gas.

[0053] Chemical synthesis

[0054]

[0055] Intermediate 2: Ethyl 6-formyl-5-nitropyridine-3-carboxylate

[0056] A mixture of ethyl 6-methyl-5-nitropyridine-3-carboxylate (Intermediate 1, 10 g, 47.58 mmol) and selenium dioxide (7.92 g, 71.36 mmol) in 1,4-dioxane (50 mL) was stirred at 110 °C for 20 h. The reaction mixture was cooled to room temperature, filtered through a pad of diatomaceous earth and the diatomaceous earth was washed with ethyl acetate. The combined filtrates were concentrated and the resulting residue was purified by flash silica chromatography (elution gradient 0% to 70% ethyl acetate in hexane). The product fractions were concentrated under reduced pressure to give ethyl 6-formyl-5-nitropyridine-3-carboxylate as a brown oil (Intermediate 2, 9.70 g, 91%). 1H NMR (500 MHz, chloroform-d) 1.48 (3H, t), 4.54 (2H, q), 8.81 (1H, d), 9.51 (1H, d), 10.32 (1H, s); m / z (ES + ) [M] + = 224.

[0057] Intermediate 3: Ethyl 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitropyridine-3-carboxylate (mixture of E / Z isomers) Intermediate 4: Ethyl 7-ethyl-6-oxo-7,8-dihydro-5H-1,5-naphthyridine-3-carboxylate

[0058] At 0 °C, ethyl 2-(diethoxyphosphoryl)butyrate (60.8 g, 240.89 mmol) was added dropwise to a stirred solution of sodium hydride (9.63 g, 240.89 mmol) (60%, in mineral oil) in anhydrous THF (100 mL) using an addition funnel to give a grey mixture. The resulting mixture was stirred at 0 °C for 10 min and warmed to room temperature over 10 minutes and stirred at 40 °C for 5 minutes. The reaction mixture was cooled to -78 °C and then a solution of ethyl 6-formyl-5-nitropyridine-3-carboxylate (Intermediate 2, 22.5 g, 100.37 mmol) in 100 mL of THF was added slowly to the cooled reaction mixture. The mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product. The resulting residue was purified by flash silica chromatography (elution gradient 0% to 50% ethyl acetate in hexanes). The product fractions were concentrated under reduced pressure to give ethyl 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitropyridine-3-carboxylate (Intermediate 3, 24.30 g, 75%) as a yellow oil (1:1 mixture of E / Z isomers). 1H NMR (500 MHz, chloroform-d) 1.13 (3H, t), 1.18 (3H, t), 1.23 (3H, t), 1.37 (3H, t), 1.45 (6H, q), 2.57 (2H, qd), 2.66 (2H, q), 4.11 - 4.24 (2H, m), 4.32 (2H, q), 4.45 - 4.56 (4H, m), 7.08 (1H, s), 7.85 (1H, s), 8.86 (2H, dd), 9.26 (1H, d), 9.43 (1H, d); m / z (ES + ) [M] + = 322

[0059] Intermediate 5: Ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylateA mixture of ethyl 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitropyridine-3-carboxylate (a 1:1 mixture of E / Z isomers) (Intermediate 3, 3.75 g, 11.63 mmol), Pd / C (1.857 g, 1.75 mmol) (10%) in ethanol (30 mL) was degassed, filled with H2 (balloon), and the reaction was stirred overnight at room temperature under a H2 atmosphere. The mixture was filtered through a bed of diatomaceous earth and the bed of diatomaceous earth was washed with ethanol. After concentration, 4M HCl in dioxane (15 mL) was added to the resulting residue and the mixture was stirred at room temperature for 30 min. The mixture was diluted with diethyl ether and the solid was filtered off, washed with diethyl ether, and dried in vacuo to give ethyl 7-ethyl-6-oxo-7,8-dihydro-5H-1,5-naphthyridine-3-carboxylate (Intermediate 4, 2.260 g, 78%) as a white solid. 1H NMR (500 MHz, DMSO-d6) 0.94 (3H, t), 1.33 (3H, t), 1.41 - 1.51 (1H, m), 1.69 - 1.81 (1H, m), 2.41 - 2.48 (1H, m), 2.94 (1H, dd), 3.20 (1H, dd), 4.35 (2H, t), 7.67 (1H, d), 8.61 (1H, d), 10.32 (1H, s); m / z (ES + ) [M + H] + = 249.

[0060] Intermediate 6: 3-Ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one

[0061] Ethyl 7-ethyl-6-oxo-7,8-dihydro-5H-1,5-naphthyridine-3-carboxylate (Intermediate 4, 2.26 g, 9.10 mmol) was dissolved in 1,4-dioxane (40 mL), DDQ (2.273 g, 10.01 mmol) was added and the mixture was stirred at reflux for 3 h. The solvent was removed under reduced pressure, saturated NaHCO3 solution was added and the residue was stirred at room temperature for 1 hr. The solid was filtered off, washed with water and then 10 mL of diethyl ether. The resulting solid was dried in vacuo to give ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (Intermediate 5, 1.738 g, 78%) as a light brown solid.

[0062] 1H NMR (500 MHz, DMSO-d6) 1.14 - 1.28 (3H, m), 1.35 (3H, t), 2.58 (2H, q), 4.38 (2H, q), 7.83 (1H, s), 8.17 (1H, s), 8.90 (1H, s), 12.05 (1H, s); m / z (ES + ) [M + H] + = 247.

[0063] Example 1: 5-[4-[(7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide

[0064] Lithium aluminum hydride (2 M, in THF (29.2 mL, 58.47 mmol)) was added dropwise to ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (Intermediate 5, 7.2 g, 29.24 mmol) in tetrahydrofuran (150 mL) under nitrogen over a 45-minute period at 0 °C. The resulting mixture was stirred at 0 °C for 1.5 h. The reaction mixture was quenched by the dropwise addition of 1 M aqHCl (29 mL). The reaction mixture was concentrated and the solid was diluted with water (ca. 150 mL) and 29 mL of 1 M HCl solution to give a yellow suspension. The solid was collected by filtration, washed with water, diethyl ether and dried to yield the crude product as a yellow solid (contaminated with some inorganic salts). This solid was suspended in a mixture of methanol and DCM (2:1) (400 mL) and heated to reflux. The solid was filtered off. This solid was redissolved in the methanol / DCM mixture and this procedure was repeated 5 times to remove most of the product from this mixture. The combined filtrates were then concentrated to ca. 100 mL and the solid was collected by filtration, washed with ether and dried in vacuo to give 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (Intermediate 6, 4.35 g, 72.8%). 1H NMR (500 MHz, DMSO-d6) 1.18 (3H, t), 2.52 - 2.56 (2H, m), 4.61 (2H, d), 5.44 (1H, t), 7.61 (1H, s), 7.74 (1H, s), 8.37 (1H, s), 11.87 (1H, br s); m / z (ES+) [M+H]+ = 205.3

[0065] Figure 4 Abbreviations or specific terms

[0066]

[0067] Thionyl chloride (6.41 mL, 88.14 mmol) was added dropwise to a suspension of 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (Intermediate 6, 3 g, 14.69 mmol) and N,N-dimethylformamide (0.114 mL, 1.47 mmol) in CH2Cl2 (60 mL) at 0 °C and the resulting solution was stirred at room temperature for 6 h. The mixture was concentrated to dryness to give crude 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one.

[0068] At 20 °C, DIPEA (12.83 mL, 73.45 mmol) was added to a stirred solution of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (crude, from above), potassium iodide (0.488 g, 2.94 mmol), and N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide 2HCl (Intermediate 7, 4.31 g, 14.69 mmol) in acetonitrile (50.00 mL). The resulting solution was stirred at 80 °C for 2 h. The solvent was removed in vacuo. The crude material was diluted with water, basified with aqueous NaHCO3, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the crude product. The resulting residue was purified by flash silica chromatography (elution gradient 0% to 15% MeOH in DCM). The product fractions were concentrated under reduced pressure to afford 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide as a pale grey partially crystalline solid (Example 1, 3.93 g, 65.8%). 1H NMR (500 MHz, DMSO-d6) 1.19 (3H, t), 2.53 - 2.59 (6H, m), 2.79 (3H, d), 3.33 - 3.39 (4H, m), 3.66 (2H, s), 7.39 (1H, dd), 7.64 (1H, s), 7.76 (1H, s), 7.83 (1H, d), 8.27 (1H, d), 8.36 - 8.40 (1H, m), 8.41 (1H, d), 11.85 (1H, s); m / z (ES + ) [M] + = 406.

[0069] Example 1 - Form A

[0070] In Example 1, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide was obtained as a partially crystalline solid by evaporation of the methanol / dichloromethane solution under reduced pressure. The crystalline material thus obtained was characterized as crystalline form A.

[0071] In the case of poor crystallinity, crystalline form A can be obtained by suspending 20 mg of the crude sample in 0.20 ml of water, methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, or other solvents at ambient temperature or at 50 °C for 1 day.

[0072] Form A was analyzed by XRPD and the results are tabulated below (Table 1) and shown in Description .

[0073] Table 1. XRPD peaks for Form A

[0074]

[0075]

[0076] Form A is characterized by providing at least one of the following 2θ values measured using CuKα radiation: 8.3, 12.4, and 19.4°.

[0077] Example 2

[0078] This in vivo study was conducted to investigate the anti-tumor effect of the combination of AZD5305 and carboplatin (a platinum chemotherapeutic agent) in a BRCA wild-type tumor model (HBCx-9, in vivo). The study design included a single-agent arm of AZD5305 and a single-agent arm of carboplatin as controls.

[0079] Materials and Methods

[0080] Abbreviations

[0081] 1 mole BRCA 1N Breast cancer susceptibility protein BRCAm BRCA-mutated CR Complete response HCl Hydrochloric acid HRD Homologous recombination DNA pathway defect NaCl Sodium chloride NaOH Sodium hydroxide PDX Patient-derived tumor xenograft PO Oral (per os) QD Once daily (quaquedie) (once a day) QD Once a week RB1 Retinoblastoma transcriptional corepressor 1 Reg Regression SC Subcutaneous SEM Standard error of the mean SLFN11 Schlafen family member 11 TGI Tumor growth inhibition TNBC Triple-negative breast cancer TV Tumor volume WT Wild type Figure 1 Figure 7

[0082] Survival

[0083] HBCx-9 is a patient-derived xenograft (PDX) model established by XenTech without prior in vitro culture. Tumor fragments were transplanted subcutaneously (SC) onto donor mice. When the tumor volume reached 700 to 1764 mm 3 ³, the donor mice were sacrificed, and the tumors were excised aseptically and dissected. After removing the necrotic areas, the tumors were cut into fragments approximately 20 mm 3 in size and transferred to the culture medium, and then SC transplanted into recipient (experimental) female nude mice. The tumors (length x width) were measured twice a week using a bilateral vernier caliper, and the tumor volume was calculated using the ellipse formula (π / 6 × width × width × length). During the entire study period, the animal body weights and tumor conditions were monitored. When the average tumor volume reached approximately 100 mm 3 ³, the mice were randomly assigned to the treatment groups. The animals were treated starting from the day after randomization. Control animals were treated orally (PO) once daily (QD) with the vehicle (deionized water acidified to pH 3.5 - 4 with HCl). AZD5305 was administered at 1 mg / kg PO QD. Carboplatin was administered at 50 mg / kg intraperitoneally (IP) once a week (QW). In the combination group, the mice were first administered carboplatin, followed by AZD5305 within 10 minutes.

[0084] Tumor growth inhibition from the start of treatment was evaluated by comparing the mean change in tumor volume between the control and treatment groups and expressed as the percentage of tumor growth inhibition (TGI, when TV ≥ starting TV) or regression (reg, when TV < starting TV). The percentage change in mean body weight from the start of treatment was also calculated for all groups. A one-tailed t-test was used to assess statistical significance. Statistical significance is expressed as follows: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.

[0085] Prior to initiating the efficacy study, a tolerance study was conducted in SCID female mice using a combination of AZD5305 at 10 mg / kg PO QD and carboplatin at 50 mg / kg IP QW, and no adverse effects on the general condition of the animals or significant changes in body weight were shown.

[0086] Formulation of test materials

[0087] AZD5305 was formulated for oral administration in a water / HCl pH 3.5 - 4 vehicle at a dose volume of 0.1 ml / 10 g. With stirring / vortexing / sonication, the solid was diluted by adding an appropriate volume of 1N HCl to a drug / HCl molar ratio of approximately 1:1.25 and 80% of the final volume of sterile deionized water until a solution was obtained. The volume of 1N HCl required was calculated according to the following equation:

[0088] Volume of 1N HCl added (ml) = 1.25 × [concentration (mg / ml) ÷ 406.48 (g / mol) ÷ 1 M] × final volume (ml)

[0089] The pH of the solution was adjusted to 3.5 to 4 with 1N HCl or 1N NaOH. The final volume was made up with sterile water for injection or deionized water, and the final pH was measured and recorded. The dosing formulation was prepared once a week and stored protected from light.

[0090] On each day of dosing, carboplatin was freshly formulated by diluting the stock solution to 5 mg / ml in 0.9% NaCl for a 50 mg / kg dose (0.1 ml / 10 g dose volume)

[0091] Results

[0092] HBCx-9 is a TNBC PDX model available from XenTech, France. It has been reported as a BRCAwt model with BRCA1 methylation [1]. HBCx-9 also shows moderate sensitivity to olaparib monotherapy [2].

[0093] In the efficacy study, AZD5305 at 1, 0.1, and 0.01 mg / kg QD and carboplatin at 50 mg / kg QW were tested as monotherapy and in combination. The treatment period lasted 28 days. All treatments were well tolerated throughout the study duration, and no significant weight loss was observed ( Figure 2 and Figure 3 AZD5305 monotherapy showed dose-dependent antitumor efficacy, producing 72% TGI; while 88% TGI was observed in the carboplatin monotherapy group. AZD5305 and carboplatin co-administration demonstrated a clear combination benefit by producing 88% tumor regression ( Figure 5 and Table 2). In addition, all animals (8 / 8) in the combination group achieved a complete response (CR; defined as TV < 14 mm 3 )( Figure 6 ).

[0094] In conclusion, in the HBCx-9 PDX in vivo model, the combination of AZD5305 and carboplatin demonstrated improved anti-tumor effects compared to each monotherapy. The combination of AZD5305 and carboplatin produced complete responses in 100% of animals and was well tolerated in mice.

[0095] Table 2: In vivo anti-tumour effects of AZD5305, carboplatin and the combination of these two agents in the HBCx-9 patient-derived explant model.

[0096]

[0097] [1] Coussy F, de Koning L, Lavigne M, et al. A large collection of integrated genomically characterized patient-derived xenografts highlighting the heterogeneity of triple-negative breast cancer. Int J Cancer. 2019; 145(7): 1902-1912. doi: 10.1002 / ijc.32266

[0098] [2] LC Riches (2020) Mol Cancer Ther 2020;19:13-25

[0099] Example 3

[0100] This study was conducted to investigate the anti-tumor effect of the combination of AZD5305 and carboplatin in a BRCA1 mutant tumor model (SUM149PT, in vivo). The study design included arms for AZD5305 monotherapy and carboplatin monotherapy as controls.

[0101] Materials and Methods

[0102] SUM149PT cells (2 × 10 6 cells) were implanted into the mammary fat pads (MFP) of female SCID mice (body weight > 18 g) together with 50% Matrigel. Tumors (length x width) were measured twice weekly by bilateral vernier calipers, and tumor volume was calculated using the ellipse formula (π / 6 × width × width × length). Animal body weight and tumor status were monitored throughout the study. When the mean tumor volume reached approximately 0.3 cm 3 , the mice were randomly assigned to treatment groups. Treatment of the animals began on the day after randomization. Control animals were treated with vehicle (deionized water acidified to pH 3.5 - 4 with HCl) orally (PO) once daily (QD) and PBS intraperitoneally (IP) once weekly (QW). AZD5305 was administered at 0.1, 0.03, or 0.01 mg / kg PO QD. Carboplatin was administered at 37.5 mg / kg IP QW. In the combination group, mice were first dosed with carboplatin, followed by AZD5305 administered within 10 minutes.

[0103] Tumor growth inhibition from the start of treatment was evaluated by comparing the mean change in tumor volume between the control and treatment groups and expressed as the percentage of tumor growth inhibition (TGI, when TV ≥ starting TV) or regression (reg, when TV < starting TV). The percentage change in mean body weight from the start of treatment was also calculated for all groups. A one-tailed t-test was used to evaluate statistical significance. Statistical significance was expressed as follows: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.

[0104] Prior to starting the efficacy study, a tolerance study was conducted in SCID female mice using the combination of AZD5305 at 10 mg / kg PO QD and carboplatin at 50 mg / kg IP QW, and no adverse effects on the general condition of the animals or significant changes in body weight were shown.

[0105] Formulation of Test Materials

[0106] AZD5305 was formulated for oral administration in a water / HCl pH 3.5 - 4 vehicle and administered at a dose volume of 0.1 ml / 10 g. With stirring / vortexing / sonication, the solid was diluted by adding an appropriate volume of 1N HCl to a drug / HCl molar ratio of approximately 1:1.25 and 80% of the final volume of sterile deionized water until a solution was obtained. The volume of 1N HCl required was calculated according to the following equation:

[0107] Volume of 1N HCl added (ml) = 1.25 × [concentration (mg / ml) ÷ 406.48 (g / mole) ÷ 1 M] × final volume (ml)

[0108] The pH of the solution was adjusted to 3.5 - 4 with 1N HCl or 1N NaOH. The final volume was made up with sterile water for injection or deionized water, and the final pH was measured and recorded. The dosing formulation was prepared once a week and stored protected from light.

[0109] On each day of dosing, carboplatin (Sigma Aldrich) was freshly prepared by diluting the stock solution to 3.75 mg / ml in 0.9% NaCl for a 37.5 mg / kg dose (0.1 ml / 10 g dose volume).

[0110] Results

[0111] In the SUM149PT TNBC BRCA1m xenograft model, in the efficacy study, AZD5305 at 0.1, 0.03, and 0.01 mg / kg QD and carboplatin at 37.5 mg / kg QW were tested as monotherapies and in combination. Throughout the 28 - day study duration, all treatments were well - tolerated and no significant weight loss was observed ( Figure 7 ). AZD5305 monotherapy showed dose - dependent antitumor efficacy, producing 24% TGI and 9% TGI at 0.1 mg / kg QD and 0.03 mg / kg QD, respectively. Administering AZD5305 at 0.01 mg / kg QD did not inhibit tumor growth. Carboplatin monotherapy produced 61% TGI. The combination of 0.1 mg / kg AZD5305 and carboplatin demonstrated a combinatorial benefit and produced 86% TGI. Even when the dose level of AZD5305 in combination with carboplatin was reduced to 0.03 mg / kg or 0.01 mg / kg, this antitumor effect was maintained (75% TGI and 79% TGI, respectively) ( Figure 8 and Table 3).

[0112] In summary, in the SUM149PT xenograft in vivo model, the combination of AZD5305 and carboplatin demonstrated improved anti-tumor efficacy compared to the monotherapy groups. Reducing the dose level of AZD5305 in combination with carboplatin by 10-fold (from 0.1 mg / kg to 0.01 mg / kg) did not affect the tumor growth inhibitory effect.

[0113] Table 3 Summary of the in vivo anti-tumor efficacy of AZD5305, carboplatin, and the combination of the two agents in the SUM149PT xenograft model.

[0114]

[0115] Example 4

[0116] This study was conducted to investigate the anti-tumor efficacy of the combination of AZD5305 and carboplatin at a range of doses in a BRCA1 / 2 wild-type tumor model (HBCx-9, in vivo). The study design included arms for AZD5305 monotherapy and carboplatin monotherapy as controls.

[0117] Materials and Methods

[0118] HBCx-9 is a patient-derived xenograft (PDX) model established by XenTech without prior in vitro culture. Tumor fragments were transplanted subcutaneously (SC) onto donor mice. When the tumor volume reached 1008 to 1764 mm3, the donor mice were sacrificed, and the tumors were excised aseptically and dissected. After removing the necrotic areas, the tumors were cut into fragments approximately 20 mm3 in size and transferred to medium, then SC transplanted into recipient (experimental) female nude mice. Tumors (length x width) were measured twice weekly using bilateral vernier calipers, and tumor volume was calculated using the ellipse formula (π / 6 × width × width × length). Animal body weight and tumor status were monitored throughout the study. When the mean tumor volume reached approximately 110 mm3, the mice were randomly assigned to treatment groups. Treatment of the animals began on the day after randomization. Control animals were treated once daily (QD) orally (PO) with vehicle (deionized water acidified to pH 3.5 - 4 with HCl). AZD5305 was administered at 1, 0.1, or 0.01 mg / kg PO QD. Carboplatin was administered at 50 mg / kg once weekly (QW) IP. In the combination group, the mice were first dosed with carboplatin, followed by AZD5305 within 10 minutes.

[0119] Tumor growth inhibition from the start of treatment was evaluated by comparing the mean change in tumor volume between the control and treatment groups and expressed as the percentage of tumor growth inhibition (TGI, when TV ≥ starting TV) or regression (reg, when TV < starting TV). The percentage change in mean body weight from the start of treatment was also calculated for all groups. A one-tailed t-test was used to assess statistical significance. Statistical significance is expressed as follows: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.

[0120] Prior to the start of the efficacy study, a tolerance study was conducted in SCID female mice using a combination of AZD5305 at 10 mg / kg PO QD and carboplatin at 50 mg / kg IP QW, and no adverse effects on the general condition of the animals or significant changes in body weight were shown.

[0121] Samples for plasma PK were obtained by collecting 400 - 600 μL of whole blood by cardiac puncture under xylazine-ketamine anesthesia. The blood was transferred to a BD Microtainer Hep-Li with separator gel tube and centrifuged at 5000 RPM for 5 - 10 minutes at 4°C. The separated plasma was collected and stored at -80°C. To determine the compound level in the plasma samples, each plasma sample (25 μl) was prepared with an appropriate dilution factor and compared to an 11-point standard calibration curve (1 - 10000 nM) prepared in DMSO and spiked into blank plasma. Acetonitrile (100 μl) was added together with the internal standard, and then centrifuged at 3000 RPM for 10 minutes. The supernatant (50 μl) was then diluted in 300 μl of water and analyzed via UPLC-MS / MS.

[0122] Formulation of test materials

[0123] AZD5305 was formulated for oral administration in a water / HCl pH 3.5 - 4 vehicle at a dose volume of 0.1 ml / 10 g. The solid was diluted with stirring / vortexing / sonication by adding an appropriate volume of 1N HCl to a drug / HCl molar ratio of approximately 1:1.25 and 80% of the final volume of sterile deionized water until a solution was obtained. The volume of 1N HCl required was calculated according to the following equation:

[0124] Volume of 1N HCl added (ml) = 1.25 × [concentration (mg / ml) ÷ 406.48 (g / mol) ÷ 1 M] × final volume (ml)

[0125] The pH of the solution was adjusted to 3.5 - 4 with 1N HCl or 1N NaOH. The final volume was made up with sterile water for injection or deionized water, and the final pH was measured and recorded. The dosing formulation was prepared once a week and stored protected from light.

[0126] On each day of dosing, carboplatin (Sandoz) was freshly prepared for a 50 mg / kg dose (0.1 ml / 10 g dose volume) by diluting the stock solution to 5 mg / ml in 0.9% NaCl.

[0127] Results

[0128] HBCx-9 is a TNBC PDX model available from XenTech, France. It has been reported as a BRCA1 / 2wt model with BRCA1 methylation and a “BRCAness signature” [1]. HBCx-9 also shows moderate sensitivity to olaparib monotherapy [2].

[0129] In the efficacy study, AZD5305 at 1, 0.1, and 0.01 mg / kg QD and carboplatin at 50 mg / kg QW were tested as monotherapies and in combination. Throughout the study duration (28 days), all treatments were well tolerated and no significant weight loss was observed ( Figure 3 ). AZD5305 monotherapy showed dose-dependent antitumor efficacy, producing 66%, 44%, and 7% TGI at 1, 0.1, and 0.01 mg / kg QD, respectively. Carboplatin monotherapy produced 68% TGI. Treatment with 1 mg / kg AZD5305 and carboplatin demonstrated a combinatorial benefit and produced 90% regression. Even when the dose level of AZD5305 in combination with carboplatin was reduced to 0.1 mg / kg, this antitumor effect was maintained (86% regression). When carboplatin was combined with 0.01 mg / kg of AZD5305, the effect was slightly worse (49% TGI). However, even this group produced a combinatorial benefit when compared to either monotherapy arm ( Figure 9 and Table 4).

[0130] In this experiment, treatment was continued for 28 days and then the duration of response was monitored after treatment cessation. ​ The insets depict the most effective groups (carboplatin combined with AZD5305 at 1 or 0.1 mg / kg), where tumors began to regrow at approximately 49 days (3 weeks after treatment cessation) and the regrowth rate was similar in both groups. Additionally, in the carboplatin + 0.01 mg / kg AZD5305 group, tumors began to regrow approximately 2 weeks after treatment discontinuation, ​ .

[0131] In summary, in the HBCx-9 PDX in vivo model, the combination of AZD5305 and carboplatin demonstrated improved anti-tumor efficacy compared to the monotherapy group. Reducing the dose level of AZD5305 in combination with carboplatin by 10-fold (from 1 mg / kg to 0.1 mg / kg) did not affect the tumor regression effect. Table 4 summarizes the in vivo anti-tumor efficacy of AZD5305, carboplatin, and the combination of the two agents in the HBCx-9 model.

[0132]

[0133] ***********

[0134] This written description uses examples to disclose the invention and enable those skilled in the art to practice the invention, including making and using any salts, substances, or compositions disclosed herein, and performing any methods or processes disclosed herein. The patentable scope of the invention is defined by the claims and may include other examples that occur to those skilled in the art. If such other examples have elements that are identical to the literal language of the claims, or if they include equivalent elements that have non-substantial differences from the literal language of the claims, then these examples are intended to be covered by the scope of the claims. While the preferred embodiments of the invention have been shown and described in this specification, such embodiments are provided by way of example only and are not intended to limit the scope of the invention in any other way. Various alternatives to the described embodiments of the invention may be employed in practicing the invention. The section headings used in this section and throughout the disclosure are not intended to be limiting.

[0135] All of the above references (patent and non-patent) are incorporated by reference into this patent application. The discussion of these references is only intended to summarize the assertions made by their authors. No admission is made that any reference (or any part of any reference) is relevant prior art (or is prior art). The applicant reserves the right to challenge the accuracy and relevance of the cited references.

Claims

1. Use of a first amount of AZD5305 or a pharmaceutically acceptable salt thereof and a second amount of a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of triple-negative breast cancer in a human subject in need thereof; wherein the first amount and the second amount together constitute a therapeutically effective amount, the platinum chemotherapeutic agent is carboplatin, and the AZD5305 has the following structure:

2. The use according to claim 1, wherein the triple-negative breast cancer is a homologous recombination defective cancer and the cancer cells contain a BRCA1 gene mutation.

3. The use according to claim 1 or 2, wherein the AZD5305 is in the form of the free base.

4. A kit comprising: A first pharmaceutical composition comprising AZD5305 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and A second pharmaceutical composition comprising a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and instructions for use, wherein the platinum chemotherapeutic agent is carboplatin, and the AZD5305 has the following structure:

5. A pharmaceutical product comprising i) AZD5305 or a pharmaceutically acceptable salt thereof, and ii) a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof, wherein the platinum chemotherapeutic agent is carboplatin, and the AZD5305 has the following structure:

6. The pharmaceutical product according to claim 5, wherein the AZD5305 or a pharmaceutically acceptable salt thereof and the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are present in a single dosage form.

7. The pharmaceutical product according to claim 5, wherein the AZD5305 or a pharmaceutically acceptable salt thereof and the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are present in separate dosage forms.

8. The pharmaceutical product according to any one of claims 5-7, wherein the AZD5305 is in the form of the free base.

Images