(s,e)-n-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide for treating cancer

Abstract

The present disclosure describes methods of treating a patient suffering from cancer comprising administering to the patient a therapy comprising Compound A: (A), or a pharmaceutically acceptable salt thereof. The cancer can be a microsatellite instability (MSI-H) cancer and / or a mismatch repair deficient (dMMR) solid tumor. Compound A can be administered as a monotherapy or as a combination therapy with an anti-PD1 antibody.

Description

VVID-765PC 184200.00318 METHODS FOR TREATING CANCERS USING INHIBITORS OF WERNER SYNDROME ATP-DEPENDENT HELICASE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application serial no.63 / 776,364 filed March 24, 2025, the contents of which are incorporated by reference herein in their entirety.FIELD

[0002] The present disclosure describes methods of using a covalent, irreversible inhibitor of WRN ATP-Dependent Helicase (WRNi) and an anti-PD1 antibody to treat microsatellite instability cancers and / or mismatch repair deficient cancers.BACKGROUND

[0003] Microsatellite instability (MSI-H) is a genetic feature of a subset of tumors harboring deficits of the Mismatch repair pathway, and MSI-H status is frequently observed across diverse indication including endometrial, stomach cancer, and colorectal cancer. In recent years, the development of immunotherapies revolutionized the management of several oncological indications and particularly high effectiveness of these therapies has been demonstrated in tumors presenting MSI-H status leading to clinical approval of these agents for this subset of patients. Despite the high effectiveness of Checkpoint Inhibitors (CPI) in MSI-H tumors approximately 50% of these patients do not respond to CPI supporting the development of novel therapeutic approaches for these patients.

[0004] Treatment standards for MSI and / or mismatch repair deficient (dMMR) tumors have shifted in recent years with the approval of several checkpoint inhibitors. While responses to immune checkpoint blockade in MSI and / or dMMR solid tumors are often durable, 40% to 70% of such cancers do not respond to immune checkpoint blockade or develop secondary resistance, and the use of checkpoint inhibitors can be limited by toxicity. Thus, novel therapies are needed for patients with MSI and / or dMMR tumors.

[0005] Different checkpoint inhibitors (e.g., anti-PD1 antibodies) have been approved for the treatment of refractory dMMR / MSI solid tumors, such as pembrolizumab, dostarlimab, cemiplimab, and nivolumab with or without ipilimumab. Despite high response rates and durable responses observed with these checkpoint inhibitors, a significant proportion of dMMR / MSI tumors do not respond or evolve resistance mechanisms (Schoenfeld, AJ and Hellmann, MD, “Acquired Resistance to Immune Checkpoint Inhibitors,” Cancer Cell, 2020, 37, 443-455). Further, adding a second checkpoint inhibitor to an anti-PD1 therapy may improve PD1 inhibitor efficacy but may also come at the cost of serious, life-threateningVVID-765PC 184200.00318 irreversible adverse events and higher patient burden regarding sequential IV administration and scheduling. Thus, a need exists for methods for treating tumors that have developed resistance to or are unresponsive to checkpoint inhibitor, e.g., anti-PD1, therapy.SUMMARY

[0006] Provided herein are methods of treating a patient suffering from a MSI-H cancer and / or a dMMR solid tumor comprising administering to the patient a therapy comprising Compound A:or a pharmaceutically acceptable salt thereof, and an anti-PD1 antibody, as described herein.

[0007] The disclosure also provides Compound A, or a pharmaceutically acceptable salt thereof, for use in treating a MSI-H cancer and / or a dMMR solid tumor, wherein Compound A is administered in combination with an anti-PD1 antibody, as described herein.

[0008] The disclosure also provides a method of treating cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of Compound A:(A), or a pharmaceutically acceptable salt thereof, and an anti-PD1 antibody, wherein the cancer is a microsatellite instability high (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

[0009] The disclosure also provides a combination therapy comprising Compound A:(A), or a pharmaceutically acceptable salt thereof, andVVID-765PC 184200.00318 an anti-PD1 antibody for use in treating a cancer, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

[0010] The disclosure also provides methods of treating cancer, the method comprising administering to the patient in need thereof a therapeutically effective amount of Compound A:N NH(A), or a pharmaceutically acceptable salt thereof, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both. In some embodiments, Compound A is administered in a monotherapy.NH

[0011] The disclosure also provides CompoundA, or a pharmaceutically acceptable salt thereof, for use in treating a cancer, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, may be a monotherapy.

[0012] Further aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description, taken in conjunction with the drawings. While the compounds and methods disclosed herein are susceptible of cases in various forms, the description hereafter includes specific cases with the understanding that the disclosure is illustrative and is not intended to limit the invention to the specific cases described herein.DETAILED DESCRIPTION

[0013] The disclosure provides methods of treating a patient suffering from cancer comprising administering to the patient a therapy comprising Compound AVVID-765PC184200.00318(A), or a pharmaceutically acceptable salt thereof, and an anti-PD1 antibody, wherein Compound A is administered in a total daily dose of 150 mg to 4000 mg based upon free base weight of Compound A, and the cancer is a microsatellite instability (MSI-H) cancer and / or a mismatch repair deficient (dMMR) solid tumor.

[0014] The disclosure also provides a method of treating cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of Compound A:(A), or a pharmaceutically acceptable salt thereof, and an anti-PD1 antibody, wherein the cancer is a microsatellite instability high (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

[0015] The disclosure also provides a combination therapy comprising Compound A:(A), or a pharmaceutically acceptable salt thereof, and an anti-PD1 antibody for use in treating a cancer, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

[0016] The disclosure also provides Compound A, or a pharmaceutically acceptable salt thereof, for use in treating a microsatellite instability (MSI-H) cancer and / or a mismatch repair deficient (dMMR) solid tumors, as described herein.

[0017] In some embodiments, the therapy of Compound A and an anti-PD1 antibody is administered for at least 3 weeks (e.g., 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks or more). In some embodiments, the therapy is administered for at least 6 months (e.g., 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or more).VVID-765PC 184200.00318

[0018] The disclosure also provides a method of treating cancer, the method comprising administering to the patient in need thereof a therapeutically effective amount of Compound A:NH(A), or a pharmaceutically acceptable salt thereof, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both. In some embodiments, Compound A is administered in a monotherapy.NH

[0019] The disclosure also provides CompoundA, or a pharmaceutically acceptable salt thereof, for use in treating a cancer, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both. In some embodiments, Compound A is administered in a monotherapy.

[0020] In some embodiments, the monotherapy of Compound A is administered for at least 3 weeks (e.g., 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks or more). In some embodiments, the therapy is administered for at least 6 months (e.g., 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or more).

[0021] As used herein, the terms “patient” and “subject” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (e.g., non-human animals) and humans. Particular patients or subjects are mammals (e.g., humans). The terms patient and subject include males and females. In some embodiments, the subject is human.Compound A, Salts thereof, Doses and Dosing Regimens

[0022] Compound A has an IIIPAC name of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide. International Patent Publication WO 2024 / 010782 describes Compound A and how to synthesize it (Example 87), the disclosure of which is incorporated by reference in its entirety. Compound A is a covalent, irreversible inhibitor of WRN helicase that causes DNA damageVVID-765PC 184200.00318 accumulation and has selective antitumor activity in MSI cell lines and in vivo mouse models, including patient-derived models.

[0023] Compound A can be administered in a pharmaceutically acceptable salt form, which can be an acid salt or a base salt. The corresponding pharmaceutically acceptable salts with acids can be obtained by standard methods known to the person skilled in the art, e.g., by dissolving Compound A in a suitable solvent such as e.g., dioxan or THF and adding an appropriate amount of the corresponding acid. The products can usually be isolated by filtration or by chromatography. The conversion of Compound A into a pharmaceutically acceptable salt with a base can be carried out by treatment of such a compound with such a base. One possible method to form such a salt is e.g. by addition of 1 / n equivalents of a basic salt such as e.g. M(OH)n, wherein M = metal or ammonium cation and n = number of hydroxide anions, to a solution of the compound in a suitable solvent (e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and to remove the solvent by evaporation or lyophilization.

[0024] Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutamate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such salts include, but are not limited to, alkali metal, alkaline earth metal, aluminum salts, ammonium, N+(C1-4alkyl)4 salts, and salts of organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine.VVID-765PC 184200.00318 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0025] The disclosed methods comprise administering Compound A, or a pharmaceutically acceptable salt thereof, in a combination therapy or as a monotherapy. When administered in a combination therapy, compound A, or a pharmaceutically acceptable salt thereof, may be administered with an anti-PD1 antibody.

[0026] The term “combination” in the present invention is used as known to persons skilled in the art. The combination comprises or consists of Compound A, or a pharmaceutically acceptable salt, and an additional agent such as an anti-PD1 antibody. “Combination” for the purposes of the invention comprises fixed combinations, combination packs, kit-of-parts, non-fixed combinations and / or components (Compound A, an anti-PD1 antibody), which are administered simultaneously or sequentially. The term “the components” refers to Compound A or a pharmaceutically acceptable salt thereof, and an anti-PD1 antibody, i.e. one component of the combination according to the invention is Compound A or a pharmaceutically acceptable salt thereof and the other component is anti-PD1 antibody. The combination according to the invention can also comprise further components.

[0027] In some embodiments, the combination may be a fixed combination. A “fixed combination” in the present invention is used as known to persons skilled in the art. It is defined as a combination comprising or containing Compound A and anti-PD1 antibody within one pharmaceutical dosage form or in one single entity. One example of a “fixed combination” is a pharmaceutical composition, wherein Compound A and anti-PD1 antibody are present in admixture. Another example of a “fixed combination” is a pharmaceutical combination, wherein Compound A and anti-PD1 antibody are present in one dosage form without being in admixture. Another example of a “fixed combination” is a pharmaceutical combination, wherein Compound A and anti-PD1 antibody are present at least partially admixture.

[0028] ’’Pharmaceutical dose form” and ’’dosage form” are synonyms. ’’Pharmaceutical dose form” or ’’dosage form” is the physical manifestation of a product that contains or comprises the active ingredient and / or inactive ingredients (e.g. carrier, excipients) that are intended to be delivered to the patient. ’’Dosage form” is the term used in the European Pharmacopoeia. ’’Dosage form” was previously used in Standard Terms, but the termVVID-765PC 184200.00318 “pharmaceutical dose form” is now used in order to harmonise with the vocabulary that is used across the Identification of Medicinal Products project (cf. https: / / www.edqm.eu / sites / default / files / standard_terms_introduction_and_guidance_for_use. pdf). Common dosage forms include pill, tablet, capsule, syrup, aerosol, liquid injection, powder, or solid crystal, and so on.

[0029] In some embodiments, the combination may be a combined pharmaceutical dose form. The “combined pharmaceutical dose form” is used to combine two or more pharmaceutical dose forms into a single term, in order to describe a medicinal product that consists of two or more manufactured items that are intended to be combined to produce a single pharmaceutical product for administration to the patient. A combined pharmaceutical dose form is not used to combine pharmaceutical dose forms that are packaged together, but administered separately rather than being combined to produce a single pharmaceutical product (see instead combination packs).

[0030] In some embodiments, the combination may be a non-fixed combination (e.g., loose combination) or kit-of-parts. A “non-fixed combination” or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination, wherein Compound A and anti-PD1 antibody are present in more than one unit or dosage form. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered, through the same route and form of administration or through different routes and form of administration.

[0031] The non-fixed combination or kit-of-parts is particularly advantageous if the separate components are administered in different dose forms, at different dose intervals, and / or via different routes. For example, in some embodiments, Compound A may be administered through one route (e.g., orally) on a daily basis and an anti-PD1 antibody may be administered through a different route (e.g., intravenously) at least 30 minutes, 60 minutes, 90 minutes, 120 minutes, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, or 3 weeks after the first daily administration of Compound A. In some other embodiments, Compound A may be provided in a package on its own. The package may also contain a user manual with information on additional combination partner(s) that may be added and administration instructions thereof. The additional combination partner(s) may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered with Compound A administration.

[0032] In some embodiments, the combination may be a combination pack.VVID-765PC 184200.00318

[0033] In a “combination pack” active substances are included in separate dosage forms marketed in the same package. The combination pack is used to combine two or more dose forms to describe products that are packaged together but are administered separately, sequentially, simultaneously, concurrently or chronologically staggered as independent pharmaceutical products. A combination is different from a combined pharmaceutical dose form.

[0034] In some embodiments, Compound A and an anti-PD1 antibody are administered successively or separately. In some embodiments, the compounds may be administered in at least two separate dosage forms. In some embodiments, the separate dosage forms are identical. In some embodiments, the separate dosage forms are different (e.g., orally and intravenously).

[0035] The release of one or more agents of the combination can also be controlled, where appropriate, to provide the desired therapeutic activity when in a single dosage form, combination pack, kit-of-parts or when in separate independent dosage forms.

[0036] The disclosed methods comprise administering Compound A, or a pharmaceutically acceptable salt, in a suitable dosage form (e.g., pharmaceutical composition). Suitable pharmaceutical compositions containing Compound A, or a pharmaceutically acceptable salt thereof, for use according to the disclosure and one or more therapeutically inert carriers, diluents, or excipients, as well as a method to prepare such a pharmaceutical compositions. In one example, the compound of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e. , carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0037] The disclosed methods comprise administering Compound A (or salt thereof) at a total daily dose of 150 mg to 4000 mg based upon free base weight of Compound A, for example, a total daily dose of 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg,VVID-765PC 184200.00318 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, 1875 mg, 1900 mg, 1925 mg, 1950 mg, 1975 mg, 2000 mg, 2025 mg, 2050 mg, 2075 mg, 2100 mg, 2125 mg, 2150 mg, 2175 mg, 2200 mg, 2225 mg, 2250 mg, 2275 mg, 2300 mg, 2325 mg, 2350 mg, 2375 mg, 2400 mg, 2425 mg, 2450 mg, 2475 mg, 2500 mg, 2525 mg, 2550 mg, 2575 mg, 2600 mg, 2625 mg, 2650 mg, 2675 mg, 2700 mg, 2725 mg, 2750 mg, 2775 mg, 2800 mg, 2825 mg, 2850 mg, 2875 mg, 2900 mg, 2925 mg, 2950 mg, 2975 mg, 3000 mg, 3025 mg, 3050 mg, 3075 mg, 3100 mg, 3125 mg, 3150 mg, 3175 mg, 3200 mg, 3225 mg, 3250 mg, 3275 mg, 3300 mg, 3325 mg, 3350 mg, 3375 mg, 3400 mg, 3425 mg, 3450 mg, 3475 mg, 3500 mg, 3525 mg, 3550 mg, 3575 mg, 3600 mg, 3625 mg, 3650 mg, 3675 mg, 3700 mg, 3725 mg, 3750 mg, 3775 mg, 3800 mg, 3825 mg, 3850 mg, 3875 mg, 3900 mg, 3925 mg, 3950 mg, 3975 mg, or 4000 mg Compound A (or salt thereof) based upon free base weight of Compound A.

[0038] In some embodiments, the total daily dose is 150 mg to 2000 mg, 200 mg to 4000 mg, 300 mg to 3750 mg, 400 mg to 3500 mg, 500 mg to 3250 mg, 600 mg to 3000 mg, 700 mg to 2750 mg, 800 mg to 2500 mg, 900 mg to 2250 mg, 1000 mg to 2000 mg, or 1250 mg to 1750 mg Compound A (or salt thereof), based upon free base weight of Compound A.

[0039] In some embodiments, the total daily dose is 150 mg to 200 mg, 250 mg to 300 mg, 400 mg to 500 mg, 800 mg to 1000 mg, 1500 mg to 1700 mg, 2000 mg to 3000 mg, 3500 mg to 4000 mg, or 893 mg to 1619 mg Compound A (or salt thereof), based upon free base weight of Compound A.

[0040] In some embodiments, the disclosed methods comprise administering a total daily dose of 150 mg to 2000 mg Compound A (or salt thereof), based upon free base weight of Compound A.

[0041] In some embodiments, the disclosed methods comprise administering a total daily dose of 150 mg Compound A (or salt thereof), based upon free base weight of Compound A, or a total daily dose of 300 mg Compound A (or salt thereof), based upon free base weight of Compound A, or a total daily dose of 600 mg Compound A (or salt thereof), based upon free base weight of Compound A, or a total daily dose of 1200 mg Compound A (or salt thereof), based upon free base weight of Compound A, or a total daily dose of 2000 mg Compound A (or salt thereof), based upon free base weight of Compound A, or a total daily dose of 2400 mg Compound A (or salt thereof), based upon free base weight of Compound A, or a total daily dose of 4000 mg Compound A (or salt thereof), based upon free base weight of Compound A.VVID-765PC 184200.00318

[0042] The disclosed methods comprise administering Compound A or a pharmaceutically acceptable salt thereof on a suitable schedule. In some embodiments, Compound A or a salt thereof is administered orally once daily. In some embodiments, Compound A or a salt thereof is administered orally twice daily. In some embodiments, Compound A or a salt thereof is administered orally three times daily.

[0043] In some embodiments, Compound A is administered orally in a dose of 150 mg to 1000 mg (e.g., 150 mg to 600 mg) once daily, twice daily, or three times daily, based upon free base weight of Compound A. For instance, in some embodiments, Compound A is administered orally a dose of 150 mg once daily, based upon free base weight of Compound A. In some embodiments, Compound A is administered orally a dose of 150 mg twice daily, based upon free base weight of Compound A. In some embodiments, Compound A is administered orally a dose of 200 mg twice daily, based upon free base weight of Compound A. In some embodiments, Compound A is administered orally a dose of 200 mg three times daily, based upon free base weight of Compound A. In some embodiments, Compound A is administered orally a dose of 300 mg twice daily, based upon free base weight of Compound A. In some embodiments, Compound A is administered orally a dose of 600 mg twice daily, based upon free base weight of Compound A. In some embodiments, Compound A is administered orally a dose of 600 mg three times daily, based upon free base weight of Compound A. In some embodiments, Compound A is administered orally a dose of 1000 mg twice daily, based upon free base weight of Compound A. In some embodiments, Compound A is administered orally a dose of 150 mg twice daily or 600 mg twice daily, based upon free base weight of Compound A.

[0044] Advantageously, in some embodiments, the dose of Compound A or a salt thereof adopted in the disclosed methods achieves manageable safety, favorable pharmacokinetics and / or promising anti-tumor activity / disease control in association with molecular and metabolic responses, as evaluated by parameters including but are not limited to Cmax, Ctrough, gastrointestinal toxicity, treatment-emergent adverse events (TRAEs), clinical benefit rate, and disease control rate (DCR).

[0045] Compound A or salt thereof can be administered as a pharmaceutical composition. The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. In particular, it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or fromVVID-765PC 184200.00318 dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

[0046] Pharmaceutical compositions can be obtained by processing Compound A as described herein with pharmaceutically acceptable, inorganic, or organic carriers or excipients. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0047] The pharmaceutical compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0048] Pharmaceutical compositions containing Compound A, or a pharmaceutically acceptable salt thereof, include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered orally. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. In general, the pharmaceutical compositions can be prepared by uniformly and intimately bringing into association Compound A with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Pharmaceutical compositions suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of Compound A as an active ingredient. In some embodiments, Compound A is administered in as an oral dosage form. In some embodiments, the tablet is a film-coated tablet. Film coated tablets are known in the art.

[0049] Compound A can be administered to patients in either a fasted state or a fed state. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof isVVID-765PC 184200.00318 administered when the patient is in a fasted state. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered when the patient is in a fed state.

[0050] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range and each endpoint, unless otherwise indicated herein, and each separate value and endpoint is incorporated into the specification as if it were individually recited herein.

[0051] In some instances, Compound A or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount. In some instances, the total daily dose administered is a therapeutically effective amount. As used herein, the term “therapeutically effective amount” refers to an amount of a compound or combination of therapeutically active compounds (e.g., more than one of the compounds disclosed herein) that ameliorates, attenuates or eliminates one or more symptoms of a particular disease or condition (e.g., cancer), or prevents or delays the onset of one of more symptoms of a particular disease or condition. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

[0052] The term “pharmaceutically acceptable” as used herein means that the referenced substance, such as a compound of the present disclosure, or a formulation containing the compound, or a particular excipient, are safe and suitable for administration to a patient or subject. The term “pharmaceutically acceptable excipient” refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered.Anti-PD1 antibody

[0053] The disclosed methods comprise administering Compound A or a pharmaceutically acceptable salt thereof and an anti-PD1 antibody. Anti-PD-1 antibodies target the programmed death-1 (PD-1) receptor on T cells. By blocking this receptor, these antibodies prevent its interaction with PD-L1, a protein often overexpressed on cancer cells, which normally inhibits T-cell activation and proliferation. This blockade enhances the immune response against cancer cells, allowing T cells to recognize and attack tumors more effectively.

[0054] In some embodiments, the anti-PD1 antibody is cemiplimab, dostarlimab, pembrolizumab, or nivolumab. In some embodiments, the anti-PD1 antibody ispembrolizumab.VVID-765PC 184200.00318

[0055] The anti-PD1 antibody is administered in a suitable amount. By way of example, in some embodiments when the anti-PD1 antibody is pembrolizumab, the methods comprise administering 200 mg pembrolizumab via IV administration every three weeks. See KEYTRUDA® product insert, which can be found at: www.merck.com / product / usa / pi_circulars / k / keytruda / keytruda_pi. pdf (revised January 2025).MSI-H and dMMR Cancers

[0056] The disclosed methods are useful for treating MSI-H cancers and / or a dMMR solid tumors. In some embodiments, the cancer is colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, small intestinal cancer, liver cancer, hepatobiliary cancer, upper urinary tract cancer, brain cancer, skin cancer (e.g., melanoma) non-small cell lung cancer, small cell lung cancer, biliary tract cancer, cervical cancer, neuroendocrine carcinoma, thyroid cancer, or prostate cancer.

[0057] In some embodiments, the cancer is thyroid cancer, colorectal cancer, melanoma, brain cancer, or non-small cell lung cancer. In some embodiments, the cancer is colorectal adenocarcinoma (CRC).

[0058] In some embodiments, the cancer is a solid tumor other than a colorectal adenocarcinoma (CRC).

[0059] The MSI status of the tumor may be determined using methods known in the field. In some embodiments, the MSI status of the tumor may be determined using the FoundationOne®CDx (F1CDx®) assay (F1CDx, www.foundationmedicine.com / sites / default / files / media / documents / 2024-06 / f1cdx_technical_labeling_062124.pdf). To determine a patient’s MSI status, F1CDx employs a fraction based (FB) MSI algorithm to categorize a tumor specimen as MSI-High (MSI-H) or microsatellite stable (MSS). The FB-MSI algorithm calculates the fraction of microsatellite loci determined to be altered or unstable (i.e. , the fraction unstable loci score) based on a genomewide analysis across >2000 microsatellite loci. For a given microsatellite locus, non-somatic alleles are discarded, and the microsatellite is categorized as unstable if remaining alleles differ from the reference genome. The final fraction unstable loci score is calculated as the number of unstable microsatellite loci divided by the number of evaluable microsatellite loci. Two FB-MSI score thresholds are applied to classify a tumor specimen as having MSI-H or MSS status. MSI-H status is reported for patients with solid tumors whose samples have FB-MSI scores > 0.0124 while MSS status is reported for patients with solid tumors whose samples have FB- MSI scores < 0.0041. Per the F1CDx assay, a patient whose tumor has an MSI-H score > 0.0124 is reported as eligible for treatment withVVID-765PC 184200.00318 pembrolizumab (KEYTRUDA®). For patients with solid tumors whose samples have FB-MSI scores >0.0041.

[0060] In some embodiments, the MSI status of the tumor may be determined using Ml Cancer Seek (www.accessdata.fda.gov / cdrh_docs / pdf24 / P240010C.pdf). The MSI status may be determined by assessing >5,000 loci for frameshift mutations. To classify a tumor as MSI-high, >39 frameshift mutations across a defined panel are required.

[0061] In some embodiments, the MSI status of the tumor may be determined using the Idylla™ CDx MSI test (www.biocartis.com / sites / default / files / 2025-11 / msi-cdx_pma_-_technical_sheet_us_-_nov2025.pdf). Idylla™ CDx MSI test is an in vitro diagnostic test intended for the qualitative detection of a panel of seven monomorphic biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A and SULF2) for identification of microsatellite instability (MSI) in colorectal cancer (CRC) tissue. The Idylla™ CDx MSI Test reports MSI status as either Microsatellite Stable (MSS) or Microsatellite Instability-High (MSI-H) or invalid.

[0062] In some embodiments, the MSI status of the tumor may be determined using the OncoMate™ MSI Dx Analysis System. The OncoMate™ MSI Dx Analysis System calculates MSI by comparing the length of seven specific fluorescently labeled microsatellite markers (5 mononucleotide, 2 pentanucleotide) in paired tumor and normal DNA samples. It uses multiplex PCR and capillary electrophoresis to detect, at a minimum, a bp shift in tumor DNA, classifying samples as MSI-High, MSI-Low, or Stable. The system analyzes DNA from formalin-fixed, paraffin-embedded (FFPE) tissue, amplifying 5 mononucleotide markers (BAT-25, BAT-26, NR-21, NR-24, MONO-27) for instability and 2 pentanucleotide markers (Penta C, Penta D) for sample identification. The OncoMate™ MSI Dx Interpretive Software directly compares the allelic profiles of the tumor sample against the matched normal sample. The software identifies MSI when there is an expansion or reduction in the length of these repetitive sequences in the tumor DNA. Specifically, MSI-High (MSI-H) is classified for having instability in >= 2 markers. MSI-Low (MSI-L) is classified for having instability in 1 marker. Microsatellite Stable (MSS) is classified for having no instability in analyzed markers.Patient Characteristics

[0063] In some embodiments, the patient suffers from an MSI and / or dMMR solid tumor. The MSI and / or dMMR solid tumor may be histologically or cytologically documented advanced (e.g., unresectable, locally-advanced, and / or metastatic). In some embodiments, the patient suffers from colorectal cancer (CRC), such as advanced CRC. In some embodiments, the patient suffers from a solid tumor other than a colorectal adenocarcinomaVVID-765PC 184200.00318 (CRC), such as endometrial cancer, gastric cancer, prostate cancer, pancreatic cancer, glioma, anal cancer, appendix cancer, bladder cancer, breast cancer, carcinoid tumor, esophageal cancer, jejunal adenocarcinoma, ovarian cancer, small intestine cancer, or soft tissue sarcoma.

[0064] In some embodiments, the patient suffers from brain metastases.

[0065] In some embodiments, the patient is treatment- naive for the MSI-H and / or dMMR cancer (i.e. , the therapy disclosed herein is a first line therapy).

[0066] In various embodiments, a patient has undergone a previous treatment for the MSI-H and / or dMMR cancer before beginning treatment with Compound A or a pharmaceutically acceptable salt thereof, as disclosed herein. In some embodiments, a patient has undergone and then progressed following or are intolerant to a previous treatment for the MSI-H and / or dMMR cancer before beginning treatment with Compound A or a pharmaceutically acceptable salt thereof, as disclosed herein. That is, the disclosed treatment with Compound A is a second (or higher) line of therapy.

[0067] In various cases, that prior therapy was an immunotherapy. In some embodiments, the prior immunotherapy was a checkpoint inhibitor (CPI). In some embodiments, the checkpoint inhibitor was a CTI.A-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor. In some embodiments, the CTLA-4 inhibitor was ipilimumab (Yervoy®) or tremelimumab (GP-675,206). In some embodiments, the PD-1 inhibitor was pembrolizumab (Keytruda®), nivolumab (Opdivo®) or RN888. In some embodiments, the PD-L1 inhibitor was atezolizumab (Tecentriq®), avelumab (Bavencio®) or durvalumab (Imfinzi™). In some embodiments, the PD-L1 inhibitor was atezolizumab (Tecentriq®).

[0068] In various cases, that prior therapy was a standard chemotherapy. In some embodiments, the patient has received 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more, prior lines of therapy.

[0069] In various cases, that prior therapy was radiotherapy. “Radiotherapy” denotes a therapy that involves or includes some form of radiation in an amount that is therapeutic to the subject under the current standard of care for breast cancer. In some cases, the radiotherapy includes palliative radiotherapy.

[0070] In various cases, the prior therapy includes a surgical procedure. Surgical procedure refers to a medical intervention comprising cutting, repairing, or removing of body tissues to treat conditions, injuries, diseases, or improve function of a subject.

[0071] In some embodiments, the patient is CPI-resistant or CPI -refractory.VVID-765PC 184200.00318 Efficacy Assessment

[0072] For the methods disclosed herein, a patient is treated for a MSI-H and / or dMMR cancer. The terms “treating”, “treat” or “treatment” and the like as used herein include preventative (e.g., prophylactic) and palliative treatment (e.g., acute alleviation of symptoms).

[0073] The patient can respond to the therapy as measured by at least a stable disease (SD), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009). An at least stable disease is one that is a stable disease, has shown a partial response (PR) or has shown a complete response (CR) (i.e. , “at least SD” = SD+PR+CR, often referred to as disease control). In some embodiments, the stable disease is neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD). In some embodiments, the patient exhibits at least a partial response (i.e., “at least PR” = PR+CR, often referred to as objective response). In some embodiments, the disease control rate (DCR) (i.e., at least stable disease) is at least 50%.

[0074] Response can be measured by one or more of decrease in tumor size, suppression or decrease of tumor growth, decrease in target or tumor lesions, delayed time to progression, no new tumor or lesion, a decrease in new tumor formation, an increase in survival or progression-free survival (PFS), and no metastases. In some embodiments, the progression of a patient’s disease can be assessed by measuring tumor size, tumor lesions, or formation of new tumors or lesions, by assessing the patient using a computerized tomography (CT) scan, a positron emission tomography (PET) scan, a magnetic resonance imaging (MRI) scan, an X-ray, ultrasound, or some combination thereof.

[0075] Progression free survival (PFS) can be assessed as described in the RECIST 1.1 protocol. In some embodiments, the patient exhibits a PFS of at least 1 month. In some embodiments, the patient exhibits a PFS of at least 3 months. In some embodiments, the patient exhibits a PFS of at least 6 months.

[0076] Additional means for assessing response are described in detail in the examples below and can generally be applied to the methods disclosed herein.

[0077] The definitions of the general terms used in the present description apply irrespectively of whether the terms in question appear alone or in combination with other groups.

[0078] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which thisVVID-765PC 184200.00318 invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.EMBODIMENTS

[0079] All separate embodiments described below can be combined.

[0080] 1. A method of treating a patient suffering from cancer comprising administering to the patient a therapy comprising Compound A:NH(A), or a pharmaceutically acceptable salt thereof, and an anti-PD1 antibody, wherein Compound A is administered in a total daily dose of 150 mg to 4000 mg based upon free base weight of Compound A, and the cancer is a microsatellite instability (MSI-H) cancer and / or a mismatch repair deficient (dMMR) solid tumor.

[0081] 2. Compound A:N NH(A), or a pharmaceutically acceptable salt thereof, for use in treating a microsatellite instability (MSI-H) cancer and / or a mismatch repair deficient (dMMR) solid tumor, wherein Compound A is administered in combination with an anti-PD1 antibody, and Compound A is administered in a total daily dose of 150 mg to 4000 mg based upon free base weight of Compound A.

[0082] 3. The method of embodiment 1 , or compound for use of embodiment 2, comprising administering a total daily dose of 150 mg Compound A, based upon free base weight.

[0083] 4. The method of embodiment 1 , or compound for use of embodiment 2, comprising administering a total daily dose of 300 mg Compound A, based upon free base weight.VVID-765PC 184200.00318

[0084] 5. The method of embodiment 1, or compound for use of embodiment 2, comprising administering a total daily dose of 600 mg Compound A, based upon free base weight.

[0085] 6. The method of embodiment 1 , or compound for use of embodiment 2, comprising administering a total daily dose of 1200 mg Compound A, based upon free base weight.

[0086] 7. The method of embodiment 1 , or compound for use of embodiment 2, comprising administering a total daily dose of 2000 mg Compound A, based upon free base weight.

[0087] 8. The method of embodiment 1 , or compound for use of embodiment 2, comprising administering a total daily dose of 2400 mg Compound A, based upon free base weight.

[0088] 9. The method of embodiment 1 , or compound for use of embodiment 2, comprising administering a total daily dose of 4000 mg Compound A, based upon free base weight.

[0089] 10. The method or compound for use of any one of embodiments 1-9, wherein Compound A or salt thereof is administered orally once daily.

[0090] 11. The method or compound for use of any one of embodiments 1-9, wherein Compound A or salt thereof is administered orally twice daily.

[0091] 12. The method or compound for use of any one of embodiments 1-9, wherein Compound A or salt thereof is administered orally three times daily.

[0092] 13. The method or compound for use of any one of embodiments 1-12, wherein the anti-PD1 antibody is cemiplimab, dostarlimab, pembrolizumab, or nivolumab.

[0093] 14. The method or compound for use of embodiment 13, wherein the anti-PD1 antibody is pembrolizumab.

[0094] 15. The method or compound for use of embodiment 14, comprising administering 200 mg pembrolizumab via IV administration every three weeks.

[0095] 16. The method or compound for use of any one of embodiments 1-15, wherein the cancer is colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, small intestinal cancer, liver cancer, hepatobiliary cancer, upper urinary tract cancer, brain cancer, skin cancer (e.g., melanoma) non-small cell lung cancer, small cell lung cancer, biliary tract cancer, cervical cancer, neuroendocrine carcinoma, thyroid cancer, or prostate cancer.VVID-765PC 184200.00318

[0096] 17. The method or compound for use of embodiment 16, wherein the cancer is thyroid cancer, colorectal cancer, melanoma, brain cancer, or non-small cell lung cancer.

[0097] 18. The method or compound for use of embodiment 16, wherein the cancer is colorectal adenocarcinoma (CRC).

[0098] 19. The method or compound for use of any one of embodiments 1-16, wherein the cancer is a solid tumor other than a colorectal adenocarcinoma (CRC).

[0099] 20. The method or compound for use of any one of embodiments 1-19, wherein Compound A or salt thereof is administered when the patient is in a fasted state.

[0100] 21. The method or compound for use of any one of embodiments 1-19, wherein Compound A or salt thereof is administered when the patient is in a fed state.

[0101] 22. The method or compound for use of any one of embodiments 1-21 , wherein the patient is treatment- naive for the cancer (i.e. , the therapy is a first line therapy).

[0102] 23. The method or compound for use of any one of embodiments 1-21 , wherein, prior to beginning the therapy, the patient previously was treated for the cancer (i.e., the therapy is a second or higher line therapy).

[0103] 24. The method or compound for use of embodiment 23, wherein at least one prior therapy comprised a checkpoint inhibitor (CPI) therapy.

[0104] 25. The method or compound for use of embodiment 24, wherein the patient is CPI-resistant or CPI-refractory.

[0105] 26. The method of any one of embodiments 1-24, wherein the therapy is administered for at least 3 weeks.

[0106] 27. The method or compound for use of embodiment 26, wherein the therapy is administered for at least 6 months.

[0107] 28. The method or compound for use of any one of embodiments 1-27, wherein the patient exhibits at least a stable disease, as measured by RECIST v1.1 , while on the therapy.

[0108] 29. The method or compound for use of any one of embodiments 1-28, wherein the disease control rate (DCR) is at least 50%.

[0109] 30. A method of treating cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of Compound A:VVID-765PC184200.00318(A), or a pharmaceutically acceptable salt thereof, and an anti-PD1 antibody, wherein the cancer is a microsatellite instability high (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

[0110] 31. The method of embodiment 30, wherein Compound A is administered in a total daily dose of 150 mg to 4000 mg, based upon free base weight of Compound A.

[0111] 32. The method of any one of embodiments 30-31 , wherein Compound A or salt thereof is administered orally once daily or orally twice daily.

[0112] 33. The method of any one of embodiments 30-32, wherein the anti-PD1 antibody is cemiplimab, dostarlimab, pembrolizumab, or nivolumab.

[0113] 34. The method of any one of embodiments 30-33, wherein the cancer is a microsatellite instability high (MSI-H) cancer or a mismatch repair deficient (dMMR) solid tumor.

[0114] 35. The method of any one of embodiments 30-34, wherein the cancer is colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, small intestinal cancer, liver cancer, hepatobiliary cancer, upper urinary tract cancer, brain cancer, skin cancer (e.g., melanoma) non-small cell lung cancer, small cell lung cancer, biliary tract cancer, cervical cancer, neuroendocrine carcinoma, thyroid cancer, or prostate cancer.

[0115] 36. A combination therapy comprising Compound A:(A), or a pharmaceutically acceptable salt thereof, and an anti-PD1 antibody for use in treating a cancer, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

[0116] 37. The combination therapy of embodiment 36, wherein Compound A is in a total daily dose of 150 mg to 4000 mg, based upon free base weight of Compound A.

[0117] 38. The combination therapy of any one of embodiments 36-37, wherein Compound A or salt thereof is for oral administration once daily or twice daily.VVID-765PC 184200.00318

[0118] 39. The combination therapy of any one of embodiments 36-38, wherein the anti-PD1 antibody is cemiplimab, dostarlimab, pembrolizumab, or nivolumab.

[0119] 40. The combination therapy of any one of embodiments 36-39, wherein the cancer is a microsatellite instability high (MSI-H) cancer or a mismatch repair deficient (dMMR) solid tumor.

[0120] 41. The combination therapy of any one of embodiments 36-40, wherein the cancer is colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, small intestinal cancer, liver cancer, hepatobiliary cancer, upper urinary tract cancer, brain cancer, skin cancer (e.g., melanoma) non-small cell lung cancer, small cell lung cancer, biliary tract cancer, cervical cancer, neuroendocrine carcinoma, thyroid cancer, or prostate cancer.

[0121] 42. A method of treating cancer, the method comprising administering to the patient in need thereof a therapeutically effective amount of Compound A:N NH(A), or a pharmaceutically acceptable salt thereof, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

[0122] 43. The method of embodiment 42, wherein Compound A is administered in a monotherapy.N NH^N'

[0123] 44. CompoundA, (A), or a pharmaceutically acceptable salt thereof, for use in treating a cancer, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

[0124] 45. Compound A, or a pharmaceutically acceptable salt thereof, of embodiment 44, which is a monotherapy.

[0125] 46. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-45, wherein Compound A is administered in a total daily dose of 150 mg to 4000 mg, based upon free base weight of Compound A.VVID-765PC 184200.00318

[0126] 47. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-46, comprising administering a total daily dose of 150 mg, 300 mg, 600 mg, 1200 mg, or 2000 mg Compound A, based upon free base weight of Compound A.

[0127] 48. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-47, wherein Compound A or salt thereof is administered orally once daily.

[0128] 49. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-48, wherein Compound A or salt thereof is administered orally twice daily.

[0129] 50. The method, or Compound A or a pharmaceutically acceptable salt thereof of embodiment 49, wherein Compound A is administered orally in a dose of 150 mg to 600 mg twice daily, based upon free base weight of Compound A.

[0130] 51. The method, or Compound A or a pharmaceutically acceptable salt thereof of embodiment 50, wherein Compound A is administered orally in a dose of 150 mg, 200 mg, 300 mg, or 600 mg twice daily, based upon free base weight of Compound A.

[0131] 52. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-51, wherein the cancer is a microsatellite instability high (MSI-H) cancer or a mismatch repair deficient (dMMR) solid tumor.

[0132] 53. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-52, wherein the cancer is colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, small intestinal cancer, liver cancer, hepatobiliary cancer, upper urinary tract cancer, brain cancer, skin cancer (e.g., melanoma) non-small cell lung cancer, small cell lung cancer, biliary tract cancer, cervical cancer, neuroendocrine carcinoma, thyroid cancer, or prostate cancer.

[0133] 54. The method, or Compound A or a pharmaceutically acceptable salt thereof of embodiment 53, wherein the cancer is thyroid cancer, colorectal cancer, melanoma, brain cancer, or non-small cell lung cancer.

[0134] 55. The method, or Compound A or a pharmaceutically acceptable salt thereof of embodiment 53, wherein the cancer is colorectal adenocarcinoma (CRC).

[0135] 56. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-53, wherein the cancer is a solid tumor other than a colorectal adenocarcinoma (CRC).VVID-765PC 184200.00318

[0136] 57. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-56, wherein Compound A or salt thereof is administered when the patient is in a fasted state.

[0137] 58. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-56, wherein Compound A or salt thereof is administered when the patient is in a fed state.

[0138] 59. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-58, wherein the patient is treatment- naive for the cancer (i.e., the therapy is a first line therapy).

[0139] 60. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-58, wherein, prior to beginning the therapy, the patient previously was treated for the cancer (i.e., the therapy is a second or higher line therapy).

[0140] 61. The method, or Compound A or a pharmaceutically acceptable salt thereof of embodiment 60, wherein at least one prior therapy comprised a checkpoint inhibitor (CPI) therapy.

[0141] 62. The method, or Compound A or a pharmaceutically acceptable salt thereof of embodiment 61, wherein the patient is CPI-resistant or CPI -refractory.

[0142] 63. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-62, wherein the therapy is administered for at least 3 weeks.

[0143] 64. The method, or Compound A or a pharmaceutically acceptable salt thereof of embodiment 63, wherein the therapy is administered for at least 6 months.

[0144] 65. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-64, wherein the patient exhibits at least a stable disease, as measured by RECIST v1.1 , while on the therapy.

[0145] 66. The method, or Compound A or a pharmaceutically acceptable salt thereof of any one of embodiments 42-65, wherein the disease control rate (DCR) is at least 50%.

[0146] 67. Compound A, or a pharmaceutically acceptable salt thereof, for use in treating a cancer, wherein the cancer is a microsatellite instability (MSI-H) cancer and / or a mismatch repair deficient (dMMR) solid tumor,Compound A has a structure ofVVID-765PC184200.00318and Compound A is administered in a total daily dose of 150 mg to 4000 mg based upon free base weight of Compound A.EXAMPLES

[0147] The following examples illustrate the present disclosure without limiting it but serve merely as representative thereof.Material and Methods

[0148] This is a first in human Phase I, open-label, multicenter, dose-escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of Compound A monotherapy in participants with MSI and / or dMMR solid tumors and in combination with pembrolizumab in participants with MSI and / or dMMR colorectal adenocarcinoma (CRC). The primary objective is to determine the maximum tolerated dose (MTD) and / or recommended Phase 2 dose (RP2D). 14 paired tumor biopsies were collected for translational analysis.

[0149] Interim Result Summary. Forty-four patients (24 F, 20 M; median age 62 years of age (32-77 years of age)) were enrolled in six dose cohorts at Compound A total daily doses from 150 mg to 2000 mg. Based on clinical first dose PK data (rapid absorption, mean Tmax 2.6 h [± 1.3h] and half-life 4.4 h [±1.8h], n=41), Compound A was dosed orally once (QD) or twice (BID) daily. Among the 44 patients (22 colorectal (CRC) and 22 non-CRC), median prior treatment lines were 3 (range 1-12); 89% had received ICIs. 35 patients had MSI tumors (18 CRC and 17 non-CRC). No dose-limiting toxicities (DLTs) have been reported and the MTD has not been reached. The most common treatment-emergent AEs across all doses were nausea (52.3%), diarrhea (34.1%), and vomiting (31.8%). Grade (G)3 treatment related AEs (TRAE) were nausea and increased AST / ALT in 2 pts each (4.3%) as well as fatigue and anemia in 1 pt each (2.1%). No Grade 4 or worse TRAEs were observed. Of the efficacy evaluable MSI patients (n= 32), four RECISTvl.1 partial responses (PRs) (2 confirmed and 2 ongoing unconfirmed PRs) were observed in post-ICI-treated MSI CRC (n=1), ovarian (n=1), and endometrial cancer (n=2) for up to 9.5+ months. Disease control rate (DCR) was 68.8% (95%CI 51.13, 86.37) and 20 (62.5%) patients achieved RECISTv1.1 stable disease (SD). 48.4% (15 / 31) of FDG-PET scan evaluable pts across all dose levelsVVID-765PC 184200.00318 showed metabolic responses to Compound A. All patients with RECIST PR showed pronounced metabolic responses (-50% to -90%). ctDNA molecular responses were observed in 2 / 2 patients with RECISTv1.1 PR, 8 / 9 patients with SD and 0 / 5 patients with disease progression.

[0150] Study Design and Population

[0151] The study consists of four parts as set forth in Table 1.Table 1. Study Parts and Participants PopulationStudy Part Purpose Participants Population Part I Dose escalation (and backfill cohorts) to MSI and / or dMMR determine the maximum tolerated dose advanced solid (MTD) and / or the recommended dose(s) tumors for expansion (RDE) or recommendedPhase 2 dose (RP2D) for Compound AmonotherapyPart II12Part HA Dose expansion to explore the safety and MSI and / or dMMR preliminary clinical activity of Compound advanced colorectal A and to define the recommended Phase adenocarcinoma2 dose (RP2D) of Compound A as (CRC) monotherapy.Part I IB Dose expansion to explore the safety and MSI and / or dMMR preliminary clinical activity of Compound advanced non-CRC A and to define the RP2D of Compound solid tumorsA as monotherapy.Part III3To assess drug-drug interactions of MSI and / or dMMR Compound A advanced solidtumorsVVID-765PC 184200.00318 Part IV1Assess the safety, tolerability, and MSI and / or dMMR preliminary efficacy of Compound A in advanced colorectal combination with pembrolizumab adenocarcinoma(CRC)CRC = coIorecta adenocarcinoma; dMMR = deficient mismatch repair; MSI = microsatellite instability1llp to two expansion cohorts (at different doses and / or dosing schedule) may be enrolled within Part HA and / or Part II B and / or Part IV. If more than one cohort is open to enrollment at the same time within Part HA and / or Part HB and / or Part IV, participants may be randomized.2The effect of food intake on the PK profile of Compound A may be explored.3Details on design and participant population will be added via a protocol amendment and are not part of the current protocol.

[0152] Part I Dose Escalation and Backfill Cohorts

[0153] The overall aim of the dose-escalation Part I is to determine the maximum tolerated dose (MTD) and / or the recommended dose(s) for expansion (RDE) or recommended Phase 2 dose (RP2D) of Compound A monotherapy and will enroll participants with any MSI and / or dMMR advanced solid tumors.

[0154] The starting dose of 150 mg was determined based on preclinical PK data, toxicokinetic data, toxicology studies and anti-tumor activity in preclinical models.

[0155] Compound A will be administered orally (po) once daily (QD) in 3-week cycles based upon the DLT observation period, planned schedule of clinical assessments and potential for combination with other anti-PD1 / PDL1 therapies.

[0156] Dose escalation will be guided by a modified Continual Reassessment Method (mCRM) with an Escalation with Overdose Control (EWOC) (Neuenschwander et al. 2008).

[0157] If the QD regimen shows unacceptable toxicity or unfavorable PK characteristics, the dosing schedule may be changed, e.g., twice daily (BID) or three times daily (TID). The cohorts with the new dosing schedule will use the total daily dose equivalent proposed by the mCRM EWOC model.

[0158] During dose escalation, backfill cohorts may be enrolled to further characterize the safety profile, PK, PD and preliminary clinical activity of Compound A and to support the selection of the RDE. The selection of dose levels for backfill cohorts and the number of participants allocated to each cohort will be based on emerging PK / PD modeling, safety data and potential early signs of clinical response. The dose levels selected for the backfill cohorts will not be higher than the highest dose cleared in the dose escalation. If dose escalation cohorts and backfill cohorts are open in parallel, the Sponsor will decide where to enroll eachVVID-765PC 184200.00318 participant. Depending on emerging data, these decisions might aim at enrichment of certain participant subgroups within the backfill cohorts, e.g., by selection for certain tumor types. If two or more backfill cohorts are open in parallel, enrollment into these cohorts may be randomized.

[0159] Part II Dose Expansion Cohorts

[0160] Part II of the study has been designed to explore the safety and preliminary clinical activity of Compound A and to define or optimize the recommended Phase 2 dose (RP2D) of Compound A as monotherapy.

[0161] Part II will enroll participants with one of the tumor types defined below:Part HA: MSI and / or dMMR advanced colorectal adenocarcinoma (CRC), and Part 11 B: any MSI and / or dMMR advanced solid tumors with the exception of CRC.

[0162] Up to two expansion cohorts (at different doses and / or dosing schedule) may be enrolled within Part HA and / or Part 11 B with up to approximately 40 participants per cohort. The decision to expand one or two Compound A dose levels and / or dosing schedules will be made based on emerging PK, PD, safety and anti-tumor activity data from Part I of the study. The Compound A dose(s) will not exceed the MTD, if reached, or the maximum Compound A dose administered in Part I. If two expansion cohorts within Part 11 A and / or Part I IB are enrolled at the same time, participants may be randomized.

[0163] The sample size of Part II may be further extended via a protocol amendment to allow for a robust benefit / risk assessment of Compound A in the respective participant populations.

[0164] Assessment of Food Effect

[0165] The effect of food intake on the PK profile of Compound A may be explored in a minimum of 8 evaluable participants in Part II of the study.

[0166] Participants will receive Compound A under normal study conditions (preferably on an empty stomach, i.e. , food intake avoided at least 2 hours before as well as 1 hour after the dose is administered) from Cycle 1 Day 1 (C1D1) and for the duration of the study except on the days the food effect is studied (C1 D8 and C1 D15). Each participant will be assessed in both the fed and fasted state, enabling intra-participant cross-over comparison. Participants assigned to the FE investigation will be randomized into one of the following groups:

[0167] Group 1 will start with fed (C1D8) followed by fasted (C1D15)

[0168] Group 2 will start with fasted (C1D8) followed by fed (C1D15)VVID-765PC 184200.00318

[0169] Part III Drug-Drug Interactions

[0170] Part III may be implemented to assess drug-drug interactions of Compound A.Details on Part III, including sample size, participant population, Compound A dose and schedule and clinical assessments will be informed by emerging data and will be added via a future protocol amendment.

[0171] Part IV Combination with Pembrolizumab

[0172] Once the RDE and / or RP2D and a preliminary safety and tolerability profile of Compound A as monotherapy have been established, the Sponsor will open a combination cohort with pembrolizumab.

[0173] Part IV of the study has been designed to explore the safety and preliminary clinical activity of selected dose(s) of Compound A in combination with a fixed approved dose of pembrolizumab in patients with untreated advanced dMMR and / or MSI CRC.

[0174] Approximately 75 participants will be enrolled in Part IV and in two stages: a combination dose finding stage (safety run-in) to evaluate selected Compound A doses in combination with pembrolizumab (200 mg IV every 3 weeks [Q3W]) followed by a dose expansion stage with up to two dose cohorts of Compound A.

[0175] The starting dose level of Compound A will be the RDE or RP2D defined after Part I of the study or at least one dose level lower than the RDE, if any toxicities are identified in Part I that may be exacerbated with the administration of pembrolizumab.

[0176] A minimum of 3 participants may be enrolled at each selected Compound A combination dose level in the Safety run-in following a 3+3 scheme. After the first 3 participants have completed Cycle 1 (Days 1-21), depending on DLT observation, additional three patients may be enrolled at the same dose level, or another safety run-in cohort may be opened at a higher or lower dose level following the same scheme.

[0177] At no time will a dose level studied in the safety run-in and expansion stage exceed the highest dose level considered safe during the dose escalation Part I of the study.

[0178] Based on the totality of data emerging during the safety run-in cohorts including safety, preliminary PK, PD and preliminary clinical activity data, the dose decision team (DDT) will decide whether to expand one or two dose level of Compound A in combination with pembrolizumab for the expansion stage. If one dose level is selected, up to 40 response evaluable participants will be treated in oneVVID-765PC 184200.00318 expansion cohort. If two dose levels of Compound A are selected, each arm will enroll approximately 20 response evaluable participants, and the two arms may be randomized. One of the arms may be further expanded to a total of 40 response-evaluable participants upon interim analysis of the data after approximately 10-20 participants.

[0179] Dose Escalation

[0180] Dose-Escalation Decision Criteria for Part I

[0181] Part I will enroll at least 3 participants in each dose escalation cohort. The starting dose of Compound A will be 150 mg po QD and the dose escalation will be guided by a mCRM with EWOC (Neuenschwander et al. 2008) until any of the stopping criteria are fulfilled. Participants enrolled in the backfill cohorts will be considered for dose decisions guided by the mCRM with EWOC.

[0182] To allow for the assessment of any severe and unexpected Compound A acute or subacute study toxicity, participants will be enrolled in a staggered manner, as follows:

[0183] For the first two dose cohorts, the second participant enrolled in each dose cohort, will receive the initial Compound A dose at least three days after the first participant.

[0184] For subsequent dose escalation cohorts (i.e. , from cohort 3 and beyond) the requirement of staggering will be based on the observed safety data in previous cohorts and will be decided between the Sponsor and the study Investigators.

[0185] The dose-limiting toxicity (DLT) observation period will be 21 days (i.e., Cycle 1) starting from C1 D1 until C1 D21 , and the subsequent dose cohort may be opened after at least 3 DLT-evaluable participants have completed their DLT window.

[0186] Participants who discontinue from study treatment prior to completing the DLT assessment window for reasons other than a DLT will be considered non-evaluable for doseescalation decisions and MTD assessments and may be replaced by an additional participant at that same dose level. Participants who take less than 75% of planned doses of Compound A during the DLT assessment window for reasons other than DLT, will be considered non-evaluable for dose-escalation decisions and MTD assessments and may be replaced.

[0187] For each new cohort, the mCRM EWOC model may recommend increasing the dose, decreasing the dose, or expanding the cohort at the same dose, depending on the DLT events observed thus far.

[0188] The final decision for the dose of the next cohort will be made by the DDT which includes Sponsor representatives and Investigators, taking all available relevant safety,VVID-765PC 184200.00318 clinical, PK, PD data (from dose escalation and backfill cohorts) and the modelrecommendation into account. The DDT will be able to overrule the mCRM EWOC model recommendation based on all of the data available, including the totality of safety data from all dose cohorts, and also safety events that occur outside of the DLT assessment window. Additional information about the dose escalation process for the study will be documented in the separate dose escalation plan (DEP).

[0189] In Part I of the study, intra-participant dose escalation may be allowed if participants have experienced disease progression (per RECIST v1.1), but the Investigator deems the participant might benefit from higher dose of Compound A upon the Investigator’s request after discussion with the Medical Monitor and careful assessment and discussion of risk versus benefit with the participant by the Investigator. The dose will not exceed the highest dose level that was deemed safe during dose-escalation.

[0190] Intraparticipant dose-escalation decisions will be made based on available safety data from the participant being considered as well as the totality of safety data available at the time of decision making. Participants who have had a DLT, will not be eligible for intra-participant dose escalation.

[0191] For analysis purposes, participants will be included in the cohort assigned at Cycle 1 Day 1, regardless of intra-participant dose escalation.

[0192] Dose-Escalation Decision Criteria for Part IV

[0193] In the combination dose finding stage (Safety run-in) to evaluate selected Compound A doses in combination with pembrolizumab (200 mg IV every 3 weeks [Q3W]), participants will be enrolled during the safety run-in in accordance with the rules listed below:

[0194] A minimum of 3 DLT-evaluable participants will be enrolled in each cohort. If none of the first 3 DLT-evaluable participants experiences a DLT, the safety run in may be stopped, further expanded for further characterization of the safety profile or the dose may be further increased to the allowed higher dose level If 1 of the first 3 DLT-evaluable participants experiences a DLT, the cohort will be expanded to a minimum of 6 participants. If there are no further DLTs in the first 6 DLT-evaluable participants the safety run in may be stopped, further expanded for further characterization of the safety profile or the dose may be further increased to the allowed dose level. If 2 or more DLT-evaluable participants in a cohort experience a DLT, this dose level will not be considered safe and will not be expanded. FurtherVVID-765PC 184200.00318 enrollment at lower dose may be allowed to assess the safety profile of the lower doses.

[0195] The DLT observation period will be 21 days (i.e., Cycle 1) starting from C1 D1 until C1 D21. Participants who discontinue from study treatment prior to completing the DLT assessment window for reasons other than a DLT will be considered non-evaluable for dose-evaluation decisions and MTD assessment, and may be replaced by an additional participant at that same dose level. Participants who take less than 75% of planned doses of Compound A or do not receive the planned pembrolizumab dose during the DLT assessment window for reasons other than DLT, will be considered non-evaluable for dose evaluation decisions and may be replaced.

[0196] The final decision for the Compound A dose of the next cohort, including the decision to de-escalate the doses of Compound A and the specific doses and / or alternate dosing schedules to evaluate, will be made by the Dose Decision Team (DDT) which includes Sponsor representatives and Investigators, taking all available relevant safety, clinical,

[0197] PK, PD data (from dose escalation and backfill cohorts) into account. Additional information about the dose escalation process for the study is documented in the separate dose escalation plan (DEP).

[0198] On the basis of a review of real-time safety data and available preliminary PK data, dose escalation may be temporarily held or modified by the Sponsor as deemed appropriate.

[0199] Dose-Limiting Toxicities

[0200] For the assessment of DLTs, all AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.

[0201] A DLT will be defined as any of the following adverse events occurring during the 21 days DLT assessment period, unless such events are attributed by the Investigator to another clearly identifiable cause (e.g., documented disease progression, concomitant or preexisting medication, or intercurrent illness).

[0202] Grade 5 event

[0203] Any study treatment-related toxicity that causes the participant to permanently discontinue treatment during C1.VVID-765PC 184200.00318

[0204] Any study treatment-related toxicity that results in a prolonged interruption of treatment for more than 14 days. In Part IV of the study: prolonged delay (> 2 weeks) in initiating Cycle 2 of pembrolizumab due to treatment-related toxicity.

[0205] Hematological DLTs:-Grade 4 neutropenia (absolute neutrophil count (ANC) < 500 cells / mL) lasting > 7 days <a>;-Grade 3 or 4 febrile neutropenia;-Grade 3 thrombocytopenia associated with clinically significant bleeding;-Grade 4 thrombocytopenia of any duration;-Grade 4 anemia;Any Grade 3 or Grade 4 non-hematologic laboratory value excluding:-Grade > 3 electrolyte abnormality that is not clinically complicated, lasts < 72 hours and resolves spontaneously or responds to appropriate medical intervention per SoC(a);-Grade33 amylase or lipase that is not associated with symptoms or clinical or imaging manifestations of pancreatitis;-Grade 3 laboratory abnormalities that are asymptomatic and considered by the Investigator not to be clinically significant.

[0206] Laboratory abnormality that results in a drug-induced liver injury:-Aminotransferase (alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST)) > 3 >< upper limit of normal (ULN) (or > 5 ULN for participants with liver metastases); and-Total bilirubin > 2 x ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase); and-No other reason can be found to explain the combination of increased ALT / AST and total bilirubin.

[0207] Non-hematological clinical DLTs:-Any Grade > 3 non-hematologic clinical (non-laboratory) toxicity excluding:-Grade 3 arthralgia and / or Grade 3 myalgia that can be adequately managed with supportive care or that improves / resolves to Grade < 1 within 7 days(a);-Grade 3 nausea or vomiting that lasts < 48 hours, and resolves to Grade < 1 either spontaneously or with the use of anti-emetics per standard of care (SoC)(a);-Grade 3 diarrhea that lasts < 72 hours, does not result in hospitalization and resolves to Grade < 1 either spontaneously or with anti-diarrheal per SoC(a);-Grade 3 fatigue for less than 7 days(a);-For Part IV only, in addition to the above, excluding:-Grade 3 rash that resolves to Grade < 2 in 7 days with therapy equivalent to prednisone 10 mg / day or less;-Grade 3 endocrinopathy that is well controlled by hormone replacement;VVID-765PC 184200.00318 -Grade 3 IRR that resolves to < Grade 1 within 24 hours;-Any other study treatment-related toxicity considered significant enough to qualify as a DLT in the opinion of the Investigator and after discussion with the Medical Monitor.(a>AEs related to laboratory, vital, or clinical abnormalities must be assessed prior to the end of the applicable time window to determine if a DLT has occurred

[0208] JUSTIFICATION FOR DOSE

[0209] A starting dose of 150 mg / day QD has been selected for this first study in humans. This is anticipated to be a safe dose based on safety margins calculated from the nonclinical toxicokinetic data, the estimated no-observed-adverse-effect level (NOAEL) in the toxicology studies, and the predicted human exposure. The predicted human exposure at this dose corresponds to the exposures observed to cause tumor stasis in the HCT-116 mouse xenograft model.

[0210] In the 28-day repeat-dose toxicology study, the STD10 in mice (the more sensitive species) was 600 mg / kg / day (1800 mg / m2 / day) and the NOAEL was 300 mg / kg / day (900 mg / m2 / day). Because the exposures at the STD10 and the NOAEL were the same in this study, the Sponsor used the NOAEL to calculate the starting dose. A mouse-to-human body surface area (BSA) conversion factor of 12.3 and a safety factor of 10 were applied to the 300 mg / kg / day NOAEL dose in the GLP mouse toxicology study to yield the resulting human dose of 144 mg QD per 60-kg patient.

[0211] The projected steady-state AUCo-24h and Cmax in humans of the 150 mg QD starting dose are 4500 ng hr / mL and 620 ng / mL, respectively. These values are at least 3.8-and 4.2-fold lower, respectively, than the Cmax and AUCo-24h observed in mice at the 300 mg / kg / day NOAEL dose.

[0212] Using modeling and simulation, the 150 mg / day dose is predicted to correspond in exposure to a dose of 5 mg / kg / day in the mouse xenograft studies. A dose of 5 mg / kg / day resulted in tumor stasis using the HCT-116 xenograft model and partial tumor growth inhibition in other xenograft models such as SW48, indicating that pharmacological activity may be expected at this dose level.

[0213] Preclinical pharmacology models showed anti-tumor activity using daily administration, therefore once daily dosing (QD) will be investigated initially in man. If QD schedule shows unacceptable toxicity or unfavorable PK characteristics the schedule may be changed e.g., to BID or TID.

[0214] Collectively, the weight-of-evidence and safety margins support the proposed Compound A starting dose of 150 mg / day.VVID-765PC 184200.00318

[0215] The anticipated therapeutic dose (ATD) of Compound A in humans is predicted to be in the range of 400 mg / day to 1000 mg / day based on tumor regression observed in different xenograft mouse models.

[0216] The quantitative predictability of these pre-clinical efficacy models is known to be limited, and therefore, the derived clinical ATD only serve as preliminary estimates, which will be further refined, once clinical data emerge.

[0217] A listing of predicted exposures at a selection of different potential doses can be seen in the below Table.Simulated Steady State PK Parameters Following Oral Administration of Different QD Doses of Compound A _Daily DoseDose(mg) (mg) Cmax (pg / mL) Cfrough (pg / mL) AU Co-24 (ua.hr / ml_) 150 QD 150 0.62 0.012 4.5150 BID 300 0.68 0.124 9.0300 QD 300 1.04 0.030 8.8300 BID 600 1.20 0.325 18600 QD 600 1.57 0.112 16600 BID 1200 1.93 0.665 301200 QD 1200 2.16 0.363 241000 BID 2000 2.30 0.803 372000 QD 2000 2.43 0.433 281200 BID 2400 2.41 0.844 392400 QD 2400 2.51 0.451 292000 BID 4000 2.67 0.956 454000 QD 4000 2.71 0.511 32

[0218] The maximum dose is proposed as 4000 mg / day in this study (e.g., 2000 mg BID). At individual doses above 1000 mg, AUC and Cmax are expected to increase less than dose proportionately and solubility limitations are expected restricting additional attainable exposure at individual doses above 2000 mg. Given the projected reduced exposure increases with doses above 2000 mg, a maximum daily Compound A dose of 4000 mg / day is proposed.

[0219] Study Inclusion Criteria

[0220] Patients are eligible to be included in the study only if all of the following criteria apply: willing and able to provide written informed consent for the trial; be > 18 years of age on the date of signing informed consent; ILife expectancy of > 12 weeks; Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1; have a MSIVVID-765PC 184200.00318 and / or dMMR, histologically or cytologically documented advanced (unresectable and / or metastatic):

[0221] Solid tumor (Part I only), CRC (Part HA only), solid tumor except CRC (Part 11 B only) and have received and then progressed following or are intolerant to at least 1 standard treatment regimen in the advanced setting including standard chemotherapy or checkpoint inhibitors according to tumor type. Where checkpoint inhibitor is available as the standard of care, all patients should have received and progressed on or following a PD-1 or a PD-L1 inhibitor for the treatment of metastatic (Stage IV) or locally advanced disease, unless such therapies contraindicated for that patient.

[0222] For Part IV only: Histologically confirmed locally advanced, or metastatic CRC with no prior systemic treatment for metastatic disease and not amenable to surgery:

[0223] Participants who have received prior neoadjuvant or adjuvant immunotherapy (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2 agent, or anti-CTLA-4 agent, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents, etc.) must have stopped their last immunotherapy or immunotherapy combination treatment before study entry without evidence of disease progression and be disease-free without systemic / local tumor treatment for > 6 months since the last dose of immunotherapy.

[0224] Participants had no history of severe immune-related adverse effects (CTCAE grade 3 and 4) from prior checkpoint inhibitors.

[0225] Patients will be enrolled based on documented MSI and / or dMMR tumor status determined as part of the routine diagnostic workup in a certified laboratory. MSI and / or dMMR tumor status may also be assessed in a certified laboratory with a test that is compliant with applicable requirements or as part of an approved performance study with an investigational IVD if applicable. MSI and / or dMMR tumor status will be defined as: a) dMMR status as assessed by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where the loss of 1 or more proteins indicates dMMR or b) MSI phenotype as determined by polymerase chain reaction (PCR) or by tissue nextgeneration sequencing (NGS).

[0226] Based on emerging data, patients may be enrolled based on MSI tumor status only.

[0227] Availability of formaldehyde-fixed paraffin-embedded (FFPE) archival tumor tissue for submission to Sponsor / central laboratory.VVID-765PC 184200.00318 • Confirmation of available archival tumor tissue sample is required during screening.• For participants without archival tissue, a biopsy from either primary or metastatic tumor lesion, deemed medically feasible, must be taken.

[0228] Presence of measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1:• Previously irradiated lesions can be considered as target lesions only if progressive disease has been unequivocally documented at that site since radiation.• If a target lesion is selected for biopsies, the target lesion must be of a size that allows RECIST v1.1 assessments over the course of the study.

[0229] For Part I backfill cohorts only:• Accessible lesion(s) that permit at least two biopsies (pre-treatment and on treatment) without unacceptable risk of a significant procedural complication.Biopsies will only be conducted if deemed clinically safe and feasible by the Investigator• If multiple lesions are available, it is preferable to obtain the on-treatment biopsy from the same lesion (or organ) as the pre-treatment biopsy, to avoid introduction of heterogeneity related to site of metastasis.• Based on emerging data, enrollment in the backfill cohorts might be restricted to certain tumor types

[0230] Adequate hematologic and end-organ function, defined using the following laboratory results obtained within 14 days prior to first dose of study treatment:• Absolute neutrophil count > 1.5 >< 109 / L without granulocyte colony-stimulating factor support. Patient with Benign Ethnic Neutropenia with ANC > 1000 are eligible.• Platelet count > 75 x 109 / L without transfusion (within 14 days prior to first dose of study treatment).• Hemoglobin > 9 g / dL without transfusion (within 14 days prior to first dose of study treatment).• Total bilirubin < 1.5 x ULN (except patients with Gilbert syndrome).- Note: participants with Gilbert’s syndrome will not be excluded from the study.The diagnosis of Gilbert’s syndrome is suspected in people who have persistent, slightly elevated levels of unconjugated bilirubin levels (< 3 x ULN) without any other apparent cause.• Aspartate transaminase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN. Participants with documented liver metastases: AST and ALT < 5 x ULN.• Creatinine clearance > 50 mL / min based on the Cockcroft-Gault estimation.VVID-765PC 184200.00318 • For participants not receiving therapeutic anticoagulation: international normalized ratio (INR) or activated partial thromboplastin time (aPTT) < 1.5 x ULN• Patients receiving therapeutic anticoagulation should be on a stable dose for at least 1 week prior to Cycle 1 Day 1 (C1D1)

[0231] Adequate cardiovascular function:• New York Heart Association (NYHA) Heart Failure Class < 2. Patients with NYHA Class 2 must have left ventricular ejection fraction > 45%.• Resting systolic blood pressure < 150 mmHg and diastolic blood pressure100 mmHg (average of > 3 readings on > 2 sessions with short break between sessions) (or no clinically significant hypertension).• Resting heart rate (HR) between 45 to 100 bpm (or no clinically significant tachycardia).

[0232] Contraception Requirements

[0233] The contraception and abstinence requirements are intended to prevent exposure of an embryo to the study treatment. The reliability of sexual abstinence for male and / or female enrolment eligibility needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not acceptable methods of preventing pregnancy.

[0234] Participants of childbearing potential (POCBP):• A POCBP is eligible to participate if they are not pregnant, not breastfeeding, and at least one of the following conditions applies:-A participant of non-childbearing potential (PONCBP)-A POCBP, who• Agree to remain abstinent (refrain from heterosexual intercourse) or use 2 non-hormonal contraceptive methods including at least one method that results in a failure rate of < 1% per year during the treatment period and for at least 1 month after the final dose of Compound A and for at least 6 months after the final dose of pembrolizumab (Part IV only). POCBP must refrain from donating eggs during this same period. Biological female participants must refrain from donating eggs during this same period. The Investigator should evaluate with the participant the best contraceptive method based on anatomy and physiology.• Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal occlusion / ligation, male sexual partner who is sterilized, and copper intrauterine devices. Barrier methods (male or female condom with or without spermicide, cap, diaphragm or sponge with spermicide) are not highly effective contraceptive methods and must beVVID-765PC 184200.00318 used alongside a highly effective method. Hormonal contraceptive methods are not considered acceptable.

[0235] Biological Male PONCBP:• During the treatment period and for at least 1 month after the final dose of Compound A and for at least 6 months after the final dose of pembrolizumab (Part IV only), agreement to:- Remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures such as a condom with a female partner of childbearing potential. The Investigator should evaluate with the participant the best contraceptive method based on anatomy and physiology.- With pregnant female partner, remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures such as a condom to avoid exposing the embryo.- Refrain from donating semen.

[0236] Study Exclusion Criteria

[0237] Patients are excluded from the study if any of the following criteria apply:Inability or unwillingness to swallow pills.Malabsorption syndrome or other condition that would interfere with enteral absorption.Known hypersensitivity or intolerance to ingredients from the study drug formulation including patients with rare genetic disorders such as galactosaemia, glucose-galactose intolerance or congenital lactase deficiency.Known uncontrolled central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control) and / or carcinomatous meningitis.Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, are clinically stable off corticosteroids for at least 14 days prior to study treatment and have measurable disease, per RECIST v1.1 , outside the CNS. This exception does not include carcinomatous meningitis, as subjects with carcinomatous meningitis are excluded regardless of clinical stability.Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not limited to tuberculosis and atypical mycobacterial disease), parasitic, or other infection (excluding fungal infections of nail beds), or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 2 weeks prior to the start of drugVVID-765PC 184200.00318 administration (related to the completion of the course of antibiotics, except if for tumor fever) or 6 months for any intracranial abscess.Participants receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study. Note: Antibiotics known to be moderate and strong CYP3A inhibitors or inducers are not allowed.Has a positive test for hepatitis B virus (HBV; defined as positive for hepatitis B surface antigen or HBV DNA) or hepatitis C virus (HCV; defined as positive for HCV antibody or HCV RNA) per local diagnostic standard and in accordance with local laws and regulations, indicating acute or chronic infection.Positive human immunodeficiency virus (HIV) test at screening per local diagnostic standard and in accordance with local laws and regulations (unless testing is not allowed by local Health Authority) or taking protease inhibitors as antiretroviral therapy for HIV.Uncontrolled diabetes or symptomatic hyperglycemia (i.e., well controlled defined as a screening hemoglobin A1c < 8% and no urinary ketoacidosis).Significant cardiovascular / cerebrovascular disease within 6 months prior to D1 of study drug administration, including any of the following:• Hypertensive crisis / encephalopathy• Unstable angina• NYHA Class III or IV cardiac disease or congestive heart failure requiring medication.• Serious cardiac arrhythmia requiring treatment (exceptions are atrial fibrillation, paroxysmal supraventricular tachycardia)• Baseline-corrected QT (through use of Fridericia's formula [QTcF]) interval > 470 ms based on average of the screening triplicate 12-lead ECG.• History of thromboembolic events (such as myocardial infarction, stroke or pulmonary embolism)• Patients with history of pulmonary embolism may be eligible if event is considered resolved in the opinion of the Investigator and as per local guidelines.History of malignancy other than the one under investigation, within 2 years prior to screening, with the exception of:• Malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival (OS) rate > 90%) and no anticipated requirement for anti-cancer therapy during the duration of the study, such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer (Gleason score Grade < 7), ductal carcinoma in situ, or Stage I uterine cancer.• Patients with multiple malignancies in the past or at the screening due to Lynch syndrome are not excluded.VVID-765PC 184200.00318 Alcohol or drug dependence or abusePatients with known WRN syndromeAny medical condition or abnormality in clinical laboratory tests that, in the Investigator’s judgement, precludes the participant’s safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results.Radiotherapy or major surgical procedure other than for diagnosis within 3 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study. Participants should be recovered from the effects of radiation and / or surgery. Palliative radiotherapy is allowed if completed within 2 weeks prior to start of study treatment.Prior treatment with any WRN helicase inhibitorSystemic anti-cancer therapy beside the one allowed in the protocol, including but not limited to chemotherapy, investigational drugs, hormonal therapy and antibody-based agents (including checkpoint inhibitors) within 28 days or at least 5 half-lives, whichever is shorter, prior to start of study treatment.T reatment-related toxicities from prior cancer therapy that have not resolved to Grade <1 CTCAE prior to study treatment except for:• Immune-related AEs such as hypothyroidism and adrenal insufficiency on a stable dosage of hormone replacement therapy• The following Grade 2 toxicities: alopecia, peripheral neuropathy, any laboratory changes that still lie within the inclusion criteria defined aboveTreatment with moderate or strong CYP3A4 inducers within 14 days prior to initiation of study treatmentTreatment with moderate or strong CYP3A4 inhibitors within 7 days prior to initiation of study treatmentPregnancy, breastfeeding, or intention of becoming pregnant during the study Note: POCBP must have a negative serum pregnancy test result within 1 week prior to initiation of study treatment and have a negative urine or serum pregnancy test at C1D1 predose.

[0238] Additional Exclusion criteria only applicable to Part IV

[0239] Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, granulomatosis with polyangiitis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis with the following exceptions:VVID-765PC 184200.00318 • Participants with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.• Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.• Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., participants with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: • Rash must cover < 10% of body surface area• Disease is well controlled at baseline and requires only low-potency topical corticosteroids.• No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 monthsHistory of interstitial lung disease or pneumonitisTreatment with systemic immunosuppressive medication (such as corticosteroids) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:• Participants who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.• Participants who received mineralocorticoids (e.g., fludrocortisone), inhaled or low dose corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.

[0240] For Participants enrolled for Food Effect assessment

[0241] The effect of food on the systemic exposure of Compound A will be explored in Part II with a minimum of 8 participants. The participants will receive Compound A in the schedule (QD or e.g. BID or TID) established during dose escalation while either fed at C1D8 and fasted at C1 D15, or vice versa.

[0242] Group 1 participants: Following an overnight fast of at least 10 hours, Compound A will be administered at C1D830 minutes after starting eating a high fat meal (i.e., 800 to 1000 calories, 50% fat; meal should be eaten in 30 minutes or less). On C1D15, Compound A will be administered following an overnight fast of at least 10 hours.VVID-765PC 184200.00318

[0243] Group 2 participants: Compound A will be administered at C1 D8 following an overnight fast of at least 10 hours. On C1 D15 following an overnight fast of at least 10 hours, Compound A will be administered 30 minutes after starting eating a high fat meal (i.e., 800 to 1000 calories, 50% fat; meal should be eaten in 30 minutes or less).

[0244] Compound A should be taken with a minimum of 240 mL (e.g., 8 fluid ounces) of water.

[0245] Additional water is permitted ad libitum except for the period of 1 hour before to 1 hour after drug administration. In both cases, food should not be consumed for at least 4 hours after the dose. The food intake during the high fat meal including calories and fat content will be recorded on the eCRF.

[0246] Participants must abstain from alcohol for 24 hours before scheduled study visit day. During the study, participants are requested to moderate their alcohol intake.Participants will be queried on a regular basis about their alcohol consumption and appropriate comments concerning this intake will be recorded on the electronic case report form (eCRF).

[0247] Administration of Pembrolizumab

[0248] Pembrolizumab will be administered by IV infusion at a fixed dose of 200 mg on Day 1 of each 21 -day cycle, following administration of Compound A. Pembrolizumab administration should begin between 30 minutes to 2 hours after the first daily oral administration of Compound A. Pembrolizumab will be administered over 30 minutes by an IV infusion. However, given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min / +10 min).

[0249] EFFICACY ASSESSMENTS

[0250] Efficacy will be monitored using tumor and response evaluations (e.g., RECIST v1.1); [18F] FDG-PET Imaging; serologic tumor markers (e.g., CEA, PSA, CA-125, etc.); safety assessments to monitor adverse events, serious adverse events, and adverse events of special interest; physical examinations; vital signs, electrocardiograms; clinical safety laboratory assessments; Eastern Cooperative Oncology Group Performance Status; Clinical Outcome Assessments (e.g., patient reported outcomes); review of medical history and demographic data.

[0251] Patient reported outcome data will be collected through use of the following instruments:• European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire- Function 17 (EORTC QLQ-F17)VVID-765PC 184200.00318 • European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire- Item Library 345 (EORTC IL345)• Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE)• European Organisation for Research and Treatment of Cancer Item List 46 (EORTC-IL46; treatment bother item)

[0252] The EORTC QLQ-F17 includes the Physical Functioning (PF), Role Functioning (RF), Emotional Functioning (EF), Cognitive Functioning (CF), and Social Functioning (SF) scales as well as the Global Health Status / Quality of Life (GHS / QoL) scale in their original wording from the validated EORTC QLQ-C30 (Aaronson et al. 1993, Fitzsimmons et al. 1999). It consists of 17 questions with a recall period of the previous week. The functioning items are scored on a 4-point scale that ranges from “not at all” to “very much,” and the GHS / QoL items are scored on a 7-point scale that ranges from “very poor” to “excellent.” Higher scale scores are reflective of better functioning and health-related quality of life.

[0253] The EORTC IL345 (For Participants with CRC in Part IV only) will be used to collect disease-related symptoms of CRC. The items were selected from the EORTC item library based on those included in the QLQ-CR29 (Gujral et al. 2007). The 5 symptoms include: abdominal pain, pain in buttocks / anal area / rectum, abdominal bloating, blood in stools, and mucus in stools. The IL345 items are rated on a 4-point scale that ranges from "not at all" to "very much”, have a recall period of the past week, and takes approximately 5 minutes to complete.

[0254] The PRO-CTCAE is a validated item library that is used to characterize the presence, frequency of occurrence, severity, and / or degree of interference with daily function of 78 participant-reportable symptomatic treatment toxicities (Basch et al. 2014, Dueck et al.2015). The PRO-CTCAE contains 124 questions that are rated either dichotomously (for determination of presence vs. absence) or on a 5-point Likert scale (for determination of frequency of occurrence, severity, and interference with daily function). Treatment toxicities can occur with observable signs (e.g., vomiting) or non-observable symptoms (e.g., nausea). The standard PRO-CTCAE recall period is the previous 7 days. A subset of 13 symptoms (i.e., nausea, vomiting, diarrhea, constipation, fatigue, arthralgia, pain, rash, neuropathy, decreased appetite, shortness of breath, concentration, and insomnia) deemed most applicable to the current treatment has been selected for this study. Participants will also be asked if there are any additional symptoms they have experienced during treatment. Over the course of the study, evaluation of these symptoms may result in additional items being added to the list of symptoms being assessed.

[0255] [18F] FDG-PET ImagingVVID-765PC 184200.00318

[0256] [18F]-FDG-PET / CT will be performed in Part I and Part II participants at specified timepoints to determine drug effect on the tumor. FDG-PET might not be required in Part II of the study, if Part I data indicate no further need to continue the quantitative assessment of therapy-induced changes in tumor [18F]-FDG uptake. [18F]-FDG-PET / CT is not required in Part IV of the study.

[0257] Compound A in advanced microsatellite instable solid tumors: a Phase 1 trial

[0258] A Phase I study of Compound A was conducted in 88 patients with microsatellite instability (MSI) and / or DNA mismatch repair (dMMR) advanced solid tumors who had progressed on standard therapy. Primary objectives were to evaluate the maximum tolerated dose (MTD), safety and tolerability. Compound A was administered once (150mg), twice (150-1000mg) or three times daily (200-600mg). MTD was not identified. Grade 3 or 4 adverse events (AEs) occurred in 41 patients (46.6%). No Grade 5 AEs occurred. AEs leading to discontinuation were uncommon (3.4%). The disease control rate across all doses in 66 patients with confirmed MSI was 74.2%; seven (10.6%) had a confirmed partial response (cPR) and 41 (62.1%) had stable disease by RECIST v1.1. Median duration of response among cPR patients was 10.2 months. Compound A shows manageable safety and encouraging activity in patients with heavily pretreated MSI advanced solid tumours.

[0259] Patient disposition and characteristics

[0260] 88 patients were enrolled into the study (45 in the dose escalation cohorts and 43 in the randomized backfill cohorts) at 17 centers in eight countries. All patients received at least one dose of Compound A monotherapy. At data cut-off, 56 patients had discontinued treatment and 32 were ongoing. The most common reason for treatment discontinuation was disease progression (n=39 / 56; 69.6%).

[0261] Among the 88 patients enrolled, median age was 60 years (range: 27-86), 50 (56.8%) were male and 77 (87.5%) were white. MSI status was confirmed in 71 (80.6%) patients. Overall, 57 (64.8%) patients had advanced CRC, eight (9.1%) had endometrial cancer, and the remaining patients had different tumor types. The median number of prior lines of therapy was three (range: 1-12); 84 (95.5%) had received prior immune checkpoint inhibitor therapy.

[0262] Dosing regimens and dose-limiting toxicity

[0263] Patients were enrolled into the following dose-escalation cohorts: 150mg once daily (QD, n=5), 150mg twice daily (BID, n=4), 300mg BID (n=10), 600mg BID (n=14), 1000mg BID (n=11), and 600mg three times a day (TID, n=1). Upon completion of the dose escalation cohorts, and after review of all available data, three randomized backfill cohortsVVID-765PC 184200.00318 were opened and patients were randomized 1:1:1 (without stratification factors) into 150mg QD (n=14), 200mg TID (n=15) and 600mg TID (n=14) cohorts. Therefore, a total of seven dosing regimens were assessed (150mg QD, 150mg BID, 300mg BID, 600mg BID, 1000mg BID, 200mg TID, and 600mg TID).

[0264] No dose-limiting toxicities (DLTs) were experienced in the dose-escalation cohorts; one patient experienced a DLT in the 600mg TID backfill cohort (n=1 / 15; 6.7%). This patient had a Grade 2 nausea that was considered significant enough to qualify as a DLT per investigator judgement; the event resolved after 8 days, following treatment with granisetron. Notably, the maximum tolerated dose (MTD) of Compound A monotherapy was not identified.

[0265] Discussion and Conclusion

[0266] Safety, pharmacokinetics, efficacy, metabolic response, and other studies were conducted (data not shown). This study identified a range of Compound A dose levels (from 150mg QD to 600mg BID) that had manageable safety, favorable pharmacokinetics and promising anti-tumor activity / disease control in association with molecular and metabolic responses. The 1000mg BID schedule was not considered for further development due to tolerability issues leading to dose interruption in five of 11 patients (45.5%) and dose reduction in six of 11 patients (54.5%). The 600mg TID regimen provided a similar cumulative daily Compound A dose to the 1000mg BID regimen, but a reduced Cmax (high Cmax correlated with gastrointestinal adverse events) and increased Ctrough (resulting in improved predicted target engagement). Despite a reduction in acute nausea, tolerability remained suboptimal, leading to dose interruptions in nine of 15 patients (60.0%) and dose reductions in seven of 15 patients (46.7%). In addition, one patient experienced a DLT (Grade 2 nausea) and one patient experienced Grade 3 rash. TID schedules were examined extensively in the backfill cohorts, with the aim of maximizing WRN inhibition and improving efficacy. However, there was no noticeable improvement in efficacy, exposure was not superior to the equivalent daily doses in a BID schedule and the TID schedule increased the administration and compliance burden on the patients in the study. Therefore, TID schedules were not proposed for further clinical development. With these various considerations in mind, the 150mg BID and 600mg BID doses were identified as the recommended doses for further development. Of note, these doses are clinically active, well tolerated, differentiated in exposure and provide Ctrough concentrations above the predicted threshold for activity.

[0267] This Phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of Compound A in patients with MSI advanced solid tumors who had progressed on standard therapy. The MTD was notVVID-765PC 184200.00318 identified. A range of Compound A dose levels that had manageable safety, favorable pharmacokinetics and promising anti-tumor activity / disease control in association with molecular and metabolic responses were identified. Based on these findings, the 150mg BID and 600mg BID doses were selected as the recommended doses for further study in Phase I expansion cohorts / Phase II studies involving patients with MSI and / or dMMR advanced solid tumors, such as CRC and endometrial cancers.

Claims

VVID-765PC 184200.00318 What is claimed is:

1. A method of treating a patient suffering from cancer comprising administering to the patient a therapy comprising Compound A:N NH^N'(A), or a pharmaceutically acceptable salt thereof, and an anti-PD1 antibody, whereinCompound A is administered in a total daily dose of 150 mg to 4000 mg based upon free base weight of Compound A, and the cancer is a microsatellite instability (MSI-H) cancer and / or a mismatch repair deficient (dMMR) solid tumor.

2. The method of claim 1, comprising administering a total daily dose of 150 mg Compound A, based upon free base weight.

3. The method of claim 1 , comprising administering a total daily dose of 300 mg Compound A, based upon free base weight.

4. The method of claim 1 , comprising administering a total daily dose of 600 mg Compound A, based upon free base weight.

5. The method of claim 1, comprising administering a total daily dose of 1200 mg Compound A, based upon free base weight.

6. The method of claim 1 , comprising administering a total daily dose of 2000 mg Compound A, based upon free base weight.

7. The method of claim 1 , comprising administering a total daily dose of 2400 mg Compound A, based upon free base weight.

8. The method of claim 1 , comprising administering a total daily dose of 4000 mg Compound A, based upon free base weight.

9. The method of any one of claims 1-8, wherein Compound A or salt thereof is administered orally once daily.

10. The method of any one of claims 1-8, wherein Compound A or salt thereof is administered orally twice daily.

11. The method of any one of claims 1-8, wherein Compound A or salt thereof is administered orally three times daily.VVID-765PC 184200.00318 12. The method of any one of claims 1-11, wherein the anti-PD1 antibody is cemiplimab, dostarlimab, pembrolizumab, or nivolumab.

13. The method of claim 12, wherein the anti-PD1 antibody is pembrolizumab.

14. The method of claim 13, comprising administering 200 mg pembrolizumab via IV administration every three weeks.

15. The method of any one of claims 1-14, wherein the cancer is colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, small intestinal cancer, liver cancer, hepatobiliary cancer, upper urinary tract cancer, brain cancer, skin cancer (e.g., melanoma) non-small cell lung cancer, small cell lung cancer, biliary tract cancer, cervical cancer, neuroendocrine carcinoma, thyroid cancer, or prostate cancer.

16. The method of claim 15, wherein the cancer is thyroid cancer, colorectal cancer, melanoma, brain cancer, or non-small cell lung cancer.

17. The method of claim 15, wherein the cancer is colorectal adenocarcinoma (CRC).

18. The method of any one of claims 1-15, wherein the cancer is a solid tumor other than a colorectal adenocarcinoma (CRC).

19. The method of any one of claims 1-18, wherein Compound A or salt thereof is administered when the patient is in a fasted state.

20. The method of any one of claims 1-18, wherein Compound A or salt thereof is administered when the patient is in a fed state.

21. The method of any one of claims 1-20, wherein the patient is treatment-naive for the cancer (i.e., the therapy is a first line therapy).

22. The method of any one of claims 1-20, wherein, prior to beginning the therapy, the patient previously was treated for the cancer (i.e., the therapy is a second or higher line therapy).

23. The method of claim 22, wherein at least one prior therapy comprised a checkpoint inhibitor (CPI) therapy.

24. The method of claim 23, wherein the patient is CPI-resistant or CPI-refractory.

25. The method of any one of claims 1-24, wherein the therapy is administered for at least 3 weeks.

26. The method of claim 25, wherein the therapy is administered for at least 6 months.VVID-765PC 184200.00318 27. The method of any one of claims 1-26, wherein the patient exhibits at least a stable disease, as measured by RECIST v1.1 , while on the therapy.

28. The method of any one of claims 1-27, wherein the disease control rate (DCR) is at least 50%.

29. A method of treating cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of Compound A:N NH^N'(A), or a pharmaceutically acceptable salt thereof, and an anti-PD1 antibody, wherein the cancer is a microsatellite instability high (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

30. The method of claim 29, wherein Compound A is administered in a total daily dose of 150 mg to 4000 mg, based upon free base weight of Compound A.

31. The method of any one of claims 29-30, wherein Compound A or salt thereof is administered orally once daily or orally twice daily.

32. The method of any one of claims 29-31 , wherein the anti-PD1 antibody is cemiplimab, dostarlimab, pembrolizumab, or nivolumab.

33. The method of any one of claims 29-32, wherein the cancer is a microsatellite instability high (MSI-H) cancer or a mismatch repair deficient (dMMR) solid tumor.

34. The method of any one of claims 29-33, wherein the cancer is colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, small intestinal cancer, liver cancer, hepatobiliary cancer, upper urinary tract cancer, brain cancer, skin cancer (e.g., melanoma) non-small cell lung cancer, small cell lung cancer, biliary tract cancer, cervical cancer, neuroendocrine carcinoma, thyroid cancer, or prostate cancer.

35. A combination therapy comprising Compound A:N NH^N'(A), or a pharmaceutically acceptable salt thereof, andVVID-765PC 184200.00318 an anti-PD1 antibody for use in treating a cancer, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

36. The combination therapy of claim 35, wherein Compound A is in a total daily dose of 150 mg to 4000 mg, based upon free base weight of Compound A.

37. The combination therapy of any one of claims 35-36, wherein Compound A or salt thereof is for oral administration once daily or twice daily.

38. The combination therapy of any one of claims 35-37, wherein the anti-PD1 antibody is cemiplimab, dostarlimab, pembrolizumab, or nivolumab.

39. The combination therapy of nay one of claims 35-38, wherein the cancer is a microsatellite instability high (MSI-H) cancer or a mismatch repair deficient (dMMR) solid tumor.

40. The combination therapy of nay one of claims 35-39, wherein the cancer is colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, small intestinal cancer, liver cancer, hepatobiliary cancer, upper urinary tract cancer, brain cancer, skin cancer (e.g., melanoma) non-small cell lung cancer, small cell lung cancer, biliary tract cancer, cervical cancer, neuroendocrine carcinoma, thyroid cancer, or prostate cancer.

41. A method of treating cancer, the method comprising administering to the patient in need thereof a therapeutically effective amount of Compound A:N NH^N'(A), or a pharmaceutically acceptable salt thereof, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

42. The method of claim 41 , wherein Compound A is administered in a monotherapy.

43. The method of any one of claims 41-42, wherein Compound A is administered in a total daily dose of 150 mg to 4000 mg, based upon free base weight of Compound A.VVID-765PC 184200.00318 44. The method of any one of claims 41-43, comprising administering a total daily dose of 150 mg, 300 mg, 600 mg, 1200 mg, or 2000 mg Compound A, based upon free base weight of Compound A.

45. The method of any one of claims 41-44, wherein Compound A or salt thereof is administered orally once daily.

46. The method of any one of claims 41-44, wherein Compound A or salt thereof is administered orally twice daily.

47. The method of claim 46, wherein Compound A is administered orally in a dose of 150 mg to 600 mg twice daily, based upon free base weight of Compound A.

48. The method of claim 47, wherein Compound A is administered orally in a dose of 150 mg, 200 mg, 300 mg, or 600 mg twice daily, based upon free base weight of Compound A.

49. The method of any one of claims 41-48, wherein the cancer is a microsatellite instability high (MSI-H) cancer or a mismatch repair deficient (dMMR) solid tumor.

50. The method of any one of claims 41-49, wherein the cancer is colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, small intestinal cancer, liver cancer, hepatobiliary cancer, upper urinary tract cancer, brain cancer, skin cancer (e.g., melanoma) non-small cell lung cancer, small cell lung cancer, biliary tract cancer, cervical cancer, neuroendocrine carcinoma, thyroid cancer, or prostate cancer.

51. The method of claim 50, wherein the cancer is thyroid cancer, colorectal cancer, melanoma, brain cancer, or non-small cell lung cancer.

52. The method of claim 50, wherein the cancer is colorectal adenocarcinoma (CRC).

53. The method of any one of claims 41-50, wherein the cancer is a solid tumor other than a colorectal adenocarcinoma (CRC).

54. The method of any one of claims 41-53, wherein Compound A or salt thereof is administered when the patient is in a fasted state.

55. The method of any one of claims 41-53, wherein Compound A or salt thereof is administered when the patient is in a fed state.

56. The method of any one of claims 41-55, wherein the patient is treatment-naive for the cancer (i.e. , the therapy is a first line therapy).VVID-765PC 184200.00318 57. The method of any one of claims 41-55, wherein, prior to beginning the therapy, the patient previously was treated for the cancer (i.e. , the therapy is a second or higher line therapy).

58. The method of claim 57, wherein at least one prior therapy comprised a checkpoint inhibitor (CPI) therapy.

59. The method of claim 58, wherein the patient is CPI-resistant or CPI-refractory.

60. The method of any one of claims 41-59, wherein Compound A is administered for at least 3 weeks.

61. The method of claim 60, wherein Compound A is administered for at least 6 months.

62. The method of any one of claims 41-61 , wherein the patient exhibits at least a stable disease, as measured by RECIST v1.1 , while on the therapy.

63. The method of any one of claims 41-62, wherein the disease control rate (DCR) is at least 50%.N N HF.^N'F64. CompoundA, (A), or a pharmaceutically acceptable salt thereof, for use in treating a cancer, wherein the cancer is a microsatellite instability (MSI-H) cancer, a mismatch repair deficient (dMMR) solid tumor, or both.

65. Compound A, or a pharmaceutically acceptable salt thereof, of claim 64, which is a monotherapy.

66. Compound A, or a pharmaceutically acceptable salt thereof, of any one of claims 64-65, which is in a total daily dose of 150 mg to 4000 mg based upon free base weight of Compound A.

67. Compound A, or a pharmaceutically acceptable salt thereof, of any one of claim 64-66, which is for oral administration once daily or twice daily.

68. Compound A, or a pharmaceutically acceptable salt thereof, of any one of claims 65-67, wherein the cancer is a microsatellite instability high (MSI-H) cancer or a mismatch repair deficient (dMMR) solid tumor.VVID-765PC 184200.00318 69. Compound A, or a pharmaceutically acceptable salt thereof, of any one of claims 65-68, wherein the cancer is colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, small intestinal cancer, liver cancer, hepatobiliary cancer, upper urinary tract cancer, brain cancer, skin cancer (e.g., melanoma) non-small cell lung cancer, small cell lung cancer, biliary tract cancer, cervical cancer, neuroendocrine carcinoma, thyroid cancer, or prostate cancer.

70. Compound A, or a pharmaceutically acceptable salt thereof, for use in treating a cancer, wherein the cancer is a microsatellite instability (MSI-H) cancer and / or a mismatch repair deficient (dMMR) solid tumor,Compound A has a structure ofN NH^N'and Compound A is administered in a total daily dose of 150 mg to 4000 mg based upon free base weight of Compound A.

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