Dosing regimen for PARP7 inhibitors

Abstract

The present invention relates to doses, administration regimens, formulations, unit dosage forms, and related of PARP7 inhibitors for the treatment of cancer. The present invention also relates to methods of treating cancer by administering a PARP7 inhibitor in combination with an antibody that binds to PD-1.

Description

[Technical Field]

[0001] The present invention relates to doses, administration regimens, formulations, unit dosage forms, and related matters of PARP7 inhibitors for treating cancer. The present invention also relates to methods of treating cancer by administering a PARP7 inhibitor in combination with an antibody that binds to PD-1. [Background technology]

[0002] Poly(ADP-ribose) polymerase (PARP) is a member of a family of 17 enzymes that regulate fundamental cellular processes such as gene expression, protein degradation, and multiple cellular stress responses (MS Cohen, P. Chang, Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat Chem Biol 14, 236-243 (2018)). PARP7 is a member of the monoPARP family of proteins, which are important regulators of stress responses. In cancer cells, genetic instability leads to the leakage of nucleic acids from the cytoplasm. Overexpression of PARP7 is a hallmark of many cancer types, leading to the suppression of nucleic acid sensing. This allows cancer cells to proliferate and evade the immune system.

[0003] PARP7 inhibitors have been reported to be useful for treating cancer.See, for example, U.S. Patent No. 10,550,105.Considering the role that PARP7 overexpression plays in the development and progression of cancer, it is clear that there is a need for an appropriate and effective dosing regimen for administering PARP7 inhibitors to patients for the treatment of cancer.The dosing regimen, unit dosage form and related embodiments described herein help to address this need. Summary of the Invention

[0004] The present invention relates to a method of treating cancer in a subject, comprising administering to the subject the compound 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (the compound of Formula I) or a pharmaceutically acceptable salt thereof, in a specified total daily dose.

[0005] The present invention further provides unit dosage forms containing a particular amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0006] The present invention further provides a method of treating cancer in a human subject, comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject at a specific mean C max , average C min , average T max or average AUC 0-12h The method comprises administering to the subject a pharmaceutical composition comprising the compound of formula (I) in an amount sufficient to provide a steady state of

[0007] The present invention further provides a solid formulation of a compound of formula I, or a pharmaceutically acceptable salt thereof, which is micronized.

[0008] The present invention further provides a solid pharmaceutical formulation comprising a specific amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0009] The present invention further provides a method of treating cancer in a subject, comprising: (i) the compound 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one, or a pharmaceutically acceptable salt thereof; and (ii) an antibody that binds to human PD-1; to the subject. [Brief explanation of the drawings]

[0010] [Figure 1A] FIG. 1A is a graph showing the mean plasma profile of a compound of Formula I for doses of 25 mg to 500 mg BID in humans on day 1 of administration.

[0011] [Figure 1B] FIG. 1B is a graph showing the mean plasma profile of a compound of Formula I for doses of 25 mg to 500 mg BID in humans on day 15 of administration.

[0012] [Figure 2] FIG. 2 is a table showing the data from FIGS. 1A-1B.

[0013] [Figure 3] FIG. 3 is a graph depicting the mean plasma profiles of dogs treated with 100 mg of the compound of formula I in micronized and non-micronized form.

[0014] Detailed Description Dosing regimen The present invention particularly relates to compounds of formula I: [ka] The present invention relates to a dosing regimen for treating cancer by administering a PARP7 inhibitor represented by Formula I or a pharmaceutically acceptable salt thereof. The chemical name of the compound represented by Formula I is 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one. This compound and its pharmaceutically acceptable salts are described in U.S. Pat. No. 10,550,105, the disclosure of which is incorporated by reference in its entirety.

[0015] The compound of Formula I or a pharmaceutically acceptable salt thereof can be administered according to the dosing regimen described herein to treat a PARP7-related disorder, such as cancer, in a subject. Accordingly, the present invention provides a method for treating cancer in a subject, comprising administering to the subject a compound of Formula I or a pharmaceutically acceptable salt thereof at a total daily dose of about 50 mg to about 1000 mg, measured as the free base. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 50 mg, about 100 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, or about 1000 mg, measured as the free base. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 50 mg, about 100 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, or about 1000 mg. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a total daily dose of about 50 mg, measured as the free base. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a total daily dose of about 100 mg, measured as the free base. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a total daily dose of about 200 mg, measured as the free base. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a total daily dose of about 300 mg, measured as the free base. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a total daily dose of about 400 mg, measured as the free base. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a total daily dose of about 500 mg, measured as the free base. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a total daily dose of about 600 mg, measured as the free base. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a total daily dose of about 700 mg measured as the free base. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a total daily dose of about 800 mg measured as the free base.In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a total daily dose of about 900 mg measured as the free base. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a total daily dose of about 1000 mg measured as the free base.

[0016] In some instances, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily, hi other instances, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily.

[0017] In some examples, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered according to a continuous administration schedule. For example, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for two or more consecutive days. In some embodiments, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for five or more consecutive days. In other embodiments, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for ten or more consecutive days. In some embodiments, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for fifteen or more consecutive days. In some examples, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for twenty or more consecutive days. In some embodiments, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for twenty one or more consecutive days.

[0018] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered via an intermittent dosing schedule. In some instances, the intermittent dosing schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for two or more consecutive days as a treatment period, followed by at least one day of no treatment with the compound or a pharmaceutically acceptable salt thereof. In some instances, the treatment period is at least seven consecutive days. In some instances, the treatment period is 7 to 21 consecutive days. In some instances, the treatment period is 14 consecutive days. In some embodiments, the no-treatment period is at least two consecutive days. In some instances, the no-treatment period is at least four consecutive days. In other instances, the no-treatment period is 4 to 10 consecutive days. In some embodiments, the no-treatment period is seven consecutive days. In some embodiments, the intermittent dosing schedule comprises at least two treatment periods, and all treatment periods are separated by no-treatment periods.

[0019] In some embodiments, the patient is administered about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, twice daily. In some embodiments, the patient is administered about 200 mg or about 300 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, twice daily. In some embodiments, the patient is administered about 200 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, twice daily. In some embodiments, the patient is administered about 300 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, twice daily. In some embodiments, the patient is administered about 100 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, twice daily.

[0020] In some embodiments, the patient is administered about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, once daily. In some embodiments, the patient is administered about 200 mg or about 300 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, once daily. In some embodiments, the patient is administered about 100 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, once daily. In some embodiments, the patient is administered about 200 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, once daily.

[0021] Pharmaceutical unit dosage forms, formulations and kits Also provided herein are unit dosage forms containing a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of about 25 mg to about 500 mg, about 100 mg to about 400 mg, or about 200 mg to about 300 mg, measured as the free base. In some instances, the unit dosage form contains a compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg, measured as the free base. In some instances, the unit dosage form is suitable for oral administration, such as in the form of a tablet or capsule.

[0022] Formulations for preparing unit dosage forms of the compound of Formula I or a pharmaceutically acceptable salt thereof, and formulations for pharmaceutical administration of the compound of Formula I or a pharmaceutically acceptable salt thereof, can contain about 30-50%, about 35-45%, or about 40% w / w of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0023] The term "unit dosage form" means physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable carrier.

[0024] As used herein, the term "pharmaceutically acceptable salt" is intended to apply to any salt suitable for pharmaceutical use, whether previously known or discovered in the future, used by those skilled in the art. "Pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines; organic acid salts of alkali or acidic residues, such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of both. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), the contents of each of which are incorporated herein by reference in their entirety.

[0025] In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt is formulated with a pharmaceutically acceptable carrier.As used herein, "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, isotonicity agents, absorption retardants, etc.The carrier may be suitable for oral, intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (for example, by injection or infusion).The exact proportion of the carrier / excipient described herein is determined by the solubility and chemical properties of the active compound, the selected administration route, and standard pharmaceutical practice.

[0026] To prepare solid compositions such as tablets, the key active ingredient is mixed with a pharmaceutically acceptable excipient or carrier to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present disclosure. As used herein, the phrase "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulant. Excipients are generally safe, non-toxic, and not biologically or otherwise undesirable, including excipients acceptable for veterinary and human pharmaceutical use. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, and the resulting composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into the types of unit dosage forms described above.

[0027] Also within the scope of this disclosure are kits containing a compound of Formula I or a pharmaceutically acceptable salt thereof, composition, or unit dosage form described herein. The kits can include one or more of the following other components: instructions for use (e.g., according to the dosing regimens described herein); other reagents, such as labels, therapeutic agents, or agents useful for chelating or conjugating the antibody to the label or therapeutic agent or radioprotective composition; equipment or other materials for preparing the antibody for administration; a pharmaceutically acceptable carrier; and equipment or other materials for administration to a subject.

[0028] Particle size and micronization The compound of Formula I can be prepared in micronized and non-micronized forms. In some embodiments, the compound of Formula I used in the dosage forms of the present invention is micronized. Micronized drug substance can be prepared, for example, by jet milling. Particle size can be determined by laser diffraction (e.g., USP 42 <429> The particle size can be measured by optical diffraction (particle size measurement). The non-micronized compound can have a particle size [d90] of about 30 μm or more. In some embodiments, the non-micronized compound has a particle size [d90] of about 30 μm to about 500 μm, about 50 μm to about 400 μm, about 100 μm to about 350 μm, or about 150 μm to about 300 μm. The micronized compound can have a particle size [d90] of less than about 30 μm. In some embodiments, the micronized compound can have a particle size [d90] of about 1 μm to about 20 μm, about 2 μm to about 18 μm, about 5 μm to about 15 μm, or about 7 μm to about 12 μm. In some embodiments, the micronized compound can have a particle size [d90] of about 8 μm, 9 μm, 10 μm, or 11 μm.

[0029] In some embodiments, the compound of Formula I used in the dosage forms and formulations of the present invention is not micronized, but is prepared in a manner that results in a small particle size, such as having a particle size [d90] of less than about 30 μm. In some embodiments, the non-micronized compound may have a particle size [d90] of about 1 μm to about 20 μm, about 2 μm to about 18 μm, about 5 μm to about 15 μm, or about 7 μm to about 12 μm. In some embodiments, the non-micronized compound may have a particle size [d90] of about 8 μm, 9 μm, 10 μm, or 11 μm.

[0030] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof having a small particle size (whether by micronization or not) is used to prepare the pharmaceutical formulations and solid dosage forms described herein. In some embodiments, a patient is administered a compound of Formula I or a pharmaceutically acceptable salt thereof having a small particle size. In some embodiments, a patient is administered about 100 mg to about 300 mg, about 150 to about 250 mg, or about 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof having a particle size [d90] of less than about 30 μm twice daily, measured as the free base. In some embodiments, the administered compound or a pharmaceutically acceptable salt thereof may have a particle size [d90] of about 1 μm to about 20 μm, about 2 μm to about 18 μm, about 5 μm to about 15 μm, or about 7 μm to about 12 μm. In some embodiments, the administered compound or its pharmaceutically acceptable salt may have a particle size [d90] of about 8 μm, 9 μm, 10 μm, or 11 μm. The administered compound or its pharmaceutically acceptable salt may be micronized to achieve a small particle size.

[0031] The present invention further provides a method for reducing the particle size of a preparation of a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprising micronizing a non-micronized preparation of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the non-micronized preparation of a compound of Formula I, or a pharmaceutically acceptable salt thereof, has a particle size [d90] of about 30 μm or greater. In some embodiments, the non-micronized preparation of a compound of Formula I, or a pharmaceutically acceptable salt thereof, has a particle size [d90] of about 30 μm to about 500 μm, about 50 μm to about 400 μm, about 100 μm to about 350 μm, or about 150 μm to about 300 μm. In some embodiments, the resulting micronized compound or pharmaceutically acceptable salt thereof may have a particle size [d90] of less than about 30 μm, e.g., about 1 μm to about 20 μm, about 2 μm to about 18 μm, about 5 μm to about 15 μm, or about 7 μm to about 12 μm. In some embodiments, the resulting micronized compound or pharmaceutically acceptable salt thereof may have a particle size [d90] of about 8 μm, 9 μm, 10 μm, or 11 μm. The present invention further provides micronized products prepared by any of the above processes.

[0032] The present invention further provides a method for increasing the bioavailability of a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprising micronizing the compound of Formula I, or a pharmaceutically acceptable salt thereof, prior to administration to a subject, wherein the increased bioavailability is compared to the bioavailability of the same amount of a non-micronized compound of Formula I, or a pharmaceutically acceptable salt thereof. The increased bioavailability is measured by a mean C max Or it can be measured by the improvement of the average AUC. For example, the average C max The mean AUC can be improved by about 1.5 to about 3 times, about 2 to about 3 times, or about 2.4 times. Furthermore, the mean AUC can be improved by about 1.2 to about 2 times, about 1.3 to about 1.8 times, or about 1.5 times.

[0033] Pharmacokinetics Also provided herein are methods of treating cancer in a subject, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, in an amount sufficient to provide a steady-state: (a) Mean C of approximately 140 ng / mL to approximately 1600 ng / mL max ; (b) a mean C of at least about 50 ng / mL to 700 ng / mL min ; (c) Average T over approximately 1 to 5 hours max ;or (d) Mean AUC of approximately 800hr*ng / mL to 10,500hr*ng / mL 0-12h .

[0034] In some embodiments, the method comprises administering to the patient a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, in an amount sufficient to provide a steady-state: (a) Mean C of approximately 200 ng / mL to approximately 800 ng / mL max ; (b) a mean C of at least about 200 ng / mL to 500 ng / mL min ; (c) Average T over approximately 2 to 4 hours max ;or (d) Mean AUC of approximately 1000hr*ng / mL to 5000hr*ng / mL 0-12h .

[0035] In some embodiments, the method comprises administering to the patient a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, in an amount sufficient to provide a steady-state: (a) Mean C of approximately 400 ng / mL to approximately 700 ng / mL max ; (b) a mean C of at least about 300 ng / mL to 500 ng / mL min ; (c) Average T over approximately 2 to 3 hours max ;or (d) Mean AUC of approximately 2000hr*ng / mL to 5000hr*ng / mL 0-12h .

[0036] In some embodiments, the method comprises administering to the patient a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, in an amount sufficient to provide a steady-state: (a) Mean C of approximately 500 ng / mL to approximately 700 ng / mL max ; (b) a mean C of at least about 300 ng / mL to 500 ng / mL min ; (c) Average T over approximately 2 to 3 hours max ;or (d) Mean AUC of approximately 3000hr*ng / mL to 4200hr*ng / mL 0-12h .

[0037] In some embodiments, the method comprises administering to the patient a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, in an amount sufficient to provide a steady-state: (a) Mean C of approximately 500 ng / mL to approximately 700 ng / mL max ,or (d) Mean AUC of approximately 3000hr*ng / mL to 4200hr*ng / mL 0-12h .

[0038] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form has a mean C of about 200 ng / mL to about 800 ng / mL. max In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is administered in an amount sufficient to provide a steady-state C of about 300 ng / mL to about 800 ng / mL. maxIn some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is administered in an amount sufficient to provide a steady-state C of about 400 ng / mL to about 700 ng / mL. max In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is administered in an amount sufficient to provide a steady state C of about 500 ng / mL to about 700 ng / mL. max In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is administered in an amount sufficient to provide a steady-state C of about 600 ng / mL to about 700 ng / mL. max The dose is administered in an amount sufficient to provide a steady state

[0039] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form has a mean C of about 200 ng / mL to about 500 ng / mL. min In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is administered in an amount sufficient to provide a steady-state C of about 300 ng / mL to about 500 ng / mL. min In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is provided in an amount sufficient to provide a steady state C of about 300 ng / mL to about 400 ng / mL. min The dose is administered in an amount sufficient to provide a steady state

[0040] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, has a mean T max In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is administered in an amount sufficient to provide a steady state T of about 2 hours to 3 hours. maxThe dose is administered in an amount sufficient to provide a steady state

[0041] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form has a mean AUC 0-12h In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is administered in an amount sufficient to provide a steady-state AUC of about 2000 hr*ng / mL to 5000 hr*ng / mL. 0-12h In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is administered in an amount sufficient to provide a steady-state AUC of about 2500 hr*ng / mL to 4500 hr*ng / mL. 0-12h In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is administered in an amount sufficient to provide a steady-state AUC of about 3000 hr*ng / mL to 4200 hr*ng / mL. 0-12h In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is administered in an amount sufficient to provide a steady-state AUC of about 1400 hr*ng / mL to 4500 hr*ng / mL. 0-12h In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, in micronized or non-micronized form, is administered in an amount sufficient to provide a steady-state AUC 0-12h The dose is administered in an amount sufficient to provide a steady state

[0042] Treatment method Provided herein is a method for treating cancer in a subject in need of treatment, comprising administering to the subject a compound of Formula I or a pharmaceutically acceptable salt thereof in micronized or non-micronized form in a unit dosage form as disclosed herein and / or according to a dosing regimen as disclosed herein, for example, a continuous dosing schedule or an intermittent dosing schedule.As described herein, a continuous dosing schedule means that the subject is administered a dose continuously, for example, substantially without interruption, throughout the entire treatment, for example, for 2 or more consecutive days, or 5 or more consecutive days, or 10 or more consecutive days, or 15 or more consecutive days, or 20 or more consecutive days, or 21 or more consecutive days, or more.The treatment period in a continuous dosing schedule can be in the range of several days, weeks, or months.As described herein, an intermittent dosing schedule means that the subject is administered a dose during which the dose is interrupted by one or more periods of not being treated with the compound. Alternatively stated, an intermittent dosing schedule means that the subject is administered a compound of Formula I or a pharmaceutically acceptable salt thereof for two or more consecutive days, followed by a period of at least one day without treatment with the compound or a pharmaceutically acceptable salt thereof. The treatment period can range from 7 consecutive days to 21 consecutive days, e.g., at least 2 consecutive days, at least 7 consecutive days, or at least 14 consecutive days. The non-treatment period can range from 4 to 10 consecutive days, e.g., at least 2 consecutive days, at least 4 consecutive days, or at least 7 consecutive days.

[0043] As used herein, the terms "treat," "treatment," and "treating" refer to the reduction or amelioration of the progression, severity, and / or duration of a disorder, e.g., a proliferative disorder, or the amelioration of one or more symptoms (preferably one or more discernible symptoms) of the disorder through the administration of one or more therapies. In certain embodiments, the terms "treat," "treatment," and "treating" refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, e.g., tumor growth, which is not necessarily discernible by the patient. In other embodiments, the terms "treat," "treatment," and "treating" refer to the inhibition of the progression of a proliferative disorder, either physical, e.g., by stabilization of discernible symptoms, physiological, e.g., by stabilization of physical parameters, or both. In other embodiments, the terms "treat," "treatment," and "treating" refer to the reduction or stabilization of tumor size or cancerous cell number.

[0044] As used herein, the term "subject" or "patient" refers to a warm-blooded animal, such as a mammal, that is afflicted with a particular disease, disorder, or condition. It is expressly understood that guinea pigs, dogs, cats, rats, mice, horses, cows, sheep, and humans are examples of animals within the meaning of this term.

[0045] The term "cancer" refers to a disease characterized by the rapid and uncontrollable growth of abnormal cells. Cancer cells can spread locally or to other parts of the body through the bloodstream or lymphatic system. The terms "tumor" and "cancer" are used interchangeably herein; for example, both terms encompass solid and liquid tumors, e.g., diffuse or circulating tumors. As used herein, the term "cancer" or "tumor" includes precancerous and malignant cancers and tumors. As used herein, the term "cancer" is meant to include any and all types of cancerous growths or oncogenic processes, metastatic tissues, or malignantly transformed cells, tissues, or organs, regardless of histopathological type or invasive stage. Examples of cancerous disorders include, but are not limited to, breast cancer, cancer of the central nervous system, endometrial cancer, kidney cancer, colon cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck (upper aerodigestive tract) cancer, urinary tract cancer, colon cancer, and cancers in which PARP7 expression is amplified. In some embodiments, cancers treatable according to the present invention include hematopoietic malignancies, such as leukemia and lymphoma. Examples of lymphoma include Hodgkin's or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkitt's lymphoma. Examples of leukemia include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0046] Other cancers that can be treated by administration of the compounds of the invention include liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, digestive tumors, head and neck cancer (upper aerodigestive tract cancer), intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0047] In some embodiments, other cancers treatable by administration of the compounds of the invention are multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper aerodigestive tract cancer), kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, and breast cancer.

[0048] Exemplary cancers whose growth can be inhibited using the compound of Formula I or a pharmaceutically acceptable salt thereof disclosed herein, or a unit dosage form thereof, include solid tumors. For example, in some embodiments, the cancer is lung cancer, such as squamous cell carcinoma of the lung (SCCL) or NSCLC. In some embodiments, the cancer is advanced squamous non-small cell lung cancer. In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the cancer is esophageal cancer. In other embodiments, the cancer is breast cancer, such as HR+ breast cancer. In some embodiments, the cancer is ovarian cancer. In other embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is a cancer in which PARP7 expression is amplified.

[0049] In some embodiments, a subject is administered a dosing regimen disclosed herein until the cancer progresses. In some embodiments, a subject is administered a dosing regimen disclosed herein until side effects become intolerable. In some embodiments, a subject is administered a dosing regimen disclosed herein until the subject withdraws consent for continued treatment. In some embodiments, a subject is administered a dosing regimen disclosed herein until the cancer is determined to be in remission. "Remission" is defined as a reduction or disappearance of signs and symptoms of cancer. In some embodiments, a subject is administered a dosing regimen disclosed herein for one or more treatment cycles of about 21 days.

[0050] Combination therapy The compound of Formula I, or a pharmaceutically acceptable salt thereof, or a dosage form containing same, may be used alone to inhibit the growth of cancerous tumors, or in combination with one or more of the following: standard of care treatments (e.g., typical for the type of cancer being treated), antibodies or antigen-binding fragments thereof, immunomodulators (e.g., activators of costimulatory molecules or inhibitors of inhibitory molecules); vaccines, e.g., therapeutic cancer vaccines; or other forms of cellular immunotherapy.

[0051] The term "combination" or "in combination with" is not intended to imply that the therapies or therapeutic agents must be administered simultaneously and / or formulated for delivery together, although these delivery methods are within the scope described herein. Therapeutic agents in a combination may be administered simultaneously with, before, or after one or more other additional therapies or therapeutic agents. Therapeutic agents or treatment protocols may be administered in any order. Generally, each agent is administered at a dose and / or time schedule determined for that agent. It will further be understood that additional therapeutic agents utilized in the combination may be administered together in a single composition or separately in different compositions. Generally, it is expected that additional therapeutic agents utilized in combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination are lower than the levels utilized individually.

[0052] Further provided herein is a method of treating cancer in a subject in need thereof by administering to the subject (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof, and (ii) an antibody that binds to human PD-1.

[0053] In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is pembrolizumab. Pembrolizumab is a humanized antibody approved by the U.S. Food and Drug Administration for the treatment of melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, cancer that is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumor, colon or rectal cancer, gastric cancer or esophagogastric junction (GEJ) adenocarcinoma, esophageal cancer or certain esophagogastric junction (GEJ) cancers, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma (MCC), renal cell carcinoma (RCC), cutaneous squamous cell carcinoma (cSCC), and triple-negative breast cancer (TNBC).

[0054] The antibody can be administered to a subject, e.g., a subject in need thereof, e.g., a human subject, by a variety of methods. In many applications, the route of administration is one of the following: intravenous injection or infusion (IV), subcutaneous injection (SC), intraperitoneal (IP) injection, or intramuscular injection. Intra-articular delivery can also be used. Other parenteral modes of administration can also be used. Examples of such modes include intra-arterial, intrathecal, intra-articular, intraorbital, intracardiac, intradermal, transtracheal, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, and epidural injections, and intrasternal injection. In some embodiments, the antibody is administered by infusion over a period of less than one hour. In some embodiments, the antibody is administered by infusion over a period of about 10 minutes to about 1 hour. In some embodiments, the antibody is administered by infusion over a period of about 15 minutes to about 45 minutes. In some embodiments, the antibody is administered by infusion over a period of about 30 minutes.

[0055] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof and the antibody are administered simultaneously. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof and the antibody are administered simultaneously or sequentially. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof and the antibody are administered simultaneously. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof and the antibody are administered sequentially.

[0056] The compound of formula I and its pharmaceutically acceptable salts can be administered to a subject, for example, a subject in need thereof, for example, a human subject, by various methods.In some embodiments, the route of administration is oral.In some embodiments, the compound of formula I or its pharmaceutically acceptable salts is administered as a pharmaceutical composition.

[0057] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered twice daily.

[0058] In some embodiments, the patient is administered about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, twice daily. In some embodiments, the patient is administered about 100 mg or about 200 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, twice daily. In some embodiments, the patient is administered about 200 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, twice daily. In some embodiments, the patient is administered about 100 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, twice daily.

[0059] In some embodiments, the patient is administered about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, once daily. In some embodiments, the patient is administered about 100 mg or about 200 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, once daily. In some embodiments, the patient is administered about 100 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, once daily. In some embodiments, the patient is administered about 200 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, measured as the free base, once daily.

[0060] In some examples, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered according to a continuous administration schedule. For example, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for two or more consecutive days. In some embodiments, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for five or more consecutive days. In other embodiments, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for ten or more consecutive days. In some embodiments, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for fifteen or more consecutive days. In some examples, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for twenty or more consecutive days. In some embodiments, the continuous administration schedule comprises administering the compound or a pharmaceutically acceptable salt thereof to the subject for twenty one or more consecutive days.

[0061] The anti-PD-1 antibody can be administered to a subject, e.g., a subject in need thereof, e.g., a human subject, by a variety of methods. In many applications, the route of administration is one of the following: intravenous injection or infusion (IV), subcutaneous injection (SC), intraperitoneal (IP) injection, or intramuscular injection. Intra-articular delivery can also be used. Other parenteral modes of administration can also be used. Examples of such modes include intra-arterial, intrathecal, intra-articular, intraorbital, intracardiac, intradermal, transtracheal, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, and epidural injections, and intrasternal injection.

[0062] The route and / or mode of administration of the antibody can also be adapted to the individual case, for example, by monitoring the subject using, for example, tomography, to visualize the tumor.

[0063] The antibody can be administered as a fixed dose or in mg / kg doses. The dose can also be selected to reduce or avoid the production of antibodies against the anti-PD-1 antibody. The administration regimen is adjusted to provide the desired response, e.g., a therapeutic response or a combined therapeutic effect. Generally, the dose of the anti-PD-1 antibody (and optionally the second agent) can be used to provide a bioavailable amount of the agent to the subject.

[0064] As used herein, dosage unit form or "fixed dose" or "fixed dose" refers to a physically discrete unit suitable as a unitary administration to a subject to be treated, each unit containing a predetermined quantity of active compound calculated to produce a desired therapeutic effect in association with the required pharmaceutical carrier, and optionally with other agents. Single or multiple doses may be given. Alternatively, or additionally, the antibody may be administered by continuous infusion. An exemplary fixed dose includes 200 mg.

[0065] Doses of anti-PD-1 antibodies can be administered at periodic intervals over a period (treatment course) sufficient to encompass, for example, at least two, three, five, ten, or more doses, e.g., once or twice daily, or about one to four times per week, or preferably once weekly, once every two weeks (every two weeks), once every three weeks, or once monthly. In some embodiments, the antibody is administered every three weeks. Factors that can affect the dosage and timing required to effectively treat a subject include, for example, the severity of the disease or disorder, the formulation, the route of delivery, previous treatments, the subject's general health and / or age, and any other diseases present. Furthermore, treatment of a subject with a therapeutically effective amount of a compound can include a single treatment or, preferably, a series of treatments.

[0066] An exemplary dosing regimen comprises administering the anti-PD-1 antibody at a fixed dose of 200 mg once every three weeks. In some embodiments, the dosing regimen comprises administering the anti-PD-1 antibody at a fixed dose of about 200 mg once every three weeks.

[0067] In some embodiments, the term "about" refers to a value plus or minus 10%. Those skilled in the art will understand that the values ​​presented herein may vary depending on experimental conditions, such as data collection or instrument variation.

[0068] In some embodiments, the cancer is breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer, urinary tract cancer, colon cancer, or cancer with amplified PARP7 expression. In some embodiments, the lung cancer is lung squamous cell carcinoma.

[0069] In some embodiments, the subject has previously been treated for cancer. In some embodiments, the previous treatment is platinum doublet chemotherapy or an immune checkpoint blockade inhibitor. In some embodiments, the previous treatment is platinum doublet chemotherapy. In some embodiments, the previous treatment is an immune checkpoint inhibitor.

[0070] In some embodiments, the previous treatment is platinum doublet chemotherapy and an immune checkpoint inhibitor. In some embodiments, the subject was treated sequentially with platinum doublet chemotherapy and an immune checkpoint inhibitor. In some embodiments, the subject was treated with a combination of platinum doublet chemotherapy and an immune checkpoint inhibitor.

[0071] Exemplary immune checkpoint inhibitors include anti-PD-1 / anti-PD-L1 and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors. In some embodiments, the immune checkpoint inhibitors include anti-PD-1 / anti-PD-L1 or anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors. In some embodiments, the immune checkpoint inhibitors include anti-PD-1 / anti-PD-L1 and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors.

[0072] In some embodiments, the subject has failed at least one previous treatment. In some embodiments, the cancer is refractory.

[0073] In some embodiments, the subject has central nervous system metastases, the subject has a baseline MRI after CNS-directed therapy that shows no evidence of progression, the subject is neurologically stable, and the subject is not receiving corticosteroid therapy. In some embodiments, the subject has a baseline MRI within 28 days after treatment.

[0074] The present invention will be described in more detail with reference to specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to yield essentially the same results. It will be understood that certain features of the present invention that are described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the present invention that are described in the context of a single embodiment for brevity may also be provided individually or in any suitable subcombination. [Example]

[0075] Example A: Dose Escalation Study of Compound of Formula I methodology This protocol is a first-in-human, Phase 1, multicenter, open-label study designed to evaluate the safety profile, including dose-limiting toxicities (DLTs) and the (maximum tolerated dose) MTD, of compound of Formula I administered as a single agent PO, and to establish a recommended Phase 2 dose (RP2D) for compound of Formula I. The study will include a dose escalation phase that will include a relative bioavailability assessment, followed by a dose expansion phase in patients with selected tumor types.

[0076] The dose-escalation phase of the study will target patients with histologically or cytologically confirmed solid tumor types (which may include solid lymphomas [e.g., mantle cell tumors]) that are refractory to standard therapy, for whom no therapies have demonstrated potential therapeutic or clinical benefit and for whom experimental therapies are a reasonable option. The dose-expansion phase of the study will explore RP2D in the following cancer types: squamous cell carcinoma of the lung (SCCL), squamous cell carcinoma of the head and neck (HNSCC), hormone receptor-positive (HR+) breast cancer, and PARP7-amplified cancers.

[0077] Secondary objectives include characterizing the safety and PK profile of the compound of Formula I, the bioavailability of tablets made with the micronized form of the compound of Formula I compared to the non-micronized form (standard tablet) of the compound of Formula I, and identifying preliminary antitumor activity. Biomarkers and their correlation with response to the compound of Formula I and other outcomes will be examined.

[0078] Standard tablets of the compound of Formula I are prepared in non-micronized form and used in all dose escalation cohorts prior to evaluation of the relative bioavailability of the micronized tablets versus the standard tablets. The micronized tablets are used in the dose expansion phase of the study after the relative bioavailability evaluation is complete.

[0079] Dose escalation phase

[0080] This includes evaluating escalating dose levels of the compound of Formula I in cohorts of 3 to 6 patients and separate cohorts to assess the relative bioavailability of micronized and non-micronized tablets.

[0081] Two schedules are utilized for the dose escalation phase: Schedule 1 examines the compound of Formula I at doses of 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 500 mg administered BID for 14 days followed by a 21-day cycle of rest. Schedule 2 will examine 21-day consecutive dosing cycles at doses of 100 mg, 200 mg, 300 mg, and 400 mg BID.

[0082] The cohort follows a traditional 3+3 design.

[0083] The first patient cohort will be assigned to Schedule 1 and will receive the compound of Formula I at a dose of 25 mg twice daily (BID) for 14 days.

[0084] Schedule 2 will begin after at least one dose escalation in Schedule 1, as determined by the Safety Review Committee (SRC). Patients in Schedule 2 will receive the compound of Formula I BID for 21 days at a dose at least one dose level lower than that being studied in the active Schedule 1 cohort. Dose escalation will occur according to findings in Schedules 1 and 2.

[0085] To obtain accurate PK estimates, in Schedule 1, the compound of Formula I is administered once daily (QD) on Day 1 of Cycle 1 (C1D1), then on a BID schedule until C1D14, with a single in-clinic dose on C1D15 and an 8-hour PK assessment (replacing the skipped C1D1 evening dose). In Schedule 2, the compound of Formula I is administered QD on C1D1, then on a BID schedule until C1D21, with an 8-hour PK assessment on C1D15. For the purposes of this study, the treatment cycle is 21 days. (C1D21 is the last day of C1; the first day of C2 is C2D1, which corresponds to Day 22 of the study.) Based on the PK data from the BID dose cohort in this study, QD, three times daily (TID) dosing (intermittent or continuous), or other schedules may also be considered.

[0086] The first study drug dose is administered on C1D1, except for the relative bioavailability cohort described below, where the first study drug dose is administered 7 days (± 3 days) prior to C1D1. Each patient in a dose cohort receives at least 85% of their prescribed dose of the compound of Formula I during C1 and undergoes follow-up safety evaluations until C2D1, unless due to treatment-related toxicity (a DLT by default), and is eligible for evaluation of a DLT. Patients not eligible for evaluation of a DLT are replaced.

[0087] Relative Bioavailability Relative bioavailability cohorts of approximately 6-8 patients will be enrolled to evaluate the relative bioavailability of tablets of the compound of Formula I manufactured in micronized form (micronized tablets) versus non-micronized tablets (standard tablets). Patients will receive a first dose of study drug administered as a 100 mg micronized tablet 7 days (±3 days) prior to C1D1. After a minimum 4-day washout period, patients will receive a second dose of study drug administered as a 100 mg standard (non-micronized) tablet on C1D1. Evaluations performed after C1D1 will be the same as those described for patients in the dose escalation cohort following Schedule 2. Based on new PK data, additional relative bioavailability cohorts at additional dose levels may be considered. After examining the PK and safety results of the relative bioavailability cohort, the micronized tablets may be used in subsequent dose escalation and / or dose confirmation cohorts. The micronized tablets will be used in the dose-expansion phase of the study after the relative bioavailability assessment is complete.

[0088] Patients enrolled in the relative bioavailability cohort will have an additional visit 7 days (± 3 days) prior to C1D1. Patients will arrive at the study center prior to administration of the first study drug dose, administered as a micronized tablet, on C1D-7 and will remain at the study center until at least 12 hours after administration of the first study drug dose. On C1D-7, patients will be fitted with a continuous Holter monitor for approximately 24 hours (i.e., until they return the next day on C1D-6 for 24-hour PK sampling). Patients will return to the study center for administration of the second study drug dose, administered as a standard tablet, on C1D1 and will remain at the study center until at least 12 hours after administration of the second study drug dose. On C1D1, patients will be fitted with a continuous Holter monitor for approximately 24 hours (i.e., immediately prior to study drug administration on C1D2). Patients return the next day (C1D2) to receive study drug (administered as a standard tablet) 24 hours (± 1 hour) after study drug administration on C1D1 and immediately following the 24-hour PK sample collection. Evaluation of relative bioavailability will be based on comparison of PK data collected within 24 hours after administration of C1D-7 and C1D1. Samples collected after C1D2 will not be considered part of the relative bioavailability dataset. Patients will continue to receive the standard tablet at all subsequent doses, and evaluations performed after C1D1 will be the same as those described for patients in the dose escalation cohort according to Schedule 2.

[0089] Dose expansion phase Four cohorts of approximately 20 patients each will be enrolled for additional testing of the safety, PK, pharmacodynamics, and antitumor activity of the compound of Formula I at RP2D. Based on nonclinical data and clinical data obtained from the dose escalation phase of the study, patient enrollment in the dose escalation phase will be limited to the following specific tumor types: SCCL, HNSCC, HR+ breast cancer, and PARP7-amplified cancer. Each cohort will enroll approximately 20 patients, and if at least 3 of 20 patients in that group experience an objective response (PR or CR) by RECIST 1.1, the sample size may be expanded to approximately 40 patients. If it is logistically impossible to enroll 20 patients in any of these cohorts, that cohort may be closed to enrollment at any time.

[0090] Supply of experimental drugs The compound of formula I is supplied as standard tablets of 25 mg, 100 mg, and 200 mg for oral administration. Tablets prepared from the compound of formula I in micronized form are supplied as 100 mg tablets for oral administration. The particle size [d90] of the micronized compound is 5-15 μm.

[0091] data Initial human PK data have been obtained for administration of the non-micronized compound of Formula I (d

[90] 228.474 μm) and are shown in FIGS.

[0092] Additional PK data were obtained comparing micronized (d

[90] 10.851 μm) and non-micronized (d

[90] 228.474 μm) compounds of Formula I. Patients were administered 100 mg of the compound of Formula I as a micronized tablet. Plasma samples were collected at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration. After a 7-day washout period, patients were administered 100 mg of the compound of Formula I as a non-micronized tablet. Plasma samples were collected at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration. Area under the curve and peak plasma concentration data were obtained via non-compartmental analysis for the micronized and non-micronized dose groups. See table below. The mean AUC was approximately 1.5-fold, and the mean C max increased by approximately 2.4 times. [Table 1]

[0093] Example B: Pharmacokinetics of Compound of Formula I after Oral Administration of Tablets and Capsules in Male Beagle Dogs

[0094] the purpose The objectives of this study were to determine the plasma pharmacokinetic profile of the compound of Formula I in male beagle dogs after oral administration and to assess the exposure of tablet and capsule formulations.

[0095] animal Male beagle dogs were purchased from Jiangsu Johnsen Bioresource CO., Ltd. The animals were 1 to 2.5 years old on the day of dosing. All animals were housed in a 12-hour light / 12-hour dark cycle environment. Animals in the oral (PO) group were fasted overnight before dosing and fed approximately 2 hours after dosing. This study was approved by the Pharmaron Institutional Animal Care and Use Committee.

[0096] Test Design A total of five male beagle dogs were dosed according to the design shown in Table 1 below. The compound of Formula I was used to prepare the dose formulation and standard stock solution. The compound of Formula I was administered as tablet and capsule doses. For animals in the PO group, pentagastrin (6.0 μg / kg, intramuscular) was administered 20 minutes before administration of the PO formulation and 1.5 hours after the first pentagastrin administration. The dose volume was 0.024 mL / kg, and the concentration was 250 μg / mL in DMSO / 1N NaOH / PBS. The dose volume and detailed administration time of pentagastrin were recorded. The gavage catheter of each animal was flushed with 10 mL of 0.001N HCl.

[0097] [Table 2]

[0098] Preparation of formulations A pentagastrin intramuscular formulation (6.0 μg / kg) was prepared by dissolving it in DMSO / 1N NaOH / physiological buffered saline (1 / 2 / 300, v / v / v) at a concentration of 250 μg / mL. The weight of each capsule dose containing the compound of Formula I was recorded, and the weights of pentagastrin and 1-ABT were recorded. Tablets, each containing 25 mg of the compound of Formula I, were supplied on behalf of the sponsor.

[0099] Capsules were filled with the appropriate amount and type (non-micronized and micronized) of compound of formula I.

[0100] Sample collection For PO administration (25 mg, 50 mg, 100 mg, 100 mg, 100 mg / dog), blood samples were collected from each animal pre-dose and 15, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours post-dose. Blood samples (0.5 mL) were collected from each animal via the jugular vein. These blood samples were placed into tubes containing dipotassium ethylenediaminetetraacetate and then centrifuged at 2000 g for 10 minutes at 4°C to generate plasma. All samples were stored at -75 ± 15°C until analysis.

[0101] Preparation of standards for LC-MS / MS analysis The compound of Formula I was prepared as a standard stock solution at 1 mg / mL (free form) in dimethyl sulfoxide using a vortex mixer. Calibration standard working solutions were prepared at concentrations of 5 ng / mL, 10 ng / mL, 20 ng / mL, 50 ng / mL, 100 ng / mL, 500 ng / mL, 1000 ng / mL, 5000 ng / mL, 10000 ng / mL, and 20000 ng / mL by serial dilution of the standard stock solution with 50% acetonitrile in water. Quality control working solutions at concentrations of 10 ng / mL, 20 ng / mL, 50 ng / mL, 1000 ng / mL, 8000 ng / mL, and 16000 ng / mL were prepared by serial dilution of the standard stock solution with 50% acetonitrile in water. These QC samples were prepared in the same manner as the calibration standards on the day of analysis.

[0102] Sample processing Calibration standards ranging from 0.5 to 2000 ng / mL (0.5 ng / mL, 1 ng / mL, 2 ng / mL, 5 ng / mL, 10 ng / mL, 50 ng / mL, 100 ng / mL, 500 ng / mL, 1000 ng / mL, 5000 ng / mL, 10000 ng / mL, and 20000 ng / mL) were achieved by adding 5 µL of each calibration standard working solution (5 ng / mL, 10 ng / mL, 20 ng / mL, 50 ng / mL, 100 ng / mL, 500 ng / mL, 1000 ng / mL, and 20000 ng / mL) to 50 µL of blank Beagle dog plasma in a total volume of 55 µL. In addition to those used for the calibration curve, quality control (QC) samples of 1 ng / mL (low-1), 2 ng / mL (low-2), 5 ng / mL (low-3), 100 ng / mL (intermediate), 800 ng / mL (high-1), and 1600 ng / mL (high-2) in blank plasma were prepared. These QC samples were prepared in the same manner as the calibration standards on the day of analysis. 55 μL of standard sample, 55 μL of QC sample, or 55 μL of unknown sample (50 μL of plasma sample containing 5 μL of 50% aqueous acetonitrile) was mixed with 200 μL of acetonitrile containing IS (internal standard, dexamethasone) to precipitate proteins. The samples were then vortexed for 30 s. After centrifugation at 3900 rpm at 4 °C for 15 min, the supernatant was diluted 7-fold with water, and 1 μL of the supernatant was injected into the LC-MS / MS system for quantitative analysis.

[0103] Data and statistical analysis Data acquisition was performed using Sciex Analyst 1.6.3 software (AB Sciex, Forster City, CA). Pharmacokinetic parameters were analyzed using noncompartmental analysis (Phoenix™ WinNonlin (登録商標) The AUC was calculated using the linear trapezoidal algorithm.

[0104] Pharmacokinetic analysis / overview The pharmacokinetics of compound of Formula I was evaluated in male beagle dogs after oral (PO) administration. PO administration was performed with compound of Formula I formulated as a tablet and with micronized and non-micronized compound of Formula I formulated as a gelatin capsule.

[0105] Oral exposure in dogs in groups A, B, and C increased with dose level, although not linearly. Exposure in dogs in group E was significantly higher than that in dogs in group D, which received capsules of micronized and non-micronized compound of Formula I, respectively. A summary of the PK results is shown in Table 2 below.

[0106] [Table 3]

[0107] Micronization of the compound of Formula I improved exposure in dogs. Micronization of the compound of Formula I increased the AUC by 2.8-fold and the C max The data are shown in Table 3 below and in Figure 3.

[0108] [Table 4]

[0109] Example C: Tablets containing a compound of formula I Tablets for oral administration in the clinical studies described in the Examples. A containing the compound of Formula I was prepared by wet granulation. Table 4 below provides exemplary tablet compositions prepared accordingly. 100 mg tablets were prepared using either micronized or non-micronized compound of Formula I.

[0110] [Table 5]

[0111] Example D: Micronized Compound of Formula I

[0112] Micronized batches of the compound of Formula I were prepared by jet milling using a nitrogen gas supply. The non-micronized starting material was prepared in a manner similar to the process for preparing crystalline compound of Formula I described in U.S. Patent No. 10,550,105. Particle size was measured using a Malvern Mastersizer 3000 equipped with a Hydro MV wet dispersion sample unit according to USP 42 <429> The particle size [d90] of the two different lots was measured to be 10.851 and 8.715 μm, respectively.

[0113] Example E: Clinical Trial Protocol for a Phase 1b / 2 Multicenter Single-Arm Study of Compound of Formula I in Combination with Pembrolizumab in Patients with Squamous Cell Carcinoma of the Lung (SCCL)

[0114] the purpose The objective of this study in the Phase 1b Safety Run-in is to determine the recommended Phase 2 dose of the compound of Formula I in combination with pembrolizumab (RP2D).

[0115] The objective of this Phase 2 study is to evaluate the antitumor activity of compound of Formula I in combination with pembrolizumab in patients with SCCL with secondary resistance to previous immune checkpoint inhibitor (ICI) treatment.

[0116] Secondary objectives include evaluating additional measures of antitumor activity, assessing the safety profile and tolerability of compound of Formula I in combination with pembrolizumab, and characterizing the pharmacokinetic (PK) properties of compound of Formula I.

[0117] Exploratory objectives include evaluating predictive biomarkers that may correlate with response and characterizing the pharmacokinetic (Pd) effects of the compound of Formula I in combination with pembrolizumab.

[0118] Study population The study will enroll male and female patients aged 18 years or older with a confirmed diagnosis of advanced non-small cell lung cancer (NSCLC) with squamous cell histology who have received prior treatment containing a platinum doublet and an approved ICI, either sequentially or in combination.

[0119] Number of patients (planned)

[0120] The trial is expected to enroll approximately 50 patients: Phase 1b Safety Run-in: up to 10 patients; Phase 2: approximately 40 patients.

[0121] research design This is an open-label, multicenter, Phase 1b / 2, single-arm study evaluating the safety and antitumor activity of compound of Formula I in combination with pembrolizumab in patients with confirmed advanced NSCLC with squamous cell histology who have received prior therapy. The study consists of a Phase 1b Safety Run-in and a Phase 2. The Phase 1b Safety Run-in and Phase 2 include four study periods: a screening period, a treatment period, an end-of-study period (a 30-day safety follow-up period), and a follow-up period (a 90-day follow-up period for evaluation of immune-related adverse events [irAEs] and disease progression).

[0122] During the Phase 1b Safety Run-in, up to 10 patients who are deemed eligible for treatment during screening will be enrolled in a 3+3 fashion and will begin treatment with continuous oral administration of 200 mg of compound of Formula I in combination with a fixed approved dose of intravenous (IV) pembrolizumab (200 mg every 3 weeks [Q3W]) twice daily (BID). A safety review committee, consisting of the investigator, medical monitor, and sponsor, will evaluate safety and available pharmacokinetic (PK) data from all treated patients and identify any dose-limiting toxicities (DLTs) occurring during the first cycle of combination treatment. Based on the emerging safety profile, dose de-escalation cohorts will be initiated to confirm the tolerability of successive dose levels of compound of Formula I in combination with pembrolizumab and confirm the RP2D.

[0123] Approximately 40 patients who are determined to be eligible for treatment during screening will begin treatment with BID continuous oral administration of the compound of Formula I at the RP2D in combination with the fixed approved dose of IV pembrolizumab during Phase 2. Patients from the Phase 1b Safety Run-in treated at the RP2D will also contribute to the Phase 2 sample size.

[0124] In both the Phase 1b Safety Run-in and Phase 2, a treatment cycle is defined as 21 days. On Day 1 of each treatment cycle, the compound of Formula I is administered orally, followed by an IV infusion of pembrolizumab at a fixed approved dose according to the approved local product label. For the remaining days of the 21-day treatment cycle, only the compound of Formula I is administered BID. Treatment cycles continue until disease progression, unacceptable treatment-related toxicity, or withdrawal of consent.

[0125] If a patient discontinues treatment with a compound of Formula I, the patient will be discontinued from the study and followed for safety and progression-free survival (PFS).

[0126] In the event of an irAE due to administration of pembrolizumab, patients will remain on treatment with single-agent treatment with the compound of Formula I. Patients who discontinue combination treatment before the occurrence of progressive disease (PD) will remain on treatment until PD is documented, the patient withdraws consent for further follow-up, or a new anti-neoplastic therapy is initiated.

[0127] If, after discussion between the investigator and the sponsor, it is determined that the patient would benefit from continued therapy, treatment with the combination or a compound of Formula I alone may be maintained in the presence of radiographic progression.

[0128] Periodic safety assessments will include routine safety laboratory evaluations, physical examinations, 12-lead electrocardiograms (ECGs), and vital signs. Continual safety assessments for treatment-emergent adverse events (TEAEs), irAEs, and concomitant medications will be performed. Computed tomography (CT) and / or magnetic resonance imaging (MRI) will be used to assess disease response to treatment. Periodic blood sampling will be used to characterize Pd and PK parameters. Exploratory biomarkers will be assessed via blood and biopsy samples.

[0129] Eligibility Criteria To be eligible for this study, patients must meet all of the following criteria: 1. Male or female patient (i) 18 years of age or older and (ii) 99 years of age or younger. 2. Definitive diagnosis of advanced / metastatic NSCLC with squamous cell histology as determined by local testing practice: a. Patients should have received prior treatment including a platinum doublet and an ICI, including anti-PD-1 / anti-PD-L1, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, either sequentially or in combination with chemotherapy plus checkpoint inhibitors. and b. The last regimen prior to enrollment in this study must be an approved checkpoint inhibitor-containing regimen with the best response being stable disease, partial response, or complete response. Note: The combination of anti-PD-1 / anti-PD-L1 and anti-CTLA-4 is considered one therapy. 3. Patients have experienced PD as determined by the investigator during or after their most recent treatment regimen. Supporting information regarding PD must be documented.

[0130] 4. Patient provides signed and dated informed consent prior to initiation of study procedures. 5. The patient agrees to undergo a biopsy to obtain a fresh tissue sample only if the procedure to obtain the biopsy is deemed to be a procedure that carries no significant risk and can be performed safely. Patient consent for tumor biopsy taking (during screening) is mandatory. a. An archival biopsy specimen taken within 12 weeks prior to screening is acceptable as a baseline biopsy. b. If obtaining a fresh biopsy is medically infeasible or if a fresh biopsy is deemed unevaluable (e.g., no tumor is present), submission of an archival specimen obtained more than 12 weeks prior to screening may be requested. 6. Eastern Cooperative Oncology Group (ECOG) activity index of 0-1.

[0131] 7. CT or MRI scan within 28 days prior to study treatment showing at least one measurable target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 8. Patient has adequate organ function as determined by the following laboratory values: Patients have adequate renal function (creatinine ≤ 1.5 × upper limit of normal [ULN]) or a glomerular filtration rate (GFR) ≥ 60 mL / min / 1.73 m 2 ) b. Patients have adequate liver function as evidenced by total bilirubin ≤ 1.5 x ULN if due to hepatic involvement by tumor (total bilirubin > 3.0 x ULN and direct bilirubin > 1.5 x ULN are excluded unless due to Gilbert's syndrome), and aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) ≤ 2.5 x ULN or ≤ 5 x ULN. c. Patients must have a hemoglobin of ≥ 9.0 g / dL and a platelet count of ≥ 100 x 10 without transfusions within the past 72 hours. 9cells / L and absolute neutrophil count (ANC) ≥ 1.5 × 10 9 Adequate bone marrow function as evidenced by cells / L. ANC ≥ 1.5 x 10 9 The / L requirement must be independent of recent growth factor support (e.g., within the past 7 days).

[0132] 9. Patients and their partners agree to use adequate contraception until 4 months after the last study drug dose after providing written informed consent as follows: a. For females: Negative pregnancy test during screening and adherence to a medically approved contraceptive regimen during and for 4 months after the treatment period, or documented surgically sterile or postmenopausal status. The use of hormonal contraception (oral or implantable) is not considered a medically approved regimen because the compounds of Formula I may interfere with the effectiveness of hormone-based contraception. b. For men: Adherence to a medically approved contraceptive regimen or documented surgical sterility during and for 4 months after the treatment period. 10. Patient is willing and able to participate in the study and comply with all study requirements.

[0133] Exclusion criteria Patients who meet any of the following criteria will be excluded from this study: 1. Patients with non-squamous histology NSCLC. Patients with mixed tumor histology are excluded. 2. Patients must not have received other investigational systemic therapy for SCCL. 3. Patients must not have received ≥2 lines of prior therapy with an ICI, including anti-PD-1 / anti-PD-L1, anti-CTLA-4 inhibitors, and ≥1 line of prior therapy with chemotherapy doublet treatment.

[0134] 4. Patient is unable to swallow oral medications and has impaired gastrointestinal (GI) function or a GI disease that may significantly alter drug absorption (e.g., active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome). 5. Prior radiation therapy, excluding limited-field palliative radiation therapy, within 2 weeks of Day 1 of Cycle 1 (C1D1). Patients have recovered from all radiation-related toxicities, do not require corticosteroids, and have not had radiation pneumonitis. A 1-week washout is permitted for palliative radiation therapy for non-CNS disease (≤2 weeks of radiation therapy). 6. Patients with CNS metastases are excluded if: - Active CNS metastases (new lesions or progression from previous imaging) requiring treatment within 28 days prior to study treatment and / or ongoing corticosteroid therapy. - Have symptomatic or untreated leptomeningeal disease.

[0135] 7. Patient has discontinued previous treatment with an ICI due to an irAE. 8. History of malignancy, except for malignancies that have been curatively treated and have not recurred within 2 years prior to study treatment; completely excised basal cell carcinoma and cutaneous squamous cell carcinoma; any malignancy that is considered indolent and has never required treatment; and completely excised carcinoma in situ of any kind. 9. Received a live virus vaccination within 30 days of the planned start of treatment. Vaccines that do not contain live viruses are acceptable.

[0136] 10. Subjects who have had any of the following within the past 6 months: myocardial infarction, or a current history of New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina pectoris, uncontrolled severe ventricular anemia, or electrocardiogram evidence of acute ischemia. 11. Have a history of long QT syndrome or polymorphic ventricular tachycardia and / or have a family history of long QT syndrome. 12. The patient is taking concomitant medications that are potent inhibitors or inducers of cytochrome P450 (CYP)-mediated metabolism or that are metabolized by CYP 2B6, 3A4, 2C19, 2C9, or other members of the IIC subfamily of CYP genes and that pose a significant risk to the patient if the dose is insufficient. Individual cases may be discussed with the medical monitor.

[0137] 13. Intake of Chinese herbal medicines within 3 weeks prior to screening, and intake of grapefruit, grapefruit juice, pomegranate juice, starfruit, or orange marmalade (using Seville oranges) within 1 week prior to screening. (Note that there are well-documented cases of CYP3A drug-drug interactions with these foods.) 14. Have an active autoimmune disease requiring systemic treatment within the past 12 months (i.e., use of disease-modifying drugs, corticosteroids, or immunosuppressants). Replacement therapy (e.g., ≤10 mg / day of prednisolone or equivalent steroids, thyroxine, insulin, or corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. Patients with vitiligo, resolved childhood asthma / atopy, type 1 diabetes, residual hypothyroidism due to an autoimmune condition, or those requiring hormone replacement alone are not excluded. 15. Receiving chronic systemic steroid therapy (e.g., prednisolone >10 mg daily or steroid equivalent for >6 months). Asthma subjects who intermittently require bronchodilators, inhaled steroids, or topical steroid injections are not excluded from the study.

[0138] 16. Have an active systemic infection (e.g., bacterial, fungal, viral) requiring treatment. 17. Known active hepatitis B or C. Active hepatitis B is defined as a known positive HBsAg result. Active hepatitis C is defined as a known positive hepatitis C antibody result and a known quantitative hepatitis C viral ribonucleic acid (RNA) result greater than the lower limit of detection of the assay. 18. Have a known mental or substance abuse disorder that would prevent cooperation with the requirements of the study.

[0139] 19. Have interstitial lung disease or a history of pneumonia requiring oral or intravenous steroids to help manage. Lymphatic spread of NSCLC is not excluded. 20. Pregnant or nursing, or expecting pregnancy or childbirth during study drug administration and during the required contraceptive period after the last dose of study drug. 21. Ongoing acute clinical AE from previous cancer therapy of National Cancer Institute (NCI) Common Criteria for Adverse Events (CTCAE) Grade 2 or higher (excluding alopecia, peripheral neuropathy, and toxic hearing loss if Grade 3 or higher).

[0140] 22. Within the past 6 months, one or more of the following events have occurred: cerebrovascular accident, deep vein thrombosis, pulmonary embolism, bleeding (CTCAE grade 3 or 4), chronic liver disease (meeting criteria for Child-Pugh class B or C), or organ transplant. 23. Therapeutic doses of systemic corticosteroids (e.g., prednisolone >10 mg daily or steroid equivalent) have been administered within the 2 weeks prior to Day 1. Topical, inhaled, nasal, and ophthalmic steroids may be used for short-term treatment of acute conditions (e.g., asthma, poison ivy contact dermatitis); for other immunosuppressants, consultation with the medical monitor will determine the dose and duration of exclusion. 24. Any other medical or personal condition that, in the investigator's opinion, may compromise patient safety or compliance or prevent the patient from successfully completing the clinical trial.

[0141] Treatment and study participation period The expected duration of the evaluation period in the Phase 1b Safety Run-in is one cycle (3 weeks), and patients will remain in the study according to the event schedule. All patients in the Phase 1b Safety Run-in and Phase 2 will remain on treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other reason as determined by the investigator's clinical judgment. Patients who discontinue treatment before experiencing disease progression will remain on treatment until PD occurs, the patient withdraws consent for further follow-up, or a new anti-neoplastic therapy is initiated. In consultation with the medical monitor, for patients who meet the criteria for PD but are deemed to benefit by the investigator, patients may continue to receive the compound of Formula I as a single agent or in combination with pembrolizumab.

[0142] Study termination occurs when all patients discontinue treatment during the study for any reason, when the 30-day or 90-day safety follow-up period is completed, when follow-up for disease progression is completed, or when the study is terminated early.

[0143] Dose Investigation: Phase 1b Safety Run-in During the Phase 1b Safety Run-in, three cohorts of patients will be enrolled in a 3+3 dose-finding design to confirm the tolerability of compound of Formula I in combination with pembrolizumab at a fixed dose of 200 mg IV every three weeks. The first three patients will receive study drug as described below (each patient will select a dose). After the first cycle, the Safety Review Committee will evaluate the tolerability of the combination according to the DLT criteria (Table 5), safety data, and PK data. Depending on the tolerability of the combination, three additional cohorts of patients will be enrolled at the same dose or a de-escalated dose of compound of Formula I to further evaluate tolerability after the first cycle and determine the RP2D. During the Phase 1b Safety Run-in, the occurrence of DLTs (Table 2) will determine the RP2D of compound of Formula I in combination with pembrolizumab as follows:

[0144] If, after Cycle 1, one or less of the first three patients experience a DLT based on SRC assessment and results, an additional three patients will be treated with a 200 mg BID dose of the compound of Formula I in combination with pembrolizumab. If, after Cycle 1, one or less of the six patients treated at that dose experience a DLT based on SRC assessment and results, the 200 mg BID dose of the compound of Formula I combination regimen will be declared RP2D, the Phase 1b Safety Run-in will be considered complete, and patients will be enrolled in Phase 2.

[0145] If DLT is determined in two or more of the three patients after the first cycle based on SRC assessment and outcome, an additional three patients will be enrolled in a de-escalation dose of 100 mg compound of Formula I BID in combination with pembrolizumab.

[0146] If, after the first cycle, a DLT is determined in one or less of three newly enrolled patients based on SRC assessments and results, an additional three patients will be treated with a BID dose of 100 mg of the compound of Formula I in combination with pembrolizumab. If, after the first cycle, a DLT is determined in one or less of six patients treated at that dose based on SRC assessments and results, the 100 mg BID dose of the compound of Formula I in combination with pembrolizumab will be declared RP2D, the Phase 1b Safety Run-in will be completed, and enrollment in Phase 2 will be considered. If a DLT is determined in two or more of six patients treated at that dose based on SRC assessments and results, the 100 mg BID dose of the compound of Formula I in combination with pembrolizumab will be deemed to be intolerable and the study will not continue.

[0147] If, after the first cycle, two or more of the three newly enrolled patients experience DLTs based on SRC assessment and results, the BID dose of 100 mg of the compound of Formula I in combination with pembrolizumab will be declared intolerable and the study will not continue.

[0148] Dose-limiting toxicity

[0149] Dose escalation of compound of Formula I is not permitted during the study. The starting dose of compound of Formula I may be de-escalated to 100 mg PO BID during the Phase 1b Safety Run-in based on the incidence of DLTs (Table 5).

[0150] The most frequent treatment-related AEs for the compound of Formula I in the ongoing Phase 1 escalation study were dysgeusia disorder or taste disorder (36%), decreased appetite (15%), fatigue (14%), nausea (12%), and anemia, constipation, diarrhea, and weight loss (10%), respectively.

[0151] The most frequent treatment-related adverse events (reported in >20%) observed with pembrolizumab monotherapy included fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, fever, cough, dyspnea, constipation, pain, and abdominal pain (Merck 2021). The safety profile of NSCLC patients (n=682) who received pembrolizumab as second- or third-line treatment in the Keynote-010 study included diarrhea, fatigue, decreased appetite, elevated liver enzymes, pneumonia, and pneumonitis. Adverse events leading to discontinuation occurred in 8% of patients, with pneumonitis being the most common (1.8%).

[0152] Pembrolizumab and the compound of Formula I have different clearance mechanisms and are not expected to have any drug-drug interactions (DDIs); however, based on available data, potential overlapping toxicities include fatigue, decreased appetite, and GI symptoms such as nausea, constipation, and diarrhea.

[0153] DLTs are shown in Table 5 and are defined as any of the following events in Cycle 1 that are considered by the investigator to be potentially related to at least the compound of Formula I and / or pembrolizumab, using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0):

[0154] [Table 6]

[0155] If a grade 3 irAE occurs in the same or a previous cohort after a previous DLT within a group, further enrollment and treatment of patients within the cohort should be withheld for up to 21 days while awaiting the outcome of the grade 3 irAE. If the grade 3 irAE does not resolve to ≤grade 1 within 21 days, it should be considered a DLT and enrollment in this cohort should be stopped.

[0156] Treatment Combination: Compound of Formula I and Pembrolizumab

[0157] Preclinical studies support the clinical evaluation of the compound of Formula I in combination with a PD-1 inhibitor. Based on the preclinical results, the addition of pembrolizumab to the compound of Formula I may enhance resensitization of patients who have developed secondary resistance to treatment with a PD-1 inhibitor by inducing the release of disruption of type I interferon signaling suppression. The preclinical data generated with this combination will form the basis of a new treatment regimen, providing an opportunity for patients with advanced metastatic SCCL who have developed secondary resistance to access a new treatment option.

[0158] In terms of safety, the compound of Formula I has been administered to 50 patients in an ongoing first-in-human Phase 1 study and has been demonstrated to have a favorable safety profile. Overall, the safety profile of the compound of Formula I is considered manageable at the RP2D for combination with pembrolizumab.

[0159] The toxicity profile of pembrolizumab as a monoclonal antibody, including irAEs, is well known and differs from the observed novel profile of compound of Formula I. However, given the fact that compound of Formula I also acts as an immunomodulator, it is expected that any potential overlapping toxicity of the combination could be monitored clinically in the clinic by routine clinical observation, laboratory testing, and, where appropriate, clinical pathological evaluation.

[0160] Given the available data on pembrolizumab and the knowledge that pembrolizumab is eliminated by catabolism, the combination is not expected to result in DDIs. However, the effect of combination treatment on the PK and exposure response of the compound of Formula I cannot be excluded, and therefore sparse sampling is performed.

[0161] Study drug packaging and labeling

[0162] Each bottle of the compound of Formula I contains 30 100 mg tablets for oral administration.

[0163] Each vial of pembrolizumab injection contains 100 mg of pembrolizumab in 4 mL of solution (25 mg / mL). Each 1 mL of solution contains 25 mg of pembrolizumab, formulated with L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and water for injection, USP.

[0164] Supply, receipt, and storage of study medication

[0165] Once the compound of Formula I is received by qualified personnel, it is stored at room temperature (15-30° C., 59-86° F.).

[0166] Once received by qualified personnel, pembrolizumab should be stored refrigerated at 2°C–8°C (36°F–46°F) in the original carton, protected from light. Pembrolizumab should not be frozen or shaken.

[0167] Preparation and administration of study drugs

[0168] On days when treatment with the compound of Formula I and pembrolizumab overlap, the compound of Formula I is taken before the infusion of pembrolizumab.

[0169] The compound of Formula I is supplied as a 100 mg tablet for oral administration and requires no preparation. The compound of Formula I is administered orally BID. Each dose of the compound of Formula I is taken under fasting conditions at the same time each day (i.e., at least 2 hours after the last food intake and at least 1 hour before the next food intake), with each dose spaced 12 hours (± 4 hours) apart. If the patient misses this ± 4 hour window, the dose should be omitted and recorded as a missed dose. The compound of Formula I should be swallowed whole and not cut, crushed, or chewed. If vomiting occurs during treatment, the patient cannot be re-administered until the next scheduled dose.

[0170] Pembrolizumab is prepared and administered as specified in the manufacturer's product labeling. Patients receive 200 mg of pembrolizumab administered IV Q3W. Pembrolizumab should be administered IV over 30 minutes. Investigators should make every effort to time the infusion as close to 30 minutes as possible. However, to account for site-specific infusion pump variability, a window of -5 to +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 minutes / +10 minutes). Therefore, adherence to the protocol-specified infusion duration requires documentation of the infusion start and end times. Pembrolizumab may be administered on days 1 through 3 of each treatment cycle for administrative reasons only.

[0171] Dose selection for each patient The compound of Formula I was well tolerated in the first-in-human Phase 1 escalation portion of the Formula I compound study, and data from there supported the initial 200 mg BID dose in the Phase 1b Safety Run-in. As shown in Table 6, toxicities observed during the study may result in dose de-escalation.

[0172] [Table 7]

[0173] Generally, if a Grade 1 event occurs, the compound of Formula I is continued, but the patient is monitored more closely. For Grade 2 or higher, the compound of Formula I may be held or discontinued. If there is an irAE due to administration of pembrolizumab, the patient will be kept on treatment with the single-agent compound of Formula I.

[0174] A combined body of evidence supports the approval of the pembrolizumab 200 mg IV Q3W regimen across a range of tumor types. The exposure-response relationship for efficacy and safety was maintained, and this regimen is approved and widely used according to the manufacturer's label.

[0175] The use of a fixed dose of pembrolizumab, when used in combination with a compound of Formula I, simplifies the dosing regimen and reduces the chance of dosing errors.

[0176] Table 7 provides monitoring and dose modification guidelines for irAEs with compound of Formula I or pembrolizumab.

[0177] [Table 8]

[0178] Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be interrupted or discontinued due to toxicity or for medical / surgical events or logistical reasons unrelated to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and / or leave). Unless otherwise discussed with the sponsor, patients should return to study therapy within 3 weeks after a scheduled interruption. The reason for the interruption should be recorded in the patient's study record.

[0179] If pembrolizumab is withheld due to toxicity associated with the combination therapy, patients may resume administration at the next scheduled dosing appointment or when toxicity has improved as described in Table 8.

[0180] Pembrolizumab was withheld in the event of grade 4 hematologic toxicity, non-hematologic toxicity ≥ grade 3 (including laboratory abnormalities), and severe or life-threatening AEs related to the combination therapy (Table 8).

[0181] [Table 9]

[0182] The dose of pembrolizumab may be further modified as described in the FDA Prescribing Information for Keytruda (pembrolizumab), Reference ID: 4308423. (https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2018 / 125514s046lbl.pdf).

[0183] If toxicity does not resolve to grade 0-1 within 12 weeks after the last infusion, pembrolizumab should be discontinued after consultation with the sponsor. Patients who require corticosteroids to manage drug-related adverse events must be on a prednisone equivalent dose of 10 mg or less per day before resuming pembrolizumab. Furthermore, failure to reduce the corticosteroid dose to ≤10 mg prednisone equivalent per day to manage drug-related adverse events within 12 weeks of the last pembrolizumab dose should prompt a discussion between the investigator and sponsor during the study regarding whether the patient can continue treatment. By agreement between the investigator and sponsor, patients with grade 2 laboratory AEs after 12 weeks may continue study treatment as long as they remain asymptomatic and controlled. If a patient is prescribed non-glucocorticoid supportive medication to manage Grade 2 hypothyroidism or Grade 2 hyperthyroidism, the patient may continue receiving study medication as long as the patient is asymptomatic and clinically stable on supportive medication.

[0184] For patients who experience a Grade 3, Grade 4, or persistent (>4 weeks) Grade 2 drug-related AE and continue to receive pembrolizumab, the start of the next cycle may be delayed by 3 weeks (i.e., one treatment cycle delay) if the patient recovers from the AE to Grade 0–1. However, for patients who experience Grade 3 or 4 pneumonitis or persistent (>4 weeks) Grade 2 drug-related pneumonitis that recurs after rechallenge from previous persistent (>4 weeks) Grade 2 drug-related pneumonitis, pembrolizumab should be permanently discontinued.

[0185] For patients who experience a recurrence of the same AE of the same grade or higher upon rechallenge with pembrolizumab, discussions between the sponsor and investigator should determine whether the patient should continue on study; however, for patients who experience a recurrence of the same SAE of the same grade or higher upon rechallenge with pembrolizumab, the patient should discontinue study drug.

[0186] Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent an immunological etiology. These adverse events may occur shortly after the first dose of treatment or several months after the last dose.

[0187] Laboratory evaluation for pharmacokinetics and disease assessment

[0188] Serial blood samples are taken to assess the concentration of the compound of Formula I in plasma. Samples can be taken at any time within the designated window. The time of collection is recorded.

[0189] Blood samples for PK analysis will be obtained at the following time points (cycle (C), day (D)):

[0190] Phase 1b Safety Run-in: ○C1D1 After administration of the compound of formula I ■ 1 to 2 hours (± 5 minutes) after administration ■ 4 hours after administration (-30 minutes / +2 hours) ○C1D8 Before administration of a compound of formula I after administration of a compound of formula I ■ 1 to 2 hours (± 5 minutes) after administration ○C1D15 Before administration of a compound of formula I After administration of the compound of formula I ■ 1 to 2 hours (± 5 minutes) after administration ○C2D1 Before administration of a compound of formula I

[0191] ●Phase 2 ○C1D1 after administration of a compound of formula I ■ 1 to 2 hours (± 5 minutes) after administration ■ 4 hours after administration (-30 minutes / +2 hours) ○C1D15 Before administration of a compound of formula I After administration of the compound of formula I ■ 1 to 2 hours (± 5 minutes) after administration ○C2D1 Before administration of a compound of formula I

[0192] Blood samples and fresh tumor samples are collected for exploratory biomarker analysis. Such blood samples and tumor tissue collected prior to administration are analyzed and evaluated for genetic or biochemical parameters that may correlate with response to the compounds of Formula I (e.g., circulating tumor deoxyribonucleic acid [DNA], PARP7 mRNA or protein levels, and potentially ribonucleic acid [RNA] expression profiling, or other analyses if sufficient tissue samples are available).

[0193] Tumor-specific genotyping and / or expression level testing of relevant cancer genes may also be performed for patients for whom such data are not yet available.

[0194] Patient consent for tumor biopsy collection during screening is mandatory. Procedures for collecting biopsies that pose a 2% or greater risk of mortality or major morbidity at the patient's clinical site and the facility where the procedure is completed should not be utilized. Archival biopsy specimens collected within 12 weeks prior to screening are acceptable as baseline biopsies. If collection of a fresh biopsy is medically infeasible or if a fresh biopsy is deemed ineligible (e.g., absence of tumor), submission of an archival sample collected more than 12 weeks prior to screening may be requested.

[0195] Optionally taking intra-treatment biopsies at C2D1 (± 1 week) is highly recommended to investigate pharmacodynamic (Pd) changes in the tumor microenvironment related to type I IFN responses (e.g., ISG expression) and their impact on adaptive immune responses (e.g., CD8+ T cells, granzyme B expression).

[0196] All samples will be stored until a suitable assay is developed / identified (maximum of 15 years).

[0197] Peripheral blood samples for exploratory Pd analysis will be collected at the following time points: Phase 1b Safety Run-in: C1D1 Before administration of a compound of formula I after administration of a compound of formula I ■ 1 to 2 hours (± 5 minutes) after administration ■ 4 hours (± 30 minutes) after administration C1D8 Before administration of a compound of formula I C1D15 Before administration of a compound of formula I C2D1 Before administration of a compound of formula I Phase 2: C1D1 Before administration of a compound of formula I C1D15 Before administration of a compound of formula I C2D1 Before administration of a compound of formula I

[0198] Measurement of clinical activity Clinical activity will be measured by radiography to determine tumor measurements and disease response at scheduled time points.

[0199] Radiographic assessments will be collected and stored centrally by a sponsor-designated CRO. Sponsors may choose to have scans independently reviewed by a central reader, as defined in their charter.

[0200] During screening, tumor lesions are classified as measurable or nonmeasurable, target or nontarget, as follows:

[0201] Measurable and non-measurable

[0202] Measurable: Lesions that can be accurately measured as ≥10 mm in at least one dimension by CT scan or caliper measurement by clinical examination, or ≥20 mm by chest radiography; record the longest diameter.

[0203] Nonmeasurable: All other lesions, including small lesions (pathological lymph nodes with longest diameter <10 mm or short axis ≥10 to <15 mm) and truly nonmeasurable lesions.

[0204] Targeted and non-targeted Target: All measurable lesions, up to a maximum of two lesions per organ, representing all involved organs, for a total of five lesions, are defined as target lesions and are measured and recorded at screening. Target lesions are selected based on their size (i.e., the lesion with the longest diameter) and suitability for accurate repeated measurements. The sum of the longest diameters of all target lesions is calculated and recorded on the eCRF as the baseline sum longest diameter.

[0205] Non-target: All other lesions not classified as target lesions (or disease sites) are defined as non-target lesions and recorded on the eCRF. Measurement of non-target lesions is not required.

[0206] For patients with measurable disease, disease response assessments will be performed within 28 days prior to C1D1 and repeated every other cycle from 5 days before to 7 days after the first study drug dose, starting on C3D1. After 1 year, disease response assessments will be performed every 9 weeks.

[0207] Disease response in target and non-target lesions will be assessed using RECIST version 1.1 according to the categories and criteria listed in Table 9. Each patient's best overall response will be reported as the best documented response across a range of objective conditions, recorded using the categories and criteria in Table 10. If an atypical radiological response is observed (e.g., delayed response, transient tumor expansion followed by shrinkage, stable size, or initial appearance of new lesions followed by stability or response), the sponsor may perform additional unplanned irRECIST assessments.

[0208] Patients with a CR or PR must be reevaluated 4 weeks after their initial evaluation to confirm their response.

[0209] [Table 10]

[0210] [Table 11]

[0211] safety An adverse event (AE) is defined in the Good Clinical Practice (GCP) guidelines of the International Council for Harmonisation (ICH) as "an untoward medical occurrence occurring in a patient or clinical trial subject receiving a medicinal product, which does not necessarily have a causal relationship with that treatment" (ICH E6:1.2).

[0212] Worsening of a pre-existing medical condition (e.g., diabetes, migraine, gout) after the first dose will be considered an AE if there is an increase in severity, frequency, or duration of the condition, or if it is associated with a significantly worse outcome.

[0213] Interventions for pre-treatment conditions (e.g., elective cosmetic surgery) or medical procedures planned before study enrollment will not be considered adverse events.

[0214] In the case of death, only the event that caused the death will be recorded as "fatal." AEs that are ongoing at the end of the study or at the time of death will be recorded as "ongoing."

[0215] Investigators are responsible for reviewing laboratory test results and determining whether abnormal values ​​in individual patients represent significant changes from baseline. Generally, laboratory abnormalities that are not clinically significant (based on the investigator's judgment) should not be recorded as AEs, but changes in laboratory values ​​that require adjustment of therapy or prior therapy are considered AEs.

[0216] In this study, death and disease progression (i.e., PD) are not considered AEs and should not be reported as such. Death is considered the result of one or more major AEs, and disease progression is considered a worsening of the underlying disease and is a criterion for discontinuing study drug. PD is not recorded as an AE.

[0217] A suspected adverse reaction is any event where there is a reasonable possibility that the drug caused the AE. In Investigational New Drug Application (IND) safety reporting, "reasonable possibility" and / or "at least possibly related" mean that there is evidence suggesting a causal relationship between the drug and the AE. A "suspected adverse reaction" implies a lower degree of certainty about the causal relationship than an "adverse reaction," which means any event caused by the drug.

[0218] An AE or suspected adverse event is considered "serious" if, in the opinion of the investigator or sponsor, it results in any of the following: · It is deadly. · Life-threatening (i.e., the patient is at immediate risk of death). · Requiring hospitalization (overnight stay) or extension of existing hospitalization. · Causes lasting or significant disability / inability to work. ·Congenital / birth defects in the offspring of test patients. · Is a significant medical event; A significant medical event is one that is not fatal, life-threatening, or requires hospitalization, but may be considered an SAE if, based on sound medical judgment, it may endanger the patient and require medical or surgical intervention to prevent any of the consequences enumerated in the definition of an SAE. Examples of such medical events include allergic bronchospasm requiring intensive care in an emergency room or at home, a blood disorder or seizure that does not result in hospitalization, or the development of a drug addiction or substance abuse.

[0219] A hospitalization that meets the definition of "serious" is any hospitalization that includes at least an overnight stay (≥24 hours) in a medical facility. For AEs that do not meet any of the definitions of serious (e.g., emergency department visits, outpatient surgery, or those requiring urgent investigation), investigators may consider them to meet the criteria for a "significant medical event" for classification as an SAE.

[0220] An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the IB or is not listed with the specificity or intensity previously observed, or if an IB is not requested or available, or if it is not consistent with risk information provided elsewhere in the general clinical trial protocol or current application.

[0221] An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the IB or is not listed with the specificity or intensity previously observed, or if an IB is not requested or available, or if it is not consistent with risk information provided elsewhere in the general clinical trial protocol or current application.

[0222] A suspected serious unexpected adverse reaction (SUSAR) is an event that meets all three of the following definitions: 1. Suspected side effects; 2. Severe; and 3. Something unexpected.

[0223] The relationship between study drug and AEs will be described using one of the following categories shown in Table 11:

[0224] [Table 12]

[0225] The intensity of each AE will be assessed by the investigator using the NCI CTCAE, version 5.0 (National Cancer Institute 2017).

[0226] AEs not listed in the NCI CTCAE will be evaluated by the investigator according to the categories in Table 12.

[0227] [Table 13]

[0228] The results for each AE are described using the categories in Table 13.

[0229] [Table 14]

[0230] For each AE, the investigator will indicate the action taken regarding administration of study drug (compound of Formula I or pembrolizumab) by category in Table 14.

[0231] [Table 15]

[0232] Any clinically significant abnormal laboratory finding or other abnormal diagnostic assessment (e.g., ECG, vital signs, etc.) detected in a participant receiving a compound of Formula I and / or pembrolizumab, or that significantly worsens compared to baseline in a participant receiving a compound of Formula I and / or pembrolizumab, will be reported as an AE. Clinical significance will be based on the investigator's judgment but generally includes findings requiring active medical management or accompanied by clinical signs.

[0233] Pregnancy (in a female study patient or the partner of a male study patient) that occurs while the patient is receiving study medication or within 30 days after the patient's last dose of study medication will not be considered serious but will be reported using the same procedures as SAEs described above.

[0234] In this study, AEs will be collected and recorded from the first dose of study drug until 30 days after the last dose of study drug. Collection and recording of irAEs will continue until 90 days after the last dose of study drug. Every effort will be made to collect and record events through direct contact.

[0235] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this disclosure, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

Claims

1. A pharmaceutical for treating cancer in a subject comprising the compound 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one, or a pharma-ceutically acceptable salt thereof, wherein the compound or a pharma-ceutically acceptable salt thereof is administered in a total daily dose of 50 mg to 1000 mg, measured as the free base.

2. 2. The method of claim 1, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in a total daily dose of 50 mg measured as the free base.

3. 2. The method of claim 1, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in a total daily dose of 100 mg measured as the free base.

4. 2. The method of claim 1, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in a total daily dose of 200 mg measured as the free base.

5. 2. The method of claim 1, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in a total daily dose of 400 mg measured as the free base.

6. 2. The method of claim 1, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in a total daily dose of 600 mg measured as the free base.

7. 2. The method of claim 1, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in a total daily dose of 800 mg measured as the free base.

8. The method of any one of claims 1 to 7, wherein the compound or a pharma- ceutically acceptable salt thereof is administered once a day.

9. The method of any one of claims 1 to 7, wherein the compound or a pharma- ceutically acceptable salt thereof is administered twice daily.

10. The method of any one of claims 1 to 9, wherein the compound or a pharma- ceutically acceptable salt thereof is administered according to a continuous dosing schedule.

11. The method of claim 10, wherein the continuous administration schedule comprises administering the compound or a pharma- ceutically acceptable salt thereof to the subject for two or more consecutive days.

12. The method of claim 10, wherein the continuous administration schedule comprises administering the compound or a pharma- ceutically acceptable salt thereof to the subject for 5 or more consecutive days.

13. The method of claim 10, wherein the continuous administration schedule comprises administering the compound or a pharma- ceutically acceptable salt thereof to the subject for 10 or more consecutive days.

14. The method of claim 10, wherein the continuous administration schedule comprises administering the compound or a pharma- ceutically acceptable salt thereof to the subject for 15 or more consecutive days.

15. 11. The method of claim 10, wherein the continuous administration schedule comprises administering the compound or a pharma- ceutically acceptable salt thereof to the subject for 20 or more consecutive days.

16. The method of claim 10, wherein the continuous administration schedule comprises administering the compound, or a pharma- ceutically acceptable salt thereof, to the subject for 21 or more consecutive days.

17. The method of any one of claims 1 to 9, wherein the compound or a pharma- ceutically acceptable salt thereof is administered according to an intermittent dosing schedule.

18. The pharmaceutical agent of claim 17, wherein the intermittent administration schedule comprises administering the compound or a pharma- ceutically acceptable salt thereof to the subject for two or more consecutive days as a treatment period, followed by a period of at least one day without treatment with the compound or a pharma- ceutically acceptable salt thereof.

19. The method of claim 18, wherein the treatment period is at least 7 consecutive days.

20. The method of claim 18, wherein the treatment period is 7 to 21 consecutive days.

21. The method of claim 18, wherein the treatment period is 14 consecutive days.

22. The pharmaceutical composition according to any one of claims 18 to 21, wherein the treatment-free period is at least 2 consecutive days.

23. The method according to any one of claims 18 to 21, wherein the treatment-free period is at least 4 consecutive days.

24. The method according to any one of claims 18 to 21, wherein the treatment-free period is 4 to 10 consecutive days.

25. The pharmaceutical composition according to any one of claims 18 to 21, wherein the treatment-free period is 7 consecutive days.

26. The method of any one of claims 18 to 24, wherein the intermittent dosing schedule comprises at least two treatment periods, wherein all of the treatment periods are separated by periods of no treatment.

27. 27. The method of any one of claims 9 to 26, wherein the patient is administered a dose of 50 mg of the compound, or a pharma- ceutically acceptable salt thereof, measured as the free base, twice daily.

28. 27. The method of any one of claims 9 to 26, wherein the patient is administered a dose of 100 mg, measured as the free base, of the compound or a pharma- ceutically acceptable salt thereof twice daily.

29. 27. The method of any one of claims 9 to 26, wherein the patient is administered a dose of 200 mg of the compound, or a pharma- ceutically acceptable salt thereof, measured as the free base, twice daily.

30. 27. The method of any one of claims 9 to 26, wherein the patient is administered a dose of 300 mg of the compound, or a pharma- ceutically acceptable salt thereof, measured as the free base, twice daily.

31. 27. The method of any one of claims 9 to 26, wherein the patient is administered a dose of 400 mg of the compound, or a pharma- ceutically acceptable salt thereof, measured as the free base, twice daily.

32. 27. The method of any one of claims 9 to 26, wherein the patient is administered a dose of 500 mg of the compound, or a pharma- ceutically acceptable salt thereof, measured as the free base, twice daily.

33. The pharmaceutical agent according to any one of claims 1 to 32, wherein the cancer is breast cancer, cancer of the central nervous system, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer, urinary tract cancer, colon cancer, or cancer in which expression of PARP7 is amplified.

34. The method of any one of claims 1 to 33, wherein the compound or a pharma- ceutically acceptable salt thereof is administered orally.

35. 35. The method of claim 34, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in an oral unit dosage form.

36. 36. The method of claim 35, wherein the oral unit dosage form is in the form of a capsule or tablet.

37. 37. The pharmaceutical composition of claim 36, wherein the compound or a pharma- ceutically acceptable salt thereof has a particle size [d90] of less than 30 μm.

38. The method of claim 36, wherein the compound or a pharma- ceutically acceptable salt thereof has a particle size [d90] of 1 μm to 20 μm.

39. The method of claim 36, wherein the compound or a pharma- ceutically acceptable salt thereof has a particle size [d90] of 5 μm to 15 μm.

40. The method of claim 36, wherein the compound or a pharma- ceutically acceptable salt thereof has a particle size [d90] of 7 μm to 12 μm.

41. 37. The medicament of claim 36, wherein the micronized compound or a pharma- ceutically acceptable salt thereof has a particle size [d90] of 8 μm, 9 μm, 10 μm or 11 μm.

42. 1. A unit dosage formulation comprising the compound 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one, or a pharma- ceutically acceptable salt thereof, in an amount of 25 mg to 500 mg, measured as the free base.

43. 43. The unit dosage formulation of claim 42, suitable for oral administration.

44. 43. The unit dosage formulation of claim 42, comprising the compound or a pharma- ceutically acceptable salt thereof in an amount of 25 mg, measured as the free base.

45. 43. The unit dosage formulation of claim 42, comprising the compound or a pharma- ceutically acceptable salt thereof in an amount of 50 mg, measured as the free base.

46. 43. The unit dosage formulation of claim 42, comprising the compound or a pharma- ceutically acceptable salt thereof in an amount of 75 mg, measured as the free base.

47. 43. The unit dosage formulation of claim 42, comprising the compound or a pharma- ceutically acceptable salt thereof in an amount of 100 mg, measured as the free base.

48. 43. The unit dosage formulation of claim 42, comprising the compound or a pharma- ceutically acceptable salt thereof in an amount of 150 mg, measured as the free base.

49. 43. The unit dosage formulation of claim 42, comprising the compound or a pharma- ceutically acceptable salt thereof in an amount of 200 mg, measured as the free base.

50. 43. The unit dosage formulation of claim 42, comprising the compound or a pharma- ceutically acceptable salt thereof in an amount of 250 mg, measured as the free base.

51. 43. The unit dosage formulation of claim 42, comprising the compound or a pharma- ceutically acceptable salt thereof in an amount of 300 mg, measured as the free base.

52. 52. The unit dosage formulation of any one of claims 42 to 51 in the form of a capsule or tablet.

53. 53. The unit dosage formulation of claim 52, wherein the particle size [d90] of the compound or a pharma- ceutically acceptable salt thereof is less than 30 μm.

54. 53. The unit dosage formulation of claim 52, wherein the particle size [d90] of the compound or its pharma- ceutically acceptable salt is from 1 μm to 20 μm.

55. 53. The unit dosage formulation of claim 52, wherein the particle size [d90] of the compound or its pharma- ceutically acceptable salt is from 5 μm to 15 μm.

56. 53. The unit dosage formulation of claim 52, wherein the particle size [d90] of the compound or its pharma- ceutically acceptable salt is from 7 μm to 12 μm.

57. 53. The unit dosage formulation of claim 52, wherein the particle size [d90] of the compound or a pharma- ceutically acceptable salt thereof is 8 μm, 9 μm, 10 μm or 11 μm.

58. 1. A pharmaceutical composition for treating cancer in a subject, comprising the compound 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one, or a pharma- ceutically acceptable salt thereof, (a) Mean C of 140 ng / mL to 1600 ng / mL max ; (b) a mean C of at least 50 ng / mL to 700 ng / mL min ; (c) Average T from 1 to 5 hours max ;or (d) Mean AUC from 800hr*ng / mL to 10500hr*ng / mL 0-12 The pharmaceutical composition comprises a sufficient amount to provide a steady state

59. The compound or a pharma- ceutical acceptable salt thereof has a mean C max 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state

60. The compound or a pharma- ceutical acceptable salt thereof has a mean C max 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state

61. The compound or a pharma- ceutical acceptable salt thereof has a mean C max 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state

62. The compound or a pharma- ceutical acceptable salt thereof has a mean C max 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state of

63. The compound or a pharma- ceutical acceptable salt thereof has a mean C min 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state

64. The compound or a pharma- ceutical acceptable salt thereof has a mean C min 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state

65. The compound or a pharma- ceutical acceptable salt thereof has a mean C min 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state

66. The compound or a pharma- ceutical acceptable salt thereof has a mean T max 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state

67. The compound or a pharma- ceutical acceptable salt thereof has a mean T max 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state

68. The compound or a pharma- ceutical acceptable salt thereof has a mean AUC 0-12h 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state

69. The compound or a pharma- ceutical acceptable salt thereof has a mean AUC of 1400 hr*ng / mL to 4500 hr*ng / mL. 0-12h 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state

70. The compound or a pharma- ceutical acceptable salt thereof has a mean AUC 0-12h 59. The pharmaceutical composition of claim 58, administered in an amount sufficient to provide a steady state

71. 1. A solid preparation of the compound 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one, or a pharma-ceutically acceptable salt thereof, wherein the particle size [d90] of the compound or a pharma-ceutically acceptable salt thereof is less than 30 μm.

72. 72. The solid formulation of claim 71, wherein the particle size [d90] of the compound or its pharma- ceutically acceptable salt is from 1 μm to 20 μm.

73. 72. The solid formulation of claim 71, wherein the particle size [d90] of the compound or its pharma- ceutically acceptable salt is from 5 μm to 15 μm.

74. 72. The solid formulation of claim 71, wherein the particle size [d90] of the compound or its pharma- ceutically acceptable salt is from 7 μm to 12 μm.

75. 72. The solid formulation of claim 71, wherein the particle size [d90] of the compound or a pharma- ceutically acceptable salt thereof is 8 μm, 9 μm, 10 μm or 11 μm.

76. A solid pharmaceutical formulation comprising the compound 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one, or a pharma- ceutically acceptable salt thereof, in an amount of 30% to 50% w / w, and at least one pharma- ceutically acceptable excipient.

77. 77. The solid pharmaceutical formulation of claim 76, wherein the compound or a pharma- ceutically acceptable salt thereof is present in an amount of 40% w / w.

78. 78. The pharmaceutical formulation of claim 77, wherein the particle size [d90] of the compound or its pharma- ceutically acceptable salt is less than 30 μm.

79. 78. The pharmaceutical formulation of claim 77, wherein the particle size [d90] of the compound or its pharma- ceutically acceptable salt is from 1 μm to 20 μm.

80. 78. The pharmaceutical formulation of claim 77, wherein the particle size [d90] of the compound or its pharma- ceutically acceptable salt is from 5 μm to 15 μm.

81. 78. The pharmaceutical formulation of claim 77, wherein the particle size [d90] of the compound or its pharma- ceutically acceptable salt is from 7 μm to 12 μm.

82. 78. The pharmaceutical formulation of claim 77, wherein the particle size [d90] of the compound or a pharma- ceutically acceptable salt thereof is 8 μm, 9 μm, 10 μm or 11 μm.

83. 1. A medicament for treating cancer in a subject, comprising: (i) the compound 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one, or a pharma- ceutically acceptable salt thereof; and (ii) an antibody that binds to human PD-1; A pharmaceutical comprising:

84. The method of claim 83, wherein the compound or a pharma- ceutically acceptable salt thereof and the antibody are administered simultaneously.

85. The method of claim 83, wherein the compound or a pharma- ceutically acceptable salt thereof and the antibody are administered sequentially.

86. The method of any one of claims 83 to 85, wherein the compound or a pharma- ceutically acceptable salt thereof is administered orally.

87. The method of any one of claims 83 to 86, wherein the antibody is administered via intravenous administration.

88. 88. The method of any one of claims 83 to 87, wherein the compound or a pharma- ceutically acceptable salt thereof is administered twice daily.

89. 88. The method of any one of claims 83 to 87, wherein the compound or a pharma- ceutically acceptable salt thereof is administered once a day.

90. 89. The method of any one of claims 83 to 88, wherein the compound or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of 200 mg, measured as the free base.

91. 89. The method of any one of claims 83 to 88, wherein the compound or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of 100 mg, measured as the free base.

92. 90. The method of any one of claims 83-87 or 89, wherein the compound or a pharma- ceutically acceptable salt thereof is administered once daily at a dosage of 100 mg, measured as the free base.

93. The method of any one of claims 83 to 92, wherein the antibody is administered once every three weeks.

94. The medicament of any one of claims 83 to 93, wherein the antibody is administered in an amount of 200 mg once every three weeks.

95. The pharmaceutical according to any one of claims 83 to 94, wherein the antibody is a humanized antibody.

96. The pharmaceutical agent of any one of claims 83 to 95, wherein the antibody is pembrolizumab.

97. 97. The method of any one of claims 83 to 96, wherein the compound or a pharma- ceutically acceptable salt thereof is administered according to a continuous dosing schedule.

98. 98. The method of claim 97, wherein the continuous administration schedule comprises administering the compound or a pharma- ceutically acceptable salt thereof to the subject for two or more consecutive days.

99. 98. The method of claim 97, wherein the continuous administration schedule comprises administering the compound or a pharma- ceutically acceptable salt thereof to the subject for 5 or more consecutive days.

100. 98. The method of claim 97, wherein the continuous administration schedule comprises administering the compound or a pharma- ceutically acceptable salt thereof to the subject for 10 or more consecutive days.

101. 98. The method of claim 97, wherein the continuous administration schedule comprises administering the compound or a pharma- ceutically acceptable salt thereof to the subject for 15 or more consecutive days.

102. 98. The method of claim 97, wherein the continuous administration schedule comprises administering the compound, or a pharma- ceutically acceptable salt thereof, to the subject for 20 or more consecutive days.

103. 98. The method of claim 97, wherein the continuous administration schedule comprises administering the compound, or a pharma- ceutically acceptable salt thereof, to the subject for 21 or more consecutive days.

104. The pharmaceutical agent according to any one of claims 83 to 103, wherein the cancer is breast cancer, cancer of the central nervous system, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer, urinary tract cancer, colon cancer, or a cancer in which expression of PARP7 is amplified.

105. The pharmaceutical composition of claim 104, wherein the lung cancer is squamous cell carcinoma.

106. The method of any one of claims 83 to 105, wherein the subject has previously undergone treatment for cancer.

107. The pharmaceutical agent of claim 106, wherein the previous treatment is platinum doublet chemotherapy or an immune checkpoint inhibitor.

108. The pharmaceutical of claim 107, wherein the immune checkpoint inhibitor is an anti-PD-1 / anti-PD-L1 or anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor.

109. The method of any one of claims 83 to 108, wherein the subject has failed at least one previous treatment.

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