CANCER TREATMENT WITH HER2 INHIBITORS AND CYP3A AND / OR P-gp MODULATORS

Abstract

The present invention relates to HER2 inhibitors useful for the prevention and / or treatment of cancer, in particular to methods of treatment or uses comprising avoiding, taboo, reducing or discontinuing the concomitant use or co-administration of CYP3A and / or P-gp modulators. The present invention also relates to HER2 inhibitors useful for the prevention and / or treatment of cancer, in particular to methods of treatment or uses comprising concomitant use, co-administration or combination of CYP3A and / or P-gp modulators.

Description

TECHNICAL FIELD

[0001] The present invention relates to HER2 inhibitors useful for the prevention and / or treatment of cancer, in particular to methods of treatment or uses comprising avoiding, contraindicating, reducing or discontinuing the concomitant use or co-administration of CYP3A and / or P-gp modulators. The present invention also relates to HER2 inhibitors useful for the prevention and / or treatment of cancer, in particular to methods of treatment or uses comprising the concomitant use, co-administration or combination of CYP3A and / or P-gp modulators. BACKGROUND

[0002] N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzoxazol-5-yl)oxy]phenyl}amino)-[1,3]-diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide (also referred to herein as Compound (1) or zongertinib) is a HER2 (ErbB2) inhibitor described in WO 2021 / 213800. Zongertinib is a potent and selective tyrosine kinase inhibitor of wild-type and mutant HER2, with no inhibition of wild-type epidermal growth factor receptor (EGFR). It is therefore useful for the treatment and / or prevention of diseases and / or conditions in which inhibition of wild-type and / or mutant HER2 has a therapeutic benefit, in particular neoplastic diseases and / or hyperproliferative diseases, such as cancer.

[0003] CYP3A4 / 5 is primarily responsible for the hepatic oxidative metabolism of Compound (1). Therefore, patients taking comedications that modulate the metabolism of CYP3A4 / 5 (i.e. inhibitors or inducers of CYP3A4 / 5) can reach plasma levels of Compound (1) outside the therapeutic window. CYP3A4 / 5 inhibitors can increase the plasma exposure of Compound (1), which can impair its tolerability; while CYP3A4 / 5 inducers can decrease the plasma exposure of Compound (1), which can impair its efficacy.

[0004] Therefore, there is still a need to increase the understanding of drug-drug interactions and to improve methods for administering cancer therapeutics in the form of Compound (1) to individuals concomitantly treated with other active agents like CYP3A and / or P-gp modulators. In addition, there is a need to inform patients about the safety and tolerability of concomitant medications in the label of Compound (1) while maintaining the efficacy of Compound (1). BRIEF DESCRIPTION OF DRAWINGS

[0005] Figure 1(A) Overview of the trial design of Example 1. Each asterisk indicates administration of compound (1). The black bars represent carbamazepine administered at different daily amounts. (B) Study design of Example 2. This open-label, two-period, fixed-sequence, drug-drug interaction study in healthy male subjects aimed to compare the test treatment (T) in Period 2 with the reference treatment (R) in Period 1. Treatment R was administration of a single oral dose of Zanabeglin 60 mg film-coated tablets only on Day 1 of Period 1. Treatment T was administration of a single oral dose of Zanabeglin 60 mg on Day 1, in conjunction with multiple oral doses of carbamazepine administered from Day -18 to Day 6 of Study Period 2. Carbamazepine was dosed at 200 mg QD for 4 days (Day -18 to Day -15), escalated to 400 mg QD for 7 days (Day -14 to Day -8), and then escalated to a final dose of 600 mg QD for 13 days (Day -7 to Day 6). As shown, blood samples were collected at various time points for analysis of Zanabeglin PK, carbamazepine PK, and 4pHC plasma concentrations. Multiple 24-hour urine collections were planned in Period 2 for quantification of the 6pHC to Cortisol ratio (6pCR). 4pHC, 4p-OH-cholesterol; 6pHC, 6p-OH-cholesterol; 6pCR, 6pHC to Cortisol ratio; EoS, end of study; PK, pharmacokinetics; QD, once daily; R, reference; SCR, screening; T, test.

[0006] Figure 2 Changes in CYP3A induction biomarkers over time. Mean (± SD) of 6pCR in urine and 4pHC in plasma over time with multiple oral doses of carbamazepine and a single dose of Zanabeglin. Panels (A) and (B) show 6pCR, and panels (C) and (D) depict 4pHC. Panels (A) and (C) are raw values before baseline correction over time, and panels (B) and (D) are PCB over time. 4pHC, 4p-OH-cholesterol; 6pCR, 6p-OH-cortisol to Cortisol ratio; PCB, percent change from baseline, calculated as (value - baseline) / baseline * 100%; SD, standard deviation.

[0007] Figure 3Mean plasma concentration-time profiles of zanabamerin following a single 60 mg oral dose of zanabamerin in the absence (R) and presence (T) of multiple doses of carbamazepine. Linear and semi-log scale (mean ± SD). For clarity of both linear and semi-log plots, only the higher SD whiskers are shown for R treatment and only the lower SD whiskers are shown for T treatment. SD whiskers that reached negative values are not shown in the semi-log plot. R: zanabamerin 60 mg on Day 1 of Period 1. T: zanabamerin 60 mg on Day 1 of Period 2 + CBZ 200 mg QD from Day -18 to Day -15, escalated to 400 mg QD from Day -14 to Day -8, escalated to 600 mg QD from Day -7 to Day 6. CBZ, carbamazepine; QD, once daily; SD, standard deviation.

[0008] Figure 4 Relative bioavailability of a single oral dose of 60 mg zanabamerin in combination with multiple oral doses of carbamazepine (T) versus a single dose of 60 mg zanabamerin alone (R). Adjusted geometric mean ratio and 90% confidence interval. R: zanabamerin 60 mg on Day 1 of Period 1. T: zanabamerin 60 mg on Day 1 of Period 2 + carbamazepine 200 mg once daily from Day -18 to Day -15, escalated to 400 mg once daily from Day -14 to Day -8, escalated to 600 mg once daily from Day -7 to Day 6. AUCo-¥, area under the plasma concentration-time curve over the time interval from 0 to infinity; AUCo-tz, area under the plasma concentration-time curve over the time interval from 0 to the last quantifiable data point; Cmax, maximum measured concentration of the analyte in plasma; gMean, geometric mean; R, reference; T, test.

[0009] Figure 5 Individual and geometric mean plasma concentration-time profiles of carbamazepine following multiple oral doses of carbamazepine in combination with a single dose of zanabamerin. Dosing regimen: zanabamerin 60 mg on Day 1 of Period 2 (defined as 0 hours) + carbamazepine 200 mg once daily from Day -18 to Day -15, escalated to 400 mg once daily from Day -14 to Day 8, and escalated to 600 mg once daily from Day -7 to Day 6. gMean, geometric mean. SUMMARY

[0010] According to a first aspect, there is provided a compound (1) or a pharmaceutically acceptable salt thereof,

[0011] (1)

[0012] use of the compound (1), or a pharmaceutically acceptable salt thereof, for the treatment of cancer, wherein the use comprises avoiding, contraindicating, reducing, or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. Alternatively, a method of treating a patient having cancer comprises administering a therapeutically effective amount of compound (1), or a pharmaceutically acceptable salt thereof, and avoiding, contraindicating, reducing, or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator.

[0013] In embodiments, the use or method comprises avoiding co-administration of a CYP3A and / or P-gp modulator.

[0014] According to a second aspect, there is provided the use of a compound (1), or a pharmaceutically acceptable salt thereof, as defined herein, for the treatment of cancer, wherein compound (1) is administered in combination with a CYP3A and / or P-gp modulator, wherein compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately, or sequentially. Alternatively, a method of treating a patient having cancer comprises administering a compound (1), or a pharmaceutically acceptable salt thereof, as defined herein, wherein compound (1) is administered in combination with a CYP3A and / or P-gp modulator, wherein compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately, or sequentially.

[0015] These two aspects can share several features. In general, each of the embodiments presented below is intended as an embodiment of both aspects, unless otherwise stated. For example, in certain embodiments, there can be a time interval during which no CYP3A and / or P-gp modulator is administered. This time interval can be a feature of both the first aspect (avoiding, contraindicating, reducing, or discontinuing concomitant use or co-administration) and the second aspect (combination). Similarly, certain embodiments involve assessing the CYP3A and / or P-gp modulator drug status. These embodiments belong to both the first aspect and the second aspect. All embodiments defining the CYP3A and / or P-gp modulator, the dosing of compound (1), and the identity of the cancer are embodiments of both aspects of the invention.

[0016] In embodiments, the use comprises a contraindicated or avoided time interval between administration of the CYP3A and / or P-gp modulator and administration of compound (1). Alternatively, a method of treating a patient having cancer comprises a contraindicated or avoided time interval between administration of the CYP3A and / or P-gp modulator and administration of compound (1).

[0017] In embodiments, the time interval during which the administration of Compound (1) is contraindicated or avoided is selected from the group consisting of at least 1 hour, at least 1 day, at least 3 days, at least 7 days, at least 14 days, and at least 21 days.

[0018] In embodiments, the use comprises assessing the CYP3A and / or P-gp modulator drug status of the patient prior to the administration of Compound (1) and contraindicate or avoid the administration of Compound (1) for a certain time interval in case the CYP3A and / or P-gp modulator drug status is positive. Alternatively, the method of treating a patient having cancer comprises assessing the CYP3A and / or P-gp modulator drug status of the patient prior to the administration of Compound (1) and contraindicate or avoid the administration of Compound (1) for a certain time interval in case the CYP3A and / or P-gp modulator drug status is positive.

[0019] In embodiments, the CYP3A and / or P-gp modulator drug status assessment is selected from the group consisting of a questionnaire, CYP3A and / or P-gp modulator blood, serum and / or plasma level determination, consulting the patient, endogenous biomarkers, and combinations thereof.

[0020] In embodiments, in case Compound (1) is administered in combination with a CYP3A and / or P-gp modulator, the daily dose of Compound (1) administered is lower than 240 mg, preferably lower than 200 mg, 180 mg or 150 mg.

[0021] In embodiments, in case Compound (1) is administered in combination with a CYP3A and / or P-gp modulator, the daily dose of Compound (1) administered is lower than 120 mg, preferably lower than 100 mg, 60 mg or 30 mg.

[0022] In embodiments, in case Compound (1) is administered in combination with a CYP3A and / or P-gp modulator, the daily dose of Compound (1) administered is higher than 120 mg, preferably higher than 150 mg, 180 mg, 200 mg or 240 mg.

[0023] In embodiments, in case Compound (1) is administered in combination with a CYP3A and / or P-gp modulator, the daily dose of Compound (1) administered is higher than 240 mg, preferably higher than 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.

[0024] In embodiments, the use or method comprises:

[0025] (i) assessing the patient for CYP3A and / or P-gp modulator drug status;

[0026] (ii) in the event that the CYP3A and / or P-gp modulator drug status is positive, administering Compound (1) to the patient at a supra-standard therapeutic effective amount;

[0027] (iii) in the event that the CYP3A and / or P-gp modulator drug status is negative, administering Compound (1) to the patient at a standard therapeutic effective amount.

[0028] In embodiments, the use or method comprises:

[0029] (i) assessing the patient for CYP3A and / or P-gp modulator drug status;

[0030] (ii) in the event that the CYP3A and / or P-gp modulator drug status is positive, administering Compound (1) at a total daily dose of 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg;

[0031] (iii) in the event that the CYP3A and / or P-gp modulator drug status is negative, administering Compound (1) to the patient at a standard therapeutic effective amount.

[0032] In embodiments, the standard therapeutic effective amount of Compound (1) is a daily dose of 120 mg or 240 mg.

[0033] In embodiments, the CYP3A and / or P-gp modulator is a CYP3A and / or P-gp inducer.

[0034] In embodiments, the CYP3A and / or P-gp modulator is a strong CYP3A4 / 5 inducer.

[0035] In embodiments, the use or method comprises avoiding co-administration of a strong CYP3A4 / 5 inducer.

[0036] In embodiments, the CYP3A and / or P-gp inducer is selected from apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampicin, St. John’s wort, brigatinib, efavirenz, enzalutamide, dexamethasone, modafinil, nevirapine, oxcarbazepine, pioglitazone, rifabutin and troglitazone.

[0037] In embodiments, the CYP3A and / or P-gp inducer is carbamazepine.

[0038] In embodiments, the cancer is selected from brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0039] In embodiments, the cancer is non-small cell lung cancer.

[0040] In embodiments, the cancer is HER2 overexpressing, HER2 amplifying, and / or HER2 mutant.

[0041] In embodiments, the cancer comprises a mutation in the tyrosine kinase domain of HER2.

[0042] In embodiments, the cancer is unresectable, advanced, and / or metastatic cancer.

[0043] According to another aspect, there is provided a pharmaceutical composition comprising Compound (1) as defined herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use in the treatment of cancer, wherein the use comprises avoiding, contraindicating, reducing, or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator. Alternatively, a method of treating a patient having cancer comprises administering a pharmaceutical composition comprising Compound (1), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, and wherein the method comprises avoiding, contraindicating, reducing, or discontinuing concomitant use or co-administration of a CYP3A and / or P-gp modulator.

[0044] According to another aspect, there is provided a pharmaceutical composition comprising Compound (1) as defined herein, and at least one pharmaceutically acceptable excipient, for use in the treatment of cancer, wherein Compound (1) is administered in combination with a CYP3A and / or P-gp modulator, wherein Compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately, or sequentially. Alternatively, a method of treating a patient having cancer comprises administering a pharmaceutical composition comprising Compound (1) as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein Compound (1) is administered in combination with a CYP3A and / or P-gp modulator, wherein Compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately, or sequentially.

[0045] In embodiments of the pharmaceutical composition, the use is as defined in any of the above embodiments.

[0046] In embodiments of the pharmaceutical composition, the CYP3A and / or P-gp modifier is as defined in any of the above embodiments.

[0047] In embodiments of the pharmaceutical composition, the cancer is as defined in any of the above embodiments. Detailed Implementation

[0048] The object of the present invention is to provide a safe and effective treatment of cancer with compound (1) in cases where CYP3A and / or P-gp modulators have been or are believed to have been administered.

[0049] Compound (1)

[0050] As used herein, the term "compound (1)" means a compound or a pharmaceutically acceptable salt thereof as defined below:

[0051] (1).

[0052] The IUPAC name of compound (1) is N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide. Compound (1) is also known as zongatinib. In the event of a discrepancy between the IUPAC name and the depicted chemical formula, the chemical formula shall prevail. Compound (1) is disclosed as example compound I-01 in WO 2021 / 213800. WO 2021 / 213800 describes [1,3]diazino[5,4-d]pyrimidines as HER2 inhibitors, such as compound (1), and provides a synthetic procedure for compound (1). The properties of compound (1) and evidence of its inhibitory effect on HER2 wild-type and YVMA kinase activity (without inhibiting EGFR) are also disclosed in WO 2021 / 213800, which is incorporated herein by reference.

[0053] As used herein, the term “compound (1)” also covers any tautomers and pharmaceutically acceptable salts and all solid forms of the compound, as well as solvates (including hydrates) and solvates of pharmaceutically acceptable salts of the compound. In particular, unless otherwise stated, any reference to “compound (1)” is intended to be understood as “compound (1) or a pharmaceutically acceptable salt thereof.”

[0054] In the implementation scheme, compound (1) is used as a free base. In the implementation scheme, a pharmaceutically acceptable salt of compound (1) is used. The term “pharmaceutically acceptable” as used herein means a compound, material, composition, and / or dosage form that is suitable for contact with human tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio, within the bounds of reasonable medical judgment.

[0055] As used herein, a “pharmaceutically acceptable salt” of compound (1) means compound (1) wherein the compound is modified by forming its acid salt or base salt. The term pharmaceutically acceptable salt, as used herein, generally includes both acid addition salts and base addition salts. A pharmaceutically acceptable acid addition salt is one that retains the bioavailability and properties of the free base and is not biologically or otherwise undesirable for forming with an inorganic or organic acid. A pharmaceutically acceptable base addition salt includes salts derived from inorganic bases or non-toxic organic bases. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral salts or organic acid salts of basic residues such as amines; base salts or organic salts of acidic residues such as carboxylic acids; and so on. For example, such salts include salts derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentian acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. In the implementation plan, pharmaceutically acceptable salts are selected from chlorides and fumarates.

[0056] Pharmaceutically acceptable salts can be synthesized from compound (1) by conventional chemical methods. Typically, such salts can be prepared by reacting the free base form of compound (1) with a sufficient amount of a suitable acid or base in water or in an organic diluent or solvent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile or mixtures thereof.

[0057] As used herein, the term "solvent" refers to an association or complex of one or more solvent molecules with compound (1). Examples of solvents include water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, tert-butyl methyl ether, tetrahydrofuran, methyl ethyl ketone, N-methylpyrrolidone, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0058] Medical uses and methods of treatment

[0059] The terms used in this document should be interpreted according to their meanings as defined in the field.

[0060] As used herein, the term "contraindication" and its grammatical variations are intended to imply medical reasons why certain individuals should not use a particular drug or medical treatment. Contraindications are specifically outlined in the documentation, labels, and instructions for prescription drugs.

[0061] As used in this article, the term “reduce” and its grammatical variations are expected to have “lowering”, “decreasing”, “lessen”, “diminish”, and “bringing down” as alternatives.

[0062] As used herein, the term "medication status" and its grammatical variations specifically refer to determining whether a patient has taken a medication within a given time interval. As further detailed below, medication status can be assessed in different ways. A positive medication status indicates that the patient has taken the medication within a given time interval, while a negative medication status indicates that the patient has not taken the medication within a given time interval.

[0063] As used herein, the term “positive drug status” and its grammatical variations should be understood to encompass situations in which the concentration of the drug in the patient’s body is higher than the standard, based on the fact that the drug was administered before or concurrently with the assessment of drug status.

[0064] As used herein, the term “negative drug status” and its grammatical variations should be understood to encompass situations in which the concentration of a drug in a patient’s body is lower than the standard, based on the fact that no drug was administered before or at the time of assessment of drug status.

[0065] As used in this article, the term “avoiding” and its grammatical variations are expected to have the terms “abstain,” “desist,” “forbear,” and “refrain” as alternatives. In some cases, the alternative terms will be equivalent. For example, “avoiding” means “refraining from.”

[0066] As used herein, the term “cease” and its forms are expected to be replaced by the terms “cease,” “stop,” “suspend,” and “quit.”

[0067] The term “concomitant use” should be understood to be interchangeable with “parallel administration,” “co-administration,” or “combination.” Therefore, the term should be understood to encompass administration at the same or different times, and via the same or different routes, provided that both medications are administered in a manner that allows both to affect the body simultaneously. For example, concomitant use can refer to medications administered concurrently, whether prescribed by the same or different practitioners or for the same or different indications. More specifically, compound (1) may be administered orally, while CYP3A and / or P-gp modulators (e.g., CYP3A and / or P-gp inducers, such as carbamazepine) may be administered orally, intravenously, via injection into an intramuscular, subcutaneously, intranasally, rectally, or buccally. “Concomitant use,” “co-administration,” “combination,” or “co-administration” preferably occur in cases where compound (1) and the CYP3A and / or P-gp modulator are each administered at least once at 14-day intervals.

[0068] As used herein, the term “common application” and its grammatical variations should be understood to be interchangeable with the terms “accompanying use,” “combination,” and “parallel application.”

[0069] As used herein, the term “concurrent application” and its grammatical variations should be understood to be interchangeable with the terms “accompanying use,” “combination,” or “joint application.”

[0070] As used herein, the term “combination” and its grammatical variations should be understood to be interchangeable with the terms “accompanying use,” “parallel application,” or “joint application.”

[0071] The term “simultaneous” and its grammatical variations refer to the substantially simultaneous administration of compound (1) and CYP3A and / or P-gp modulators.

[0072] The term “sequential” and its grammatical variations include the application of one or more doses of an active ingredient over a first time period (e.g., over hours, days, or weeks), followed by the application of one or more doses of another active ingredient over a second time period (e.g., over hours, days, or weeks).

[0073] The term “separate” and its grammatical variations mean that the compound (1) and the CYP3A and / or P-gp modulator are administered to the patient simultaneously, in parallel, sequentially, successively, alternatively or otherwise separately (without a specific time limit) as separate entities, dosage forms or non-fixed combinations.

[0074] "CYP3A" refers to the most abundant and clinically significant subfamily of cytochrome P450 enzymes. The CYP3A subfamily has four human allotypes (3A4, 3A5, 3A7, and 3A43), with CYP3A4 being the most commonly associated with drug interactions. As used herein, "CYP3A" includes CYP3A4, CYP3A5, CYP3A7, and CYP3A43. Preferably, as used herein, "CYP3A" refers to CYP3A4 and / or 5. CYP3A allotypes account for approximately 50% of total cytochrome P450 in the liver and are widely expressed throughout the gastrointestinal tract, kidneys, and lungs, and are therefore ultimately responsible for a large portion of first-pass metabolism. This is important because an increase or decrease in first-pass metabolism can have the effect of administering a smaller or larger equivalent dose of a drug than is normally expected.

[0075] "P-gp" refers to the glycoprotein transmembrane transporter MDR1 / ABCB1, which is a transporter protein encoded by the ABCB1 gene. P-gp is particularly located at interfacial tissues (such as the intestine, kidney, liver, and brain barrier) and is involved in the transport and / or efflux of various compounds.

[0076] As used herein, the term "regulator" and its grammatical variations refer to molecules that increase or decrease the expression and / or activity of proteins, such as enzymes or transporters, particularly CYP3A and / or P-gp. It is intended to include both inducers and inhibitors.

[0077] As used herein, the term “inducer” and its grammatical variations refer to molecules that increase or enhance the expression and / or activity of proteins, such as enzymes or transporters, particularly CYP3A and / or P-gp. Such increases or enhancements can arise from increased protein synthesis or decreased protein degradation and can be measured according to any method known in the art. In particular, “inducer” refers to molecules recognized by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) as inducers of CYP3A and / or P-gp.

[0078] As used herein, the terms “strong CYP3A inducer” and “strong CYP3A4 / 5 inducer” have the same meaning as given by FDA and / or EMA guidance, such as the ICHM12 guidance on Drug Interaction Studies and the FDA’s Table of Substrates Inhibitors and Inducers, available at: https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers, last modified June 5, 2023. Specifically, a strong inducer of CYP3A, or more specifically CYP3A4 / 5, can reduce the AUC of a sensitivity index CYP substrate by ≥ 80%. Examples of strong CYP3A inducers include, but are not limited to, carbamazepine, phenytoin, and rifampin.

[0079] As used herein, CYP3A and / or P-gp regulators include and are interchangeable with the following: CYP3A regulators, P-gp regulators, and CYP3A and P-gp regulators. As used herein, CYP3A and / or P-gp regulators preferably refer to CYP3A and / or P-gp inducers, including CYP3A inducers, P-gp inducers, and CYP3A and P-gp inducers.

[0080] The terms “standard prescription dose,” “normal prescription dose,” “standard therapeutic dose,” “standard administration schedule,” “standard schedule,” “regular dose,” and “standard dose” are used interchangeably and refer to the standard and authorized prescription drug dose as specified on the label or instruction leaflet. The standard dose may vary depending on the form or route of administration of the drug.

[0081] As used herein, the term "contraindication or avoidance interval" refers to the period during which CYP3A and / or P-gp regulators are not administered.

[0082] In a preferred embodiment, the use includes avoiding or discontinuing the concomitant or co-administered use of CYP3A and / or P-gp modulators. Alternatively, methods of treating patients with cancer include avoiding or discontinuing the concomitant or co-administered use of CYP3A and / or P-gp modulators.

[0083] In a preferred embodiment, the use includes concomitant or co-administered use of CYP3A and / or P-gp modulators and compound (1). Alternatively, methods of treating patients with cancer include concomitant or co-administered use of CYP3A and / or P-gp modulators and compound (1).

[0084] In a preferred embodiment, the use includes avoiding or discontinuing the concomitant or co-administered use of a CYP3A modifier. Alternatively, methods of treating a patient with cancer include avoiding or discontinuing the concomitant or co-administered use of a CYP3A modifier. In a preferred embodiment, the use includes avoiding or discontinuing the concomitant or co-administered use of a P-gp modifier. Alternatively, methods of treating a patient with cancer include avoiding or discontinuing the concomitant or co-administered use of a P-gp modifier. In a preferred embodiment, the use includes avoiding or discontinuing the concomitant or co-administered use of both CYP3A and P-gp modifiers. Alternatively, methods of treating a patient with cancer include avoiding or discontinuing the concomitant or co-administered use of both CYP3A and P-gp modifiers.

[0085] In a preferred embodiment, the use includes avoiding or discontinuing the concomitant or co-administered therapeutically effective amounts of CYP3A and / or P-gp modulators. Alternatively, methods of treating patients with cancer include avoiding or discontinuing the concomitant or co-administered therapeutically effective amounts of CYP3A and / or P-gp modulators.

[0086] In a preferred embodiment, the use includes the concomitant or co-administration of a therapeutically effective amount of CYP3A and / or P-gp modulators and compound (1). Alternatively, a method of treating a patient with cancer includes the concomitant or co-administration of a therapeutically effective amount of CYP3A and / or P-gp modulators and compound (1).

[0087] In a preferred embodiment, the use includes avoiding the concomitant or co-administered therapeutically effective amounts of CYP3A modulators. Alternatively, a method of treating a patient with cancer includes avoiding the concomitant or co-administered therapeutically effective amounts of CYP3A modulators. In a preferred embodiment, the use includes avoiding the concomitant or co-administered therapeutically effective amounts of P-gp modulators. Alternatively, a method of treating a patient with cancer includes avoiding the concomitant or co-administered therapeutically effective amounts of P-gp modulators. In a preferred embodiment, the use includes avoiding the concomitant or co-administered therapeutically effective amounts of both CYP3A and P-gp modulators. Alternatively, a method of treating a patient with cancer includes avoiding the concomitant or co-administered therapeutically effective amounts of both CYP3A and P-gp modulators.

[0088] In a preferred embodiment, the use includes discontinuing the concomitant or co-administered therapeutically effective amount of a CYP3A modifier. Alternatively, a method of treating a patient with cancer includes discontinuing the concomitant or co-administered therapeutically effective amount of a CYP3A modifier. In a preferred embodiment, the use includes discontinuing the concomitant or co-administered therapeutically effective amount of a P-gp modifier. Alternatively, a method of treating a patient with cancer includes discontinuing the concomitant or co-administered therapeutically effective amount of a P-gp modifier. In a preferred embodiment, the use includes discontinuing the concomitant or co-administered therapeutically effective amount of both CYP3A and P-gp modifiers. Alternatively, a method of treating a patient with cancer includes discontinuing the concomitant or co-administered therapeutically effective amount of both CYP3A and P-gp modifiers.

[0089] In a preferred embodiment, the use includes contraindicating or reducing the concomitant or co-administered use of CYP3A and / or P-gp modulators. Alternatively, methods of treating patients with cancer include contraindicating or reducing the concomitant or co-administered use of CYP3A and / or P-gp modulators.

[0090] In a preferred embodiment, the use includes contraindicating or reducing the concomitant or co-administered use of CYP3A modifiers. Alternatively, methods of treating patients with cancer include contraindicating or reducing the concomitant or co-administered use of CYP3A modifiers. In a preferred embodiment, the use includes contraindicating or reducing the concomitant or co-administered use of P-gp modifiers. Alternatively, methods of treating patients with cancer include contraindicating or reducing the concomitant or co-administered use of P-gp modifiers. In a preferred embodiment, the use includes contraindicating or reducing the concomitant or co-administered use of both CYP3A and P-gp modifiers. Alternatively, methods of treating patients with cancer include contraindicating or reducing the concomitant or co-administered use of both CYP3A and P-gp modifiers.

[0091] In a preferred embodiment, the use includes contraindicating or reducing the concomitant or co-administered therapeutically effective amounts of CYP3A and / or P-gp modulators. Alternatively, methods of treating patients with cancer include contraindicating or reducing the concomitant or co-administered therapeutically effective amounts of CYP3A and / or P-gp modulators.

[0092] In a preferred embodiment, the use includes contraindication to the use or co-administration of a therapeutically effective amount of a CYP3A modifier. Alternatively, a method of treating a patient with cancer includes contraindication to the use or co-administration of a therapeutically effective amount of a CYP3A modifier. In a preferred embodiment, the use includes contraindication to the use or co-administration of a therapeutically effective amount of a P-gp modifier. Alternatively, a method of treating a patient with cancer includes contraindication to the use or co-administration of a therapeutically effective amount of a P-gp modifier. In a preferred embodiment, the use includes contraindication to the use or co-administration of both CYP3A and P-gp modifiers. Alternatively, a method of treating a patient with cancer includes contraindication to the use or co-administration of both CYP3A and P-gp modifiers.

[0093] In a preferred embodiment, the use includes reducing the concomitant or co-administered therapeutically effective amount of a CYP3A modifier. Alternatively, a method of treating a patient with cancer includes reducing the concomitant or co-administered therapeutically effective amount of a CYP3A modifier. In a preferred embodiment, the use includes reducing the concomitant or co-administered therapeutically effective amount of a P-gp modifier. Alternatively, a method of treating a patient with cancer includes reducing the concomitant or co-administered therapeutically effective amount of a P-gp modifier. In a preferred embodiment, the use includes reducing the concomitant or co-administered therapeutically effective amount of both CYP3A and P-gp modifiers. Alternatively, a method of treating a patient with cancer includes reducing the concomitant or co-administered therapeutically effective amount of both CYP3A and P-gp modifiers.

[0094] In a preferred embodiment, the use includes a contraindication or avoidance time interval between the administration of CYP3A and / or P-gp modifier and the administration of compound (1). In a preferred embodiment, the use includes a contraindication or avoidance time interval between the administration of CYP3A modifier and the administration of compound (1). In a preferred embodiment, the use includes a contraindication or avoidance time interval between the administration of P-gp modifier and the administration of compound (1). In a preferred embodiment, the use includes a contraindication or avoidance time interval between the administration of CYP3A and / or P-gp modifier and the administration of compound (1). In a preferred embodiment, the use includes a avoidance time interval between the administration of CYP3A and / or P-gp modifier and the administration of compound (1). During the contraindication and / or avoidance time interval, the administration of CYP3A and / or P-gp modifier to the patient prior to treatment with compound (1) is not permitted. During the contraindication and / or avoidance time intervals, patients are not permitted to be given therapeutically effective amounts of CYP3A and / or P-gp modulators prior to treatment of patients including compound (1).

[0095] In a preferred embodiment, the method of treating a patient with cancer includes a contraindication or avoidance time interval between the administration of CYP3A and / or P-gp modifier and the administration of compound (1). In a preferred embodiment, the method of treating a patient with cancer includes a contraindication or avoidance time interval between the administration of CYP3A modifier and the administration of compound (1). In a preferred embodiment, the method of treating a patient with cancer includes a contraindication or avoidance time interval between the administration of P-gp modifier and the administration of compound (1). In a preferred embodiment, the method of treating a patient with cancer includes a contraindication or avoidance time interval between the administration of CYP3A and / or P-gp modifier and the administration of compound (1). In a preferred embodiment, the method of treating a patient with cancer includes a contraindication time interval between the administration of CYP3A and / or P-gp modifier and the administration of compound (1). In a preferred embodiment, the method of treating a patient with cancer includes a avoidance time interval between the administration of CYP3A and / or P-gp modifier and the administration of compound (1).

[0096] In a preferred embodiment, the time interval for prohibition or avoidance is selected from at least 1 hour, at least 1 day, at least 3 days, at least 7 days, at least 14 days, and at least 21 days.

[0097] Preferably, the time interval for contraindication or avoidance is at least 14 days. This applies to all embodiments described herein that include a time interval for contraindication or avoidance.

[0098] In a preferred embodiment, the use includes preferably assessing the patient's CYP3A and / or P-gp modulator status before administering compound (1), and contraindicating or avoiding the administration of compound (1) for a certain time interval if the CYP3A and / or P-gp modulator status is positive. In a preferred embodiment, the use includes assessing the patient's CYP3A modulator status before administering compound (1), and contraindicating or avoiding the administration of compound (1) for a certain time interval if the CYP3A modulator status is positive. In a preferred embodiment, the use includes assessing the patient's P-gp modulator status before administering compound (1), and contraindicating or avoiding the administration of compound (1) for a certain time interval if the P-gp modulator status is positive. Alternatively, this article provides a method for treating a patient with cancer, the method comprising preferably assessing the patient’s CYP3A and / or P-gp modulator status prior to administration of compound (1), and contraindicating or avoiding administration of compound (1) for a certain time interval if the CYP3A and / or P-gp modulator status is positive.

[0099] In a preferred embodiment, the use includes preferably assessing the patient's CYP3A and / or P-gp modulator status before administering compound (1), and adapting the administration of compound (1) for a certain time interval if the CYP3A and / or P-gp modulator status is positive. In a preferred embodiment, the use includes preferably assessing the patient's CYP3A modulator status before administering compound (1), and adapting the administration of compound (1) for a certain time interval if the CYP3A modulator status is positive. In a preferred embodiment, the use includes preferably assessing the patient's P-gp modulator status before administering compound (1), and adapting the administration of compound (1) for a certain time interval if the P-gp modulator status is positive. In the sense of this application, adaptation means changing a standard administration schedule (including the daily dose of compound (1)) or administration timetable relative to a standard schedule that is effective for patients who are not co-administering CYP3A and / or P-gp modulators. Adaptation may include, for example, administering increased or decreased daily doses of compound (1) and / or CYP3A and / or P-gp modulators. Increases or decreases in daily dose are intended relative to doses of compound (1) as described herein, particularly standard therapeutic doses or daily doses of 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg, preferably 120 mg or 240 mg daily doses.

[0100] In a preferred embodiment, the use includes preferably assessing the patient's CYP3A and / or P-gp modulator status before administering compound (1), and, if the CYP3A and / or P-gp modulator status is positive, adapting the administration of compound (1) for a certain time interval during which the CYP3A / P-gp modulator is administered to the patient. In a preferred embodiment, the use includes preferably assessing the patient's CYP3A modulator status before administering compound (1), and, if the CYP3A modulator status is positive, adapting the administration of compound (1) for a certain time interval during which the CYP3A / P-gp modulator is administered to the patient. In a preferred embodiment, the use includes preferably assessing the patient's P-gp modulator status before administering compound (1), and, if the P-gp modulator status is positive, adapting the administration of compound (1) for a certain time interval during which the CYP3A / P-gp modulator is administered to the patient.

[0101] According to one aspect of the invention, there is provided the use of compound (1) or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein said use includes preferably assessing a patient’s CYP3A and / or P-gp modulator pharmacological status prior to administration of compound (1), and, if the CYP3A and / or P-gp modulator pharmacological status is positive, adjusting the concentration of compound (1) administered daily for a certain time interval. Alternatively, this document provides a method for treating a patient with cancer, the method comprising preferably assessing a patient’s CYP3A and / or P-gp modulator pharmacological status prior to administration of compound (1), and, if the CYP3A and / or P-gp modulator pharmacological status is positive, adjusting the concentration of compound (1) administered daily for a certain time interval.

[0102] According to one aspect of the invention, there is provided the use of compound (1) or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein said use includes preferably assessing the patient's CYP3A and / or P-gp modulator pharmacological status prior to administration of compound (1), and, if the CYP3A and / or P-gp modulator pharmacological status is positive, adjusting the daily administration of the CYP3A and / or P-gp modulator concentration for a certain time interval. Alternatively, this document provides a method for treating a patient with cancer, the method comprising preferably assessing the patient's CYP3A and / or P-gp modulator pharmacological status prior to administration of compound (1), and, if the CYP3A and / or P-gp modulator pharmacological status is positive, adjusting the daily administration of the CYP3A and / or P-gp modulator concentration for a certain time interval.

[0103] In a preferred embodiment, the use or method includes:

[0104] (i) Preferably, the patient’s CYP3A and / or P-gp modulator status is assessed prior to administration of compound (1);

[0105] (ii) Do not administer compound (1) to patients in cases where CYP3A and / or P-gp modulator status is positive;

[0106] (iii) Administer compound (1) to the patient when the CYP3A and / or P-gp modulator status is negative.

[0107] In a preferred embodiment, the use or method includes:

[0108] (i) Preferably, the patient’s CYP3A and / or P-gp modulator status is assessed prior to administration of compound (1);

[0109] (ii) Do not administer compound (1) to patients in cases where CYP3A and / or P-gp modulator status is positive;

[0110] (iii) When the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to the patient at a therapeutically effective amount.

[0111] In a preferred embodiment, the use or method includes:

[0112] (i) Preferably, the patient’s CYP3A and / or P-gp modulator status is assessed prior to administration of compound (1);

[0113] (ii) In cases where the CYP3A and / or P-gp modulator drug status is positive, do not administer compound (1) to the patient for a certain period of time;

[0114] (iii) Administer compound (1) to the patient when the CYP3A and / or P-gp modulator status is negative.

[0115] In a preferred embodiment, the use or method includes:

[0116] (i) Preferably, the patient’s CYP3A and / or P-gp modulator status is assessed prior to administration of compound (1);

[0117] (ii) In cases where the CYP3A and / or P-gp modulator drug status is positive, the compound (1) shall not be administered to the patient for at least 3 days, at least 7 days, at least 14 days, or at least 21 days.

[0118] (iii) Administer compound (1) to the patient when the CYP3A and / or P-gp modulator status is negative.

[0119] In a preferred embodiment, the use or method includes:

[0120] (i) Preferably, the patient’s CYP3A and / or P-gp modulator status is assessed prior to administration of compound (1);

[0121] (ii) In cases where the CYP3A and / or P-gp modulator drug status is positive, the compound (1) shall not be administered to the patient for at least 3 days, at least 7 days, at least 14 days, or at least 21 days.

[0122] (iii) When the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to the patient at a therapeutically effective amount.

[0123] In a preferred embodiment, the use or method includes:

[0124] (i) Preferably, the patient’s carbamazepine status is assessed before administration of compound (1);

[0125] (ii) In cases where the carbamazepine status is positive, the compound (1) shall not be administered to the patient for at least 3, 7, 14 or 21 days.

[0126] (iii) Administer compound (1) to the patient when the carbamazepine status is negative.

[0127] In a preferred embodiment, the use or method includes:

[0128] (i) Preferably, the patient’s CYP3A and / or P-gp modulator status is assessed prior to administration of compound (1);

[0129] (ii) In cases where the CYP3A and / or P-gp modulator drug status is positive, compound (1) is administered to the patient at a level below the standard therapeutically effective amount;

[0130] (iii) When the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to the patient at a standard therapeutically effective amount.

[0131] In a preferred embodiment, the use or method includes:

[0132] (i) Preferably, the patient’s CYP3A and / or P-gp modulator status is assessed prior to administration of compound (1);

[0133] (ii) If the CYP3A and / or P-gp modulator drug status is positive, compound (1) is administered to the patient at a dose higher than the standard therapeutically effective dose;

[0134] (iii) When the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to the patient at a standard therapeutically effective amount.

[0135] In a preferred embodiment, the use or method includes:

[0136] (i) Preferably, the patient’s CYP3A and / or P-gp inducer status is assessed prior to administration of compound (1);

[0137] (ii) In cases where the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered to the patient at a level below the standard therapeutically effective amount;

[0138] (iii) When the CYP3A and / or P-gp inducer status is negative, compound (1) is administered to the patient at a standard therapeutically effective dose. Preferably, the standard therapeutically effective dose is 120 mg or 240 mg.

[0139] In a preferred embodiment, the use or method includes:

[0140] (i) Preferably, the patient’s CYP3A and / or P-gp inducer status is assessed prior to administration of compound (1);

[0141] (ii) In cases where CYP3A and / or P-gp inducer status is positive, compound (1) is administered to the patient at a total daily dose of less than 240 mg;

[0142] (iii) When the CYP3A and / or P-gp inducer status is negative, compound (1) is administered to the patient at a standard therapeutically effective dose. Preferably, the standard therapeutically effective dose is 240 mg.

[0143] In a preferred embodiment, the use or method includes:

[0144] (i) Preferably, the patient’s CYP3A and / or P-gp inducer status is assessed prior to administration of compound (1);

[0145] (ii) In cases where the CYP3A and / or P-gp inducer status is positive, compound (1) is administered to the patient at a total daily dose of less than 120 mg;

[0146] (iii) When the CYP3A and / or P-gp inducer status is negative, compound (1) is administered to the patient at a standard therapeutically effective dose. Preferably, the standard therapeutically effective dose is 120 mg.

[0147] In a preferred embodiment, the use or method includes:

[0148] (i) Preferably, the patient’s CYP3A and / or P-gp inducer status is assessed prior to administration of compound (1);

[0149] (ii) When the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered to the patient at a total daily dose of 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, or 180 mg (preferably 30 mg, 60 mg, or 100 mg);

[0150] (iii) When the CYP3A and / or P-gp inducer status is negative, compound (1) is administered to the patient at a standard therapeutically effective dose. Preferably, the standard therapeutically effective dose is 120 mg or 240 mg.

[0151] In a preferred embodiment, the use or method includes:

[0152] (i) Preferably, the patient’s CYP3A and / or P-gp inducer status is assessed prior to administration of compound (1);

[0153] (ii) In cases where the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered to the patient at a level higher than the standard therapeutically effective amount;

[0154] (iii) When the CYP3A and / or P-gp inducer status is negative, compound (1) is administered to the patient at a standard therapeutically effective dose. Preferably, the standard therapeutically effective dose is 120 mg or 240 mg.

[0155] In a preferred embodiment, the use or method includes:

[0156] (i) Preferably, the patient’s CYP3A and / or P-gp inducer status is assessed prior to administration of compound (1);

[0157] (ii) When the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered to the patient at a total daily dose of more than 240 mg, preferably 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg;

[0158] (iii) When the CYP3A and / or P-gp inducer status is negative, compound (1) is administered to the patient at a standard therapeutically effective dose. Preferably, the standard therapeutically effective dose is 240 mg.

[0159] In a preferred embodiment, the use or method includes:

[0160] (i) Preferably, the patient’s CYP3A and / or P-gp inducer status is assessed prior to administration of compound (1);

[0161] (ii) When the CYP3A and / or P-gp inducer drug status is positive, compound (1) is administered to the patient at a total daily dose of more than 120 mg, preferably 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg;

[0162] (iii) When the CYP3A and / or P-gp inducer status is negative, compound (1) is administered to the patient at a standard therapeutically effective dose. Preferably, the standard therapeutically effective dose is 120 mg.

[0163] In a preferred embodiment, the use or method includes:

[0164] (i) Preferably, the patient’s CYP3A and / or P-gp inducer status is assessed prior to administration of compound (1);

[0165] (ii) When the CYP3A and / or P-gp inducer drug status is positive, the compound (1) is administered at a total daily dose of 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg (preferably 300 mg or 360 mg);

[0166] (iii) When the CYP3A and / or P-gp inducer status is negative, compound (1) is administered to the patient at a standard therapeutically effective dose. Preferably, the standard therapeutically effective dose is 120 mg or 240 mg.

[0167] In a preferred embodiment, the use or method includes:

[0168] (i) Preferably, the patient’s carbamazepine status is assessed before administration of compound (1);

[0169] (ii) In cases where carbamazepine status is positive, compound (1) is administered to the patient at a dose below the standard therapeutically effective dose for at least 3 days, at least 7 days, at least 14 days, or at least 21 days.

[0170] (iii) In cases where carbamazepine status is negative, compound (1) is administered to the patient at a standard therapeutically effective dose. Preferably, the standard therapeutically effective dose is 120 mg or 240 mg.

[0171] In a preferred embodiment, the use or method includes:

[0172] (i) Preferably, the patient’s carbamazepine status is assessed before administration of compound (1);

[0173] (ii) In cases where carbamazepine status is positive, compound (1) is administered to the patient at a dose higher than the standard therapeutic effective dose for at least 3 days, at least 7 days, at least 14 days, or at least 21 days.

[0174] (iii) In cases where carbamazepine status is negative, compound (1) is administered to the patient at a standard therapeutically effective dose. Preferably, the standard therapeutically effective dose is 120 mg or 240 mg.

[0175] In a preferred embodiment, the use or method includes CYP3A and / or P-gp modulator drug status assessment selected from questionnaires, determination of CYP3A and / or P-gp modulator blood, serum and / or plasma levels, patient consultation, endogenous biomarkers, and combinations thereof.

[0176] In a preferred embodiment, the use includes CYP3A and / or P-gp modulator drug status assessment selected from questionnaires, determination of CYP3A and / or P-gp modulator blood, serum and / or plasma levels, patient consultation, or combinations thereof.

[0177] In a preferred embodiment, the method includes CYP3A and / or P-gp modulator drug status assessment selected from questionnaires, determination of CYP3A and / or P-gp modulator blood, serum and / or plasma levels, patient consultation, or a combination thereof.

[0178] In a preferred embodiment, the use or method includes CYP3A and / or P-gp modulator drug status assessment, which is the determination of serum CYP3A and / or P-gp modulator levels.

[0179] In a preferred embodiment, the assessment of CYP3A and / or P-gp modulator drug status is based on endogenous biomarkers, i.e., their measurement results. Preferably, the endogenous biomarkers are the ratio of 6β-OH-cortisol to cortisol in urine (6βCR) or the amount of 4β-OH-cholesterol (4βHC) in plasma. In particular, the CYP3A and / or P-gp modulator drug status can be assessed by measuring 6βCR in urine and / or 4βHC in plasma, for example, according to the procedure described in Example 2. While 6βCR in urine and 4βHC in plasma are not quantitative, higher levels of these preferred endogenous biomarkers can indicate an increase in CYP3A activity, for example, due to the administration of a CYP3A inducer.

[0180] In a preferred embodiment, the CYP3A and / or P-gp regulator is a CYP3A and / or P-gp inducer. In a preferred embodiment, the CYP3A and / or P-gp regulator is a CYP3A inducer, a P-gp inducer, or a CYP3A and P-gp inducer. Further embodiments corresponding to those described herein are disclosed, wherein the expression "CYP3A and / or P-gp regulator" is replaced by "CYP3A and / or P-gp inducer".

[0181] In a preferred embodiment, the CYP3A and / or P-gp regulator is a strong CYP3A inducer. Preferably, the strong CYP3A inducer is a strong CYP3A4 / 5 inducer. Further embodiments corresponding to those described herein are disclosed, wherein the expression "CYP3A and / or P-gp regulator" is replaced by "strong CYP3A inducer".

[0182] In a preferred embodiment, the CYP3A and / or P-gp inducer is selected from apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort, brigatinib, efavirenz, enzalutamide, dexamethasone, modafinil, nevirapine, oxcarbazepine, pioglitazone, rifabutin, and troglitazone.

[0183] In a preferred embodiment, the CYP3A and / or P-gp inducer is carbamazepine. In a preferred embodiment, the use of compound (1) in the treatment of cancer avoids concomitant or co-administered use with carbamazepine. In a preferred embodiment, the use of compound (1) in the treatment of cancer is contraindicated by concomitant or co-administered use with carbamazepine. In a preferred embodiment, the use of carbamazepine is reduced by concomitant or co-administered use with compound (1) in the treatment of cancer. Carbamazepine is a CYP3A inducer, particularly a strong inducer of CYP3A4 / 5, and an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, P-gp, UGT, and MRP2. Therefore, in addition to CYP3A and / or P-gp, certain embodiments of the invention may also be applicable to inducers of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT, and / or MRP2.

[0184] “UGT” refers to the UDP-glucuronyltransferase superfamily, all of which are included in the term “UGT” as used in this article.

[0185] "MRP2" refers to the multidrug resistance protein (MRP), which belongs to the ATP-binding cassette (ABC) transporter family. It is encoded by the gene ABCC2.

[0186] In a preferred embodiment, the use of a therapeutically effective amount of compound (1) in the treatment of cancer avoids the concomitant or co-administered use of a therapeutically effective amount of carbamazepine. In a preferred embodiment, the use of a therapeutically effective amount of compound (1) in the treatment of cancer is contraindicated by the concomitant or co-administered use of a therapeutically effective amount of carbamazepine. In a preferred embodiment, the use of a therapeutically effective amount of carbamazepine is reduced by the concomitant or co-administered use of compound (1) in the treatment of cancer.

[0187] In a preferred embodiment, the method of treating a patient with cancer includes administering compound (1) and avoiding concomitant or co-administered carbamazepine. In a preferred embodiment, the method of treating a patient with cancer includes administering compound (1) and prohibiting concomitant or co-administered carbamazepine. In a preferred embodiment, the method of treating a patient with cancer includes administering compound (1) and minimizing concomitant or co-administered carbamazepine.

[0188] In a preferred embodiment, a method of treating a patient with cancer includes administering a therapeutically effective amount of compound (1) and avoiding concomitant or co-administered therapeutically effective amounts of carbamazepine. In a preferred embodiment, a method of treating a patient with cancer includes administering a therapeutically effective amount of compound (1) and prohibiting concomitant or co-administered therapeutically effective amounts of carbamazepine. In a preferred embodiment, a method of treating a patient with cancer includes administering a therapeutically effective amount of compound (1) and reducing concomitant or co-administered therapeutically effective amounts of carbamazepine.

[0189] In a preferred embodiment, the use of compound (1) in the treatment of cancer avoids the concomitant or co-administered use of carbamazepine for intervals of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In a preferred embodiment, the use of compound (1) in the treatment of cancer is contraindicated by the concomitant or co-administered use of carbamazepine for intervals of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In a preferred embodiment, the time intervals of at least 3 days, at least 7 days, at least 14 days, or at least 21 days of carbamazepine use are reduced before the concomitant or co-administered use of compound (1) in the treatment of cancer.

[0190] In a preferred embodiment, the use of a therapeutically effective amount of compound (1) in the treatment of cancer avoids the concomitant or co-administered use of a therapeutically effective amount of carbamazepine at intervals of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In a preferred embodiment, the use of a therapeutically effective amount of compound (1) in the treatment of cancer is contraindicated by the concomitant or co-administered use of a therapeutically effective amount of carbamazepine at intervals of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In a preferred embodiment, the use of a therapeutically effective amount of carbamazepine at intervals of at least 3 days, at least 7 days, at least 14 days, or at least 21 days is reduced before the concomitant or co-administered use of a therapeutically effective amount of compound (1) in the treatment of cancer.

[0191] In a preferred embodiment, a method of treating a patient with cancer includes administering compound (1) and avoiding concomitant or co-administered carbamazepine at intervals of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In a preferred embodiment, a method of treating a patient with cancer includes administering compound (1) and prohibiting concomitant or co-administered carbamazepine at intervals of at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In a preferred embodiment, a method of treating a patient with cancer includes administering compound (1) and reducing the concomitant or co-administered carbamazepine at intervals of at least 3 days, at least 7 days, at least 14 days, or at least 21 days prior to administering compound (1).

[0192] In a preferred embodiment, a method of treating a patient with cancer includes administering a therapeutically effective amount of compound (1) and avoiding concomitant or co-administered administration of a therapeutically effective amount of carbamazepine for at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In a preferred embodiment, a method of treating a patient with cancer includes administering a therapeutically effective amount of compound (1) and prohibiting concomitant or co-administered administration of a therapeutically effective amount of carbamazepine for at least 3 days, at least 7 days, at least 14 days, or at least 21 days. In a preferred embodiment, a method of treating a patient with cancer includes administering a therapeutically effective amount of compound (1) and reducing the concomitant or co-administered administration of a therapeutically effective amount of carbamazepine for at least 3 days, at least 7 days, at least 14 days, or at least 21 days prior to administering compound (1).

[0193] In a preferred embodiment, the use or method as defined above includes not applying CYP3A and / or P-gp regulators.

[0194] According to one aspect of the invention, there is provided the use of compound (1) or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein said compound (1) or a pharmaceutically acceptable salt thereof includes the use of CYP3A and / or P-gp modulators without administration. Alternatively, this document provides a method of treating a patient with cancer, the method comprising administering compound (1) without administration of CYP3A and / or P-gp modulators.

[0195] In a preferred embodiment, a method of treating a patient with cancer includes administering a therapeutically effective amount of compound (1) without administering a therapeutically effective amount of CYP3A and / or P-gp modulator. Alternatively, the use of compound (1) for treating cancer includes administering a therapeutically effective amount of compound (1) without administering a therapeutically effective amount of CYP3A and / or P-gp modulator.

[0196] In a preferred embodiment, the use includes not applying CYP3A and / or P-gp regulators for a specified time interval. Alternatively, the method includes not applying CYP3A and / or P-gp regulators for a specified time interval. Preferably, the time interval is as defined herein, for example, it is at least 3 days, at least 7 days, at least 14 days, or at least 21 days.

[0197] In a preferred embodiment, a method of treating a patient with cancer includes administering compound (1) without administering carbamazepine. Alternatively, the use of compound (1) for treating cancer includes administering compound (1) without administering carbamazepine.

[0198] In a preferred embodiment, a method of treating a patient with cancer includes administering a therapeutically effective amount of compound (1) without administering a therapeutically effective amount of carbamazepine. Alternatively, the use of compound (1) in treating cancer includes administering a therapeutically effective amount of compound (1) without administering a therapeutically effective amount of carbamazepine.

[0199] The object of the present invention is also to provide safe and effective medical uses and treatment methods for the co-administration of compound (1) or pharmaceutical compositions comprising compound (1) and other drugs such as CYP3A and / or P-gp modulators (especially CYP3A and / or P-gp inducers). In this case, compound (1) or pharmaceutical compositions comprising compound (1) are administered to a patient who is also using other drugs such as CYP3A and / or P-gp modulators, especially CYP3A and / or P-gp inducers. This medical use or treatment method is particularly helpful in the treatment of cancer. All embodiments described herein involving “avoid” or “contraindicated” modulators are equally applicable to the “combination,” “co-administration,” “concomitant use,” or “parallel administration” of compound (1) and CYP3A and / or P-gp modulators, especially CYP3A and / or P-gp inducers.

[0200] According to another aspect, a compound (1) or a pharmaceutically acceptable salt thereof as defined in this application is provided for use in treating and / or preventing cancer, wherein the compound (1) is administered in combination with a CYP3A and / or P-gp modulator, wherein the compound (1) and the CYP3A and / or P-gp modulator are administered simultaneously, separately, or sequentially. Preferably, the compound (1) and the CYP3A and / or P-gp modulator are each administered at least once over a 14-day period.

[0201] According to another aspect, a pharmaceutical combination is provided, the pharmaceutical combination comprising:

[0202] (i) a compound (1) as defined herein or a pharmaceutically acceptable salt thereof; and

[0203] (ii) CYP3A and / or P-gp regulators or their pharmaceutically acceptable salts;

[0204] Wherein (i) and (ii) are administered simultaneously, separately, or sequentially. Preferably, the drug combination is used for the treatment or prevention of cancer. Preferably, compound (1) and CYP3A and / or P-gp modulator are each administered at least once over a 14-day period.

[0205] According to another aspect, a method for treating and / or preventing cancer is provided, wherein the method comprises administering a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof in combination with a CYP3A and / or a P-gp modifier or a pharmaceutically acceptable salt thereof. Preferably, the compound (1) and the CYP3A and / or P-gp modifier are each administered at least once over a 14-day period.

[0206] According to another aspect, a method for treating and / or preventing cancer is provided, wherein the method comprises administering a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof, wherein when the compound (1) is administered in combination with a CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is reduced. The reduction in daily dose is intended relative to a standard dose of the compound (1), and the reduction specifically results in a daily dose of 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg, preferably a daily dose of 120 mg or 240 mg.

[0207] According to another aspect, a method for treating and / or preventing cancer is provided, wherein the method comprises administering a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof, wherein when the compound (1) is administered in combination with CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is reduced to less than 240 mg.

[0208] According to another aspect, a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof is provided for use in treating and / or preventing cancer, wherein when the compound (1) is administered in combination with a CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is reduced to less than 240 mg.

[0209] According to another aspect, a method for treating and / or preventing cancer is provided, wherein the method comprises administering a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof, wherein when the compound (1) is administered in combination with CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is reduced to 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, 180 mg or 200 mg.

[0210] According to another aspect, a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof is provided for use in treating and / or preventing cancer, wherein when the compound (1) is administered in combination with a CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is reduced to 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, 180 mg or 200 mg.

[0211] According to another aspect, a method for treating and / or preventing cancer is provided, wherein the method comprises administering a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof, wherein when the compound (1) is administered in combination with CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is reduced to less than 120 mg.

[0212] According to another aspect, a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof is provided for use in treating and / or preventing cancer, wherein when the compound (1) is administered in combination with a CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is reduced to less than 120 mg.

[0213] According to another aspect, a method for treating and / or preventing cancer is provided, wherein the method comprises administering a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof, wherein when the compound (1) is administered in combination with CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is reduced to 30 mg, 60 mg or 100 mg.

[0214] According to another aspect, a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof is provided for use in treating and / or preventing cancer, wherein when the compound (1) is administered in combination with a CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is reduced to 30 mg, 60 mg or 100 mg.

[0215] According to another aspect, a method for treating and / or preventing cancer is provided, wherein the method comprises administering a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof, wherein when the compound (1) is administered in combination with a CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is increased. The increase in daily dose is intended relative to a standard dose of the compound (1), and said increase specifically results in a daily dose of 30 mg, 60 mg, 100 mg, 120 mg, 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg, preferably a daily dose of 120 mg or 240 mg.

[0216] According to another aspect, a method for treating and / or preventing cancer is provided, wherein the method comprises administering a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof, wherein when the compound (1) is administered in combination with CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is increased to above 240 mg.

[0217] According to another aspect, a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof is provided for use in treating and / or preventing cancer, wherein when the compound (1) is administered in combination with a CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is increased to above 240 mg.

[0218] According to another aspect, a method for treating and / or preventing cancer is provided, wherein the method comprises administering a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof, wherein when the compound (1) is administered in combination with CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is increased to 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.

[0219] According to another aspect, a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof is provided for use in treating and / or preventing cancer, wherein when the compound (1) is administered in combination with a CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is increased to 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.

[0220] According to another aspect, a method for treating and / or preventing cancer is provided, wherein the method comprises administering a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof, wherein when the compound (1) is administered in combination with CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is increased to above 120 mg.

[0221] According to another aspect, a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof is provided for use in treating and / or preventing cancer, wherein when the compound (1) is administered in combination with a CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is increased to above 120 mg.

[0222] According to another aspect, a method for treating and / or preventing cancer is provided, wherein the method comprises administering a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof, wherein when the compound (1) is administered in combination with CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is increased to 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.

[0223] According to another aspect, a compound (1) as defined in this application or a pharmaceutically acceptable salt thereof is provided for use in treating and / or preventing cancer, wherein when the compound (1) is administered in combination with a CYP3A and / or a P-gp modulator or a pharmaceutically acceptable salt thereof, the daily dose of the administered compound (1) is increased to 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.

[0224] Pharmaceutical compositions

[0225] This document provides a pharmaceutical composition comprising a compound as defined below (1).

[0226] (1)

[0227] The pharmaceutical composition is used for the treatment of cancer, and at least one pharmaceutically acceptable excipient, wherein the use includes avoiding, contraindicating, reducing, or discontinuing the concomitant or co-administered use of CYP3A and / or P-gp modifiers. Alternatively, a method of treating a patient with cancer is disclosed, the method comprising administering a pharmaceutical composition comprising the compound (1) as defined above and at least one pharmaceutically acceptable excipient, and wherein the method includes avoiding, contraindicating, reducing, or discontinuing the concomitant or co-administered use of CYP3A and / or P-gp modifiers. Preferably, in these embodiments, the compound (1) is administered according to the dosage and dosage regimen described below. All embodiments described herein regarding the use of compound (1) for the treatment of cancer or the method of treating a patient with cancer with compound (1) are applicable to the use of the pharmaceutical composition for the treatment of cancer or the method of treating a patient with cancer with the pharmaceutical composition, wherein the use or method includes avoiding, contraindicating, reducing, or discontinuing the concomitant or co-administered use of CYP3A and / or P-gp modifiers.

[0228] In a preferred embodiment, this document provides a pharmaceutical composition comprising the compound (1) as described above and at least one pharmaceutically acceptable excipient, the pharmaceutical composition being used for the treatment of cancer, wherein said use includes avoiding, contraindicating, reducing, or discontinuing the concomitant or co-administered use of CYP3A and / or P-gp inducers. Alternatively, a method of treating a patient with cancer is disclosed, the method comprising administering a pharmaceutical composition comprising the compound (1) as defined above and at least one pharmaceutically acceptable excipient, and wherein said method includes avoiding, contraindicating, reducing, or discontinuing the concomitant or co-administered use of CYP3A and / or P-gp inducers.

[0229] This document also provides a pharmaceutical composition comprising the compound (1) as described above and at least one pharmaceutically acceptable excipient, for use in treating cancer, wherein said use includes co-administration, concomitant use, or combination of compound (1) and CYP3A and / or P-gp modulators. Alternatively, a method of treating a patient with cancer is disclosed, comprising administering a pharmaceutical composition comprising the compound (1) as defined above and at least one pharmaceutically acceptable excipient, wherein said method includes co-administration, concomitant use, or combination of compound (1) and CYP3A and / or P-gp modulators. Preferably, in these embodiments, compound (1) is administered according to the dosage and dosing regimen described below. All embodiments described herein regarding the use of compound (1) for treating cancer or the method of treating a patient with cancer with compound (1) are applicable to the use of a pharmaceutical composition for treating cancer or the method of treating a patient with cancer with a pharmaceutical composition, wherein said use or method includes co-administration, concomitant use, or combination of compound (1) and CYP3A and / or P-gp modulators.

[0230] In a preferred embodiment, this document provides a pharmaceutical composition comprising the compound (1) as described above and at least one pharmaceutically acceptable excipient, the pharmaceutical composition being used for the treatment of cancer, wherein said use includes co-administration, concomitant use, or combination of compound (1) and CYP3A and / or P-gp inducers. Alternatively, a method of treating a patient with cancer is disclosed, the method comprising administering a pharmaceutical composition comprising the compound (1) as defined above and at least one pharmaceutically acceptable excipient, and wherein said method includes co-administration, concomitant use, or combination of compound (1) and CYP3A and / or P-gp inducers.

[0231] The term "pharmaceuticalally acceptable excipient" refers to a non-toxic component that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutical compositions may contain conventionally non-toxic pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that can be used in the compositions of this invention include fillers, disintegrants, flow aids, lubricants, and coating agents. The compositions may further comprise pharmaceutically acceptable excipients selected from: buffers, dispersants, surfactants, wetting agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, processing aids, colorants, sweeteners, flavoring agents, diluents, and other known additives that can be used in the manufacture of pharmaceutical products.

[0232] In a preferred embodiment, compound (1) or the pharmaceutical composition is administered orally. Compound (1) or the pharmaceutical composition may be administered as tablets, hard gelatin capsules or soft gelatin capsules, pills, granules or suspensions. In a preferred embodiment, compound (1) or the pharmaceutical composition is in the form of tablets.

[0233] Use for the treatment of cancer

[0234] As used in this article, cancer is, in some cases, a “hyperproliferative disorder” and refers to a condition in which cell growth increases beyond normal levels. Hyperproliferative disorders include malignant diseases, such as cancer, and non-malignant diseases. As used in this article, cancer is also sometimes referred to as a “tumor disease.” A tumor disease is a disease or medical condition associated with cancer or an indication for cancer. Cancer can be classified according to the tissue type from which it originates (histological type) and according to the primary site or the location where the cancer first develops in the body.

[0235] In one embodiment, compound (1) is provided in a dosage regimen as described herein for the treatment and / or prevention of cancer, wherein said use includes avoiding, contraindicating, reducing or discontinuing the concomitant or co-administered use of CYP3A and / or P-gp modulators.

[0236] Another aspect relates to a method of treating and / or preventing cancer, wherein the method includes the step of administering compound (1) or a pharmaceutical composition as described herein to a patient at the dosage regimen described herein, wherein the method includes avoiding, contraindicating, reducing, or discontinuing the concomitant or co-administered use of CYP3A and / or P-gp modulators. In an embodiment, the method includes administering to a person in need of such treatment a disclosed therapeutically effective amount of compound (1) as described herein or a pharmaceutical composition comprising compound (1).

[0237] Another aspect relates to a method of treating and / or preventing cancer, wherein the method includes the step of administering compound (1) or a pharmaceutical composition as described herein to a patient at the dosage regimen described herein, wherein the method includes the concomitant or co-administration of a CYP3A and / or P-gp modulator. In an embodiment, the method includes administering to a person in need of such treatment a therapeutically effective amount of compound (1) as described herein or a pharmaceutical composition comprising compound (1), and administering a therapeutically effective amount of a CYP3A and / or P-gp modulator or a pharmaceutical composition comprising a CYP3A and / or P-gp modulator.

[0238] On the other hand, it relates to the use of compound (1) for the treatment and / or prevention of cancer, wherein the use includes the steps of administering compound (1) in accordance with the dosage regimen described herein and administering the pharmaceutical composition in conjunction with or in combination with CYP3A and / or P-gp modifiers or in accordance with the dosage regimen described herein.

[0239] In the implementation, the cancer or tumor contains HER2 aberrations. This means that the cells of the cancer or tumor have HER2 aberrations. As used herein, the expressions “HER2 aberration,” “HER2 aberration,” and their grammatical variations have the meanings commonly given to them in the art and include any variation or alteration of the HER2 protein or its encoding gene, such as: overexpression of the HER2 protein, amplification of the HER2 encoding gene, mutations in the HER2 encoding gene and / or the HER2 protein (particularly nonsynonymous mutations, somatic mutations, mutations in specific regions (e.g., in the tyrosine kinase domain, in exon 20), etc.), and gene rearrangements of HER2 and / or NRG1. When a cancer contains HER2 aberrations, it may be referred to as a HER2 aberrant type. When a cancer contains overexpressed HER2 protein, it may be referred to as a HER2 overexpressing type. When a cancer contains amplification of the HER2 encoding gene, it may be referred to as a HER2 amplified type. When a cancer contains mutations in the HER2 encoding gene and / or the HER2 protein, it may be referred to as a HER2 mutant type.

[0240] In the implementation scheme, the cancer is HER2 overexpression, HER2 amplification, and / or HER2 mutation. In the implementation scheme, the cancer includes mutations in the tyrosine kinase domain of HER2. In the implementation scheme, the cancer is HER2 exon 20 mutant cancer.

[0241] In the implementation plan, the cancer involves gene rearrangements of HER2 and / or NRG1.

[0242] As used in this article, “HER2 overexpression” refers to cancer in which the cells of the cancer or tumor express HER2 at levels detectable by immunohistochemistry (e.g., IHC 2+ and IHC 3+) and / or by measuring ERBB2 messenger RNA.

[0243] As used herein, “HER2 amplification” refers to cancer in which cancer or tumor cells exhibit more than 2, particularly more than 3, 4, 5, 6, 7, 8, 9 or 10, preferably more than 6 copies of the HER2 gene ERBB2.

[0244] HER2 expression, gene copy number, and amplification can be measured, for example, by determining nucleic acid sequencing (e.g., genomic DNA or cDNA sequencing), measuring mRNA expression, measuring protein abundance, or combinations thereof. HER2 assays include immunohistochemistry (IHC); in situ hybridization (including fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH)); ELISA; and RNA quantification using technologies such as reverse transcription polymerase chain reaction (RT-PCR), microarray analysis, and next-generation sequencing (NGS). HER2 expression in or above cancer sample cells can be compared to reference cells. Reference cells can be non-cancerous cells obtained from the same subject as the sample cells. Reference cells can also be non-cancerous cells obtained from different subjects or subject populations.

[0245] When cancer is HER2 overexpressed and / or HER2 amplified in or on cells, it can be called "HER2 positive".

[0246] As used herein, “HER2 mutant” refers to cancer carrying at least one mutation (i.e., an alteration in the nucleic acid sequence of the HER2 encoding gene and / or an alteration in the amino acid sequence of the HER2 protein), including but not limited to those listed below. Mutations can be detected using any method known to those skilled in the art, such as molecular diagnostic methods, including but not limited to polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), heteroduplex analysis, restriction fragment length polymorphism (RFLP), next-generation sequencing (NGS), and whole-exome sequencing.

[0247] In the embodiments of the HER2-mutant cancer described herein, the mutation is a non-synonymous mutation. As used herein, the term “non-synonymous” has the meaning commonly given to it in the art, and in particular refers to a mutation in the nucleic acid sequence of the HER2-encoding gene that alters the amino acid sequence of the HER2 protein.

[0248] In the embodiments of the HER2-mutant cancer, the mutation is a somatic mutation. As used herein, the term "somatic" has the meaning commonly given to it in the art, and in particular refers to a mutation in the nucleic acid sequence of the HER2-encoding gene that occurs in cells other than gametes, germ cells, or gametophytes.

[0249] In the implementation of the HER2-mutant cancer, the mutation is a non-synonymous cell mutation.

[0250] In the implementation of the HER2-mutant cancer, the mutation is a non-synonymous cell mutation in the tyrosine kinase domain of HER2.

[0251] In the embodiment of the HER2-mutant cancer, the mutation is in the tyrosine kinase domain of HER2, specifically in exon 20 of HER2. In the latter case, the cancer may be referred to as HER2 exon 20 mutant.

[0252] As used in this article, “HER2 mutant” can also refer to rearrangements involving the HER2 gene ERBB2 and / or the NRG1 gene.

[0253] As used herein, cancer containing mutations in the tyrosine kinase domain of HER2 is cancer in which cancer or tumor cells contain at least one mutation in the tyrosine kinase domain of HER2 (range of amino acids 694 to 883 and / or exons 18 to 21).

[0254] As used herein, “cancer with HER2 exon 20 mutation” or “HER2 exon 20 mutated cancer” refers to cancer in which cancer or tumor cells have at least one HER2 exon 20 mutation, including but not limited to the mutations listed below.

[0255] Exon 20 of ERBB2 (HER2) encodes a portion of the kinase domain and extends from amino acids 769 to 835. Each mutation, insertion, duplication, or deletion within this region is defined as an exon 20 mutation containing the following mutations: p.A772_G773insMMAY; p.Y772_A775_dup (YVMA); p.A775_G776insYVMA; p.Y772insYVMA; p.M774delinsWLV; p.A775_G776insSVMA; p.A775_G776insVVMA; p.A775_G776insYVMS; p.A775_G776insC; p.A776_delinsVC; p.A776_delinsLC; p.A776_ delinsVV;p.A776_delinsAVGC;p.A776_delinsIC;p.A776_V777delinsCVC;p.V777_insE;V777_G77 8insV;p.V777_G778insC;p.V777_G778insCG;p.V777_S779dup;p.V777L;p.V777M;p.G778_P780dup (GSP); p.G778_S779insCPG; p.G778_S779insG; p.G776_delinsVC; p.G776_V777delinsAVGCV; p.G776delinsLC; p.G776_V777delinsAVCV; p.G776delinsVV; p.G776_V777insL; p.G776_V777insVGC; p.G776C; p.G776A; p.G776L; p.G776V; p.P780_Y781insGSP ("p." refers to HER2 protein).

[0256] In addition, HER2 mutations exist outside exon 20 and include the following mutations: p.S310A; p.S310F; p.S310Y; p.R678Q; p.G727A; p.T733I; p.L755S; p.L755A; p.L755F; p.L755P; p.L755S; p.V842I; p.D769Y; p.D769H; p.R103Q; p.G1056S; p.I767M; p.L869R; p.L869R; p.T733I; p.T862A; p.V697L; p.R929W; p.D277H; p.D277Y; p.G660D (“p.” refers to the HER2 protein).

[0257] Examples of tyrosine kinase mutations include: p.G727A; p.T733I; p.L755S; p.L755A; p.L755F; p.L755P; p.L755S; p.V842I; p.D769Y; p.D769H; p.I767M; p.L869R; p.L869R; p.T733I; p.T862A; p.V697L.

[0258] In the implementation plan, cancer is one of, but not limited to, the following cancers, tumors, or other proliferative diseases:

[0259] Cancers / tumors / cancers of the head and neck: for example, tumors / cancers / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lips, gums, alveolar ridge, retromolar triangle, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including floor of tongue, tonsils, tonsillar column, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including superior larynx, glottis, subglottis, vocal cords), hypopharynx, and salivary glands (including minor salivary glands);

[0260] Lung cancers / tumors / carcinomas: for example, non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioloalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma);

[0261] Mediastinal growths: for example, neurogenic tumors (including neurofibroma, schwannoma, malignant schwannoma, neurosarcoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminomatous tumor), thymic tumors (including thymoma, thymic lipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymal tumor, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma);

[0262] Cancers / tumors / cancers of the gastrointestinal (GI) tract: such as tumors / cancers / cancers of the esophagus, stomach (gastric cancer), pancreas, liver and biliary tract (including hepatocellular carcinoma (HCC), such as childhood HCC, fibrolamellar HCC, mixed HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocarcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor); gallbladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stromal tumor (GIST)), appendix;

[0263] Tumors / cancers of the genitourinary system (including kidneys, such as renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms tumor), adrenoidoma, Grawitz tumor; ureter; bladder, such as urachal carcinoma, urothelial carcinoma; urethra, such as distal, bulbar, prostatic; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis);

[0264] Testicular cancer / tumor / cancer: for example, seminoma, non-seminomatous tumor;

[0265] Gynecological cancers / tumors / cancers: for example, tumors / cancers / cancers of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, and uterine body (including endometrium and basal layer);

[0266] Breast cancers / tumors / carcinomas: for example, breast cancer (invasive ductal, colloidal, lobular, tubular, glandular cystic, papillary, medullary, mucinous), hormone receptor-positive breast cancer (estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer), HER2-positive breast cancer, triple-negative breast cancer, Paget's disease of the breast.

[0267] Cancers / tumors / cancers of the endocrine system: for example, endocrine glands, thyroid gland (thyroid cancer / tumor; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma / tumor), adrenal cortex (adrenocortical carcinoma / tumor), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, carotid body, islet cell tumor, tumors / cancers / cancers of the paraganglionic nerve, pancreatic endocrine tumors (PET; non-functional PET, pancreatic polypeptide tumor (Ppoma), gastrinoma, insulinoma, vasodilator intestinal peptide tumor (VIPoma), glucagonoma, somatostatinoma, growth hormone releasing factor tumor (GRFoma), adrenocorticotropic hormone tumor (ACTHoma)), carcinoid tumors;

[0268] Soft tissue sarcomas: such as fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumors of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve schwannoma (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroma, neuroepithelial tumor, extraosseous Ewing's sarcoma, paraganglioma, extraosseous chondrosarcoma, extraosseous osteosarcoma, mesenchymal tumor, alveolar soft tissue sarcoma, epithelioid sarcoma, extrarenal rhabdomyosarcoma, and desmoplastic small cell tumors;

[0269] Osteosarcoma: For example, myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including periosteal, periosteal, highly malignant surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, ameloblastoma, (fibro) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma;

[0270] Mesothelioma: For example, pleural mesothelioma, peritoneal mesothelioma;

[0271] Skin cancers: such as basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial, malignant freckle-like nevus, acral freckle-like nevus, nodular, intraocular melanoma), actinic keratosis, and eyelid cancer;

[0272] Central nervous system and brain vegetations: e.g., astrocytomas (cerebrum, cerebellum, diffuse, fibrotic, anaplastic, pilocytic, protoplasmic, thrombocytic), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, gangliocytoma, neuroblastoma, retinoblastoma, schwannoma (e.g., auditory), spinal cord axis tumors; peripheral nervous system cancers;

[0273] Lymphomas and leukemias: For example, B-cell non-Hodgkin lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt lymphoma (BL)), T-cell non-Hodgkin lymphoma (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphocytic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphocytic B-cell lymphoma (B-LBL), immunocytomas, chronic B-cell lymphocytic leukemia (Bchlorine L), chronic T-cell lymphocytic leukemia (Tchlorine L), B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma Central nervous system lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-dominant HD (NLPHD), tuberous sclerosis HD (NSHD), mixed cellular HD (MCHD), lymphocyte-rich classical HD, lymphocyte-depleted HD (LDHD)), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid / myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myeloid / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML);

[0274] Cancer of unknown origin (CUP).

[0275] The characteristics mentioned above, which refer to all cancers / tumors / carcinomas originating from a specific location in the body, are intended to include both primary tumors and metastatic tumors derived therefrom. Preferably, cancers as defined herein (including in any embodiments involving, for example, cancer types) are metastatic, advanced, and / or unresectable.

[0276] All the cancers / tumors / carcinomas mentioned above can be further distinguished by their histopathological classification:

[0277] Epithelial cancers, such as squamous cell carcinoma (SCC) (carcinoma in situ, superficial invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); eosinophilic cell carcinoma;

[0278] Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematologic malignancies, mixed and undifferentiated carcinomas.

[0279] In some implementations, the cancer is a solid tumor. In some implementations, the cancer manifests as at least one solid tumor.

[0280] In some implementation schemes, the cancer is selected from brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecological cancer, head and neck tumors, lung cancer, nervous system cancers, and skin cancer.

[0281] Preferably, the brain cancer is glioblastoma or glioma.

[0282] Preferably, the breast cancer is lobular breast cancer. Alternatively, the breast cancer is preferably metastatic.

[0283] Preferably, the endocrine carcinoma is a schwannoma, more preferably a HER2-mutant schwannoma.

[0284] Preferably, the gastrointestinal cancer is selected from anal cancer, appendix cancer, biliary tract cancer, colorectal cancer, esophageal cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, liver cancer, pancreatic cancer, and small bowel cancer.

[0285] Preferably, the urogenital cancer is selected from bladder cancer, kidney cancer, and prostate cancer.

[0286] Alternatively, the gastrointestinal cancer may be a gastrointestinal neuroendocrine tumor, preferably a HER2-mutant type. Still preferably, the gastrointestinal cancer is selected from gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and esophageal adenocarcinoma, particularly metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, and metastatic esophageal adenocarcinoma.

[0287] Preferably, the gynecological cancer is selected from cervical cancer, uterine cancer, endometrial cancer, and ovarian cancer.

[0288] As used herein, "head and neck tumor" preferably refers to head and neck cancer. Preferably, the head and neck tumor is salivary gland cancer or a tumor.

[0289] Preferably, the lung cancer is non-small cell lung cancer (NSCLC).

[0290] Preferably, the nervous system cancer is a peripheral nervous system cancer, more preferably a HER2-amplified peripheral nervous system cancer.

[0291] Preferably, the skin cancer is not melanoma, i.e., non-melanoma skin cancer.

[0292] In some implementation schemes, the cancer is selected from glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, schwannoma, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophageal and gastric cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small bowel cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non-small cell lung cancer (NSCLC), peripheral nervous system cancers, and non-melanoma skin cancer.

[0293] In some implementations, the cancer is selected from the following HER2-overexpressing, HER2-amplified, and / or HER2-mutated (especially HER2 exon 20-mutated) cancers: glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, schwannoma, anal cancer, appendix cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophageal and gastric cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small bowel cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non-small cell lung cancer (NSCLC), peripheral nervous system cancers, and non-melanoma skin cancer.

[0294] In some implementation schemes, the cancer is selected from brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, stomach cancer, esophageal tumors, head and neck tumors, salivary gland cancer, gastrointestinal cancer, small bowel cancer, gallbladder tumors, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0295] In some implementations, the cancer is selected from the following HER2 overexpressing, HER2 amplified, and / or HER2 mutated (especially HER2 exon 20 mutated) cancers: brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal tumors, head and neck tumors, salivary gland cancer, gastrointestinal cancer, small bowel cancer, gallbladder tumors, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0296] In some implementation schemes, the cancer is selected from brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, stomach cancer, esophageal tumors, head and neck tumors, gastrointestinal cancer, gallbladder tumors, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0297] In the implementation plan, cancer is selected from the following HER2 overexpression, HER2 amplification and / or HER2 mutation (especially HER2 exon 20 mutation): brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophageal tumors, head and neck tumors, gastrointestinal cancer, gallbladder tumors, kidney cancer, liver cancer, lung cancer and prostate cancer.

[0298] In other embodiments, the cancer is selected from breast cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer, or lung cancer. In yet another embodiment, the cancer is selected from lung cancers / tumors / carcinomas: for example, non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioloalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, mixed oat cell carcinoma). In yet another embodiment, the cancer is NSCLC. In yet another embodiment, the cancer is HER2 exon 20 mutated NSCLC.

[0299] In another implementation, the cancer is unresectable. In yet another implementation, the cancer is unresectable HER2 exon 20 mutant NSCLC.

[0300] In a preferred embodiment, the cancer is advanced or metastatic. In a further preferred embodiment, the cancer is advanced and metastatic. In a further preferred embodiment, when the cancer is metastatic, the metastases are located in the lungs, lymph nodes, bone, or liver. In a further preferred embodiment, the cancer is advanced cancer that includes metastases, and the metastases are located in the lungs, lymph nodes, bone, or liver.

[0301] Alternatively, the cancer may be unresectable.

[0302] In a preferred embodiment, the cancer is an unresectable advanced cancer, including solid tumors and solid metastases, and the metastases are located in the lungs, liver, lymph node tissue, or bone.

[0303] In a preferred embodiment, the cancer is advanced NSCLC, which includes solid, unresectable tumors and metastases, and the metastases are located in the lungs, liver, lymph node tissue, or bone.

[0304] In a preferred embodiment, the cancer is HER2 exon 20 mutant advanced NSCLC, which includes solid unresectable tumors and metastases, and the metastases are located in lung or lymph node tissue or bone.

[0305] In the implementation scheme, the cancer is advanced, unresectable, or metastatic NSCLC carrying a HER2 mutation, wherein the HER2 mutation is in a tyrosine kinase domain. Preferably, in this implementation scheme, compound (1) is administered as a first-line therapy. Still preferably, in this implementation scheme, compound (1) as described herein is administered as a second-line therapy or an additional line of therapy.

[0306] In this embodiment, the cancer is HER2-positive metastatic breast cancer. Preferably, in this embodiment, compound (1) as described herein is administered as a first-line therapy. Still preferably, in this embodiment, compound (1) as described herein is administered as a second-line therapy or an additional line of therapy.

[0307] In the implementation scheme, the cancer is HER2-positive metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, or metastatic esophageal adenocarcinoma. Preferably, in this implementation scheme, compound (1) as described herein is administered as a first-line therapy. Still preferably, in this implementation scheme, compound (1) as described herein is administered as a second-line therapy or an additional line of therapy.

[0308] Compound (1) dosage

[0309] The object of the present invention is to provide a safe and effective dosing regimen for administering compound (1) or a pharmaceutical composition comprising compound (1) at the stated dosage regimen while avoiding other drugs such as CYP3A and / or P-gp modulators. This dosing regimen is particularly helpful for use in the treatment of cancer. Furthermore, this dosing regimen of compound (1) or a pharmaceutical composition comprising compound (1) is particularly helpful in methods of treating patients with cancer. Additionally, the dosing regimen also appears suitable as a second-line or additional line of treatment in patients who have previously received one or more types of cancer treatment.

[0310] Another object of the present invention is to provide a safe and effective dosing regimen for co-administering compound (1) or pharmaceutical compositions comprising compound (1) and other drugs such as CYP3A and / or P-gp modulators (especially CYP3A and / or P-gp inducers). In this case, compound (1) or pharmaceutical compositions comprising compound (1) are administered to a patient who is also using other drugs such as CYP3A and / or P-gp modulators, especially CYP3A and / or P-gp inducers. This dosing regimen is particularly helpful for use in the treatment of cancer. All embodiments relating to modulators that are “avoided” or “contraindicated” in this section also apply to the “combination,” “co-administration,” or “concomitant use” of compound (1) and CYP3A and / or P-gp modulators, especially CYP3A and / or P-gp inducers.

[0311] As used herein, a “dosing regimen” or “dosing schedule” means the administration of a compound (1) according to any one or more characteristics, including but not limited to: daily dose, once or twice daily administration, oral administration, administration for a certain duration, administration after systemic anticancer therapy, etc.

[0312] As used in this article, “daily dose” refers to the amount of the active substance (i.e., compound (1)) administered to the patient within a 24-hour time frame. The 24-hour time frame does not necessarily begin at noon or midnight.

[0313] On the one hand, it was unexpectedly found that, in cases where the stated use includes avoiding, contraindicating, reducing or discontinuing the use of or co-administering CYP3A and / or P-gp modulators, as described above and in the examples below, the use of compound (1) at a daily dose of at least 30 mg is safe and effective for treating cancer.

[0314] On the other hand, it was unexpectedly found that, in cases where the stated use includes the concomitant or co-administration of CYP3A and / or P-gp modulators, as described in the examples above and below, the use of compound (1) at a daily dose of at least 30 mg is safe and effective in treating cancer.

[0315] The implementation schemes described below (especially those relating to daily doses, dosing schedules, etc.) can be applied to each of the two aspects described in the first two paragraphs.

[0316] In a preferred embodiment, compound (1) is administered at a daily dose of at least 60 mg.

[0317] In a preferred embodiment, compound (1) is administered at a daily dose of at least 60 mg, and CYP3A and / or P-gp modulator are administered at a daily dose of at least 100 mg.

[0318] In a preferred embodiment, compound (1) is administered at a daily dose of at least 80 mg.

[0319] In a preferred embodiment, compound (1) is administered at a daily dose of at least 120 mg.

[0320] In a preferred embodiment, compound (1) is administered at a daily dose of at least 180 mg.

[0321] In a preferred embodiment, compound (1) is administered at a daily dose of at least 200 mg.

[0322] In a preferred embodiment, compound (1) is administered at a daily dose of at least 240 mg.

[0323] In a preferred embodiment, compound (1) is administered at a daily dose of at least 300 mg.

[0324] In a preferred embodiment, compound (1) is administered at a daily dose of 30 mg to 600 mg.

[0325] In a preferred embodiment, compound (1) is administered at a daily dose of 60 mg to 600 mg.

[0326] In a preferred embodiment, compound (1) is administered at a daily dose of 80 mg to 600 mg.

[0327] In a preferred embodiment, compound (1) is administered at a daily dose of 120 mg to 600 mg.

[0328] In a further preferred embodiment, compound (1) is administered at a daily dose of 30 mg to 300 mg.

[0329] In a further preferred embodiment, compound (1) is administered at a daily dose of 30 mg to 300 mg.

[0330] In a further preferred embodiment, compound (1) is administered at a daily dose of 60 mg to 300 mg.

[0331] In a further preferred embodiment, compound (1) is administered at a daily dose of 80 mg to 300 mg.

[0332] In a further preferred embodiment, compound (1) is administered at a daily dose of 120 mg to 300 mg.

[0333] In a preferred embodiment, the compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.

[0334] In a preferred embodiment, the compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg.

[0335] In a preferred embodiment, the compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg or 360 mg.

[0336] In a preferred embodiment, the compound (1) is administered at a daily dose of 30 mg, 60 mg, 120 mg, 180 mg, 200 mg, 240 mg or 300 mg.

[0337] In a preferred embodiment, the compound (1) is administered at a daily dose of 60 mg, 120 mg, 180 mg, 200 mg, 240 mg, 300 mg, or 360 mg.

[0338] In a preferred embodiment, compound (1) is administered at a daily dose of 120 mg or 240 mg.

[0339] In a preferred embodiment, compound (1) is administered at a daily dose of 30 mg.

[0340] In a preferred embodiment, compound (1) is administered at a daily dose of 60 mg.

[0341] In a preferred embodiment, compound (1) is administered at a daily dose of 80 mg.

[0342] In a preferred embodiment, compound (1) is administered at a daily dose of 120 mg.

[0343] In a preferred embodiment, compound (1) is administered at a daily dose of 180 mg.

[0344] In a preferred embodiment, compound (1) is administered at a daily dose of 200 mg.

[0345] In a preferred embodiment, compound (1) is administered at a daily dose of 240 mg.

[0346] In a preferred embodiment, compound (1) is administered at a daily dose of 300 mg.

[0347] In a preferred embodiment, compound (1) is administered at a daily dose of 360 mg.

[0348] In a preferred embodiment, compound (1) is administered at a daily dose of 400 mg.

[0349] In a preferred embodiment, compound (1) is administered at a daily dose of 420 mg.

[0350] In a preferred embodiment, compound (1) is administered at a daily dose of 480 mg.

[0351] In a preferred embodiment, compound (1) is administered at a daily dose of 500 mg.

[0352] In a preferred embodiment, compound (1) is administered at a daily dose of 540 mg.

[0353] In a preferred embodiment, compound (1) is administered at a daily dose of 600 mg.

[0354] In a preferred embodiment, compound (1) is administered once or twice daily. This means that the daily dose is administered as a single dose daily, or the daily dose is divided into two separate administrations, each administered at a different time point on the day (i.e., within 24 hours). When compound (1) is administered twice daily, the two separate administrations are preferably separated by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours, preferably 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours, still preferably 8, 9, 10, 11, or 12 hours, and even more preferably an interval of approximately 12 hours.

[0355] In a preferred embodiment, compound (1) is administered once daily. In a preferred embodiment, compound (1) is administered as a single dose every 24 hours.

[0356] In a preferred embodiment, compound (1) is applied once or twice daily. In a preferred embodiment, compound (1) is applied twice every 24 hours.

[0357] In a preferred embodiment, each of the two daily administrations of compound (1) corresponds to half of the daily dose. By administering the required daily dose of compound (1) in two doses containing the same amount, a simple and error-proof application scheme can be provided.

[0358] In a further preferred embodiment, compound (1) is administered for at least 21 consecutive days. In a further preferred embodiment, the 21 days of compound (1) administration is multiplied by X, where X is a natural number equal to or greater than 1. As used herein, “21 days” and “3 weeks” are intended to be synonyms. It is also possible, in overall cancer treatment, to include, for example, a dose-free interval of at least 1, 2, 3, 4, 5, 6, or 7 days between treatment periods including the administration of compound (1).

[0359] In some embodiments, the compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg, or twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.

[0360] In some embodiments, the compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg, or twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.

[0361] In some embodiments, the compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg, or twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg, and the CYP3A and / or P-gp modulator is administered once daily at a daily dose of 200 mg, 300 mg, 400 mg, 500 mg or 600 mg.

[0362] In some embodiments, the compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg or 360 mg, or twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg or 360 mg.

[0363] In some embodiments, the compound (1) is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg or 300 mg, or twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg or 300 mg (1).

[0364] In some implementations, the compound is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg (1).

[0365] In some implementations, the compound is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg (1).

[0366] In some implementations, the compound is administered once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, or 300 mg (1).

[0367] In some implementations, the compound is administered once daily at a daily dose of 120 mg or 240 mg (1).

[0368] In a preferred embodiment, the compound (1) is administered once daily at a dose of 60 mg.

[0369] In a preferred embodiment, the compound (1) is administered once daily at a daily dose of 120 mg.

[0370] In a preferred embodiment, the compound (1) is administered once daily at a daily dose of 180 mg.

[0371] In a preferred embodiment, the compound (1) is administered once daily at a daily dose of 240 mg.

[0372] In a preferred embodiment, the compound (1) is administered once daily at a daily dose of 300 mg.

[0373] In a preferred embodiment, the compound (1) is administered once daily at a daily dose of 360 mg.

[0374] In a preferred embodiment, the compound (1) is administered once daily at a daily dose of 400 mg.

[0375] In a preferred embodiment, the compound (1) is administered once daily at a daily dose of 420 mg.

[0376] In a preferred embodiment, the compound (1) is administered once daily at a daily dose of 480 mg.

[0377] In a preferred embodiment, the compound (1) is administered once daily at a daily dose of 500 mg.

[0378] In a preferred embodiment, the compound (1) is administered once daily at a daily dose of 540 mg.

[0379] In a preferred embodiment, the compound (1) is administered once daily at a daily dose of 600 mg.

[0380] In some implementations, the compound is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg, or 600 mg (1).

[0381] In some implementations, the compound is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 600 mg (1).

[0382] In some implementations, the compound is administered twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, or 300 mg (1).

[0383] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 30 mg. Preferably, in this embodiment, each administration is 15 mg.

[0384] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 60 mg. Preferably, in this embodiment, each administration is 30 mg.

[0385] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 120 mg. Preferably, in this embodiment, each administration is 60 mg.

[0386] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 200 mg. Preferably, in this embodiment, each administration is 100 mg.

[0387] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 300 mg. Preferably, in this embodiment, each administration is 150 mg.

[0388] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 360 mg. Preferably, in this embodiment, each administration is 180 mg.

[0389] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 400 mg. Preferably, in this embodiment, each administration is 200 mg.

[0390] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 420 mg. Preferably, in this embodiment, each administration is 210 mg.

[0391] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 480 mg. Preferably, in this embodiment, each administration is 240 mg.

[0392] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 500 mg. Preferably, in this embodiment, each administration is 250 mg.

[0393] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 540 mg. Preferably, in this embodiment, each administration is 270 mg.

[0394] In a preferred embodiment, compound (1) is administered twice daily at a daily dose of 600 mg. Preferably, in this embodiment, each administration is 300 mg.

[0395] In the implementation plan, compound (1) is administered orally.

[0396] In the implementation scheme, compound (1) is administered as a tablet.

[0397] In some embodiments, the compound (1) is administered orally once daily (preferably as a tablet) at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.

[0398] In some embodiments, the compound (1) is administered orally once daily (preferably as a tablet) at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.

[0399] In some embodiments, compound (1) is administered orally once daily at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg (preferably as tablets), and CYP3A and / or P-gp modulators are administered orally once daily at a daily dose of 200 mg, 300 mg, 400 mg, 500 mg or 600 mg (preferably as tablets).

[0400] In some embodiments, the compound (1) is administered orally once daily (preferably as a tablet) at a daily dose of 60 mg, 120 mg, 180 mg, 240 mg or 300 mg.

[0401] In some embodiments, compound (1) is administered orally once daily at a dose of 60 mg (preferably as a tablet).

[0402] In some embodiments, compound (1) is administered orally once daily at a dose of 120 mg (preferably as a tablet).

[0403] In some embodiments, compound (1) is administered orally once daily at a dose of 180 mg (preferably as a tablet).

[0404] In some embodiments, compound (1) is administered orally once daily at a dose of 240 mg (preferably as a tablet).

[0405] In some embodiments, compound (1) is administered orally once daily at a dose of 300 mg (preferably as a tablet).

[0406] In some embodiments, compound (1) is administered orally once daily at a dose of 360 mg (preferably as a tablet).

[0407] In some implementations, compound (1) is administered orally once daily at a dose of 400 mg (preferably as a tablet).

[0408] In some embodiments, compound (1) is administered orally once daily at a dose of 420 mg (preferably as a tablet).

[0409] In some embodiments, compound (1) is administered orally once daily at a daily dose of 480 mg (preferably as a tablet).

[0410] In some implementations, compound (1) is administered orally once daily at a dose of 500 mg (preferably as a tablet).

[0411] In some implementations, compound (1) is administered orally once daily at a dose of 540 mg (preferably as a tablet).

[0412] In some implementations, compound (1) is administered orally once daily at a dose of 600 mg (preferably as a tablet).

[0413] In some embodiments, the compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 400 mg, 420 mg, 480 mg, 500 mg, 540 mg or 600 mg.

[0414] In some embodiments, the compound (1) is administered orally twice daily (preferably as a tablet) at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.

[0415] In some embodiments, the compound (1) is administered orally twice daily (preferably as a tablet) at a daily dose of 30 mg, 60 mg, 120 mg, 200 mg or 300 mg.

[0416] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 30 mg. Preferably, in this embodiment, each administration is 15 mg.

[0417] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 60 mg. Preferably, in this embodiment, each administration is 30 mg twice daily.

[0418] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 120 mg. Preferably, in this embodiment, each administration is 60 mg.

[0419] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 200 mg. Preferably, in this embodiment, each administration is 100 mg.

[0420] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 300 mg. Preferably, in this embodiment, each administration is 150 mg.

[0421] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 360 mg. Preferably, in this embodiment, each administration is 180 mg twice daily.

[0422] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 400 mg. Preferably, in this embodiment, each administration is 200 mg twice daily.

[0423] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 420 mg. Preferably, in this embodiment, each administration is 210 mg.

[0424] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 480 mg. Preferably, in this embodiment, each administration is 240 mg twice daily.

[0425] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 500 mg. Preferably, in this embodiment, each administration is 250 mg.

[0426] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 540 mg. Preferably, in this embodiment, each administration is 270 mg twice daily.

[0427] In some embodiments, compound (1) is administered orally (preferably as a tablet) twice daily at a daily dose of 600 mg. Preferably, in this embodiment, each administration is 300 mg twice daily.

[0428] In a preferred embodiment, the dosage regimen for compound (1) defined above can also be combined, and the daily dose can also be changed during treatment. Thus, treatment can be started, for example, by administering a daily dose of 30 mg (once or twice daily), and the dose can be switched to a higher or lower daily dose (applied once or twice daily).

[0429] In some embodiments, compound (1) is administered orally (preferably as a tablet) once or twice daily at a dose of 60 mg, and CYP3A and / or P-gp modulators are administered orally (preferably as tablets) once daily at a dose of 200 mg. Alternatively, methods of treating patients with cancer include administering compound (1) orally (preferably as a tablet) once or twice daily at a dose of 60 mg, and CYP3A and / or P-gp modulators administered orally (preferably as tablets) once daily at a dose of 200 mg.

[0430] In some embodiments, compound (1) is administered orally (preferably as tablets) once or twice daily at a dose of 60 mg, and CYP3A and / or P-gp modulators are administered orally (preferably as tablets) once daily at a dose of 400 mg. Alternatively, methods of treating patients with cancer include administering compound (1) orally (preferably as tablets) once or twice daily at a dose of 60 mg, and CYP3A and / or P-gp modulators administered orally (preferably as tablets) once daily at a dose of 400 mg.

[0431] In some embodiments, compound (1) is administered orally (preferably as tablets) once or twice daily at a dose of 60 mg, and CYP3A and / or P-gp modulators are administered orally (preferably as tablets) once daily at a dose of 600 mg. Alternatively, methods of treating patients with cancer include administering compound (1) orally (preferably as tablets) once or twice daily at a dose of 60 mg, and CYP3A and / or P-gp modulators administered orally (preferably as tablets) once daily at a dose of 600 mg.

[0432] In some embodiments, compound (1) is administered orally (preferably as a tablet) once or twice daily at a daily dose of 120 mg or 240 mg, and CYP3A and / or P-gp modulators are administered orally (preferably as a tablet) once daily at a daily dose of 200 mg. Alternatively, methods of treating patients with cancer include administering compound (1) orally (preferably as a tablet) once daily at a daily dose of 120 mg or 240 mg, and CYP3A and / or P-gp modulators are administered orally (preferably as a tablet) once daily at a daily dose of 200 mg.

[0433] In some embodiments, compound (1) is administered orally once daily at a dose of 120 mg or 240 mg (preferably as tablets), and CYP3A and / or P-gp modulators are administered orally once daily at a dose of 400 mg (preferably as tablets). Alternatively, methods of treating patients with cancer include administering compound (1) orally once daily at a dose of 120 mg or 240 mg (preferably as tablets), and CYP3A and / or P-gp modulators are administered orally once daily at a dose of 400 mg (preferably as tablets).

[0434] In some embodiments, compound (1) is administered orally once daily at a dose of 120 mg or 240 mg (preferably as tablets), and CYP3A and / or P-gp modulators are administered orally once daily at a dose of 600 mg (preferably as tablets). Alternatively, methods of treating patients with cancer include administering compound (1) orally once daily at a dose of 120 mg or 240 mg (preferably as tablets), and CYP3A and / or P-gp modulators are administered orally once daily at a dose of 600 mg (preferably as tablets).

[0435] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0436] The following examples are provided to illustrate the present invention in more detail, but do not constitute a limitation thereof.

[0437] Example 1 : Study to test whether carbamazepine influences the amount of compound (1) in the blood in healthy men

[0438] The involvement of seven major hepatic CYP isoforms in the metabolism of compound (1) was evaluated in human liver microsomes (HLM) treated with selective inhibitors of CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 / 5. Based on these data, CYP 3A4 / 5 was found to be primarily responsible for the hepatic oxidative metabolism of compound (1).

[0439] In addition, zongetinib is considered a weak substrate of P-gp.

[0440] Therefore, concomitant medications with CYP3A and / or P-gp inducers may cause a clinically relevant decrease in plasma exposure to compound (1). Therefore, it is necessary to investigate the effects of CYP3A and / or P-gp inducers on the pharmacokinetics of compound (1) in plasma to establish concomitant therapy recommendations.

[0441] The main objective of this study was to investigate the effects of multiple oral doses of the strong CYP3A inducer carbamazepine on the pharmacokinetics of a single dose of compound (1) in plasma.

[0442] Carbamazepine is an indicated anticonvulsant, used among other indications, particularly for the treatment of epilepsy and neuropathic pain. After oral administration, carbamazepine is slowly and almost completely absorbed. Pharmacokinetic steady state is reached after 2 to 8 days. Plasma protein binding is between 70% and 80%. Carbamazepine is oxidized, deaminated, hydroxylated, and esterified with glucuronic acid in the liver. After a single dose, carbamazepine t... 1 / 2 It is approximately 36 hours. After multiple doses, t 1 / 2 It is reduced by about 50% due to enzyme induction.

[0443] Therapeutic carbamazepine is usually administered once daily (qd) or twice daily (bid) in a range of 400 to 1200 mg / day. The maximum daily dose of 1600 mg should generally not be exceeded, as higher doses are associated with a higher risk of side effects. Extended-release tablets are recommended to be taken with or after meals.

[0444] The primary endpoints included the determination of the following pharmacokinetic parameters of compound (1):

[0445] ·AUC 0-∞ (Area under the plasma concentration-time curve over time intervals extrapolated from 0 to infinity)

[0446] ·C max (Maximum measurable concentration of analyte in plasma)

[0447] Secondary endpoints include the determination of the following pharmacokinetic parameters of compound (1):

[0448] ·AUC 0-tz (Area under the plasma analyte concentration-time curve from 0 to the last quantifiable data point)

[0449] Calculate additional pharmacokinetic endpoints, depending on the circumstances.

[0450] In addition to pharmacokinetic parameters, other safety parameters were assessed during the trial. Safety parameters included routine laboratory tests (e.g., hematological or coagulation parameters), electrocardiogram, skin examination, and neurological examination (general level of alertness, orientation, eye movements, pupil size and pupillary responsiveness, reflexes, assessment of muscle strength, gait, Romberg test, tremor, point-to-point movement, and sensitivity).

[0451] The trial was conducted as an open-label, two-treatment, two-phase, fixed-sequence crossover trial in healthy male subjects to compare test treatment (T) and reference treatment (R). The treatments were:

[0452] • Treatment R: A single oral dose of 60 mg of the compound is administered only as a film-coated tablet (1).

[0453] • Treatment of T: A single oral dose of 60 mg of compound (1) was administered as a film-coated tablet, along with multiple oral doses of carbamazepine (adjusted gradually from 200 mg qd to more than 400 mg qd up to 600 mg qd).

[0454] Compound (1) was administered under fasting conditions, and carbamazepine was administered after dinner. Administration of compound (1) was performed after the subject had fasted overnight; fasting began no later than 10 hours prior to the scheduled administration. Administration of carbamazepine was performed after dinner. It was acceptable if only a portion of dinner was consumed. During the first treatment period (Period 1 = Visit 2), all subjects received treatment R, and during the second treatment period (Period 2 = Visit 3), all subjects received treatment T. Visit 3 immediately followed Visit 2, i.e., day 8 was the last day of Visit 2, and day 8 of Visit 2 coincided with day -19 of Visit 3.

[0455] Treatment period

[0456] Each subject participated in two treatment periods (Period 1: Day -1 to Day 8; Period 2: Day -19 to Day 8). Day 8 of Period 1 and Day -19 of Period 2 were the same day.

[0457] An overview of the experimental design is provided in Figure 1 (A)

[0458] The following selection criteria apply:

[0459] • Based on investigator assessment of healthy male subjects, such as based on a complete medical history, including physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), and clinical laboratory tests;

[0460] • Age 18 to 50 years old (inclusive);

[0461] • Body Mass Index (BMI) between 18.5 and 29.9 kg / m² 2 (Including end values);

[0462] • Before being allowed to enter a trial, a written informed consent form must be signed and dated in accordance with the International Council for Harmonisation-Good Clinical Practice (ICH-GCP) and local regulations.

[0463] The following exclusion criteria apply:

[0464] • Any medical examination results (including BP, PR or ECG, neurological examination or skin examination) that deviate from the normal range and are assessed by the investigator as clinically relevant;

[0465] • Repeated measurements of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 beats per minute (bpm);

[0466] • Any laboratory value outside the clinically relevant reference range as determined by the investigator;

[0467] • Any evidence that the investigator assesses as clinically relevant comorbidity;

[0468] • Gastrointestinal disorders, liver disorders, kidney disorders, respiratory disorders, cardiovascular disorders, metabolic disorders, immune disorders, or hormonal disorders;

[0469] • Cholecystectomy or other gastrointestinal surgeries that may interfere with the pharmacokinetics of the investigational drug (other than appendectomy or simple hernia repair).

[0470] • Central nervous system disorders (including but not limited to any type of epilepsy or stroke) and other related neurological or mental disorders;

[0471] • A history of orthostatic hypotension, syncope, or amnesia;

[0472] • Use of any drug that may reasonably affect the trial results within 30 days of the planned administration of the investigational drug (including drugs that prolong the QT / QTc interval or any type of vaccination).

[0473] Other exclusion criteria apply.

[0474] Dosage selection in the experiment

[0475] The carbamazepine dose chosen for this trial reflects the standard clinical dose and is considered sufficient to produce significant CYP3A induction. The step-down regimen has been successfully used in previous studies, but the modification is that carbamazepine is administered once daily (qd) instead of twice daily (bid) in this study. This is because tolerability of carbamazepine is expected to improve if administered only at night.

[0476] The expected dose of compound (1) selected for this trial (60 mg of compound (1)) will result in plasma concentrations within the range of concentrations explored to date in previous trials and associated with good safety and tolerability.

[0477] Blood samples for pharmacokinetic analysis

[0478] Blood Sampling Overview

[0479] Table 1 provides an overview of blood sampling for compound (1).

[0480]

[0481] Table 1

[0482] Table 2 provides an overview of carbamazepine blood sampling.

[0483]

[0484] Table 2

[0485] Sample preparation

[0486] Quantification of compound (1) and carbamazepine was performed in plasma. For quantification of the concentrations of compound (1) and carbamazepine in plasma, 2.7 mL of blood was drawn from an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetate)-anticoagulant aspiration tube at the times indicated in Table 1 for compound (1) and Table 2 for carbamazepine. Blood was drawn by indwelling intravenous catheter or by venipuncture with a metal needle.

[0487] For the quantitative determination of compound (1) and carbamazepine, EDTA-anticoagulated blood samples were centrifuged at approximately 2000 x g to 4000 x g at 4°C to 8°C for approximately 10 min. Two plasma aliquots were obtained and stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The process from blood collection to transfer of the plasma aliquots to a refrigerator should be completed within 60 min (carbamazepine) or 120 min (compound (1)), respectively, during which the blood sample and aliquots were temporarily stored at room temperature. The time when each aliquot was placed in the refrigerator was recorded. The aliquots were stored upright at the test site at approximately -20°C or below until transferred to the analytical laboratory on dry ice. The second aliquot was transferred to the analytical laboratory after the bioanalyst confirmed that the first aliquot had arrived safely. At the analytical laboratory, the plasma sample was stored at approximately -20°C or below until analysis.

[0488] Analytical method for the quantification of compound (1) and carbamazepine

[0489] The concentrations of compound (1) and carbamazepine in plasma were determined by validated LC-MS / MS (liquid chromatography-tandem mass spectrometry).

[0490] Statistical analysis was performed on the following analysis set:

[0491] • Treatment Set (TS): The treatment set includes all subjects treated with at least one dose of compound (1) or carbamazepine. The treatment set will be used for safety analysis.

[0492] • Pharmacokinetic Parameter Analysis Set (PKS): This set includes all subjects from the Treatment Set (TS) who provided at least one defined primary or secondary PK endpoint and were not excluded due to regimenal deviations related to PK evaluation or due to the non-evaluability of PK (as specified in the following subsection, “Pharmacokinetics”). Therefore, even if a subject contributes only one PK parameter value for statistical evaluation within a given period, they are included in the PKS. Descriptive and model-based analyses of PK parameters are performed based on the PKS.

[0493] The extent of drug-drug interactions was estimated using the ratio of the geometric means of the primary and secondary endpoints (test / reference). Two-sided 90% confidence intervals (CIs) were also provided. This approach corresponds to two one-sided t-test procedures, each at a 5% significance level. Since the primary focus is estimation rather than testing, no formal hypothesis testing or associated acceptance range was specified. The statistical model was performed using analysis of variance (ANOVA) on a logarithmic scale, including both subjects and treatment effects. CIs were calculated based on the residuals from the ANOVA. Descriptive statistics for all endpoints were calculated.

[0494] Example 2: Influence of carbamazepine (strong CYP3A inducer) on the pharmacokinetics of sunitinib in healthy male volunteers Figure 1

[0495] summary

[0496] Introduction: Zongatinib is a potent, selective, HER2 inhibitor that does not inhibit wild-type EGFR. Based on in vitro data, the oxidative hepatic metabolism of Zongatinib is primarily driven by CYP3A4 / 5. Therefore, Zongatinib may be a victim of strong CYP3A inducers (like carbamazepine).

[0497] Objective: This study aimed to investigate the effects of multiple oral doses of carbamazepine on the pharmacokinetics of a single oral dose of zogatinib in healthy male subjects.

[0498] Methods: This open-label, two-period, fixed-order clinical drug-drug interaction study examined the pharmacokinetics of a single 60 mg oral dose of zogatinib in the absence (R) or presence (T) of multiple oral doses of carbamazepine. The area under the plasma concentration-time curve (AUC) was used from time 0 to infinity and to the last quantifiable time point. 0-∞ AUC 0-tz ) and maximum measurable plasma concentration (C max The degree of drug-drug interaction is estimated by the adjusted geometric mean ratio (GMR) of T to R and the 90% confidence interval (CI).

[0499] Results: Sixteen participants (all Caucasian males) received zogatinib alone in phase 1, and 15 of them received both zogatinib and carbamazepine in phase 2. Following co-administration with carbamazepine, the AUC of zogatinib decreased to 36.5% (AUC). 0-∞ The GMR for AUC0-tz was 32.0% to 41.6%, and the 90% CI for AUC0-∞ was 41.6%. 0-tz The C-value was 31.9% to 41.7%. max It decreased to 56.4% (90% CI: 45.1% to 70.6%).

[0500] Conclusion: When co-administered with the strong CYP3A inducer carbamazepine, the exposure to zogatinib was moderately reduced.

[0501] Keywords

[0502] Drug interactions

[0503] Zangetinib

[0504] Pharmacokinetics

[0505] Non-small cell lung cancer

[0506] • Tyrosine kinase inhibitors

[0507] Carmasepine

[0508] Enzyme induction

[0509] introduce

[0510] Human epidermal growth factor receptor 2 (HER2, also known as NEU or EGFR2, encoded by ERBB2) is a member of the epidermal growth factor receptor (EGFR) gene family of receptor tyrosine kinases. HER2 signaling is initiated upon heterodimerization with other EGFR family members or homodimerization at high HER2 concentrations, leading to a downstream phosphorylation signaling cascade involved in cell growth, proliferation, and differentiation. 1–4 HER2 is a recognized oncogenic target. In addition to HER2 amplification and overexpression, which have been successfully targeted in many cancer types such as breast and gastric cancer, activating mutations in HER2 have also been identified as unique oncogenic drivers and therapeutic targets. 1,2,5–8

[0511] HER2 mutations have been identified in up to 4% of non-small cell lung cancer (NSCLC). 1,2,9–14 The most frequently identified mutation is the in-frame insertion YVMA in exon 20 (p.A775_G776insYVMA). 2,5,15 Currently, there are only limited targeted therapy options for NSCLC with HER2 aberrations. 16 For patients with HER2-mutant NSCLC, traditional chemotherapy-based treatment options, associated with significant dose-limiting toxicities and poor long-term efficacy, remain part of the first-line recommendations. 14 Clinically approved and investigational tyrosine kinase inhibitors are non-selective for HER2 and are limited by dose-limiting toxicities mediated by EGFR wild-type, highlighting an unmet medical need for NSCLC patients with HER2 insertion mutations. 17

[0512] Based on in vitro testing, zogatinib is a highly potent and selective HER2 tyrosine kinase inhibitor. It covalently binds to both wild-type and mutant HER2 receptors (including exon 20 insertions) without inhibiting wild-type EGFR. It is being investigated at multiple dose levels in patients with HER2 aberration-positive solid tumors in the Phase I Beamion LUNG-1 study (NCT04886804). 18Zongatinib is being further investigated in patients with advanced NSCLC carrying HER2 mutations in the Phase III Beamion LUNG-2 study (NCT06151574).

[0513] Zanagtinib is a low-clearance drug. Based on identified metabolites produced when radiolabeled zanagtinib is incubated with human hepatocytes, zanagtinib is primarily metabolized via oxidation (48%–62% of total metabolism), glucuronidation (13%–25% of total metabolism), and glutathione conjugation (13%–26% of total metabolism). In follow-up in vitro studies using human liver microsomes and recombinant enzymes, CYP3A4 / 5 was identified as primarily responsible for hepatic oxidative metabolism. Furthermore, zanagtinib is considered a weak substrate for the efflux transporter P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Because CYP3A accounts for 48%–62% of total hepatic metabolic clearance in vitro, concomitant drugs that induce CYP3A activity may lead to a clinically relevant reduction in zanagtinib plasma exposure. Therefore, it is crucial to evaluate the effect of strong CYP3A inducers on the pharmacokinetics (PK) of zanagtinib in human subjects.

[0514] Carbamazepine (recommended by the U.S. Food and Drug Administration (FDA) as a strong CYP3A inducer) was selected as the perpetrator drug in this clinical drug interaction (DDI) study. 19 Carbamazepine is slowly and almost completely absorbed after oral administration. 20–22 As a substrate and inducer of CYP3A4 and 2B6, carbamazepine induces its own metabolism. Its half-life initially ranged from 25 to 65 hours, and can be shortened to 12 to 17 hours with repeated dosing. 21,23 In addition to its strong induction of CYP3A, carbamazepine has been reported to induce various other CYP variants (1A2, 2B6, 2C8, 2C9, 2C19), UGT enzymes, transporter P-gp, and multidrug resistance protein 2 (MRP2). 24,25 The most common side effects of carbamazepine include dizziness, drowsiness, ataxia, nausea, and vomiting. Tolerance is usually improved by gradually increasing the daily dose. 26

[0515] Endogenous biomarkers, including the ratio of 6β-OH-cortisol in urine to cortisol (6βCR) and 4β-OH-cholesterol in plasma (4βHC), are frequently used in DDI studies to assess CYP3A activity in vivo. 27–32 With increased CYP3A activity, cortisol and cholesterol metabolism also increase accordingly, reflected in elevated levels of 6βCR in urine and 4βHC in plasma.29 Although they are not quantitative, these endogenous biomarkers provide a minimally invasive and practical method for determining the temporal course of changes in CYP3A activity during clinical DDI studies. 31,32

[0516] The primary objective of this study was to investigate the effects of multiple oral doses of carbamazepine (a strong CYP3A inducer, as well as an inducer of UGT enzymes and P-gp) on the pharmacokinetic (PK) response of a single oral dose of zogatinib in healthy male subjects. Further objectives included evaluating carbamazepine plasma concentrations and assessing the safety and tolerability of zogatinib and carbamazepine. Additionally, frequent sampling of urinary 6βCR and plasma 4βHC was conducted during carbamazepine administration to investigate the time course of CYP3A induction by carbamazepine.

[0517] method

[0518] Research Design

[0519] This open-label, two-period, fixed-sequence clinical DDI study (EU CT No. 2022-503046-50-00; clinicaltrials.gov NCT06028464) in healthy male subjects aimed to compare test treatment (T) with reference treatment (R). R consisted of a single oral dose of zogatinib 60 mg film-coated tablets administered on day 1 of study period 1. T consisted of a single oral dose of zogatinib 60 mg on day 1, along with multiple oral doses of carbamazepine (CMP) administered on days -18 through 6 of study period 2. Figure 1 (B) Carbamazepine was administered at 200 mg once daily (QD) for 4 days (days -18 to -15), gradually increased to 400 mg QD for 7 days (days -14 to -8), and then gradually increased to a final dose of 600 mg QD for 13 days (days -7 to -6). Zangatinib was administered orally once daily with 240 mL of water at approximately 8:00 AM after a 10-hour fast. Carbamazepine was also administered orally with 240 mL of water at approximately 8:00 PM daily after dinner. Studies are shown in... Figure 1 (B)

[0520] After obtaining written informed consent and having it dated in accordance with the International Council for Harmonisation of Technical Requirements for Clinical Trials (ICH) and local regulations, sixteen participants aged 18 to 55 years with a body mass index (BMI) of 18.5 to 29.9 kg / m² are planned to participate. 2Healthy male participants were admitted to the study. Healthy participants were identified based on a complete medical history, including physical examination, vital signs, a 12-lead electrocardiogram (ECG), and clinical laboratory tests, according to the researchers' assessment. Key exclusion criteria include clinically relevant comorbidities; central nervous system disorders and other neurological or psychiatric disorders; gastrointestinal surgery that may interfere with the pharmacokinetics (PK) of the investigational drug; a history of relevant orthostatic hypotension; relevant chronic or acute infections; a history of relevant allergies; current smokers; alcohol abuse; drug abuse or positive drug screening; use of a drug that may reasonably affect the trial results within 30 days of the planned administration of the investigational drug; intake of the investigational drug in another clinical trial within 60 days or five half-lives (whichever is longer); known Asian ancestry; any lifetime history of suicidal behavior within the past 12 months or any suicidal ideation of type 2 to 5 according to the Columbia Suicide Severity Rating Scale (C-SSRS); hyponatremia; white blood cell, platelet, or hemoglobin levels below the lower limit of normal; alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) levels exceeding the upper limit of normal by 10%. Concomitant therapies are not permitted. Short-term use of ibuprofen is acceptable in cases of adverse events (AEs) requiring analgesic treatment (such as headache). Grapefruit, Seville oranges and their juices, as well as dietary supplements and products containing St. John's wort, are not permitted from 7 days before the first administration of zongatinib in Phase 1 until after the collection of the last PK sample in Phase 2.

[0521] From obtaining written informed consent from participants until the end of the trial, adverse events and concomitant therapies were continuously assessed. This study was conducted in accordance with the protocol, the ethical principles described in the Declaration of Helsinki, the ICH harmonized guidelines for GCP, relevant Boehringer Ingelheim Standard Operating Procedures, EU Regulation 536 / 2014, and other relevant regulations. The study protocol was reviewed and approved by the national competent authority (Federal Institute for Drugs and Medical Devices, BfArM) and the independent ethics committee (Ethik-Kommission der Medizinischen Fakultät der Universität Duisburg-Essen) (Essen, Germany). Informed consent documents were reviewed and approved by the Independent Ethics Committee, and all participants provided written informed consent prior to the commencement of the study.

[0522] Pharmacokinetics and Bioanalytical Methods

[0523] Blood samples for analyzing zogatinib concentrations were collected before administration and up to 168 hours after administration, during periods 1 and 2. Blood samples for analyzing carbamazepine trough concentrations were collected throughout period 2. During period 2, urine samples for analyzing 6βCR and blood samples for analyzing 4βHC were collected at 24-hour intervals, parallel to the carbamazepine blood samples. The sampling protocol is shown in [details omitted]. Figure 5 (B)

[0524] All blood samples used to analyze the plasma concentrations of carbamazepine, zongetinib, and 4βHC were collected from the antecubital or forearm vein into EDTA-anticoagulant aspiration tubes and centrifuged to obtain plasma aliquots.

[0525] Plasma concentrations of zogatinib, 4βHC, and carbamazepine, as well as 6β-OH-cortisol and urinary cortisol concentrations, were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Calibration curves for undiluted samples were linear within the desired concentration range. Overall mean accuracy and precision of quality control (QC) samples met acceptance criteria.

[0526] Pharmacokinetic Analysis and Statistical Methods

[0527] The area under the plasma concentration-time curve (AUC) of zogatinib from time 0 to infinity 0-∞ ) and maximum measurable plasma concentration (C max The primary endpoint is AUC (AUC) from time 0 to the last quantifiable data point. 0-tz The primary endpoint is secondary. The extent of DDI is estimated by the ratio of T to the geometric mean (gMean) of R (T / R) and the two-sided 90% confidence intervals (CI) for both the primary and secondary endpoints. The statistical model is an analysis of variance (ANOVA) on a logarithmic scale, including the effect of the subjects and the treatment. Confidence intervals are calculated based on the residuals from the ANOVA.

[0528] Calculate additional PK parameters (including the time from drug administration to the maximum measurable plasma concentration (t)). max ), plasma terminal half-life (t 1 / 2 The apparent clearance in plasma after oral administration (CL / F) was used as a further endpoint. Additional further endpoints included the safety and tolerability of zongatinib and carbamazepine, plasma carbamazepine concentration, urinary 6βCR, and plasma 4βHC. Descriptive statistics for all endpoints were calculated. Phoenix WinNonlin was used. TMThe software (Phoenix version 8.1.1, Certara USA Inc., Princeton, New Jersey, USA) was used to calculate the PK parameters. SAS was used. TM (Current version 9.4, SAS Institute Inc., Cary, North Carolina, USA) Statistical analysis was performed.

[0529] result

[0530] Participants

[0531] A total of 16 subjects were enrolled in the trial and assigned to the same treatment sequence to receive two treatments in a fixed order (RT). All 16 subjects received the first treatment (R), and 15 subjects received the second treatment (T). One subject did not start the second treatment due to a positive drug test result prior to the second treatment period. No major protocol deviations were reported. All 16 subjects were male and white. The mean age of the subjects (standard deviation [SD]; range) was 41.5 years (11.0; 26 to 55). The mean BMI (SD; range) was 25.9 kg / m². 2 (3.1; 19.6 to 29.9).

[0532] CYP3A induced by carbamazepine

[0533] Following multiple oral administrations of carbamazepine tablets (gradually adjusted from 200 mg QD to 400 mg QD, and then gradually adjusted to a final dose of 600 mg QD), the plasma trough concentration of carbamazepine steadily increased, peaking 108 hours before administration of zongatinib, and then slightly decreased. Figure 2 During the pretreatment period with carbamazepine, both urinary 6βCR and plasma 4βHC increased over time. Figure 3 The increase in 6βCR plateaued 60 hours (-60 hours) before zoninginib administration, with the geometric mean percentage change (PCB) relative to baseline ranging from 228% to 250% between -60 hours and 156 hours. Inter-individual variability in urinary 6βCR was moderate (gCV: 34.0% to 54.7%). For plasma 4βHC, the increase slowed 12 hours before zoninginib administration, with a geometric mean PCB of 332%. Plasma 4βHC increased slowly until 156 hours, with a final geometric mean increase of 393%. Plasma 4βHC exhibited low inter-individual variability (gCV: 16.3% to 26.3%).

[0534] Effects of carbamazepine on zongatinib

[0535] In period 1, following a single oral dose of 60 mg zogatinib tablet, plasma concentrations of zogatinib rapidly increased and peaked at 2.0 hours (median t). max Range: 1.0 to 3.0 hours), where the geometric mean C max The concentration was 914 nmol / L. After reaching peak value, the plasma concentration of zongatinib decreased in a multiphasic manner, with a geometric mean CL / F of 151 mL / min and a geometric mean t. 1 / 2 The duration was 38.7 hours. Following co-administration of carbamazepine in phase 2, the plasma concentration of zogatinib increased rapidly, but to a lesser extent than in phase 1, with a lower C-value. max (Geometric mean is 516 nmol / L), but t max No relevant changes were observed (median: 1.5 hours; range: 1.0 to 4.0 hours). After reaching peak concentration, plasma concentrations of zogatinib decreased more rapidly with co-administration of carbamazepine. Figure 3 The geometric mean CL / F of zogatinib increased to as high as 2.75-fold, with a value of 415 mL / min, and the geometric mean t of zogatinib... 1 / 2 The duration of action was reduced from 38.7 hours to 23.9 hours (Table 3). The overall inter-individual variability of key PK parameters between the two periods was low to moderate (gCV: 10.7% to 45.1%; Table 3). In both periods, all plasma concentrations prior to zoninginib administration were below the limit of quantitation, indicating adequate clearance between the two periods. Notably, carbamazepine appeared to reduce the inter-subject variability (gCV) of zoninginib plasma concentrations ( Figure 4 ).

[0536] Based on model-based analysis conducted via ANOVA, AUC 0-∞ and AUC 0-tz The adjusted geometric mean ratios (T / R) were 36.5% (90% CI: 32.0% to 41.6%) and 36.5% (90% CI: 31.9% to 41.7%), respectively, indicating that co-treatment with carbamazepine reduced AUC by approximately 64%. max The adjusted geometric mean ratio (T / R) was 56.4% (90% CI: 45.1% to 70.6%), indicating that co-treatment with carbamazepine reduced C max Reduced by approximately 44% ​ ).

[0537] Table 3: Comparison of pharmacokinetic parameters of a single 60 mg oral dose of zogatinib in the absence of (R) or in the presence of (T) multiple doses of carbamazepine.

[0538]

[0539] † Median value

[0540] ‡ Range: minimum to maximum value

[0541] AUC, the area under the concentration-time curve of the analyte in plasma; AUC 0 -∞ AUC over a time interval from 0 to infinity; AUC 0-tz AUC over the time interval from 0 to the last quantifiable data point; CL / F, apparent clearance of the analyte in plasma after oral administration; C max The maximum measurable concentration of the analyte in plasma; gCV, geometrical coefficient of variation; gMean, geometrical mean; R, reference; T, test; t 1 / 2 The final half-life of the analyte in plasma; t max The time from drug administration to the maximum measurable concentration of the analyte in plasma.

[0542] Summary of security results

[0543] Of the 16 participants in the study, 13 (81%) reported adverse events (AEs) during treatment, and 12 (75%) reported investigator-defined drug-related AEs. These were primarily observed during treatment phase T (i.e., the phase of treatment with carbamazepine; Tables 4 and 5).

[0544] The most frequent drug-related adverse events (AEs) were fatigue (6 subjects [38%]) and constipation (3 subjects [19%]), primarily occurring during the carbamazepine treatment phase. Other drug-related AEs reported by more than one subject were only abdominal discomfort, back pain, and pruritus (two subjects each [13%]), also occurring during the carbamazepine treatment phase. During the zogatinib-only treatment phase, fatigue was the only drug-related AE reported in one subject [6%]. No adverse events were reported as CTCAE Grade 3 or serious AEs. Most AEs were CTCAE Grade 1, with some being Grade 2.

[0545] During the carbamazepine-only treatment phase, one subject reported a mild increase in gamma-glutamyl transferase (up to 133 U / L; normal: < 60 U / L) and ALT (up to 112 U / L; normal: < 50 U / L). Additionally, no clinically relevant findings were reported in safety labs, vital signs, or ECG.

[0546] Adverse event form

[0547] The table below shows subjects with adverse events (AEs) categorized by different treatment stages.

[0548] - "Zongatinib" phase: AEs occurring from the start of Zongatinib administration in phase 1 until the first administration of carbamazepine in phase 2.

[0549] - "Zongatinib + Carbamazepine Loading Phase": AEs occurring from the start of the carbamazepine loading phase until 14 days after the first dose of zongatinib.

[0550] - "Carbamazepine Loading" Phase: AEs occurring in the subsequent portion of the carbamazepine loading phase up to the second phase of zogestinib administration.

[0551] - "Zongatinib + Carbamazepine" phase: From the second dose of Zongatinib until the occurrence of AE within 14 days thereafter.

[0552] - "Total Carbamazepine" stage: A summary of the stages using carbamazepine.

[0553] - "Total Zangetinib" phase: A summary of the phases of Zangetinib use.

[0554] Table 4: Frequency of adverse events during treatment in subjects by treatment, major system organ classification and preferred term - treatment set [N (%)].

[0555]

[0556]

[0557] ALT, alanine aminotransferase; GGT, gamma-glutamyl transferase; zonger, zongertinib; carbamazepine; on-trt, during treatment.

[0558] Table 5: Frequency of adverse events in drug-related treatments among subjects by treatment, major system organ classification, and preferred term - treatment set [N (%)].

[0559]

[0560]

[0561] ALT, alanine aminotransferase; GGT, gamma-glutamyl transferase; zonger, zongertinib; carbamazepine; on-trt, during treatment.

[0562] discuss

[0563] The primary objective of this study was to investigate the pharmacokinetic (PK) effect of multiple oral doses of carbamazepine on a single oral dose of zogatinib. A reduction in zogatinib exposure (AUC reduction of approximately 64% and C) was observed during carbamazepine co-administration.max The 44% reduction indicates that zomenitinib is susceptible to induction primarily by CYP3A, with potential contributions from UGT enzymes and P-gp. Indeed, carbamazepine primarily induces its effects through activation of the receptor transcription factors pregnane X receptor (PXR) and constitutive androstenedione receptor (CAR), mediating gene transcription of various enzymes and transporters in addition to strong induction by CYP3A4 / 5. 24,33 Induction by other enzymes and transporters (such as UGT and P-gp) could theoretically contribute to reducing zogatinib exposure, predicting a “worse-than-ideal” outcome than strong CYP3A induction alone. Given that CYP3A contributes 48%–62% of the total hepatic metabolic clearance of zogatinib in vitro, the reduction in zogatinib exposure is considered to be primarily driven by strong CYP3A induction. Carbamazepine is classified by the FDA as a strong-index CYP3A inducer, as defined by reducing the AUC of a sensitive substrate for a given metabolic pathway by ≥ 80%. In a previous study by Lutz et al., in a similar dosing regimen to this DDI study, midazolam (a sensitive CYP3A substrate) showed an AUC reduction of approximately 79% after co-administration with carbamazepine. max Reduced by 68%. 34 Compared to the DDI results for midazolam, the reduction in zongatinib exposure observed in our study was considered moderate.

[0564] Zanagetinib has a shorter half-life and is accompanied by an increased apparent clearance rate (CL / F), indicating an accelerated elimination period due to CYP3A induction. Zanagetinib's C max The reduction in concentration may be a combination of increased systemic clearance and potentially increased first-pass effects in the liver and intestinal wall. Interestingly, the plasma PK profile of zogatinib co-treatment with carbamazepine appeared to be associated with lower inter-subject variability compared to zogatinib alone. The high variability in plasma concentrations during the reference period could potentially be explained by variability in the expression of enzymes and transporters responsible for eliminating zogatinib. For example, CYP3A4 expression has been reported to have extremely high population variability (>100-fold). 35 By leveraging carbamazepine's strong induction of CYP3A4 expression, subjects can achieve similarly high expression levels, thereby reducing the variability in zomenitinib plasma concentrations.

[0565] The carbamazepine dosage selection in this study was based on a previous healthy volunteer study that reported a carbamazepine dosing regimen of 200 mg / day for 4 days, followed by 400 mg / day for 7 days, and then 600 mg / day for 21 days resulting in maximum CYP3A induction (based on 6βCR in urine) on day 18 of this regimen. 36In our study, subjects were pretreated with carbamazepine for more than 14 days, which is the maximum duration of CYP3A induction generally accepted by regulatory agencies (like the FDA). 37 To further confirm the CYP3A induction process in this study, we additionally collected urinary 6βCR and plasma 4βHC at different time points during carbamazepine treatment and observed a rapid increase in both biomarkers due to carbamazepine treatment. 6βCR appeared to have plateaued 60 hours before zonagtinib administration, indicating that the interaction was studied at maximal induction. On the other hand, plasma 4βHC showed a more delayed peak, and its concentration continued to increase slowly at the last sampling point, likely due to the longer half-life of plasma 4βHC (i.e., 17 days, compared to approximately 1 hour for cortisol and its metabolites). 38 Similar to the evaluations in previous literature, 38–41 Plasma 4βHC appears to be a less sensitive but more stable biomarker, exhibiting lower variability compared to urinary 6βCR. Overall, the increase in endogenous biomarkers suggests a high likelihood of achieving maximum CYP3A induction prior to zongatinib administration.

[0566] Step-up adjustments are commonly used for carbamazepine dosing to improve tolerability. Based on recommendations from researchers in previous carbamazepine clinical studies, the reference studies mentioned above... 36 The twice-daily dosing of carbamazepine used in this study was modified to once-daily evening dosing to further improve drug tolerability. 25 The safety and tolerability of carbamazepine in the current study were considered good. Most adverse events (AEs) were CTCAE grade 1, and only a few were grade 2. No dizziness or vertigo was observed in this study (as in previous publications). 36,42,43 (As previously reported), this may be because the once-daily dose of carbamazepine was administered at night (instead of twice-daily). Due to the risk profile of carbamazepine, close monitoring of safety parameters (including safety laboratory tests, neurological examination, skin examination, ECG, vital signs, and suicide assessment) is recommended in trials using carbamazepine in healthy volunteers. Recent reports of symptomatic thrombocytopenia (requiring subject withdrawal) in carbamazepine studies in healthy volunteers underscore this necessity. 42 In this trial, a single dose of 60 mg zongatinib or in combination with carbamazepine was safe and well-tolerated.

[0567] in conclusion

[0568] Following strong induction of CYP3A drug metabolism, zogatinib exposure was moderately reduced. Compared to zogatinib alone, co-administration of zogatinib with multiple doses of carbamazepine resulted in a reduction of approximately 64% in AUC and approximately 44% in Cmax. In this study, both zogatinib and carbamazepine were considered safe and well-tolerated in healthy male subjects.

[0569] References:

[0570] 1. Moasser MM. The oncogene HER2: its signaling and transformingfunctions and its role in human cancer pathogenesis. Oncogene. 2007;26(45):6469-6487. doi:10.1038 / sj.onc.1210477

[0571] 2.Jebbink M, Langen AJ de, Boelens MC, Monkhorst K, Smit EF. Theforce of HER2 – A druggable target in NSCLC? Cancer Treat Rev. 2020;86:101996. doi:10.1016 / j.ctrv.2020.101996

[0572] 3.Bai X, Sun P, Wang

[0573] 4.Graus‐Porta D, Beerli RR, Daly JM, Hynes NE. ErbB‐2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateralsignaling. EMBO J. 1997;16(7):1647-1655. doi:10.1093 / emboj / 16.7.1647

[0574] 5.Wang Y, Jiang T, Qin Z, et al. HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptortyrosine kinase inhibitor pyrotinib. Ann Oncol. 2019;30(3):447-455. doi:10.1093 / annonc / mdy542

[0575] 6.Shigematsu H, Takahashi T, Nomura M, et al. Somatic Mutations ofthe HER2 Kinase Domain in Lung Adenocarcinomas. Cancer Res. 2005;65(5):1642-1646. doi:10.1158 / 0008-5472.can-04-4235

[0576] 7.Yan M, Parker BA, Schwab R, Kurzrock R. HER2 aberrations in cancer:Implications for therapy. Cancer Treat Rev. 2014;40(6):770-780. doi:10.1016 / j.ctrv.2014.02.008

[0577] 8.Li BT, Ross DS, Aisner DL, et al. HER2 Amplification and HER2Mutation Are Distinct Molecular Targets in Lung Cancers. J Thorac Oncol.2016;11(3):414-419. doi:10.1016 / j.jtho.2015.10.025

[0578] 9.Ninomiya K, Hata T, Yoshioka H, et al. A Prospective Cohort Studyto Define the Clinical Features and Outcome of Lung Cancers Harboring HER2Aberration in Japan (HER2-CS STUDY). Chest. 2019;156(2):357-366. doi:10.1016 / j.chest.2019.01.011

[0579] 10.Peters S, Zimmermann S. Targeted therapy in NSCLC driven by HER2insertions. Transl lung cancer Res. 2014;3(2):84-88. doi:10.3978 / j.issn.2218-6751.2014.02.06

[0580] 11.Stephens P, Hunter C, Bignell G, et al. Intragenic ERBB2 kinasemutations in tumours. Nature. 2004;431(7008):525-526. doi:10.1038 / 431525b

[0581] 12.Pillai RN, Behera M, Berry LD, et al. HER2 mutations in lungadenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer.2017;123(21):4099-4105. doi:10.1002 / cncr.30869

[0582] 13.Wang SE, Narasanna A, Perez-Torres M, et al. HER2 kinase domainmutation results in constitutive phosphorylation and activation of HER2 andEGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell. 2006;10(1):25-38. doi:10.1016 / j.ccr.2006.05.023

[0583] 14.Nützinger J, Lee JB, Low JL, et al. Management of HER2 alterationsin non-small cell lung cancer – The past, present, and future. Lung Cancer.2023;186:107385. doi:10.1016 / j.lungcan.2023.107385

[0584] 15.Arcila ME, Chaft JE, Nafa K, et al. Prevalence, ClinicopathologicAssociations, and Molecular Spectrum of ERBB2 (HER2) Tyrosine KinaseMutations in Lung Adenocarcinomas. Clin Cancer Res. 2012;18(18):4910-4918.doi:10.1158 / 1078-0432.ccr-12-0912

[0585] 16.Uy NF, Merkhofer CM, Baik CS. HER2 in Non-Small Cell Lung Cancer:A Review of Emerging Therapies. Cancers. 2022;14(17):4155. doi:10.3390 / cancers14174155

[0586] 17.Riudavets M, Sullivan I, Abdayem P, Planchard D. Targeting HER2 innon-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review ontherapeutic strategies in NSCLC harbouring HER2 alterations. Esmo Open. 2021;6(5):100260. doi:10.1016 / j.esmoop.2021.100260

[0587] 18.Heymach J, Opdam F, Barve M, et al. A Phase I, Open-Label, DoseConfirmation, Escalation, and Expansion Trial of BI 1810631 as Monotherapy inPatients with Advanced or Metastatic Solid Tumors with HER2 Aberrations. ClinLung Cancer. 2022. doi:10.1016 / j.cllc.2022.10.008

[0588] 19.The_Food_and_Drug_Administration. Table of Substrates, Inhibitorsand Inducers. https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.Published 2023. Accessed April 4, 2024.

[0589] 20.Bertilsson L, Tomson T. Clinical Pharmacokinetics andPharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide.Clin Pharmacokinet. 1986;11(3):177-198. doi:10.2165 / 00003088-198611030-00001

[0590] 21.Novartis Pharmaceuticals Corporation. Tegretol (carbamazepine)[package insert]. U.S. Food and Drug Administration website.https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2015 / 016608s097,018281s045,018927s038,020234s026lbl.pdf. Revised August 2015. Accessed April 4, 2024.

[0591] 22.Tolou-Ghamari Z, Zare M, Habibabadi JM, Najafi MR. A quick reviewof carbamazepine pharmacokinetics in epilepsy from 1953 to 2012. J Res MédSci: Off J Isfahan Univ Méd Sci. 2013;18(Suppl 1):S81-5.

[0592] 23.Fuhr LM, Marok FZ, Hanke N, Selzer D, Lehr T. Pharmacokinetics ofthe CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug–Drug InteractionPotential: A Physiologically Based Pharmacokinetic Modeling Approach.Pharmaceutics. 2021;13(2):270. doi:10.3390 / pharmaceutics13020270

[0593] 24.Bolleddula J, Gopalakrishnan S, Hu P, Dong J, Venkatakrishnan K.Alternatives to rifampicin: A review and perspectives on the choice of strongCYP3A inducers for clinical drug–drug interaction studies. Clin Transl Sci.2022;15(9):2075-2095. doi:10.1111 / cts.13357

[0594] 25.Giessmann T, May K, Modess C, et al. Carbamazepine regulatesintestinal P‐glycoprotein and multidrug resistance protein MRP2 andinfluences disposition of talinolol in humans. Clin Pharmacol Ther. 2004;76(3):192-200. doi:10.1016 / j.clpt.2004.04.011

[0595] 26.Ferrendelli JA. Concerns with Antiepileptic Drug Initiation:Safety, Tolerability, and Efficacy. Epilepsia. 2001;42(s4):28-30. doi:10.1111 / j.1528-1167.2001.00006.x

[0596] 27.Penzak SR, Rojas‐Fernandez C. 4β‐Hydroxycholesterol as anEndogenous Biomarker for CYP3A Activity: Literature Review and CriticalEvaluation. J Clin Pharmacol. 2019;59(5):611-624. doi:10.1002 / jcph.1391

[0597] 28.Diczfalusy U, Kanebratt KP, Bredberg E, Andersson TB, Böttiger Y,Bertilsson L. 4β‐Hydroxycholesterol as an endogenous marker for CYP3A4 / 5activity. Stability and half‐life of elimination after induction withrifampicin. Brit J Clin Pharmaco. 2009;67(1):38-43. doi:10.1111 / j.1365-2125.2008.03309.x

[0598] 29.Dutreix C, Lorenzo S, Wang Y. Comparison of two endogenousbiomarkers of CYP3A4 activity in a drug–drug interaction study betweenmidostaurin and rifampicin. Eur J Clin Pharmacol. 2014;70(8):915-920. doi:10.1007 / s00228-014-1675-0

[0599] 30.Dutreix C, Munarini F, Lorenzo S, Roesel J, Wang Y. Investigationinto CYP3A4-mediated drug–drug interactions on midostaurin in healthyvolunteers. Cancer Chemother Pharmacol. 2013;72(6):1223-1234. doi:10.1007 / s00280-013-2287-6

[0600] 31.Mao J, Martin I, McLeod J, et al. Perspective: 4β-hydroxycholesterol as an emerging endogenous biomarker of hepatic CYP3A. DrugMetab Rev. 2017;49(1):18-34. doi:10.1080 / 03602532.2016.1239630

[0601] 32.Galteau MM, Shamsa F. Urinary 6β-hydroxycortisol: a validated testfor evaluating drug induction or drug inhibition mediated through CYP3A inhumans and in animals. Eur J Clin Pharmacol. 2003;59(10):713-733. doi:10.1007 / s00228-003-0690-3

[0602] 33.Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D.Enzyme induction with antiepileptic drugs: Cause for concern? Epilepsia.2013;54(1):11-27. doi:10.1111 / j.1528-1167.2012.03671.x

[0603] 34.Lutz JD, Kirby BJ, Wang L, et al. Cytochrome P450 3A InductionPredicts P‐glycoprotein Induction; Part 2: Prediction of Decreased SubstrateExposure After Rifabutin or Carbamazepine. Clin Pharmacol Ther. 2018;104(6):1191-1198. doi:10.1002 / cpt.1072

[0604] 35.Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism:Regulation of gene expression, enzyme activities, and impact of geneticvariation. Pharmacol Ther. 2013;138(1):103-141. doi:10.1016 / j.pharmthera.2012.12.007

[0605] 36.Stockis A, Chanteux H, Rosa M, Rolan P. Brivaracetam andcarbamazepine interaction in healthy subjects and in vitro. Epilepsy Res.2015;113:19-27. doi:10.1016 / j.eplepsyres.2015.03.003

[0606] 37.U.S. Food and Drug Administration. Clinical Drug InteractionStudies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug InteractionsGuidance for Industry. https: / / www.fda.gov / regulatory-information / search-fda-guidance-documents / clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. Accessed May 24, 2024.

[0607] 38.Dutreix C, Lorenzo S, Wang Y. Comparison of two endogenousbiomarkers of CYP3A4 activity in a drug–drug interaction study betweenmidostaurin and rifampicin. Eur J Clin Pharmacol. 2014;70(8):915-920. doi:10.1007 / s00228-014-1675-0

[0608] 39.Penzak SR, Rojas‐Fernandez C. 4β‐Hydroxycholesterol as anEndogenous Biomarker for CYP3A Activity: Literature Review and CriticalEvaluation. J Clin Pharmacol. 2019;59(5):611-624. doi:10.1002 / jcph.1391

[0609] 40.Diczfalusy U, Kanebratt KP, Bredberg E, Andersson TB, Böttiger Y,Bertilsson L. 4β‐Hydroxycholesterol as an endogenous marker for CYP3A4 / 5activity. Stability and half‐life of elimination after induction withrifampicin. Brit J Clin Pharmaco. 2009;67(1):38-43. doi:10.1111 / j.1365-2125.2008.03309.x

[0610] 41.Mao J, Martin I, McLeod J, et al. Perspective: 4β-hydroxycholesterol as an emerging endogenous biomarker of hepatic CYP3A. DrugMetab Rev. 2017;49(1):18-34. doi:10.1080 / 03602532.2016.1239630

[0611] 42.Kanefendt F, Dallmann A, Chen H, et al. Assessment of the CYP3A4Induction Potential by Carbamazepine: Insights from Two Clinical DDI Studiesand PBPK Modeling. Clin Pharmacol Ther. 2024. doi:10.1002 / cpt.3151

[0612] 43.David OJ, Behrje R, Pal P, Hara H, Lates CD, Schmouder R.Pharmacokinetic Interaction Between Fingolimod and Carbamazepine in HealthySubjects. Clin Pharmacol Drug Dev. 2018;7(6):575-586. doi:10.1002 / cpdd.459

Claims

1. A compound (1) as defined below, or a pharmaceutically acceptable salt thereof, (1) The use of the compound (1) or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the use includes avoiding, contraindicating, reducing or discontinuing the concomitant or co-administered use of CYP3A and / or P-gp modulators.

2. The compound (1) according to claim 1 for the stated use, wherein the stated use includes avoiding co-application of CYP3A and / or P-gp modifiers.

3. A compound (1) as defined below, or a pharmaceutically acceptable salt thereof, (1) The compound (1) or a pharmaceutically acceptable salt thereof is used for the treatment of cancer, wherein the compound (1) is administered in combination with a CYP3A and / or a P-gp modulator, wherein the compound (1) and the CYP3A and / or the P-gp modulator are administered simultaneously, separately or sequentially.

4. The compound (1) for the use according to any one of claims 1 to 3, wherein the use includes a contraindication or avoidance time interval between the application of the CYP3A and / or P-gp regulator and the application of compound (1).

5. The compound (1) for the purpose according to claim 4, wherein the time interval for contraindication or avoidance is selected from at least 1 hour, at least 1 day, at least 3 days, at least 7 days, at least 14 days and at least 21 days.

6. The compound (1) for the use according to any one of claims 1 to 5, wherein the use comprises assessing the patient’s CYP3A and / or P-gp modulator drug status prior to administration of the compound (1), and contraindicating or avoiding administration of the compound (1) for a certain time interval if the CYP3A and / or P-gp modulator drug status is positive.

7. The compound (1) for the use according to claim 6, wherein the CYP3A and / or P-gp modulator drug status assessment is selected from questionnaires, determination of CYP3A and / or P-gp modulator blood, serum and / or plasma levels, consultation with the patient, endogenous biomarkers, and combinations thereof.

8. The compound (1) for the purpose according to any one of claims 1 to 7, wherein when the compound (1) is administered in combination with CYP3A and / or a P-gp regulator, the daily dose of the administered compound (1) is greater than 120 mg, preferably greater than 150 mg, 180 mg, 200 mg or 240 mg.

9. The compound (1) for the purpose according to any one of claims 1 to 8, wherein when the compound (1) is administered in combination with CYP3A and / or a P-gp regulator, the daily dose of the administered compound (1) is greater than 240 mg, preferably greater than 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg.

10. The compound (1) for the said use according to any one of claims 1 to 9, wherein the use includes: (i) Assess the patient’s CYP3A and / or P-gp modulator status; (ii) If the CYP3A and / or P-gp modulator drug status is positive, compound (1) is administered to the patient at a dose higher than the standard therapeutically effective dose; (iii) When the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to the patient at a standard therapeutically effective amount.

11. The compound (1) for the said use according to any one of claims 1 to 10, wherein the use includes: (i) Assess the patient’s CYP3A and / or P-gp modulator status; (ii) When the CYP3A and / or P-gp modulator drug status is positive, the compound (1) is administered at a total daily dose of 150 mg, 180 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 600 mg; (iii) When the CYP3A and / or P-gp modulator drug status is negative, compound (1) is administered to the patient at a standard therapeutically effective amount.

12. The compound (1) for the said use according to claim 10 or 11, wherein the standard therapeutically effective amount of the compound (1) is a daily dose of 120 mg or 240 mg.

13. The compound (1) for the use according to any one of claims 1 to 12, wherein the CYP3A and / or P-gp regulator is a CYP3A and / or P-gp inducer.

14. The compound (1) for the use according to any one of claims 1 to 13, wherein the CYP3A and / or P-gp regulator is a strong CYP3A4 / 5 inducer.

15. The compound (1) for the purpose according to claim 2, wherein the CYP3A and / or P-gp regulator is a strong CYP3A4 / 5 inducer.

16. The compound (1) for the use according to any one of claims 1 to 15, wherein the CYP3A and / or P-gp regulator is selected from apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort, brigatinib, efavirenz, enzalutamide, dexamethasone, modafinil, nevirapine, oxcarbazepine, pioglitazone, rifabutin, and troglitazone.

17. The compound (1) for the use according to any one of claims 1 to 16, wherein the CYP3A and / or P-gp regulator is carbamazepine.

18. The compound (1) for the use according to any one of claims 1 to 17, wherein the cancer is selected from brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small bowel cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

19. The compound (1) for the use according to any one of claims 1 to 18, wherein the cancer is non-small cell lung cancer.

20. The compound (1) for the use according to any one of claims 1 to 19, wherein the cancer is HER2 overexpressing, HER2 amplified, and / or HER2 mutant.

21. The compound (1) for the use according to any one of claims 1 to 20, wherein the cancer comprises a mutation in the tyrosine kinase domain of HER2.

22. The compound (1) for the use according to any one of claims 1 to 21, wherein the cancer is an unresectable, advanced and / or metastatic cancer.

23. A pharmaceutical composition comprising a compound (1) as defined below or a pharmaceutically acceptable salt thereof. (1) The pharmaceutical composition is used for the treatment of cancer, and at least one pharmaceutically acceptable excipient, wherein the use includes avoiding, contraindicating, reducing or discontinuing the concomitant or co-administered use of CYP3A and / or P-gp modulators.

24. A pharmaceutical composition comprising a compound (1) as defined below or a pharmaceutically acceptable salt thereof. (1) The pharmaceutical composition is used for the treatment of cancer, and at least one pharmaceutically acceptable excipient, wherein compound (1) is administered in combination with a CYP3A and / or a P-gp modulator, wherein compound (1) and the CYP3A and / or the P-gp modulator are administered simultaneously, separately or sequentially.

25. The pharmaceutical composition according to claim 23 or 24, wherein the use is as defined in any one of claims 2 or 4 to 12.

26. The pharmaceutical composition according to any one of claims 23 to 25, wherein the CYP3A and / or P-gp modulator is as defined in any one of claims 13 to 17.

27. The pharmaceutical composition according to any one of claims 23 to 26, wherein the cancer is as defined in any one of claims 18 to 22.

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