Methods of treating tenosynovial giant cell tumor

Abstract

The present application provides, inter alia, methods of treating tenosynovial giant cell tumor in a patient in need thereof, wherein the methods comprise administering to the patient a compound represented by Formula (I). Formula (I).

Description

Cross-references

[0001] This application claims priority to U.S. Provisional Application No. 63 / 594,018, filed October 29, 2023; U.S. Provisional Application No. 63 / 622,689, filed January 19, 2024; U.S. Provisional Application No. 63 / 574,671, filed April 4, 2024; U.S. Provisional Application No. 63 / 650,146, filed May 21, 2024; and U.S. Provisional Application No. 63 / 683,741, filed August 16, 2024, the contents of which are each incorporated herein by reference. Background Technology

[0002] Colony-stimulating factor 1 receptor (CSF1R) and its ligand, colony-stimulating factor 1 (CSF1), form a lineage-dependent relationship for normal macrophage development and mononuclear globulin differentiation. Therefore, the proliferation of tumor-associated macrophages (TAMs), as well as the maintenance of their differentiation state and immunosuppressive phenotype, depend on CSF1R (also known as FMS) kinase activity. The role of TAMs in promoting invasive and immunosuppressive tumor microenvironments is well-established. TAMs mediate tumor growth, angiogenesis, invasion, metastasis, and immunosuppression through the secretion and response of various cytokines or other soluble factors. After tumor education, TAMs can evade immune surveillance by suppressing cytotoxic T cell immune responses, thereby protecting tumors from T cell clearance. For example, TAMs express PD-L1, a known immunosuppressive checkpoint molecule that induces T cell inactivation.

[0003] Several inhibitors targeting CSF1R have progressed to clinical stages as direct-acting antitumor therapies and potential immunotherapies. Many of these drugs also inhibit closely related type III tyrosine receptor kinases KIT, PDGFRα / β, and FLT3, whose efficacy may be limited by off-target toxicity. Antibodies targeting CSF1R are much more specific, but due to blocking CSF1 clearance and other drawbacks, they result in plasma CSF1 (the ligand of CSF1R) levels increasing by >10,000-fold.

[0004] Giant cell tumors of the tendon sheath (TGCT) are proliferative and inflammatory diseases, including solid tumors previously known as pigmented villonodular synovitis (PVNS) and giant cell tumors of the intra- or extra-articular tendon sheath (GCTTS). They are rare tumors of the joint or tendon sheath in which synovial mononuclear cells, a mixture of multinucleated giant cells, foam cells, hemosiderin-containing macrophages, and inflammatory cells, undergo destructive proliferation. Two types of TGCT exist: localized or nodular forms (where the tumor involves the tendon supporting the joint, or only in a region of the joint) and diffuse forms (involving the entire endothelial region). Treatment involves surgical resection of the tumor. However, marginal resection is often difficult to perform on diffuse TGCT, leading to a high recurrence rate. It may be characterized by CSF1 overexpression.

[0005] There is a need for selective small molecule CSF1R inhibitors, which are suitable for treating conditions associated with TAM proliferation (including solid tumors of various cancers) and for treating mesenchymal tumors such as TGCT, including diffuse tenosynovial giant cell tumor (DTGCT) and localized tenosynovial giant cell tumor. Summary of the Invention

[0006] In one embodiment, this application describes a method for treating a patient with giant cell tumor of the tendon sheath who requires but is not suitable for surgical treatment, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I).

[0007] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) The patient achieved a partial or complete response after at least 25 weeks of administration of the compound, as determined by RECIST v1.1.

[0008] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) The patient achieved a partial or complete response after at least 25 weeks of administration of the compound, as determined by independent imaging review (IRR) based on tumor volume score (TVS).

[0009] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by the following to the patient twice a week: Formula (I) Among them, after at least 25 weeks of administration of the compound, the patient had an improved range of active activity compared to before the administration of the compound.

[0010] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After at least 25 weeks of administration of the compound, the patient achieved an increase in the PROMIS-PF score compared to before administration of the compound.

[0011] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After at least 25 weeks of administration of the compound, the patient achieved an increase in the Worst Stiffness Numeric Rating Scale score compared to before administration of the compound.

[0012] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After at least 25 weeks of administration of the compound, the patient achieved an increase in the EQ-Visual Analog Scale (EQ-VAS) score compared to before administration of the compound.

[0013] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After at least 25 weeks of administration of the compound, the patient achieved a decrease of 30% or more in the Brief Pain Inventory Numerical Rating Scale score compared to before administration of the compound.

[0014] In another embodiment, this application provides a method for treating a patient with elevated creatine phosphokinase (CPK) levels, wherein the patient is administered 30 mg of a compound represented by formula (I) twice weekly during treatment for treatment of tenosynovial giant cell tumor: Formula (I) The method involves administering the compound to the patient at a dose of less than 30 mg twice a week. Attached Figure Description

[0015] Figure 1 This study demonstrates the duration of response at week 25, as determined by an independent imaging review (IRR) based on RECIST v1.1, for responders who received 30 mg of compound (I) twice weekly, in the study of Example 1.

[0016] Figure 2 This study demonstrates the duration of response determined by independent imaging review (IRR) based on tumor volume score (TVS) at week 25 for responders who received 30 mg of compound (I) twice a week in the study of Example 1.

[0017] Figure 3 The change in active range of activity (ROM) relative to baseline was shown at week 25 in patients receiving 30 mg of compound (I) twice a week (vectinib) compared to patients receiving placebo.

[0018] Figure 4 The study in Example 1 shows the change in PROMIS physical function (PROMIS-PF) relative to baseline at week 25 in patients receiving 30 mg of compound (I) twice a week (vecetinib) compared to patients receiving placebo.

[0019] Figure 5 The study in Example 1 shows the change in the numerical rating scale (NRS) of the most severe stiffness relative to baseline at week 25 in patients receiving 30 mg of compound (I) twice a week (vecetinib) compared to patients receiving placebo.

[0020] Figure 6The changes in EQ-Visual Analogue Scale (EQ-VAS) relative to baseline were shown at week 25 in patients receiving 30 mg of compound (I) twice a week (vectinib) compared to patients receiving placebo.

[0021] Figure 7A depicts the optimal percentage change in target lesions obtained using RECIST v1.1 for IRR assessment in patients during the study of Example 1. Figure 7B depicts a forest plot of objective response for patient subgroups.

[0022] Figure 8 This figure depicts the proportion of patients who responded to treatment with compound (Vecetinib) of formula (I) and experienced functional or symptomatic improvement in the study of Example 1. The figure also depicts the number of indicators of patient response to treatment, as described in this application.

[0023] Figures 9A and 9B depict the changes in active range of activity (ROM) relative to baseline at week 25 in the study of Example 2 for each cohort. Associations greater than 100% are due to the reference range. These figures show individual patient values. In cohort A (Figure 9A), relative to baseline, increase: n = 23; no change: n = 5; decrease: n = 4. In cohort B (Figure 9B), relative to baseline, increase: n = 9; no change: n = 3; decrease: n = 1.

[0024] Figure 10 This figure shows the percentage of patients who experienced treatment-specific adverse events (TEAEs) at an incidence rate greater than or equal to 15% before and after 12 months of treatment with vectinib, graded by the highest severity level, in the study of Example 2. The safety cohort included patients who received at least one dose of the study drug. Severity was assessed by the investigator according to the toxicity grading (Grade 1 [mild] to Grade 5 [death]) as described in the National Cancer Institute CTCAE v4.03. Time indicates the earliest start date of the highest severity grade of each TEAE; if the highest severity grade TEAE occurred within the first 12 months of treatment, lower severity grade events occurring after 12 months are not included in this figure. Legend: AST, aspartate aminotransferase; COVID-19, coronavirus disease of 2019; CPK, creatine phosphokinase; CTCAE v4.03, Common Terminology Standard for Adverse Events version 4.03; LDH, lactate dehydrogenase; TEAE, treatment-related adverse events. Detailed Implementation

[0025] The features and other details of this application will now be described in more specific terms. Certain terms used in this application specification, embodiments, and appended claims are concentrated herein. These definitions should be read in light of the remainder of this application and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by those skilled in the art.

[0026] definition The compound represented by formula (I) described in this application is also called "vimseltinib". The compound represented by formula (I) described in this application also refers to 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one.

[0027] As used in this application, the crystalline dihydrate form of the compound represented by formula (I) is: The crystalline dihydrate form of the compound represented by formula (I) is also referred to in this application as "vecetinib dihydrate".

[0028] All ranges described in this application include endpoints, including the endpoints of ranges describing "between two values". The terms "substantially" and "about" are each interpreted as modifying a term or numerical value such that it is not absolute. For a given technique used to measure a numerical value, this includes at least the degree of expected experimental error, technical error, and instrument error.

[0029] As used in this application, the terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and humans. The compounds described in this application can be applied not only to mammals such as humans, but also to other mammals, such as animals requiring veterinary treatment, such as livestock (e.g., dogs, cats, and similar animals), agricultural animals (e.g., cows, sheep, pigs, horses, and similar animals), and laboratory animals (e.g., rats, mice, guinea pigs, and similar animals). Mammals treated by the methods described in this application are preferably mammals requiring treatment for the conditions described in this application, such as humans.

[0030] As used in this application, "TGCT" refers to giant cell tumor of the tendon sheath.

[0031] As used in this application, "DTGCT" refers to diffuse giant cell tumor of the tendon sheath.

[0032] As used in this application, "treatment" includes any effect that causes improvement of a condition, disease, symptom, etc., such as relief, reduction, regulation, or elimination.

[0033] As used in this application, "PROMIS-PF" refers to the Patient Reported Outcomes Measurement Information System Physical Function.

[0034] The compounds described in this application, such as those of formula (I), can be formulated into pharmaceutical compositions using pharmaceutically acceptable carriers and administered via a variety of routes. In some embodiments, such compositions are administered orally. In some embodiments, such compositions are administered parenterally (by injection) (e.g., compositions formulated for local injection at a tumor site, such as tenosynovial giant cell tumors, such as diffuse or localized tenosynovial giant cell tumors). In some embodiments, such compositions are administered percutaneously. In some embodiments, such compositions are administered intravenously (IV). In some embodiments, such compositions are administered intramuscularly (IM). Such pharmaceutical compositions and methods of their preparation are well known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro et al., eds., 19th edition, Mack Publishing Co., 1995).

[0035] Throughout this application, numerous patents, patent applications, and publications are cited. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety to provide a more complete description of the state of the art as known to a person skilled in the art up to the filing date of this application. In the event of any inconsistency between these patents, patent applications, and publications and this application, this application shall prevail.

[0036] Treatment This application partially provides a method for treating giant cell tumors of the tendon sheath.

[0037] In one embodiment, this application describes a method for treating a patient with giant cell tumor of the tendon sheath who requires but is not suitable for surgical treatment, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I).

[0038] In some implementations, the patient is not a candidate for surgery. In some implementations, the patient is unsuitable for surgery (e.g., surgery to treat TGCT). In some implementations, the surgical procedure is considered high-risk. In some implementations, the patient has refused surgical treatment.

[0039] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) The patient achieved a partial or complete response after at least 25 weeks of administration of the compound, as determined by RECIST v1.1.

[0040] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) The patient achieved a partial or complete response after at least 25 weeks of administration of the compound, as determined by independent imaging review (IRR) based on tumor volume score (TVS).

[0041] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by the following to the patient twice a week: Formula (I) Among them, after at least 25 weeks of administration of the compound, the patient had an improved range of active activity compared to before the administration of the compound.

[0042] In some implementations, after at least 25 weeks of administration of the compound, the patient achieves a change of at least 18% in active range of motion compared to before administration of the compound.

[0043] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After at least 25 weeks of administration of the compound, the patient achieved an increase in the PROMIS-PF score compared to before administration of the compound.

[0044] In some implementations, after at least 25 weeks of administration of the compound, the patient achieves a PROMIS-PF score that is at least 4 points higher than the patient's PROMIS-PF score before administration of the compound.

[0045] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After at least 25 weeks of administration of the compound, the patient achieved an increase in the score on the most severe stiffness numerical rating scale compared to before the administration of the compound.

[0046] In some implementations, after at least 25 weeks of administration of the compound, the patient achieves a score of up to -2 on the Most Severe Rigidity Rating Scale compared to before administration of the compound.

[0047] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After at least 25 weeks of administration of the compound, the patient achieved an increase in the EQ-Visual Analog Scale (EQ-VAS) score compared to before administration of the compound.

[0048] In some implementations, after at least 25 weeks of administration of the compound, the patient achieves an EQ-VAS score that is at least 13 points higher than the patient's EQ-VAS score before administration of the compound.

[0049] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After at least 25 weeks of administration of the compound, the patient achieved a decrease of ≥30% in the Short Form Pain Rating Scale (SNRS) score compared to before administration of the compound.

[0050] In some implementations, after at least 25 weeks of administration of the compound, the patient maintains an increase in anesthetic use of less than 30% compared to before the administration of the compound.

[0051] In another embodiment, this application provides a method for treating a patient with elevated creatine phosphokinase (CPK) levels, wherein the patient is administered 30 mg of a compound represented by formula (I) twice weekly during treatment for treatment of tenosynovial giant cell tumor: Formula (I) The method involves administering the compound to the patient at a dose of less than 30 mg twice a week.

[0052] In some embodiments, the dosage is selected from 14 mg twice a week and 20 mg twice a week. In some embodiments, the dosage is 20 mg twice a week. In some embodiments, the dosage is 14 mg twice a week.

[0053] In some embodiments, the tenosynovial giant cell tumor is a diffuse tenosynovial giant cell tumor. In some embodiments, the tenosynovial giant cell tumor is a localized tenosynovial giant cell tumor. In some embodiments, the patient has previously undergone surgery to treat the tenosynovial giant cell tumor. In some embodiments, the patient has previously received systemic therapy for the treatment of the tenosynovial giant cell tumor. In some embodiments, the systemic therapy is selected from imatinib and nilotinib. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's lower limb. In some embodiments, the joint of the lower limb is selected from the knee, ankle, and hip joints. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's upper limb. In some embodiments, the joint of the upper limb is selected from the patient's elbow, shoulder, wrist, and hand joints. In some embodiments, the patient is given a compound of formula (I) in crystalline dihydrate form in an amount sufficient to provide 30 mg of the compound of formula (I) twice weekly. In some embodiments, the compound is administered to the patient for 25, 35, or 45 weeks. In some embodiments, the compound is administered to the patient for 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 months. In some embodiments, the compound is administered to the patient for 1, 2, 3, or 4 years.

[0054] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) The patient achieved a partial or complete response after 25 weeks of administration of the compound, as determined by RECISTv1.1.

[0055] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) The patient achieved a partial or complete response after 25 weeks of administration of the compound, as determined by independent imaging review (IRR) based on tumor volume score (TVS).

[0056] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by the following to the patient twice a week: Formula (I) After 25 weeks of administration of the compound, the patient had an improved range of active movement compared to before administration of the compound.

[0057] In some implementations, after 25 weeks of administration of the compound, the patient achieves a change of at least 18% in active range of motion compared to before administration of the compound.

[0058] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After 25 weeks of administration of the compound, the patient achieved an increase in the PROMIS-PF score compared to before administration of the compound.

[0059] In some implementations, after 25 weeks of administration of the compound, the patient achieved a PROMIS-PF score that was at least 4 points higher than the patient's PROMIS-PF score before administration of the compound.

[0060] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After 25 weeks of administration of the compound, the patient achieved an increase in the score on the most severe stiffness numerical rating scale compared to before administration of the compound.

[0061] In some implementations, after 25 weeks of administration of the compound, the patient achieves a score of up to -2 on the Most Severe Rigidity Rating Scale compared to before administration of the compound.

[0062] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After 25 weeks of administration of the compound, the patient achieved an increase in the EQ-Visual Analog Scale (EQ-VAS) score compared to before administration of the compound.

[0063] In some implementations, after 25 weeks of administration of the compound, the patient achieves an EQ-VAS score that is at least 13 points higher than the patient's EQ-VAS score before administration of the compound.

[0064] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After 25 weeks of administration of the compound, the patient achieved a decrease of greater than or equal to 30% in the Short Form Pain Rating Scale (SNRS) score compared to before administration of the compound.

[0065] In some implementations, after 25 weeks of administration of the compound, the patient maintains an increase in anesthetic use of less than 30% compared to before the administration of the compound.

[0066] In some embodiments, the tenosynovial giant cell tumor is a diffuse tenosynovial giant cell tumor. In some embodiments, the tenosynovial giant cell tumor is a localized tenosynovial giant cell tumor. In some embodiments, the patient has previously undergone surgery to treat the tenosynovial giant cell tumor. In some embodiments, the patient has previously received systemic therapy for the treatment of the tenosynovial giant cell tumor. In some embodiments, the systemic therapy is selected from imatinib and nilotinib. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's lower limb. In some embodiments, the joint of the lower limb is selected from the knee, ankle, and hip joints. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's upper limb. In some embodiments, the joint of the upper limb is selected from the patient's elbow, shoulder, wrist, and hand joints. In some embodiments, the patient is administered a compound of formula (I) in crystalline dihydrate form in an amount sufficient to provide 30 mg of the compound of formula (I) twice weekly. In some embodiments, the patient is administered the compound for 25, 35, or 45 weeks. In some embodiments, the compound is administered to the patient for 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 months. In some embodiments, the compound is administered to the patient for 1, 2, 3, or 4 years.

[0067] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) The patient achieved a partial or complete response after 25 weeks of administration of the compound, as determined by RECIST v1.1.

[0068] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) The patient achieved a partial or complete response after 25 weeks of administration of the compound, as determined by independent imaging review (IRR) based on tumor volume score (TVS).

[0069] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by the following to the patient twice a week: Formula (I) Among them, after 25 weeks of administration of the compound to the patient, the patient had an improved range of active activity compared to before administration of the compound.

[0070] In some implementations, after 25 weeks of administration of the compound to the patient, the patient achieves a change of at least 18% in active range of motion compared to before administration of the compound.

[0071] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) Among them, after 25 weeks of administration of the compound to the patient, the patient achieved an increase in PROMIS-PF score compared to before administration of the compound.

[0072] In some implementations, after 25 weeks of administration of the compound to the patient, the patient achieves a PROMIS-PF score that is at least 4 points higher than the patient's PROMIS-PF score before administration of the compound.

[0073] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) Among them, after 25 weeks of administration of the compound to the patient, the patient achieved an increase in the score of the most severe stiffness numerical rating scale compared with before the administration of the compound.

[0074] In some implementations, after 25 weeks of administration of the compound to the patient, the patient achieves a score of up to -2 on the Most Severe Rigidity Rating Scale compared to before administration of the compound.

[0075] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After 25 weeks of administration of the compound to the patient, the patient achieved an increase in the EQ-Visual Analog Scale (EQ-VAS) score compared to before administration of the compound.

[0076] In some implementations, after 25 weeks of administration of the compound to the patient, the patient achieves an EQ-VAS score that is at least 13 points higher than the patient's EQ-VAS score before administration of the compound.

[0077] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After 25 weeks of administration of the compound to the patient, the patient achieved a reduction of greater than or equal to 30% in the Short Form Pain Rating Scale (SNRS) score compared to before administration of the compound.

[0078] In some implementations, after 25 weeks of administration of the compound to the patient, the patient maintains an increase in anesthetic use of less than 30% compared to before administration of the compound.

[0079] In some embodiments, the compound is administered to the patient twice a week (e.g., 30 mg twice a week, 20 mg twice a week, or 14 mg twice a week), wherein during the two-week period, the second administration of the compound to the patient is approximately two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen days after the first administration of the compound. In some embodiments, the compound is administered to the patient twice a week (e.g., 30 mg twice a week, 20 mg twice a week, or 14 mg twice a week), wherein during the two-week period, the second administration of the compound to the patient is approximately four days after the first administration of the compound. In some embodiments, the compound is administered to the patient twice a week (e.g., 30 mg twice a week, 20 mg twice a week, or 14 mg twice a week), wherein during the two-week period, the first administration of the compound to the patient is on day 1, the second administration of the compound to the patient is on day 5, the third administration of the compound to the patient is on day 8, and the fourth administration of the compound to the patient is on day 12.

[0080] In some embodiments, the tenosynovial giant cell tumor is a diffuse tenosynovial giant cell tumor. In some embodiments, the tenosynovial giant cell tumor is a localized tenosynovial giant cell tumor. In some embodiments, the patient has previously undergone surgery to treat the tenosynovial giant cell tumor. In some embodiments, the patient has previously received systemic therapy for the treatment of the tenosynovial giant cell tumor. In some embodiments, the systemic therapy is selected from imatinib and nilotinib. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's lower limb. In some embodiments, the joint of the lower limb is selected from the knee, ankle, and hip joints. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's upper limb. In some embodiments, the joint of the upper limb is selected from the patient's elbow, shoulder, wrist, and hand joints. In some embodiments, the patient is given a compound of formula (I) in crystalline dihydrate form in an amount sufficient to provide 30 mg of the compound of formula (I) twice a week.

[0081] As used herein and unless otherwise specified, when describing the crystalline form of a compound represented by formula (I), the term "substantially pure" means that the crystalline form of the compound's dihydrate is substantially free of other solid or amorphous forms. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) that is substantially pure. In some embodiments, unless otherwise specified, this application provides a crystalline dihydrate form of a compound represented by formula (I) that is substantially free of any other solid or amorphous forms. In some embodiments, the crystalline dihydrate form of a compound represented by formula (I) comprises more than about 80% by weight of the crystalline dihydrate form and less than about 20% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of a compound represented by formula (I) comprises more than about 90% by weight of the crystalline dihydrate form and less than about 10% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of the compound represented by formula (I) comprises more than about 95% by weight of the crystalline dihydrate form and less than about 5% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of the compound represented by formula (I) comprises more than about 97% by weight of the crystalline dihydrate form and less than about 3% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of the compound represented by formula (I) comprises more than about 98% by weight of the crystalline dihydrate form and less than about 2% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of the compound represented by formula (I) comprises more than about 99% by weight of the crystalline dihydrate form and less than about 1% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of the compound represented by formula (I) comprises more than about 99.5% by weight of the crystalline dihydrate form and less than about 0.5% by weight of other solid or amorphous forms of the compound represented by formula (I).

[0082] As used in this application, "substantially free of any other solid or amorphous forms" means that the solid form of the compound represented by formula (I) contains about 20% or less, about 10% or less, about 5% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less of other solid or amorphous forms of the compound represented by formula (I), as measured, for example by XRPD. Therefore, the statement that the dihydrate crystalline form of the compound represented by formula (I) described in this application is substantially free of any other solid or amorphous forms should be understood as containing more than 80% (w / w), more than 90% (w / w), more than 95% (w / w), more than 98% (w / w), about 99% or less, or more than 99.5% (w / w) of the dihydrate crystalline form of the compound represented by formula (I). Therefore, in some embodiments, the crystalline dihydrate form of the compound represented by formula (I) may contain 0.5% to 20% (w / w), 5% to 20% (w / w), or 5% to 10% (w / w) of one or more other solid or amorphous forms of the compound represented by formula (I).

[0083] In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 80% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 90% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 95% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 97% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 98% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 99% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 99.5% by weight.

[0084] In any of the methods described in this application, a giant cell tumor of the tendon sheath can affect (e.g., located within) one or more joints of a patient. Affected joints may include the elbow, knee, hip, hand, jaw, shoulder, wrist, and foot joints. In some embodiments, the methods described in this application can affect (e.g., located within) any joint.

[0085] In some embodiments, as described in the methods disclosed herein, a loading dose regimen of compound (I) is not administered to the patient before administering compound (I) to the patient. In some embodiments, as described in the methods disclosed herein, a loading dose regimen of compound (I) is not administered to the patient immediately before administering compound (I).

[0086] In one embodiment, this application describes a method for treating a patient with giant cell tumor of the tendon sheath who requires but is not suitable for surgical treatment, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application describes a method for treating a patient with giant cell tumor of the tenosynovium who requires but is not suitable for surgical treatment of the tenosynovium, comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week, wherein a loading dose regimen of the compound is not administered to the patient immediately prior to administration.

[0087] In some implementations, the patient is not a candidate for surgery. In some implementations, the patient is unsuitable for surgery (e.g., surgery to treat TGCT). In some implementations, the surgical procedure is considered high-risk. In some implementations, the patient has refused surgical treatment.

[0088] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) to the patient twice weekly, wherein after at least 25 weeks of administration of the compound, the patient achieves a partial or complete response, as determined by RECIST v1.1, and wherein a loading dose regimen of the compound is not administered to the patient immediately prior to administration.

[0089] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) twice weekly to the patient, wherein after at least 25 weeks of administration of the compound, the patient achieves a partial or complete response, as determined by independent imaging review (IRR) based on tumor volume score (TVS), and wherein a loading dose regimen is not administered to the patient immediately prior to administration of the compound.

[0090] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) to the patient twice a week, wherein after at least 25 weeks of administration of the compound, the patient has improved active range of motion compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately prior to administration of the compound.

[0091] In some implementations, after at least 25 weeks of administration of the compound, the patient achieves a change of at least 18% in active range of motion compared to before administration of the compound.

[0092] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) to the patient twice a week: wherein, after at least 25 weeks of administration of the compound, the patient achieves an increase in the PROMIS-PF score compared to before administration of the compound, and wherein, when administering the compound to the patient, a loading dose regimen is not administered immediately before administration.

[0093] In some implementations, after at least 25 weeks of administration of the compound, the patient achieves a PROMIS-PF score that is at least 4 points higher than the patient's PROMIS-PF score before administration of the compound.

[0094] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) to the patient twice weekly, wherein after at least 25 weeks of administration of the compound, the patient achieves an improvement in the score on the Most Severe Stiffness Numerical Rating Scale compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately prior to administration of the compound.

[0095] In some implementations, after at least 25 weeks of administration of the compound, the patient achieves a score of up to -2 on the Most Severe Rigidity Rating Scale compared to before administration of the compound.

[0096] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) to the patient twice a week, wherein after at least 25 weeks of administration of the compound, the patient achieves an increase in his / her EQ-VAS score compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately before administration of the compound.

[0097] In some implementations, after at least 25 weeks of administration of the compound, the patient achieves an EQ-VAS score that is at least 13 points higher than the patient's EQ-VAS score before administration of the compound.

[0098] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound represented by formula (I) twice weekly to the patient, wherein after at least 25 weeks of administration of the compound, the patient achieves a reduction of greater than or equal to 30% in the score on the Brief Pain Rating Scale (BAR) compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately prior to administration of the compound.

[0099] In some implementations, after at least 25 weeks of administration of the compound, the patient maintains an increase in anesthetic use of less than 30% compared to before the administration of the compound.

[0100] In another embodiment, this application provides a method for treating a patient with elevated creatine phosphokinase (CPK) levels, wherein the patient is administered 30 mg of a compound represented by formula (I) twice weekly during treatment for treatment of tenosynovial giant cell tumor: Formula (I) The method includes administering the compound to the patient twice a week at a dose of less than 30 mg, wherein a loading dose regimen is used to administer the compound to the patient without prior administration of the compound to the patient. In some embodiments, this application provides a method for treating a patient with elevated creatine phosphokinase (CPK) levels, the patient being administered 30 mg of a compound represented by formula (I) twice a week during treatment for treatment of tenosynovial giant cell tumor, the method comprising administering the compound to the patient twice a week at a dose of less than 30 mg, wherein a loading dose regimen is used to administer the compound to the patient without prior administration of the compound to the patient.

[0101] In some embodiments, the dosage is selected from 14 mg twice a week and 20 mg twice a week. In some embodiments, the dosage is 20 mg twice a week. In some embodiments, the dosage is 14 mg twice a week.

[0102] In some embodiments, the tenosynovial giant cell tumor is a diffuse tenosynovial giant cell tumor. In some embodiments, the tenosynovial giant cell tumor is a localized tenosynovial giant cell tumor. In some embodiments, the patient has previously undergone surgery to treat the tenosynovial giant cell tumor. In some embodiments, the patient has previously received systemic therapy for the treatment of the tenosynovial giant cell tumor. In some embodiments, the systemic therapy is selected from imatinib and nilotinib. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's lower limb. In some embodiments, the joint of the lower limb is selected from the knee, ankle, and hip joints. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's upper limb. In some embodiments, the joint of the upper limb is selected from the patient's elbow, shoulder, wrist, and hand joints. In some embodiments, the compound represented by formula (I) is administered to the patient in a crystalline dihydrate form in an amount sufficient to provide 30 mg of the compound represented by formula (I) twice weekly. In some embodiments, the compound is administered to the patient for 25, 35, or 45 weeks. In some embodiments, the compound is administered to the patient for 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 months. In some embodiments, the compound is administered to the patient for 1, 2, 3, or 4 years.

[0103] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) to the patient twice a week, wherein after 25 weeks of administration of the compound, the patient achieves a partial or complete response, as determined by RECIST v1.1, and wherein a loading dose regimen of the compound is not administered to the patient immediately prior to administration.

[0104] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) twice weekly to the patient, wherein after 25 weeks of administration of the compound, the patient achieves a partial or complete response, as determined by independent imaging review (IRR) based on tumor volume score (TVS), and wherein a loading dose regimen is not administered to the patient immediately prior to administration of the compound.

[0105] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by the following to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) to the patient twice a week, wherein after 25 weeks of administration of the compound, the patient has improved active range of motion compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately prior to administration of the compound.

[0106] In some implementations, after 25 weeks of administration of the compound, the patient achieves a change of at least 18% in active range of motion compared to before administration of the compound.

[0107] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) twice weekly to the patient, wherein after 25 weeks of administration of the compound, the patient achieves an increase in the PROMIS-PF score compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately before administration of the compound.

[0108] In some implementations, after 25 weeks of administration of the compound, the patient achieved a PROMIS-PF score that was at least 4 points higher than the patient's PROMIS-PF score before administration of the compound.

[0109] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) twice weekly to the patient, wherein after 25 weeks of administration of the compound, the patient achieves an improvement in the score on the Most Severe Stiffness Numerical Rating Scale compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately prior to administration of the compound.

[0110] In some implementations, after 25 weeks of administration of the compound, the patient achieves a score of up to -2 on the Most Severe Rigidity Rating Scale compared to before administration of the compound.

[0111] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) twice weekly to the patient, wherein after 25 weeks of administration of the compound, the patient achieves an increase in the EQ-VAS score compared to before administration of the compound, and wherein a loading dose regimen is used when administering the compound to the patient, not immediately prior to administration.

[0112] In some implementations, after 25 weeks of administration of the compound, the patient achieves an EQ-VAS score that is at least 13 points higher than the patient's EQ-VAS score before administration of the compound.

[0113] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound represented by formula (I) twice weekly to the patient, wherein after 25 weeks of administration of the compound, the patient achieves a reduction of greater than or equal to 30% in the score on the Brief Pain Rating Scale (BAR) compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately prior to administration of the compound.

[0114] In some implementations, after 25 weeks of administration of the compound, the patient maintains an increase in anesthetic use of less than 30% compared to before the administration of the compound.

[0115] In some embodiments, the dosage is selected from 14 mg twice a week and 20 mg twice a week. In some embodiments, the dosage is 20 mg twice a week. In some embodiments, the dosage is 14 mg twice a week.

[0116] Patients receiving compound (I) may or may not receive another active ingredient (e.g., a breast cancer resistance protein (BCRP) substrate or a P-glycoprotein (P-gp) substrate) to treat additional medical conditions. In some embodiments, the additional medical conditions are selected from the following: hypercholesterolemia, diabetes (e.g., diabetes mellitus), hypertension, deep vein thrombosis, and depression. In some embodiments, the breast cancer resistance protein (BCRP) substrate is not administered to the patient at the time of administration of compound (I). In some embodiments, the breast cancer resistance protein (BCRP) substrate is not administered to the patient prior to administration of compound (I). In some embodiments, the breast cancer resistance protein (BCRP) substrate is not administered to the patient within four hours of administration of compound (I). In some embodiments, the BCRP substrate is selected from the group consisting of: statins, sulfonylureas (e.g., glyburide), tyrosine kinase inhibitors, and anticoagulants. In some embodiments, the P-glycoprotein (P-gp) substrate is not administered to the patient at the time of administration of compound (I). In some embodiments, the P-glycoprotein (P-gp) substrate is not administered to the patient before administration of compound (I). In some embodiments, the P-glycoprotein (P-gp) substrate is not administered to the patient within two hours of administration of compound (I). In some embodiments, the P-gp substrate is selected from the group consisting of: antihypertensive drugs (e.g., calcium channel blockers or angiotensin II receptor blockers (ARBs)), antiviral drugs, and tricyclic antidepressants.

[0117] In some embodiments, the tenosynovial giant cell tumor is a diffuse tenosynovial giant cell tumor. In some embodiments, the tenosynovial giant cell tumor is a localized tenosynovial giant cell tumor. In some embodiments, the patient has previously undergone surgery to treat the tenosynovial giant cell tumor. In some embodiments, the patient has previously received systemic therapy for the treatment of the tenosynovial giant cell tumor. In some embodiments, the systemic therapy is selected from imatinib and nilotinib. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's lower limb. In some embodiments, the joint of the lower limb is selected from the knee, ankle, and hip joints. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's upper limb. In some embodiments, the joint of the upper limb is selected from the patient's elbow, shoulder, wrist, and hand joints. In some embodiments, the compound represented by formula (I) is administered to the patient in a crystalline dihydrate form in an amount sufficient to provide 30 mg of the compound represented by formula (I) twice weekly. In some embodiments, the compound is administered to the patient for 25, 35, or 45 weeks. In some embodiments, the compound is administered to the patient for 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 months. In some embodiments, the compound is administered to the patient for 1, 2, 3, or 4 years.

[0118] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) to the patient twice a week, wherein after 25 weeks of administration of the compound, the patient achieves a partial or complete response, as determined by RECIST v1.1, and wherein a loading dose regimen of the compound is not administered to the patient immediately prior to administration.

[0119] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) twice weekly to the patient, wherein after 25 weeks of administration of the compound, the patient achieves a partial or complete response, as determined by independent imaging review (IRR) based on tumor volume score (TVS), and wherein a loading dose regimen is not administered to the patient immediately prior to administration of the compound.

[0120] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) to the patient twice a week, wherein after 25 weeks of administration of the compound, the patient has improved active range of motion compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately prior to administration of the compound.

[0121] In some implementations, after 25 weeks of administration of the compound to the patient, the patient achieves a change of at least 18% in active range of motion compared to before administration of the compound.

[0122] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) twice weekly to the patient, wherein after 25 weeks of administration of the compound, the patient achieves an increase in their PROMIS-PF score compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately prior to administration of the compound.

[0123] In some implementations, after 25 weeks of administration of the compound to the patient, the patient achieves a PROMIS-PF score that is at least 4 points higher than the patient's PROMIS-PF score before administration of the compound.

[0124] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound of formula (I) twice weekly to the patient, wherein after 25 weeks of administration of the compound, the patient achieves an improvement in the score on the Most Severe Stiffness Numerical Rating Scale compared to before administration of the compound, and wherein a loading dose regimen is used when administering the compound to the patient, without immediately prior to administration.

[0125] In some implementations, after 25 weeks of administration of the compound to the patient, the patient achieves a score of up to -2 on the Most Severe Rigidity Rating Scale compared to before administration of the compound.

[0126] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week, wherein after 25 weeks of administration of the compound, the patient achieves an increase in their EQ-VAS score compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately before administration of the compound.

[0127] In some implementations, after 25 weeks of administration of the compound to the patient, the patient achieves an EQ-VAS score that is at least 13 points higher than the patient's EQ-VAS score before administration of the compound.

[0128] In another embodiment, this application provides a method for treating a patient with tenosynovial giant cell tumor, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) In some embodiments, this application provides a method for treating a patient with tenosynovial giant cell tumor, comprising administering 30 mg of a compound represented by formula (I) twice weekly to the patient, wherein after 25 weeks of administration of the compound, the patient achieves a reduction of greater than or equal to 30% in the score on the Brief Pain Rating Scale (BAR) compared to before administration of the compound, and wherein a loading dose regimen is not administered to the patient immediately before administration of the compound.

[0129] In some implementations, after 25 weeks of administration of the compound to the patient, the patient maintains an increase in anesthetic use of less than 30% compared to before administration of the compound.

[0130] In some embodiments, the dosage is selected from 14 mg twice a week and 20 mg twice a week. In some embodiments, the dosage is 20 mg twice a week. In some embodiments, the dosage is 14 mg twice a week.

[0131] In some embodiments, the compound is administered to the patient twice a week (e.g., 30 mg twice a week, 20 mg twice a week, or 14 mg twice a week), wherein during the two-week period, the second administration of the compound to the patient is approximately two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen days after the first administration of the compound. In some embodiments, the compound is administered to the patient twice a week (e.g., 30 mg twice a week, 20 mg twice a week, or 14 mg twice a week), wherein during the two-week period, the second administration of the compound to the patient is approximately four days after the first administration of the compound. In some implementations, the compound is administered to the patient twice a week (e.g., 30 mg twice a week, 20 mg twice a week, or 14 mg twice a week), wherein during the two-week period, the first administration of the compound to the patient is on day 1, the second administration of the compound to the patient is on day 5, the third administration of the compound to the patient is on day 8, and the fourth administration of the compound to the patient is on day 12.

[0132] In some embodiments, the tenosynovial giant cell tumor is a diffuse tenosynovial giant cell tumor. In some embodiments, the tenosynovial giant cell tumor is a localized tenosynovial giant cell tumor. In some embodiments, the patient has previously undergone surgery to treat the tenosynovial giant cell tumor. In some embodiments, the patient has previously received systemic therapy for the treatment of the tenosynovial giant cell tumor. In some embodiments, the systemic therapy is selected from imatinib and nilotinib. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's lower limb. In some embodiments, the joint of the lower limb is selected from the knee, ankle, and hip joints. In some embodiments, the tenosynovial giant cell tumor is located in a joint of the patient's upper limb. In some embodiments, the joint of the upper limb is selected from the patient's elbow, shoulder, wrist, and hand joints. In some embodiments, the compound represented by formula (I) is administered to the patient in a crystalline dihydrate form in an amount sufficient to provide 30 mg of the compound represented by formula (I) twice weekly.

[0133] As used herein and unless otherwise specified, when describing the crystalline form of a compound represented by formula (I), the term "substantially pure" means that the crystalline form of the compound's dihydrate is substantially free of other solid or amorphous forms. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) that is substantially pure. In some embodiments, unless otherwise specified, this application provides a crystalline dihydrate form of a compound represented by formula (I) that is substantially free of any other solid or amorphous forms. In some embodiments, the crystalline dihydrate form of a compound represented by formula (I) comprises more than about 80% by weight of the crystalline dihydrate form and less than about 20% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of a compound represented by formula (I) comprises more than about 90% by weight of the crystalline dihydrate form and less than about 10% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of the compound represented by formula (I) comprises more than about 95% by weight of the crystalline dihydrate form and less than about 5% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of the compound represented by formula (I) comprises more than about 97% by weight of the crystalline dihydrate form and less than about 3% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of the compound represented by formula (I) comprises more than about 98% by weight of the crystalline dihydrate form and less than about 2% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of the compound represented by formula (I) comprises more than about 99% by weight of the crystalline dihydrate form and less than about 1% by weight of other solid or amorphous forms of the compound represented by formula (I). In some embodiments, the crystalline dihydrate form of the compound represented by formula (I) comprises more than about 99.5% by weight of the crystalline dihydrate form and less than about 0.5% by weight of other solid or amorphous forms of the compound represented by formula (I).

[0134] As used in this application, "substantially free of any other solid or amorphous form" means that the solid form of the compound represented by formula (I) contains about 20% or less, about 10% or less, about 5% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less of any other solid or amorphous form of the compound represented by formula (I), as measured, for example by XRPD. Therefore, "substantially free of any other solid or amorphous form" as described in this application for the dihydrate crystalline form of the compound represented by formula (I) should be understood to contain more than 80% (w / w), more than 90% (w / w), more than 95% (w / w), more than 98% (w / w), about 99% or less, or more than 99.5% (w / w) of the crystalline form of the compound represented by formula (I) in dihydrate form. Therefore, in some embodiments, the crystalline dihydrate form of the compound represented by formula (I) may contain 0.5% to 20% (w / w), 5% to 20% (w / w), or 5% to 10% (w / w) of one or more other solid or amorphous forms of the compound represented by formula (I).

[0135] In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 80% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 90% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 95% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 97% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 98% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 99% by weight. In some embodiments, this application provides a crystalline dihydrate form of a compound represented by formula (I) with a purity greater than 99.5% by weight.

[0136] In any of the methods described herein, a giant cell tumor of the tendon sheath may affect (e.g., located within) one or more joints of a patient. Affected joints may include the elbow, knee, hip, hand, jaw, shoulder, wrist, and foot joints. In some embodiments, the methods described herein may affect (e.g., located within) any joint.

[0137] Dosage interruption and adjustment Due to adverse events experienced by the patient, dose adjustments may be made in the method of administering the compound represented by formula (I) as described in this application. In some embodiments, the dose adjustment is a dose interruption. In some embodiments, the dose adjustment is a permanent cessation of administration. In some embodiments, the dose adjustment is a dose reduction. In some embodiments, the dose of the compound represented by formula (I) administered to the patient is reduced from 30 mg twice a week (e.g., a capsule containing 30 mg of the anhydrous form of the compound represented by formula (I), or, for example, a capsule containing 32.5 mg of the crystalline dihydrate form of the compound represented by formula (I)) to 20 mg twice a week (e.g., a capsule containing 20 mg of the anhydrous form of the compound represented by formula (I), or, for example, a capsule containing 21.7 mg of the crystalline dihydrate form of the compound represented by formula (I)). In some embodiments, the dose of the compound represented by formula (I) administered to the patient is reduced from 30 mg twice a week (e.g., a capsule containing 30 mg of the anhydrous form of the compound represented by formula (I), or a capsule containing 32.5 mg of the crystalline dihydrate form of the compound represented by formula (I)) to 14 mg twice a week (e.g., a capsule containing 14 mg of the anhydrous form of the compound represented by formula (I), or a capsule containing 15.2 mg of the crystalline dihydrate form of the compound represented by formula (I)). In some embodiments, the dose of the compound represented by formula (I) administered to the patient is reduced from 20 mg twice weekly (e.g., a capsule containing 20 mg of the anhydrous form of the compound represented by formula (I), or a capsule containing 21.7 mg of the crystalline dihydrate form of the compound represented by formula (I)) to 14 mg twice weekly (e.g., a capsule containing 14 mg of the anhydrous form of the compound represented by formula (I), or a capsule containing 15.2 mg of the crystalline dihydrate form of the compound represented by formula (I)). In some embodiments, adverse reactions are selected from the group consisting of hepatobiliary elevation and treatment-related skin or subcutaneous conditions. In some embodiments, treatment-related skin or subcutaneous conditions are selected from the group consisting of maculopapular rash, pruritus, urticaria, eczema, and dry skin.

[0138] According to the method described in this application, additional treatment may also be administered to the patient before or during the application of a compound represented by formula (I) to prevent or improve adverse events. In some embodiments, a topical composition (e.g., an emollient) is applied to the patient before and / or during the application of a compound represented by formula (I) to prevent or alleviate adverse skin reactions.

[0139] Example Example 1. A phase III, randomized, placebo-controlled, double-blind study of vecetinib in patients with TGCT. This study is a two-part, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of vectinib in patients with TGCT who are ineligible for surgery and have not received prior anti-CSF1 / CSF1R therapy (previous therapy with imatinib or nilotinib is permitted). In Part 1, patients (n=123) were randomized 2:1 to receive either vectinib (n=83) or placebo (n=40) twice weekly for 24 weeks. Vectinib or the matched placebo was administered orally on an empty stomach at approximately the same time on days 1 and 5 (±1 day) each week, with an interval of ≥24 hours between doses. MRI of the affected joints was performed at screening, on day 1 of cycle 4 (week 13, ±7 day), and at the end of Part 1. Part 2 is an ongoing open-label study in which patients in both the vectinib and placebo groups received vectinib.

[0140] The primary endpoint of this study was the objective response rate (ORR) at week 25, measured by blinded independent imaging review (IRR) according to the Responsive Evaluation Criteria for Solid Tumor Response (RECIST) version 1.1. Key secondary endpoints included: objective response rate at week 25 stratified by tumor volume score (TVS) and determined by IRR; active range of motion (ROM) at week 25; PROMIS Physical Function (PROMIS-PF) score; maximum severity numerical rating scale (NRS) score at week 25; EQ-Visual Analogue Scale (EQ-VAS) score at week 25; and a reduction of ≥30% in the Brief Pain Scale (BPI) for maximum severity pain at week 25; and an increase in anesthetic use of less than 30% (BPI-30). Other secondary endpoints included duration of response (DOR) and safety.

[0141] Qualification Criteria Eligible patients are ≥18 years of age and have a histologically confirmed diagnosis of TGCT, where surgical resection would potentially lead to increased functional limitation or serious complications. Patients have at least one measurable lesion ≥2 cm, assessed by a central radiologist using the Responsive Criteria for Solid Tumor Response (RECIST) version 1.1 based on magnetic resonance imaging (MRI).

[0142] Patients who have previously received systemic therapy targeting CSF1 or CSF1R (including vecetinib) are excluded; however, patients who have previously received imatinib and / or nilotinib are permitted. Patients who have also received any TGCT therapy (including investigational therapy) during the screening period, have undergone major surgery within ≤14 days prior to the first dose of the investigational drug, or have participated in a non-TGCT investigational drug study within 30 days of screening are also excluded.

[0143] The demographic and baseline disease characteristics of the ITT population are provided in Table 1 below.

[0144] Table 1

[0145] Endpoint Analysis This study met its primary endpoint in the intention-to-treat (ITT) population, demonstrating a statistically significant and clinically meaningful improvement in the primary endpoint of ORR at week 25, as determined by IRR according to RECIST 1.1. In the ITT population, the ORR at week 25 was 40% (95% CI: 29%, 51%) in the vecetinib group and 0% (95% CI: 0%, 9%) in the placebo group, resulting in a 40% (95% CI: 29%, 51%) difference in response (vecetinib vs. placebo) (p<0.0001). Furthermore, the median duration of response was not reached, with vecetinib ranging from (0.03+, 11.7+) months. Figure 1 Almost all patients receiving vecetinib experienced clinical benefit (CR+PR+SD), as shown in Figure 7A as the percentage of best change in target lesions assessed by IRR. Figure 7B shows that all groups were predisposed to vecetinib treatment when ORR was assessed by demographic characteristics. The analysis of the primary endpoint provided in Table 2 shows that the ORR of vecetinib at week 25, as determined by IRR according to RECIST v1.1, was statistically significantly higher than that of placebo (40% vs. 0%, 40% difference [95% CI: 29%, 51%], bilateral p<0.0001).

[0146] Table 2

[0147] Tumor volume score The Tumor Volume Score (TVS) is a semi-quantitative magnetic resonance imaging scoring system that describes tumor quality. It is based on an estimated 10% increase in volume when the affected synovial cavity or tendon sheath is at its maximum expansion. The score ranges from 0 to 10, with a score of 10 indicating a tumor if the volume equals the volume of the maximally expanded synovial cavity or tendon sheath; a score of 0 indicates no tumor.

[0148] A complete response indicates the disappearance of all tumor tissue. A partial response is defined as a reduction in TVS of at least 50% relative to baseline. Progressive disease is defined as an increase in TVS of at least 30% relative to baseline. Using the lowest value (nadir) as a reference, stable disease is defined as a reduction insufficient to meet the criteria for a partial response, or an increase insufficient to meet the criteria for progressive disease. If TVS cannot be assessed due to reasons such as insufficient or missing imaging, the response is considered unmeasurable.

[0149] Vescitinib demonstrated a statistically significant and clinically meaningful improvement in ORR at week 25, as determined by IRR based on TVS. In the ITT population, the ORR of vescitinib at week 25, as determined by IRR based on TVS, was statistically significantly higher than that of placebo (67% vs. 0%, 67% [95% CI: 56%, 77%], bilateral p < 0.0001). The median duration of response was not reached, with vescitinib ranging from (0.03+, 13.9+) months. Figure 2 The analysis of this endpoint is provided in Table 3.

[0150] Table 3

[0151] Active activity range calculation value Active range of motion (ROM; in degrees) was assessed using a goniometer and normalized using reference standards provided by the American Medical Association to calculate relative active ROM. For joints with more than one movement measured, the range of motion with the smallest (most severe) relative ROM value was used as the baseline when assessing subsequent changes in relative active joint range of motion.

[0152] Vecitinib demonstrated a statistically significant and clinically meaningful improvement in the mean change in active ROM relative to baseline (CFB) at week 25 (18.4% vs. 3.8%, a difference of 14.6% [95% CI: 4.0%, 25.3%], bilateral p = 0.0077). Figure 3 The CFB of active ROM was presented. The analysis of this endpoint is provided in Table 4. Changes relative to baseline were modeled using the fixed effects of treatment group, time point, treatment group-time point interaction, region (US vs. non-US), joint type (knee, ankle, or other joints), and baseline ROM.

[0153] Table 4

[0154] The response rate for active ROM at week 25 was 48% (N=79) for vecetinib and 20% (N=38) for placebo (difference 28% [95% CI: 12%, 45%], p=0.0025).

[0155] Vecitinib demonstrated a statistically significant and clinically meaningful improvement in mean CFB at PROMIS-PF at week 25 (4.6 vs. 1.3, a difference of 3.3 [95% CI: 1.4, 5.2], bilateral p = 0.0007). Figure 4 The CFB of PROMIS-PF is presented. The analysis of this endpoint is provided in Table 5. Changes relative to baseline were modeled using fixed effects of treatment group, time point, treatment group-time point interaction, region (US vs. non-US), tumor location (lower extremities vs. all other locations), and baseline PROMIS-PF.

[0156] Table 5

[0157] At week 25, the response rate of vecetinib to PROMIS-PF was 43% (N=79), compared to 25% (N=38) for placebo (difference of 18% [95% CI: 1%, 36%], p=0.046).

[0158] Vecitinib demonstrated a statistically significant and clinically meaningful improvement in mean CFB of the most severe rigid NRS at week 25 (-2.1 vs. -0.3, difference -1.8 [95% CI: -2.5, -1.1], bilateral p=0.0001). Figure 5 CFB was observed for the most severe rigid NRS. Analysis of this endpoint is provided in Table 6. Changes relative to baseline were modeled using fixed effects of treatment group, time point, treatment group-time point interaction, region (US vs. non-US), tumor location (lower extremities vs. all other locations), and the most severe rigid NRS at baseline.

[0159] Table 6

[0160] The response rate to the most severe rigid NRS at week 25 was 39% (N=79) with vectinib, compared to 15% (N=38) with placebo (difference 24% [95% CI: 8%, 39%], p=0.0080).

[0161] Vecitinib demonstrated a statistically significant and clinically meaningful improvement in mean CFB of EQ-VAS at week 25 (13.5 vs. 6.1, a difference of 7.4 [95% CI: 1.4, 13.4], bilateral p = 0.0155). Figure 6 CFB is presented for EQ-VAS scores. Analysis of this endpoint is provided in Table 7. Changes relative to baseline were modeled using fixed effects of treatment group, time point, treatment group-time point interaction, region (US vs. non-US), tumor location (lower extremities vs. all other locations), and baseline EQ-VAS.

[0162] Table 7

[0163] The response rate of vectinib at week 25 was 37% (N=79), compared with 25% (N=38) for placebo (difference of 12% [95% CI: -5%, 29%], p=0.16).

[0164] Vecitinib demonstrated a statistically significant and clinically meaningful improvement in the BPI-30 response rate for most severe pain at week 25 (48% vs. 23%, a difference of 26% [95% CI: 4%, 42%], bilateral p = 0.0056). Analysis of this endpoint is provided in Table 8.

[0165] Table 8

[0166] *Stratification was performed based on stratification factors of IRT. BPI: Brief Pain Scale; BPI-30 response for most severe pain: a reduction of ≥30% in the BPI most severe pain NRS and an increase of <30% in anesthetic use; CMH: Cochran-Mantel-Haenszel.

[0167] The response rate for vectinib to the most severe pain at week 25 was 48% (N=79), compared to 23% (N=38) for placebo (difference 26% [95% CI: 4%, 42%], p=0.0056).

[0168] Figure 8This presentation shows the percentage of patients experiencing functional and symptomatic improvements in active ROM, PROMIS-PF, most severe stiffness NRS, and BPI most severe pain response, calculated by treatment and REICST v1.1 tumor response. Changes relative to baseline for PROMIS-PF, most severe stiffness NRS, and EQ-VAS responses were ≥3, ≤-2, and ≥7, respectively. BPI most severe pain response was defined as a reduction in most severe pain of ≥30% without an increase in narcotic analgesic use of ≥30%. (CR, Complete Response; BPI, Brief Pain Scale; NRS, Numerical Rating Scale; PR, Partial Response; PRO, Patient-Reported Outcome; PROMIS-PF; PRO Measurement Information System for Physical Function; RECIST v1.1, Standards for Evaluation of Solid Tumor Response version 1.1; ROM; Range of Activity; SD, Stable Disease; TGCT, Giant Cell Tumor of Tenosynovitis). Symptomatic improvements were observed in patients receiving vecetinib who had an objective tumor response or stable disease (SD) according to RECIST v1.1. Compared with placebo, more patients using vecetinib experienced improvements across multiple measures.

[0169] Security Vecitinib was well tolerated, and the safety profile in the study was consistent with previously published data. No evidence of cholestatic hepatotoxicity was found in patients treated with vecitinib. In the vecitinib group, 5% of patients experienced treatment-interventional adverse events (TEAEs) leading to treatment discontinuation. The table below lists TEAEs greater than 15% in either group during Part 1 of the study. Table 9 summarizes the safety data from the study.

[0170] Table 9

[0171] (1) The safety cohort consisted of 122 patients. One patient was randomized to the placebo group but did not receive the study drug. ^ indicates no adverse events (AEs) according to CTCAE v5.0 criteria.

[0172] In addition, no more than one patient experienced a serious adverse event (SAE). One subcutaneous abscess-related SAE was observed. Furthermore, grade 3 / 4 TEAEs with an incidence greater than 5% were observed for increased creatine phosphokinase (CPK) (10%).

[0173] The updated results after 6 months showed a sustained tumor response to vectinib and a safety profile consistent with previous reports.

[0174] Example 2. Results from a Phase 1 / 2 study of vecetinib in the TGCT This is a phase I / II open-label, multicenter study evaluating the safety and efficacy of vecetinib in patients with TGCT. In phase I, 32 patients were assigned to three cohorts at various doses. In phase II, 66 patients were assigned to two cohorts at the recommended phase 2 dose of 30 mg twice weekly: Cohort A (n=46) consisted of TGCT patients who had not previously received anti-CSF1 / CSF1R therapy (previous therapy with imatinib or nilotinib was permitted); Cohort B (n=20) consisted of TGCT patients who had previously received anti-CSF1 / CSF1R therapy (patients who had received only imatinib or nilotinib monotherapy were ineligible for inclusion).

[0175] Regarding antitumor activity and duration of treatment, efficacy was assessed in 93 patients using RECIST version 1.1 at the data cutoff date. Table 10 presents response data based on IRR.

[0176] Table 10

[0177] NR: Not met In addition, updated data from cohorts A and B of the phase II study showed that patients experienced clinically meaningful symptomatic benefits at week 25, including multiple secondary efficacy measures based on the ORR (cohort A) of TVS, active range of motion, physical function, stiffness, and pain.

[0178] Regarding safety and tolerability, treatment with vecetinib was well tolerated in patients with TGCT, consistent with previously published data, with no evidence of cholestatic hepatotoxicity, and treatment discontinuation due to TEAE occurred in 9% of patients.

[0179] Longer follow-up showed that vectinib was consistently well-tolerated and had a manageable safety profile in TGCT patients who received or did not receive prior anti-CSF1 / CSF1R therapy and were ineligible for surgery. Table 11 presents response data for cohorts A and B at the second cutoff date based on IRR.

[0180] Table 11

[0181] NR: Not met As of the second data cutoff, patients showed no progression, as assessed by IRR. Furthermore, most patients in cohort B experienced an increase in active ROM at the second data cutoff, as shown in Table 12 below. In Table 12, the analysis only included patients with active ROM assessment at baseline and week 25.

[0182] Table 12

[0183] Furthermore, most patients in cohort A experienced an increase in active ROM, with a mean change (standard deviation [SD]) of 19.7 (43.5) percentage points from baseline at week 25. Figure 9A depicts the majority of patients in cohort A experiencing an increase in active ROM, with a mean change (standard deviation [SD]) of 19.7 (43.5) percentage points from baseline at week 25.

[0184] Patient-reported outcomes (cohort B) Patient-reported outcomes were obtained for patients in Cohort B who received vectinib at week 25. At week 25, 55% (11 / 20) of patients experienced a BPI response (defined as a pain reduction of ≥30% without an increase in the use of narcotic analgesics of ≥30%) for both most severe pain and average pain. Two patients (40%) who had an objective response according to RECIST v 1.1 at week 25 were also BPI responders. The majority of patients with stable disease at week 25 (78%) were also BPI responders, including those with both BPI and efficacy data available at week 25 (n=14), where the percentage represents the proportion of patients with stable disease who had a partial response or a pain reduction of ≥30%.

[0185] At week 25, 63% and 58% of patients had clinically meaningful improvements in the PROMIS-PF and NRS (Numerical Rating Scale for Stiffness), respectively.

[0186] In addition, Table 13 presents a summary of the clinical outcome assessments at week 25 of the aforementioned second cutoff date: Table 13

[0187] a This includes patients with active ROM values ​​at baseline and at week 25.

[0188] b A response was defined as an increase of at least 10% at week 25.

[0189] c This includes patients with PROMIS-PF values ​​at baseline and at week 25.

[0190] d A response was defined as an increase of at least 3 points at week 25.

[0191] e This includes patients with the most severe stiffness NRS values ​​at baseline and at week 25.

[0192] fA response was defined as a reduction of at least 2 points at week 25.

[0193] g A response is defined as a 30% or greater reduction in the mean BPI of the most severe pain, without an increase of 30% or greater in the use of narcotic analgesics.

[0194] Abbreviations: BPI (Brief Pain Inventory); NRS (Numerical Rating Scale); PROMIS-PF (Patient Reported Outcomes Measurement Information System for Physical Function); ROM (Range of Activity); SD (Standard Deviation).

[0195] Table 14 below shows the results of the most severe pain at week 25 according to the BPI of objective response based on RECIST v1.1.

[0196] Table 14

[0197] a This included patients with both BPI and efficacy data available at week 25 (n = 39).

[0198] b This included patients with both BPI and efficacy data available at week 25 (n = 14).

[0199] c A response is defined as a pain reduction of ≥30% without an increase of ≥30% in the use of narcotic analgesics.

[0200] Abbreviations: BPI, Brief Pain Scale; IRR, Independent Radiological Review; RECIST v1.1, Evaluation Criteria for Response in Solid Tumors, version 1.1.

[0201] Table 15 below shows the results of the most severe rigid NRS response at week 25 according to RECIST v1.1 based on objective response.

[0202] Table 15

[0203] a This included patients with both BPI and efficacy data available at week 25 (n = 39).

[0204] b This included patients with both BPI and efficacy data available at week 25 (n = 14).

[0205] c A response is defined as a pain reduction of ≥30% without an increase of ≥30% in the use of narcotic analgesics.

[0206] Abbreviations: BPI, Brief Pain Scale; IRR, Independent Radiological Review; RECIST v1.1, Evaluation Criteria for Response in Solid Tumors, version 1.1.

[0207] Most TEAEs were grade 1 or 2 (Table 2). In cohort A, grade 3 / 4 TEAEs in >5% of patients were increased blood creatine phosphokinase (CPK, 48%) and hypertension (9%); in cohort B, these TEAEs were increased blood CPK (35%), hypertension (15%), and eczema (10%). No evidence of cholestatic hepatotoxicity or drug-induced liver injury was found. The median (range) duration of treatment in cohort A was 22.2 (0.2–36.6) months, and in cohort B it was 11.1 (0.7–36.1) months. The safety profile was consistent with continuous treatment; most serious events occurred within the first 12 months of treatment, such as through... Figure 10 As shown.

[0208] Example 3. Dosage interruption and adjustment of vecetinib This is the dose interruption and adjustment protocol in a Phase III, randomized, placebo-controlled, double-blind study of vecetinib to evaluate its efficacy and safety in patients with tenosynovial giant cell tumors. Vecetinib administration may be interrupted and / or adjusted at any time at the investigator's discretion due to adverse events (AEs). Vecetinib may also be interrupted for other reasons in consultation with the sponsoring medical monitor. Any vecetinib interruption unrelated to AEs will be limited to 28 days. After resuming vecetinib following a dose interruption, the investigator must continue the original visit schedule for participants calculated based on Day 1 of Cycle 1. Clinical visits and assessments should continue during the dose interruption period.

[0209] Severity assessment Researchers must determine and document the severity of all serious and non-serious adverse events (AEs). The severity of AEs must be graded using NCI-CTCAE v5.0 (NCI-CTCAE, 2020). New AEs should be reported when the severity of an existing adverse event changes (including improvement or worsening of the event).

[0210] The severity of adverse events (AEs) not appearing on the CTCAE scale must be determined according to Table 16.

[0211] Table 16. Severity Grading Scale

[0212] Abbreviation: AE = Adverse Event Dosage interruption and adjustment For any duration of treatment-related grade 3 adverse events (AEs), vectinib must be discontinued, except for the following: asymptomatic / non-clinically significant grade ≥3 CPK elevation without myalgia, worsening renal function, rhabdomyolysis, or signs of myocardial injury (e.g., myoglobinuria, CPK isoenzyme profile, troponin), and no additional evaluation / testing is required; treatment-related grade 3 nausea, vomiting, and diarrhea that resolve to grade 1 or baseline within 2 days of optimal treatment; treatment-related transient grade 3 fatigue (lasting less than 3 days); treatment-related transient (lasting less than 3 days) >3 laboratory abnormalities that can be resolved with optimal supplementation or support.

[0213] For treatment-related Grade 3 adverse events that lead to dose interruption, unless otherwise stated in the management table, vectinib may be resumed at the same dose when the toxicity returns to Grade 1 or baseline, or at the investigator’s discretion to reduce the dose.

[0214] For all other treatment-related adverse events (AEs) that lead to dose interruption, unless otherwise stated in the administration table, vectinib can be resumed at the same dose.

[0215] For participants with treatment-related Grade 4 adverse events (AEs), vecetinib will be permanently discontinued, except for transient laboratory abnormalities and Grade 4 neutropenia lasting 7 days or less as described above. If the investigator and sponsor deem continued treatment with vecetinib to be in the best interest of the participant, the vecetinib dose will be reduced by at least one dose level upon resumption of treatment after one or more of the relevant toxicities have returned to Grade 1 or to baseline.

[0216] Dose reduction steps If a dose reduction is required, the dose reduction steps are described in Table 17.

[0217] Table 17. Dosage reduction steps for vecetinib and vecetinib dihydrate

[0218] If a dose reduction of vecetinib is required, the dose may be reincreased based on an agreement between the investigator and the sponsor.

[0219] Participants will be allowed to reduce their dose by two levels. If a reduction of more than two dose levels is required, vectinib will be discontinued.

[0220] Toxicity, Dose Interruption and Management Guidelines for elevated levels in liver and gallbladder laboratories Recommended dose interruptions and management of treatment-related hepatobiliary laboratory elevations are shown in Table 18.

[0221] Table 18. Dose interruption and management of treatment-related hepatobiliary laboratory elevations

[0222] Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Standard for Adverse Events; INR = International Normalized Ratio; ULN = Upper Limit of Normal Value.

[0223] Note: Cases conforming to Hay's Law must be reported as serious adverse events, and vecetinib must be discontinued immediately.

[0224] Guidelines for extending QTcF intervals Table 19 provides recommended dose interruptions and management for treatment-related extended QTcF intervals.

[0225] Table 19. Recommended dose interruptions and management of treatment-related prolongation of QTcF intervals

[0226] Abbreviations: CTCAE = Common Terminology Standard for Adverse Events; ECG = Electrocardiogram; QTc = Corrected QT interval; QTcF = QT interval corrected according to Fridericia formula.

[0227] Guidelines for Adverse Events in Dermatology Recommended dose interruption and management for treatment of related skin and subcutaneous conditions, as well as recommendations for the management of dry skin, are presented in Table 20.

[0228] General guidelines for treatment-related dermatological adverse events: Symptoms and signs of hypersensitivity reactions should be monitored at each clinical visit; the “9s rule” (see Appendix 2) should be used to calculate body surface area (BSA) for CTCAE classification; participants should be advised to use fragrance-free detergents and soaps, apply sunscreen with an SPF of ≥30, and moisturize their skin at least once daily (preferably twice daily); standardized photographs of any ≥Grade 2 dermatological AE should be submitted to the sponsor; if a participant experiences a treatment-related dermatological AE, a skin biopsy sample (i.e., needle biopsy) may be collected locally. If a sample is collected, it should be transported to the central laboratory for histopathological and potential molecular marker analysis. Specific instructions on sample collection and transportation will be provided in a separate laboratory manual.

[0229] Table 20. Recommended dose interruption and management of treatment-related adverse events

[0230] Abbreviations: AE = Adverse Event; bid = Twice daily; CBC = Complete Blood Count; CTCAE = Common Terminology Standard for Adverse Events; GABA = Gamma-aminobutyric acid; H1 = Histamine-1; IgE = Immunoglobulin E.

[0231] a Guidelines for standardized imagery will be provided separately.

Claims

1. A method for treating a patient with a giant cell tumor of the tendon sheath who requires but is not suitable for surgical treatment, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I).

2. A method for treating a patient with giant cell tumor of the tendon sheath, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) The patient achieved a partial or complete response, as determined by RECIST v1.1, after at least 25 weeks of administration of the compound.

3. A method for treating a patient with giant cell tumor of the tendon sheath, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) The patient achieved a partial or complete response after at least 25 weeks of administration of the compound, as determined by independent imaging review (IRR) based on tumor volume score (TVS).

4. A method of treating a patient with giant cell tumor of the tendon sheath, the method comprising administering 30 mg of a compound represented as follows to the patient twice a week: Formula (I) Wherein, after at least 25 weeks of administration of the compound, the patient has an improved range of active activity compared to before administration of the compound to the patient.

5. The method of claim 4, wherein after at least 25 weeks of administration of the compound, the patient achieves a change of at least 18% in active range of motion compared to before administration of the compound to the patient.

6. A method for treating a patient with giant cell tumor of the tendon sheath, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) After at least 25 weeks of administration of the compound, the patients achieved an increase in their PROMIS-PF scores compared to before administration of the compound.

7. The method of claim 6, wherein after at least 25 weeks of administration of the compound, the patient achieves a PROMIS-PF score at least 4 points higher than the PROMIS-PF score of the patient before administration of the compound.

8. A method of treating a patient with giant cell tumor of the tendon sheath, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) Wherein, after at least 25 weeks of administration of the compound, the patient achieved an increase in the score on the Worst Stiffness Numeric Rating Scale compared with before administration of the compound.

9. The method of claim 8, wherein after at least 25 weeks of administration of the compound, the patient achieves a score of at most -2 on the Most Severe Rigidity Numerical Rating Scale compared to before administration of the compound to the patient.

10. A method of treating a patient with giant cell tumor of the tendon sheath, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) Wherein, after administration of the compound for at least 25 weeks, the patient achieved an increase in the EQ-Visual Analog Scale (EQ-VAS) score compared to before administration of the compound to the patient.

11. The method of claim 10, wherein after at least 25 weeks of administration of the compound, the patient achieves an EQ-VAS score at least 13 points higher than the patient's EQ-VAS score before administration of the compound.

12. A method for treating a patient with giant cell tumor of the tendon sheath, the method comprising administering 30 mg of a compound represented by formula (I) to the patient twice a week: Formula (I) Wherein, after at least 25 weeks of administration of the compound, the patient achieves a decrease of greater than or equal to 30% in the Brief Pain Inventory Numerical Rating Scale score compared to before administration of the compound.

13. The method of claim 12, wherein after at least 25 weeks of administration of the compound, the patient maintains an increase in anesthetic use of less than 30% compared to before administration of the compound to the patient.

14. A method for treating a patient with elevated creatine phosphokinase (CPK) levels, wherein the patient is administered 30 mg of a compound represented by formula (I) twice weekly during treatment for treatment of tenosynovial giant cell tumor: Formula (I) The method involves administering the compound to the patient at a dose of less than 30 mg twice a week.

15. The method of claim 14, wherein the dose is 20 mg twice a week.

16. The method of claim 14, wherein the dose is 14 mg twice a week.

17. The method according to any one of claims 1 to 16, wherein the giant cell tumor of the tendon sheath is a diffuse giant cell tumor of the tendon sheath.

18. The method according to any one of claims 1 to 16, wherein the giant cell tumor of the tendon sheath is a localized giant cell tumor of the tendon sheath.

19. The method according to any one of claims 1 to 18, wherein the patient has previously undergone surgery to treat the giant cell tumor of the tendon sheath.

20. The method according to any one of claims 1 to 19, wherein the patient has previously been given systemic therapy for the treatment of giant cell tumor of the tendon sheath.

21. The method of claim 20, wherein the systemic therapy is selected from imatinib and nilotinib.

22. The method according to any one of claims 1 to 21, wherein the giant cell tumor of the tendon sheath is present in a joint of the patient's lower limb.

23. The method of claim 22, wherein the joint of the lower limb is selected from the knee joint, ankle joint, and hip joint.

24. The method according to any one of claims 1 to 21, wherein the tenosynovial giant cell tumor is present in a joint of the patient's upper limb.

25. The method of claim 24, wherein the joint of the upper limb is selected from the patient's elbow joint, shoulder joint, wrist joint, and hand joint.

26. The method according to any one of claims 1 to 25, wherein the patient is given a compound of formula (I) in the form of a crystalline dihydrate in an amount sufficient to provide 30 mg of the compound of formula (I) twice a week.

27. The method according to any one of claims 1 to 26, wherein a loading dose regimen of the compound represented by formula (I) is not administered to the patient before administering the compound represented by formula (I) to the patient.

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