Methods of administering besudil to treat chronic graft versus host disease

Abstract

The present application provides methods of administering besudil mesylate to cGVHD patients.

Description

Technical Field

[0001] The present application relates to belumosudil mesylate (REZUROCK TM ) is administered to a patient to treat chronic graft-versus-host disease (cGVHD). Background Art

[0002] Chronic graft-versus-host disease (cGVHD) is an immune-mediated inflammatory and fibrotic disorder. It is a potential serious complication after solid organ transplantation and allogeneic hematopoietic cell transplantation (alloHCT). cGVHD affects up to 70% of all alloHCT recipients, with an incidence of 20%-50% in children. It is the main cause of non-relapsed death more than 2 years after alloHCT. In the United States, the estimated prevalence of cGVHD is 14,000 patients (as of 2016). (Bachier CR et al.: Epidemiology and real-world treatment of chronic graft-versus-host disease post allogeneichematopoietic cell transplantation: A US claims analysis. Published at ASH 2019 held in Orlando, FL from December 7 to 10, 2019) ("Bachier et al.").

[0003] As assessed by Lee Symptom Scale (Lee Symptom Scale, LSS) (which measures the impact of cGVHD on the function and health of patients), the quality of life (QOL) of cGVHD patients is seriously impaired. It is reported that only one-third of patients with cGVHD and starting systemic treatment survive, are in remission and stop immunosuppressive therapy within 5 years. (Lee SJ et al.: Success of immunosuppressive treatments in patients with chronic graft-versus-host disease.Biol Blood Marrow Transpl24:555-562,2018) ("Lee et al.").

[0004] The pathophysiology of cGVHD can be divided into three stages: early inflammation caused by tissue damage, dysregulation of the adaptive immune system, and chronic inflammation and abnormal tissue repair with fibrosis.

[0005] First-line therapy for moderate to severe chronic graft-versus-host disease (cGVHD) as defined by the National Institutes of Health (NIH) is corticosteroids alone or in combination with sirolimus or a calcineurin inhibitor. However, up to 70% of patients require additional lines of therapy. (Bachier CR et al.). In addition, long-term use of corticosteroids is associated with significant side effects. (Lee et al.).

[0006] Management of cGVHD continues to evolve with the advent of targeted therapies. cGVHD is characterized by overproduction of the proinflammatory cytokines IL-21 and IL-17 and overactivation of T follicular helper cells and B cells, which in turn leads to overproduction of antibodies.

[0007] The management of cGVHD has been developing with the emergence of targeted therapy. In 2017, the U.S. Food and Drug Administration approved ibrutinib (a Bruton's tyrosine kinase inhibitor) for the treatment of adults with cGVHD after failure of one or more systemic therapy lines. In patients with cGVHD requiring >25% body surface area erythema rash or NIH oral score>4, a study using ibrutinib reported an overall response rate (ORR) of 67% and a discontinuation rate of 43% due to adverse events (TEAEs) occurring during treatment. (Waller EK et al.: Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-Year update of aphase 1b / 2study. Biol Blood Marrow Transpl 25: 2002-2007, 2019).

[0008] There is still opportunity to investigate additional treatment options for patients with cGVHD, including those who have failed ≥1 line of therapy. Summary of the invention

[0009] The present application provides a method for administering besudil mesylate (REZUROCK TM ) to treat cGVHD.

[0010] In one embodiment, the present application provides the use of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound) and / or besudinil mesylate for patients who experience one or more treatment-related adverse reactions when receiving a clinically recommended dose of the compound, the use comprising: if the patient experiences at least one adverse reaction of grade 3 or higher, stopping administration of the compound to the patient; and if the at least one adverse reaction is not upgraded to grade 4 and the patient recovers to grade 1 or lower after cessation of treatment, resuming administration of the compound at a clinically recommended dose for the patient.

[0011] In one embodiment, the present application provides a use of a compound or besudinil mesylate and / or a method for treating cGVHD in a subject, comprising the following steps: administering the compound to a patient at a clinically recommended dose for the patient; monitoring the patient for adverse reactions; if the patient experiences at least one grade 3 adverse reaction, stopping administration of the compound to the patient; and when at least one adverse reaction of the patient has recovered to grade 1 or lower, resuming administration of the compound to the patient.

[0012] In another embodiment, the present application provides that if said patient experiences at least one Grade 4 adverse reaction, administration of said compound to said patient is permanently stopped.

[0013] The present application and further embodiments may be more fully understood by referring to the detailed description and examples which are intended to illustrate non-limiting embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 is a CONSORT flow diagram describing the Phase IIa open-label dose-finding study of besudil of Example 1.

[0015] Figure 2 Figure 2 is a forest plot of subgroup analysis of ORR in the safety population. Subgroups were defined based on baseline assessment.

[0016] Figure 3A The best individual response of an organ system among responders is described. n = number of responder population for overall severity rating and number of specific organs involved at baseline. Percentages are calculated based on the corresponding n.

[0017] Figure 3BFigure 2 is a heat map of response and progression for all patients in the safety population. (A) Best response of an organ. (B) Organ response at progression or end of study. Of the 11 patients with joint progression, seven had a P-ROM decrease of only one unit.

[0018] Figure 4A The time to response among besudil responders is described. The percentages are calculated based on the number of responder populations.

[0019] Figure 4B Describes the response time of selected organs among responders. Percentages are calculated based on the number of responder populations.

[0020] Figure 5A Describe the durability of response to besudeletil in patients with cGVHD. Kaplan-Meier curves of estimated DOR for responders

[0021] Figure 5B Durability of response to besudil in patients with cGVHD is described. Kaplan-Meier curves of estimated time to next systemic treatment for cGVHD (TTNT) in the safety population.

[0022] Figure 5C Durability of response to besudil in patients with cGVHD is described. Kaplan-Meier curves of estimated FFS (including causes of failure) in the safety population.

[0023] Figure 5D To describe the durability of response to besudil in patients with cGVHD. Kaplan-Meier curves for estimated overall survival in the safety population.

[0024] Fig. 6A Changes in CD41 Treg percentages compared with Treg baseline (regulatory T cells, total) following treatment with besudil are described. Pre-drug peripheral blood samples were collected on C1D1 (cycle 1 day 1), C2D1 (cycle 2 day 1), C4D1 (cycle 4 day 1), C7D1 (cycle 7 day 1), and at the end-of-treatment visit.

[0025] Figure 6B Changes in CD41 Treg percentages after treatment with besudil compared with Treg baseline (regulatory T cell responders) are described. Pre-drug peripheral blood samples were collected on C1D1 (cycle 1 day 1), C2D1 (cycle 2 day 1), C4D1 (cycle 4 day 1), C7D1 (cycle 7 day 1), and at the end-of-treatment visit.

[0026] Figure 6C Changes in CD41 Treg percentages after treatment with besudil compared with Treg baseline (regulatory T cell nonresponders) are described. Pre-drug peripheral blood samples were collected on C1D1 (cycle 1 day 1), C2D1 (cycle 2 day 1), C4D1 (cycle 4 day 1), C7D1 (cycle 7 day 1), and at the end-of-treatment visit.

[0027] Figure 7 is a CONSORT flow diagram describing the Phase II randomized study of besudil of Example 2.

[0028] Figure 8 It is the forest diagram of the subgroup analysis (mITT) of ORR.High ORR was observed in all subgroups analyzed in the mITT population, and efficacy was maintained regardless of previous treatment.The 50th percentile of cGVHD duration before enrollment was 29 months.Response assessments performed at or after the start of new systemic therapy for cGVHD were excluded from analysis.

[0029] Fig. 9 ORRs by organ system in the mITT population are described. Organ-specific analysis in the mITT population demonstrated ORRs in skin, eye, mouth, liver, lung, joints / fascia, upper gastrointestinal tract, lower gastrointestinal tract, and esophagus. CRs were seen in all affected organs.

[0030] Fig. 10A Durability of response to different doses of besudil is described. Kaplan-Meier plot of DOR in the responder population. DOR is defined as the time from response until documented progression or initiation of another systemic therapy for cGVHD; data on durability continue to mature.

[0031] Fig. 10B Durability of response to different doses of besudinil is described. Kaplan-Meier curves of estimated FFS (including reasons for failure) in the mITT population. FFS was defined as the absence of cGVHD treatment change, NRM, and recurrent malignancy.

[0032] Fig. 10C Durability of response to different doses of besudinil is depicted. Kaplan-Meier curves of estimated OS in the mITT population.

[0033] Fig.11 The clinical study design of Example 2 is described. DETAILED DESCRIPTION Overview

[0034] Besudiol is an oral selective inhibitor of rho-associated coiled-coil-containing protein kinase 2 (ROCK2). ROCK2 inhibition plays a role in adaptive immune system disorders and fibrosis due to abnormal tissue repair. Besudiol has an IC of approximately 100 nM and 3 μM, respectively. 50 Value inhibits ROCK2 and ROCK1.

[0035] Besudild downregulates proinflammatory responses in ex vivo or in vitro human T cell assays by modulating STAT3 / STAT5 phosphorylation and altering the Th17 / Treg balance. In vitro, besudild also inhibits abnormal profibrotic signaling. By controlling ROCK2 activity, besudild mediates signaling in immune cell function and fibrotic pathways, thereby alleviating the effects caused by this debilitating disease, such as inflammation of multiple tissues and fibrotic changes that may involve multiple organs including the lungs, hepatobiliary system, musculoskeletal system, gastrointestinal (GI) tract, and skin.

[0036] In vivo, besudil exhibits activity in animal models of chronic GVHD.

[0037] Besudiol mesylate is marketed as REZUROCK in the United States and other countries. TM Sold to treat patients with chronic GVHD (cGVHD) (in some cases, after failure of at least two prior lines of systemic therapy). The chemical name of the compound besudelin is: 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide. The compound besudelin is also known as KD025. REZUROCK TM The active pharmaceutical ingredient is besudeli mesylate, whose molecular formula is C 27 H 28 N6O5S, molecular weight is 548.62 g / mol, chemical name is 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide methanesulfonate (1:1).

[0038] The chemical structure of besudil mesylate is as follows:

[0039] Besudil and methods for making the compound are described in the following U.S. Patents: U.S. Patent No. 8,357,693, U.S. Patent No. 9,815,820, U.S. Patent No. 10,183,931, and U.S. Patent No. 10,696,660.

[0040] The present application provides a method for administering besudil mesylate (REZUROCK TM) with risk management steps to address potential adverse reactions. definition

[0041] As used herein, "about" includes the exact amount modified by the term "about" as well as the amount expected to be within experimental error (such as, for example, within 15%, 10%, or 5%). For example, "about 200 mg" means "200 mg" as well as the mg range within experimental error (e.g., within the range of 200 mg ± 15%, 10%, or 5%). As used herein, the term "about" can be used to modify ranges as well as specific values.

[0042] As used herein, "administering" or "administering to" (e.g., including use of the term with reference to stopping administration of an API (including a compound or besudil) to a subject and / or resuming administration of an API (including a compound or besudil) to a subject) refers to the act of prescribing one or more drugs containing the API for a subject to take during treatment, the act of dispensing the one or more drugs to a subject, and / or the act of physically receiving or ingesting the one or more drugs. Thus, an API (e.g., a compound or besudil) can be "administered" by: a physician or other medical professional who writes a prescription for the one or more drugs; and / or a pharmacist who fills the prescription and / or dispenses the one or more drugs to a subject; and / or a patient or subject who ingests the drug and / or his or her companion or caregiver who provides the drug to the subject, each of whom may also "stop" administration of the API and / or "resume" administration of the API.

[0043] "Adverse reaction" means an undesirable and harmful or uncomfortable physiological reaction to the patient or the treatment process caused by treatment with API. In certain embodiments, adverse reactions include but are not limited to infection, gastrointestinal dysfunction, respiratory system disorders, chest disorders or mediastinal disorders, vascular disorders, musculoskeletal disorders or connective tissue disorders, nervous system disorders, metabolic disorders and / or skin and subcutaneous disorders.

[0044] In other embodiments, more common adverse reactions may include, but are not limited to, fatigue, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyl transferase, decreased lymphocytes, and hypertension. Adverse reactions may be detected directly or indirectly.

[0045] “API” stands for “active pharmaceutical ingredient.”

[0046] "Allogeneic hematopoietic stem cell transplantation (allo-HSCT)" (also called bone marrow transplantation or stem cell transplantation) or "allogeneic hematopoietic cell transplantation (allo-HCT)" refers to the process of transplanting hematopoietic cells from a donor into a recipient who is not an identical twin. The source of hematopoietic stem cells for allogeneic transplantation can be peripheral blood stem cells (PBSC) or bone marrow (BM). In some cases, umbilical cord blood can be used. The donor and recipient can match on human leukocyte antigen (HLA) genes, such as brothers and sisters. The donor and recipient can be parents and children who are only half-matched (haploid compatible).

[0047] When the term "besudiil" is used in this application, it should be understood that unless the context clearly indicates otherwise, the term can cover any form of the compound besudiil and its pharmaceutically acceptable salts. The term "besudiil" refers to both the compound besudiil (e.g., free base form, amorphous form or crystalline form) and the pharmaceutically acceptable salts of besudiil (e.g., as REZUROCK TM The term "besudil" refers to any form of besudil that can be used in a formulation or pharmaceutical composition for administering the compound to a patient.

[0048] "Ceasing" or "cessation" when used with respect to the administration of an API means that the API is no longer administered to the patient, either temporarily or permanently. For example, if the patient experiences a treatment-related Grade 3 adverse reaction, it may be possible to temporarily "cease" administration of the API (and resume administration if the patient recovers to Grade 0 or 1), or if the patient experiences a treatment-related Grade 4 adverse reaction, administration of the API should be permanently stopped or discontinued.

[0049] "Clinical endpoint" or "study endpoint" refers to an event or result in a clinical trial, which can be objectively measured to determine the results and potential beneficial effects of a drug or dosage regimen designed in a clinical trial. Examples of clinical endpoints include the following. Overall response rate (ORR) is the percentage of people with partial response (PR) or complete response (CR) to treatment in a certain period of time in a study or treatment group. Failure-free survival (FFS) refers to the time from the first dose of besudiil to the failure event, or the interval between the beginning of besudiil and the addition of a new cGVHD therapy, the recurrence of the underlying disease or non-recurrent death (NRM). Overall survival (OS) refers to the length of time from the diagnosis date of the disease or the treatment of the disease. Duration of response (DOR) refers to the time from the initial response (e.g., PR or CR) until the best response progress from cGVHD recorded, from the initial response to the start of another systemic cGVHD therapy or death. The time of the next treatment (TTNT) refers to the time to the start of subsequent systemic cGVHD therapy.

[0050] "Clinically recommended amount" or "clinically recommended dose" refers to the amount or dose of the API recommended and / or approved by a person skilled in the art of medicinal chemistry for administration to a patient to treat the disease state in question after clinical trials, for example, as described in Examples 1 and 2 of the present application. In some embodiments, the clinically recommended dose of besudinil mesylate is 200 mg per day, in some embodiments 200 mg per day, orally administered with food.

[0051] "CYP3A" refers to the CYP3A family of p-450 isozymes, including CYP3A4.

[0052] When the term "grade" is used to represent the grade level of adverse reactions, the term is intended to be defined according to the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 version scale of adverse events. CTCAE shows a unique clinical description of the severity of 1 to 5 grades and each adverse reaction based on this general guideline: Grade 1-mild (asymptomatic or mild symptoms; only clinical or diagnostic observations; no intervention is indicated); Grade 2-moderate (indicating minimal, local or non-invasive intervention); Grade 3-severe (medically significant but not directly life-threatening; indicating hospitalization or extended hospitalization; disability; limiting self-care); Grade 4-life-threatening (indicating emergency intervention); and Grade 5-death.

[0053] "Immunosuppressive therapy" (IST) refers to therapy that is usually administered for at least six months after allo-HSCT in an attempt to prevent GVHD. Examples of IST include sirolimus, prednisone, and calcineurin inhibitors (e.g., tacrolimus and cyclosporine).

[0054] The Lee Symptom Scale (LSS) total score measures the impact on patient function and health status. The Lee Symptom Scale is a 30-item scale developed to measure symptoms of cGVHD and is described in Lee SJ et al., Development and validation of a scale to measure symptoms of chronic graft-versus host disease. Biol Blood Marrow Transplant 2002; 8: 444-452.

[0055] "Line of treatment" or "line of therapy" describes the order or sequence in which different therapies are given to a patient as his or her disease progresses. The initial treatment (first-line therapy) may not work or may stop working after a period of time. After the first-line therapy is discontinued, a second, different treatment (second-line therapy) may be given. When the second-line therapy does not work or stops working, a subsequent line of therapy may be given. Some patients may be given multiple lines of therapy during the course of their disease.

[0056] The first-line therapy for moderate to severe chronic graft-versus-host disease (cGVHD) defined by the National Institutes of Health (NIH) can be a single corticosteroid or a combination of corticosteroids and sirolimus or a calcineurin inhibitor. (Carpenter PA et al.: A phase II / III randomized, multicenter trial of prednisone / sirolimus versus prednisone / sirolimus / calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica 103: 1915-1924, 2018).

[0057] The example of corticosteroid therapy for the treatment of cGVHD includes but is not limited to prednisone, prednisolone, methylprednisolone and budesonide. The example of previous systemic therapy for the treatment of cGVHD includes but is not limited to prednisone, tacrolimus, extracorporeal photopheresis (ECP), sirolimus, ibrutinib, ruxolitinib, mycophenolate mofetil (MMF), rituximab, methotrexate (MTX), cyclosporine, imatinib, ixazomib and ofatumumab.

[0058] "Monitoring" with respect to the evaluation of adverse reactions means observing, checking, and / or evaluating the progress of one or more adverse reactions at at least two time points (in some embodiments, over a period of time; in some embodiments, once a month; in some embodiments, at least once a month). Monitoring can be performed by interviewing, patient self-reporting, visual observation, physical examination, use of instruments, laboratory tests, and / or any other means for detecting adverse reactions. Anyone who may be involved in administering the API to a subject as defined above may also be involved in monitoring adverse reactions.

[0059] A "myeloablative transplant" is a transplant procedure that uses very high doses of chemotherapy or radiation therapy before transplanting autologous or allogeneic hematopoietic stem cells. A nonmyeloablative transplant or reduced-intensity transplant involves the patient receiving less intensive chemotherapy before transplanting allogeneic hematopoietic stem cells.

[0060] The “NIH Pulmonary Symptom Score” or “NIH cGVHD Pulmonary Score” is a score based on clinical symptoms ranging from 0 to 3. A score of 0 is used for no symptoms, 1 for symptoms of shortness of breath when going up and down stairs, 2 for symptoms of shortness of breath on level ground, and 3 for shortness of breath at rest or requiring oxygen.

[0061] Unless the context requires otherwise, "or" is used in its inclusive sense (equivalent to "and / or").

[0062] As used herein, "patient" or "subject" includes animals or humans, and in one embodiment, includes humans.

[0063] A "pharmaceutical composition" refers to a mixture of substances, including a pharmaceutical agent, suitable for administration to an individual. For example, a pharmaceutical composition can include a sterile aqueous solution or an API formulated in an oral dosage form (such as a tablet or capsule).

[0064] "Pharmaceutically acceptable salts" means physiologically and pharmaceutically acceptable salts of the compounds provided herein. "Pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines); alkali metal or organic salts of acidic residues (such as carboxylic acids); and the like. The pharmaceutically acceptable salts of the present invention include, for example, conventional non-toxic salts of the parent compound formed by non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of the two (usually preferably a non-aqueous medium, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile).

[0065] As used herein (eg, with respect to an adverse event), "risk" means there is a possibility (even if small or remote) that the adverse event will occur.

[0066] "Side effect" means any physiological response attributable to the treatment with the API rather than to the disease or disorder for which the API is being administered. Side effects may include "adverse events" (or AEs) or "adverse reactions," or may be harmless or even beneficial.

[0067] "Steroid-resistant" (SR) cGVHD is defined as cGVHD that progresses on the use of steroids or corticosteroids (in one embodiment, on the use of prednisone).

[0064] "Treatment-emergent" when used with respect to an adverse reaction or adverse event means an adverse reaction or adverse event, or a symptom thereof, that manifests during the period of exposure of the patient to the API (eg, that occurs during the course of treatment).

[0065] "Therapy-related" when used with respect to an adverse reaction or adverse event means an adverse reaction that occurs during the period of exposure to the API and that, based on a clinical assessment of the patient's diagnosis, one or more conditions, and / or physiological profile, is more likely to be attributable to exposure to the API than to other causes or pre-existing conditions (other than the disease state for which the treatment is being provided). For example, if a clinical assessment of the patient informs that one or more adverse reactions are related to a pre-existing disease or disorder and are unlikely to be related to the API, the adverse reaction would not be considered "therapy-related."

[0068] A "therapeutically effective amount" of an API refers to an amount sufficient to achieve treatment of the disease state being treated when administered to a human to treat a disease (e.g., cGVHD). As applied to human cGVHD, "treating" or "treatment" includes (1) reducing the risk of cGVHD and / or inhibiting cGVHD, i.e., preventing or reducing the occurrence of cGVHD or its clinical symptoms; and (2) alleviating cGVHD, i.e., causing regression, reversal or improvement of cGVHD or reducing the number, frequency, duration or severity of its clinical symptoms.

[0069] The therapeutically effective amount of the API may vary depending on the health and physical condition of the subject to be treated, the degree of disease progression, the assessment of the medical condition, and other relevant factors. It is expected that the therapeutically effective amount may fall within the range that can be determined by experimentation and by reference to clinical trial data and results described, for example, in Examples 1 and 2 of the present application and in the scientific literature. Exemplary Embodiments

[0070] In one embodiment, the present application provides the use of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound) for patients who experience one or more treatment-related adverse reactions when receiving a clinically recommended dose of the compound, the use comprising: If the patient experiences at least one adverse reaction of grade 3 or higher, discontinuing administration of the compound to the patient; and If the at least one adverse reaction does not escalate to Grade 4 level and the patient recovers to Grade 1 level or lower after treatment cessation, dosing of the compound is resumed at the clinically recommended dose for the patient.

[0071] In one embodiment, the present application provides the use of the compound or besudil mesylate, the use comprising the following steps: administering the compound to the patient at a clinically recommended dose for the patient; Monitor said patients for adverse reactions; If the patient experiences at least one Grade 3 adverse reaction, discontinuing administration of the compound to the patient; and When the patient's at least one adverse reaction has recovered to Grade 1 or less, administration of the compound to the patient is resumed.

[0072] In some embodiments, the patient's at least one adverse reaction has recovered to Grade 0 following cessation of compound administration, and administration is resumed.

[0073] In some embodiments, at least one adverse reaction in said patient is Grade 4, wherein administration of said compound to said patient is permanently discontinued.

[0074] In some embodiments, the patient is monitored for adverse reactions over a period of time; in some embodiments, the monitoring is performed monthly; in some embodiments, the monitoring is performed at least monthly.

[0075] In some embodiments, the present application provides a clinically recommended dose of 200 mg per day for a patient before and after the patient experiences one or more treatment-related adverse reactions.

[0076] In some embodiments, the present application provides a clinically recommended dose for patients, which is 200 mg once a day, taken with food, before and / or after one or more adverse reactions.

[0077] In some embodiments, the present application provides a clinically recommended dose of 400 mg per day for the patient before and after the patient experiences one or more treatment-related adverse reactions; in some embodiments, if the patient is also administered one or more PPIs and / or CYP3A inducers (in some embodiments, one or more strong CYP3A4 inducers), the dose is administered to the patient.

[0078] In some embodiments, the present application provides for using a clinically recommended dose for the patient after the patient recovers to Grade 1 level or lower and the administration of the compound is resumed, which clinically recommended dose is reduced, for example, compared to the clinically recommended dose administered to the patient before the onset of at least one adverse reaction.

[0079] In some embodiments, the present application provides a clinically recommended dose for patients, which is in the range of 200 mg a day to 400 mg a day.

[0080] In some embodiments, the patient is being treated for chronic graft-versus-host disease (cGVHD); in some embodiments, the patient is being treated for cGVHD wherein the patient has failed at least two prior lines of systemic therapy for said cGVHD.

[0081] In some embodiments, the present application provides the use of Common Terminology Criteria for Adverse Events (CTCAE) for assessing or grading the severity of adverse reactions in patients; in some embodiments, the CTCAE version is 5.0.

[0082] In some embodiments, the at least one adverse reaction experienced by the patient is infection, fatigue, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyl transferase, decreased lymphocytes, or hypertension.

[0083] In some embodiments, the at least one adverse reaction experienced by the patient is a viral infection, a bacterial infection, or an infection with an unidentified pathogen.

[0084] In some embodiments, at least one adverse reaction experienced by the patient is an infection with an unknown pathogen, wherein the infection with an unknown pathogen is acute sinusitis, device-related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, dental infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis, or septic shock.

[0085] In some embodiments, the at least one adverse reaction experienced by the patient is fatigue, edema, or fever.

[0086] In some embodiments, the at least one adverse reaction experienced by the patient is gastrointestinal dysfunction; in some embodiments, the gastrointestinal dysfunction is nausea, diarrhea, abdominal pain, or dysphagia.

[0087] In some embodiments, the at least one adverse reaction experienced by the patient is a respiratory disorder, a chest disorder, or a mediastinal disorder; in some embodiments, it is dyspnea, a cough, or a nasal congestion.

[0088] In some embodiments, the at least one adverse event experienced by the patient is a vascular disorder; in some embodiments, bleeding or hypertension.

[0089] In some embodiments, the at least one adverse reaction experienced by the patient is a musculoskeletal disorder or a connective tissue disorder; in some embodiments, the musculoskeletal disorder or a connective tissue disorder is musculoskeletal pain, muscle spasm, or arthralgia.

[0090] In some embodiments, the at least one adverse effect experienced by the patient is a neurological disorder; in some embodiments, a headache or a migraine.

[0091] In some embodiments, the at least one adverse effect experienced by the patient is a metabolic disorder; in some embodiments, the metabolic disorder is decreased appetite.

[0092] In some embodiments, the patient experiences a skin or subcutaneous disorder; in some embodiments, the skin or subcutaneous disorder is a rash or pruritus.

[0093] In other embodiments, the present application provides a method for treating a patient who experiences one or more treatment-related adverse reactions when receiving a clinically recommended dose of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound), the method comprising: If the patient experiences at least one adverse reaction of grade 3 or higher, discontinuing administration of the compound to the patient; and If the at least one adverse reaction does not escalate to Grade 4 level and the patient recovers to Grade 1 level or lower after treatment cessation, dosing of the compound is resumed at the clinically recommended dose for the patient.

[0094] In some embodiments, the methods provided herein include the patient experiencing at least one adverse reaction at the Grade 3 level, and resuming administration of the compound to the patient when the at least one adverse reaction of the patient has recovered to Grade 1 or lower.

[0095] In some embodiments, the methods provided herein include the patient experiencing at least one grade 4 adverse reaction, and permanently stopping administration of the compound to the patient.

[0096] In the embodiments disclosed in the present application, including the uses and methods of treatment provided in the present application, the clinically recommended dose for the patient may be in the range of 200 mg to 400 mg per day; in some embodiments, the clinically recommended dose for the patient is 200 mg per day; in some embodiments, after the patient recovers to grade 1 level or lower and the administration of the compound is resumed, the clinically recommended dose for the patient is a reduced dose compared to the clinically recommended dose before the patient experiences adverse reactions.

[0097] In some embodiments, the subject has undergone an allogeneic hematopoietic stem cell transplant, and the allogeneic hematopoietic stem cell transplant is a matched HSCT. In some embodiments, the allogeneic hematopoietic stem cell transplant is a haploidentical HSCT.

[0098] In some embodiments, besudil treatment is continued based on the patient's tolerance until active cGVHD symptoms subside or progress. The number of cycles and duration of treatment depend on the patient. In some embodiments, besudil is administered to the patient in one or more 28-day cycles.

[0099] In some embodiments, the range of cycle number is 3 to 15. In some embodiments, the range of cycle number is 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4. In some embodiments, the range of cycle number is 5 to 11. In some embodiments, the range of cycle number is 6 to 12. In some embodiments, the range of cycle number is 5 to 10, 5 to 9, or 5 to 8. In some embodiments, the range of cycle number is 5 to 7. In some embodiments, the range of cycle number is 5 to 6. In some embodiments, the cycle number is 5. In some embodiments, the cycle number is 6. In some embodiments, the cycle number is 7. In some embodiments, the cycle number is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0100] In some embodiments, the number of cycles ranges from 3 cycles to loss of response. In some embodiments, the number of cycles ranges from 4 cycles to loss of response. In some embodiments, the number of cycles ranges from 5 cycles to loss of response. In some embodiments, the number of cycles ranges from 6 cycles to loss of response. In some embodiments, the number of cycles ranges from 7 cycles to loss of response. In some embodiments, the number of cycles ranges from 8 cycles to loss of response. In some embodiments, the number of cycles is greater than 3, 4, 5, 10, 15, 20, 25, or 30, or until a desired response is achieved.

[0101] In some embodiments, the subject experiences an improvement as defined by the Lee Symptom Scale (LSS). In some embodiments, the subject experiences a reduction in LSS score of at least 7 points. In some embodiments, the subject experiences a reduction in LSS score of at least 10 points. In some embodiments, the improvement is maintained in at least two consecutive assessments. In some embodiments, the LSS score is assessed at baseline and on Day 1 of each cycle starting from Day 1 of Cycle 2.

[0102] In some embodiments, the subject has chronic graft-versus-host disease and has failed one to three prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has chronic graft-versus-host disease and has failed at least two prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has chronic graft-versus-host disease and has failed two to five prior lines of systemic therapy for chronic graft-versus-host disease. In some embodiments, the subject has failed at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten prior lines of systemic therapy for chronic graft-versus-host disease.

[0103] In some embodiments, the subject experienced a complete response to the last treatment for graft-versus-host disease prior to besudiil. In some embodiments, the subject experienced a partial response to the last treatment for graft-versus-host disease prior to besudiil. In some embodiments, the subject experienced stable disease during the last graft-versus-host disease treatment prior to besudiil.

[0104] In some embodiments, the prior line of systemic therapy for chronic graft-versus-host disease has been discontinued.

[0105] In some embodiments, the prior line of systemic therapy is selected from prednisone, tacrolimus, ECP, sirolimus, ibrutinib, ruxolitinib, MMF, rituximab, MTX, cyclosporine, imatinib, ixazomib, and ofatumumab.

[0106] In some embodiments, the cGVHD is steroid-resistant (SR) cGVHD.In some embodiments, the subject is resistant to the last line of treatment prior to besudil treatment.

[0107] In some embodiments, the subject is receiving concomitant corticosteroid therapy. In some embodiments, the concomitant corticosteroid therapy is selected from prednisone, prednisolone, methylprednisolone and budesonide. In some embodiments, the concomitant corticosteroid therapy is prednisone. In some embodiments, the dose of the concomitant corticosteroid therapy is reduced after at least 1 cycle of besudil treatment. In some embodiments, the dose of the concomitant corticosteroid therapy is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60% or at least about 70% after at least 1 cycle of besudil treatment. In some embodiments, the dose of concomitant corticosteroid therapy is reduced by about 10% to about 70%, about 15% to about 65%, about 20% to about 60%, about 30% to about 60%, about 35% to about 60%, about 40% to about 60%, or about 45% to about 55% after at least 1 cycle of besudiil treatment. In some embodiments, concomitant corticosteroid therapy is discontinued after at least 1 cycle of besudiil treatment.

[0108] In some embodiments, the subject is receiving concomitant calcineurin inhibitor therapy.

[0109] In some embodiments, the subject has at least 4 organs affected. In some embodiments, the subject has at least 3 organs affected. In some embodiments, the subject has at least 2 organs affected. Besudil Tablets

[0110] In one embodiment, besudil is formulated as a tablet for oral administration. Besudil mesylate is a yellow powder that is almost insoluble in water. Besudil tablets can be prepared for oral administration. Each tablet contains 200 mg of free base, equivalent to 242.5 mg of besudil mesylate. The tablets may also contain the following inactive ingredients: microcrystalline cellulose, hypromellose, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, and magnesium stearate. The tablet film is composed of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and yellow iron oxide. Each 200 mg tablet is a light yellow film-coated oval tablet with a concave pattern "KDM" on one side and a concave pattern "200" on the other side. The tablets are stored at room temperature 20°C to 25°C (68°F to 77°F); short trips are allowed at 15°C to 30°C (59°F to 86°F). Overview

[0111] The following abbreviations may aid in considering the embodiments and description of the present application. abbreviation Example Example 1: Phase IIa open-label dose-finding study of besudil Subject Eligibility

[0112] Eligible patients were allogeneic bone marrow transplant or allogeneic hematopoietic cell transplant (alloHCT) recipients, aged ≥18 years, with persistent cGVHD manifestations after one to three prior lines of systemic therapy, and were receiving corticosteroids with or without calcineurin inhibitors and / or concurrent extracorporeal photopheresis. Besudroil was continued until cGVHD progressed or toxicity was unacceptable. Study Design and Treatment

[0113] Patients were enrolled in three ordered groups: Group 1 received besudil 200 mg once daily; Group 2 received besudil 200 mg twice daily (twice a day); and Group 3 received besudil 400 mg once daily. Figure 1 ) Before enrolling the subsequent cohort, the safety data of each previous cohort were analyzed after eight patients reached two months of treatment to ensure that there were no safety signals. The 2-month time frame was selected because all clinically significant adverse events (AEs) related to besudild to date occurred within ≤36 days of starting besudild. No safety issues were found, allowing for planned dose escalation.

[0114] Besudiol was administered orally in 28-day cycles until disease progression or unacceptable toxicity. Progression was defined according to the 2014 NIH cGVHD consensus criteria. Long-term follow-up was performed every 8 weeks until the end of the study. After 4 weeks of besudiol therapy, corticosteroid therapy could be tapered at the discretion of the investigator. Screening was performed within 28 days of the first study dose. After two cycles, the response was initially assessed; however, this was modified to evaluate the response on Day 1 of each cycle starting on Day 1 of Cycle 2. Study End Points

[0115] The primary efficacy endpoint is ORR, defined as the proportion of patients who obtain complete response (CR) or partial response (PR) according to the 2014NIH cGVHD consensus criteria at any time point. Only after besudi, the response assessment before the next line of therapy is counted in ORR. All reactions are evaluated by researchers. Secondary endpoints include: the number and percentage of patients with steroid-dependent cGVHD who respond best to PR or CR, duration of response (DOR), response rate of organ system, LSS score, reduction in corticosteroid dose, time to next treatment (TTNT), failure-free survival (FFS) and overall survival (OS). The safety and tolerability of besudi was evaluated by AE assessment, physical examination, vital sign measurement, laboratory test and electrocardiogram during the whole study. Pre-drug samples were collected for pharmacodynamic (PD) evaluation, which included the evaluation of immune cell subtypes in peripheral blood. Statistical analysis

[0116] The sample size was 16 patients per group, and in the study, the probability of ≥1 study participant experiencing an AE with an underlying rate ≥14% was >90%, which was derived from the probability calculation for the assumed sample size. Assuming the optimal ORR is 25%, which is determined to be clinically significant, the study is expected to have approximately 90% probability of showing that ≥2 patients in each group have responded. This study was unable to show significant differences between groups in efficacy, AE or PD analysis. The primary analysis was performed using the safety population, which was defined as enrolled patients who received ≥1 dose of study drug treatment. The Clopper-Pearson (exact) method was used to construct a two-sided 95% CI for ORR. The Kaplan-Meier (KM) method was used to calculate estimates of FFS and OS. result Subjects

[0117] A total of fifty-four patients were enrolled in the ordered cohorts: 17 patients in cohort 1, 16 patients in cohort 2, and 21 patients in cohort 3 ( Figure 1 ). As of the data cutoff date for this analysis, the median follow-up duration was as follows: 36 months for Cohort 1, 32 months for Cohort 2, and 24 months for Cohort 3. The overall median follow-up duration was 29 months (range: 1-39 months).

[0118] Demographic data and baseline characteristics are generally comparable between groups (Table 1, Table 2). The median age at baseline was 52 years (range: 20-75 years). In Group 1, the median time from cGVHD diagnosis to treatment was the longest, at 26 months (compared with 18 months in Group 2 and 16 months in Group 3, respectively). According to the researchers' assessment, 78% of patients suffered from severe cGVHD. Half of the patients had ≥4 organs involved, and compared with patients with lung involvement in Group 1 (24%) and patients with lung involvement in Group 2 (19%), there were more patients with lung involvement in Group 3 (48%). The baseline median corticosteroid dose (mg / kg / d, prednisone equivalent) of each group was 0.22, 0.19 and 0.17, respectively. Patients in Group 1 had received a median of three previous treatment lines, while patients in Groups 2 and 3 had received a median of two previous treatment lines. 73% (35 of 48, data for six patients were unavailable) of patients were resistant to their last line of treatment before study entry. CONSORT diagram ( Figure 1 ) shows patient allocation. The median treatment duration was as follows: 8.5 months (range: 2-39 months) for cohort 1, 7.5 months (range: 1-35 months) for cohort 2, and 9 months (range: 1-29 months) for cohort 3. 28% of patients have received besudil for >18 months. Reasons for discontinuation of besudil included: progression of cGVHD (n=22), patient voluntary withdrawal (n=8), recurrence of underlying disease (n=7), investigator decision (n=3), AE considered possibly related to treatment (n=3), and death (n=2). LTFU means long-term follow-up.

[0119] Table 1. Baseline demographics and clinical characteristics Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; cGVHD, chronic graft-versus-host disease; CMV, cytomegalovirus; LOT, line of therapy; MDS, myelodysplastic syndrome. a The denominator excluded patients with unknown status (a total of six patients). b Disease severity was determined using the physician-reported global cGVHD activity assessment form.

[0120] Table 2. Additional baseline demographics Abbreviations: ATG, antithymocyte globulin; cGVHD, chronic graft-versus-host disease; CNI, calcineurin inhibitor; CS, corticosteroid; ECP, extracorporeal photopheresis; MMF, mycophenolate mofetil; MTX, methotrexate. Effectiveness

[0121] Overall response rate. In the safety population (N=54), the ORR (95% CI) was 65% (51% to 77%). The ORR (95% CI) of each group was similar: 65% (38% to 86%) in group 1, 69% (41% to 89%) in group 2, and 62% (38% to 82%) in group 3 (Table 3). The efficacy data of subgroups and secondary endpoints are presented as combined data of each group. Table 3. Efficacy and CS reduction Abbreviations: cGVHD, chronic graft-versus-host disease; CS, corticosteroid; LOT, line of therapy; LSS, Lee Symptom Scale; ORR, overall response rate. a Disease severity was determined using the physician-reported global cGVHD activity assessment form. b Changes in cGVHD symptom burden were measured by the LSS. A clinically meaningful improvement in symptom burden was defined as a reduction of at least seven points in the LSS summary score.

[0122] Responses were achieved across key subgroups, including an ORR of 60% (25 of 42) in patients with severe cGVHD, 66% (23 of 35) in patients who had received ≥2 prior lines of systemic therapy, 63% (22 of 35) in patients who were refractory to their last line of therapy before enrollment, and 70% (19 of 27) in patients with ≥4 organ involvement ( Figure 2 ). All responses at the patient level were PRs; however, organ-specific analysis showed that CRs were achieved in all affected organs except the lung, with PR being the best response achieved ( Figure 3A and Figure 3B ). Figure 3B The best response by organ showed three partial responses achieved in the lung at a dose of 400 mg once daily.

[0123] Responses were generally rapid, with >75% of all responses achieved by the first response assessment at Week 8 ( Figure 4AFour of the 35 reactions occurred after 24 weeks of besudil treatment, with late organ reactions observed in the lungs, joints and / or fascia, and eyes ( Figure 4B ).

[0124] Among responders, the median DOR for KM in each group was 35 weeks ( Figure 5A ). For patients who had received ≥2 prior lines of systemic therapy, the median DOR for KM was 38 weeks.

[0125] The time until the next treatment. The median TTNT of KM was 14 months ( Figure 5B Subsequent systemic cGVHD therapies included tacrolimus, sirolimus, ibrutinib, ruxolitinib, extracorporeal photopheresis, and mycophenolate mofetil.

[0126] FFS and OS. FFS rates (95% CI) at 6, 12, and 24 months were 76% (62% to 85%), 47% (33% to 60%), and 33% (21% to 46%), respectively ( Figure 5C ). FFS was defined as the time from the first dose of besudil to the failure event. Reasons for failure included: starting new systemic therapy (n=27), recurrence of underlying disease (n=7), and death (n=2). The important endpoint was the percentage of patients who achieved FFS with response (CR / PR) at 12 months, which accounted for 24% of patients in this study. The OS rates (95% CI) at 12 and 24 months were 91% (79% to 96%) and 82% (69% to 90%), respectively ( Figure 5D ).

[0127] QOL assessment. Clinically meaningful improvements in LSS scores during besudil treatment were observed in 50% of patients, defined as a decrease in LSS summary score of ≥7 points. Clinically meaningful improvements in LSS scores were reported in 35% of all patients (37% of responders and 32% of non-responders) at serial assessments.

[0128] Corticosteroid taper. During besudil treatment, 67% of patients reduced their corticosteroid dose and 19% completely discontinued corticosteroid therapy. The mean corticosteroid dose reduction was 45%. The median time to discontinuation of corticosteroid therapy was 29 weeks (range: 8-77 weeks). The mean corticosteroid dose reduction was 55% for responders and 26% for nonresponders (Table 3). Security

[0129] Belumosudil was well tolerated and patients with >56 patient-years of belumosudil exposure were >56 years old. The median relative dose intensity was 98% overall. In each group, the percentage of patients with a relative dose intensity >95% was 77%, 63%, and 71%, respectively. 9% of patients underwent dose reduction, and the median duration of reduction was 97 days (range: 21-859 days). 41% of patients underwent dose interruption, and the median duration of interruption was 10 days (range: 2-39 days).

[0130] AE is consistent with the AE expected in the group of patients with advanced cGVHD receiving corticosteroid therapy.AE reported in ≥20% of patients are: upper respiratory tract infection (46%), diarrhea (33%), fatigue (33%), nausea (33%), liver function test elevation (33%), dyspnea (30%), headache (24%), peripheral edema (24%), cough (22%) and hypertension (20%) (Table 4).Severe AEs were reported in 43% of patients, and those reported in >1% of patients were: dyspnea (7%), lung infection (6%), hypoxia (4%) and influenza-like illness (4%).61% of patients had AE≥3 grades, of which the most common were dyspnea (13%), liver function test elevation (7%), hyperglycemia (7%) and hypoxia (7%) (Table 4).≥3 grade cytopenia was reported in two patients (4%). These occurred at the time of recurrence of the underlying malignancy in patients who had otherwise maintained normal blood counts during their besudil treatment.

[0131] Table 4. Safety overview Abbreviations: AE, adverse event; SAE, serious adverse event; URI, upper respiratory tract infection.

[0132] The use of besudiil did not report cases of cytomegalovirus (CMV) infection or reactivation. Three patients discontinued besudiil due to potential drug-related AEs (group 1: diarrhea and headache; group 3: fatigue). Four patients (all in group 3) died during the study (secondary to leukemia relapse, pneumonia (unknown pathogen), cardiac arrest and cGVHD progression), and death was not attributed to besudiil. There was no dose response regarding the observed AEs. PD analysis

[0133] In the exploratory PD analysis of peripheral blood mononuclear cells in each group, the percentage of CD41Treg showed an increasing trend in the early stage of besudelimil treatment on day 1 of cycle 2. A simultaneous decrease in Th17 cells was also observed. Th17 cells continued to decrease from C4D1 to C6D25. The percentage of CD41Treg continued to increase from C4D1 to C7D1, as shown in Figure 2. Figures 6A-6C Due to the small sample size, data related to steroid dose were limited and no statistical analysis could be performed.

[0134] This study is the first to evaluate besudilide treatment in human patients with cGVHD. All phenotypes of cGVHD were included, with no requirement for inflammatory or fibrotic manifestations. Patients with advanced multi-organ cGVHD treated with besudilide achieved an ORR of 65% with improved QOL, reduced corticosteroid doses, and limited toxicity. With a relatively small sample size, there was no difference in ORR between the groups.

[0135] The response rate achieved with besudild was meaningful and consistent across subgroups, including patients with severe cGVHD, patients who had received ≥2 prior lines of systemic therapy, patients who were resistant to their last line of therapy before enrollment, and patients with ≥4 organs involved. Among patients with non-severe cGVHD, the ORR was 83%, suggesting the need for further study of how besudild can benefit patients early in their disease. All responses at the patient level were PRs; no CRs were achieved. However, given the severity and extent of the manifestations of fibrotic cGVHD in this patient population, CRs were not expected to be achieved in all organs, as some advanced fibrotic changes in the eyes, mouth, lungs, or joints and / or fascia may be irreversible. CRs were observed in all organs except the lungs, where PRs were achieved.

[0136] Besudiil reaction kinetics showed that most responders quickly obtained responses within 8 weeks after receiving besudiil. Besudiil is well tolerated, and the median DOR of all responders is 35 weeks. The ability to continue to adhere to therapy depends on the safety and long-term tolerance profile of the intervention. The median treatment duration is 8 months (range: 1-39 months). 28% of patients continue to adhere to besudiil for> 18 months. No CMV infection or reactivation was reported, although 57% of patients were CMV seropositive. The incidence of TEAEs and TEAEs of grade ≥3 between each group was similar. The combination of well-tolerated therapy and the efficacy of induction response is converted into a 2-year OS rate of 82%, a median TTNT of 14 months, and FFS rates of 76% and 47% at 6 and 12 months, respectively.

[0137] In a prospective study conducted by the cGVHD Consortium, the 12-month FFS with response (CR / PR) after first-line therapy was 12% to 15%. (Martin PJ, Storer BE, Inamoto Y et al.: An endpoint associated with clinical benefit after initial treatment for chronic graft-versus-host disease. Blood 130: 360-367, 2017). In this study (after 1-3 previous therapy lines), the 12-month FFS rate with response was 24%.

[0138] In the study of the present application embodiment, besudil therapy is associated with a corticosteroid reduction effect. The current treatment paradigm relies on corticosteroids as the mainstay of therapy; however, the associated long-term toxicity forces the use of the lowest possible dose or discontinuation whenever possible. The use of corticosteroid therapy is closely related to quality of life because the side effect profile of corticosteroid therapy causes a symptom burden on patients. A reduction in corticosteroid dose was observed in both responders and non-responders to besudil. Approximately 20% of patients were able to discontinue corticosteroid therapy during besudil treatment. Even in the absence of an NIH-defined response, patients experience clinical benefit, as demonstrated by an improvement in LSS scores or a reduction in corticosteroid doses.

[0139] In this study, responses were achieved in patients with evidence of fibrosis in the lungs, joints and / or fascia, and eyes. In some cases, these responses were observed after 24 weeks of treatment, further emphasizing the benefits of maintaining effective therapy to obtain clinical benefit, especially for patients with difficult-to-treat disease. Because a lower dose of besudil at 200-mg once daily was equally safe and effective, that dose was further compared to a 200-mg twice daily dose in the study described in Example 2 to evaluate dose recommendations. Example 2: Phase II Randomized Study of Besudil The study of Example 2 is a randomized, open-label, multicenter study of besudeli mesylate in patients with chronic GVHD who have received 2 to 5 previous lines of systemic therapy and require additional treatment. Patients were excluded from the study if at least one of the following conditions occurred: the patient's platelet count was <50×10 9 / L; absolute neutrophil count <1.5×10 9 / L; AST or ALT>3×ULN; total bilirubin>1.5×ULN; QTc(F)>480ms; eGFR<30mL / min / 1.73m2 ; or FEV1 ≤ 39%. 66 patients were treated with 200 mg of REZUROCK orally once daily. Concomitant treatment with supportive care therapy for chronic GVHD was allowed. Concomitant treatment with GVHD prophylaxis and standard of care systemic chronic GVHD therapy was allowed as long as the subject was on a stable dose for at least 2 weeks prior to the study. No new systemic chronic GVHD therapy was allowed to be started on the study. Subject Eligibility

[0140] Eligible subjects were allogeneic hematopoietic cell transplant recipients, aged ≥12 years, with persistent cGVHD manifestations after 2 to 5 prior lines of systemic therapy. Subjects were required to be on stable corticosteroid therapy 2 weeks prior to screening and to have a Karnofsky or Lansky performance status score of ≥60. Concomitant use of certain immunosuppressive drugs was allowed as no drug-drug interactions were foreseen. Subjects were excluded if at least one of the following occurred: recurrence of the subject's underlying malignancy; forced expiratory volume in 1 second (FEV1) ≤39% or NIH pulmonary symptom score of 3; post-transplant lymphoproliferative disease; liver transaminases (aspartate transaminase [AST] or alanine transaminase [ALT]) >3 times the upper limit of normal; total bilirubin >1.5 times the upper limit of normal for any reason; or currently receiving ibrutinib. Study Design and Treatment

[0141] Eligibility screening was performed within 14 days starting from Day 1 of Cycle 1. Treatment consisted of oral administration of besudil 200 mg once daily (Group A) or 200 mg twice daily (Group B) to subjects with cGVHD ( Figure 7 ). Randomization was stratified (1: 1) according to the severity of cGVHD and previous ibrutinib exposure. Besudiil was continuously administered in a 28-day treatment cycle until clinically significant progression of cGVHD or unacceptable toxicity occurred. Progress was defined using organ-specific cGVHD response assessment, as defined by the 2014NIH consensus development project on Criteria for Clinical Trials incGVHD (referred to as the 2014NIH cGVHD consensus criteria) of the standards for clinical trials in cGVHD. After taking besudiil ≥ 2 weeks, corticosteroid therapy can be gradually reduced at the discretion of the researcher. If there is no evidence to prove clinical benefit according to the researcher, the subject who did not achieve a response after 12 cycles of besudiil treatment should withdraw. Study End Points

[0142] The primary endpoint is the best ORR at any time, which is defined as the proportion of subjects achieving complete response (CR) or partial response (PR) according to the 2014NIH consensus criteria. All responses are evaluated by researchers at the research site. Secondary endpoints include duration of response (DOR), response time, changes in LSS summary scores, failure-free survival (FFS), reduction in corticosteroid doses, and overall survival (OS). DOR is measured by the following time: the time from the initial PR or CR until the recorded cGVHD progresses from the best response, the time from the initial response to the start of another systemic cGVHD therapy or death. The 7-day LSS summary score is calculated based on the recommended value of the developer and compared with the score at baseline; Improvement of ≥7 points is considered clinically significant. FFS is defined as the interval between starting Besudi and adding new cGVHD therapy, relapse or NRM. The safety of Besudi was evaluated by adverse events (AE) and serious AE (SAE) assessments. Relative dose intensity (RDI) is used as a surrogate measure of drug tolerability and is defined as actual dose intensity / planned dose intensity, where dose intensity is defined as the cumulative dose (mg / d) over the exposure duration. Actual dose intensity refers to the sum of the actual doses received over the exposure duration and includes dose reductions and / or interruptions. Statistical analysis

[0143] The sample size is based on the primary efficacy endpoint (optimal ORR), 1 interim analysis is planned, and the target ORR is 55%. With a target sample size of 63 subjects per treatment group and an estimated 10% withdrawal rate, each treatment group is estimated to have about 90% power to produce a 95% confidence interval (CI) for ORR, excluding 30% as the lower boundary. Based on consultations with key opinion leaders, 30% ORR is considered to be clinically significant in this deep pre-treatment population with cGVHD and unmet medical needs. For the primary endpoint of the best ORR, multiplicity adjustment was performed using the Hochberg process. The modified intention-to-treat (mITT) population (defined as randomized subjects who received ≥1 dose of besudildil) was used for the primary analysis. After 126 subjects were enrolled in the mITT population, interim analysis, primary analysis, and follow-up analysis were planned at approximately 2, 6, and 12 months, respectively. Here, we report data from a 12-month analysis. CI was calculated using the Clopper-Pearson interval (exact) method. result Subject characteristics

[0144] A total of 132 subjects were enrolled in the clinical study. In general, baseline demographics and clinical characteristics were comparable between each treatment group (Table 5). At enrollment, the median subject age was 56 years old (range: 21-77). The median time from cGVHD diagnosis to enrollment was 28 months (range: 2-162). At screening, based on the 2014NIH consensus criteria, 31% of subjects suffered from moderate cGVHD, and 67% suffered from severe cGVHD; 52% of subjects had ≥4 organs involved. At baseline, 36% of the subjects' lungs were involved, and 38% of these subjects had an NIH lung symptom score of 2. Subjects were previously treated with a systemic therapy line with a median of 3. 72% of subjects (n = 79) had cGVHD resistant to their last line of systemic therapy, 34% of subjects (n = 45) had previously received ibrutinib, 29% of subjects (n = 38) had previously received ruxolitinib, and 72% of subjects (n = 95) had received ≥3 previous lines of therapy. The median baseline corticosteroid dose was 0.2 mg / kg (range 0.03-1.07) of prednisone equivalents per day. The mean baseline corticosteroid dose was 0.25 mg / kg (range 0.03-1.07) of prednisone equivalents per day.

[0145] Table 5. Baseline demographics and clinical characteristics Data are n (%) unless otherwise noted. Percentages may not add up to 100% due to rounding. ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CMV, cytomegalovirus; DLBCL, diffuse large B-cell lymphoma; GI, gastrointestinal; MDS, myelodysplastic syndrome; MMF, mycophenolate mofetil; MTX, methotrexate. *Disease severity was determined using the NIH Global cGVHD Severity Score. Classified as concomitant systemic cGVHD medication on Cycle 1 Day 1. **One subject was determined to be unevaluable due to not having symptoms consistent with cGVHD at baseline; therefore, the graphs in Table 5 may be adjusted accordingly.

[0146] CONSORT diagram ( Figure 7) shows subject deployment. The median treatment duration was 10 months (range: 0.4-22.0) and the median follow-up was 14 months (range: 1-22). 44% of the subjects had received ≥12 months of treatment. At the time of data analysis, 37% of the subjects continued to receive besudil. Reasons for discontinuation included: cGVHD progression (n=21), voluntary withdrawal (n=13), AE (n=16), physician decision (n=11), progression of underlying malignancy (n=5), death due to underlying malignancy or disease progression (n=4), other (n=7), and non-adherence to study medication (n=3). Effectiveness

[0147] The best ORRs for besudil 200 mg once daily and 200 mg twice daily were 74% (95% CI, 62-84) and 77% (95% CI, 65-87), respectively (Table 6). High ORRs (61%-85%) were observed in all subgroups ( Figure 8 ). Responses were pooled across groups unless otherwise noted. The efficacy of besudol was maintained regardless of prior ibrutinib therapy (n=46) or ruxolitinib therapy (n=38). The ORR (95% CI, 51-83) was 68% in the subgroup with prior ruxolitinib therapy. The ORR (95% CI, 59-86) was 74% in the subgroup with prior ibrutinib therapy.

[0148] Table 6. Efficacy endpoints for two groups within the mITT population Unless otherwise noted, data are n (%). *Changes in cGVHD symptom burden were measured using the LSS. A clinically meaningful improvement in symptom burden was defined as a decrease in the LSS score of ≥7 points. **One subject was determined to be unevaluable due to not having symptoms consistent with cGVHD at baseline; therefore, the graphs in Table 6 may be adjusted accordingly.

[0149] Best ORR (including CR) was evaluated for all affected organs. In the mITT population, organ-specific analysis demonstrated a best ORR of 37% for skin, 42% for eye, 55% for mouth, 39% for liver, 26% for lung, 71% for joints / fascia, 52% for upper gastrointestinal (GI) tract, 69% for lower GI tract, and 45% for esophagus. Fig. 9; Table 7). Overall, 7 subjects achieved CR in all affected organs. Of the 12 subjects with pulmonary reactions, 3 subjects were scored as CR based on normalization of FEV1 (median increase 23%; range: 18-25), and another 3 subjects were scored as CR based on a decrease in the NIH pulmonary symptom score from 1 to 0 in the absence of pulmonary function testing. An additional six subjects had a PR with an increase in FEV1 ≥10% (median increase of 10% for all subjects who achieved a PR; range: 0-15) or a decrease in the NIH pulmonary symptom score to 1 when pulmonary function testing was not available. Of the 41 subjects with skin reactions, 11 subjects had a decrease in cirrhotic features, 15 subjects had a decrease in body surface area involvement, and 13 subjects had an improvement in body surface area involvement and cirrhotic features. Two subjects had skin reactions based on the investigator's clinical assessment rather than the 2014 NIH consensus criteria.

[0150] Table 7. Summary of ORR by Dose and Organ System BID, twice daily; CR, complete response; GI, gastrointestinal; ORR, overall response rate; PR, partial response; QD, daily. **One subject was determined to be unevaluable due to not having symptoms consistent with cGVHD at baseline; therefore, the graphs in Table 6 may be adjusted accordingly.

[0151] The overall median time to response was 5 weeks (range: 4-66) ( Fig. 10A ). 91% of responses occurred within 6 months of treatment, and the remaining 9% of responses were seen after 6 to 12 months of treatment. 59% of responders maintained responses for ≥20 weeks. In the responder population, the median DOR was 54 weeks. The overall FFS rates at 6 and 12 months were 75% (95% CI, 66-81) and 56% (95% CI, 47-64), respectively ( Fig. 10B Overall, low nonrelapse mortality (NRM) (7%) and relapse rates (3%) were observed. The most common failure event was initiation of new systemic cGVHD therapy (38%). The 2-year OS rate was 89% (95% CI, 82-93) ( Fig. 10C ).

[0152] During treatment with besudil, 65% of subjects reduced their corticosteroid dose. In the mITT population, the mean corticosteroid dose was reduced by 45%, and in responders, the mean corticosteroid dose was reduced by 54%. Twenty-one percent of subjects discontinued corticosteroid therapy. In addition, 22% of those subjects successfully discontinued calcineurin inhibitor (CNI) therapy, and 20% and 21% of the subjects discontinued sirolimus and mycophenolate mofetil, respectively.

[0153] Clinically meaningful improvements (≥7 point reduction) from baseline in the 7-day LSS summary score were observed in 59% and 62% of the ITT population with besudil 200 mg once daily and 200 mg twice daily, respectively. Such improvements were observed in 69% and 71% of responders and 29% and 33% of non-responders in the besudil 200 mg once daily and 200 mg twice daily groups, respectively. Security

[0154] Besudiol is well tolerated, and the median RDI is 99.7%. 81% of subjects received RDI>95%. AEs were consistent with the expected AEs in patients with cGVHD receiving corticosteroid therapy and other immunosuppressive therapies (IST) (Table 8). 38% of subjects had ≥1 SAE; the most common was pneumonia (7%). The most common (≥5%) grade 3 or 4 AEs were pneumonia (8%), hypertension (6%) and hyperglycemia (5%). 24% of subjects had elevated liver function tests (LFTs); at baseline, 5% of subjects had elevated g-glutamyl transferase (GGT), 5% of subjects had elevated AST, 3% of subjects had elevated ALT, 3% of subjects had elevated LFTs, and 1% of subjects had increased bilirubin. The most common liver-related AE was elevated GGT (12%). Of the 83 subjects who discontinued treatment, 28 subjects (21%) discontinued due to overall AEs, 16 subjects (12%) discontinued due to possible drug-related AEs, 5 subjects (4%) discontinued due to progression of underlying malignant disease, and 21 subjects (16%) discontinued due to progression of cGVHD. Fourteen subjects died during the study, 2 due to multi-organ failure and infection possibly related to besudol, 2 due to cardiac arrest, 2 due to respiratory failure, 1 due to hemothorax on lung biopsy, 1 due to relapse of acute myeloid leukemia, and 6 during long-term follow-up (LTFU) (>28 days after the last dose). Anemia of grade ≥3 was reported in 3% of subjects, neutropenia in 2% of subjects, and thrombocytopenia in 2% of subjects. There was 1 case of Epstein-Barr viremia requiring treatment and 1 case of cytomegalovirus (CMV) reactivation; neither case was related to besudol treatment.

[0155] Table 8. Security Overview All data are n(%). *Six subjects died during long-term follow-up (LTFU) (>28 days after the last dose). **One subject was determined to be unevaluable due to not having symptoms consistent with cGVHD at baseline; therefore, the graphs in Table 8 may be adjusted accordingly.

[0156] The study of this Example 2 demonstrated promising efficacy and favorable safety profile of besudelin therapy for patients with steroid-resistant (SR) cGVHD. In the 200-mg once-daily treatment group and the 200-mg twice-daily treatment group, the study population (consisting of subjects with severe cGVHD with multi-organ involvement and fibrosis manifestations treated after a median of 3 previous systemic therapy lines) achieved a best ORR of 74% and 77%, respectively.

[0157] Responses to besudild were sustained and clinically meaningful, regardless of response to prior therapy, severity of cGVHD, and number of organs involved. Responses were observed in all organs, which is clinically meaningful because CRs and PRs were achieved in difficult-to-treat organs such as the lungs and liver, as well as organs with fibrotic manifestations such as the skin. cGVHD severely impairs quality of life, especially in patients with multi-organ involvement of fibrosis, and treatment of these patients can be challenging. The observation of CRs and PRs, as well as improvements in LSS, limited interactions, and lack of drug toxicity are promising results that demonstrate that besudild treatment may have the potential to improve patients' overall health. Seven subjects achieved CR in all affected organs. In cGVHD, CR may be difficult to achieve in all affected organs because irreversible changes occur in several organs, most notably the eyes and lungs. The clinical benefit and tolerability of besudild therapy demonstrate the potential to stop the expected cycle of therapy for cGVHD seen in clinical practice. In the 12-month analysis, 59% of responders had sustained responses for ≥20 weeks. At the 12-month analysis, among responders, the median DOR was 54 weeks.

[0158] In a patient population susceptible to AEs and infections caused by immunosuppressive therapy (IST), besudiil is well tolerated, allowing most subjects to continue to adhere to therapy to obtain clinically meaningful results and improvements in quality of life, which can be maintained by continuing treatment. Only 12% of subjects discontinued besudiil due to possible drug-related AEs. The median treatment duration was 10 months (range: 0.4-22.0), and after this time point, 37% of subjects continued to receive besudiil. AEs are manageable, and few ≥ grade 3 SAEs can be attributed to besudiil. The SAE rate between the two treatment groups is comparable. Many current cGVHD treatment options are immunosuppressive and therefore increase the risk of infection, which may cause hematologic toxicity, including leukopenia, anemia, and thrombocytopenia. There was ≥ grade 3 cytopenia in <4% of subjects, and there was only one report of cytomegalovirus (CMV) reactivation unrelated to besudiil treatment. Cytopenias and CMV infection present as serious complications of cGVHD and cGVHD treatment; therefore, the low rate of grade ≥3 cytopenias and low CMV infection rates are promising features of the safety profile of besudil.

[0159] In this study, all subjects received besudil. It is not considered appropriate to require randomization to the best available therapy because the subject has previously progressed after ≥2 lines of systemic therapy, with a historically low response rate. In fact, the subjects in this study had tried a median of 3 previous best available therapy lines for cGVHD before enrollment, with ECP (48%), ibrutinib (34%), ruxolitinib (29%) and rituximab (21%) being used in particular among all agents. In subjects with resistance to their last line of therapy, the best ORR was 75%. Example 3: Risk Management of Side Effects

[0160] In the previous clinical studies in Examples 1 and 2, 83 adult patients with chronic GVHD were treated with besudil 200 mg once daily. The median duration of treatment was 9.2 months (range: 0.5 to 44.7 months). Fatal adverse reactions were reported in one patient with severe nausea, vomiting, diarrhea, and multi-organ failure.

[0161] A fatal adverse reaction was reported in one patient with severe nausea, vomiting, diarrhea, and multi-organ failure.

[0162] Permanent discontinuation of besudil due to adverse reactions occurred in 18% of patients. Adverse reactions leading to permanent discontinuation of besudil in >3% of patients included nausea (4%). Adverse reactions leading to dose interruptions occurred in 29% of patients. Adverse reactions leading to dose interruptions in ≥2% of patients were infection (11%), diarrhea (4%), and (2% each) fatigue, dyspnea, hemorrhage, hypertension, abnormal liver function tests, nausea, pyrexia, edema, and renal failure.

[0163] The most common (≥20%) adverse reactions (including laboratory abnormalities) were infections, fatigue, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyl transferase, lymphocytopenia, and hypertension.

[0164] Table 9 summarizes the non-laboratory adverse reactions. Table 9. Non-laboratory adverse reactions in ≥10% of patients with chronic GVHD treated with besudil a Infections with unidentified pathogens included acute sinusitis, device-related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, dental infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis, or septic shock. b Including influenza, rhinovirus infection, gastroenteritis virus infection, viral upper respiratory tract infection, bronchitis virus infection, Epstein-Barr (EB) viremia, Epstein-Barr virus infection, parainfluenza virus infection, varicella-zoster virus infection, and viral infection. c These include cellulitis, Helicobacter infection, Staphylococcal bacteremia, catheter site cellulitis, Clostridium difficile colitis, Escherichia urinary tract infection, gastroenteritis, Escherichia coli infection, Pseudomonas infection, and bacterial urinary tract infection. d Including fatigue, weakness, and unexplained discomfort. e Including peripheral edema, systemic edema, facial edema, local edema, and edema. fIncluding nausea and vomiting. g Including abdominal pain, upper abdominal pain, and lower abdominal pain. h Including dyspnea, exertional dyspnea, apnea, orthopnea, and sleep apnea syndrome. i Including cough and cough with phlegm. j These include contusions, hematomas, epistaxis, increasing tendency to bruising, conjunctival hemorrhage, blood in the stool, oral bleeding, catheter site bleeding, hematuria, hemothorax, and purpura. k Including pain in the limbs, back pain, side abdominal pain, limb discomfort, musculoskeletal chest pain, neck pain, and musculoskeletal pain. l Including headaches and migraines. m Including rash, maculopapular rash, erythematous rash, systemic rash, and exfoliative dermatitis. n Includes pruritus and generalized pruritus.

[0165] Table 10 summarizes the laboratory abnormalities of besudil. Table 10. Selected laboratory abnormalities in patients with chronic GVHD treated with besudil.

[0166] Table 11 summarizes the recommended dose modifications of besudil for adverse reactions. *Based on CTCAE v 4.03 Example 4: US REZUROCK TM (Besudil) FDA label ---------------------------Indications and Usage--------------------------

[0168] REZUROCK is a kinase inhibitor indicated for the treatment of adult and pediatric patients 12 years of age and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.(1) -----------------------Dosage and administration----------------------

[0169] Recommended dose: 200 mg orally once daily with food. (2.1) ---------------------Dosage form and strength--------------------

[0170] Tablet: 200 mg. (3) ------------------------------Contraindications----------------------------

[0171] None. (4) ------------------------------------Warnings and precautions----------------------

[0172] Embryo-Fetal Toxicity: May cause harm to the fetus. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.1, 8.1, 8.3) ----------------------------Drug Interactions-----------------------------

[0173] Strong CYP3A inducers: Increase REZUROCK dose to 200 mg twice daily. (7.1) Proton Pump Inhibitors: Increase the dose of REZUROCK to 200 mg twice daily. (7.1) ------------------------------Adverse Reactions-----------------------------

[0174] The most common (≥20%) adverse reactions (including laboratory abnormalities) were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyl transferase, lymphocytopenia, and hypertension. (6.1) -----------------------Use in special populations-----------------------

[0175] Lactation: Breastfeeding is not recommended. (8.2) See 17 for patient counseling information and FDA-approved patient labeling. Full Prescribing Information 1 Indications and Usage

[0176] REZUROCK is indicated for the treatment of adult and pediatric patients 12 years of age and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. 2 Dosage and administration 2.1 Recommended Dosage

[0177] The recommended dose of REZUROCK is 200 mg, administered orally once daily until chronic GVHD progresses to the point where new systemic therapy is required.

[0178] Instruct patients as follows: Swallow REZUROCK tablets whole. Do not cut, crush, or chew the tablets. Take REZUROCK with meals at approximately the same time each day [see Clinical Pharmacology (12.3)]. If a dose of REZUROCK is missed, instruct patients not to take an additional dose to make up for the missed dose.

[0179] Treatment with REZUROCK has not been studied in patients with pre-existing severe renal or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with REZUROCK [see Clinical Pharmacology (12.3)]. 2.2 Dose adjustment for adverse reactions

[0180] Monitor total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at least monthly.Adjust the dose of REZUROCK for adverse reactions according to Table 12. Table 12: Recommended Dose Modifications of REZUROCK for Adverse Reactions *Based on CTCAE v 4.03 2.3 Dosage Adjustment Due to Drug Interactions Strong CYP3A inducers

[0181] When coadministered with strong CYP3A inducers, increase the dose of REZUROCK to 200 mg twice daily [see Drug Interactions (7.1)].

[0182] Proton pump inhibitors

[0183] When coadministered with a proton pump inhibitor, increase the dose of REZUROCK to 200 mg twice daily [see Drug Interactions (7.1)]. 3 Dosage forms and specifications

[0184] Each 200 mg tablet is a light yellow film-coated oval tablet with a debossed design of "KDM" on one side and a debossed design of "200" on the other side. 4 Contraindications

[0185] none. 5 Warnings and Precautions 5.1. Embryo-fetal toxicity

[0186] Based on findings in animals and its mechanism of action, REZUROCK may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of besudil to pregnant rats and rabbits during the period of organogenesis produced adverse developmental outcomes, including embryo-fetal mortality and malformations at maternal exposures (AUC) lower than these parameters in patients at the recommended dose. Advise pregnant women to be aware of the potential risk to the fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)]. 6 Adverse Reactions 6.1 Clinical Trial Experience

[0187] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chronic graft-versus-host disease

[0188] In two clinical trials (Study KD025-213 and Study KD025-208), 83 adult patients with chronic GVHD were treated with REZUROCK 200 mg once daily [see Clinical Studies (14.1)]. The median duration of treatment was 9.2 months (range, 0.5 to 44.7 months).

[0189] One patient reported fatal adverse reactions, including severe nausea, vomiting, diarrhea, and multi-organ failure.

[0190] Permanent discontinuation of REZUROCK due to adverse reactions occurred in 18% of patients. Adverse reactions leading to permanent discontinuation of REZUROCK in >3% of patients included nausea (4%). Adverse reactions leading to dose interruptions occurred in 29% of patients. Adverse reactions leading to dose interruptions in ≥2% were infections (11%), diarrhea (4%), and asthenia, dyspnea, hemorrhage, hypotension, abnormal liver function tests, nausea, pyrexia, edema, and renal failure (2% each).

[0191] The most common (≥20%) adverse reactions (including laboratory abnormalities) were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyl transferase, lymphocytopenia, and hypertension. Table 13 summarizes the non-laboratory adverse reactions. Table 13: Treatment with REZUROCK > Non-laboratory adverse reactions in 10% of patients with chronic GVHD aInfection by unspecified pathogens, including acute sinusitis, device-related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, dental infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis, and septic shock. bIncluding influenza, rhinovirus infection, viral gastroenteritis, viral upper respiratory tract infection, viral bronchitis, Epstein-Barr viremia, Epstein-Barr virus infection, parainfluenza virus infection, varicella-zoster virus infection, and viral infection. c Includes cellulitis, Helicobacter infection, staphylococcal bacteremia, catheter site cellulitis, Clostridium difficile colitis, Escherichia coli urinary tract infection, Escherichia coli gastroenteritis, Pseudomonas infection, and bacterial urinary tract infection. dIncludes fatigue, weakness, and asthenia. eIncludes peripheral edema, systemic edema, facial edema, local edema, and edema. fIncluding nausea and vomiting. gIncludes abdominal pain, upper abdominal pain, and lower abdominal pain. hIncludes dyspnea, dyspnea on exertion, apnea, orthopnea, and sleep apnea syndrome. iIncluding cough and wet cough. jIncludes contusions, hematomas, epistaxis, increasing tendency to bruising, conjunctival hemorrhage, hematochezia, oral hemorrhage, catheter site hemorrhage, hematuria, hemothorax, and purpura. kIncludes extremity pain, back pain, flank pain, extremity discomfort, musculoskeletal chest pain, neck pain, musculoskeletal pain. lIncluding headaches and migraines. mIncludes rash, maculopapular rash, erythematous rash, systemic rash, and exfoliative dermatitis. nIncluding itching and itching all over the body. Table 14 summarizes the laboratory abnormalities with REZUROCK. Table 14: Selected Laboratory Abnormalities in Patients with Chronic GVHD Treated with REZUROCK 7. Drug Interactions 7.1 Effects of Other Drugs on REZUROCK Strong CYP3A inducers

[0192] Coadministration of REZUROCK with strong CYP3A inducers decreases besudil exposure [see Clinical Pharmacology (12.3)], which may reduce the efficacy of REZUROCK. Increase the dose of REZUROCK when coadministered with strong CYP3A inducers [see Dosage and Administration (2.3)]. Proton pump inhibitors

[0193] Coadministration of REZUROCK with proton pump inhibitors decreases besudil exposure [see Clinical Pharmacology (12.3)], which may reduce the efficacy of REZUROCK. Increase the dose of REZUROCK when coadministered with proton pump inhibitors [see Dosage and Administration (2.3)]. 8 Use in special populations 8.1 Pregnancy Risk Overview

[0194] Based on findings from animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], REZUROCK may cause fetal harm when administered to a pregnant woman. There are no available human data on the use of REZUROCK in pregnant women to evaluate the drug-associated risk. In animal reproduction studies, administration of besudil to pregnant rats and rabbits during the period of organogenesis produced adverse developmental outcomes, including growth alterations, embryo-fetal mortality, and embryo-fetal malformations at maternal exposures (AUC) that were approximately ≥3 times (rats) and ≥0.07 times (rabbits) those at the human exposure (AUC) at the recommended dose (see Animal Data). Inform pregnant women and females of reproductive potential of the potential risk to a fetus.

[0195] In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. data Animal data

[0196] Embryo-fetal development studies were conducted in rats, where besudil was administered to pregnant animals at oral doses of 25, 50, 150 and 300 mg / kg / day during the organogenesis period in a pilot study, and at doses of 15, 50 and 150 mg / kg / day in a pivotal study. In the pilot study, maternal toxicity and embryo-fetal development effects were observed. Maternal toxicity (reduced weight gain) occurred at doses of 150 and 300 mg / kg / day. Increased post-implantation loss occurred at 50 and 300 mg / kg / day. Fetal malformations were observed at ≥50 mg / kg / day, including the absence of anus and tail, umbilicus protrusion and dome-shaped head. The exposure (AUC) of rats at 50 mg / kg / day was approximately 3 times that of humans at the recommended dose of 200 mg.

[0197] In the embryo-fetal development study of rabbits, oral doses of besudil were administered to pregnant animals during the organogenesis period at 50, 125 and 225 mg / kg / day, resulting in maternal toxicity and embryo-fetal developmental effects. Maternal toxicity (weight loss and death) was observed at doses of ≥125 mg / kg / day. Embryo-fetal effects, including spontaneous abortion, increased post-implantation loss, decreased percentage of live fetuses, malformations and reduced fetal weight, were observed at doses of >50 mg / kg / day. Malformations included the following malformations: tail (short), ribs (branched, fused or deformed), sternum (fused) and neural arches (fused, dislocated and deformed). The exposure (AUC) of rabbits at a dose of 50 mg / kg / day was approximately 0.07 times that of humans at the recommended dose of 200 mg. 8.2 Lactation Risk Overview

[0198] There are no available data regarding the presence of besudil or its metabolites in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions from besudil in the breastfed child, advise lactating women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose. 8.3 Females and Males of Reproductive Potential

[0199] REZUROCK may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy test

[0200] Verify the pregnancy status of females of reproductive potential prior to initiating treatment with REZUROCK. contraception measure female

[0201] Advise females of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose of REZUROCK. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. male

[0202] Advise males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose of REZUROCK. Infertility female

[0203] Based on findings in rats, REZUROCK may impair female fertility. The effects on fertility were reversible [see Nonclinical Toxicology (13.1)]. male

[0204] Based on findings in rats and dogs, REZUROCK may impair male fertility. The effects on fertility were reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use

[0205] The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years of age and older. The use of REZUROCK in this age group is supported by evidence from adequate and rigorously controlled studies of REZUROCK in adults, in which additional population pharmacokinetic data demonstrated that age and body weight have no clinically meaningful effects on the pharmacokinetics of the drug substance, that exposure to the drug substance is expected to be similar between adult patients and pediatric patients 12 years of age and older, and that the course of disease is sufficiently similar in adult and pediatric patients to allow extrapolation of data from adult patients to pediatric patients.

[0206] The safety and effectiveness of REZUROCK have not been established in pediatric patients less than 12 years of age. 8.5 Elderly Use

[0207] Of the 186 patients with chronic GVHD in clinical studies of REZUROCK, 26% were 65 years and older. No clinically meaningful differences in the safety or effectiveness of REZUROCK were observed compared to younger patients. 11 Drug instructions

[0208] Besudiol is a kinase inhibitor. The active pharmaceutical ingredient is besudiol mesylate, with a molecular formula of C27H28N6O5S and a molecular weight of 548.62 g / mol. The chemical name of besudiol mesylate is 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide mesylate (1:1). The chemical structure is as follows:

[0209] Besudil mesylate is a yellow powder that is practically insoluble in water, slightly soluble in methanol and DMF, and soluble in DMSO.

[0210] REZUROCK tablets are for oral administration. Each tablet contains 200 mg of free base, equivalent to

[0211] 242.5 mg besudil mesylate. The tablets also contain the following inactive ingredients: microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0212] The tablet film consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and yellow iron oxide. 12 Clinical Pharmacology 12.1 Mechanism of Action

[0213] Besudild is an inhibitor of rho-associated coiled-coil-containing protein kinase (ROCK), which inhibits ROCK2 and ROCK1 with IC50 values ​​of approximately 100 nM and 3 μM, respectively. Besudild downregulates proinflammatory responses in ex vivo or in vitro human T cell assays by modulating STAT3 / STAT5 phosphorylation and altering the Th17 / Treg balance. In vitro, besudild also inhibits aberrant profibrotic signaling. In vivo, besudild exhibits activity in animal models of chronic GVHD. 12.2 Pharmacodynamics

[0214] The exposure-response relationship and time course of the pharmacodynamic response to besudil have not been determined. 12.3 Pharmacokinetics

[0215] Unless otherwise specified, the following pharmacokinetic parameters are presented for chronic GVHD patients dosed with 200 mg of besudiil once daily. The mean (coefficient of variation, CV%) steady-state AUC and Cmax of besudiil were 22700 (48%) h·ng / mL and 2390 (44%) ng / mL, respectively. The Cmax and AUC of besudiil increased in a roughly proportional manner over the dose range of 200 and 400 mg (1 to 2 times, once daily, the recommended dose). The accumulation ratio of besudiil was 1.4. absorb

[0216] Following once-daily or twice-daily dosing of 200 mg besudil in patients, the median Tmax of besudil at steady state ranged from 1.26 to 2.53 hours. Following a single besudil dose in healthy subjects, the mean (CV%) bioavailability was 64% (17%). Effects of food

[0217] In healthy subjects, the Cmax and AUC of besudil increased 2.2-fold and 2-fold, respectively, following administration of a single besudil dose with a high-fat, high-calorie meal (800 to 1,000 calories, approximately 50% of total caloric content from fat) compared to the fasting state. The median Tmax was delayed by 0.5 hours. distributed

[0218] Following a single dose of besudil in healthy subjects, the geometric mean volume of distribution was 184 L (geoCV% 67.7%).

[0219] In vitro, the binding rates of besudil to human serum albumin and human α1-acid glycoprotein were 99.9% and 98.6%, respectively. eliminate

[0220] In patients, the mean (CV%) elimination half-life of besudil was 19 hours (39%) and the clearance was 9.83 L / hour (46%). metabolism

[0221] In vitro, besudil is metabolized primarily by CYP3A4 and, to a lesser extent, by CYP2C8, CYP2D6, and UGT1A9. excretion

[0222] Following a single oral dose of radiolabeled besudil in healthy subjects, 85% of the radioactivity was recovered in the feces (30% unchanged) and less than 5% of the radioactivity was recovered in the urine. Special Populations

[0223] The age (18 to 77 years), sex, weight (38.6 to 143 kg), or mild to moderate renal impairment (eGFR ≥ 60 and < 90 mL / min / 1.72 m 2 To eGFR ≥ 30 and < 60 mL / min / 1.72 m 2 ), no clinically significant differences in besudild pharmacokinetics were observed. The effect of severe renal impairment on the pharmacokinetics of besudild has not been studied. Drug interaction studies The impact of other drugs on clinical studies of besudil and model-guided approaches

[0224] Strong Cytochrome P450 (CYP) 3A Inhibitors: There were no clinically meaningful effects on besudil exposure when co-administered with itraconazole in healthy subjects.

[0225] Strong CYP3A inducers: In healthy subjects, co-administration of rifampin decreased the Cmax of besudil by 59% and the AUC of besudil by 72%.

[0226] Moderate CYP3A Inducers: In healthy subjects, co-administration of efavirenz is predicted to decrease the Cmax of besudil by 32% and the AUC of besudil by 35%.

[0227] Proton Pump Inhibitors: In healthy subjects, co-administration of rabeprazole decreased the Cmax of besudil by 87% and the AUC of besudil by 80%, and omeprazole decreased the Cmax of besudil by 68% and the AUC of besudil by 47%. Effects of Besudil on other drugs

[0228] CYP3A Substrates: Co-administration of besudil is expected to increase the Cmax and AUC of midazolam, a sensitive CYP3A substrate, by approximately 1.3-fold and 1.5-fold, respectively.

[0229] CYP2C9 Substrates: Co-administration of besudil is not expected to have a clinically meaningful effect on the exposure of CYP2C9 substrates (e.g., warfarin).

[0230] CYP2C8 Substrates: Coadministration of besudil is not expected to have a clinically meaningful effect on the exposure of CYP2C8 substrates that are not OATP1B1 substrates. In vitro studies Transporter systems: Besudild is a substrate of P-gp. Besudild inhibits BCRP, P-gp, and OATP1B1 at clinically relevant concentrations. Enzyme systems: Besudil is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1, and UGT1A9. 13 Nonclinical Toxicology 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[0231] Carcinogenicity studies have not been conducted with besudil.

[0232] Besudil was not genotoxic in the in vitro bacterial mutagenicity (Ames) assay, the in vitro chromosome aberration assay in human peripheral blood lymphocytes (HPBL), or the in vivo rat bone marrow micronucleus assay.

[0233] In a combined male and female rat fertility study, male animals treated with besudil were mated with untreated female animals, or untreated male animals were mated with female animals treated with besudil. Besudil was orally administered to male rats at a dose of 50, 150 or 275 mg / kg / day 70 days before mating and throughout the mating period, and was orally administered to female rats 14 days before mating and until the 7th day of gestation. At a dose of 275 mg / kg / day, adverse findings in female rats (treated with besudil or untreated but mated with treated male rats) included increased pre-implantation or post-implantation losses and reduced numbers of viable embryos. Administration of besudil to male rats at a dose of 275 mg / kg / day resulted in the discovery of sperm abnormalities (reduced motility, decreased counts, and increased percentages of abnormal sperm) and testicular / epididymal organ changes (weight loss and degeneration).

[0234] At 275 mg / kg / day, fertility was reduced in treated males or females and reached statistical significance in males. Adverse changes in male and female reproductive organs also occurred in general toxicology studies; findings included sperm degeneration in dogs at 35 mg / kg / day of besudol and reduced follicular development in the ovaries of rats at 275 mg / kg / day. Changes were partially or completely reversed during recovery. Exposures (AUC) in dogs at 35 mg / kg / day and in rats at 275 mg / kg / day were 0.5 times and 8-9 times, respectively, the clinical exposure at the recommended dose of 200 mg per day. 14 Clinical Research 14.1 Chronic Graft-Versus-Host Disease

[0235] Study KD025-213 (NCT03640481) is a randomized, open-label, multicenter study investigating REZUROCK for the treatment of patients with chronic GVHD who have received 2 to 5 prior lines of systemic therapy and require additional therapy. Patients were excluded from the study if they had: platelets <50×10 9 / L; absolute neutrophil count <1.5×10 9 / L; AST or ALT>3×ULN; total bilirubin>1.5×ULN; QTc(F)>480ms; eGFR<30mL / min / 1.73m 2; or FEV1 ≤ 39%. 66 patients were treated with REZUROCK 200 mg orally once daily. Concomitant treatment with supportive care therapy for chronic GVHD was allowed. Concomitant treatment with GVHD prophylaxis and standard of care systemic chronic GVHD therapy was allowed as long as the subject had been taking a stable dose for at least 2 weeks prior to the study. No new systemic chronic GVHD therapy was allowed to be started during the study.

[0236] Demographic data and baseline characteristics are summarized in Table 15.

[0237] Table 15: Demographics and Baseline Characteristics of Patients with Chronic GVHD a The denominator excludes patients whose status is unknown b Prednisone equivalent / kg

[0238] The efficacy of REZUROCK is based on the overall response rate (ORR) by day 1 of cycle 7, where an overall response includes a complete response or a partial response according to the 2014 NIH response criteria. The ORR results are presented in Table 16. The ORR was 75% (95% CI: 63, 85). The median duration of response calculated from the first response to progression, death, or new systemic therapy for chronic GVHD was 1.9 months (95% CI: 1.2, 2.9). The median time to first response was 1.8 months (95% CI: 1.0, 1.9). Among patients who achieved a response, 62% (95% CI: 46, 74) of patients had not died or started new systemic therapy for at least 12 months since the start of the response. Table 16: Overall Response Rates by Cycle 7 Day 1 in Chronic GVHD Patients in Study KD025-213 a Estimate using the Clopper-Pearson method

[0239] The ORR results were supported by an exploratory analysis of patient-reported symptom bother, which showed that 52% (95% CI: 40, 65) of patients had a reduction of at least 7 points in the Lee Symptom Scale total score by Day 1 of Cycle 7. 16 How to supply / Storage and handling

[0240] REZUROCK 200 mg tablets are supplied as light yellow film-coated oval tablets containing 200 mg of besudil (equivalent to 242.5 mg of besudil mesylate). Each tablet has a debossed pattern "KDM" on one side and a debossed pattern "200" on the other side and is packaged as follows:

[0241] 30 200 mg tablets per bottle: NDC 79802-200-30

[0242] Store at room temperature 20°C to 25°C (68°F to 77°F); short-term travel permitted at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

[0243] Dispense to patients only in the original container. Store in the original container to protect from moisture. Close cap tightly after each opening. Do not discard desiccant. 17 Patient Counseling Information

[0244] Advise patients to read the FDA-approved patient labeling (Patient Information). Embryo-fetal toxicity : Inform pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose [see Warnings and Precautions (5.1)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose [see Use in Specific Populations (8.2)]. Infertility Inform males and females of reproductive potential that REZUROCK may impair fertility [see Use in Specific Populations (8.3)]. Drug administration Inform patients to take REZUROCK orally once daily with food as directed by their physician and that the oral dose (tablet) should be swallowed whole with a glass of water at approximately the same time each day without cutting, crushing, or chewing the tablet [see Dosage and Administration (2.1)]. Advise patients that if they miss a daily dose of REZUROCK, they should take it as soon as possible on the same day and resume their normal schedule the next day. Patients should not take an additional dose to make up for the missed dose [see Dosage and Administration (2.1)]. Drug interactions Advise patients to inform their healthcare provider of all concomitant medications, including prescription and over-the-counter medicines, vitamins, and herbal products [see Drug Interactions (7)].

[0245] Although the present invention has been described in considerable detail by way of illustration and example for purposes of clarity and understanding, the description and example should not be construed as limiting the scope of the present invention. The disclosures of all patents and scientific literature cited in this application are expressly incorporated into this application in their entirety by reference.

Claims

1. Use of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound) for patients who experience one or more treatment-related adverse reactions when receiving a clinically recommended dose of the compound, the use comprising: If the patient experiences at least one adverse reaction of grade 3 or higher, discontinuing administration of the compound to the patient; as well as If the at least one adverse reaction does not escalate to Grade 4 level and the patient recovers to Grade 1 level or lower after treatment cessation, dosing of the compound is resumed at the clinically recommended dose for the patient.

2. The method according to claim 1, comprising the steps of: (a) administering the compound to the patient at a clinically recommended dose for the patient; (b) monitoring the patient for adverse reactions; (c) if the patient experiences at least one Grade 3 adverse reaction, stopping administration of the compound to the patient; as well as (d) when at least one adverse reaction in said patient has recovered to Grade 1 or less, resuming administration of said compound to said patient.

3. The use according to claim 1 or 2, wherein at least one adverse reaction of the patient has recovered to grade 0 after stopping administration of the compound.

4. The use according to claim 1, comprising the following steps: If the patient experiences at least one adverse reaction of grade 4, administration of the compound to the patient is permanently discontinued.

5. The method according to any one of claims 2 to 3, wherein the patient is monitored for adverse reactions at least once a month.

6. Use according to any one of claims 1 to 5, wherein the compound is besudil mesylate.

7. The use according to any one of claims 1 to 6, wherein the clinically recommended dose for the patient is 200 mg a day before and after the patient experiences at least one treatment-related adverse reaction.

8. The use according to any one of claims 1 to 7, wherein the clinically recommended dose for the patient is 200 mg, taken once a day with food.

9. The use according to any one of claims 1 to 6, wherein the clinically recommended dose for the patient is 400 mg a day before and after the patient experiences at least one treatment-related adverse reaction.

10. The use according to any one of claims 1 to 3 or claims 5 to 9, wherein after the patient recovers to Grade 1 level or lower and administration of the compound is resumed, the clinically recommended dose for the patient is reduced.

11. The use according to any one of claims 1 to 10, wherein the clinically recommended dose for the patient is in the range of 200 mg a day to 400 mg a day.

12. The use according to any one of claims 1 to 11, wherein the patient suffers from chronic graft-versus-host disease (cGVHD).

13. The use according to claim 12, wherein the patient has failed at least two previous lines of systemic therapy for the cGVHD.

14. The use according to any one of claims 1 to 13, wherein at least one adverse reaction of the patient is graded according to the Common Terminology Assessment Criteria for Adverse Events (CTCAE).

15. The method of any one of claims 1 to 14, wherein the at least one adverse reaction is infection, fatigue, nausea, diarrhea, dyspnea, cough, edema, bleeding, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyl transferase, decreased lymphocytes, or hypertension.

16. The use according to claim 14, wherein the at least one adverse reaction is viral infection, bacterial infection or infection by an unknown pathogen.

17. The use according to claim 16, wherein the infection with unknown pathogens is acute sinusitis, device-related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, dental infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis or septic shock.

18. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is fatigue, edema or fever.

19. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is gastrointestinal dysfunction.

20. The use according to claim 19, wherein the gastrointestinal dysfunction is nausea, diarrhea, abdominal pain or dysphagia.

21. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a respiratory disorder, a chest disorder or a mediastinal disorder.

22. The use according to claim 21, wherein the respiratory disorder, chest disorder or mediastinal disorder is dyspnea, cough or nasal congestion.

23. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a vascular disorder.

24. The use according to claim 23, wherein the vascular disorder is bleeding or hypertension.

25. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a musculoskeletal disorder or a connective tissue disorder.

26. Use according to claim 25, wherein the musculoskeletal disorder or connective tissue disorder is musculoskeletal pain, muscle spasm or arthralgia.

27. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a nervous system disorder.

28. The use according to claim 27, wherein the neurological disorder is headache or migraine.

29. The use according to any one of claims 1 to 14, wherein the at least one adverse reaction is a metabolic disorder.

30. The use according to claim 29, wherein the metabolic disorder is decreased appetite.

31. A method of treating a patient who experiences one or more treatment-related adverse reactions while receiving a clinically recommended dose of 2-{3-[4-(1H-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide or a pharmaceutically acceptable salt thereof (compound), the method comprising: If the patient experiences at least one adverse reaction of grade 3 or higher, discontinuing administration of the compound to the patient; as well as If the at least one adverse reaction does not escalate to Grade 4 level and the patient recovers to Grade 1 level or lower after treatment cessation, dosing of the compound is resumed at the clinically recommended dose for the patient.

32. The method of claim 31, wherein the patient experiences at least one adverse reaction at the Grade 3 level, the method comprising resuming administration of the compound to the patient when the patient's at least one adverse reaction has recovered to Grade 1 or lower.

33. The method of claim 31, wherein the patient experiences at least one Grade 4 adverse event, the method comprising permanently stopping administration of the compound to the patient.

34. The method according to claim 31 or 32, wherein the clinically recommended dose for the patient is in the range of 200 mg a day to 400 mg a day.

35. The method according to any one of claims 31 to 34, wherein the clinically recommended dose for the patient is in the range of 200 mg a day to 400 mg a day.

36. The method according to any one of claims 31 to 34, wherein the clinically recommended dose for the patient is 200 mg a day.

37. The method of any one of claims 31 to 32 or 34 to 36, wherein after the patient recovers to Grade 1 level or less and administration of the compound is resumed, the clinically recommended dose is reduced compared to the clinically recommended dose administered to the patient before the at least one adverse reaction occurred.

38. The method according to any one of claims 31 to 37, wherein the compound is besudil mesylate.

39. The method according to any one of claims 31 to 38, or the use according to any one of claims 1 to 11, wherein the patient suffers from chronic graft-versus-host disease (cGVHD).

40. The method of claim 39, wherein the patient has failed at least two prior lines of systemic therapy for the cGVHD.

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