Use of brigatinib to treat cancer in pediatric patients.

Description

1 / 60 Use of brigatinib to treat cancer in pediatric patients. Divided from BR 11 2020 018770 4, deposited on 03 / 18 / 2019

[001] This application claims priority over U.S. Provisional Application No. 62 / 645,089, filed March 19, 2018, the entirety of which is incorporated herein by reference. FIELD OF THE INVENTION

[002] This document provides methods for the treatment of cancers (e.g., inflammatory myofibroblastic tumor and anaplastic large cell lymphoma) in pediatric patients using brigatinib, as monotherapy or in combination with one or more secondary therapeutic agents. FUNDAMENTALS OF THE INVENTION

[003] Brigatinib is a novel orally administered (PO) tyrosine kinase inhibitor (TKI). Brigatinib potently inhibits activated variants of anaplastic lymphoma kinase (ALK).

[004] ALK is a tyrosine kinase encoded on chromosome 2 that plays a physiological role in early brain development. Expression levels are low in adults; however, ALK can be altered and become active in several malignant diseases, including non-small cell lung cancer (NSCLC), an adult disease, as well as inflammatory myofibroblastic tumor (IMT) and anaplastic large cell lymphoma (ALCL), which predominantly affect pediatric or young adult patients. In each of these conditions, the most frequent ALK alterations involve the formation of fusion genes due to chromosomal rearrangements. Holla et al., Cold Spring Harb. Mol. Case Stud. 2017, 3(1), a001115. The first ALK genetic rearrangement discovered in NSCLC involved a fusion between the microtubule-associated protein-like protein 4 (EML4) gene of Petition 870260054695, dated 05 / 06 / 2026, p. 13 / 86 2 / 60 echinoderm and the tyrosine kinase (KD) domain of ALK. Since then, a number of additional ALK fusion partners have been described that are believed to result in aberrant signaling and oncogenic transformation. Rikova et al., Cell 2007, 131(6), 1190-203; Takeuchi et al., Clin. Cancer Res. 2009, 15(9), 3143-9. In contrast to the fusion genes seen in NSCLC, IMT, and ALCL, activating full-length ALK mutations without rearrangement occur in neuroblastoma, another predominantly pediatric cancer. Holla et al., 2017.

[005] Three ALK inhibitors, crizotinib, ceritinib, and alectinib, are approved in Europe for the treatment of patients with advanced anaplastic lymphoma kinase-positive (ALK+) NSCLC. In addition, brigatinib has received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of metastatic ALK+ NSCLC in patients who have progressed on or are intolerant to crizotinib, and the European Marketing Authorisation Application (MAA) for the use of brigatinib in the treatment of patients with ALK+ NSCLC who have previously been treated with crizotinib is under review. Although the ALK inhibitor crizotinib is an effective treatment for ALK+ NSCLC, 26% to 35% of patients do not respond, and most progress within 1 year.Ultimately, ALK-dependent resistance mechanisms are observed in approximately 30% of NSCLC patients treated with crizotinib, primarily due to the acquisition of secondary mutations in the ALK fusion gene that interfere with crizotinib binding and / or amplification. Gainor et al., Clin. Cancer Res. 2013, 19(15), 4273-81; Katayama et al., Clin. Cancer Res. 2015, 21(10), 2227-35; Toyokawa et al., J. Thorac. Oncol. 2015, 10(7), e55-7. Importantly, newer agents, including brigatinib, have demonstrated the ability to overcome many of these resistance mechanisms. Zhang et al., Clin. Cancer Res. 2016, 22(22), 5527-38. In in vitro studies, brigatinib was a more potent ALK inhibitor than crizotinib. Petition 870260054695, dated 05 / 06 / 2026, p. 14 / 86 3 / 60 ceritinib and alectinib, and is the only one of these agents to maintain substantial activity against all 17 secondary ALK mutants of EML4-ALK tested at relevant exposure levels achieved in patients.

[006] In addition to promising non-clinical findings, brigatinib demonstrated substantial systemic and intracranial responses in a first-in-human study (FIH) (Study AP26113-11-101) and a phase 2 study (Study AP26113-13-201; the ALTA trial) among adult patients with ALK+ NSCLC who were refractory to crizotinib. In ALTA, robust objective response rates (ORR) and durability of response were observed with a dose of 180 mg per day, which was initiated after a 7-day introduction with 90 mg per day (90^180 mg once daily (QD)). In this study, investigator-confirmed ORR, duration of response (DOR), and progression-free survival (PFS) at the 90^180 mg QD dose were 55.5% and 13.8 and 15.6 months, respectively.A phase 3 trial (Study AP26113-13-301; ALTA 1L) is underway with the primary objective of comparing the efficacy of brigatinib to crizotinib based on PFS in patients with locally advanced ALK+ or metastatic NSCLC who are not exposed to ALK inhibitor treatment.

[007] NSCLC is primarily an adult disease, as cases are extremely rare in children and adolescents. However, as mentioned earlier, ALK is rearranged, mutated, or amplified in a variety of tumors relevant to the pediatric population, including IMT, ALCL, and neuroblastoma. Therefore, ALK remains a rational therapeutic target for pediatric patients with these conditions. Takita, Cancer Sci. 2017, 108(10), 1913-20.

[008] The first of these cancers, IMT, is a very rare solid tumor characterized by spindle-shaped myofibroblastic cells with a chronic inflammatory component that occurs mainly in children and adolescents, Petition 870260054695, dated 05 / 06 / 2026, p. 15 / 86 4 / 60 mainly in the lung, soft tissues, and abdominal region. Chromosomal translocations leading to ALK activation are present in 50% to 70% of IMTs and are more common at younger ages; the most common are tropomyosin 3 / 4 (TPM3 / 4)-ALK fusions, but, as in NSCLC, EML4-ALK inversions are also observed. Alaggio et al., Cancer 2009, 116(1), 216-26; Griffin et al., Cancer Res. 1999, 59(12), 2776-80; Antonescu et al., Am. J. Surg. Pathol. 2015, 39(7), 957-67. Treatment of IMT is generally limited to surgical resection, and there are no standard pharmacological approaches for advanced / recurrent disease or when complete resection is not possible. Dalton et al., J. Pediatr. Surg. 2016, 51(4), 541-4.

[009] The second of these conditions, ALCL, is a rare form (~110 new cases / year in Europe) of non-Hodgkin lymphoma (NHL) that also occurs predominantly in children and adolescents. It is characterized by the proliferation of lymphoid T cells or null cells expressing CD30. Up to 90% of pediatric patients with ALCL have ALK+ disease, while adult patients with ALCL are less frequently ALK positive (50%). Damm-Welk et al., Blood 2007, 110(2), 670-7; Gustafson et al., Ann. Diagn. Pathol. 2009, 13(6), 413-27. Translocations involving nucleophosmin 1 (NPM1)-ALK and TPM3-ALK fusions account for 75% to 80% and 12% to 18%, respectively, of ALK+ ALCL. Holla et al., 2017; Pulford et al., J. Cell Physiol. 2004, 199(3), 330-58. ALCL is highly chemosensitive and various chemotherapy regimens have been used in both frontline and refractory settings.

[010] Finally, neuroblastoma is a rare malignant disease in childhood (<100 new ALK+ cases / year in Europe), originating from the embryonic sympathetic nervous system. Unlike IMT and ALCL, where ALK translocations predominate, activating point mutations of ALK are important. Petition 870260054695, dated 05 / 06 / 2026, p. 16 / 86 5 / 60 drivers of oncogenesis in neuroblastoma, with ALK mutations present in almost all cases of familial neuroblastoma and between 6% and 10% of spontaneous disease. Louis et al., Annu. Rev. Med. 2015, 66, 49-63; Mosse et al., Nature 2008, 455(7215), 930-5. Other significant driving oncogenes are well established in neuroblastoma, the most prominent being MYCN amplification. Standard treatments for neuroblastoma involve chemotherapy, resection, radiotherapy, biological treatments, and immunotherapy, depending on risk status. Berlanga et al., Expert Opin. Emerg. Drugs 2017, 22(1), 63-75.

[011] With regard to IMT, there are no approved or rigorously studied pharmacological approaches for the management of this condition. As such, patients who are ineligible for resection due to complex lesions or other factors represent the greatest unmet need of the IMT patient population. Therefore, new agents that can control unresectable lesions or serve as neoadjuvant therapy to enable resection are needed and would represent a major advance for these patients.

[012] Today, most European pediatric groups use the ALCL99 chemotherapy regimen as standard therapy for ALCL. This approach is derived from the BFM protocol previously used in aggressive B-cell NHL. Treatment regimens differ somewhat between studies, but generally involve cyclophosphamide, doxorubicin, vincristine, corticosteroids, ifosfamide, and etoposide administered for 4 to 6 months, with high-dose methotrexate and cytarabine for central nervous system (CNS) prophylaxis. Eyre et al., European Journal of Haematology 2014, 93(6), 455-68; Turner et al., Br. J. Haematol. 2016, 173(4), 560-72. The EFS rate observed in the largest of the ALCL99-based studies completed to date was 73% at 2 years. After initial therapy, approximately 20% to 40% of patients with ALCL Petition 870260054695, dated 05 / 06 / 2026, page 17 / 86 6 / 60 subsequently develop recurrent disease. Patients at highest risk of recurrence appear to be those with MDD+ status and anti-ALK antibody titers <1 / 750. Mussolin et al., Leukemia 2013, 27(2), 416-22. However, a primary goal of ongoing research should include identifying treatment regimens that prevent recurrence in patients with known high-risk ALCL, and there is a significant unmet need for improved therapies for these patients. Consequently, ALCL patients exhibiting high-risk characteristics (e.g., MDD at diagnosis or low ALK antibody titers) may benefit from more aggressive or diverse frontline interventions that lead to a deeper response, aiming to prevent or avoid recurrence, particularly since recurrence is associated with a poor prognosis. SUMMARY

[013] This document provides methods for treating cancer in a pediatric cancer patient, comprising administering to the patient a therapeutically effective amount of Compound A of the formula: or a pharmaceutically acceptable salt thereof. Compound A may be administered as monotherapy or in combination therapy with one or more second-line therapeutic agents.

[014] In one modality, the cancer is inflammatory myofibroblastic tumor (IMT), anaplastic large cell lymphoma (ALCL), or neuroblastoma. In a Petition 870260054695, dated 05 / 06 / 2026, page 18 / 86 In the 7 / 60 modality, the cancer is either inflammatory myofibroblastic tumor (IMT) or anaplastic large cell lymphoma (ALCL).

[015] This document also provides pharmaceutical compositions, dosage forms, dosage regimens and kits that can be used in conjunction with the methods described above. BRIEF DESCRIPTION OF THE FIGURES

[016] Figure 1 shows a comparison of simulated systemic brigatinib exposures (AUC) in pediatric patients receiving 40 mg / m2 of the oral solution versus adult patients receiving 90 mg of the oral tablet.

[017] Figure 2 shows an overview of clinical studies for brigatinib.

[018] Figure 3 shows the proposed doses for brigatinib for clinical study 1. DETAILED DESCRIPTION DEFINITIONS

[019] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as commonly understood by one skilled in the art to which this disclosure pertains. All patents, applications, published applications and other publications referred to in this document are incorporated by reference in their entirety. The headings used in this document are for organizational purposes only and in no way limit the invention described herein.

[020] As used in this document and unless otherwise specified, the term administer or administration refers to the act of physically transmitting a substance from the way it exists outside the body into a patient, such as by oral, mucosal, intradermal, intravenous, intramuscular and / or any other method of physical transmission described in this document or known in the art. When a disease, Petition 870260054695, dated 05 / 06 / 2026, page 19 / 86 8 / 60 When a disorder or condition, or a symptom thereof, is being treated, the substance is typically administered after the onset of the disease, disorder or condition or its symptoms. When a disease, disorder or condition, or its symptoms, are being prevented, the substance is typically administered before the onset of the disease, disorder or condition or its symptoms.

[021] As used in this document and unless otherwise specified, the terms treatment, treat, and treating shall encompass the full spectrum of intervention for a disease, disorder, or condition from which the subject is suffering, such as to alleviate, slow, stop, or reverse one or more symptoms of the disease, disorder, or condition, or to slow the progression of the disease, disorder, or condition, even if the disease, disorder, or condition is not actually eliminated. Treatment may include, for example, a decrease in the severity of a symptom, the number of symptoms, and / or the frequency of recurrence. Treatment of cancer may include, for example, inhibition of tumor growth, interruption of tumor growth, and / or regression of existing tumors.

[022] As used in this document and unless otherwise specified, the terms prevent, preventing and prevention include a method of delaying and / or stopping the onset of a disorder, disease or condition and / or its corresponding symptoms; preventing a subject from acquiring a disorder, disease or condition; or reducing the risk of a subject acquiring a disorder, disease or condition.

[023] As used in this document and unless otherwise specified, the terms alleviate and relieve refer to attenuating or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. Terms may also refer to the reduction of adverse effects associated with Petition 870260054695, dated 05 / 06 / 2026, p. 20 / 86 9 / 60 an active ingredient. Sometimes, the beneficial effects that a subject obtains from a prophylactic or therapeutic agent do not result in a cure for the disorder, disease, or condition.

[024] An improvement in cancer or cancer-related disease can be characterized as a complete or partial response. “Complete response” refers to an absence of clinically detectable disease with normalization of any previously abnormal radiographic study, bone marrow and cerebrospinal fluid (CSF), or abnormal monoclonal protein measurements. “Partial response” refers to at least approximately a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% decrease in all measurable tumor burden (i.e., the number of malignant cells present in the subject, or the measured volume of tumor masses, or the amount of abnormal monoclonal protein) in the absence of new lesions. The term “treatment” encompasses both a complete and partial response.

[025] As used in this document and unless otherwise specified, the terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[026] As used in this document and unless otherwise specified, the terms “tumor” and “solid tumor,” as used in this document, refer to all lesions and growth and proliferation of neoplastic cells, whether malignant or benign, and all precancerous and cancerous cells and tissues. “Neoplastic,” as used in this document, refers to any form of unregulated or unregulated cell growth, malignant or benign, resulting in abnormal tissue growth. Therefore, “neoplastic cells” include both malignant and benign cells with unregulated or unregulated cell growth. Petition 870260054695, dated 05 / 06 / 2026, page 21 / 86 10 / 60

[027] As used in this document and unless otherwise specified, the terms subject and patient are used interchangeably. As used in this document, a subject may be a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats, etc.) or a primate (e.g., monkey and human). In specific embodiments, the subject is a human. In one embodiment, the subject is a mammal (e.g., a human) possessing a disease, disorder, or condition described in this document. In another embodiment, the subject is a mammal (e.g., a human) at risk of developing a disease, disorder, or condition described in this document.

[028] As used in this document and unless otherwise specified, the term effective amount or therapeutically effective amount refers to the amount of a compound, or combination of one or more compounds when administered (e.g., sequentially or simultaneously) that elicits the desired biological or medicinal response, e.g., destroys target cancer cells or slows or halts cancer progression in a subject. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and the disease condition to be treated, e.g., the subject's weight and age, the severity of the disease condition, the route of administration, and the like, which can be easily determined by one skilled in the art. The term also applies to a dose that induces a particular response in target cells, e.g., reduction of platelet adhesion and / or cell migration.For example, the therapeutically effective amount of a combination therapy refers to the amounts of each therapeutic agent in the combination therapy that, when administered in combination, has a beneficial effect. In certain modalities, the beneficial effect is additive. In certain modalities, the... Petition 870260054695, dated 05 / 06 / 2026, page 22 / 86 The combined effect of 11 / 60 is synergistic. Furthermore, it should be recognized by one skilled in the art that, in the case of combination therapy, the amount of each therapeutic agent may be used independently in a “subtherapeutic amount,” that is, less than the therapeutically effective amount of the therapeutic agent alone.

[029] As used in this document and unless otherwise specified, the term a “subtherapeutic amount” of an agent or therapy is an amount less than the effective amount for that agent or therapy as a single agent, but when combined with an effective or subtherapeutic amount of another agent or therapy may produce a result desired by the physician, due to, for example, synergy in the resulting effective effects or reduced side effects.

[030] As used in this document and unless otherwise specified, combination therapy or “in combination with” refers to the use of more than one therapeutic agent to treat a specific disorder or condition. By “in combination with,” there is no intention to imply that the agents must be administered at the same time and / or formulated for delivery together, although such methods of delivery are within the scope of this disclosure.A therapeutic agent may be administered concurrently with, before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before) or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after) one or more other additional agents. Petition 870260054695, dated 05 / 06 / 2026, page 23 / 86 12 / 60 therapeutic agents in a combination therapy may also be administered on an alternating dosing schedule, with or without a rest period (e.g., no therapeutic agent is administered on certain days of the schedule). Administration of a therapeutic agent “in combination with” another therapeutic agent includes, but is not limited to, sequential administration and concomitant administration of the two agents. In general, each therapeutic agent is administered at a dose and / or on a time schedule determined for that specific agent. Higher combinations, e.g., triple therapy, are also contemplated in this document.

[031] As used in this document and unless otherwise specified, the term “concomitant administration” or “co-administration” refers to two or more therapeutic agents being administered to the same subject at the same time (simultaneously) or nearly at the same time. “Nearly at the same time” encompasses sequential administration where the time between administrations is due solely to the speed of the individual administering the active agents, rather than an intentional delay between administrations, for example, the time required for a single healthcare professional to administer a first therapeutic agent in accordance with accepted clinical practices and standards and then administer a second therapeutic agent in accordance with accepted clinical practices and standards.In one modality, "almost simultaneously" encompasses administrations within a time period of fifteen minutes or less, thirty minutes or less, one hour or less, two hours or less, six hours or less, up to about twelve hours or less. In another modality, concurrent administration occurs within a time period of no more than about fifteen minutes, no more than about thirty minutes, no more than about one hour, no more than... Petition 870260054695, dated 05 / 06 / 2026, p. 24 / 86 13 / 60 which is about two hours, or no more than about six hours, and does not extend beyond 12 hours.

[032] As used in this document and unless otherwise specified, the term “sequential administration” refers to the administration of at least two therapeutic agents at different times, whether the route of administration is identical or different. In a particular embodiment of sequential administration, the administration of one of the therapeutic agents is completed before the administration of the other or others begins. The delay between the administration of different therapeutic agents may be intentional, for example, for the purpose of achieving certain beneficial therapeutic effects. In one embodiment, the sequential administrations occur at a time separation of not less than about thirty minutes, not less than about one hour, not less than about two hours, not less than about six hours, not less than about twelve hours, or not less than about 24 hours.In one embodiment, the sequential administrations occur at a time interval of not less than about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, or even more. In another embodiment, the sequential administrations occur at a time interval of not less than 12 hours.

[033] As used in this document and unless otherwise specified, the term “synergistic effect” refers to a situation where the combination of two or more agents produces a greater effect than the sum of the effects of each of the individual agents. The term encompasses not only a reduction in the symptoms of the disorder being treated, but also, for example, an improved side effect profile, improved tolerability, improved patient adherence, improved efficacy, or any other improved clinical outcome. Petition 870260054695, dated 05 / 06 / 2026, p. 25 / 86 14 / 60

[034] As used in this document and unless otherwise specified, the term “about” or approximately means an acceptable error for a particular value determined by one skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term about or approximately means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term about or approximately means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[035] As used in this document and unless otherwise specified, the term pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter-ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. For reviews of suitable salts, see, for example, BERGE et al., J. Pharm. Sci. 66:1-19 (1977) and Remington: The Science and Practice of Pharmacy, 205th Ed., A. Gennaro, Lippincott Williams & Wilkins, 2000.Non-limiting examples of suitable acid salts include: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, lactic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Non-limiting examples of suitable base salts include: sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like, specifically such as isopropylamine, trimethylamine, etc. Petition 870260054695, dated 05 / 06 / 2026, page 26 / 86 15 / 60 diethylamine, triethylamine, tripropylamine and ethanolamine.

[036] As used in this document, the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption retardants and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except to the extent that any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the disclosure is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

[037] As used in this document, the terms “carrier,” “adjuvant,” or “vehicle” are used interchangeably in this document, and include any and all solvents, diluents and other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 205th Ed., A. Gennaro, Lippincott Williams & Wilkins, 2000 discloses various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation.Except to the extent that any conventional carrier medium is incompatible with the compounds of the disclosure, such as by producing any undesirable biological effect or interacting in some other harmful way with any other pharmaceutically acceptable component(s) of the composition, its use is contemplated and falls within the scope of this disclosure.

[038] Unless otherwise indicated, the compounds described in this Petition 870260054695, dated 05 / 06 / 2026, p. 27 / 86 The 16 / 60 document includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds that have the present structure except for the substitution of a hydrogen atom by a deuterium or tritium atom, or the substitution of a carbon atom by an enriched carbon13C or 14C atom are within the scope of the disclosure.

[039] Unless otherwise indicated, the compounds described in this document include all stereochemical forms of the structure, for example, R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of disclosure. In the compounds described in this document, where relative stereochemistry is defined, the diastereomeric purity of such a compound may be at least 80%, at least 90%, at least 95%, or at least 99%. As used in this document, the term diastereomeric purity refers to the amount of a compound with the represented relative stereochemistry, expressed as a percentage of the total amount of all diastereomers present. Treatment Methods

[040] In one embodiment, a method for treating cancer in a pediatric cancer patient is provided in this document, comprising administering to the patient a therapeutically effective amount of Compound A of the formula: or a pharmaceutically acceptable salt thereof. Petition 870260054695, dated 05 / 06 / 2026, page 28 / 86 17 / 60

[041] In one embodiment, a method for preventing cancer in a pediatric patient is provided in this document, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[042] Compound A is also known as brigatinib and has a chemical name of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine. Brigatinib is described in WO 2009 / 143389, which is incorporated herein by reference. Example 122 of WO 2009 / 143389 describes the synthesis of brigatinib. Several polymorphic forms of brigatinib are described in WO 2016 / 065028, which is incorporated herein by reference.

[043] Compound A, or a pharmaceutically acceptable salt thereof, may be administered as monotherapy or in combination therapy with one or more second-line therapeutic agents.

[044] In one modality, the patient is <22 years old. In one modality, the patient is <18 years old. In one modality, the patient is between >1 and <22 years old. In one modality, the patient is between >1 and <18 years old. In one modality, the patient is between 1 and 17 years old. In one modality, the patient is between >2 and <22 years old. In one modality, the patient is between >2 and <18 years old. In one modality, the patient is between 2 and 17 years old. In one modality, the patient is between >4 and <22 years old. In one modality, the patient is between >4 and <18 years old. In one modality, the patient is between 4 and 17 years old.

[045] In one embodiment, the cancer is anaplastic lymphoma kinase positive (ALK+). As used in this document and unless otherwise specified, an “ALK positive” (ALK+) cancer refers to a cancer Petition 870260054695, dated 05 / 06 / 2026, page 29 / 86 18 / 60 characterized by inappropriately high expression of an ALK gene or the presence of a mutation in an ALK gene that alters the biological activity of an ALK nucleic acid molecule or polypeptide. As used in this document and unless otherwise specified, an ALK mutation or mutant comprises one or more deletions, substitutions, or additions in the amino acid or nucleotide sequences of ALK or fragments thereof. ALK mutants also include ALK fusion proteins and ALK fusion genes. The ALK mutant may also include one or more deletions, substitutions, or additions, or a fragment thereof, provided that the mutant retains kinase phosphorylation activity.In one embodiment, the ALK mutant is EML4-ALK, a fusion between the echinoderm microtubule-associated protein type 4 (EML4) gene and the ALK tyrosine kinase domain, including any EML4-ALK secondary mutant, such as those described in U.S. Patent No. 9,611,283, the entirety of which is incorporated herein by reference.

[046] In one embodiment, ALK+ cancer is determined by an FDA-approved test or other tests known in the art. Tests that may be used include, for example, FoundationOne CDx™ (F1CDx) (an in vitro sequencing-based diagnostic device for the detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and selected gene rearrangements, as well as genomic signatures, including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens); VENTANA ALK (D5F3) CDx assay (qualitative detection of anaplastic lymphoma kinase protein (ALK) in formalin-fixed, paraffin-embedded (FFPE) instrument-stained non-small cell lung carcinoma (NSCLC) tissue) Petition 870260054695, dated 05 / 06 / 2026, page 30 / 86 19 / 60 BenchMark XT or BenchMark ULTRA automated staining); and the Vysis ALK Break Apart FISH Probe Kit test (a qualitative test to detect rearrangements involving the ALK gene via fluorescence in situ hybridization (FISH) in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens). In one embodiment, the test is a fluorescence in situ hybridization (FISH) test, for example, the Vysis ALK Break Apart FISH Probe Kit test. Additional information for FDA-approved tests can be found at, for example, https: / / www.fda.gov / MedicalDevices / ProductsandMedicalProcedures / InVitroDiagnostics / ucm303030.htm; Additional information for the Vysis ALK Break Apart Fish Probe Kit can be found at, for example, https: / / www.molecular.abbott / us / en / products / oncology / vysis-alk-breakapart-fish-probe-kit; the entirety of which is incorporated herein by reference.

[047] In one modality, the cancer is a solid tumor. In one modality, the cancer is an advanced solid tumor. In one modality, the cancer is an advanced ALK+ solid tumor. In one modality, the cancer is an advanced ALK+ solid tumor that has failed one or more prior standard of care (SOC) treatments.

[048] In one modality, the cancer is neuroblastoma. In one modality, the cancer is relapsed or refractory neuroblastoma. In one modality, the cancer is relapsed neuroblastoma. In one modality, the cancer is refractory neuroblastoma. In one modality, the cancer is ALK+ neuroblastoma. In one modality, the cancer is relapsed or refractory ALK+ neuroblastoma.

[049] In one form, the cancer is an inflammatory myofibroblastic tumor (IMT). In one form, the cancer is unresectable or recurrent IMT. In one Petition 870260054695, dated 05 / 06 / 2026, page 31 / 86 In the 20 / 60 modality, the cancer is unresectable IMT. In one modality, the cancer is recurrent IMT. In one modality, the cancer is ALK+ IMT. In one modality, the cancer is unresectable or recurrent ALK+ IMT.

[050] In one modality, the cancer is a hematologic cancer. In one modality, the cancer is a lymphoma, leukemia, or myeloma. In one modality, the cancer is a lymphoma. In one modality, the cancer is a non-Hodgkin lymphoma. In one modality, the cancer is anaplastic large cell lymphoma (ALCL). In one modality, the cancer is relapsed or refractory ALCL. In one modality, the cancer is relapsed ALCL. In one modality, the cancer is refractory ALCL. In one modality, the cancer is ALCL ALK+. In one modality, the cancer is relapsed or refractory ALCL ALK+. In one modality, the cancer is newly diagnosed ALCL. In one modality, the cancer is newly diagnosed ALCL with a high risk of recurrence. In one modality, the cancer is newly diagnosed ALCL ALK+ with a high risk of recurrence.

[051] Several traits associated with a high risk of recurrence have been identified among patients with ALCL. The presence of one or more of the features of mediastinal involvement, visceral involvement defined as lung, liver or spleen involvement, and skin involvement are all prognostic for recurrence by multivariate analysis. Le Deley et al., Blood 2008, 111(3), 1560-6; ​​Le Deley et al., Journal of Clinical Oncology 2010, 28(25), 3987-93. Other factors that may be associated with a high risk of treatment failure in children with ALCL include NPM1-ALK in peripheral blood by polymerase chain reaction (PCR) and / or bone marrow infiltration that is detectable by molecular techniques at the time of diagnosis (i.e., minimal disseminated disease (MDD)), low anti-ALK antibody titers at the time of diagnosis, and detection of minimal residual disease (MRD) by PCR for NPM1-ALK in blood after the first course of chemotherapy. Petition 870260054695, of 05 / 06 / 2026, p. 32 / 86 21 / 60 Welk et al., 2007; Mussolin et al., Leukemia 2005, 19(9), 1643-7; Ait-Tahar et al., Blood 2010, 115(16), 3314-9; Damm-Welk et al., Blood 2014, 123(3), 334-7; Turner et al., 2016.

[052] Mussolin and colleagues investigated the prognostic value of MDD and the anti-ALK immune response in children with NPM-ALK+ ALCL to determine if the risk of recurrence could be stratified by these factors. Mussolin et al., 2013. Among 128 patients included in the study, 26 (20%) were considered to have high-risk disease based on the presence of MDD+ status and antibody titer <1 / 750. Five-year PFS and overall survival (OS) were 28% and 72% among this high-risk patient group. In contrast, PFS / OS were 93% / 98% for low-risk patients (MDD- with an antibody titer >1 / 750) and 68% / 84% among intermediate-risk patients (MDD- and antibody titers <1 / 750 or MDD+ and antibody titer >1 / 750).

[053] In one modality, high recurrence risk is characterized by the presence of one or more selected features among mediastinal involvement, visceral involvement defined as lung, liver, or spleen involvement, skin involvement, NPM1-ALK in peripheral blood, bone marrow infiltration, low anti-ALK antibody titers at diagnosis, and detection of minimal residual disease (MRD) for NPM1-ALK in blood after the first course of chemotherapy. In one modality, high recurrence risk is characterized by positive minimal disseminated disease (MDD+) at diagnosis. In one modality, high recurrence risk is characterized by low anti-ALK antibody titer at diagnosis. In one modality, high recurrence risk is characterized by anti-ALK antibody titer < 1 / 750 at diagnosis.

[054] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered orally. In one embodiment, Compound Petition 870260054695, dated 05 / 06 / 2026, p. 33 / 86 22 / 60 Compound A, or a pharmaceutically acceptable salt thereof, is administered as a tablet. In one embodiment, the tablet has a dosage of 30 mg, 90 mg, or 180 mg of Compound A. In one embodiment, the tablet is a white, film-coated tablet.

[055] Compound A, or a pharmaceutically acceptable salt thereof, may be administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID) and three times daily (TID). In addition, administration may be continuous, i.e., every day, or intermittent. The term intermittent or intermittently as used in this document is intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of Compound A, or a pharmaceutically acceptable salt thereof, is administration one to six days per week, in administration cycles (e.g., daily administration for two to eight consecutive weeks, followed by a rest period with no administration for up to one week), or administration on alternate days.

[056] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily (QD). In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered twice daily (BID).

[057] In certain embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered cyclically to a patient. Cycle therapy involves administering an active agent for a period of time, followed by a rest period, and repeating this sequential administration. Cycle therapy may avoid or reduce the side effects of one of the therapies and / or improve the effectiveness of the treatment.

[058] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg / m2a about Petition 870260054695, dated 05 / 06 / 2026, p. 34 / 86 23 / 60 150 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30 mg / m2 to about 100 mg / m2. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30 mg / m2 to about 60 mg / m2. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 40 mg / m2 to about 80 mg / m2. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 40 mg / m2 to about 100 mg / m2.

[059] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145 or about 150 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg / m2. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg / m2. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20 mg / m2.In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 30 mg / m2. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 40 mg / m2. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 50 mg / m2. Petition 870260054695, dated 05 / 06 / 2026, p. 35 / 86 24 / 60 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 60 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 70 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 80 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 90 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 100 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 110 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 120 mg / m2.In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 130 mg / m2. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 140 mg / m2. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 150 mg / m2.

[060] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered in an amount sufficient to achieve an area under the curve (AUC) exposure in pediatric patients that would not exceed 80% of those achieved at the clinical dose in adults.

[061] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered in an amount sufficient to provide AUC- of Compound A in the range of about 1000 to about 40000 ng^hr / mL, about 2000 to about 30000 ng^hr / mL, about 4000 to about 25000 ng^hr / mL, or about 5000 to about 20000 ng^hr / mL. In one embodiment, Petition 870260054695, dated 05 / 06 / 2026, p. 36 / 86 In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered in an amount sufficient to provide an AUC of Compound A in the range of about 4,000 to about 25,000 ng^hr / mL. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered in an amount sufficient to provide an AUC of Compound A in the range of about 5,000 to about 20,000 ng^hr / mL. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered in an amount sufficient to provide an AUC of Compound A of about 10,000 ng^hr / mL.

[062] In one embodiment, Compound A (i.e., free base) is administered. In one embodiment, a pharmaceutically acceptable salt (e.g., HCl salt) of Compound A is administered. In one embodiment, the amount administered refers to the measured amount of Compound A.

[063] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, may be administered as monotherapy or in combination therapy with one or more second therapeutic agents. In one embodiment, the methods provided in this document further comprise administering to the patient a therapeutically effective amount of a second therapeutic agent.

[064] In one embodiment, a method is provided in this document for treating cancer in a pediatric cancer patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent.

[065] In one modality, the second therapeutic agent is the ALCL99 chemotherapy regimen. This approach is derived from the BFM protocol previously used in aggressive B-cell NHL. Treatment regimens differ somewhat between studies, but generally involve cyclophosphamide, Petition 870260054695, dated 05 / 06 / 2026, page 37 / 86 26 / 60 doxorubicin, vincristine, corticosteroids, ifosfamide, and etoposide administered for 4 to 6 months, with high-dose methotrexate and cytarabine for central nervous system (CNS) prophylaxis. Eyre et al., 2014; Turner et al., 2016.

[066] In one embodiment, the second therapeutic agent is cyclophosphamide, doxorubicin, vincristine, corticosteroid, ifosfamide, etoposide, methotrexate, or cytarabine, or a combination thereof. In one embodiment, the corticosteroid is dexamethasone or hydrocortisone, or a combination thereof.

[067] In one embodiment, the second therapeutic agent includes dexamethasone. In one embodiment, the second therapeutic agent includes dexamethasone, which is administered at a dose of approximately 2.5 mg / m2 to approximately 20 mg / m2. In one embodiment, the second therapeutic agent includes dexamethasone, which is administered at a dose of approximately 5 mg / m2 to approximately 10 mg / m2. In one embodiment, the second therapeutic agent includes dexamethasone, which is administered at a dose of approximately 5 mg / m2. In one embodiment, the second therapeutic agent includes dexamethasone, which is administered at a dose of approximately 10 mg / m2.

[068] In one embodiment, the second therapeutic agent includes cyclophosphamide. In one embodiment, the second therapeutic agent includes cyclophosphamide, which is administered at a dose of approximately 100 mg / m2 to approximately 300 mg / m2. In one embodiment, the second therapeutic agent includes cyclophosphamide, which is administered at a dose of approximately 200 mg / m2.

[069] In one embodiment, the second therapeutic agent includes ifosfamide. In one embodiment, the second therapeutic agent includes ifosfamide, which is administered at a dose of approximately 400 mg / m2 to approximately 1200 mg / m2. In one embodiment, the second therapeutic agent includes ifosfamide, which is administered at a dose of approximately 800 mg / m2. Petition 870260054695, dated 05 / 06 / 2026, p. 38 / 86 27 / 60

[070] In one embodiment, the second therapeutic agent includes methotrexate. In one embodiment, the second therapeutic agent includes methotrexate, which is administered at a dose of about 1.5 g / m2 to about 4.5 g / m2. In one embodiment, the second therapeutic agent includes methotrexate, which is administered at a dose of about 3 g / m2.

[071] In one embodiment, the second therapeutic agent includes etoposide. In one embodiment, the second therapeutic agent includes etoposide, which is administered at a dose of 50 mg / m2 to approximately 150 mg / m2. In one embodiment, the second therapeutic agent includes etoposide, which is administered at a dose of approximately 100 mg / m2.

[072] In one embodiment, the second therapeutic agent includes cytarabine. In one embodiment, the second therapeutic agent includes cytarabine, which is administered at a dose of approximately 75 mg / m2 and is administered twice daily. In one embodiment, the second therapeutic agent includes cytarabine, which is administered at a dose of approximately 150 mg / m2 and is administered twice daily.

[073] In one embodiment, the second therapeutic agent includes doxorubicin. In one embodiment, the second therapeutic agent includes doxorubicin, which is administered at a dose of approximately 12.5 mg / m2 to approximately 37.5 mg / m2. In one embodiment, the second therapeutic agent includes doxorubicin, which is administered at a dose of approximately 25 mg / m2.

[074] In certain embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered cyclically to a patient. Cycle therapy involves administering an active agent for a period of time, followed by a rest period, and repeating this sequential administration. Cycle therapy may avoid or reduce the side effects of one of the therapies and / or improve the Petition 870260054695, dated 05 / 06 / 2026, p. 39 / 86 28 / 60 treatment effectiveness.

[075] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for one or more 7-day cycles. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for one or more 21-day cycles. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for one or more 28-day cycles.

[076] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for at least 4 cycles. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for at least 6 cycles. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for at least 8 cycles. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for at least 12 cycles.

[077] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of the 21-day cycle.

[078] In one embodiment, the second therapeutic agent includes dexamethasone, which is administered on days 1-5 of the 21-day cycle.

[079] In one embodiment, the second therapeutic agent includes cyclophosphamide, which is administered on days 1 and 2 of the 21-day cycle.

[080] In one embodiment, the second therapeutic agent includes cyclophosphamide, which is administered on days 1-5 of the 21-day cycle.

[081] In one embodiment, the second therapeutic agent includes a combination of hydrocortisone, methotrexate, and cytarabine, which are administered Petition 870260054695, dated 05 / 06 / 2026, p. 40 / 86 29 / 60 on day 1 of the 21-day cycle.

[082] In one embodiment, the second therapeutic agent includes ifosfamide, which is administered on days 1-5 of the 21-day cycle.

[083] In one embodiment, the second therapeutic agent includes methotrexate, which is administered on day 1 of the 21-day cycle.

[084] In one embodiment, the second therapeutic agent includes etoposide, which is administered on days 4 and 5 of the 21-day cycle.

[085] In one embodiment, the second therapeutic agent includes cytarabine, which is administered on days 4 and 5 of the 21-day cycle.

[086] In one embodiment, the second therapeutic agent includes doxorubicin, which is administered on days 4 and 5 of the 21-day cycle.

[087] In one embodiment, a method for treating unresectable or recurrent IMT in a pediatric patient is provided herein, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In one embodiment, the IMT is unresectable or recurrent ALK+ IMT. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30 mg / m2 to about 100 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 40 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 60 mg / m2.In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 80 mg / m2. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 100 mg / m2. Petition 870260054695, dated 05 / 06 / 2026, p. 41 / 86 30 / 60

[088] In one embodiment, a method for treating relapsed or refractory ALCL in a pediatric patient is provided herein, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In one embodiment, the ALCL is relapsed or refractory ALCL ALK+. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30 mg / m2 to about 100 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 30 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 40 mg / m2. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 60 mg / m2.In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 80 mg / m2. In another embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of approximately 100 mg / m2.

[089] In one embodiment, a method for treating ALCL in a pediatric patient is provided in this document, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an ALCL regimen.99

[090] In one embodiment, a method for treating ALCL in a pediatric patient is provided herein, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with dexamethasone, ifosfamide, methotrexate, etoposide, and cytarabine. In one embodiment, treatment continues for one or more 21-day cycles. In a Petition 870260054695, dated 05 / 06 / 2026, p. 42 / 86 In the 31 / 60 modality, Compound A, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of the 21-day cycle; dexamethasone is administered on days 1-5 of the 21-day cycle; ifosfamide is administered on days 1-5 of the 21-day cycle; methotrexate is administered on day 1 of the 21-day cycle; etoposide is administered on days 4 and 5 of the 21-day cycle; and cytarabine is administered on days 4 and 5 of the 21-day cycle.In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of the 21-day cycle; dexamethasone is administered at a dose of approximately 10 mg / m2 on days 1-5 of the 21-day cycle; ifosfamide is administered at a dose of approximately 800 mg / m2 on days 1-5 of the 21-day cycle; methotrexate is administered at a dose of approximately 3 g / m2 (e.g., over 3 hours) on day 1 of the 21-day cycle; etoposide is administered at a dose of approximately 100 mg / m2 on days 4 and 5 of the 21-day cycle; and cytarabine is administered at a dose of approximately 150 mg / m2 twice daily on days 4 and 5 of the 21-day cycle.

[091] In one embodiment, a method for treating ALCL in a pediatric patient is provided herein, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with dexamethasone, methotrexate, cyclophosphamide, and doxorubicin. In one embodiment, treatment continues for one or more 21-day cycles. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered on days 1–21 of the 21-day cycle; dexamethasone is administered on days 1–5 of the 21-day cycle; methotrexate is administered on day 1 of the 21-day cycle; cyclophosphamide is administered on days 1–5 of the 21-day cycle; and doxorubicin is administered on days 4 and 5 of the 21-day cycle. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is Petition 870260054695, dated 05 / 06 / 2026, p. 43 / 86 32 / 60 administered on days 1-21 of the 21-day cycle; dexamethasone is administered at a dose of approximately 10 mg / m2 on days 1-5 of the 21-day cycle; methotrexate is administered at a dose of approximately 3 g / m2 (e.g., over 3 hours) on day 1 of the 21-day cycle; cyclophosphamide is administered at a dose of approximately 200 mg / m2 on days 1-5 of the 21-day cycle; and doxorubicin is administered at a dose of approximately 25 mg / m2 on days 4 and 5 of the 21-day cycle. Pharmaceutical Compositions

[092] Pharmaceutical compositions that are useful for the methods provided in this document are also provided herein. The therapeutic agents used in the methods provided in this document, individually or in any combination thereof, may be comprised in the same or different pharmaceutical compositions.

[093] In one embodiment, pharmaceutical compositions and dosage forms comprising Compound A, or a pharmaceutically acceptable salt thereof, are provided in this document. In another embodiment, the pharmaceutical compositions and dosage forms further comprise one or more excipients.

[094] In one embodiment, pharmaceutical compositions and dosage forms are provided in this document, comprising Compound A, or a pharmaceutically acceptable salt thereof, and lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), magnesium stearate and hydrophobic colloidal silica.

[095] In one embodiment, brigatinib (Compound A) is provided for oral use as film-coated tablets containing 30 mg, 90 mg or 180 mg of brigatinib and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), stearate Petition 870260054695, dated 05 / 06 / 2026, p. 44 / 86 33 / 60 magnesium and hydrophobic colloidal silica. The tablet coating consists of talc, polyethylene glycol, polyvinyl alcohol, and titanium dioxide.

[096] Additional pharmaceutical formulations comprising brigatinib are described in international application No. PCT / US2018 / 021128, which is incorporated herein by reference. Other Combination Therapies

[097] Methods for other combination therapies are also provided in this document wherein, in addition to a first therapeutic agent provided in this document (e.g., Compound A) and a second therapeutic agent provided in this document (e.g., ALCL99 chemotherapy regimen), one or more agents (e.g., third therapeutic agent or therapy) known to modulate other pathways, or the same pathway, may be used. In certain embodiments, such methods comprise administering Compound A to a subject in need, optionally in combination with an ALCL99 chemotherapy regimen and further in combination with one or more additional therapeutic agents, such as anticancer agents, chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide, when desired, a synergistic or additive therapeutic effect.

[098] The route of administration of the third therapeutic agent or therapy is independent of the route of administration of the first and second agents. The third therapeutic agent or therapy may be administered orally, parenterally, intraperitoneally, intravenously, intra-arterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraocularly, via local catheter or stent delivery, subcutaneously, intra-adipose, intra-articularly, intrathecally, or in a slow-release dosage form.

[099] One or more third active ingredients or agents may be Petition 870260054695, dated 05 / 06 / 2026, page 45 / 86 34 / 60 used in the methods provided in this document. Third active agents may be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).

[100] Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies and, in particular, therapeutic antibodies to cancer antigens. Typical large molecule active agents are biological molecules, such as naturally occurring or synthetic proteins or recombinant proteins.

[101] Third active agents that are small molecules may also be used to alleviate adverse effects associated with the administration of a combination therapy provided in this document. However, like some large molecules, many are believed to be capable of providing an additive or synergistic effect when administered with (e.g., before, after, or simultaneously with) a combination provided in this document. Examples of small molecule third active agents include, but are not limited to, anticancer agents, antibiotics, immunosuppressive agents, and steroids.

[102] Examples of additional anticancer agents to be used in the methods or compositions described in this document include, but are not limited to: acivin; aclarubicin, acodazol hydrochloride, acronin; adozelesin; aldesleucin; altretamine; ambomycin; amethanthrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastate; benzodepa; bicalutamide; bisanthrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; Petition 870260054695, dated 05 / 06 / 2026, page 46 / 86 35 / 60 celecoxib (COX-2 inhibitor); chlorambucil; cyrolemicin; cisplatin; cladribine; clofarabine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dabrafenib; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexole sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogyline; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; omacetaxine; ormaplatin; oxisuran; paclitaxel; paclitaxel protein-bound particles for injectable suspension (albumin-bound); pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosphamide; pipobroman; poposulfan; pyroxantrone hydrochloride; plicamycin; plomestane; sodium porfimer; porphyromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprin; safingol; safingol hydrochloride;semustina; simtrazene; sorafenib; sparphosate; Petition 870260054695, dated 05 / 06 / 2026, page 47 / 86 36 / 60 sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talismomycin; tecogalan sodium; docetaxel; tegafur; teloxantrone hydrochloride; temoporphine; teniposide; teroxirone; testolactone; thiamipine; thioguanine; thiotepa; thiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; vemurafenib; verteporphine; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.

[103] Other anticancer drugs to be included in the methods and compositions include, but are not limited to: 20-epi-1,25-dihydroxyvitamin D3; 5-ethinyluracil; abiraterone; aclarubicin; acilfulvene; adecipenol; adozelesin; aldesleucine; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; D antagonists; G antagonists; antarelix; anti-dorsalizing protein 1; antiandrogens; antiestrogens; antineoplastons; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; bacatin III derivatives; balanol; batimastate; BCR / ABL antagonists; benzochlorines; benzoylstaurosporine; beta-lactam derivatives; beta-alethin;betaclamycin B; betulinic acid; bFGF inhibitors; bicalutamide; bisanthrene; bisaziridinylspermine; bisnafida; bistratene A; bizelesin; breflate; bropirimine; budotitane; sulfoximine; Petition 870260054695, dated 05 / 06 / 2026, page 48 / 86 37 / 60 butyonine; calcipotriol; calfostine C; camptothecin derivatives; capecitabine; carboxamide-aminotriazole; carboxiamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitors (CKIs); castanospermine; cecropin B; cetrorelix; clorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analog; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; Ara-C ocphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorespermine; dihydro-5azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemeno; emitefur; epirubicin; epristeride; estramustine analogues; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texafirin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; hydramantoin; ilmofosine; ilomastat; imatinib (e.g., Gleevec®); imiquimod; immunostimulating peptides; insulin-like growth factor receptor 1 inhibitors; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalychondrin B; itasetron; Petition 870260054695, dated 05 / 06 / 2026, page 49 / 86 38 / 60 jasplaquinoline; caalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte interferon alpha; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexole; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetium texafirin; lysophilin; lytic peptides; maytansine; mannostatin A; marimastate; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotocin fibroblast growth factor saponin; mitoxantrone; mofarotene; molgramostim; cetuximab; human chorionic gonadotropin;Mycobacterial cell wall skeleton + monophosphoryl lipid A; mopidamol; anticancer mustard agents; micaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestipe; naloxone + pentazocine; napavin; nafterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidants; nitrulin; oblimersen (Genasense®); O6-benzylguanine; octreotide; oquicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; Paclitaxel analogues; paclitaxel derivatives; paclitaxel protein-bound particles for injectable suspension (albumin-bound); palauamine; palmitoylrhizoxine; pamidronic acid; panaxitriol; panomiphene; parabactin; pazeliptin; pegaspargase; peldesin; pentosan sodium polysulfate; pentostatin; pentrozole;perflubron; perfosfamide; alcohol; Petition 870260054695, dated 05 / 06 / 2026, page 50 / 86 39 / 60 perillyl; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitors; platinum complexes; platinum compounds; platinum-triamine complexes; sodium porfimer; porfiromycin; prednisone; bis-acridone propyl; prostaglandin J2; proteasome inhibitors; protein A-based immune modulators; protein kinase C inhibitors; microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxyl polyoxyethylene hemoglobin conjugates; raf antagonists; raltitrexed; ramosetron; farnesyl ras transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylated reteliptin; rhenium etidronate Re 186; rhizoxin; ribozymes; RII retinamide; roituchin; ruptured; roquinimex; rubiginone B1; ruboxyl; safingol; saintopine; sarmustine; sarcophytol A;sargramostim; Sdi-1 mimics; semustine; senescence-derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; sizofirane; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin-binding protein; sonermine; sparphosic acid; spikemycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stipiamide; stromelysin inhibitors; sulfinsine; vasoactive intestinal peptide antagonists; suradist; suramin; swainsonine; talimustine; tamoxifen metiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; telurapyrillium; telomerase inhibitors; temoporphine; teniposide; tetrachlordecaoxide; tetrazomine; taliblastine; thiocoralin; thrombopoietin; thrombopoietin mimic; thymalfasin; thymopoietin receptor agonists; thymotrinan; thyroid-stimulating hormone; ethyl ethyltin purpurin; tirapazamine; titanocene dichloride; topsentin; toremifene; translational inhibitors; tretinoin;triacetyluridine; triciribine; trimetrexate; triptorelin; Petition 870260054695, dated 05 / 06 / 2026, page 51 / 86 40 / 60 tropisetron; turosteride; tyrosine kinase inhibitors; tirrostines; UBC inhibitors; ubenimex; urogenital sinus-derived growth factor inhibitor; urokinase receptor antagonists; vapreotide; variolin B; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltin; vitaxin; vorozole; zanotron; zeniplatin; zilascorb; and zinostatin estimalamer.

[104] Other useful third active agents in the methods or compositions include, but are not limited to, rituximab, oblimersen (Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, gefitinib (Iressa®), taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, interferon alfa, pegylated interferon alfa (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, interleukin 2, granulocyte-macrophage colony-stimulating factor, dacarbazine, vinorelbine, zoledronic acid, palmitorelbine, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel,Paclitaxel protein-bound particles for injectable suspension (albumin-bound), ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt®), sulindac, and etoposide.

[105] Other specific third active agents useful in the methods or compositions include, but are not limited to, sorafenib, dabrafenib, vemurafenib, trametinib, cobimetinib, binimetinib, selumetinib, PD325901, CI-1040 (PD184352), TAK-733, AT7867, AZD 8055, BX-912, silmitasertib, pictilisib, MK-2206, pilaralisib, gefitinib, erlotinib, lapatinib, osimertinib, OSI-027, AZD8055, sapanisertib, dactolisib, BGT226, voxtalisib, apitolisib, omipalisib, PF-04691502, gedatolisib, PP242, lenalidomide, or Petition 870260054695, dated 05 / 06 / 2026, page 52 / 86 41 / 60 pomalidomide. Medical kits

[106] Medical kits are also provided in this document. In certain embodiments, a medical kit comprising Compound A or a pharmaceutically acceptable salt of this document is provided in this document.

[107] In certain embodiments, the kits comprise Compound A or a pharmaceutically acceptable salt thereof and a second therapeutic agent as described in this document, in suitable packaging and written materials that may include instructions for use, discussion of clinical studies, listing of side effects and the like. In certain embodiments, such kits may also include information such as, for example, references to scientific literature, package insert materials, clinical trial results and / or summaries thereof and the like, which indicate or establish the activities and / or benefits of the composition and / or describe the dosage, administration, side effects, drug interactions or other information useful to the healthcare professional. In certain embodiments, such information may be based on the results of several studies, for example, studies using experimental animals involving in vivo models and / or studies based on clinical trials in humans.In certain embodiments, the kit may also comprise another agent. In certain embodiments, Compound A or a pharmaceutically acceptable salt thereof of this disclosure and a second therapeutic agent are provided as separate compositions in separate containers within the kit. In certain embodiments, Compound A or a pharmaceutically acceptable salt thereof of this disclosure and a second therapeutic agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil packaging for...) Petition 870260054695, dated 05 / 06 / 2026, page 53 / 86 42 / 60 minimize exposure to air and similar components) are known in the art and may be included in the kit. The kits described in this document may be supplied, marketed and / or promoted to healthcare professionals, including physicians, nurses, pharmacists, formulation staff and the like. The kits may also, in some embodiments, be marketed directly to the consumer. EXAMPLES Example 1: Extrapolation and Interrelation Between Adult and Pediatric Populations

[108] As there are currently no pediatric clinical pharmacokinetic (PK) data available for brigatinib, the projection of brigatinib's pediatric clinical PK from adult PK was performed using an allometric approach. The main aspects of this analysis are summarized below.

[109] The use of an allometric escalation approach is supported by knowledge of brigatinib clearance mechanisms and its corresponding ontogeny, which indicate maturation of clearance in pediatric patients aged > 1 year. Consequently, simulations based on a previously developed population PK model were performed to guide dose selection for the phase 1 pediatric dose-confirmation study, taking into account the adult dosing regimen for ALK+ NSCLC. The proposed study is an open-label phase 1 dose-escalation in patients >2 years old with solid or measurable or evaluable ALK+ CNS or ALCL tumors refractory to therapy and for whom no known curative treatment is available.

[110] In the pivotal phase 2 study in adults with ALK+ NSCLC, 2 dosing regimens were evaluated: (1) 90 mg QD; (2) 90 mg QD at Week 1 followed by escalation to 180 mg QD for patients who tolerated the Petition 870260054695, dated 05 / 06 / 2026, page 54 / 86 43 / 60 introduction of 90 mg QD for 7 days. Based on the demonstration of longer PFS with 180 mg QD, the recommended clinical dose of brigatinib in adults is 90 mg orally QD for the first 7 days followed by a dose increase to 180 mg QD based on patient tolerability. This approach of a 7-day lead at a lower dose offers risk mitigation for EOPEs. Therefore, a similar dosing regimen is proposed in pediatric development with a 7-day lead period. To mitigate the risk of EOPEs in pediatric patients, brigatinib doses selected for Week 1 of treatment are informed by clinical experience in adults and designed to achieve systemic exposures no greater than those of the 90 mg daily dose in adults.

[111] The adult population PK model described brigatinib PK using a 3-compartment model with a transit absorption compartment model. The final covariate model included linear functions relating body weight to clearance and volume parameters. In addition, age and albumin concentration were considered statistically significant covariates in clearance.

[112] For the purposes of simulating pediatric PK, the linear covariate functions relating body weight to clearance and volume parameters were replaced by allometric functions, which employed scaling coefficients (i.e., exponents) of 0.75 for clearance parameters and 1 for volume. The adapted model was used to derive, by simulation, the dosage in pediatric patients that would achieve exposures similar to those observed in adult patients after a reference dose of 90 mg QD. Virtual pediatric patients were simulated based on body size versus age distributions in the National Health and Nutrition Examination Survey (NHANES) dataset provided by the Centers for Disease Control and Prevention. Petition 870260054695, dated 05 / 06 / 2026, page 55 / 86 44 / 60 Disease Prevention (CDC). The pediatric patient population was stratified by age (1000 patients per month of age; 1 to 18 years) and sex (50:50; male:female).

[113] Based on a crossover study comparison of brigatinib exposure from an oral solution administered in the human radioactive mass balance study (Study AP26113-13-104) and tablet PK in adults (Study AP26113-16-110), the relative bioavailability of a brigatinib oral solution is approximately 42% higher in terms of AUC compared to the tablet. Therefore, a relative bioavailability factor (tablet AUC / oral solution ratio of 1.42) was incorporated into the pediatric simulations.

[114] Simulations using the adapted model indicated that brigatinib exposures in pediatric patients aged 1 to less than 18 years after administration of 40 mg / m2 of brigatinib as an oral solution would be comparable to those achieved in adult patients receiving 90 mg QD as an oral tablet (Figure 1).

[115] Based on these simulations, systemic exposures in pediatric patients receiving doses of 40 mg / m2QD ^ 80 mg / m2QD should be comparable to those achieved with the recommended clinical dose for adults of 90 mg QD ^ 180 mg QD. In the planned phase 1 pediatric study, the initial dose level (30 mg / m2QD ^ 60 mg / m2QD; Dose Level 1) was selected to achieve model-predicted pediatric exposures (AUC) that would not exceed 80% of those achieved at the clinical dose in adults (90 mg QD ^ 180 mg QD), consistent with approaches typically used in phase 1 pediatric studies. The planned subsequent dose level (40 mg / m2QD ^ 80 mg / m2QD; Dose Level 2) should achieve 100% of adult exposures. An additional dose level is planned if the dose of 40 mg / m2QD ^ 80 mg / m2QD is Petition 870260054695, dated 05 / 06 / 2026, page 56 / 86 45 / 60 tolerated. To mitigate the risk of EOPEs, the Week 1 brigatinib dose at Dose Level 3 (40 mg / m2QD ^ 100 mg / m2QD) is 40 mg / m2QD (i.e., a dose level expected to provide systemic exposures that match those achieved in adults at the initial dose of 90 mg QD). The planned maximum dose of 100 mg / m2QD was selected to achieve systemic exposures approximately comparable to those at the highest acceptably tolerated dose of 240 mg QD in adults in Study AP26113-11-101.

[116] The rationale for the continued escalation in the pediatric population beyond Dose Level 2 was informed by the following considerations: • Adult experience with brigatinib in ALK+ NSCLC where longer PFS was observed with doses of 90 mg QD ^ 180 mg QD vs. 90 mg QD, suggesting that it cannot be assumed that exposures associated with 180 mg QD would maximize efficacy in ALK+ pediatric cancers. • Pediatric clinical experience with the ALK inhibitor crizotinib achieved an MTD / RP2D of 280 mg / m2 with an associated systemic exposure that is ~50% higher than adult clinical exposures with 250 mg BID.

[117] For these reasons, a direct extrapolation approach is not proposed for the pediatric development of brigatinib. Instead, clinical experience in adults, as well as available pediatric and adult data on the ALK inhibitor crizotinib, were leveraged, with dose selection for the phase 1 pediatric program informed by population PK modeling and simulation. Similarly, population PK modeling of the phase 1 pediatric PK data will be used to guide dose selection for subsequent efficacy and safety studies in pediatric patient populations. Example 2: Pediatric Clinical Studies General Strategy Petition 870260054695, dated 05 / 06 / 2026, page 57 / 86 46 / 60

[118] Two clinical studies in patients aged 2 years and older with ALCL or IMT are being conducted for brigatinib: (a) an open-label, phase 1 / 2 dose-escalation and expansion study (Study 1) and (b) a randomized phase 2 study (Study 2).

[119] During the phase 1 portion of Study 1, brigatinib monotherapy dose escalation occurs according to a Rolling-6 design in subjects with any advanced ALK+ or ALCL ALK+ solid tumor that has failed prior standard treatment (Part A-1). After the RP2D of brigatinib monotherapy is determined, phase 2 disease-specific expansion cohorts open and enroll patients with unresectable or recurrent ALK+ IMT (Part B, Cohort B-1) or relapsed / refractory ALCL ALK+ (Part B, Cohort B-2). At this time, dose escalation is also initiated with brigatinib in combination with a standard chemotherapy regimen (ALCL99 regimen) among newly diagnosed ALCL ALK+ patients at high risk of recurrence to determine the RP2D of brigatinib when used in combination with ALCL99 (Part A-2).

[120] The sample size for Cohort B-1 of Study 1 is approximately 28 subjects.

[121] Study 2 will be initiated if sufficient safety, tolerability, and preliminary efficacy are observed among ALCL patients in Parts A-2 and B of Study 1. The patient population enrolled in Study 2 includes previously untreated pediatric ALCL ALK+ patients at high risk of recurrence, defined as MDD+ status and low anti-ALK antibody titers (<1 / 750) at the time of diagnosis. This subgroup exhibits the greatest unmet need and response to existing treatments, as evidenced by 5-year PFS and OS of 28% and 72%, respectively, and may benefit from more aggressive or diversified frontline interventions. Petition 870260054695, dated 05 / 06 / 2026, page 58 / 86 47 / 60 leading to a more profound response, with the goal of preventing or avoiding relapse. In contrast, patients with low and intermediate risk exhibit a much better response to current treatments with 5-year PFS / OS of 93% / 98% and 68% / 84%, respectively. Mussolin et al., 2013. The study incorporates a randomized, comparator-controlled design to allow for a rigorous assessment of the safety and efficacy of the ALCL99 / brigatinib combination versus ALCL99 alone.

[122] The sample size for the phase 2 study of previously untreated high-risk ALCL is approximately 104 patients, who are randomized 1:1 to receive brigatinib in combination with ALCL99 or ALCL99 alone.

[123] The designs of both clinical studies are illustrated in Figure 2. Pediatric PK / PD Studies

[124] Serial plasma samples are collected during the phase 1 portion of the initial trial (Study 1) to characterize brigatinib PK in the pediatric population. Due to potential blood volume limitations, a sparser sampling scheme is used in younger children. An integrated population pharmacokinetic modeling approach is used, in which data from the phase 1 trial are combined with previously acquired PK data in healthy adult subjects and NSCLC patients. Allometric functions are incorporated to estimate the effects of body size measurements (e.g., body surface area [BSA], weight) on clearance and volume parameters. Sources of variability in brigatinib PK (i.e., covariates) are explored, and the effects of previously estimated covariates in adults are updated based on the combined pediatric and adult dataset.The model's performance is evaluated through graphical adequacy assessment, statistical criteria, and predictive visual verification. The model is used for derivation. Petition 870260054695, dated 05 / 06 / 2026, page 59 / 86 48 / 60 exposure parameters for each pediatric subject were compared with adult exposure metrics to guide the selection of additional doses.

[125] Patients in the phase 1 pediatric study receive brigatinib as an oral solution. In subsequent studies, the oral tablet formulation may be used in patients able to swallow solid oral dosage forms. The dosing approach for the tablet formulation (e.g., binarized dosing) is informed by integrated population pharmacokinetic analyses that are conducted using available adult data and pediatric data collected during the phase 1 study. Population pharmacokinetic analysis provides an updated estimate of the relative bioavailability of the oral solution formulation versus the tablet formulation.

[126] PK data are obtained from the phase 2 expansion cohorts of patients with IMT and ALCL in the initial study (Study 1) and the separate phase 2 study of patients with ALCL (Study 2). Sparse PK data are collected with sampling schemes informed by the results of the phase 1 pediatric PK data modeling. Integrated pharmacokinetic analyses of the population of data collected in the pediatric clinical development program are performed to confirm the adequacy of the proposed dosing in the evaluated pediatric age range. The model is used to derive exposure parameters for each pediatric patient and contributes to the assessment of efficacy-to-exposure and safety-to-exposure relationships for brigatinib in a pediatric population. Clinical Efficacy and Safety Studies Study 1: Phase 1 / 2 Study of Brigatinib in Patients 2 Years Older with Malignant Diseases with a Genetic Alteration in Anaplastic Lymphoma Kinase (ALK). Petition 870260054695, dated 05 / 06 / 2026, pp. 60 / 86 49 / 60

[127] Primary Objectives • To estimate the MTD / RP2D regimen of brigatinib monotherapy administered PO QD as a liquid formulation in a pediatric patient population. • To estimate the MTD / RP2D regimen of brigatinib administered PO QD as a liquid formulation in combination with the ALCL99 treatment regimen in high-risk newly diagnosed ALCL ALK+ pediatric patients. • To evaluate the safety and tolerability of brigatinib administered as monotherapy and in combination with ALCL99 in a pediatric patient population. • To characterize the pharmacokinetics of brigatinib in a population of pediatric patients administered as monotherapy and in combination with the ALCL99 treatment regimen.

[128] Secondary objectives • To define the antitumor activity of brigatinib in disease-specific expansion cohorts (IMT and ALCL in relapse / refractory)

[129] Primary Evaluation Criteria • Part A-1: ​​Determination of brigatinib RP2D in monotherapy. • Part A-2: Determination of brigatinib RP2D in combination with ALCL99. • Part B Cohort B-1: ORR. • Part B Cohort B-2: ORR.

[130] Secondary Evaluation Criteria • Part A-1 and A-2: MTD, DLTs, safety and tolerability and PK. • Part B, Cohorts B-1 and B-2: Pain, PFS, OS, safety and tolerability.

[131] Main Inclusion Criteria

[132] For all patients (Part A and B): Petition 870260054695, dated 05 / 06 / 2026, pp. 61 / 86 50 / 60 • Patients must have an advanced solid tumor or lymphoma confirmed histologically or cytologically. • Patients must have an activating ALK aberration in their tumor detected by a certified assay (i.e., Clinical Laboratory Improvement Amendments (CLIA) in the US) prior to screening. The report of this test must be submitted for eligibility. ALK immunohistochemistry can be used as a substitute for fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) for patients with IMT or ALCL. • Patients should not be receiving other investigational medications within 30 days of study initiation or during the study. • The patient must meet the organ and system function requirements as established in the protocol.

[133] For Part A-1: • Due to the unknown potential for early-onset pulmonary adverse reactions in pediatric patient populations and the need to monitor for reportable patient symptoms such as dyspnea, patients should be >4 years of age (the lower age limit will be reduced to 2 years in subsequent cohorts after review of safety and tolerability data). • Patients must have at least ONE of the following: (1) recurrent / progressive disease at any time before study enrollment, (2) refractory disease, (3) persistent disease. • They are refractory or intolerant to all available standard therapies. • Patients must have fully recovered from the acute toxic effects of any chemotherapy, immunotherapy, or radiotherapy they have previously undergone before entering this study. • Patients should not be receiving any other agent. Petition 870260054695, dated 05 / 06 / 2026, page 62 / 86 51 / 60 anticancer or radiotherapy at the start of the study or during the study.

[134] For Part A-2: • Patients must be older than 2 years and younger than 22 years. • Patients must have high-risk ALCL ALK+ status. • Patients should not have received any prior systemic chemotherapy.

[135] For Part B, Cohort B-1: • Patients must be older than 2 years. • Having unresectable or recurrent IMT ALK+

[136] For Part B, Cohort B-2: • Patients must be older than 2 years and younger than 22 years. • Having ALCL ALK+ in relapse or refractory.

[137] Main Exclusion Criteria • Patients with symptomatic CNS metastases who are neurologically unstable or require an increasing dose of corticosteroids. • Patients receiving strong or moderate CYP3A inhibitors or inducers in the 14 days prior to the first dose of the study drug. • Having previously received an ALK inhibitor (Part A-2 and Part B only).

[138] Sample Size • Part A-1: ​​Up to 18 evaluable patients >4 years of age with advanced ALK+ solid tumors or ALCL who have failed previous standard of care. A minimum of 15 patients aged <18 years. • Part A-2: Up to 12 evaluable patients >2 and <22 years of age with newly diagnosed high-risk ALCL. A minimum of 9 patients aged <18 years. • Part B, Cohort B-1: 28 patients >2 years of age with IMT Petition 870260054695, dated 05 / 06 / 2026, pages 63 / 86 52 / 60 unresectable / recurrent. A minimum of 15 patients aged <18 years. • Part B, Cohort B-2: 10 patients >2 and <22 years of age with relapsed / refractory ALCL. A minimum of 8 subjects <18 years of age.

[139] Duration of Follow-up

[140] Patients with PR or stable disease will continue to receive brigatinib as a single agent for up to 1 year, subject to agreement between the sponsor and the investigator, until disease progression or unacceptable toxicity.

[141] Treatments

[142] BSA-based brigatinib dosing is used to normalize systemic exposures across the planned age range. The 1-week initiation paradigm (90 mg QD for 7 days followed by 180 mg QD continuously) recommended for adult patients with ALK+ NSCLC is used. The initial dose level was selected to achieve pediatric exposures (AUC) that do not exceed 80% of those achieved with the clinical dose in adults. The planned maximum dose of 100 mg / m2QD is selected to achieve systemic exposures approximately comparable to those at the highest tolerated dose of 240 mg QD in adults.

[143] The proposed doses for each segment of the study are illustrated in Figure 3.

[144] The treatments to be administered in Study 1 are as follows:

[145] Part A-1: • Monotherapy with brigatinib (oral solution for all patients).

[146] Part A-2: • Six cycles of ALCL99+ / -brigatinib followed by brigatinib monotherapy. Table 1 Petition 870260054695, dated 05 / 06 / 2026, pp. 64 / 86 53 / 60 ALCL99 Pre-phase • Dexamethasone: 5 mg / m2 on Days 1-2, 10 mg / m2 (divided twice daily) on Days 3-5. • Cyclophosphamide: 200 mg / m2 on Days 1 and 2. • Hydrocortisone, Methotrexate, Intrathecal Cytarabine (dose based on age): on Day 1. • Brigatinib will be administered on Days 1-21 of each course below as follows: - initial dose of Brigatinib on Days 1-7. - dose escalation of Brigatinib on Days 8 onwards. Course A (21-day cycle) • Brigatinib on Days 1-21. • Dexamethasone 10 mg / m2 on Days 1-5. • Ifosfamide: 800 mg / m2 on Days 1-5. • Methotrexate 3 g / m2 for 3 hours on Day 1. • Etoposide 100 mg / m2 on Days 4 and 5. • Cytarabine 150 mg / m2 x 2 on Days 4 and 5. Course B (21-day cycle) • Brigatinib on Days 1-21. • Dexamethasone 10 mg / m2 on Days 1-5. • Methotrexate 3 g / m2 for 3 hours on Day 1. • Cyclophosphamide 200 mg / m2 on Days 1-5. • Doxorubicin 25 mg / m2 on Days 4 and 5.

[147] Part B: • Brigatinib monotherapy. Oral solution and tablets (tablet doses for patients able to swallow solid oral dosage forms; tablet doses to be determined from pharmacokinetic data collected in Part A-1 and considerations of relative bioavailability).

[148] Duration of Treatment • For Part A-1 and Part B: Treatment continues until disease progression or unacceptable toxicity. • Part A-2: A total of 6 cycles of ALCL99+ / -brigatinib are administered. Patients in either arm who exhibit CR or CRu after 2 treatment cycles may proceed to transplantation, at the investigator's discretion. Petition 870260054695, dated 05 / 06 / 2026, pages 65 / 86 54 / 60 • Patients with PR or stable disease will continue to receive brigatinib as a single agent for up to 1 year, subject to agreement between the sponsor and the investigator, until disease progression or unacceptable toxicity.

[149] Statistical Considerations

[150] Part A-1: ​​Part A-1 of the study follows a Rolling-6 design. Two to six patients are simultaneously accumulated at one dose level. Decisions about which dose level to enroll a patient at are based on the number of patients experiencing DLTs and the number of patients still at risk of developing a DLT at the time of a new patient's enrollment. Patients are assessed for DLTs within the first 28 days of treatment. A non-compartmental analysis of brigatinib pharmacokinetics is performed. PK parameters are summarized descriptively with summary statistics. The pharmacokinetic data further contribute to the population pharmacokinetic analyses.

[151] In addition to determining the MTD, a descriptive summary of the toxicities is reported.

[152] Part A-2: Part A-2 of the study follows a Rolling-6 design. Two to six patients are simultaneously accumulated at a brigatinib dose level administered with the ALCL99 regimen. Decisions about which dose level to enroll a patient at are based on the number of patients experiencing DLTs and the number of patients still at risk of developing a DLT at the time of a new patient's enrollment. Patients are assessed for DLTs within the first 28 days of treatment. A non-compartmental analysis of brigatinib pharmacokinetics is performed. PK parameters are summarized descriptively with summary statistics. Pharmacokinetic data further contribute to the pharmacokinetic analyses. Petition 870260054695, dated 05 / 06 / 2026, pages 66 / 86 55 / 60 of the population.

[153] In addition to determining the MTD, a descriptive summary of the toxicities is reported.

[154] Part B, Cohort B-1: Cohort B-1 of the study uses confirmed ORR using RECIST v1.1 as the primary assessment criterion. All patients receiving at least 1 dose of brigatinib are analyzed. Twenty-eight patients provide approximately 90% potency to rule out an uninteresting rate of 20% if the true response rate is 50% with a one-sided alpha of 0.025. An interim futility analysis is conducted on the first 14 patients enrolled in the study. If the conditional potency to rule out an uninteresting rate of 20% is low, the study may be terminated due to futility. The pharmacokinetic data collected in this cohort contribute to the population pharmacokinetic analyses.

[155] Part B, Cohort B-2: The B-2 cohort of the study uses confirmed ORR using RECIST v1.1 as the primary assessment criterion and EFS at 2 years as the main secondary assessment criterion. Approximately 10 patients are enrolled in the study. The pharmacokinetic data collected in this cohort contribute to the population pharmacokinetic analyses. D.4.3.2 Study 2: Randomized Phase 2 Study of Brigatinib in Combination with Dexamethasone, Ifosfamide, Methotrexate, Etoposide, and Cytarabine followed by Brigatinib in Combination with Dexamethasone, Methotrexate, Cyclophosphamide, and Doxorubicin (ALCL99 Regimen) Versus ALCL99 Regimen Alone in High-Risk ALCL-Treated Patients.

[156] Primary Objectives • To evaluate the efficacy of brigatinib in combination with ALCL99 in patients >2 years old with high-risk ALCL, not previously treated. Petition 870260054695, dated 05 / 06 / 2026, pp. 67 / 86 56 / 60 • Evaluate the safety and tolerability of brigatinib in combination with ALCL99.

[157] Pharmacokinetic Objective • To collect plasma concentration-time data to contribute to population pharmacokinetic analyses.

[158] Primary Assessment Criteria • EFS at 2 years.

[159] Secondary Assessment Criteria • ORR, DOR, response time and SO.

[160] Main Inclusion Requirements • Patients must be >2 years old and <22 years old. • Patients must have high-risk ALCL ALK+ -MDD+ at the time of diagnosis and antibody titer <1 / 750. • Patients must have an ALK activation aberration detected by a certified assay (i.e., CLIA in the US) prior to screening. The report of this test must be submitted for eligibility. ALK immunohistochemistry can be used as a substitute for FISH or NGS. • Patients should not be receiving other investigational medications within 30 days of study initiation or during the study. • The patient must meet the organ and system function requirements as established in the protocol.

[161] Main Exclusion • Patients with symptomatic CNS metastases who are neurologically unstable or require an increasing dose of corticosteroids. • Patients receiving strong or moderate CYP3A inhibitors or inducers in the 14 days prior to the first dose of the study drug. • Having previously received an ALK inhibitor. Petition 870260054695, dated 05 / 06 / 2026, pages 68 / 86 57 / 60 • Patients should not have received any prior systemic chemotherapy for ALCL.

[162] Sample Size • Approximately 104 patients >2 to <22 years of age are randomized 1:1 to receive brigatinib in combination with ALCL99 or ALCL99 alone. (85 to 97 patients are <18 years of age.)

[163] Follow-up Duration • Patients are followed for up to 3 years from randomization.

[164] Treatments • Brigatinib is provided as an oral solution or tablets for patients who are able to swallow oral dosage forms. The brigatinib + ALCL99 treatment regimen used in Study 2 follows that explored in Part A-2 of Study 1.

[165] Statistical Considerations

[166] Assuming a bilateral alpha of 0.05, a 2-year EFS of 24% in patients treated with ALCL99 alone, and 50% in patients treated with brigatinib in combination with ALCL99, the study requires 74 observed events to have 80% potency at the final analysis. An interim futility analysis is planned after the first 29 events have been observed. The trial is stopped for futility if the conditional potency in the interim analysis is less than 20%. This potency projection is based on a bilateral log-rank test and is controlled at the 0.05 bilateral level, adjusting for the proposed interim analysis plan. The number of events is fixed, but the enrollment number (N~104) may change based on an assessment of the overall pooled event rate between treatment groups (before enrollment closes).

[167] A tabular overview of all planned clinical studies is provided in the following table. Petition 870260054695, dated 05 / 06 / 2026, pages 69 / 86 58 / 60 Table 2 Population Type Objectives Treatment Study Main Study Design Number of Study Criteria (Formulation (Dose) subjects Evaluation Control, Route) Age Range Study 1 Brigatinib Monotherapy • Dose Escalation: Safety, • Brigatinib • Advanced Monotherapy + Brigatinib Tolerability (solution for solid tumors or RP2D and, oral in the brigatinib ALCL phase that failed monotherapy Pharmacokinetics 1; solution (30 mg / m2 SOC prior (N=15, of 100 <18 years of age) brigatinib tablets in 1 / 2 phase 2) • Brigatinib • Combination Expansion to and • ALCL99 and (ALCL dose: ALCL with ALCL99 expansion of (chemotherapy TBD) + relapsed / refractory Dose parameters (N=15, <18 years of age). No standard complement of controlled pharmacokinetics) ALCL99. • IMT expansion: unresectable / recurrent IMT (N=10, <18 years old) pediatric brigatinib ORR Petition 870260054695, dated 05 / 06 / 2026, pp. 70 / 86 59 / 60 years old). Brigatinib + ALCL99 • Newly diagnosed high-risk ALCL patient (N=12, <18 years of age). Study 2 • ALCL99, • ALCL99 + • Brigatinib 85 to 97 patients brigatinib and (dose of 2 to 17 years of age (solution Phase Efficacy and TBD) + age with ALCL oral or EFS, ORR 2 Safety newly diagnosed standard doses based on ALCL99. high risk swallowing ability)

[168] The methods described in this document are intended to be merely exemplary, and those skilled in the art will recognize, or will Petition 870260054695, dated 05 / 06 / 2026, pp. 71 / 86 60 / 60 capable of determining, using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered within the scope of disclosure.

[169] All patents, patent applications and publications referenced in this document are incorporated herein in their entirety. Citation or identification of any reference in this application is not an admission that such reference is available as a prior art to this application. The full scope of the disclosure is best understood with reference to the appended claims. Petition 870260054695, dated 05 / 06 / 2026, p. 72 / 86

Claims

1 / 5 CLAIMS 1. Use of Compound A of the formula: or a pharmaceutically acceptable salt thereof, characterized in that it is for the manufacture of a pharmaceutical composition, dosage form, dosage regimen or kit for treating cancer in a pediatric cancer patient, wherein the cancer is an inflammatory myofibroblastic tumor (IMT), anaplastic large cell lymphoma (ALCL) or neuroblastoma.

2. Use according to claim 1, characterized in that the cancer is anaplastic lymphoma kinase positive (LAK+).

3. Use according to claim 1 or 2, characterized in that the cancer is TMI or LAGC.

4. Use according to claim 1 or 2, characterized in that the cancer is neuroblastoma.

5. Use according to claim 1 or 2, characterized in that the cancer is TMI.

6. Use according to claim 5, characterized in that the TMI is unresectable or recurrent TMI.

7. Use according to claim 1 or 2, characterized in that the cancer is LAGC.

8. Use according to claim 7, characterized in that LAGC is relapsed or refractory LAGC.

9. Use according to claim 7, characterized in that LAGC is newly diagnosed LAGC. Petition 870260054695, dated 05 / 06 / 2026, page 73 / 86 2 / 5 10. Use according to claim 9, characterized in that the LAGC is a newly diagnosed LAGC with a high risk of recurrence.

11. Use according to claim 10, characterized in that the high risk of recurrence is characterized by positive minimal disseminated disease (MDD+) at the time of diagnosis or anti-LAK antibody titers < 1 / 750 at the time of diagnosis.

12. Use according to any one of claims 1 to 11, characterized in that Compound A, or a pharmaceutically acceptable salt thereof, is formulated to: (a) be used orally; (b) be used once daily (QD); (c) be used at a dose of about 30 mg / m2 to about 100 mg / m2; and / or (d) be used at a dose of about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg / m2.

13. Use in accordance with any one of claims 1 to 12, characterized in that it further comprises the formulation of a second therapeutic agent.

14. Use according to claim 13, characterized in that the second therapeutic agent is cyclophosphamide, doxorubicin, vincristine, corticosteroid, ifosfamide, etoposide, methotrexate or cytarabine, or a combination thereof.

15. Use according to claim 14, characterized in that the corticosteroid is dexamethasone or hydrocortisone, or a combination thereof.

16. Use in accordance with any of claims 13 to 15, characterized in that the second therapeutic agent includes dexamethasone, which is formulated to be used at a dose of about 5 mg / m2 to about 10 mg / m2.

17. Use in accordance with any of claims 13 to 16, characterized in that the second therapeutic agent includes cyclophosphamide, which is formulated to be used at a dose of approximately 200 mg / m2.

18. Use in accordance with any of claims 13 to 17, characterized in that the second therapeutic agent includes ifosfamide, which is formulated to be used at a dose of approximately 800 mg / m2.

19. Use in accordance with any of claims 13 to 18, characterized in that the second therapeutic agent includes methotrexate, which is formulated to be used at a dose of approximately 3 g / m2.

20. Use in accordance with any of claims 13 to 19, characterized in that the second therapeutic agent includes etoposide, which is formulated to be used at a dose of approximately 100 mg / m2.

21. Use in accordance with any of claims 13 to 20, characterized in that the second therapeutic agent includes cytarabine, which is formulated to be used at a dose of approximately 150 mg / m2 and is formulated to be used twice daily.

22. Use in accordance with any of claims 13 to 21, characterized in that the second therapeutic agent includes doxorubicin, which is formulated to be used at a dose of approximately 25 mg / m2.

23. Use according to any one of claims 13 to 22, characterized in that Compound A, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are formulated to be used for one or more 21-day cycles.

24. Use according to claim 23, characterized in that Petition 870260054695, dated 05 / 06 / 2026, p. 75 / 86 4 / 5 Compound A, or a pharmaceutically acceptable salt thereof, is formulated to be used on days 1 to 21 of the 21-day cycle.

25. Use according to claim 23 or 24, characterized in that the second therapeutic agent includes dexamethasone, which is formulated to be used on days 1 to 5 of the 21-day cycle.

26. Use according to any one of claims 23 to 25, characterized in that the second therapeutic agent includes cyclophosphamide, which is formulated to be used: (a) on days 1 and 2 of the 21-day cycle; or (b) on days 1 to 5 of the 21-day cycle.

27. Use in accordance with any of claims 23 to 26, characterized in that the second therapeutic agent includes a combination of hydrocortisone, methotrexate, and cytarabine, which are formulated for use on day 1 of the 21-day cycle.

28. Use in accordance with any of claims 23 to 27, characterized in that the second therapeutic agent includes ifosfamide, which is formulated to be used on days 1 to 5 of the 21-day cycle.

29. Use in accordance with any of claims 23 to 28, characterized in that the second therapeutic agent includes methotrexate, which is formulated to be used on day 1 of the 21-day cycle.

30. Use in accordance with any of claims 23 to 29, characterized in that the second therapeutic agent includes etoposide, which is formulated to be used on days 4 and 5 of the 21-day cycle.

31. Use in accordance with any of claims 23 to 30, characterized in that the second therapeutic agent includes cytarabine, which is formulated to be used on days 4 and 5 of the 21-day cycle.

32. Use in accordance with any of claims 23 to 31, Petition 870260054695, dated 05 / 06 / 2026, p. 76 / 86 5 / 5 characterized in that the second therapeutic agent includes doxorubicin, which is formulated to be used on days 4 and 5 of the 21-day cycle.

33. Invention of a product, process, system, kit or use, characterized by the fact that it comprises one or more elements described in this patent application. Petition 870260054695, dated 05 / 06 / 2026, pp. 77 / 86

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