Methods of treating cancer in pediatric patients

Abstract

Provided herein are methods of treating cancer in a pediatric patient, and particularly, methods for treating cancer (e.g., inflammatory myofibroblastoma, anaplastic large cell lymphoma, and neuroblastoma) in a pediatric patient using bugatinib as monotherapy or a combination therapy with one or more second therapeutic agents.

Description

[0001] This application is a divisional application of a patent application with application number 201980025695.X, application date March 18, 2019, and invention name “Method for treating cancer in pediatric patients”.

[0002] This application claims priority to U.S. Provisional Application No. 62 / 645,089, filed on March 19, 2018, the entire contents of which are incorporated herein by reference. Technical Field

[0003] Provided herein are methods of treating cancer (e.g., inflammatory myofibroblastic tumor and anaplastic large cell lymphoma) in pediatric patients using brigatinib as a monotherapy or in combination therapy with one or more second therapeutic agents. Background Art

[0004] Brigatinib is a novel orally (PO) administered tyrosine kinase inhibitor (TKI). Brigatinib potently inhibits the activated variant of anaplastic lymphoma kinase (ALK).

[0005] ALK is a tyrosine kinase encoded on chromosome 2 that plays a physiological role in early brain development. Adult expression levels are low; however, ALK can change and become active in a variety of malignant tumors, including adult diseases, i.e., non-small cell lung cancer (NSCLC), and inflammatory myofibroblastic tumors (IMT) and anaplastic large cell lymphoma (ALCL) that mainly affect pediatric patients or young people. In each of these conditions, the most common ALK changes 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 gene rearrangement found in NSCLC involves a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase domain (KD). Since then, many other ALK fusion partners that are thought to cause abnormal signaling and oncogenic transformation have been described. 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 mutations of full-length ALK without rearrangement occur in another major childhood cancer, neuroblastoma. Holla et al., 2017.

[0006] Three ALK inhibitors, crizotinib, ceritinib, and alectinib, have been 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 United States Food and Drug Administration (FDA) for the treatment of ALK+ metastatic NSCLC in patients who have progressed on or are intolerant to crizotinib, and a European Marketing Authorisation Application (MAA) for the use of brigatinib in patients with ALK+ NSCLC previously 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, which are primarily attributed 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 drugs, including brigatinib, have shown the ability to overcome many 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, ceritinib, and alectinib, and was the only one of these drugs to have substantial activity against all 17 secondary ALK mutants of EML4-ALK tested at relevant exposure levels achieved in patients.

[0007] In addition to promising nonclinical study results, brigatinib has demonstrated substantial systemic and intracranial responses in adult patients with crizotinib-refractory ALK+ NSCLC in a first-in-human (FIH) study (Study AP26113-11-101) and a Phase 2 study (Study AP26113-13-201; the ALTA trial). In ALTA, a stable objective response rate (ORR) and durability of response were observed with a 180 mg daily dose, which was initiated after a 7-day lead-in at 90 mg daily (90→180 mg once daily (QD)). In this study, investigator-assessed confirmed ORR, duration of response (DOR), and progression-free survival (PFS) were 55.5% and 13.8 and 15.6 months, respectively, at the 90→180 mg QD dose. A phase 3 trial (Study AP26113-13-301; ALTA 1L) was conducted with the primary objective to compare the efficacy of brigatinib with crizotinib based on PFS in patients with ALK+ locally advanced or metastatic NSCLC who had not received prior ALK inhibitor therapy.

[0008] NSCLC is primarily an adult disease, as cases in children and adolescents are extremely rare. However, as previously described, 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 reasonable therapeutic target for pediatric patients with these conditions. Takita, Cancer Sci. 2017, 108(10), 1913-20.

[0009] The first of these cancers, IMT, is a very rare solid tumor characterized by spindle-shaped myofibroblasts with a chronic inflammatory component that occurs primarily in children and adolescents, primarily in the lungs, soft tissues, and abdominal areas. Chromosomal translocations leading to ALK activation are present in 50% to 70% of IMTs and are more common in young people; the most common is the tropomyosin 3 / 4 (TPM3 / 4)-ALK fusion, but as in NSCLC, EML4-ALK inversions are also seen. 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 options for advanced / recurrent disease or when complete resection is not possible. Dalton et al., J. Pediatr. Surg. 2016, 51(4), 541-4.

[0010] The second of these conditions, ALCL, is a rare (about 110 new cases per year in Europe) form of non-Hodgkin lymphoma (NHL) that also occurs primarily in children and adolescents. It is characterized by the proliferation of lymphoid T cells or null cells that express CD30. Up to 90% of pediatric ALCL patients have ALK+ disease, while adult ALCL patients 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% of ALK+ ALCL, respectively. Holla et al., 2017; Pulford et al., J. Cell Physiol. 2004, 199(3), 330-58. ALCL is very chemosensitive, and several chemotherapy regimens have been used in both first-line and refractory settings.

[0011] Finally, neuroblastoma is a rare (<100 new ALK+ cases / year in Europe) childhood malignancy arising from the embryonic sympathetic nervous system. In contrast to IMT and ALCL, which are dominated by ALK translocations, activating point mutations of ALK are important drivers of tumorigenesis in neuroblastoma, with ALK mutations present in almost all familial neuroblastoma cases and between 6% and 10% of spontaneous diseases. Louis et al., Annu. Rev. Med. 2015, 66, 49-63; Mosse et al., Nature 2008, 455(7215), 930-5. Other important driver oncogenes are well established in neuroblastoma, the most prominent of which is the amplification of MYCN. Standard treatments for neuroblastoma include chemotherapy, resection, radiotherapy, biological therapy, and immunotherapy, depending on the risk profile. Berlanga et al., Expert Opin. Emerg. Drugs 2017, 22(1), 63-75.

[0012] With regard to IMT, there are no approved or rigorously studied pharmacological options for the control of this condition. Therefore, patients with unresectable disease due to complex lesions or other factors represent the highest unmet need in the IMT patient population. Therefore, novel agents that can control unresectable disease or serve as neoadjuvant therapy to achieve resection are needed and would represent a significant advance for these patients.

[0013] Today, most European pediatric groups use the ALCL99 chemotherapy regimen as the standard treatment for ALCL. This approach is derived from the BFM regimen previously used in aggressive B-cell NHL. Treatment regimens vary among studies, but generally involve cyclophosphamide, doxorubicin, vincristine, corticosteroids, ifosfamide, and etoposide for 4 to 6 months, with high-dose methotrexate and cytarabine for central nervous system (CNS) prevention. Eyre et al., European Journal of Haematology 2014, 93 (6), 455-68; Turner et al., Br. J. Haematol. 2016, 173 (4), 560-72. In the largest study based on ALCL99 completed to date, the observed EFS rate at 2 years was 73%. After initial treatment, approximately 20% to 40% of patients with ALCL subsequently develop recurrent disease. Patients at highest risk of relapse appear to be those with MDD+ status and anti-ALK antibody titers ≤ 1 / 750. Mussolin et al., Leukemia 2013, 27(2), 416-22. Nevertheless, the main goals of ongoing research must include identifying treatment options to prevent relapse in patients with known high-risk ALCL, and there is still an unmet need for better therapies for these patients. Therefore, ALCL patients who exhibit high-risk features (e.g., MDD or low ALK antibody titers at diagnosis) may benefit from more aggressive or different first-line interventions that promote deeper responses, with the goal of preventing or arresting relapse, especially since relapse is associated with a poor prognosis. Summary of the invention

[0014] Provided herein are methods for treating cancer in a pediatric patient having cancer, comprising administering to the patient a therapeutically effective amount of Compound A having the formula:

[0015]

[0016] or a pharmaceutically acceptable salt thereof. Compound A can be administered as a monotherapy or in combination therapy with one or more second therapeutic agents.

[0017] In one embodiment, the cancer is inflammatory myofibroblastic tumor (IMT), anaplastic large cell lymphoma (ALCL), or neuroblastoma. In one embodiment, the cancer is inflammatory myofibroblastic tumor (IMT) or anaplastic large cell lymphoma (ALCL).

[0018] Also provided herein are pharmaceutical compositions, dosage forms, dosing regimens, and kits that can be used in conjunction with the above methods. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Shown to receive 40mg / m 2 Comparison of simulated brigatinib systemic exposure (AUC) in pediatric patients receiving the oral solution versus adult patients receiving the 90 mg oral tablet.

[0020] Figure 2 An overview of clinical studies of brigatinib is shown.

[0021] Figure 3 The suggested dose of brigatinib for Clinical Study 1 is shown. DETAILED DESCRIPTION

[0022] definition

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. All patents, applications, published applications and other publications referenced herein are incorporated herein by reference in their entirety. The headings used herein are for organizational purposes only and in no way limit the invention described herein.

[0024] As used herein and unless otherwise indicated, the term "administer" or "administration" refers to the act of physically delivering a substance present in vitro to a patient's body, for example, by oral, mucosal, intradermal, intravenous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art. When treating a disease, disorder, or condition, or a symptom thereof, the administration of the substance is generally performed after the onset of the disease, disorder, or condition, or a symptom thereof. When preventing a disease, disorder, or condition, or a symptom thereof, the administration of the substance is generally performed before the onset of the disease, disorder, or condition, or a symptom thereof.

[0025] As used herein and unless otherwise indicated, the term "treatment / treat / treating" is intended to include all interventions for a disease / disorder or condition suffered by a subject, such as alleviating, slowing, stopping or reversing one or more symptoms of a disease, disorder or condition or delaying the progression of a disease, disorder or condition, even if the disease, disorder or condition is not actually eliminated. Treatment may include, for example, reducing the severity of symptoms, the number of symptoms, and / or the frequency of recurrence. Treatment of cancer may include, for example, inhibiting tumor growth, preventing tumor growth, and / or causing regression of an already existing tumor.

[0026] As used herein and unless otherwise indicated, the terms "prevent," "preventing," and "prevention" are intended to include methods of delaying and / or excluding the onset of a disorder, disease or condition and / or its attendant symptoms; preventing a subject from acquiring a disorder, disease or condition; or reducing the risk of a subject acquiring a disorder, disease or condition.

[0027] As used herein and unless otherwise indicated, the term "alleviate" or "alleviating" refers to relieving or alleviating one or more symptoms (e.g., pain) of a disorder, disease, or condition. The term may also refer to reducing side effects associated with an active ingredient. Sometimes, the beneficial effects that a subject obtains from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.

[0028] The improvement of cancer or cancer-related diseases can be characterized as complete or partial response. "Complete response" refers to the absence of clinically detectable disease in the case of normalization of any previously abnormal radiological examinations, bone marrow and cerebrospinal fluid (CSF) or abnormal monoclonal protein measurements. "Partial response" refers to at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% reduction of all measurable tumor burdens in the absence of new lesions (i.e., the number of malignant tumor cells present in the subject or the measured tumor mass volume or the number of abnormal monoclonal proteins). The term "treatment" covers complete response and partial response.

[0029] As used herein, and unless otherwise indicated, the terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0030] As used herein and unless otherwise indicated, the terms "tumor" and "solid tumor" as used herein refer to all pathological and neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. As used herein, "neoplastic" refers to any form of abnormally regulated or unregulated cell growth, whether malignant or benign, that results in abnormal tissue growth. Thus, "neoplastic cells" include malignant and benign cells with abnormally regulated or unregulated cell growth.

[0031] As used herein and unless otherwise indicated, the terms "subject" and "patient" are used interchangeably. As used herein, a subject can be a mammal, such as a non-primate (e.g., cattle, pigs, horses, cats, dogs, rats, etc.) or a primate (e.g., monkeys and humans). In a specific embodiment, the subject is a human. In one embodiment, the subject is a mammal (e.g., a human) suffering from a disease, disorder, or condition described herein. In another embodiment, the subject is a mammal (e.g., a human) at risk of developing a disease, disorder, or condition described herein.

[0032] As used herein and unless otherwise indicated, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or a combination of one or more compounds that, when administered (e.g., sequentially or simultaneously), causes a desired biological or medical response, such as destroying target cancer cells or slowing or stopping the progression of a subject's cancer. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, the mode of administration, etc., which can be easily determined by a person skilled in the art. The term also applies to doses that cause a specific response in target cells (e.g., reducing platelet adhesion and / or cell migration). For example, a "therapeutically effective amount" of a combination therapy refers to an amount of each therapeutic agent of the combination therapy that has a beneficial effect when administered in combination. In certain embodiments, the effect of the combination is additive. In certain embodiments, the effect of the combination is synergistic. In addition, those skilled in the art will recognize that in the case of a combination therapy, the amount of each therapeutic agent can be used independently in a "subtherapeutic amount", i.e., less than the therapeutically effective amount of the individual therapeutic agents.

[0033] As used herein and unless otherwise indicated, the term "subtherapeutic amount" of an agent or therapy is an amount that is less than the effective amount of that agent or therapy as a single agent, but when combined with an effective amount or a subtherapeutic amount of another agent or therapy, may produce the result desired by the physician due to, for example, synergy in the effective effect produced or reduced side effects.

[0034] As used herein and unless otherwise indicated, combination therapy or "with ... combination" refers to the use of more than one therapeutic agent to treat a particular disorder or condition. "With ... combination" is not intended to imply that therapeutic agents must be administered simultaneously and / or that the therapeutic agents are formulated for delivery together, although these delivery methods are within the scope of the present disclosure. Therapeutic agents can be administered simultaneously with one or more other additional agents, 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) 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). The therapeutic agents in the combination therapy may also be administered in an alternating dosing regimen with or without a rest period (e.g., no therapeutic agent is administered on certain days of the regimen). 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. Typically, each therapeutic agent is administered at a dose and / or time regimen determined for that particular agent. More advanced combinations, such as triple therapy, are also contemplated herein.

[0035] As used herein and unless otherwise indicated, the term "concomitant administration" or "co-administration" refers to the administration of two or more therapeutic agents to the same subject at the same time (simultaneously) or approximately at the same time. "Approximately simultaneously" includes sequential administration, wherein the time period between administrations is solely due to the speed at which the active agents are administered to the individual, rather than an intentional delay between administrations, such as the time period required for a single health care practitioner to administer a first therapeutic agent in accordance with accepted clinical practice and standards, and then administer a second therapeutic agent in accordance with accepted clinical practice and standards. In one embodiment, "approximately simultaneously" encompasses administration 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 one embodiment, concomitant 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 about two hours, or no more than about six hours, and cannot exceed 12 hours.

[0036] As used herein and unless otherwise indicated, the term "sequential administration" refers to at least two therapeutic agents being administered at different times, and the route of administration is the same or different. In the specific embodiment of sequential administration, the administration of a therapeutic agent is completed before another or other therapeutic agents begin to be administered. The delay between the administration of different therapeutic agents may be intentional, for example, for the purpose of achieving some beneficial therapeutic effects. In one embodiment, sequential administration is performed with a time interval of not less than about 30 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, sequential administration occurs with 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 longer. In one embodiment, sequential administration is performed with a time interval of not less than 12 hours.

[0037] As used herein and unless otherwise indicated, the term "synergistic effect" refers to a situation where the combination of two or more agents produces an effect that is greater than the sum of the effects of each individual agent. The term includes not only alleviation of symptoms of the disease to be treated, but also includes, for example, improved side effects, improved tolerability, improved patient compliance, improved efficacy, or any other improved clinical outcome.

[0038] As used herein and unless otherwise indicated, the term "about" or "approximately" means an acceptable error for a particular value, as determined by one of ordinary skill in the art, which error depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0039] As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. For a review of suitable salts, see, for example, BERGE et al., J. Pharm. Sci. 66: 1-19 (1977) and Remington: The Science and Practice of Pharmacy, 20th 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, etc. Non-limiting examples of suitable basic 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, particularly such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0040] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the vectors or cells of the present invention, it is contemplated for use in the therapeutic compositions of the present disclosure. Supplementary active ingredients may also be incorporated into the compositions.

[0041] As used herein and unless otherwise indicated, the terms "carrier", "adjuvant" or "vehicle" are used interchangeably herein and include any and all solvents, diluents or other liquid vehicles, dispersing aids or suspending aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 20th Ed., A. Gennaro, Lippincott Williams & Wilkins, 2000 discloses various carriers and known preparation techniques for pharmaceutically acceptable compositions. Unless any conventional carrier medium is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effect or otherwise interacting with any other component of the pharmaceutically acceptable composition in a harmful manner, its use is encompassed within the scope of the present disclosure.

[0042] Unless otherwise stated, the compounds described herein include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a structure having the present invention but with a hydrogen atom replaced by deuterium or tritium or a carbon atom replaced by an isotopically enriched atom may be present in the isotope. 13 C- or 14 Compounds with carbon substitutions at C are within the scope of the present disclosure.

[0043] Unless otherwise specified, the compounds described herein include all stereochemical forms of the described structure; for example, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers of the compounds of the invention as well as mixtures of enantiomers and diastereomers are within the scope of the present disclosure. In compounds described herein where the relative stereochemistry is defined, the diastereomeric purity of such compounds may be at least 80%, at least 90%, at least 95%, or at least 99%. As used herein, the term "diastereomeric purity" refers to the amount of a compound having the depicted relative stereochemistry expressed as a percentage of the total amount of all diastereomers present.

[0044] Treatment

[0045] In one embodiment, provided herein is a method for treating cancer in a pediatric patient having cancer, comprising administering to the patient a therapeutically effective amount of Compound A having the formula:

[0046]

[0047] or a pharmaceutically acceptable salt thereof.

[0048] In one embodiment, provided herein is a method for preventing cancer in a pediatric patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0049] Compound A is also known as brigatinib and has the chemical name 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.

[0050] Compound A or a pharmaceutically acceptable salt thereof can be administered as a monotherapy or in combination therapy with one or more second therapeutic agents.

[0051] In one embodiment, the patient is <22 years old. In one embodiment, the patient is ≤18 years old. In one embodiment, the patient is ≥1 year old and <22 years old. In one embodiment, the patient is ≥1 year old and ≤18 years old. In one embodiment, the patient is 1 to 17 years old. In one embodiment, the patient is ≥2 years old and <22 years old. In one embodiment, the patient is ≥2 years old and ≤18 years old. In one embodiment, the patient is 2 to 17 years old. In one embodiment, the patient is ≥4 years old and <22 years old. In one embodiment, the patient is ≥4 years old and ≤18 years old. In one embodiment, the patient is 4 to 17 years old.

[0052] In one embodiment, cancer is anaplastic lymphoma kinase positive (ALK+). As used herein and unless otherwise specified, "ALK positive" (ALK+) cancer refers to a cancer characterized by an inappropriate high expression of the ALK gene or a mutation in the ALK gene that changes the biological activity of the ALK nucleic acid molecule or polypeptide. As used herein and unless otherwise specified, "mutation" or "mutant" of ALK includes one or more deletions, substitutions or additions in the amino acid or nucleotide sequence of ALK or its fragment. ALK mutants also include ALK fusion proteins and ALK fusion genes. The ALK mutants may also include one or more deletions, substitutions or additions or their fragments, as long as the mutants retain kinase phosphorylation activity. In one embodiment, the ALK mutant is an echinoderm microtubule-associated protein-like 4 (EML4) gene and an ALK tyrosine kinase domain fusion EML4-ALK, including any secondary mutants of EML4-ALK, such as those described in U.S. Patent No. 9,611,283, the entire contents of which are incorporated herein by reference.

[0053] In one embodiment, ALK+ cancer is determined by an FDA-approved test or other test known in the art. Tests that may be used include, for example, FoundationOne CDx TM (F1CDx) (a sequencing-based in vitro diagnostic device for the detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutation burden (TMB) using DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens); VENTANA ALK (D5F3) CDx assay (a qualitative test for the detection of anaplastic lymphoma kinase (ALK) protein in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue stained using the BenchMark XT or BenchMark ULTRA automated staining instruments); and Vysis ALK BreakApart FISH Probe Kit test (a qualitative test for the detection of rearrangements involving the ALK gene by 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 fluorescent in situ hybridization (FISH) test, such as the Vysis ALK Break Apart FISH probe kit test. For additional information about FDA-approved tests, see, for example, https: / / www.fda.gov / MedicalDevices / ProductsandMedicalProcedures / InVitroDi agnostics / ucm303030.htm; for additional information about the Vysis ALK Break Apart FISH probe kit, see, for example, https: / / www.molecular.abbott / us / en / products / oncology / vysis-alk-break-apart-fish-probe-kit; the entire contents of which are incorporated herein by reference.

[0054] In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is an advanced solid tumor. In one embodiment, the cancer is an ALK+ advanced solid tumor. In one embodiment, the cancer is an ALK+ advanced solid tumor that has failed one or more previous standard of care (SOC) treatments.

[0055] In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is relapsed or refractory neuroblastoma. In one embodiment, the cancer is relapsed neuroblastoma. In one embodiment, the cancer is refractory neuroblastoma. In one embodiment, the cancer is ALK+ neuroblastoma. In one embodiment, the cancer is relapsed or refractory ALK+ neuroblastoma.

[0056] In one embodiment, the cancer is inflammatory myofibroblastic tumor (IMT). In one embodiment, the cancer is an unresectable or recurrent IMT. In one embodiment, the cancer is an unresectable IMT. In one embodiment, the cancer is a recurrent IMT. In one embodiment, the cancer is an ALK+IMT. In one embodiment, the cancer is an unresectable or recurrent ALK+IMT.

[0057] In one embodiment, the cancer is a hematological cancer. In one embodiment, the cancer is a lymphoma, leukemia, or myeloma. In one embodiment, the cancer is a lymphoma. In one embodiment, the cancer is non-Hodgkin's lymphoma. In one embodiment, the cancer is anaplastic large cell lymphoma (ALCL). In one embodiment, the cancer is relapsed or refractory ALCL. In one embodiment, the cancer is relapsed ALCL. In one embodiment, the cancer is refractory ALCL. In one embodiment, the cancer is ALK+ALCL. In one embodiment, the cancer is relapsed or refractory ALK+ALCL. In one embodiment, the cancer is newly diagnosed ALCL. In one embodiment, the cancer is newly diagnosed ALCL with a high risk of relapse. In one embodiment, the cancer is newly diagnosed ALK+ALCL with a high risk of relapse.

[0058] Several features associated with a high risk of relapse have been identified in ALCL patients. By multivariate analysis, the presence of one or more features of mediastinal involvement, visceral involvement defined as lung, liver or spleen involvement, and skin involvement all predicted relapse. 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 detected by polymerase chain reaction (PCR) and / or bone marrow infiltration (i.e., minimal disseminated disease (MDD)) detectable by molecular techniques at diagnosis, low anti-ALK antibody titers at diagnosis, and minimal residual disease (MRD) detection by PCR for NPM1-ALK in blood after the first chemotherapy course. Damm-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.

[0059] Mussolin and colleagues investigated the prognostic value of MDD and anti-ALK immune responses in children with NPM-ALK+ALCL to determine whether these factors could stratify the risk of relapse. Mussolin et al., 2013. Of the 128 patients included in the study, 26 (20%) were considered to have high-risk disease based on the presence of MDD+ status and antibody titers ≤1 / 750. In this high-risk patient group, five-year PFS and overall survival (OS) were 28% and 72%. In contrast, PFS / OS was 93% / 98% for low-risk patients (MDD- and antibody titers>1 / 750) and 68% / 84% in intermediate-risk patients (MDD- and antibody titers≤1 / 750 or MDD+ and antibody titers>1 / 750).

[0060] In one embodiment, the high risk of recurrence is characterized by the presence of one or more features selected from the following: mediastinal involvement, visceral involvement defined as involvement of the lungs, liver, or spleen, skin involvement, NPM1-ALK in peripheral blood, bone marrow infiltration, low anti-ALK antibody titers at diagnosis, and minimal residual disease (MRD) detection of NPM1-ALK in the blood after the first chemotherapy course. In one embodiment, the high risk of recurrence is characterized by minimal disseminated disease positive (MDD+) at diagnosis. In one embodiment, the high risk of recurrence is characterized by low anti-ALK antibody titers at diagnosis. In one embodiment, the high risk of recurrence is characterized by anti-ALK antibody titers ≤1 / 750 at diagnosis.

[0061] In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered orally. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered in tablet form. In one embodiment, the tablet has a 30 mg, 90 mg or 180 mg dosage strength of Compound A. In one embodiment, the tablet is a white film-coated tablet.

[0062] Compound A or its pharmaceutically acceptable salt can be administered once a day (QD), or divided into multiple daily doses, such as twice a day (BID) and three times a day (TID). In addition, administration can be continuous (i.e., every day) or intermittent. As used herein, the term "intermittent" or "intermittently" is intended to mean stopping and starting at regular or irregular intervals. For example, the intermittent administration of Compound A or its pharmaceutically acceptable salt is administered one to six days per week, administered in cycles (e.g., administered daily for two to eight weeks, followed by a rest period of no administration for up to one week) or administered every other day.

[0063] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered once a day (QD). In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, is administered twice a day (BID).

[0064] In certain embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to the patient in cycles. Cycling therapy involves administering an active agent for a period of time, then resting for a period of time, and repeating this sequential administration. Cycling therapy can avoid or reduce the side effects of one of the therapies and / or improve the efficacy of the treatment.

[0065] In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 10 mg / m 2 About 150 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 30 mg / m 2 About 100 mg / m 2In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 30 mg / m 2 About 60 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 40 mg / m 2 About 80 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 40 mg / m 2 About 100 mg / m 2 dosage administration.

[0066] In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at 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 / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 20 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 30 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 40 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 50 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 60 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of about 70 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 80 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 90 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 100 mg / m 2In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of about 110 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 120 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 130 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 140 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 150 mg / m 2 dosage administration.

[0067] In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to provide a pediatric patient with an area under the curve (AUC) exposure that is no more than 80% of the area under the curve obtained in an adult at a clinical dose.

[0068] 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 1000 to about 40000 ng·h / mL, about 2000 to about 30000 ng·h / mL, about 4000 to about 25000 ng·h / mL, or about 5000 to about 20000 ng·h / mL. ∞ 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 4000 to about 25000 ng·h / mL. ∞ 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 5000 to about 20000 ng·h / mL. ∞ In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to provide an AUC of Compound A of about 10000 ng·h / mL. ∞ The amount of application.

[0069] In one embodiment, Compound A (ie, free base) is administered. In one embodiment, a pharmaceutically acceptable salt (eg, HCl salt) of Compound A is administered. In one embodiment, the amount administered refers to the amount measured as the amount of Compound A.

[0070] In one embodiment, Compound A or a pharmaceutically acceptable salt thereof can be administered as a monotherapy or in combination therapy with one or more second therapeutic agents. In one embodiment, the methods provided herein further comprise administering to the patient a therapeutically effective amount of a second therapeutic agent.

[0071] In one embodiment, provided herein is a method for treating cancer in a pediatric patient having cancer, 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.

[0072] In one embodiment, the second therapeutic agent is the ALCL99 chemotherapy regimen. This regimen is derived from the BFM regimen previously used for aggressive B-cell NHL. Treatment regimens vary among studies, but generally involve cyclophosphamide, doxorubicin, vincristine, corticosteroids, ifosfamide, and etoposide given for 4 to 6 months with central nervous system (CNS) prophylaxis with high-dose methotrexate and cytarabine. Eyre et al., 2014; Turner et al., 2016.

[0073] In one embodiment, the second therapeutic agent is cyclophosphamide, doxorubicin, vincristine, a corticosteroid, ifosfamide, etoposide, methotrexate, or cytarabine, or a combination thereof. In one embodiment, the corticosteroid is dexamethasone or hydrocortisone, or a combination thereof.

[0074] In one embodiment, the second therapeutic agent comprises dexamethasone. In one embodiment, the second therapeutic agent comprises dexamethasone at about 2.5 mg / m 2 Up to 20 mg / m 2 In one embodiment, the second therapeutic agent comprises dexamethasone at a dose of about 5 mg / m 2 Up to 10 mg / m 2 In one embodiment, the second therapeutic agent comprises dexamethasone at a dose of about 5 mg / m 2 In one embodiment, the second therapeutic agent comprises dexamethasone at about 10 mg / m 2 dosage administration.

[0075] In one embodiment, the second therapeutic agent comprises cyclophosphamide. In one embodiment, the second therapeutic agent comprises cyclophosphamide at about 100 mg / m 2 Up to 300 mg / m 2 In one embodiment, the second therapeutic agent comprises cyclophosphamide at about 200 mg / m 2 dosage administration.

[0076] In one embodiment, the second therapeutic agent comprises ifosfamide. In one embodiment, the second therapeutic agent comprises ifosfamide at about 400 mg / m 2 Up to 1200 mg / m 2 In one embodiment, the second therapeutic agent comprises ifosfamide at about 800 mg / m 2dosage administration.

[0077] In one embodiment, the second therapeutic agent comprises methotrexate. In one embodiment, the second therapeutic agent comprises methotrexate at about 1.5 g / m 2 To about 4.5g / m 2 In one embodiment, the second therapeutic agent comprises methotrexate, which is administered at a dose of about 3 g / m 2 dosage administration.

[0078] In one embodiment, the second therapeutic agent comprises etoposide. In one embodiment, the second therapeutic agent comprises etoposide at 50 mg / m 2 Up to 150 mg / m 2 In one embodiment, the second therapeutic agent comprises etoposide at about 100 mg / m 2 dosage administration.

[0079] In one embodiment, the second therapeutic agent comprises cytarabine. In one embodiment, the second therapeutic agent comprises cytarabine at about 75 mg / m 2 Up to 225 mg / m 2 In one embodiment, the second therapeutic agent comprises cytarabine at about 150 mg / m 2 The dose is administered and is administered twice daily.

[0080] In one embodiment, the second therapeutic agent comprises doxorubicin. In one embodiment, the second therapeutic agent comprises doxorubicin at 12.5 mg / m 2 Up to 37.5 mg / m 2 In one embodiment, the second therapeutic agent comprises doxorubicin at about 25 mg / m 2 dosage administration.

[0081] In certain embodiments, Compound A or a pharmaceutically acceptable salt thereof and a second therapeutic agent are cyclically administered to the patient. Cycling therapy involves administering the active agent for a period of time, then resting for a period of time, and repeating this sequential administration. Cycling therapy can avoid or reduce the side effects of one of the therapies and / or improve the efficacy of the treatment.

[0082] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent are administered for one or more 7-day cycles. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent are administered for one or more 21-day cycles. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent are administered for one or more 28-day cycles.

[0083] In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent are administered for at least 4 cycles. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent are administered for at least 6 cycles. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent are administered for at least 8 cycles. In one embodiment, Compound A, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent are administered for at least 12 cycles.

[0084] In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered on days 1-21 of a 21 day cycle.

[0085] In one embodiment, the second therapeutic agent comprises dexamethasone, which is administered on days 1-5 of a 21 day cycle.

[0086] In one embodiment, the second therapeutic agent comprises cyclophosphamide, which is administered on days 1 and 2 of a 21 day cycle.

[0087] In one embodiment, the second therapeutic agent comprises cyclophosphamide, which is administered on days 1-5 of a 21 day cycle.

[0088] In one embodiment, the second therapeutic agent comprises a combination of hydrocortisone, methotrexate, and cytarabine administered on day 1 of a 21 day cycle.

[0089] In one embodiment, the second therapeutic agent comprises ifosfamide, which is administered on days 1-5 of a 21 day cycle.

[0090] In one embodiment, the second therapeutic agent comprises methotrexate, which is administered on day 1 of a 21 day cycle.

[0091] In one embodiment, the second therapeutic agent comprises etoposide, which is administered on days 4 and 5 of a 21 day cycle.

[0092] In one embodiment, the second therapeutic agent comprises cytarabine, which is administered on days 4 and 5 of a 21 day cycle.

[0093] In one embodiment, the second therapeutic agent comprises doxorubicin, which is administered on days 4 and 5 of a 21 day cycle.

[0094] In one embodiment, provided herein is a method for treating unresectable or recurrent IMT in a pediatric patient, 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 about 30 mg / m 2About 100 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 30 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 40 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 60 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 80 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 100 mg / m 2 dosage administration.

[0095] In one embodiment, provided herein is a method for treating relapsed or refractory ALCL in a pediatric patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, ALCL is relapsed or refractory ALK+ALCL. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 30 mg / m 2 About 100 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 30 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 40 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 60 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 80 mg / m 2 In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at about 100 mg / m 2 dosage administration.

[0096] In one embodiment, provided herein is a method for treating ALCL in a pediatric patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an ALCL99 regimen.

[0097] In one embodiment, provided herein is a method for treating ALCL in a pediatric patient, comprising administering to the patient a therapeutically effective amount of a combination of Compound A or a pharmaceutically acceptable salt thereof and dexamethasone, ifosfamide, methotrexate, etoposide, and cytarabine. In one embodiment, the treatment lasts 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 a 21-day cycle; dexamethasone is administered on days 1-5 of a 21-day cycle; ifosfamide is administered on days 1 to 5 of a 21-day cycle; methotrexate is administered on day 1 of a 21-day cycle; etoposide is administered on days 4 and 5 of a 21-day cycle; and cytarabine is administered on days 4 and 5 of a 21-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered on days 1-21 of a 21-day cycle; dexamethasone is administered on days 1-5 of a 21-day cycle at about 10 mg / m 2 Ifosfamide is administered at a dose of approximately 800 mg / m on days 1-5 of a 21-day cycle. 2 Methotrexate is administered at a dose of about 3 g / m on day 1 of a 21-day cycle. 2 etoposide at about 100 mg / m on days 4 and 5 of a 21-day cycle 2 and cytarabine at about 150 mg / m on days 4 and 5 of a 21-day cycle. 2 The dose is administered twice daily.

[0098] In one embodiment, provided herein is a method for treating ALCL in a pediatric patient, comprising administering to the patient a therapeutically effective amount of a combination of Compound A or a pharmaceutically acceptable salt thereof and dexamethasone, methotrexate, cyclophosphamide, and doxorubicin. In one embodiment, the treatment lasts 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 a 21-day cycle; dexamethasone is administered on days 1-5 of a 21-day cycle; methotrexate is administered on day 1 of a 21-day cycle; cyclophosphamide is administered on days 1-5 of a 21-day cycle; and doxorubicin is administered on days 4 and 5 of a 21-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered on days 1-21 of a 21-day cycle; dexamethasone is administered on days 1-5 of a 21-day cycle at a dose of about 10 mg / m 2 Methotrexate is administered at a dose of about 3 g / m on day 1 of a 21-day cycle. 2 Cyclophosphamide is administered at a dose of about 200 mg / m on days 1-5 of a 21-day cycle. 2 and doxorubicin at about 25 mg / m on days 4 and 5 of a 21-day cycle 2dosage administration.

[0099] Pharmaceutical composition

[0100] Also provided herein are pharmaceutical compositions useful in the methods provided herein.The therapeutic agents used in the methods provided herein can be contained in the same or different pharmaceutical compositions, alone or in any combination thereof.

[0101] In one embodiment, provided herein are pharmaceutical compositions and dosage forms comprising Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical compositions and dosage forms further comprise one or more excipients.

[0102] In one embodiment, provided herein are pharmaceutical compositions and dosage forms comprising Compound A or a pharmaceutically acceptable salt thereof and lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), magnesium stearate, and hydrophobic colloidal silicon dioxide.

[0103] In one embodiment, brigatinib (Compound A) is provided for oral use as a film-coated tablet containing 30 mg, 90 mg or 180 mg of brigatinib and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), magnesium stearate and hydrophobic colloidal silicon dioxide. The tablet coating consists of talc, polyethylene glycol, polyvinyl alcohol and titanium dioxide.

[0104] Other pharmaceutical formulations containing brigatinib are described in International Application No. PCT / US2018 / 021128, which is incorporated herein by reference.

[0105] Other combination therapies

[0106] Also provided herein are methods for other combination therapies, in which in addition to the first therapeutic agent provided herein (e.g., Compound A) and the second therapeutic agent provided herein (e.g., ALCL99 chemotherapy regimen), one or more agents known to regulate other pathways or the same pathway (e.g., a third therapeutic agent or therapy) may also be used. In certain embodiments, such methods include administering Compound A to a subject in need thereof, optionally in combination with an ALCL99 chemotherapy regimen, and further in combination with one or more other therapeutic agents such as anticancer agents, chemotherapeutic agents, therapeutic antibodies, and radiation therapy to provide a synergistic or additive therapeutic effect when needed.

[0107] 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 can be administered orally, parenterally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, intrarectally, buccally, intranasally, intraliposomally, by inhalation, vaginally, intraocularly, via local delivery through a catheter or stent, subcutaneously, intrafatally, intraarticularly, intrathecally, or in a sustained release dosage form.

[0108] One or more third active ingredients or agents can be used in the methods provided herein.The third active agent can be a macromolecule (eg, a protein) or a small molecule (eg, a synthetic inorganic, organometallic or organic molecule).

[0109] Examples of macromolecular active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, particularly therapeutic antibodies directed against cancer antigens. Typical macromolecular active agents are biomolecules, such as naturally occurring or synthetic or recombinant proteins.

[0110] The third active agent as a small molecule can also be used to alleviate the side effects associated with the administration of the combination therapy provided herein. However, like some macromolecules, when used together with the combination provided herein (e.g., before, after or simultaneously), many small molecules are considered to provide an additive or synergistic effect. Examples of small molecule third active agents include, but are not limited to, anticancer agents, antibiotics, immunosuppressants and steroids.

[0111] Examples of additional anticancer agents to be used in the methods or compositions described herein include, but are not limited to, acivicin; aclarubicin; nocodazole hydrochloride; aclonine; adolesin; aldesleukin; hexamethylmelamine; ambomycin; amenthranol acetate; amsacrine; anastrozole; anthramycin; asparaginase; triclindane; azacitidine; azatepa; azomycin; batimastat; benzotepa; bicalutamide; bisantrene hydrochloride; binefad dimesylate; bisezole; bleomycin sulfate; buquina sodium; bropiridamine; busulfan; cactinomycin; carlotestosterone; caracetamide; carbetim; carboplatin; carmustine; carrubicin hydrochloride; carzeresin; cedifingol; celecoxib (COX-2 inhibitor ); chlorambucil; cilomycin; cisplatin; cladribine; clofarabine; clinator mesylate; cyclophosphamide; cytarabine; dacarbazine; dabrafenib; dactinomycin; daunorubicin hydrochloride; decitabine; dextromaplatin; dezaguanine; dezaguanine mesylate; diazaquinone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drolostanone propionate; azomycin; edatrexa; elonicetate hydrochloride; elsarucin; enloplatin; enprobamate; epipiperidone; epirubicin hydrochloride; erbulazole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etobanin; fadrozole hydrochloride; fazarabine; retinoic acid phenamide; floxuridine; fludarabine phosphate; fluorouracil oxazolidinone; flucitabine; fosquinolone; fostrimoxine sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; imofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menolipir; mercaptopurine; methotrexate; methotrexate sodium; chlorpheniramine; metodepa; mibutidamide; mitokacin; mitoclocycline; mitoxantrone; mitomycin; mitosperm; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogamycin; omatasin; ormaplatin; oxysulen; paclitaxel ; Paclitaxel protein-bound particles for injectable suspension (albumin-bound); pegaspargase; pelimycin; pentamidine; pelimycin sulfate; perphosphamide; piperobroman; piperosulfan; piroxicam hydrochloride; plicamycin; plometane; porfimer sodium; porphyrin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazolidinone; liboadenosine; safingol; safingol hydrochloride; semustine; sintrazine; sorafenib; sodium phosphoacetylaspartate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptomelanocin; streptozotocin; sulfonylurea; talismycin; tecogalan sodium; docetaxel; tegafur; tetrolone hydrochloride; temoporphine; teniposide; tiroxilon; testolactone; thiopurine;Thioguanine; thiotepa; thiazolamide nucleoside; tirapazamine; toremifene citrate; triptolon acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronide; triptorelin; tobradox hydrochloride; uracil mustard; uracil imine; vapreotide; vemurafenib; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinpitidine sulfate; vinca glyceride sulfate; vinpocetine sulfate; vinorelbine tartrate; vinprodine sulfate; vinorelbine sulfate; vorozole; zeniplatin; ninstatin; and zorubicin hydrochloride. ;

[0112] Other anticancer drugs to be included in the methods or compositions include, but are not limited to, 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adenosine; adolesin; aldesleukin; ALL-TK antagonists; hexamethylmelamine; amoxicillin; amifotin; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; androlide; angiogenesis inhibitors; antagonist D; antagonist G; anrelix; anti-dorsal morphogenetic protein-1; antiandrogens; antiestrogens; antineoplastons; antisense oligonucleotides; glycine aphidoxine; apoptosis gene regulators; apoptosis regulators; purine acid; ara-CDP-DL-PTBA; arginine deaminase; oxananin (a sulacrine); atamestane; amustine; axinstatin 1; axinstatin 2; axinstatin 3; azasetron; azatoxin; diazotyrosine; baccatin III derivatives; balanovol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; β-lactam derivatives; β-alexin; betamycin B; betulinic acid; bFGF inhibitors; bicalutamide; bisantrene; diaziridinylspermine; binafad; bistratene A; bizeresin; breflate; bropiridamine; budotitan; buthionine sulfoxide; calcipotriol; calretinin C; camptothecin derivatives; capecitabine; carboxamido-amino-triazole; carboxyamido-triazole; CaRest M3; CARN 700; cartilage source inhibitor; carzelesin; casein kinase inhibitor (ICOS); castanospermine; bactericidal peptide B; cetrorelix; chlorin; chloroquinoxaline sulfonamide; cicaprost; cisporphyrin; cladribine; clomiphene analogs; clotrimazole; crissomycin A; crissomycin B; combretastatin A4; combretastatin analogs; conagenin; crambescidin 816; crestol; candidin 8; candidin A derivatives; curacin A; cyclopentanthraquinone; cycloplatam; cypemycin; Ara-C ocfosfate; cytolytic factor; cytostatin; daclizumab; decitabine; dehydroepiphyrin B; deslorelin; dexamethasone; right ifosfamide; right razoxane; right verapamil; suberquinone; epiphyrin B; didox; diethylnorspermine; dihydro-5-azacytidine nucleoside; 9-dihydropaclitaxel; dioxamycin; diphenylspiromustine; docetaxel; docosin; dolasetron; deoxyfluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; eticomustine; edelfosine; edrecolomab;Eflornithine; Elemene; Ethifur; Epirubicin; Apelite; Estramustine analogs; Estrogen agonists; Estrogen antagonists; Etanidazole; Etoposide phosphate; Exemestane; Fadrozole; Fazarabine; Retinoic acid phenolamide; Filgrastim; Finasteride; Flavopiridol; Fluzolastine; Flustarone; Fludarabine; Fludanoprostine hydrochloride; Folomek; Fomemax tan; fostramoxine; fotemustine; gadolinium dexaporphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hyperforin; ibandronic acid; idarubicin; idoxifene; idarucifen; imatinib; imofosine; ilomastat; imatinib (e.g., ); imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferons; interleukins; iodobenzylguanidine; iodoxorubicin; 4-sweet potato alcohol; iropra; irsoladin; isofenazole; isohomohypon B; itasetron; jasplakinolide; kahalalide F; triacetate lamellae-N; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptostam olstatin; letrozole; leukemia inhibitory factor; interferon alpha; leuprolide + estrogen + progesterone; leuprolide; levamisole; lirazole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; earthworm phospholipids; lometrexol; lonidamine; losoxantrone; loxoribine; lutetium texporphyrin; lysofylline; lytic peptides; metansine; mannosidase inhibitors tatin) A; marimastat; masorofol; maspin; stromelysin inhibitor; matrix metalloproteinase inhibitor; menolipir; melbourne; metirol; methionase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; milistostim; mitoguanazone; dibromodulanol; mitomycin analogs; mitonadamide; metotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotin; morasporastin; cetuximab, human chorionic gonadotropin; mono Phosphoryl lipid A + mycobacterial cell wall skeleton; mopidarol; mustard anticancer agent; mecaprol B; mycobacterial cell wall extract; myriaporone; N-acetyl pyridazine; N-substituted benzamide; nafarelin; nagretide; naloxone + pentozocin; naprovir; natifida; natograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; lissamycin; nitric oxide regulator; nitric oxide antioxidant; nitrullyn; oblimersen O 6-benzylguanine; octreotide; oxaquin; oligonucleotides; onapristone; ondansetron; ondansetron; olacin; oral cytokine inducers; ormaplatin; osatron; oxaliplatin; oxadifen; paclitaxel; paclitaxel analogs; paclitaxel derivatives; paclitaxel protein-bound particles for injectable suspension (albumin-bound); panoramine; palmitoyl rhizoxin; pamidronate; panaxatriol; panomifen; parabecin; pazeptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflurane; perfosfamide; perillyl alcohol; benzazomycin; phenylacetate; phosphatase inhibitors; picibannib ; pilocarpine hydrochloride; pirarubicin; pyrexine; prestin A; prestin B; plasminogen activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; porfimer sodium; porfibrin; prednisone; propyl diacridone; prostaglandin J2; protease inhibitor; protein A-based immunomodulator; protein kinase C inhibitor, microalgae; protein tyrosine phosphatase inhibitor; purine nucleoside phosphorylase inhibitor; rhodamine; pyrazoloacridine; pyridoxalyl hemoglobin polyoxyethylene conjugate; raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; demethylated retiritin; etidronate rhenium Re 186; rhizoxin; ribozyme; RII retinamide; roxitocin; romotide; roquimek; rubiginone B1; ruboxyl; safinol; saintopin; samustine; sacaforto A; sargramostim; Sdi 1 mimetic; semustine; senescence-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; sizoran; sobuzoxane; borcarbazine sodium; sodium phenylacetate; soforo; somatomedin binding protein; sonarmin; sparphosphonate; spicamycin D; spiromustine; slanlopitine; spongestatin 1; squalamine; stipiamide; stromelysin inhibitor; sofiroxin; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; tamustine; tamoxifen methyliodide; tauromustine; taza Rotene; Tecogalan sodium; Furamid, Tellopyrium; Telomerase inhibitors; Temoporphine; Teniposide; Tetrachlorodecaoxide; Tizomine; Thialiblastine; Thiokorelin; Thrombopoietin; Thrombopoietin mimetics; Thymofasin; Thymopoietin receptor agonists; Thymotrione; Thyrotropin; Ethylprotinin; Tirapazamine; Titanocene dichloride; Toprostenol; Toremifene; Translation inhibitors, retinoic acid; Triacetyluridine; Triciribine; Trimetrexate; Triptorelin; Tropisetron; Torosterol; Tyrosine kinase inhibitors; Tyrosine phosphorylation inhibitors;UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonist; vapreotide; vanrelin B; vilarezo; vanlamine; vandal; verteporfin; visatine; vitacin; vorozole; zanoteron; zeniplatin; benzyl retinol (zilascorb); and statins ester. ;

[0113] Other third active agents that can be used in the methods or compositions include, but are not limited to, rituximab, oblimersen, Remicade, docetaxel, celecoxib, melphalan, dexamethasone Steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temozolomide (temodar), carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, gefitinib Paclitaxel, taxotere, fluorouracil, folinic acid, irinotecan, xeloda, interferon alfa, pegylated interferon alfa (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxel, paclitaxel, vinblastine, interleukin-2, granulocyte-macrophage colony-stimulating factor, dacarbazine, vinorelbine, zoledronic acid, phosphinic acid, palmitronate, clarithromycin, busulfan, prednisone, bisphosphonates, arsenic trioxide, vincristine, doxorubicin Paclitaxel, Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound), Ganciclovir, Doxorubicin, Estramustine Sodium Phosphate Sulindac and etoposide.

[0114] Other specific third active agents that can be used in the methods or compositions include, but are not limited to, sorafenib, dabrafenib, vemurafenib, trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, 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 pomalidomide.

[0115] Medical test kit

[0116] Also provided herein are medical kits. In certain embodiments, provided herein are medical kits comprising Compound A or a pharmaceutically acceptable salt thereof.

[0117] In certain embodiments, the kit includes compound A or its pharmaceutically acceptable salt as described herein and a second therapeutic agent and written materials in suitable packaging, which may include instructions for use, clinical research discussions, side effect lists, etc. In certain embodiments, such kits may also include information indicating or establishing the activity and / or advantages of the composition and / or describing administration, application, side effects, drug interactions, or other information useful to healthcare providers, such as scientific literature references, package insert materials, clinical trial results, and / or summaries of these, etc. In certain embodiments, such information may be based on the results of various studies, such as studies using experimental animals involving in vivo models and studies based on human clinical trials. In certain embodiments, the kit may also include another agent. In certain embodiments, compound A of the present disclosure or its pharmaceutically acceptable salt and a second therapeutic agent are provided in a separate container in the kit as a separate composition. In certain embodiments, compound A of the present disclosure or its pharmaceutically acceptable salt and a second therapeutic agent are provided in a container of the kit as a single composition. Suitable packaging and other use items (e.g., measuring cups for liquid preparations, foil packages that expose air to a minimum, etc.) are known in the art and may be included in the kit. The kits described herein can be provided, sold, and / or promoted to healthcare providers, including physicians, nurses, pharmacists, prescribers, etc. In some embodiments, the kits can also be sold directly to consumers.

[0118] Example

[0119] Example 1: Extrapolation and Correlation between Adult and Pediatric Populations

[0120] Because no pediatric clinical PK data for brigatinib are currently available, an allometric approach was used to extrapolate the pediatric clinical PK of brigatinib from the adult PK. The key aspects of this analysis are summarized below.

[0121] The use of an allometric schedule is supported by knowledge of the clearance mechanisms of brigatinib and its corresponding ontogeny, which suggest that clearance is mature in pediatric patients >1 year of age. Therefore, simulations based on a previously developed population PK model have been performed to guide dose selection for the pediatric Phase 1 dose confirmation study taking into account dosing schedules for ALK+ NSCLC in adults. The proposed study is an open-label Phase 1 dose escalation in patients ≥2 years of age with measurable or evaluable ALK+ solid or CNS tumors or ALCL that is refractory to therapy and for whom no known curative treatment is available.

[0122] In a pivotal Phase 2 study in adults with ALK+ NSCLC, 2 dosing regimens were evaluated: (1) 90 mg QD; (2) 90 mg QD in week 1, followed by an escalation to 180 mg QD for those patients who tolerated a 7-day 90 mg QD lead-in. Based on the demonstrated longer PFS at 180 mg QD, the recommended clinical dose of brigatinib in adults is 90 mg QD orally for the first 7 days, followed by a dose increase to 180 mg QD based on patient tolerability. This 7-day lead-in regimen at a lower dose reduces the risk of EOPE. Therefore, a similar dosing regimen is recommended in pediatric development, using a 7-day lead-in period. To reduce the risk of EOPE in pediatric patients, the dose of brigatinib selected in week 1 of treatment should be informed by adult clinical experience and designed to achieve systemic exposure no greater than that at the 90 mg daily dose in adults.

[0123] Adult population PK model A 3-compartment model with a transport-absorption compartment model was used to describe brigatinib PK. The final covariate model included a linear function relating body weight to clearance and volume parameters. In addition, age and albumin concentration were considered as statistically significant covariates for clearance.

[0124] For the purpose of simulating pediatric PK, the linear covariate function that makes body weight related to clearance and volume parameters is replaced by an allometric function, and the allometric function uses a proportional coefficient (i.e., exponent) of clearance as 0.75 and a proportional coefficient of volume parameters as 1. The improved model is used to derive dosimetry in pediatric patients by simulation, and the exposure achieved is similar to the exposure observed in adult patients after a 90mg QD reference dose. In the National Health and Nutrition Examination Survey (NHANES) data set provided by the Centers for Disease Control and Prevention (CDC), virtual pediatric patients were simulated based on the body size contrast age distribution. The pediatric patient population was stratified by age (1000 patients per month; 1 to 18 years old) and gender (50:50; male: female).

[0125] Based on a cross-study comparison of brigatinib exposure from oral solution administered in a human radioactivity mass balance study (Study AP26113-13-104) and tablet PK in adults (Study AP26113-16-110), the relative bioavailability of oral brigatinib solution was expected to be approximately 42% higher in AUC relative to tablet. Therefore, a relative bioavailability factor (oral solution / tablet AUC ratio of 1.42) was incorporated into the pediatric simulations.

[0126] Simulations using the modified model showed that pediatric patients aged 1 year to less than 18 years old could receive 40 mg / m2 of oral solution. 2 Brigatinib exposure following brigatinib will be equivalent to that achieved in adult patients receiving 90 mg QD oral tablet form ( Figure 1 ).

[0127] Based on these simulations, it is expected that patients receiving 40 mg / m 2 QD→80mg / m 2 Systemic exposures in pediatric patients at QD doses were equivalent to those achieved at the recommended adult clinical dose of 90 mg QD → 180 mg QD. In the planned pediatric Phase 1 study, the starting dose level (30 mg / m 2 QD→60mg / m 2 QD; dose level 1) to achieve model-predicted pediatric exposures (AUC) that do not exceed 80% of the exposure achieved in adults at clinical doses (90 mg QD → 180 mg QD), consistent with the regimen typically used in pediatric Phase 1 studies. Subsequent dose levels (40 mg / m 2 QD→80mg / m2 QD; dose level 2) achieves 100% of adult exposure. 2 QD→80mg / m 2 If the QD dose was tolerated, an additional dose level was planned. To reduce the risk of EOPE, dose level 3 (40 mg / m 2 QD→100mg / m 2 The first week brigatinib dose in the QD group was 40 mg / m 2 QD (i.e., a dose level expected to provide systemic exposure equivalent to that achieved in an adult at a 90 mg QD ingestion dose). 2 The maximum planned dose QD was to achieve systemic exposure approximately equivalent to the systemic exposure in adults at the highest acceptable tolerated dose of 240 mg QD in Study AP26113-11-101.

[0128] The rationale for continued escalation beyond dose level 2 in the pediatric population is informed by the following considerations:

[0129] ●The adult experience with brigatinib in ALK+ NSCLC, where longer PFS was observed at the 90 mg QD→180 mg QD vs 90 mg QD dose, suggests that it cannot be assumed that the exposure associated with 180 mg QD will maximize efficacy in ALK+ pediatric cancers.

[0130] ●Pediatric clinical experience with the ALK inhibitor crizotinib, which achieved 280 mg / m 2 The MTD / RP2D of 50 mg / dL was approximately 50% higher than the clinical exposure in adults at 250 mg BID.

[0131] For these reasons, direct extrapolation has not been proposed for the pediatric development of brigatinib. Instead, clinical experience in adults and available pediatric and adult data on the ALK inhibitor crizotinib have been utilized, with dose selection for the pediatric phase 1 program informed by population PK modeling and simulations. Similarly, population PK modeling of the pediatric phase 1 PK data will be used to guide dose selection in subsequent efficacy and safety studies in pediatric patient populations.

[0132] Example 2: Pediatric Clinical Study

[0133] General Strategy

[0134] Brigatinib was studied in two clinical studies in patients 2 years of age and older with ALCL or IMT: (a) an open-label, Phase 1 / 2 dose-escalation and expansion study (Study 1) and (b) a Phase 2 randomized study (Study 2).

[0135] During the Phase 1 portion of Study 1, dose escalation of brigatinib monotherapy was performed in subjects with any advanced ALK+ solid tumor or ALK+ ALCL who had failed prior standard of care treatment according to any Rolling-6 design (Part A-1). After determining the RP2D of brigatinib monotherapy, an expansion cohort of Phase 2 specific disease was opened and patients with unresectable or recurrent ALK+ IMT (Part B Cohort B-1) or relapsed / refractory ALK+ ALCL (Part B Cohort B-2) were recruited. At this time, in newly diagnosed ALK+ ALCL patients at high risk of recurrence, dose escalation was also started using brigatinib in combination with a standard chemotherapy regimen (ALCL99 regimen) to determine the RP2D of brigatinib when used in combination with ALCL99 (Part A-2).

[0136] The sample size of Cohort B-1 of Study 1 was approximately 28 subjects.

[0137] If adequate safety, tolerability and preliminary efficacy are observed in ALCL patients in Parts A-2 and B of Study 1, Study 2 will be started. The patient population recruited in Study 2 includes pediatric patients with previously untreated ALK+ALCL and at high risk of relapse, defined as MDD+ status at diagnosis and low anti-ALK antibody titer (≤1 / 750). This subgroup shows the highest unmet needs 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 different first-line interventions that drive deeper responses, with the goal of preventing or stopping relapse. In contrast, patients with low and intermediate risks show better responses to current treatments, with 5-year PFS / OS of 93% / 98% and 68% / 84, respectively. Mussolin et al., 2013. The study incorporated a randomized comparator-controlled design to allow a rigorous evaluation of the safety and efficacy of the combination of ALCL99 with brigatinib versus ALCL99 alone.

[0138] The sample size for the Phase 2 study of previously untreated high-risk ALCL was approximately 104 patients, who were randomized in a 1:1 manner to receive either the combination of brigatinib and ALCL99 or ALCL99 alone.

[0139] The designs of the two clinical studies are shown in Figure 2 middle.

[0140] Pediatric PK / PD studies

[0141] During the Phase 1 portion of the initial trial (Study 1), serial plasma samples were collected to characterize the PK of brigatinib in the pediatric population. Due to potential blood volume limitations, a sparse sampling scheme was used in young children. A comprehensive population PK modeling scheme was used, whereby data from the Phase 1 trial were combined with previously obtained PK data in healthy adult subjects and patients with NSCLC. Incorporation of allometric functions was used to assess the effects of body measurements (e.g., body surface area [BSA], body weight) on clearance and volume parameters. The sources of variation (i.e., covariates) of brigatinib PK were explored, and the effects of previously assessed adult covariates were updated based on the combined pediatric and adult data sets. Model performance was assessed by graphical evaluation of goodness of fit, statistical criteria, and visual prediction checks. The model was used to derive exposure parameters for each pediatric subject and compared with adult exposure metrics to guide further dose selection.

[0142] Brigatinib was administered to patients in the pediatric Phase 1 study as an oral solution. In subsequent studies, the oral tablet formulation may be used in patients who are able to swallow solid oral dosage forms. The dosing regimen (e.g., split dosing) of the tablet formulation was informed by a comprehensive population PK analysis using available adult and pediatric data collected during the Phase 1 study. The population PK analysis provides an updated estimate of the relative bioavailability of the oral solution formulation versus the tablet formulation.

[0143] PK data were obtained in a Phase 2 expansion cohort of IMT and ALCL patients in the initial study (Study 1) and in a separate Phase 2 study of ALCL patients (Study 2). Sparse PK data were collected by a sampling scheme informed by the results of modeling the Phase 1 pediatric PK data. A comprehensive population PK analysis was performed on the data collected throughout the pediatric clinical development program to confirm whether the proposed dosimetry was adequate within the assessed pediatric age range. The model was used to derive exposure parameters for each pediatric patient and to help assess the exposure-efficacy and exposure-safety relationships of brigatinib in the pediatric population.

[0144] Clinical efficacy and safety studies

[0145] Study 1: Phase 1 / 2 Study of Brigatinib in Patients 2 Years and Older with Malignancies with Anaplastic Lymphoma Kinase (ALK) Genetic Alterations

[0146] Main Objectives

[0147] ●Evaluate the MTD / RP2D schedule of brigatinib monotherapy administered PO QD as a liquid formulation in a pediatric patient population.

[0148] • To evaluate the MTD / RP2D regimen of brigatinib administered PO QD as a liquid formulation in combination with an ALCL99 treatment regimen in pediatric patients with newly diagnosed, high-risk ALK+ ALCL.

[0149] To assess the safety and tolerability of brigatinib administered as monotherapy and in combination with ALCL99 in a pediatric patient population.

[0150] ● Characterize the PK of brigatinib administered as monotherapy and in combination with ALCL99 treatment regimens in a pediatric patient population.

[0151] Secondary Objectives

[0152] ●Defining the antitumor activity of brigatinib in disease-specific expansion cohorts (IMT and relapsed / refractory ALCL)

[0153] Primary Endpoints

[0154] • Part A-1: ​​Determination of the RP2D of brigatinib in monotherapy.

[0155] • Part A-2: Determination of the RP2D of brigatinib in combination with ALCL99.

[0156] ●Part B Group B-1: ORR.

[0157] ●Part B Group B-2: ORR.

[0158] Secondary Endpoints

[0159] • Parts A-1 and A-2: MTD, DLT, safety and tolerability, and PK.

[0160] ●Part B Cohorts B-1 and B-2: DOR, PFS, OS, safety, and tolerability.

[0161] Main inclusion criteria

[0162] For all patients (Parts A and B):

[0163] ●Patients must have histologically or cytologically confirmed advanced solid tumors or lymphomas.

[0164] ● Prior to screening, patients are required to have an activated ALK abnormality in their tumor as detected by a certified assay (i.e., Clinical Laboratory Improvement Amendments (CLIA)). Submission of a report of this test is required to qualify. ALK immunohistochemistry can be used as an alternative to fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) for patients with IMT or ALCL.

[0165] ● Patients were not allowed to receive other study medications within 30 days of study entry or during the study.

[0166] ●Patients must meet the organ function and system function requirements stated in the protocol.

[0167] For Section A-1:

[0168] ●Due to the unknown potential for early onset of pulmonary adverse reactions in the pediatric patient population and the need to monitor patient-reportable symptoms such as dyspnea, patients must 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).

[0169] ● Patients must have at least one of the following: (1) relapsed / progressive disease at any time prior to study enrollment, (2) refractory disease, (3) persistent disease.

[0170] ●Refractory or intolerant to all available standard therapies.

[0171] ● Prior to entry into this study, patients must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiation therapy.

[0172] Patients were not allowed to receive any other anticancer agents or radiation therapy at study entry or during the study.

[0173] For Section A-2:

[0174] ●Patients must be ≥2 years and <22 years old.

[0175] ●Patients must have high-risk ALK+ALCL.

[0176] ●Patients were not allowed to receive any prior systemic chemotherapy.

[0177] For Part B Group B-1:

[0178] ●Patients must be ≥ 2 years old.

[0179] ● Patients with unresectable or recurrent ALK+IMT.

[0180] For Part B Group B-2:

[0181] ●Patients must be ≥2 years and <22 years old.

[0182] ●Suffering from relapsed or refractory ALK+ALCL.

[0183] Main exclusion criteria

[0184] ●Patients with neurological instability or symptomatic CNS metastases requiring increased doses of corticosteroids.

[0185] ●Patients who have received strong or moderate CYP3A inhibitors or inducers within 14 days prior to the first dose of study drug.

[0186] ●Previous treatment with an ALK inhibitor (Part A-2 and Part B only).

[0187] Sample size

[0188] ● Part A-1: ​​Up to 18 evaluable patients ≥ 4 years of age with advanced ALK+ solid tumors or ALCL who have failed prior standard of care. At least 15 patients ≤ 18 years of age.

[0189] ● Part A-2: Up to 12 evaluable patients ≥ 2 years and < 22 years of age with newly diagnosed high-risk ALCL. At least 9 patients ≤ 18 years of age.

[0190] ● Part B Cohort B-1: 28 patients ≥2 years old with unresectable / recurrent IMT. At least 15 patients ≤18 years old.

[0191] • Part B Cohort B-2: 10 patients ≥2 and <22 years old with relapsed / refractory ALCL. At least 8 subjects ≤18 years old.

[0192] Follow-up duration

[0193] Following agreement between the sponsor and investigator, patients who experienced a PR or stable disease continued to receive brigatinib as a single agent for up to 1 year until disease progression or unacceptable toxicity.

[0194] treat

[0195] BSA-based brigatinib dosing was used to normalize systemic exposure within the planned age range. A 1-week introduction paradigm (90 mg QD for 7 days followed by 180 mg QD) was used as recommended for adult patients with ALK+ NSCLC. The starting dose level was selected to achieve a pediatric exposure (AUC) that did not exceed 80% of the exposure achieved at the adult clinical dose. 100 mg / m 2 The maximum planned dose QD was to achieve systemic exposure approximately equivalent to the exposure in adults at the maximum tolerated dose of 240 mg QD.

[0196] Figure 3 The doses proposed for each phase of the study are shown.

[0197] The treatments to be administered in Study 1 are as follows:

[0198] Section A-1:

[0199] Brigatinib monotherapy (oral solution for all patients).

[0200] Section A-2:

[0201] ALCL99 + / - brigatinib followed by six cycles of brigatinib monotherapy.

[0202]

[0203] Part B:

[0204] Brigatinib monotherapy. Oral solution and tablets (tablet dose for patients who are able to swallow solid oral dosage forms; tablet dose determined by PK data collected in Part A-1 and relative bioavailability considerations).

[0205] Duration of treatment:

[0206] ●For Part A-1 and Part B: Continue treatment until disease progression or unacceptable toxicity.

[0207] • Part A-2: A total of 6 cycles of ALCL99 + / - brigatinib were administered. Patients in either group who experienced CR or CRu after 2 treatment cycles could proceed to transplantation at the discretion of the investigator.

[0208] ●After agreement between the sponsor and investigator, patients who experienced a PR or stable disease continued to receive brigatinib as a single agent for up to 1 year until disease progression or unacceptable toxicity.

[0209] Statistical considerations

[0210] Part A-1: ​​Part A-1 of the study followed a Rolling-6 design. Two to six patients cumulatively reached one dose level at a time. The decision on the dose level to recruit patients was based on the number of patients who experienced DLT and the number of patients who were still at risk of developing DLT when new patients entered. Patients were evaluated for DLT in the first 28 days of treatment. Non-compartmental analysis of PK of brigatinib was performed. PK parameters were summarized descriptively by summary statistics. PK data additionally facilitated population PK analysis.

[0211] In addition to the determination of the MTD, a descriptive summary of toxicities is reported.

[0212] Part A-2: Part A-2 of the study followed a Rolling-6 design. Two to six patients cumulatively reached the brigatinib dose level administered using the ALCL99 regimen at the same time. The decision on the dose level of the recruited patients was based on the number of patients who experienced DLT and the number of patients who were still at risk of developing DLT when new patients entered. Patients were evaluated for DLT in the first 28 days of treatment. Non-compartmental analysis of brigatinib's PK was performed. PK parameters were descriptively summarized by summary statistics. PK data also facilitated population PK analysis.

[0213] In addition to the determination of the MTD, a descriptive summary of toxicities is reported.

[0214] Part B Cohort B-1: Cohort B-1 of the study uses ORR confirmed by RECIST v1.1 as the primary endpoint. All patients who received at least 1 dose of brigatinib were analyzed. Twenty-eight patients provide approximately 90% power to rule out a 20% futility rate if the true response rate is 50% and a 1-sided alpha of 0.025. An interim analysis for futility was performed on the first 14 patients enrolled in the study. If the conditional power to rule out a 20% futility rate is low, the study may be closed for futility. PK data collected in this cohort will aid in the population PK analysis.

[0215] Part B Cohort B-2: Cohort B-2 of the study uses ORR confirmed by RECIST v1.1 as the primary endpoint and EFS at 2 years as the key secondary endpoint. Approximately 10 patients will be enrolled in the study. PK data collected in this cohort will facilitate population PK analysis.

[0216] D.4.3.2 Study 2: Randomized Phase 2 Study of the Combination of Brigatinib with Dexamethasone, Ifosfamide, Methotrexate, Etoposide, and Cytarabine Followed by the Combination of Brigatinib with Dexamethasone, Methotrexate, Cyclophosphamide, and Doxorubicin (ALCL99 Regimen) Versus the ALCL99 Regimen Alone in Previously Untreated Patients with High-Risk ALK+ ALCL

[0217] Main Objectives

[0218] To evaluate the efficacy of brigatinib in combination with ALCL99 in patients ≥2 years of age with high-risk, previously untreated ALCL.

[0219] To assess the safety and tolerability of the combination of brigatinib and ALCL99.

[0220] PK Target

[0221] ● Collect plasma concentration-time data to aid in population PK analysis.

[0222] Primary Endpoints

[0223] ●EFS at 2 years.

[0224] Secondary Endpoints

[0225] ORR, DOR, duration of response, and OS.

[0226] Mainly included

[0227] ●Patients must be ≥2 years and <22 years old.

[0228] ●Patients must have high-risk ALK+ ALCL—MDD+ and antibody titer ≤1 / 750 at diagnosis.

[0229] ● Prior to screening, patients are required to have an activated ALK abnormality detected by a certified assay (ie, CLIA in the US). Submission of a report of this test is required to qualify. ALK immunohistochemistry can be used as an alternative to FISH or NGS.

[0230] ● Patients were not allowed to receive other study medications within 30 days of study entry or during the study.

[0231] ●Patients must meet the organ function and system function requirements stated in the protocol.

[0232] Main exclusions

[0233] ●Patients with neurological instability or symptomatic CNS metastases requiring increased doses of corticosteroids.

[0234] ●Patients who have received strong or moderate CYP3A inhibitors or inducers within 14 days prior to the first dose of study drug.

[0235] ●Previous treatment with ALK inhibitors.

[0236] ●Patients have received any prior systemic chemotherapy for ALCL.

[0237] Sample size

[0238] ●Approximately 104 patients aged ≥2 years to <22 years were randomly assigned in a 1:1 fashion to receive either brigatinib in combination with ALCL99 or ALCL99 alone. (85 to 97 patients were ≤18 years.)

[0239] Follow-up duration

[0240] ●Patients were followed for up to 3 years after randomization.

[0241] treat

[0242] Brigatinib is available as an oral solution or tablet for patients who are able to swallow oral dosage forms. The brigatinib + ALCL99 treatment regimen used in Study 2 followed the regimen explored in Part A-2 of Study 1.

[0243] Statistical considerations:

[0244] Assuming a 2-sided alpha of 0.05, a 2-year EFS of 24% in patients treated with ALCL99 alone and 50% in patients treated with a combination of brigatinib and ALCL99, the study requires the observation of 74 events with 80% power at the final analysis. After the first 29 events are observed, an interim analysis of futility is planned. If the conditional power of the interim analysis is less than 20%, the trial of futility is stopped. This power prediction is based on a 2-sided log-rank test and is controlled at a 2-sided 0.05 level to adjust for the proposed interim analysis plan. The number of events is fixed, but the number of recruits (N~104) can be changed based on an assessment of the overall event rate aggregated across treatment groups (before the end of recruitment).

[0245] The table below provides a tabular overview of all planned clinical studies.

[0246]

[0247]

[0248] The embodiments described herein are intended to be exemplary only, and those skilled in the art will recognize or be able to ascertain using only routine experimentation, numerous equivalents to the specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the present disclosure.

[0249] Typical embodiments of the present invention include:

[0250] 1. A method for treating cancer in a pediatric patient having cancer, comprising administering to the patient a therapeutically effective amount of Compound A having the formula:

[0251]

[0252] or a pharmaceutically acceptable salt thereof, wherein the cancer is inflammatory myofibroblastic tumor (IMT), anaplastic large cell lymphoma (ALCL) or neuroblastoma.

[0253] 2. The method of embodiment 1, wherein the cancer is anaplastic lymphoma kinase positive (ALK+).

[0254] 3. The method of embodiment 1 or 2, wherein the cancer is IMT or ALCL.

[0255] 4. The method of embodiment 1 or 2, wherein the cancer is neuroblastoma.

[0256] 5. The method of embodiment 1 or 2, wherein the cancer is IMT.

[0257] 6. The method of embodiment 5, wherein the IMT is unresectable or recurrent IMT.

[0258] 7. The method of embodiment 1 or 2, wherein the cancer is ALCL.

[0259] 8. The method of embodiment 7, wherein the ALCL is relapsed or refractory ALCL.

[0260] 9. The method of embodiment 7, wherein the ALCL is newly diagnosed ALCL.

[0261] 10. The method of embodiment 9, wherein the ALCL is newly diagnosed ALCL with a high risk of recurrence.

[0262] 11. The method of embodiment 10, wherein the high risk of recurrence is characterized by minimally disseminated disease positivity (MDD+) at diagnosis or an anti-ALK antibody titer ≤ 1 / 750 at diagnosis.

[0263] 12. The method of any one of embodiments 1 to 11, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally.

[0264] 13. The method of any one of embodiments 1 to 12, wherein Compound A or a pharmaceutically acceptable salt thereof is administered once a day (QD).

[0265] 14. The method of any one of embodiments 1 to 13, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at about 30 mg / m 2 About 100 mg / m 2 dosage administration.

[0266] 15. The method of embodiment 14, wherein Compound A or a pharmaceutically acceptable salt thereof is administered at about 30, about 40, about 50, about 60, about 70, about 80, about 90 or about 100 mg / m 2 dosage administration.

[0267] 16. The method of any one of embodiments 1 to 15, further comprising administering to the patient a therapeutically effective amount of a second therapeutic agent.

[0268] 17. The method of embodiment 16, wherein the second therapeutic agent is cyclophosphamide, doxorubicin, vincristine, corticosteroids, ifosfamide, etoposide, methotrexate, or cytarabine, or a combination thereof.

[0269] 18. The method of embodiment 17, wherein the corticosteroid is dexamethasone or hydrocortisone or a combination thereof.

[0270] 19. The method of any one of embodiments 16 to 18, wherein the second therapeutic agent comprises dexamethasone at about 5 mg / m 2 About 10 mg / m 2 dosage administration.

[0271] 20. The method of any one of embodiments 16 to 19, wherein the second therapeutic agent comprises cyclophosphamide at about 200 mg / m 2 dosage administration.

[0272] 21. The method of any one of embodiments 16 to 20, wherein the second therapeutic agent comprises ifosfamide at about 800 mg / m 2 dosage administration.

[0273] 22. The method of any one of embodiments 16 to 21, wherein the second therapeutic agent comprises methotrexate at about 3 g / m 2 dosage administration.

[0274] 23. The method of any one of embodiments 16 to 22, wherein the second therapeutic agent comprises etoposide at about 100 mg / m 2 dosage administration.

[0275] 24. The method of any one of embodiments 16 to 23, wherein the second therapeutic agent comprises cytarabine at about 150 mg / m 2 The dose is administered and is administered twice daily.

[0276] 25. The method of any one of embodiments 16 to 24, wherein the second therapeutic agent comprises doxorubicin at about 25 mg / m 2 dosage administration.

[0277] 26. The method of any one of embodiments 16 to 25, wherein Compound A, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for one or more 21-day cycles.

[0278] 27. The method of embodiment 26, wherein Compound A or a pharmaceutically acceptable salt thereof is administered on days 1 to 21 of the 21-day cycle.

[0279] 28. The method of embodiment 26 or 27, wherein the second therapeutic agent comprises dexamethasone, which is administered on days 1 to 5 of the 21-day cycle.

[0280] 29. The method of any one of embodiments 26 to 28, wherein the second therapeutic agent comprises cyclophosphamide, which is administered on days 1 and 2 of the 21-day cycle.

[0281] 30. The method of any one of embodiments 26 to 28, wherein the second therapeutic agent comprises cyclophosphamide, which is administered on days 1 to 5 of the 21-day cycle.

[0282] 31. The method of any one of embodiments 26 to 30, wherein the second therapeutic agent comprises a combination of hydrocortisone, methotrexate, and cytarabine administered on day 1 of the 21-day cycle.

[0283] 32. The method of any one of embodiments 26 to 31, wherein the second therapeutic agent comprises ifosfamide, which is administered on days 1 to 5 of the 21-day cycle.

[0284] 33. The method of any one of embodiments 26 to 32, wherein the second therapeutic agent comprises methotrexate administered on day 1 of the 21-day cycle.

[0285] 34. The method of any one of embodiments 26 to 33, wherein the second therapeutic agent comprises etoposide administered on days 4 and 5 of the 21-day cycle.

[0286] 35. The method of any one of embodiments 26 to 34, wherein the second therapeutic agent comprises cytarabine administered on days 4 and 5 of the 21-day cycle.

[0287] 36. The method of any one of embodiments 26 to 35, wherein the second therapeutic agent comprises doxorubicin administered on days 4 and 5 of the 21-day cycle.

[0288] All patents, patent applications and publications cited herein are incorporated herein by reference in their entirety. The citation or identification of any reference in this application does not admit that this reference can be used as the prior art of this application. The full scope of this disclosure will be better understood with reference to the attached claims.

Claims

1. A method for treating cancer in a pediatric patient having cancer, comprising administering to the patient a therapeutically effective amount of Compound A having the formula: or a pharmaceutically acceptable salt thereof, wherein the cancer is inflammatory myofibroblastic tumor (IMT), anaplastic large cell lymphoma (ALCL) or neuroblastoma.

2. The method of claim 1, wherein the cancer is anaplastic lymphoma kinase positive (ALK+).

3. The method of claim 1 or 2, wherein the cancer is IMT or ALCL.

4. The method of claim 1 or 2, wherein the cancer is neuroblastoma.

5. The method of claim 1 or 2, wherein the cancer is IMT.

6. The method of claim 5, wherein the IMT is unresectable or recurrent IMT.

7. The method of claim 1 or 2, wherein the cancer is ALCL.

8. The method of claim 7, wherein the ALCL is relapsed or refractory ALCL.

9. The method of claim 7, wherein the ALCL is newly diagnosed ALCL.

10. The method of claim 9, wherein the ALCL is newly diagnosed ALCL with a high risk of recurrence.

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