Treatment methods for cancer in pediatric patients

Abstract

Providing cancer treatment options for pediatric patients. [Solution] The present invention provides a method for treating cancer in pediatric patients (e.g., inflammatory myofibroblastic tumor, anaplastic large cell lymphoma, and neuroblastoma) using brigatinib as monotherapy or in combination with one or more second therapeutic agents. The present invention provides a method for treating cancer in a pediatric patient, comprising administering to the patient a therapeutically effective dose of compound A of the following formula or a pharmaceutically acceptable salt thereof. Compound A can be administered as monotherapy or in combination with one or more second therapeutic agents.

Description

[Technical Field]

[0001] This application claims priority under U.S. Provisional Patent Application No. 62 / 645,089, filed on 19 March 2018, which is incorporated herein by reference in its entirety.

[0002] The present invention provides a method for treating cancer in pediatric patients (e.g., inflammatory myofibroblastic tumor and anaplastic large cell lymphoma) using brigatinib as monotherapy or in combination with one or more second therapeutic agents. [Background technology]

[0003] Brigatinib is a novel orally administered (PO) tyrosine kinase inhibitor (TKI). Brigatinib potently inhibits the activating variant of anaplastic lymphoma kinase (ALK).

[0004] ALK is a tyrosine kinase encoded on chromosome 2 that plays a physiological role in early brain development. While ALK expression levels are low in adults, it can be altered and activated in non-small cell lung cancer (NSCLC), adult diseases, and several malignancies, including inflammatory myofibroblastic tumors (IMT) and anaplastic large cell lymphoma (ALCL), which primarily affect children or adolescents. In each of these conditions, the most common ALK alteration involves the formation of fusion genes through chromosomal rearrangements. (Holla et al., Cold Spring Harb. Mol. Case Stud. 2017, 3(1), a001115). The first ALK gene rearrangement discovered in NSCLC involved a fusion of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the ALK tyrosine kinase domain (KD). Since then, numerous additional ALK fusion partners thought to cause signaling abnormalities and oncogenic transformations 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, neuroblastoma, another major childhood cancer, produces full-length ALK activating mutations without rearrangements. Holla et al., 2017.

[0005] In Europe, three ALK inhibitors—crizotinib, ceritinib, and alectinib—are approved for the treatment of patients with advanced anaplastic lymphoma kinase-positive (ALK+) NSCLC. In addition, brigatinib has received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of metastatic ALK+ NSCLC in patients whose disease has progressed despite or who are intolerant to crizotinib, and a European Marketing Authorization (MAA) application is under review for the use of brigatinib in the treatment of ALK+ NSCLC patients who have previously received crizotinib treatment. While the ALK inhibitor crizotinib is an effective treatment for ALK+ NSCLC, 26% to 35% of patients do not respond, and the majority of these patients progress within one year. Ultimately, in approximately 30% of NSCLC patients treated with crizotinib, an ALK-dependent resistance mechanism is observed, primarily due to secondary mutations in the ALK fusion gene that prevent crizotinib binding and / or amplification. 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 been shown to overcome many of these resistance mechanisms. Zhang et al., Clin. Cancer Res. 2016, 22(22), 5527-38. In in vitro studies, brigatinib was a more potent ALK inhibitor than crizotinib, ceritinib, and alectinib, and was the only one of these drugs to maintain sufficient activity against all 17 EML4-ALK secondary variants tested under appropriate patient exposure levels.

[0006] In addition to promising nonclinical findings, brigatinib demonstrated significant systemic and intracranial responses in a first-in-human (FIH) trial (Study AP26113-11-101) and a phase 2 trial in adult ALK+NSCLC patients refractory to crizotinib (Study AP26113-13-201, ALTA trial). In ALTA, a robust objective response rate (ORR) and sustained response were observed at a dose of 180 mg per day (starting at 90 mg per day after a 7-day lead-in (once daily (QD), 90 → 180 mg)). In this trial, at the 90 → 180 mg QD dose, the investigator-assessed confirmed ORR was 55.5%, the duration of response (DOR) was 13.8 months, and the progression-free survival (PFS) was 15.6 months. The Phase 3 trial (Study AP26113-13-301, ALTA 1L) is currently underway with the primary objective of comparing the efficacy of brigatinib and crizotinib, based on PFS, in locally advanced or metastatic ALK+NSCLC patients who have not previously received ALK inhibitor treatment.

[0007] Since NSCLC is extremely rare in children and adolescents, it is generally considered an adult disease. However, as mentioned above, ALK is rearranged, mutated, or amplified in various tumors associated with the pediatric population, including IMT, ALCL, and neuroblastoma. Therefore, ALK remains a reasonable therapeutic target in pediatric patients with these conditions. Takita, Cancer Sci. 2017, 108(10), 1913-20.

[0008] One of these cancers, IMT, is a very rare solid tumor characterized by spindle-shaped myofibroblasts with a chronic inflammatory pattern, occurring primarily in children and adolescents, mainly in the lungs, soft tissues, and abdomen. In 50%–70% of IMTs, there is a chromosomal translocation that activates ALK, which is more common in younger ages. The most common is the fusion of tropomyosin 3 / 4 (TPM3 / 4) with ALK, but inversions of EML4 with ALK are also seen, as in NSCLC. 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 for IMT is generally limited to surgical resection, and there is no standard pharmacological approach for progressive / recurrent disease or when complete resection is not possible. Dalton et al., J.Pediatr.Surg. 2016, 51(4), 541-4.

[0009] The second of these conditions, ALCL, is a rare form of non-Hodgkin lymphoma (NHL) (approximately 110 new cases per year in Europe), and this disease also primarily affects children and adolescents. ALCL is characterized by the proliferation of CD30-expressing T lymphocytes or null cells. Up to 90% of pediatric ALCL patients have ALK+ disease, while the frequency of ALK positivity in adult ALCL patients is lower than in pediatric patients (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 fusion account for 75-80% of ALK+ ALCL cases, while translocations involving TPM3-ALK fusion account for 12-18%. Holla et al., 2017; Pulford et al., J. Cell Physiol. 2004, 199(3), 330-58. ALCL is highly sensitive to chemotherapy, and several chemotherapy regimens are used in both frontline and refractory cases.

[0010] Neuroblastoma is a rare childhood malignancy originating from the fetal sympathetic nervous system (annual number of new ALK+ cases in Europe: less than 100). Unlike IMT and ALCL, where ALK translocations play a significant role, in neuroblastoma, ALK activation point mutations are a key driver of tumorigenesis, with ALK mutations found in almost all cases of familial neuroblastoma, as well as in 6% to 10% of spontaneous cases. (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, most notably amplification of MYCN. Standard treatment for neuroblastoma includes chemotherapy, resection, radiotherapy, biological therapy, and immunotherapy, depending on the risk status. Berlanga et al.,Expert Opin.Emerg.Drugs 2017,22(1),63-75.

[0011] Regarding IMT, there are no approved or rigorously tested pharmacological approaches to manage the condition. That is, patients who are not candidates for resection due to complex lesions or other factors represent the greatest unmet need within the IMT patient population. Therefore, there is a need for novel drugs that can function as neoadjuvant therapies to control or make unresectable lesions resectable, which would represent a significant advance for these patients.

[0012] Today, the ALCL99 chemotherapy regimen is used as the standard of care for ALCL in most pediatric populations in Europe. This approach is derived from the BFM protocol previously used for invasive B-cell NHL. Treatment regimens vary somewhat from trial to trial, but typically include cyclophosphamide, doxorubicin, vincristine, corticosteroids, ifosfamide, and etoposide for 4–6 months, along with high doses of methotrexate and cytarabine for central nervous system (CNS) prophylaxis. (Eyre et al., European Journal of Haematology 2014, 93(6), 455-68; Turner et al., Br.J.Haematol. 2016, 173(4), 560-72). The largest EFS rate observed in the largest ALCL99-based trial completed to date was 73% at 2 years. After initial therapy, approximately 20% to 40% of ALCL patients develop relapsing disease later. Patients at highest risk of relapse appear to be those with MDD+ status and anti-ALK antibody titers of 1 / 750 or less. (Mussolin et al., Leukemia) 2013, 27(2), 416-22. However, the primary objective of ongoing trials should include identifying treatment regimens that prevent relapse in patients with known high-risk ALCL, and there is a high unmet need for improved therapy for these patients. Therefore, ALCL patients exhibiting high-risk traits (e.g., MDD at diagnosis or low ALK antibody titers) can benefit from more aggressive or diverse frontline interventions that promote greater response, aimed at preventing or proactively relapsing, especially since relapse is associated with a poor prognosis. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Holla et al.,Cold Spring Harb.Mol.Case Stud.2017,3(1),a001115 [Non-Patent Document 2] Rikova et al.,Cell 2007,131(6),1190-203, [Non-Patent Document 3] Takeuchi et al.,Clin.Cancer Res.2009,15(9),3143-9 [Overview of the Initiative] [Means for solving the problem]

[0014] The present invention provides a method for treating cancer in a pediatric patient, wherein the patient is given compound A of the following formula. [ka] The method involves administering a therapeutically effective dose of either compound A or a pharmaceutically acceptable salt thereof. Compound A may be administered as monotherapy or in combination with one or more second therapeutic agents.

[0015] In one embodiment, the cancer is inflammatory myofibroblastic tumor (IMT), anaplastic large cell lymphoma (ALCL), or neuroblastoma.

[0016] Furthermore, the present invention provides pharmaceutical compositions, dosage forms, administration regimens, and kits that can be used in conjunction with the above-described methods. The present invention provides, for example, the following items: (Item 1) A method for treating cancer in a pediatric patient, wherein the patient is given compound A of the following formula. [ka] The method comprising administering a therapeutically effective dose of a pharmaceutically acceptable salt thereof, wherein the cancer is inflammatory myofibroblastic tumor (IMT), anaplastic large cell lymphoma (ALCL), or neuroblastoma. (Item 2) The method described in item 1, wherein the aforementioned cancer is anaplastic lymphoma kinase positive (ALK+). (Item 3) The method according to item 1 or 2, wherein the cancer is IMT or ALCL. (Item 4) The method according to item 1 or 2, wherein the cancer is neuroblastoma. (Item 5) The method according to item 1 or 2, wherein the cancer is IMT. (Item 6) The method according to item 5, wherein the IMT is unresectable or recurrent IMT. (Item 7) The method according to item 1 or 2, wherein the cancer is ALCL. (Item 8) The method according to item 7, wherein the ALCL is relapsed or refractory ALCL. (Item 9) The method according to item 7, wherein the aforementioned ALCL is a newly diagnosed ALCL. (Item 10) The method according to item 9, wherein the ALCL is newly diagnosed ALCL and is high-risk relapse ALCL. (Item 11) The method according to item 10, wherein the high-risk relapse is characterized by positive microdisseminated disease lesions (MDD+) at the time of diagnosis or an anti-ALK antibody titer of 1 / 750 or less at the time of diagnosis. (Item 12) The method according to any one of items 1 to 11, wherein compound A or a pharmaceutically acceptable salt thereof is administered orally. (Item 13) The method according to any one of items 1 to 12, wherein compound A or a pharmaceutically acceptable salt thereof is administered once a day (QD). (Item 14) The method according to any one of items 1 to 13, wherein compound A or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 mg / m 2 ~about 100 mg / m 2 The method according to any one of items 1 to 13, wherein compound A or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 mg / m (Item 15) The method according to item 14, wherein compound A or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 mg / m 2 , about 40 mg / m 2 , about 50 mg / m 2 , about 60 mg / m 2 , about 70 mg / m 2 , about 80 mg / m 2 , about 90 mg / m 2 or about 100 mg / m 2 The method according to item 14, wherein compound A or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 mg / m (Item 16) The method according to any one of items 1 to 15, further comprising administering a therapeutically effective amount of a second therapeutic agent to the patient. (Item 17) The method according to item 16, wherein the second therapeutic agent is cyclophosphamide, doxorubicin, vincristine, corticosteroid, ifosfamide, etoposide, methotrexate or cytarabine, or a combination thereof. (Item 18) The method according to item 17, wherein the adrenocortical steroid is dexamethasone, hydrocortisone, or a combination thereof. (Item 19) The second therapeutic agent contains dexamethasone, and the amount of dexamethasone is approximately 5 mg / m². 2 ~about 10mg / m 2 The method described in any one of items 16-18, administered in the specified dose. (Item 20) The second therapeutic agent comprises cyclophosphamide, with the cyclophosphamide content being approximately 200 mg / m². 2 The method described in any one of items 16-19, administered in the specified dose. (Item 21) The second therapeutic agent contains ifosfamide, and the ifosfamide is present at approximately 800 mg / m². 2 The method described in any one of items 16-20, administered in the specified dose. (Item 22) The second therapeutic agent contains methotrexate, and the methotrexate is present at approximately 3 g / m². 2 The method described in any one of items 16 to 21, administered in the specified dose. (Item 23) The second therapeutic agent contains etoposide, and the etoposide is present in an amount of approximately 100 mg / m². 2 The method described in any one of items 16 to 22, administered in the specified dose. (Item 24) The second therapeutic agent contains cytarabine, and the amount of cytarabine is approximately 150 mg / m². 2 The method described in any one of items 16 to 23, administering the drug at the specified dose twice a day. (Item 25) The second therapeutic agent contains doxorubicin, and the dose of doxorubicin is approximately 25 mg / m². 2 The method described in any one of items 16-24, administered in the specified dose. (Item 26) The method according to any one of items 16 to 25, comprising administering compound A or a pharmaceutically acceptable salt thereof, and the second therapeutic agent, for one or more cycles with a 21-day period. (Item 27) The method according to item 26, wherein compound A or a pharmaceutically acceptable salt thereof is administered on days 1 to 21 of the 21-day cycle. (Item 28) The method according to item 26 or 27, wherein the second therapeutic agent comprises dexamethasone, and the dexamethasone is administered on days 1 to 5 of the 21-day cycle. (Item 29) The method according to any one of items 26 to 28, wherein the second therapeutic agent comprises cyclophosphamide, and the cyclophosphamide is administered on the first and second days of the 21-day cycle. (Item 30) The method according to any one of items 26 to 28, wherein the second therapeutic agent comprises cyclophosphamide, and the cyclophosphamide is administered on days 1 to 5 of the 21-day cycle. (Item 31) The method according to any one of items 26 to 30, wherein the second therapeutic agent comprises a combination of hydrocortisone, methotrexate, and cytarabine, and the combination is administered on the first day of the 21-day cycle. (Item 32) The method according to any one of items 26 to 31, wherein the second therapeutic agent comprises ifosfamide, and the ifosfamide is administered on days 1 to 5 of the 21-day cycle. (Item 33) The method according to any one of items 26 to 32, wherein the second therapeutic agent comprises methotrexate, and the methotrexate is administered on the first day of the 21-day cycle. (Item 34) The method according to any one of items 26 to 33, wherein the second therapeutic agent comprises etoposide, and the etoposide is administered on the 4th and 5th days of the 21-day cycle. (Item 35) The method according to any one of items 26 to 34, wherein the second therapeutic agent comprises cytarabine, and the cytarabine is administered on the 4th and 5th days of the 21-day cycle. (Item 36) The method according to any one of items 26 to 35, wherein the second therapeutic agent comprises doxorubicin, and the doxorubicin is administered on the 4th and 5th days of the 21-day cycle. [Brief explanation of the drawing]

[0017] [Figure 1] This shows a comparison of simulated systemic exposure (AUC) of brigatinib in pediatric patients administered 40 mg / m2 of oral solution with that of adult patients administered 90 mg of oral tablet. [Figure 2] This shows an overview of the clinical trials for brigatinib. [Figure 3] This shows the proposed dosage of brigatinib in Clinical Trial 1. [Modes for carrying out the invention]

[0018] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains. 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 are not intended to limit the inventions described herein.

[0019] As used herein, and unless otherwise specified, the terms “administer” or “dosage” mean the act of physically delivering a substance to a patient in the manner it is in extracorporeal, such as by oral delivery, mucosal delivery, intradermal delivery, intravenous delivery, intramuscular delivery, and / or any other physical delivery method described herein or known in the art. When treating a disease, disorder, or condition or its symptoms, the administration of the substance is typically performed after the onset of the disease, disorder, or condition or its symptoms. When preventing a disease, disorder, or condition or its symptoms, the administration of the substance is typically performed before the onset of the disease, disorder, or condition or its symptoms.

[0020] As used herein, and unless otherwise specified, the terms “treatment,” “to treat,” and “to treat” are intended to encompass all areas of intervention in the disease, disorder, or condition affecting the subject, including alleviating, reducing, stopping, or reversing one or more symptoms of the disease, disorder, or condition, or slowing the progression of the disease, disorder, or condition, even if the disease, disorder, or condition does not actually disappear. Treatment may include, for example, a reduction in the severity of symptoms, a decrease in the number of symptoms, and / or a decrease in the frequency of recurrence. Treatment of cancer may include, for example, the suppression of tumor growth, the inhibition of tumor growth, and / or the regression of existing tumors.

[0021] As used herein, and unless otherwise specified, the terms “prevent,” “prevent,” and “prevent” are intended to include methods of delaying and / or preventing the onset of a disorder, disease or condition and / or symptoms associated therewith, methods of preventing a subject from contracting a disorder, disease or condition, or methods of reducing the risk of a subject contracting a disorder, disease or condition.

[0022] As used herein, and unless otherwise specified, the terms “alleviate” and “alleviate” mean to reduce or lessen one or more symptoms (e.g., pain) of a disorder, disease, or condition. These terms may also mean reducing the adverse effects associated with the active ingredient. In some cases, the disorder, disease, or condition may not be cured by the beneficial effects obtained from the preventive or therapeutic agent.

[0023] Improvement in cancer or cancer-related disease can be characterized as a complete response or a partial response. “Complete response” means that there is no clinically detectable disease and any previously abnormal radiographic results, bone marrow and cerebrospinal fluid (CSF) measurements, or abnormal monoclonal protein measurements have normalized. “Partial response” means that, without new lesions, the measurable total tumor volume (i.e., the number of malignant cells present in the subject, the volume measurement of the tumor mass, or the amount of abnormal monoclonal protein) has decreased by at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. The term “treatment” encompasses both complete and partial responses.

[0024] As used herein, and unless otherwise specified, the terms “cancer” and “cancerous” refer to or describe a physiological condition in mammals that is typically characterized by uncontrolled cell growth.

[0025] As used herein, and unless otherwise specified, the terms “tumor” and “solid tumor” mean all lesions and neoplastic cell growth and proliferation, whether malignant or benign, as well as all precancerous cells, cancer cells, precancerous tissues and cancerous tissues. “Neoplastic” means, as used herein, any form of dysregulated or uncontrolled cell growth, whether malignant or benign, that causes abnormal growth of tissue. Thus, “neoplastic cells” include malignant and benign cells exhibiting dysregulated or uncontrolled cell growth.

[0026] As used herein, and unless otherwise specified, the terms “subject” and “patient” are used synonymously. As used herein, the subject may be a non-primate animal (e.g., a cattle, pig, horse, cat, dog, rat, etc.) or a mammal (e.g., a monkey and a human). In specific embodiments, the subject is a human. In one embodiment, the subject is a mammal (e.g., a human) that has the disease, disorder, or condition described herein. In another embodiment, the subject is a mammal (e.g., a human) at risk of developing the disease, disorder, or condition described herein.

[0027] As used herein, and unless otherwise specified, the terms “effective dose” or “therapeutic dose” mean the amount of a compound or a combination of one or more compounds that, when administered (e.g., sequentially or simultaneously), elicits a desired biological or pharmacokinetic response, such as destroying target cancer cells or slowing or inhibiting cancer progression in a subject. The therapeutic dose may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated, such as the subject’s weight and age, the severity of the disease state, and the mode of administration, and a person skilled in the art can easily determine the amount. This term also applies to doses that induce a specific response in target cells, such as a reduction in platelet adhesion and / or cell migration. For example, the “therapeutic dose” of a combination therapy means the amount of each therapeutic agent in the combination therapy that, when administered together, has a beneficial effect. In certain embodiments, the combined effect is additive. In certain embodiments, the combined effect is synergistic. Furthermore, in the case of combination therapy, those skilled in the art should recognize that the amount of each therapeutic agent can be used independently at a "less than therapeutic dose," that is, less than the therapeutically effective dose of the single therapeutic agent.

[0028] As used herein, and unless otherwise specified, the term “less than therapeutic dose” of a drug or therapeutic agent means a quantity less than the effective dose of the drug or therapeutic agent as a single agent, but which, when combined with another drug or therapeutic agent in an effective or therapeutic dose, can achieve the desired outcome for the physician, for example, through synergistic effects in the resulting efficacy or reduction of side effects.

[0029] As used herein, and unless otherwise specified, combination therapy or “in combination with ~” means using two or more therapeutic agents to treat a particular disorder or condition. “In combination with ~” is not intended to imply that the therapeutic agents must be administered simultaneously and / or compounded for delivery together, but such delivery methods are within the scope of this disclosure. The therapeutic agent can be administered simultaneously with one or more additional drugs, either before the additional drug (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 the additional drug (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). Therapeutic agents in combination therapy can be administered on an alternating schedule, with or without drug-free periods (for example, not administering the agent on a specific day in the administration schedule). Administration of a therapy "in combination" with another therapy includes, but is not limited to, sequential and simultaneous administration of the two drugs. Generally, each therapy agent is administered at a dose and / or time schedule specified for that particular drug. Even more combinations, such as triple therapy, are also envisioned in this invention.

[0030] As used herein, and unless otherwise specified, the terms “concomitant administration” or “co-administration” refer to the administration of two or more therapeutic agents to the same subject at the same time (simultaneously) or nearly simultaneously. “Nearly simultaneously” includes sequential administration, in which case the time between doses is not an intentional delay period but merely the time due to the speed of the individual tasks of administering the activators, for example, the time required for one healthcare provider to administer the first therapeutic agent and then the second therapeutic agent, in accordance with established clinical practice and norms. In one embodiment, “nearly simultaneously” includes administration within a period of 15 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, or up to approximately 12 hours. In one embodiment, concurrent administration is performed within a period of approximately 15 minutes or less, approximately 30 minutes or less, approximately 1 hour or less, approximately 2 hours or less, or approximately 6 hours or less, and not exceeding 12 hours.

[0031] As used herein, and unless otherwise specified, the term “sequential administration” means administering at least two therapeutic agents at different time points, either via the same or different routes. In certain embodiments of sequential administration, the administration of one therapeutic agent is completed before the administration of another therapeutic agent(s). The delay between the administration of different therapeutic agents may be intentional, for example, to obtain a specific beneficial therapeutic effect. In one embodiment, sequential administration is performed with intervals of about 30 minutes or more, about 1 hour or more, about 2 hours or more, about 6 hours or more, about 12 hours or more, or about 24 hours or more. In one embodiment, sequential administration is performed with intervals of about 1 day or more, about 2 days or more, about 3 days or more, about 4 days or more, about 5 days or more, about 6 days or more, about 7 days or more, or longer. In one embodiment, sequential administration is performed with intervals of 12 hours or more.

[0032] As used herein, and unless otherwise specified, the term “synergistic effect” refers to a situation in which the combined effect of two or more drugs is greater than the sum of the effects of each individual drug. This term includes not only the reduction of symptoms of the disorder being treated, but also, for example, improvements in the side effect profile, improved tolerability, improved patient compliance, improved efficacy, or any other clinical outcome.

[0033] As used herein, and unless otherwise specified, the terms “about” or “approximately” mean a tolerance for a particular value as defined by those skilled in the art (the tolerance being, in part, dependent on the method of measuring or determining the value). In certain embodiments, the terms “about” or “approximately” mean within one standard deviation, within two standard deviations, within three standard deviations, or within four standard deviations. In certain embodiments, the terms “about” or “approximately” mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0034] As used herein, and unless otherwise specified, the term “pharmaceutically acceptable salt” refers to salts derived from various organic and inorganic counterions known in the art. pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. For a discussion 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 acidic 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, and salicylic acid. Non-limiting examples of suitable basic salts include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, specifically including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0035] As used herein, and unless otherwise specified, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” include all solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such media and agents with pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, they are intended to be used in the therapeutic compositions of the present disclosure. Auxiliary active ingredients may also be incorporated into the compositions.

[0036] As used herein, and unless otherwise specified, the terms “carrier,” “adjuvant,” and “vehicle” are used synonymously and include all solvents, diluents, and other liquid vehicles suitable for a particular dosage form, dispersants or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Remington: The Science and Practice of Pharmacy, 20th Ed., A. Gennaro, Lippincott Williams & Wilkins, 2000 discloses various carriers used in compounding pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds of this disclosure by causing any undesirable biological effect or otherwise interacting hazardously with any other component(s) of a pharmaceutically acceptable composition, its use is intended to be within the scope of this disclosure.

[0037] Unless otherwise stated, the compounds described herein include those that differ only in the presence of one or more isotope-rich atoms. For example, a hydrogen atom may be replaced by deuterium or tritium, or a carbon atom may be replaced by 13 C concentrated carbon or 14 Compounds having the structure of the present invention are within the scope of this disclosure, except that they are replaced with carbon-enriched carbon.

[0038] Unless otherwise stated, the compounds described herein include all stereochemical forms of their structure, e.g., R and S configurations for each chiral center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as enantiomer mixtures and diastereomer mixtures, are within the scope of this disclosure. For compounds described herein where relative stereochemistry is defined, the diastereomer purity of such compounds may be at least 80%, at least 90%, at least 95%, or at least 99%. As used herein, the term “diastereomer purity” refers to the amount of a compound having the indicated relative stereochemistry, expressed as a percentage of the total amount of all diastereomers present.

[0039] Treatment method In one embodiment, the present invention provides a method for treating cancer in a pediatric patient, wherein the patient is given compound A of the following formula. [ka] or a method comprising administering a therapeutically effective dose of a pharmaceutically acceptable salt thereof.

[0040] In one embodiment, the present invention provides a method for preventing cancer in a pediatric patient, comprising administering to the patient a therapeutically effective dose of compound A or a pharmaceutically acceptable salt thereof.

[0041] Compound A, also known as brigatinib, has the chemical name 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazine-1-yl)piperidine-1-yl]phenyl}pyrimidine-2,4-diamine. Brigatinib is described in WO2009 / 143389, the patent of which is incorporated herein by reference. Example 122 of WO2009 / 143389 describes the synthesis of brigatinib. Several crystalline polymorphs of brigatinib are described in WO2016 / 065028, the patent of which is incorporated herein by reference.

[0042] Compound A or a pharmaceutically acceptable salt thereof may be administered as monotherapy or in combination with one or more second therapeutic agents.

[0043] In one embodiment, the patient is under 22 years old. In one embodiment, the patient is 18 years old or younger. In one embodiment, the patient is 1 year old or older but under 22 years old. In one embodiment, the patient is 1 year old or older but under 18 years old. In one embodiment, the patient is between 1 and 17 years old. In one embodiment, the patient is 2 years old or older but under 22 years old. In one embodiment, the patient is 2 years old or older but under 18 years old. In one embodiment, the patient is between 2 and 17 years old. In one embodiment, the patient is 4 years old or older but under 22 years old. In one embodiment, the patient is 4 years old or older but under 18 years old. In one embodiment, the patient is between 4 and 17 years old.

[0044] In one embodiment, the cancer is anaplastic lymphoma kinase positive (ALK+). As used herein, and unless otherwise specified, “ALK-positive” (ALK+) cancer means cancer characterized by inappropriately high expression of the ALK gene or by a mutation in the ALK gene that alters the biological activity of the ALK nucleic acid molecule or polypeptide. As used herein, and unless otherwise specified, “mutation” or “variant” of ALK includes one or more deletions, substitutions or additions, or fragments thereof in the amino acid or nucleotide sequence of ALK. ALK variants also include ALK fusion proteins and ALK fusion genes. ALK variants may also include one or more deletions, substitutions or additions, or fragments thereof, provided that the variant retains kinase phosphorylation activity. In one embodiment, the ALK mutant is EML4-ALK, which is a fusion of the echinoderm microtubule-binding protein-like 4 (EML4) gene and the ALK tyrosine kinase domain, and includes any secondary mutant of EML4-ALK, such as those described in U.S. Patent No. 9,611,283 (which is incorporated herein by reference in its entirety).

[0045] In one embodiment, ALK+ cancer is determined by an FDA-approved test or other tests known in the art. Available tests include, for example, FoundationOne CDx(F1CDx) (a sequencing-based in vitro diagnostic device for detecting genomic signatures, including substitutions, insertions, and deletions (indels), copy number changes (CNAs), specified gene rearrangements, and microsatellite instability (MSI) and tumor mutational burden (TMB) in 324 genes using DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens), VENTANA ALK(D5F3)CDx Assay (qualitative detection of anaplastic lymphoma kinase (ALK) protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue stained with an automated staining device such as BenchMark XT or BenchMark ULTRA), and testing with the Vysis ALK Break Apart FISH Probe Kit (fluorescence in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens). Examples include qualitative tests for detecting rearrangements involving the ALK gene by situ hybridization (FISH). In one embodiment, the test is a fluorescence in situ hybridization (FISH) test, for example, a test using the Vysis ALK Break Apart FISH Probe Kit. Further information on FDA-approved tests can be found, for example, at https: / / www.fda.gov / MedicalDevices / ProductsandMedicalProcedures / InVitroDiagnostics / ucm303030.htm, and further information on the Vysis ALK Break Apart FISH Probe Kit can be found, for example, at https: / / www.molecular.abbott / us / en / products / oncology / vysis-alk-break-apart-fish-probe-kit, both of which are incorporated herein by reference in their entirety.

[0046] 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 previously failed one or more standard care (SOC) treatments.

[0047] In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is recurrent or refractory neuroblastoma. In one embodiment, the cancer is recurrent neuroblastoma. In one embodiment, the cancer is refractory neuroblastoma. In one embodiment, the cancer is ALK+ neuroblastoma. In one embodiment, the cancer is recurrent or refractory ALK+ neuroblastoma.

[0048] In one embodiment, the cancer is inflammatory myofibroblastic tumor (IMT). In one embodiment, the cancer is unresectable or recurrent IMT. In one embodiment, the cancer is unresectable IMT. In one embodiment, the cancer is recurrent IMT. In one embodiment, the cancer is ALK+IMT. In one embodiment, the cancer is unresectable or recurrent ALK+IMT.

[0049] 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 a non-Hodgkin 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 recurrence. In one embodiment, the cancer is newly diagnosed ALK+ALCL with a high risk of recurrence.

[0050] Several traits associated with a high risk of relapse have been identified in ALCL patients. The presence of one or more of the following features—mediastinal lesions, visceral lesions defined as lung, liver, or spleen lesions, and skin lesions—are all prognostic factors for relapse based on multivariate analysis. Le Deley et al., Blood 2008, 111(3), 1560-6, Le Deley et al., Journal of Clinical Oncology 2010, 28(25), 3987-93. Other factors that may be associated with a high risk of treatment refractory in children with ALCL include bone marrow infiltration (i.e., minimally disseminated disease (MDD)) detectable by polymerase chain reaction (PCR) in peripheral blood NPM1-ALK and / or by molecular techniques at diagnosis, low anti-ALK antibody titers at diagnosis, and detection of minimal residual disease (MRD) by PCR for serum NPM1-ALK after the first course of chemotherapy. 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. al.,2016.

[0051] Mussolin et al. investigated prognostic values ​​for MDD and anti-ALK immune responses in children with NPM-ALK+ALCL to determine if these factors could stratify relapse risk. (Mussolin et al., 2013). Of the 128 patients enrolled in the study, 26 (20%) were considered to have high-risk disease based on their MDD+ status and antibody titer <1 / 750. In this high-risk group, the 5-year progression-free survival (PFS) was 28% and overall survival (OS) was 72%. In contrast, the PFS / OS ratios were 93% / 98% for low-risk patients (MDD-, antibody titer >1 / 750) and 68% / 84% for intermediate-risk patients (MDD-, antibody titer <1 / 750, or MDD+ and antibody titer >1 / 750).

[0052] In one embodiment, high relapse risk is characterized by the presence of one or more features selected from mediastinal lesions, visceral lesions defined as lung, liver, or spleen lesions, skin lesions, peripheral blood NPM1-ALK, bone marrow infiltration, low anti-ALK antibody titer at diagnosis, and detection of minimal residual disease (MRD) with respect to blood NPM1-ALK after the first course of chemotherapy. In one embodiment, high relapse risk is characterized by being positive for microdisseminated lesions (MDD+) at diagnosis. In one embodiment, high relapse risk is characterized by a low anti-ALK antibody titer at diagnosis. In one embodiment, high relapse risk is characterized by an anti-ALK antibody titer of 1 / 750 or less at diagnosis.

[0053] 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 as a tablet. In one embodiment, the tablet has a dose strength of 30 mg, 90 mg, or 180 mg of compound A. In one embodiment, the tablet is a white film-coated tablet.

[0054] Compound A or a pharmaceutically acceptable salt thereof may be administered once daily (QD), or the daily dose may be divided into multiple doses, such as twice daily (BID) and three times daily (TID). In addition, the administration may be continuous, i.e., daily, or intermittent. The terms “intermittent” or “intermittently” as used herein are intended to mean interruptions and commencements at either equal or unequal intervals. For example, intermittent administration of Compound A or a pharmaceutically acceptable salt thereof may be administered 1 to 6 days per week, cyclically (e.g., daily administration for 2 to 8 consecutive weeks followed by a drug-free period of up to 1 week), or every other day.

[0055] In one embodiment, compound A or a pharmaceutically acceptable salt thereof is administered once daily (QD). In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered twice daily (BID).

[0056] In certain embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the patient cyclically. Cyclical therapy involves administering the activator over a period of time, followed by a period of rest, and repeating this sequential administration. Cyclical therapy can avoid or reduce the side effects of one of the therapeutic agents and / or improve the effectiveness of the treatment.

[0057] In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 10 mg / m³ 2 ~about 150mg / m 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 30 mg / m². 2 ~about 100mg / m 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 30 mg / m². 2 ~about 60mg / m 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 40 mg / m². 2 ~about 80mg / m 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 40 mg / m². 2 ~about 100mg / m 2 Administer in the specified dose.

[0058] In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 10 mg / m³ 2 , about 15mg / m 2 , about 20mg / m 2 , about 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 55mg / m 2 , about 60mg / m 2 , about 65mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2, about 85mg / m 2 , about 90mg / m 2 , about 95mg / m 2 , about 100mg / m 2 , about 105mg / m 2 , about 110mg / m 2 , about 115mg / m 2 , about 120mg / m 2 , about 125mg / m 2 , about 130mg / m 2 , about 135mg / m 2 , about 140mg / m 2 , about 145mg / m 2 Or approximately 150 mg / m² 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 30 mg / m². 2 , about 40mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 Or approximately 100 mg / m² 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 10 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 20 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 30 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 40 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 50 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 60 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 70 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 80 mg / m². 2Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 90 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 100 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 110 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 120 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 130 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 140 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is administered at approximately 150 mg / m². 2 Administer in the specified dose.

[0059] In one embodiment, compound A or a pharmaceutically acceptable salt thereof is administered to pediatric patients in a sufficient amount such that the area under the curve (AUC), which is the exposure level, does not exceed 80% of the AUC obtained at the clinical dose for adults.

[0060] In one embodiment, compound A or a pharmaceutically acceptable salt thereof is the AUC of compound A. ∞ The AUC is administered in a sufficient amount such that it is in the range of approximately 1000 to approximately 40000 ng·hr / mL, approximately 2000 to approximately 30000 ng·hr / mL, approximately 4000 to approximately 25000 ng·hr / mL, or approximately 5000 to approximately 20000 ng·hr / mL. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is the AUC of compound A. ∞ Administer in a sufficient amount such that the AUC is in the range of approximately 4000 to approximately 25000 ng·hr / mL. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is the AUC of compound A. ∞ Administer in a sufficient amount such that the AUC is in the range of approximately 5000 to approximately 20000 ng·hr / mL. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is the AUC of compound A. ∞Administer a sufficient amount so that the concentration is approximately 10,000 ng·hr / mL.

[0061] In one embodiment, compound A (i.e., free base) is administered. In another embodiment, a pharmaceutically acceptable salt of compound A (e.g., HCl salt) is administered. In another embodiment, the dose refers to the amount measured in terms of compound A.

[0062] In one embodiment, compound A or a pharmaceutically acceptable salt thereof may be administered as monotherapy or in combination with one or more second therapeutic agents. In one embodiment, the method provided in the present invention further comprises administering to a patient a therapeutically effective dose of the second therapeutic agent.

[0063] In one embodiment, the present invention provides a method for treating cancer 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 a second therapeutic agent.

[0064] In one embodiment, the second therapeutic agent is the chemotherapy regimen ALCL99. This regimen is derived from the BFM protocol previously used in invasive B-cell NHL. The treatment regimen, although varying somewhat from study to study, typically includes the administration of cyclophosphamide, doxorubicin, vincristine, corticosteroids, ifosfamide, and etoposide for 4–6 months, along with high doses of methotrexate and cytarabine for central nervous system (CNS) prophylaxis. Eyre et al., 2014, Turner et al., 2016.

[0065] 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.

[0066] In one embodiment, the second therapeutic agent comprises dexamethasone. In one embodiment, the second therapeutic agent comprises dexamethasone, and the dexamethasone is about 2.5 mg / m 2 ~ about 20 mg / m 2 and is administered at a dose of. In one embodiment, the second therapeutic agent comprises dexamethasone, and the dexamethasone is about 5 mg / m 2 ~ about 10 mg / m 2 and is administered at a dose of. In one embodiment, the second therapeutic agent comprises dexamethasone, and the dexamethasone is about 5 mg / m 2 and is administered at a dose of. In one embodiment, the second therapeutic agent comprises dexamethasone, and the dexamethasone is about 10 mg / m 2 and is administered at a dose of.

[0067] In one embodiment, the second therapeutic agent comprises cyclophosphamide. In one embodiment, the second therapeutic agent comprises cyclophosphamide, and the cyclophosphamide is about 100 mg / m 2 ~ about 300 mg / m 2 and is administered at a dose of. In one embodiment, the second therapeutic agent comprises cyclophosphamide, and the cyclophosphamide is about 200 mg / m 2 and is administered at a dose of.

[0068] In one embodiment, the second therapeutic agent comprises ifosfamide. In one embodiment, the second therapeutic agent comprises ifosfamide, and the ifosfamide is about 400 mg / m 2 ~ about 1200 mg / m 2 and is administered at a dose of. In one embodiment, the second therapeutic agent comprises ifosfamide, and the ifosfamide is about 800 mg / m 2 and is administered at a dose of.

[0069] In one embodiment, the second therapeutic agent comprises methotrexate. In one embodiment, the second therapeutic agent comprises methotrexate, and the methotrexate is about 1.5 g / m 2 ~ about 4.5 g / m 2It is administered in the following dose. In one embodiment, the second therapeutic agent comprises methotrexate, the methotrexate being approximately 3 g / m². 2 Administer in the specified dose.

[0070] In one embodiment, the second therapeutic agent comprises etoposide, and the amount of etoposide is 50 mg / m². 2 ~about 150mg / m 2 It is administered in the following dose. In one embodiment, the second therapeutic agent contains etoposide, which is approximately 100 mg / m². 2 Administer in the specified dose.

[0071] In one embodiment, the second therapeutic agent comprises cytarabine, and the amount of cytarabine is approximately 75 mg / m². 2 ~about 225mg / m 2 It is administered in the specified dose, twice a day. In one embodiment, the second therapeutic agent contains cytarabine, which is approximately 150 mg / m². 2 Administer at the specified dose, twice a day.

[0072] In one embodiment, the second therapeutic agent comprises doxorubicin, and the doxorubicin is present in a concentration of 12.5 mg / m². 2 ~Approx. 37.5mg / m 2 It is administered in the following dose. In one embodiment, the second therapeutic agent contains doxorubicin, which is approximately 25 mg / m². 2 Administer in the specified dose.

[0073] In certain embodiments, compound A or a pharmaceutically acceptable salt thereof, and a second therapeutic agent are administered to the patient cyclically. Cyclical therapy involves administering the activator over a period of time, followed by a period of rest, and repeating this sequential administration. Cyclical therapy can avoid or reduce the side effects of one of the therapeutic agents and / or improve the effectiveness of the treatment.

[0074] In one embodiment, compound A or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for one or more cycles with a 7-day period. In one embodiment, compound A or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for one or more cycles with a 21-day period. In one embodiment, compound A or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for one or more cycles with a 28-day period.

[0075] In one embodiment, compound A or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for at least 4 cycles. In one embodiment, compound A or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for at least 6 cycles. In one embodiment, compound A or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for at least 8 cycles. In one embodiment, compound A or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered for at least 12 cycles.

[0076] In one embodiment, compound A or a pharmaceutically acceptable salt thereof is administered on days 1 to 21 of a 21-day cycle.

[0077] In one embodiment, the second therapeutic agent comprises dexamethasone, which is administered on days 1 to 5 of a 21-day cycle.

[0078] In one embodiment, the second therapeutic agent comprises cyclophosphamide, which is administered on the first and second days of a 21-day cycle.

[0079] In one embodiment, the second therapeutic agent comprises cyclophosphamide, which is administered on days 1 to 5 of a 21-day cycle.

[0080] In one embodiment, the second therapeutic agent comprises a combination of hydrocortisone, methotrexate, and cytarabine, which is administered on day 1 of a 21-day cycle.

[0081] In one embodiment, the second therapeutic agent comprises ifosfamide, which is administered on days 1 to 5 of a 21-day cycle.

[0082] In one embodiment, the second therapeutic agent comprises methotrexate, which is administered on the first day of a 21-day cycle.

[0083] In one embodiment, the second therapeutic agent comprises etoposide, which is administered on the 4th and 5th days of a 21-day cycle.

[0084] In one embodiment, the second therapeutic agent comprises cytarabine, which is administered on the 4th and 5th days of a 21-day cycle.

[0085] In one embodiment, the second therapeutic agent comprises doxorubicin, which is administered on the 4th and 5th days of a 21-day cycle.

[0086] In one embodiment, the present invention provides a method for treating unresectable or recurrent IMT in a pediatric patient, comprising administering to the patient a therapeutically effective dose of compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the IMT is unresectable or recurrent ALK+IMT. In one embodiment, the amount of compound A or a pharmaceutically acceptable salt thereof is approximately 30 mg / m². 2 ~about 100mg / m 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 30 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 40 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 60 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 80 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 100 mg / m². 2 Administer in the specified dose.

[0087] In one embodiment, the present invention provides a method for treating recurrent or refractory ALCL in a pediatric patient, comprising administering to the patient a therapeutically effective dose of compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the ALCL is recurrent or refractory ALK+ALCL. In one embodiment, the dose of compound A or a pharmaceutically acceptable salt thereof is approximately 30 mg / m². 2 ~about 100mg / m 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 30 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 40 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 60 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 80 mg / m². 2 Administer in the following dose. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is approximately 100 mg / m². 2 Administer in the specified dose.

[0088] In one embodiment, the present invention provides 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 the ALCL99 regimen.

[0089] In one embodiment, the present invention provides a method for treating ALCL in a pediatric patient, comprising administering to the patient a therapeutically effective dose of compound A or a pharmaceutically acceptable salt thereof in combination with dexamethasone, ifosfamide, methotrexate, etoposide, and cytarabine. In one embodiment, the treatment is continued for one or more cycles of 21 days. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is administered on days 1 to 21 of the 21-day cycle, dexamethasone is administered on days 1 to 5 of the 21-day cycle, ifosfamide is administered on days 1 to 5 of the 21-day cycle, methotrexate is administered on day 1 of the 21-day cycle, etoposide is administered on days 4 and 5 of the 21-day cycle, and cytarabine is administered on days 4 and 5 of the 21-day cycle. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is administered on days 1 to 21 of a 21-day cycle, and dexamethasone is administered at approximately 10 mg / m². 2 The dose is administered on days 1-5 of a 21-day cycle, with ifosfamide at approximately 800 mg / m². 2 The dose is administered on days 1-5 of a 21-day cycle, with methotrexate being approximately 3 g / m² (e.g., over 3 hours). 2 The dose is administered on day 1 of a 21-day cycle, with etoposide at approximately 100 mg / m². 2 The drug is administered at this dose on days 4 and 5 of the 21-day cycle, with cytarabine at approximately 150 mg / m². 2 The drug is administered at this dosage twice a day, on the 4th and 5th days of a 21-day cycle.

[0090] In one embodiment, the present invention provides a method for treating ALCL in a pediatric patient, comprising administering to the patient a therapeutically effective dose of compound A or a pharmaceutically acceptable salt thereof in combination with dexamethasone, methotrexate, cyclophosphamide, and doxorubicin. In one embodiment, the treatment is continued for one or more cycles of 21 days. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is administered on days 1 to 21 of the 21-day cycle, dexamethasone is administered on days 1 to 5 of the 21-day cycle, methotrexate is administered on day 1 of the 21-day cycle, cyclophosphamide is administered on days 1 to 5 of the 21-day cycle, and doxorubicin is administered on days 4 and 5 of the 21-day cycle. In one embodiment, compound A or a pharmaceutically acceptable salt thereof is administered on days 1 to 21 of the 21-day cycle, and dexamethasone is administered at approximately 10 mg / m². 2 The dose is administered on days 1-5 of a 21-day cycle, with methotrexate being approximately 3 g / m² (e.g., over 3 hours). 2 The dosage is administered on day 1 of a 21-day cycle, with cyclophosphamide being approximately 200 mg / m². 2 The dosage is administered on days 1-5 of a 21-day cycle, with doxorubicin at approximately 25 mg / m². 2 This dosage is administered on the 4th and 5th days of a 21-day cycle.

[0091] Pharmaceutical composition Furthermore, the present invention provides pharmaceutical compositions useful for the method provided herein. Each of the therapeutic agents used in the method provided herein, or any combination thereof, can be included in the same pharmaceutical composition or different pharmaceutical compositions.

[0092] In one embodiment, the present invention provides a pharmaceutical composition and dosage form comprising compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition and dosage form further comprises one or more excipients.

[0093] In one embodiment, the present invention provides compound A or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions and dosage forms comprising lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate, and hydrophobic colloidal silica.

[0094] In one embodiment, brigatinib (compound A) is supplied orally as a film-coated tablet containing 30 mg, 90 mg, or 180 mg of brigatinib, along with the inert components lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate, and hydrophobic colloidal silica. The tablet coating consists of talc, polyethylene glycol, polyvinyl alcohol, and titanium dioxide.

[0095] Further pharmaceutical formulations containing brigatinib are described in International Application No. PCT / US2018 / 021128, which is incorporated herein by reference.

[0096] Further combination therapy Furthermore, the present invention provides a further combination therapy that may use one or more agents (e.g., a third therapeutic agent) known to modulate other or the same pathway, in addition to the first therapeutic agent (e.g., compound A) and the second therapeutic agent (e.g., ALCL99 chemotherapy regimen) provided in the present invention. In certain embodiments, such a method may include administering compound A to a subject in need of treatment, optionally in combination with the ALCL99 chemotherapy regimen, and further in combination with one or more additional therapeutic agents such as anticancer agents, chemotherapeutic agents, therapeutic antibodies, and radiotherapy, to produce a synergistic or additional therapeutic effect, if desired.

[0097] The route of administration for the third therapeutic agent is independent of the routes of administration for the first and second agents. The third therapeutic agent may be administered orally, parenterally, intraperitoneally, intravenously, intra-arterially, transdermally, sublingually, intramuscularly, rectally, transorally, intranasally, via liposomes, by inhalation, vaginally, intraocularly, locally via catheter or stent, subcutaneously, intrafatally, intra-articularly, intrathecally, or in a sustained-release form.

[0098] The method provided in the present invention may use one or more third active ingredients or agents. The third activator may be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic molecule, organometallic molecule, or organic molecule).

[0099] Examples of macromolecule activators include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, particularly therapeutic antibodies against cancer antigens. Typical macromolecule activators are biomolecules such as native proteins, synthetic proteins, or recombinant proteins.

[0100] A third small molecule activator can also be used to mitigate adverse effects associated with the administration of the combination therapy agents provided in this invention. However, like some macromolecules, many are thought to produce additive or synergistic effects when administered together with the combination agents provided in this invention (for example, before, after, or simultaneously with the combination agent). Examples of third small molecule activators include, but are not limited to, anticancer drugs, antibiotics, immunosuppressants, and steroids.

[0101] Examples of additional anticancer agents to be used in the methods or compositions described herein include asibicin, acralubicin, acodazole hydrochloride, acronin, adzeresin, aldesleukin, altretamine, ambomycin, ametantrone acetate, amsacrin, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batymastam, benzodepa, bicalutamide, bisanthren hydrochloride, bisnafide dimesylate, bizeresin, bleomycin sulfate, brequinal sodium, and bropyrim Busulfan, kactinomycin, carsterone, calasemide, carvetimer, carboplatin, carmustine, carbicin hydrochloride, carzeresin, cedefingol, celecoxib (COX-2 inhibitor), chlorambucil, ciloremycin, cisplatin, cladribine, clofarabine, cristatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dabrafenib, dactinomycin, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquan, docetaxel, doxorubicin, Doxorubicin hydrochloride, droloxifen, droloxifen citrate, dromostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, erusamitrusin, enloplatin, empromart, epipropidine, epirubicin hydrochloride, erbrozole, esorbicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etopurine, fadrozol hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurocitabine , fosquidone, fosquidone sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, irmofosin, iproplatin, irinotecan, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, rialozol hydrochloride, lomethelexol sodium, lomustine, loxoxantrone hydrochloride, masopropyl, meitansine, mechloretamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogalyl, mercaptopurine, methotrexate, methotrexate sodium,Metoprine, Metsuredepa, Mitindomide, Mitocalcin, Mitochromin, Mitogiline, Mitomarcin, Mitomycin, Mitospel, Mitotan, Mitoxantrone hydrochloride, Mycophenolic acid, Nocodazole, Nogaramycin, Omasetaxin, Ormaplatin, Oxythran, Paclitaxel, Paclitaxel protein-binding particles for suspension injection (albumin-bound), Pegasparagase, Periomycin, Pentamustine, Pepromycin sulfate Syn, perphosphamide, pipobromane, piposulfan, piroxantrone hydrochloride, plicamycin, promethane, porfimer sodium, porphyromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofulin, ribopurine, safingol, safingol hydrochloride, semustine, simtrazene, sorafenib, sparphosate sodium, sparsomycin, spirogermanium hydrochloride , spiromustin, spiroplatin, streptonigrin, streptozocin, thalisomycin, tecogalan sodium, taxotere, tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxylone, testactone, thiamiprine, thioguanine, thiotepa, thiazophrine, tirapazamin, toremifene citrate, trestron acetate, trisilibine phosphate, trimethrexate, trimetho Examples include, but are not limited to, Lexate, Triptorelin, Tubrozol hydrochloride, Uracil mustard, Uredepa, Vapreotide, Vemurafenib, Verteporfin, Vinblastine sulfate, Vincristine sulfate, Vindesine, Vindesine sulfate, Vinepidine sulfate, Bingricinate sulfate, Vinleulosine sulfate, Vinorelbine tartrate, Vinrosidine sulfate, Vinzolidine sulfate, Borozol, Zeniplatin, Dinostatin, and Zolubicin hydrochloride.

[0102] Other anticancer drugs to be included in the methods or compositions of the present invention include 20-epi-1,25-dihydroxyvitamin D3, 5-ethinyluracil, abiraterone, acralubicin, acylfluben, adesipenolic acid, adzelesin, aldesleukin, ALL-TK antagonist, altretamine, ambamustine, amidox, amiphostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrografolide, angiogenesis inhibitors, antagonist D, antagonist G, Antarelix, anti-dorsal formation protein-1, anti-androgens, anti-estrogens, antineoplastons, antisense oligonucleotides, aphydicolin glycinate, apoptosis gene modulators, apoptosis regulators, aprinic acid, and ara-CDP-DL -PTBA, arginine deaminase, asracurin, atamestan, atrimustin, axinastatin 1, axinastatin 2, axinastatin 3, azesetron, azatoxin, azatyrosine, baccatin III derivatives, valanol, batimastat, BCR / ABL antagonists, benzochlorin, benzoyl staurosporine, β-lactam derivatives, β-aretin, betacramycin B, betulinic acid, bFGF inhibitors, bicalutamide, bisanthren, bisaziridinylspermine, bisnafide, bistratin A, bizeresin, brefrate, bropyrimin, budotitan, butionine sulfoximine, calcipotriol, carphostin C, camptothecin derivatives, capecitabine, carboxamide-amino-triazole, carboxamide triazole, CaRest M3, CARN700, cartilage-derived inhibitors, carzeresin, casein kinase inhibitors (ICOS), castanospermine, cecropine B, cetrorelix, chlorine, chloroquinoxalinesulfonamide, cicaprost, cisporphyrin, cladribine, clomiphene analog, clotrimazole, colismycin A, colismycin B, combretastatin A4, combretastatin analog, conagenin, crambesidine 816, cristinator, cryptophycin 8, cryptophycin A derivative, crasin A, cyclopentanetraquinone, cycloplatam, cypemycin, Ara-C ocphosphate, cytolytic factors, cytostatin, dacliximab,Decitabine, Dehydrodydemnin B, Deslorerin, Dexamethasone, Dexphosphamide, Dexrazoxane, Dexverapamil, Diadiquan, Didemnin B, Zidox, Diethylnorspermine, Dihydro-5-Azacitidine, 9-Dihydrotaxol, Dioxamycin, Diphenylspiromustine, Docetaxel, Docosanol, Dracetron, Doxifluridine, Doxorubicin, Doroxifen, Dronabinol, Duocalmycin SA, Ebselen, Ecomustine, Edelfosine, Edrecolomab, Eflornithine, Elemen, E Mitefur, epirubicin, epristeride, estramustine analog, estrogen agonist, estrogen antagonist, etanidazole, etoposide phosphate, exemestane, fadrozol, fazarabine, fenretinide, filgrastim, finasteride, flavopyridol, frezelastine, fluasterone, fludarabine, fluorodaunornicin hydrochloride, forphenimex, formestan, fotemustine, fotemustine, gadolinium texaphylline, gallium nitrate, gallocitabine, ganirelix, gelatinase inhibitor, Mucitabine, glutathione inhibitors, hepsulfame, heregulin, hexamethylenebisacetamide, hypericin, ibandronate, idarubicin, doxifen, idramanthon, irmofosin, ilomastat, imatinib (e.g., Gleevec®), imiquimod, immunostimulatory peptides, insulin-like growth factor-1 receptor inhibitors, interferon agonists, interferon, interleukin, iobenguan, iododoxorubicin, 4-ipomeanol, ilopract, ilsogladine, isobengazole, isohomohalicone Drin B, Itasetron, Jasplakinolide, Kahalalide F, Lamelalin-N Triacetate, Lanreotide, Reinamycin, Renograstim, Lentinan Sulfate, Leptolstatin, Letrozole, Leukemia Inhibitor, Leukocyte α-Interferon, Leuprolide + Estrogen + Progesterone, Leuprorelin, Levamizole, Rialozol, Linear Polyamine Analogue, Novel Oily Disaccharide Peptide, Novel Oily Platinum Compound, Lissoclinamide 7, Lovaplatin, Rombrisin, Lomethelexol, Ronidamin, Loxoxantrone, Loxoribine, Lulutotecan,Lutetium texafiri, lysophyllin, lysipeptide, mytansine, mannostatin A, marimastat, masopropyl, maspin, matrilysine inhibitor, matrix metalloproteinase inhibitor, menogalil, melbaron, meterelin, methioninase, metoclopramide, MIF inhibitor, mifepristone, miltefosine, mirimostim, mitogwazone, mitractol, mitomycin analog, mitonafid, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mophalotene, moglamostim, cetuximab, human Chorionic gonadotropin, monophosphoryl lipid A + mycobacterium cell wall skeleton, mopidamol, mustard anticancer agent, micaperoxide B, mycobacterium cell wall extract, myriapolon, N-acetyldinaline, N-substituted benzamide, nafarelin, nagressip, naloxone + pentazocine, napabine, naphterpine, naltograstim, nedaplatin, nemorubicin, neridronic acid, nilutamide, nisamycin, nitric oxide modulator, nitrogen oxide antioxidant, nitrulline, oblimersen (Genasense®), O, 6- Benzyl guanine, octreotide, oxenone, oligonucleotides, onapristone, ondansetron, ondansetron, oracin, oral cytokine inducers, ormaplatin, osaterone, oxaliplatin, oxaunomycin, paclitaxel, paclitaxel analogues, paclitaxel derivatives, paclitaxel protein-conjugated particles (albumin-bound) for suspension injection, parauamine, palmitoyl lyzoxin, pamidronic acid, panaxytriol, panomiphene, parabactin, pazeriptin, pegasparagauze, perdecine, pe Sodium polysulfate, pentostatin, pentrozole, perflubron, perphosphamide, periryl alcohol, phenazinomycin, phenyl acetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, pyritrexime, placetin A, placetin B, plasminogen activator inhibitors, platinum complexes, platinum compounds, platinum-triamine complexes, sodium porfimer, porphyromycin, prednisone, propylbis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based Immunomodulators, protein kinase C inhibitors, microalgae, protein tyrosine phosphatase inhibitors, purpurin, pyrazoloacridin, pyridoxylated hemoglobin polyoxyethylene conjugate, RAF antagonists, larcitrexed, ramosetron, RAS farnesyl protein transferase inhibitors, RAS inhibitors, RAS-GAP inhibitors, demethylated reteroliptin, etidronate rhenium Re186, rhizoxin, ribozyme, RII retinamide, rohypnol, romulutide, ro Kinimex, Rubiginone B1, Ruboxil, Safinol, Saintpin, Salmustine, Sarcophytol A, Salglamostim, Sdi1 mimetic, Semustine, Aging-derived inhibitor 1, Sense oligonucleotide, Signal transduction inhibitor, Schizophyllan, Sobuzoxane, Sodium borocaptate, Sodium phenylacetate, Sorbelol, Somatomedin-binding protein, Sonelmin, Sparphosic acid, Spicamycin D, Spiromustine, Suprenopentin, Spongestatin 1, Squalamine, Stipiamid, Stromélysin inhibitor, Sulfinosine,Superactive vasoactive intestinal peptide antagonist, sradista, suramin, swinesonin, talimustin, tamoxifen methiozide, tauromustine, tazarotene, tecogalan sodium, tegafur, telrapyrilium, telomerase inhibitor, temoporfin, teniposide, tetrachlorodecaoxide, tetrazomine, talibrastin, thiocholalin, thrombopoietin, thrombopoietin mimetic, thymalfacin, thymopoietin receptor agonist, thymotrinan, thyroid-stimulating hormone, tineethylethiopurine, tyrapazamine, titanocene dichloride, top Examples include, but are not limited to, sentine, toremifene, translation inhibitors, tretinoin, triacetyluridine, trisirivine, trimethrexate, triptorelin, tropisetron, tulosteride, tyrosine kinase inhibitors, tilphostine, UBC inhibitors, ubenimex, urogenital tract-derived growth inhibitors, urokinase receptor antagonists, vapreotide, variolin B, veraresol, veramine, verzin, verteporfin, vinorelbine, vinxaltin, vitaxin, borozol, zanoterone, zeniplatin, zirascorb, and dinostatin stimulamers.

[0103] Other third active agents useful in the methods or compositions of the present invention include rituximab, oblimersen (Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temodal, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, gefitinib (Iressa®), taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, interferon α, pegylated interferon α (e.g., PEG Examples include, but are not limited to, INTRON-A, capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, paclitaxel, vinblastine, interleukin-2, granulocyte-macrophage colony-stimulating factor, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, paclitaxel protein-conjugated particles for suspension injection (albumin-conjugated), ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt®), sulindac, and etoposide.

[0104] Other specific third activators useful in the methods or compositions of the present invention include sorafenib, dabrafenib, vemurafenib, trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040 (PD184352), TAK-733, AT7867, AZD8055, BX-912, silmitaseltib, and pictilisib. Examples include, but are not limited to, MK-2206, piralalisib, gefitinib, erlotinib, lapatinib, osimertinib, OSI-027, AZD8055, sapanicertib, dactricib, BGT226, voxtalisib, apitricib, omiparisib, PF-04691502, gedatricib, PP242, lenalidomide, or pomalidomide.

[0105] Medical kit Furthermore, the present invention provides a medical kit. In a particular embodiment, the present invention provides a medical kit comprising compound A or a pharmaceutically acceptable salt thereof.

[0106] In certain embodiments, the kit includes compound A or a pharmaceutically acceptable salt thereof in a suitable package, and a second therapeutic agent as described herein, as well as written materials, which may include instructions for use, a review of clinical trials, a list of side effects, etc. In certain embodiments, such a kit may also include information such as reference scientific literature, package inserts, clinical trial results and / or summaries thereof (displaying or demonstrating the activity and / or benefits of the composition and / or describing dosage, administration, side effects, drug interactions), or other information useful to healthcare providers. In certain embodiments, such information may be based on the results of various studies, e.g., studies using experimental animals with in vivo models, and human clinical trial-based studies. In certain embodiments, the kit may further include another agent. In certain embodiments, compound A or a pharmaceutically acceptable salt thereof of the present disclosure and the second therapeutic agent are supplied as separate compositions in separate containers within the kit. In certain embodiments, compound A or a pharmaceutically acceptable salt thereof of the present disclosure and the second therapeutic agent are supplied as a single composition in one container within the kit. Suitable packaging and additional articles for use (e.g., measuring cups for liquid preparations, foil packaging to minimize exposure to air, etc.) are known in the art and may be included in the kit of the present invention. The kit described herein can be supplied, sold and / or promoted to healthcare providers, including physicians, nurses, pharmacists, and pharmaceutical authorities. In some embodiments, the kit may be sold directly to consumers. [Examples]

[0107] Example 1: Extrapolation and intrapolation between adult and pediatric populations Since there is currently no available pediatric clinical pharmacokinetic (PK) data for brigatinib, we estimated its pediatric PK from adult PK data using an allometric approach. Key aspects of this analysis are outlined below.

[0108] The use of an allometric scaling approach is supported by knowledge of the clearance mechanism of brigatinib and the corresponding ontogeny (indicating the maturity of clearance in pediatric patients over 1 year of age). Therefore, based on adult administration regimens for ALK+NSCLC, simulations based on previously developed population PK models were performed to provide guidance for dose selection for a pediatric phase 1 dose confirmation trial. The proposed trial is an open-label phase 1 dose escalation study in patients aged 2 years or older with measurable or evaluable ALK+ solid tumors, CNS tumors, or ALCL that are refractory to therapy and for which no known curative treatments are available.

[0109] In a key Phase 2 trial in adults with ALK+NSCLC, two dose regimens were evaluated: (1) 90 mg QD, and (2) a regimen in which patients received 90 mg QD in the first week, followed by an escalation to 180 mg QD in patients who tolerated a 7-day lead-in trial with 90 mg QD. Based on the demonstration of longer PFS with 180 mg QD, the recommended clinical dose of brigatinib in adults is 90 mg orally for the first 7 days. After administering a QD dose, the dose is increased to 180 mg QD based on patient tolerance. This approach, which includes a 7-day lead-in period with a low dose, reduces the risk of EOPE. Therefore, a similar dosing regimen, along with a 7-day lead-in period, is proposed for development in pediatric patients. To reduce the risk of EOPE in pediatric patients, the brigatinib dose selected for treatment in week 1 is derived from clinical experience in adults and designed to ensure a systemic exposure not exceeding that of a 90 mg / day dose in adults.

[0110] The pharmacokinetic activity (PK) of brigatinib was elucidated using a three-compartment model based on the transabsorption compartment model, employing an adult population PK model. The final covariate model included linear functions of body weight and volume parameters with respect to clearance. In addition, age and albumin concentration were considered statistically significant covariates for clearance.

[0111] To simulate pediatric pharmacokinetics (PK), the covariate linear function of body weight and volume parameters with respect to clearance was replaced with an allometric function, with scaling factors (i.e., exponents) set to 0.75 for clearance and 1 for the volume parameter. Using this modified model, simulations were conducted to derive drug doses in pediatric patients that would result in exposure levels comparable to those observed in adult patients after a baseline dose of 90 mg QD. Hypothetical pediatric patients were simulated based on the age-specific distribution of body size in the National Health and Nutrition Examination Survey (NHANES) dataset provided by the Centers for Disease Control and Prevention (CDC). The pediatric patient population was stratified by age (1000 patients per month, 1–18 years) and sex (male:female = 50:50).

[0112] Based on a cross-sectional study comparing brigatinib exposure levels obtained from oral solution administered in human radioactivity mass balance studies (Study AP26113-13-104) and tablet PK in adults (Study AP26113-16-110), the relative bioavailability of oral brigatinib solution is predicted to be approximately 42% higher in terms of AUC compared to tablets. Therefore, the relative bioavailability coefficient (oral solution / tablet AUC ratio: 1.42) was incorporated into the pediatric simulation.

[0113] Simulations using this modified model showed that the concentration was 40 mg / m². 2It was shown that brigatinib exposure in pediatric patients aged 1 to under 18 years after taking brigatinib as an oral solution would be comparable to the exposure obtained in adult patients who took 90 mg QD as an oral tablet (Figure 1).

[0114] Based on these simulations, 40 mg / m² 2 QD → 80 mg / m² 2 The systemic exposure in pediatric patients receiving the QD dose is predicted to be comparable to the systemic exposure obtained with the recommended clinical dose in adults (90 mg QD → 180 mg QD). In the pediatric Phase 1 trial we have formulated, we will typically use an approach consistent with that used in pediatric Phase 1 trials, starting at a dose level of 30 mg / m² to ensure that the model predicted pediatric exposure (AUC) does not exceed 80% of the exposure obtained with the clinical dose in adults (90 mg QD → 180 mg QD). 2 QD → 60 mg / m² 2 QD (dose level 1) was selected. The subsequent dose level (40 mg / m²) was determined. 2 QD → 80 mg / m² 2 At QD (dose level 2), 100% of the adult exposure is expected to be achieved. 40 mg / m² 2 QD → 80 mg / m² 2 If the QD dose is tolerated, one additional dose level will be formulated. To reduce the risk of EOPE, dose level 3 (40 mg / m²) will be used. 2 QD → 100 mg / m² 2 In QD), the first week's brigatinib dose was 40 mg / m². 2 QD (i.e., 90 mg in adults) This is the dose level that is predicted to result in a systemic exposure that matches the systemic exposure obtained with the lead-in dose of QD. 100 mg / m² 2 The maximum formulation dose, known as QD, was selected to achieve a systemic exposure level approximately equivalent to that of the 240 mg QD dose, which was the maximum tolerable dose accepted in adults in Study AP26113-11-101.

[0115] The following considerations provided justification for continuing dose escalation beyond dose level 2 in the pediatric population. In adult clinical trials of brigatinib in ALK+NSCLC, longer PFS was observed with the 90mg QD → 180mg QD dose compared to the 90mg QD dose, suggesting that the exposure associated with 180mg QD cannot be assumed to maximize efficacy in ALK+ pediatric cancer. • In pediatric clinical trials of the ALK inhibitor crizotinib, the dosage was 280 mg / m². 2 This results in MTD / RP2D, and the resulting systemic exposure is approximately 50% higher than the adult clinical exposure with 250 mg BID.

[0116] For these reasons, we do not propose a direct extrapolation approach for the deployment of brigatinib in children. Instead, dose selection for the pediatric Phase 1 program will be performed using population PK modeling and simulation, leveraging available pediatric and adult data from adult clinical trials, as well as data for the ALK inhibitor crizotinib. Similarly, population PK modeling of pediatric Phase 1 PK data will be used to guide dose selection for subsequent efficacy and safety studies in the pediatric patient population.

[0117] Example 2: Pediatric Clinical Trial General Strategy In patients aged 2 years or older with ALCL or IMT, two clinical trials will be conducted for brigatinib: (a) an open-label Phase 1 / 2 dose-escalation and expansion study (Study 1), and (b) a Phase 2 randomized study (Study 2).

[0118] In the Phase 1 portion of Study 1, dose escalation of brigatinib monotherapy will be initiated according to a Rolling-6 design in subjects with any advanced ALK+ solid tumor or ALK+ALCL that has previously failed standard care treatment (Part A-1). After determining the RP2D for brigatinib monotherapy, a Phase 2 disease-specific expansion cohort will be initiated to enroll patients with unresectable or recurrent ALK+IMT (Part B, Cohort B-1) or recurrent / refractory ALK+ALCL (Part B, Cohort B-2). At this point, dose escalation of brigatinib in combination with a standard chemotherapy regimen (ALCL99 regimen) will also be initiated in newly diagnosed ALK+ALCL patients at high recurrence risk to determine the RP2D for brigatinib in combination with ALCL99 (Part A-2).

[0119] The sample size for Cohort B-1 in Trial 1 was approximately 28 participants.

[0120] If sufficient safety, tolerability, and preliminary efficacy are observed in ALCL patients in Parts A-2 and B of Study 1, Study 2 will be initiated. The patient population enrolled in Study 2 will include previously untreated pediatric patients with ALK+ ALCL who are at high risk of relapse (defined as having MDD+ status at diagnosis and low anti-ALK antibody titers (≤1 / 750)). This subgroup has the highest unmet needs and response to existing treatments, as indicated by a 5-year PFS of 28% and OS of 72%, and may benefit from more aggressive or diverse frontline interventions that induce greater responses to prevent or proactively prevent relapses. In contrast, low-risk and moderate-risk patients have an even higher response to current treatments, with 5-year PFS / OS of 93% / 98% and 68% / 84%, respectively. Mussolin et al., 2013. The trial will incorporate a randomized controlled drug design to rigorously evaluate the safety and efficacy of ALCL99 in combination with brigatinib compared to ALCL99 alone.

[0121] The Phase 2 trial in previously untreated high-risk ALCL patients had a sample size of approximately 104 patients, who were randomly divided in a 1:1 ratio to receive either brigatinib in combination with ALCL99 or ALCL99 alone.

[0122] The designs for both clinical trials are shown in Figure 2.

[0123] Pediatric PK / PD trials During the Phase 1 portion of the initial trial (Trial 1), stepwise plasma samples will be collected to characterize the pharmacokinetic activity (PK) of brigatinib in the pediatric population. For younger children, a sampling scheme with wider intervals will be used due to the potential for limited blood volume. A combined population PK modeling approach will be used to combine data from the Phase 1 trial with previously obtained PK data from healthy adult subjects and NSCLC patients. Allometric functions will be incorporated to estimate the effects of body mass measurements (e.g., body surface area [BSA], body weight) on clearance and volume parameters. The causes of brigatinib PK variation (i.e., covariates) will be explored, and the effects of previously estimated covariates in adults will be revised based on a combined pediatric and adult dataset. Model performance will be evaluated using goodness-of-fit graphs, statistical criteria, and visual predictive checks. The model will be used to derive exposure parameters for each pediatric subject and compare them with adult exposure indicators to provide guidance for further dose selection.

[0124] In pediatric Phase 1 trials, brigatinib will be administered as an oral solution. In subsequent trials, oral tablets may be used for patients who can swallow solid oral dosage forms. The administration approach for the tablet formulation (e.g., binning) will be determined by a combined population PK analysis using available adult data and pediatric data collected in Phase 1 trials. The population PK analysis will revise estimates of the relative bioavailability of the oral solution formulation compared to the tablet formulation.

[0125] PK data will be obtained in the Phase 2 expanded cohort of IMT and ALCL patients in the initial trial (Trial 1), and in a separate Phase 2 trial of ALCL patients (Trial 2). Sparse PK data will be collected using a sampling scheme determined by the results of modeling Phase 1 pediatric PK data. An integrated population PK analysis will be performed on the data collected throughout the pediatric clinical development program to confirm the validity of the proposed dosage for the evaluated age range of children. The model will be used to derive exposure parameters for each pediatric patient and will contribute to the evaluation of the exposure-efficacy and exposure-safety relationships of brigatinib in the pediatric population.

[0126] Clinical trials for efficacy and safety Study 1: Phase 1 / 2 trial of brigatinib in malignant tumor patients aged 2 years or older with anaplastic lymphoma kinase (ALK) gene mutations. main goal To estimate the MTD / RP2D regimen for brigatinib monotherapy administered as a liquid formulation via PO QD in a pediatric patient population. To estimate the MTD / RP2D regimen of brigatinib administered via PO QD as a liquid formulation to be combined with the ALCL99 treatment regimen in newly diagnosed high-risk ALK+ALCL pediatric patients. • To evaluate the safety and tolerability of brigatinib administered as monotherapy and in combination with ALCL99 in a pediatric patient population. To characterize the pharmacokinetics (PKs) of brigatinib in pediatric patient populations, both as monotherapy and in combination with the ALCL99 treatment regimen.

[0127] secondary goal To define the antitumor activity of brigatinib within disease-specific expanded cohorts (IMT and relapsed / refractory ALCL).

[0128] Key evaluation criteria • Part A-1: ​​Determining RP2D for brigatinib in monotherapy. Part A-2: Determining the RP2D of brigatinib to be combined with ALCL99. • Part B cohort B-1: ORR. • Part B Cohort B-2: ORR.

[0129] Secondary evaluation items Parts A-1 and A-2: MTD, DLT, safety and tolerability, and PK. • Part B cohorts B-1 and B-2: DOR, PFS, OS, safety, and tolerability.

[0130] Main inclusion criteria

[0131] All patients (Parts A and B): • The patient must have a histologically or cytologically confirmed advanced solid tumor or lymphoma. • Patients must have activated ALK abnormalities within their tumor, detected prior to screening by a certified assay (i.e., the U.S. Clinical Laboratory Improvement Amendments (CLIA)). The report obtained from this test must be submitted for eligibility. In IMT or ALCL patients, ALK immunohistochemistry may be used instead of fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS). Patients must not take any other investigational drugs within 30 days of participating in the trial or during the trial. The patient must meet the organ and system function requirements specified in the protocol.

[0132] Part A-1: Due to the unknown potential for early-onset pulmonary adverse reactions in the pediatric patient population, and the need to monitor for reportable symptoms in patients, such as dyspnea, patients must be at least 4 years old (the lower age limit will be lowered to 2 years in subsequent cohorts after reviewing safety and tolerability data). Patients must have at least one of the following conditions at any point prior to enrollment in the trial: (1) a relapsing / progressive disease, (2) a refractory disease, or (3) a persistent disease. • The condition is refractory or intolerant to all available standard therapies. Patients must be fully recovered from all acute toxic effects of previous chemotherapy, immunotherapy, or radiotherapy prior to participating in this trial. Patients must not be receiving any other anticancer drugs or radiation therapy at the time of or during participation in the trial.

[0133] Part A-2: • The patient must be between 2 and 22 years old. • The patient must have high-risk ALK+ALCL. • The patient must not have previously received any systemic chemotherapy.

[0134] Part B, Cohort B-1: • The patient must be at least 2 years old. • Unresectable or recurrent ALK+IMT.

[0135] Part B, Cohort B-2: • The patient must be between 2 and 22 years old. • Relapsed or refractory ALK+ALCL.

[0136] Main exclusion criteria Patients who are neurologically unstable or have symptomatic CNS metastases requiring escalating doses of corticosteroids. Patients who have taken a potent or moderate CYP3A inhibitor or inducer within 14 days prior to the first dose of the study drug. • Previously taken ALK inhibitors (Parts A-2 and B only).

[0137] Sample size • Part A-1: ​​18 or fewer evaluable patients aged 4 years or older with progressive ALK+ solid tumors or ALCL that have previously failed standard care. 15 or more patients aged 18 years or younger. • Part A-2: There are 12 or fewer evaluable patients aged 2 years or older but under 22 years with newly diagnosed high-risk ALCL. There are 9 or more patients aged 18 years or younger. • Part B, Cohort B-1: 28 patients aged 2 years or older with unresectable / recurrent IMT. More than 15 patients aged 18 years or younger. • Part B, Cohort B-2: 10 patients aged 2 years or older but under 22 years with relapsed / refractory ALCL. At least 8 subjects were under 18 years old.

[0138] Follow-up period

[0139] For patients who show either a partial response (PR) or stabilization of their disease, if the sponsor and investigator agree, brigatinib monotherapy may be continued for up to one year, or until disease progression or unacceptable toxicity occurs.

[0140] treatment

[0141] Systemic exposure was normalized over the established age range using a BSA-based dose of brigatinib. The recommended 1-week lead-in paradigm for adult ALK+NSCLC patients (7 days at 90 mg QD followed by continuous administration at 180 mg QD) was used. The starting dose level was selected so that the pediatric exposure (AUC) did not exceed 80% of the exposure obtained at the clinical dose in adults. 100 mg / m² 2 The maximum prescribed dose (QD) is selected so that the systemic exposure is approximately equivalent to the systemic exposure at the maximum tolerable dose of 240 mg QD in adults.

[0142] The proposed dosages for each part of this study are shown in Figure 3.

[0143] The treatments to be performed in Trial 1 are as follows:

[0144] Part A-1: • Brigatinib monotherapy (oral solution for all patients).

[0145] Part A-2: After administering 6 cycles of ALCL99+ / - brigatinib, brigatinib monotherapy is performed. [Table 1]

[0146] Part B: • Brigatinib monotherapy: Oral liquid and tablets (tablet dosage for patients who can swallow solid oral dosage forms. The tablet dosage will be determined based on the PK data collected in Part A-1 and consideration of relative bioavailability.)

[0147] Treatment period • Parts A-1 and B: Treatment should be continued until disease progression or unacceptable toxicity occurs. • Part A-2: ALCL99+ / - brigatinib is administered for a total of 6 cycles. Patients in any arm who achieve CR or CRu after 2 cycles of treatment may, at the discretion of the investigator, proceed to transplantation. Patients who show either a partial response (PR) or stabilization of their disease may continue receiving brigatinib as monotherapy for up to one year, or until disease progression or unacceptable toxicity occurs, if agreed upon by the sponsor and the investigator.

[0148] Statistical considerations

[0149] Part A-1: ​​Part A-1 of the trial follows a Rolling-6 design. Two to six patients are recruited simultaneously for each dose level. The decision of which dose level to enroll patients in is based on the number of patients with DLTs and the number of patients still at risk of developing DLTs at the time of new patient enrollment. Patient DLTs are assessed during the first 28 days of treatment. A non-compartmental analysis of brigatinib PK is performed. PK parameters are descriptively summarized using summary statistics. PK data further contribute to population PK analysis.

[0150] In addition to determining the MTD, a summary of the toxicity description will be reported.

[0151] Part A-2: Part A-2 of the study follows a Rolling-6 design. Two to six patients are simultaneously recruited for each dose level of brigatinib administered with the ALCL99 regimen. The decision of which dose level to enroll patients in is based on the number of patients with DLTs and the number of patients still at risk of developing DLTs at the time of new patient enrollment. Patient DLTs are assessed during the first 28 days of treatment. A non-compartmental analysis of brigatinib PK is performed. PK parameters are descriptively summarized using summary statistics. PK data further contribute to population PK analysis.

[0152] In addition to determining the MTD, a summary of the toxicity description will be reported.

[0153] Part B, Cohort B-1: In Cohort B-1 of the trial, the primary endpoint will be the confirmed ORR using RECIST v1.1. All patients who received at least one dose of brigatinib will be analyzed. With 28 patients, a one-sided α=0.025 and a true response rate of 50% will result in approximately 90% power to reject the 20% threshold rate. An interim analysis for futility will be performed with the first 14 patients enrolled in the trial. If the conditional power to reject the 20% threshold rate is low, the trial may be terminated due to futility. The PK data collected in this cohort will contribute to the population PK analysis.

[0154] Part B, Cohort B-2: In Cohort B-2 of the study, the primary endpoint will be the definitive ORR using RECIST v1.1, and the important secondary endpoint will be the EFS at 2 years. Approximately 10 patients will be enrolled in this study. The PK data collected in this cohort will contribute to the population PK analysis.

[0155] D4.3.2 Study 2: A randomized phase 2 study comparing brigatinib administered in combination with dexamethasone, ifosfamide, methotrexate, etoposide, and cytarabine, followed by brigatinib administered in combination with dexamethasone, methotrexate, cyclophosphamide, and doxorubicin (ALCL99 regimen), with ALCL99 regimen alone, in previously untreated high-risk ALK+ALCL patients. main goal • To evaluate the efficacy of brigatinib in combination with ALCL99 in previously untreated high-risk ALCL patients aged 2 years or older. • Evaluate the safety and tolerability of brigatinib in combination with ALCL99.

[0156] PK goal • Collect plasma concentration-time data that contributes to population PK analysis.

[0157] Key evaluation criteria EFS at 2 years

[0158] Secondary evaluation items ORR, DOR, time to response, and OS

[0159] Main inclusion criteria • The patient must be between 2 and 22 years old. The patient must have high-risk ALK+ALCL, be MDD+ at the time of diagnosis, and have an antibody titer of 1 / 750 or less. Patients must have activated ALK abnormalities detected by a certified assay (i.e., CLIA in the United States) prior to screening. The report obtained from this test must be submitted for eligibility. ALK immunohistochemistry may be used instead of FISH or NGS. Patients must not take any other investigational drugs within 30 days of participating in the trial or during the trial. The patient must meet the organ and system function requirements specified in the protocol.

[0160] Main exclusion criteria Patients who are neurologically unstable or have symptomatic CNS metastases requiring escalating doses of corticosteroids. Patients who have taken a potent or moderate CYP3A inhibitor or inducer within 14 days prior to the first dose of the study drug. • I have previously taken ALK inhibitors. • Patients who have previously received any systemic chemotherapy for ALCL.

[0161] Sample size Approximately 104 patients aged 2 years or older but under 22 years of age were randomly divided in a 1:1 ratio to receive either brigatinib in combination with ALCL99 or ALCL99 alone (85-97 patients were under 18 years of age).

[0162] Follow-up period Patients will be followed for up to three years from the time of randomization.

[0163] treatment Brigatinib will be provided as an oral liquid or as tablets for patients who can swallow oral dosage forms. The brigatinib + ALCL99 treatment regimen used in Study 2 will follow the one discussed in Part A-2 of Study 1.

[0164] Statistical considerations:

[0165] Assuming a two-sided alpha of 0.05, a 2-year EFS of 24% in patients treated with ALCL99 alone, and a 2-year EFS of 50% in patients treated with brigatinib in combination with ALCL99, the trial would need to observe 74 events to achieve 80% power in the final analysis. After observing the first 29 events, one interim analysis for futility will be planned. If the conditional power at the time of the interim analysis is less than 20%, the trial will be terminated due to futility. This power prediction is based on a two-sided log-rank test, controlled at a two-sided level of 0.05, and the interim analysis plan will be adjusted accordingly. While the number of events is constant, the number of enrollments (N: approximately 104) may be changed based on an assessment of the overall event rate across treatment groups (before the end of enrollment).

[0166] The table below provides a summary of all the clinical trials that have been formulated. [Table 2]

[0167] The embodiments described herein are intended to be illustrative only, and those skilled in the art will recognize many equivalents of specific compounds, materials, and procedures, or confirm them through simple routine experiments. Any such equivalents shall be deemed to be within the scope of this disclosure.

[0168] All patents, patent applications, and publications referenced herein are incorporated herein by reference in their entirety. Wherever references are cited or specified in this application, this does not constitute an endorsement that such references are available as prior art to this application. The full scope of this disclosure will be better understood by referring to the appended claims.

Claims

[Claim 1] The invention as shown in the drawings.

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