HK40040887A - Methods of treating cancer in pediatric patients - Google Patents

Description

Methods of treating cancer in pediatric patients

This application claims priority from U.S. provisional application No. 62/645,089, filed on 3/19/2018, the entire contents of which are incorporated herein by reference.

Technical Field

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

Background

Bugatinib is a novel orally (PO) administered Tyrosine Kinase Inhibitor (TKI). Bugatinib is effective in inhibiting activated variants of Anaplastic Lymphoma Kinase (ALK).

ALK is a tyrosine kinase encoded on chromosome 2 that plays a physiological role in early brain development. Low adult expression levels; however, ALK can be altered and become active in a variety of malignancies, including the adult disease, non-small cell lung cancer (NSCLC), as well as Inflammatory Myofibroblastoma (IMT) and Anaplastic Large Cell Lymphoma (ALCL), which primarily affect pediatric patients or young adults. In each of these conditions, the most common alteration of ALK involves the formation of a fusion gene due to chromosomal rearrangements. Holla et al, Cold Spring harb. mol. case stud.2017,3(1), a 001115. The first gene rearrangement of ALK found in NSCLC involves a fusion between the echinoderm microtubule-associated protein-like 4(EML4) gene and the ALK tyrosine Kinase Domain (KD). Since then, many other ALK fusion partners have been described that are thought to cause aberrant signaling and oncogenic transformation. Rikova et al, Cell 2007,131(6), 1190-203; takeuchi et al, clin. cancer res.2009,15(9), 3143-9. The activating mutation of full-length ALK without rearrangement occurs in another major childhood cancer, neuroblastoma, compared to the fusion genes seen in NSCLC, IMT and ALCL. Holla et al, 2017.

Three ALK inhibitors, crizotinib (crizotinib), ceritinib (ceritinib) and erlotinib (alectinib), have been approved in europe for the treatment of patients with anaphase anaplastic lymphoma kinase positive (ALK +) NSCLC. In addition, bucatinib has gained accelerated FDA approval for the treatment of ALK + metastatic NSCLC in patients who progress or are intolerant to crizotinib, and European Market Authorization Application (MAA) for the treatment of ALK + NSCLC patients who were previously treated with crizotinib with bucatinib is under review. Although the ALK inhibitor crizotinib is an effective treatment for ALK + NSCLC, 26% to 35% of patients do not respond and most progress within 1 year. Finally, an ALK-dependent resistance mechanism was observed in approximately 30% of NSCLC patients treated with crizotinib, primarily due to the acquisition of secondary mutations in the ALK fusion gene that interfere with crizotinib binding and/or amplification. Gainor et al, Clin. cancer Res.2013,19(15), 4273-81; katayama et al, clin. cancer res.2015,21(10), 2227-35; toyokawa et al, j.thorac.oncol.2015,10(7), e 55-7. Importantly, new drugs, including brigatinib, have shown the ability to overcome many resistance mechanisms. Zhang et al, clin. In vitro studies, bugatinib is a more potent ALK inhibitor of bizotinib, ceritinib and eltatinib, and is the only one of these drugs that has substantial activity against all 17 secondary ALK mutants of EML4-ALK tested at relevant exposure levels achieved in patients.

In addition to promising non-clinical findings, bugatinib also showed substantial systemic and intracranial responses in adult patients with crizotinib-resistant ALK + NSCLC in the first human (FIH) study (study AP26113-11-101) and phase 2 study (study AP 26113-13-201; ALTA test). In ALTA, stable Objective Response Rate (ORR) and persistence of response were observed with a 180mg daily dose that began 7 days after 90mg introduction per day (90 → 180mg once daily (QD)). In this study, the confirmed ORR, duration of response (DOR), and Progression Free Survival (PFS) assessed by the investigator at 90 → 180mg QD dose were 55.5% and 13.8 months and 15.6 months, respectively. A phase 3 trial (study AP 26113-13-301; ALTA 1L) was performed, the primary objective of which was to compare the efficacy of buccininib to crizotinib based on PFS in patients with ALK + locally advanced or metastatic NSCLC who did not receive treatment with an ALK inhibitor.

NSCLC is primarily an adult disease because cases of children and adolescents are extremely rare. However, as previously described, ALK is rearranged, mutated, or amplified in a variety of tumors associated with the pediatric population, including IMT, ALCL, and neuroblastoma. ALK is therefore still a reasonable therapeutic target for pediatric patients with these conditions. Takita, Cancer Sci.2017,108(10), 1913-20.

The first of these cancers, IMT, is a very rare solid tumor characterized by spindle-shaped myofibroblasts with a chronic inflammatory component, occurring mainly in children and adolescents, mainly in the lung, soft tissue and abdominal regions. Chromosomal translocations leading to ALK activation are present in 50% to 70% of IMTs, and are more common in young people; the most common is the tropomyosin 3/4(TPM3/4) -ALK fusion, but as in NSCLC, the EML4-ALK inversion can also be seen. Alaggio et al, Cancer 2009,116(1), 216-26; griffin et al, Cancer Res.1999,59(12), 2776-80; antonescu et al, am.J.Surg.Pathol.2015,39(7), 957-67. IMT treatment is usually limited to surgical resection and there is no standard pharmacological protocol for advanced/recurrent disease or when complete resection is not possible. Dalton et al, J.Pediatr.Surg.2016,51(4), 541-4.

The second of these conditions, ALCL, is a rare (about 110 new cases per year in europe) form of non-hodgkin lymphoma (NHL), also occurring primarily in children and adolescents. Characterized by the proliferation of lymphoid T cells or null cells expressing CD 30. Up to 90% of pediatric ALCL patients suffer from ALK + disease, while the incidence of ALK positivity in adult ALCL patients is low (50%). Damm-Welk et al, Blood 2007,110(2), 670-7; gustafson et al, Ann. Diagn. Pathol.2009,13(6), 413-27. Translocations involving nuclear phosphoprotein 1(NPM1) -ALK and TPM3-ALK fusions account for 75% to 80% and 12% to 18% of ALK + ALCL, respectively. Holla et al, 2017; pulford et al, J.cell Physiol.2004,199(3), 330-58. ALCL is very sensitive to chemicals and several chemotherapeutic regimens are used in first line and refractory situations.

Finally, neuroblastoma is a rare (in europe <100 new ALK + cases/year) childhood malignancy caused by the embryonic sympathetic nervous system. In contrast to IMT and ALCL, which are based on ALK translocation, point-of-activation mutations of ALK are an important driver of tumorigenesis in neuroblastoma, with ALK mutations present in almost all familial neuroblastoma cases and between 6% and 10% of spontaneous diseases. Louis et al, annu.rev.med.2015,66, 49-63; mosse et al, Nature 2008,455(7215), 930-5. Other important driver oncogenes are well established in neuroblastoma, the most prominent of which is the amplification of MYCN. Standard treatments for neuroblastoma include chemotherapy, ablation, radiation therapy, biological therapy and immunotherapy, depending on the risk profile. Berlanga et al, Expert Opin.

There is no approved or strictly studied pharmacological protocol for IMT that controls this condition. Thus, patients who fail to resect due to complex lesions or other factors represent the highest unmet need for the IMT patient population. Therefore, there is a need for new drugs that can control the focus of unresectable resection or be used as a new adjuvant therapy to achieve resection, which would bring significant progress to these patients.

Nowadays, ALCL99 chemotherapy regimen is used by most european paediatric communities as a standard therapy for ALCL. This approach was derived from the BFM protocol previously used in aggressive B cell NHL. Treatment regimens vary in the study, but generally involve administration of cyclophosphamide, doxorubicin, vincristine, corticosteroids, ifosfamide, and etoposide for 4 to 6 months, with high doses of methotrexate and cytarabine for Central Nervous System (CNS) prevention. Eyre et al, European Journal of Haematology 2014,93(6), 455-68; turner et al, Br.J. Haematol.2016,173(4), 560-72. In the largest study based on ALCL99 completed to date, the observed EFS rate at 2 years was 73%. After initial treatment, approximately 20% to 40% of patients with ALCL will subsequently develop relapsed disease. The patients at the highest risk of relapse appear to be those with an MDD + status and an anti-ALK antibody titer ≦ 1/750. Mussolin et al, Leukemia 2013,27(2), 416-22. Nevertheless, the main goal of ongoing research must include the identification of treatment regimens that prevent relapse in patients with known high risk ALCL, and these patients still have an unmet need for better therapies. Thus, ALCL patients exhibiting high risk characteristics (e.g., MDD at diagnosis or low ALK antibody titers) may benefit from a more aggressive or different first-line intervention that promotes a deeper response with the aim of preventing or arresting relapse, particularly as it is associated with poor prognosis.

Disclosure of Invention

Provided herein are methods for treating cancer in a pediatric patient having cancer comprising administering to the patient a therapeutically effective amount of compound a having the formula:

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

In one embodiment, the cancer is Inflammatory Myofibroblastoma (IMT), Anaplastic Large Cell Lymphoma (ALCL), or neuroblastoma. In one embodiment, the cancer is Inflammatory Myofibroblastoma (IMT) or Anaplastic Large Cell Lymphoma (ALCL).

Also provided herein are pharmaceutical compositions, dosage forms, dosing regimens and kits that can be used in conjunction with the above methods.

Drawings

FIG. 1 shows receiving 40mg/m²Comparison of simulated systemic exposure (AUC) of bucatinib in pediatric patients versus adult patients receiving 90mg oral tablets of oral solution.

Figure 2 shows a clinical study summary of brigatinib.

Figure 3 shows the recommended dose of brigatinib for clinical study 1.

Detailed Description

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entirety. The headings used herein are for organizational purposes only and are not meant to be limiting of the invention described herein.

As used herein and unless otherwise specified, the term "administering" refers to the act of physically delivering a substance present outside the body to the body of a patient, for example, by oral, mucosal, intradermal, intravenous, intramuscular delivery, and/or any other physical delivery method described herein or known in the art. When treating a disease, disorder or condition, or symptoms thereof, administration of the substance is typically performed after the onset of the disease, disorder or condition, or symptoms thereof. When preventing a disease, disorder or condition, or symptoms thereof, administration of the substance is typically performed prior to the onset of the disease, disorder or condition, or symptoms thereof.

As used herein and unless otherwise specified, the term "treating" is intended to include all interventions for a disease/disorder or condition suffered by a subject, such as to alleviate, slow, halt or reverse one or more symptoms of the disease, disorder or condition or to delay the progression of the disease, disorder or condition, even if not actually abrogate the disease, disorder or condition. Treatment may include, for example, lessening the severity of symptoms, the number of symptoms, and/or the frequency of relapse. Treatment of cancer may include, for example, inhibiting tumor growth, arresting tumor growth, and/or causing regression of an already existing tumor.

As used herein and unless otherwise indicated, the term "preventing" is intended to include delaying and/or excluding the onset of a disorder, disease or condition and/or its attendant symptoms; preventing the subject from acquiring the disorder, disease, or condition; or reducing the risk of acquiring a disorder, disease, or condition in a subject.

As used herein and unless otherwise specified, the term "alleviating" refers to alleviating or alleviating one or more symptoms (e.g., pain) of a disorder, disease, or condition. The term may also refer to reducing side effects associated with the active ingredient. Sometimes, the beneficial effect obtained by the subject from the prophylactic or therapeutic agent does not result in a cure of the disorder, disease, or condition.

An improvement in cancer or cancer-related disease can be characterized as a complete or partial response. By "complete response" is meant the absence of clinically detectable disease upon normalization to any prior abnormal radiological examination, bone marrow and cerebrospinal fluid (CSF), or abnormal monoclonal protein measurements. By "partial response" is meant at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% reduction in all measurable tumor burden (i.e., the number of malignant tumor cells present in the subject or the measured tumor mass volume or the number of abnormal monoclonal proteins) in the absence of new lesions. The term "treatment" encompasses complete responses and partial responses.

As used herein and unless otherwise indicated, the terms "cancer" and "cancerous" refer to or describe the physiological condition of a mammal that is generally characterized by unregulated cell growth.

As used herein and unless otherwise indicated, the terms "tumor" and "solid tumor" as used herein refer to all diseased and neoplastic cell growth and proliferation (whether malignant or benign) as well as all precancerous and cancerous cells and tissues. As used herein, "neoplastic" refers to any form of abnormally regulated or unregulated cell growth, whether malignant or benign, that results in abnormal tissue growth. Thus, "neoplastic cells" include malignant and benign cells with or without abnormal regulation of cell growth.

As used herein and unless otherwise specified, the terms "subject" and "patient" are used interchangeably. As used herein, a subject can be a mammal, such as a non-primate (e.g., bovine, porcine, equine, feline, canine, rat, etc.) or a primate (e.g., monkey and human). In a specific embodiment, the subject is a human. In one embodiment, the subject is a mammal (e.g., a human) having a disease, disorder, or condition described herein. In another embodiment, the subject is a mammal (e.g., a human) at risk of developing a disease, disorder, or condition described herein.

As used herein and unless otherwise specified, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of one or more compounds that, when administered (e.g., sequentially or simultaneously), elicits a desired biological or medical response, such as destruction of target cancer cells or slowing or arresting the progression of cancer in a subject. The therapeutically effective amount may vary according to the intended application (in vitro or in vivo) or subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the mode of administration, and the like, which can be readily determined by one skilled in the art. The term also applies to doses that elicit a specific response in the target cells (e.g., reducing platelet adhesion and/or cell migration). For example, a "therapeutically effective amount" of a combination therapy refers to an amount of each therapeutic agent of the combination therapy which, when administered in combination, has a beneficial effect. In certain embodiments, the combined effect is additive. In certain embodiments, the effect of the combination is synergistic. Furthermore, one skilled in the art will recognize that in the case of combination therapy, the amount of each therapeutic agent can be used independently in a "sub-therapeutic amount," i.e., less than the therapeutically effective amount of the therapeutic agent alone.

As used herein and unless otherwise indicated, the term "subtherapeutic amount" of an agent or therapy is an amount that is less than the effective amount of that agent or therapy as a single dose, but which when combined with an effective amount or subtherapeutic amount of another agent or therapy can produce a result desired by a physician, for example, due to a synergistic or reduced side effect in the resulting effective effect.

As used herein and unless otherwise specified, combination therapy or "in combination with … …" refers to the use of more than one therapeutic agent 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 that the therapeutic agents are formulated for delivery together, although such methods of delivery are within the scope of the present disclosure. The therapeutic agent can be administered simultaneously, prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks) or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks) one or more other additional agents. The therapeutic agents in the combination therapy may also be administered in an alternating dosing regimen with or without intermittent cycles (e.g., no therapeutic agent administered on certain days of the regimen). Administration of a therapeutic agent "in combination" with another therapeutic agent includes, but is not limited to, sequential and concomitant administration of the two agents. Typically, each therapeutic agent is administered in a dosage and/or time regimen determined for that particular agent. More advanced combinations, such as triple therapy, are also contemplated herein.

As used herein and unless otherwise specified, the terms "concomitantly administering" or "coadministration" refer to the simultaneous (simultaneous) or about simultaneous administration of two or more therapeutic agents to the same subject. "about simultaneously" includes sequential administration, wherein the time period between administrations is due solely to the rate of administration of the active agent to the individual, and not the intentional delay between administrations, e.g., the time period required for an individual healthcare practitioner to administer a first therapeutic agent according to accepted clinical practice and standards, and then administer a second therapeutic agent according to accepted clinical practice and standards. In one embodiment, "about the same time" encompasses administration over a period of fifteen minutes or less, thirty minutes or less, one hour or less, two hours or less, six hours or less, up to about twelve hours or less. In one embodiment, the concomitant administration occurs over a period of no more than about fifteen minutes, no more than about thirty minutes, no more than about one hour, no more than about two hours, or no more than about six hours, and cannot exceed 12 hours.

As used herein and unless otherwise specified, the term "sequentially administering" means that at least two therapeutic agents are administered at different times, with the same or different routes of administration. In particular embodiments of sequential administration, administration of one therapeutic agent is completed before administration of the other or other therapeutic agents begins. The delay between administration of the different therapeutic agents may be intentional, for example, for the purpose of achieving certain beneficial therapeutic effects. In one embodiment, sequential administration is carried out at intervals of not less than about thirty minutes, not less than about one hour, not less than about two hours, not less than about six hours, not less than about twelve hours, or not less than about 24 hours. In one embodiment, sequential administration occurs at intervals of not less than about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, or longer. In one embodiment, the sequential administration is performed at intervals of not less than 12 hours.

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

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

As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. For an overview of suitable salts see, e.g., BERGE et al, J.Pharm.Sci.66:1-19(1977) and Remington: The Science and Practice of Pharmacy,20th Ed., A.Gennaro, Lippincott Williams & Wilkins, 2000. Non-limiting examples of suitable acid salts include: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, lactic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Non-limiting examples of suitable basic salts include: sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amine basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine, among others.

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

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

Unless otherwise indicated, compounds described herein include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a compound having the structure of the invention but with one hydrogen atom replaced by deuterium or tritium or one carbon atom enriched¹³C-or¹⁴Carbon-substituted compounds of C are within the scope of the present disclosure.

Unless otherwise indicated, the compounds described herein include all stereochemical forms of the structures; for example, the R and S configuration of each asymmetric center. Thus, single stereochemical isomers as well as mixtures of enantiomers and diastereomers of the compounds of the present invention are within the scope of the present disclosure. In the compounds defined by the relative stereochemistry described herein, the diastereomeric purity of such compounds can be at least 80%, at least 90%, at least 95%, or at least 99%. As used herein, the term "diastereomeric purity" refers to the amount of a compound with the relative stereochemistry depicted, expressed as a percentage of the total amount of all diastereomers present.

Method of treatment

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

Or a pharmaceutically acceptable salt thereof.

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

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

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

In one embodiment, the patient is <22 years old. In one embodiment, the patient is ≦ 18 years old. In one embodiment, the patient is ≧ 1 year and <22 years of age. In one embodiment, the patient is ≧ 1 year and ≦ 18 years. In one embodiment, the patient is 1 to 17 years old. In one embodiment, the patient is ≧ 2 years old and <22 years old. In one embodiment, the patient is ≧ 2 years and ≦ 18 years. In one embodiment, the patient is 2 to 17 years old. In one embodiment, the patient is ≧ 4 years old and <22 years old. In one embodiment, the patient is ≧ 4 years and ≦ 18 years. In one embodiment, the patient is 4 to 17 years old.

In one embodiment, the cancer is anaplastic lymphoma kinase positive (ALK +). As used herein and unless otherwise indicated, "ALK positive" (ALK +) cancer refers to a cancer characterized by inappropriately high expression of the ALK gene or by the presence of mutations in the ALK gene that alter the biological activity of the ALK nucleic acid molecule or polypeptide. As used herein and unless otherwise indicated, a "mutation" or "mutant" of ALK includes one or more deletions, substitutions, or additions in the amino acid or nucleotide sequence of ALK or a fragment thereof. ALK mutants also include ALK fusion proteins and ALK fusion genes. The ALK mutants may also comprise one or more deletions, substitutions or additions, or fragments thereof, so long as the mutants retain kinase phosphorylation activity. In one embodiment, the ALK mutant is a fusion between the echinoderm microtubule-associated protein-like 4(EML4) gene and the ALK tyrosine kinase domain, EML4-ALK, including 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.

In one embodiment, ALK + cancer is determined by FDA approved tests or other tests known in the art. Tests that may be used include, for example, Foundation one CDx ^TM(F1CDx) (sequencing-based in vitro diagnostic device for detecting substitutions, insertions and deletion changes (indels) among 324 genes as well as Copy Number Alterations (CNA) and selective gene rearrangements, and genomic signatures including microsatellite instability (MSI) and Tumor Mutation Burden (TMB) using DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens); VENTANA ALK (D5F3) CDx assay (qualitative test for denatured lymphoma kinase (ALK) protein in Formalin Fixed Paraffin Embedded (FFPE) non-small cell lung cancer (NSCLC) tissues stained using a BenchMark XT or BenchMark ULTRA autostainer); and the Vysis ALK Break Apart FISH probe kit test (qualitative test involving rearrangement of the ALK gene detected by Fluorescence In Situ Hybridization (FISH) in Formalin Fixed Paraffin Embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens. In one embodiment, the assay is a Fluorescence In Situ Hybridization (FISH) assay, such as the Vysis ALK Break Apart FISH probe kit assay. For additional information on FDA approved testing, see, e.g., https:// www.fda.gov/medical devices/products and medical procedures/InVitroDia diagnostics/ucm303030. htm; for additional information on the Vysis ALK Break Apart FISH probe kit, see, e.g., https:// www.molecular.abbott/us/en/products/oncology/Vysis-ALK-Break-fit-FISH-probe-kit; the entire contents of which are incorporated herein by reference.

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

In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is a relapsed 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 relapsed or refractory ALK + neuroblastoma.

In one embodiment, the cancer is Inflammatory Myofibroblastoma (IMT). In one embodiment, the cancer is IMT that cannot be resected or relapsed. In one embodiment, the cancer is unresectable IMT. In one embodiment, the cancer is relapsed IMT. In one embodiment, the cancer is ALK + IMT. In one embodiment, the cancer is an unresectable or relapsed ALK + IMT.

In one embodiment, the cancer is a hematologic cancer. In one embodiment, the cancer is lymphoma, leukemia, or myeloma. In one embodiment, the cancer is lymphoma. In one embodiment, the cancer is non-hodgkin's lymphoma. In one embodiment, the cancer is Anaplastic Large Cell Lymphoma (ALCL). In one embodiment, the cancer is relapsed or refractory ALCL. In one embodiment, the cancer is relapsed ALCL. In one embodiment, the cancer is refractory ALCL. In one embodiment, the cancer is ALK + ALCL. In one embodiment, the cancer is relapsed or refractory ALK + ALCL. In one embodiment, the cancer is newly diagnosed ALCL. In one embodiment, the cancer is newly diagnosed ALCL with a high risk of recurrence. In one embodiment, the cancer is newly diagnosed ALK + ALCL with a high risk of recurrence.

Several characteristics have been identified in ALCL patients that are associated with a high risk of relapse. By multivariate analysis, the presence of one or more characteristics of mediastinal involvement, visceral involvement defined as lung, liver or spleen involvement, and skin involvement, all predict recurrence. Le Deley et al, Blood 2008,111(3), 1560-6; le Deley et al, Journal of Clinical Oncology 2010,28(25), 3987-93. Other factors that may be associated with a high risk of treatment failure in children with ALCL include NPM1-ALK in peripheral blood detected by Polymerase Chain Reaction (PCR) and/or bone marrow infiltration detectable by molecular techniques at diagnosis (i.e., minimal transmitted disease (MDD)), low anti-ALK antibody titers at diagnosis, and Minimal Residual Disease (MRD) detection by PCR of NPM1-ALK in blood after a 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, 2016.

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

In one embodiment, the high risk of relapse is characterized by the presence of one or more characteristics selected from the group consisting of: mediastinal involvement, visceral involvement defined as lung, liver or spleen involvement, skin involvement, NPM1-ALK in peripheral blood, bone marrow infiltration, low anti-ALK antibody titers at diagnosis, and Minimal Residual Disease (MRD) detection of NPM1-ALK in blood after a first course of chemotherapy. In one embodiment, the high risk of relapse is characterized by minimal transmitted disease positivity (MDD +) at the time of diagnosis. In one embodiment, a high risk of relapse is characterized by low anti-ALK antibody titers at the time of diagnosis. In one embodiment, the high risk of relapse is characterized by an anti-ALK antibody titer at the time of diagnosis of ≦ 1/750.

In one embodiment, compound a or a pharmaceutically acceptable salt thereof is administered orally. In one embodiment, compound a or a pharmaceutically acceptable salt thereof is administered in the form of a tablet. In one embodiment, the tablet has a dose strength of compound a of 30mg, 90mg or 180 mg. In one embodiment, the tablet is a white film coated tablet.

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

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

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

In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 10mg/m²To about 150mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 30mg/m²To about 100mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 30mg/m²To about 60mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 40mg/m²To about 80mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is administered in an amount of about40mg/m²To about 100mg/m²The dosage of (a).

In one embodiment, compound a, or a pharmaceutically acceptable salt thereof, is present in an amount of about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, or about 150mg/m ²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is present at about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 10mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 20mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 30mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 40mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 50mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 60mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 70mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 80mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 90mg/m ²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is present at about 100mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is present at about 110mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 120mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is present at about 130mg/m²The dosage of (a). In one embodimentWherein Compound A or a pharmaceutically acceptable salt thereof is present at about 140mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is present at about 150mg/m²The dosage of (a).

In one embodiment, compound a or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to expose an area under the curve (AUC) of a pediatric patient to no more than 80% of the area under the curve obtained at clinical doses for an adult.

In one embodiment, compound a or a pharmaceutically acceptable salt thereof is present in an amount sufficient to provide an AUC of compound a in the range of about 1000 to about 40000 ng-h/mL, about 2000 to about 30000 ng-h/mL, about 4000 to about 25000 ng-h/mL, or about 5000 to about 20000 ng-h/mL _∞The amount of (c) is administered. In one embodiment, compound a or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to provide an AUC of compound a ranging from about 4000 to about 25000 ng-h/mL_∞The amount of (c) is administered. In one embodiment, compound a or a pharmaceutically acceptable salt thereof is present in an amount sufficient to provide an AUC of compound a in the range of about 5000 to about 20000 ng-h/mL_∞The amount of (c) is administered. In one embodiment, compound a or a pharmaceutically acceptable salt thereof is administered at a rate sufficient to provide an AUC of compound a of about 10000 ng-h/mL_∞The amount of (c) is administered.

In one embodiment, compound a (i.e., the free base) is administered. In one embodiment, a pharmaceutically acceptable salt (e.g., HCl salt) of compound a is administered. In one embodiment, the amount administered refers to an amount measured as the amount of compound a.

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

In one embodiment, provided herein is a method for treating cancer in a pediatric patient having cancer, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent.

In one embodiment, the second therapeutic agent is an ALCL99 chemotherapy regimen. This protocol was derived from the BFM protocol previously used for aggressive B cell NHL. Treatment regimens vary in the study, but generally involve administration of cyclophosphamide, doxorubicin, vincristine, corticosteroids, ifosfamide, and etoposide for 4 to 6 months, with high doses of methotrexate and cytarabine for Central Nervous System (CNS) prevention. Eyre et al, 2014; turner et al, 2016.

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.

In one embodiment, the second therapeutic agent comprises dexamethasone. In one embodiment, the second therapeutic agent comprises dexamethasone at about 2.5mg/m²To 20mg/m²The dosage of (a). In one embodiment, the second therapeutic agent comprises dexamethasone at about 5mg/m²To 10mg/m²The dosage of (a). In one embodiment, the second therapeutic agent comprises dexamethasone at about 5mg/m ²The dosage of (a). In one embodiment, the second therapeutic agent comprises dexamethasone at about 10mg/m²The dosage of (a).

In one embodiment, the second therapeutic agent comprises cyclophosphamide. In one embodiment, the second therapeutic agent comprises cyclophosphamide at about 100mg/m²To 300mg/m²The dosage of (a). In one embodiment, the second therapeutic agent comprises cyclophosphamide at about 200mg/m²The dosage of (a).

In one embodiment, the second therapeutic agent comprises ifosfamide. In one embodiment, the second therapeutic agent comprises ifosfamide, which is present at about 400mg/m²To 1200mg/m²The dosage of (a). In one embodiment, the second therapeutic agent comprises ifosfamide, which is present at about 800mg/m²The dosage of (a).

In a fruitIn embodiments, the second therapeutic agent comprises methotrexate. In one embodiment, the second therapeutic agent comprises methotrexate at about 1.5g/m²To about 4.5g/m²The dosage of (a). In one embodiment, the second therapeutic agent comprises methotrexate at about 3g/m²The dosage of (a).

In one embodiment, the second therapeutic agent comprises etoposide. In one embodiment, the second therapeutic agent comprises etoposide at 50mg/m ²To 150mg/m²The dosage of (a). In one embodiment, the second therapeutic agent comprises etoposide at about 100mg/m²The dosage of (a).

In one embodiment, the second therapeutic agent comprises cytarabine. In one embodiment, the second therapeutic agent comprises cytarabine at about 75mg/m²To 225mg/m²And administered twice daily. In one embodiment, the second therapeutic agent comprises cytarabine at about 150mg/m²And administered twice daily.

In one embodiment, the second therapeutic agent comprises doxorubicin. In one embodiment, the second therapeutic agent comprises doxorubicin at 12.5mg/m²To 37.5mg/m²The dosage of (a). In one embodiment, the second therapeutic agent comprises doxorubicin at about 25mg/m²The dosage of (a).

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

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

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.

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

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

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

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

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

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

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

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

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

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

In one embodiment, provided herein is a method for treating unresectable or relapsed IMT in a pediatric patient comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof. In one embodiment, the IMT is an unresectable or relapsed ALK + IMT. In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 30mg/m ²To about 100mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 30mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 40mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 60mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 80mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is present at about 100mg/m²The dosage of (a).

In one embodiment, provided herein is a method for treating relapsed or refractory ALCL in a pediatric patient, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof. In one embodiment, ALCL is relapsed or refractory ALK + ALCL. In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 30mg/m²To about 100mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 30mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 40mg/m ²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 60mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is at about 80mg/m²The dosage of (a). In one embodiment, compound a or a pharmaceutically acceptable salt thereof is present at about 100mg/m²The dosage of (a).

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

In one embodiment, provided herein is a method for treating ALCL in a pediatric patient, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof in combination with dexamethasone, ifosfamide, methotrexate, etoposide, and cytarabine. In one embodiment, treatment is continued for one or more 21 day cycles. In one embodiment, compound a or a pharmaceutically acceptable salt thereof is administered on days 1-21 of a 21 day cycle; dexamethasone is administered on days 1-5 of the 21 day cycle; ifosfamide is administered on days 1 to 5 of a 21 day cycle; methotrexate is administered on day 1 of a 21-day cycle; etoposide is administered on days 4 and 5 of a 21 day cycle; and cytarabine was administered on days 4 and 5 of the 21 day cycle. In one embodiment, compound a or a pharmaceutically acceptable salt thereof is administered on days 1-21 of a 21 day cycle; dexamethasone is administered at about 10mg/m on days 1-5 of the 21 day cycle ²The dosage of (a); ifosfamide at about 800mg/m on days 1-5 of a 21 day cycle²The dosage of (a); methotrexate is administered at about 3g/m on day 1 of a 21-day cycle²Is administered (e.g., within 3 hours); etoposide is administered at about 100mg/m on days 4 and 5 of a 21-day cycle²The dosage of (a); and cytarabine at about 150mg/m on days 4 and 5 of the 21-day cycle²The dose of (a) is administered twice daily.

In one embodiment, provided herein is a method for treating ALCL in a pediatric patient, comprising administering to the patient a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof in combination with dexamethasone, methotrexate, cyclophosphamide, and doxorubicin. In one embodiment, treatment is continued for one or more 21 day cycles. In one embodiment, compound a or a pharmaceutically acceptable salt thereof is administered on days 1-21 of a 21 day cycle; dexamethasone is administered on days 1-5 of the 21 day cycle; methotrexate is administered on day 1 of a 21-day cycle; cyclophosphamide is administered on days 1-5 of a 21 day cycle; and aThe mycin was administered on days 4 and 5 of a 21 day cycle. In one embodiment, compound a or a pharmaceutically acceptable salt thereof is administered on days 1-21 of a 21 day cycle; dexamethasone is administered at about 10mg/m on days 1-5 of the 21 day cycle ²The dosage of (a); methotrexate is administered at about 3g/m on day 1 of a 21-day cycle²Is administered (e.g., within 3 hours); cyclophosphamide is administered at about 200mg/m on days 1-5 of a 21 day cycle²The dosage of (a); and doxorubicin at about 25mg/m on days 4 and 5 of the 21-day cycle²The dosage of (a).

Pharmaceutical composition

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

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

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

In one embodiment, there is provided bucinib (compound a) for oral use as a film coated tablet containing 30mg, 90mg or 180mg of bucinib and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type a), magnesium stearate and hydrophobic colloidal silicon dioxide. The tablet coating is composed of talcum powder, polyethylene glycol, polyvinyl alcohol and titanium dioxide.

Other pharmaceutical formulations comprising brigatinib are described in international application No. PCT/US2018/021128, which is incorporated herein by reference.

Other combination therapies

Also provided herein are methods for other combination therapies, wherein one or more agents known to modulate other pathways or the same pathway (e.g., a third therapeutic agent or therapy) may be used in addition to the first therapeutic agent provided herein (e.g., compound a) and the second therapeutic agent provided herein (e.g., ALCL99 chemotherapy regimen). In certain embodiments, such methods comprise administering compound a to a subject in need thereof, optionally in combination with an ALCL99 chemotherapy regimen, and further in combination with one or more other therapeutic agents, such as anti-cancer agents, chemotherapeutic agents, therapeutic antibodies, and radiation therapy, to provide a synergistic or additive therapeutic effect when needed.

The route of administration of the third therapeutic agent or therapy is independent of the route of administration of the first and second agents. The third therapeutic agent or therapy may be administered orally, parenterally, intratectorily, intravenously, intraarterially, transdermally, sublingually, intramuscularly, intrarectally, buccally, intranasally, intraliposomally, by inhalation, vaginally, intraocularly, via local delivery via a catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a sustained release dosage form.

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

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

A third active agent that is a small molecule may also be used to alleviate side effects associated with administration of the combination therapies provided herein. However, like some macromolecules, many small molecules are believed to be capable of providing additive or synergistic effects when administered with the combinations provided herein (e.g., before, after, or simultaneously therewith). Examples of small molecule third active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.

Examples of additional anti-cancer agents to be used within the methods or compositions described herein include, but are not limited to: acivicin; aclarubicin; nocodazole hydrochloride; (ii) abelmoscine; (ii) Alexanox; aldesleukin; altretamine; an apramycin; amenthraquinone acetate; amsacrine; anastrozole; anthranilic acid; an asparaginase enzyme; a triptyline; azacitidine; azatepa; (ii) azomycin; batimastat; benzotepa; bicalutamide; bisantrene hydrochloride; bisnefaede dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; briprimine; busulfan; actinomycin c (cactinomycin); (ii) carroterone; a carbimide; a carbapenem; carboplatin; carmustine; a doxorubicin hydrochloride; folding to get new; cediogo; celecoxib (COX-2 inhibitor); chlorambucil; a sirolimus; cisplatin; cladribine; clofarabine; cllinaltol mesylate; cyclophosphamide; cytarabine; dacarbazine; dabrafenib; dactinomycin; daunorubicin hydrochloride; decitabine; (ii) dexomaplatin; tizanoguanine; dizyguanine mesylate; diazaquinone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drotandrosterone propionate; azomycin; edatrexae; (ii) nilisil hydrochloride; elsamitrucin; enloplatin; an enpu urethane; epinastine; epirubicin hydrochloride; (ii) ebuzole; isosbacin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etophenine; drozole hydrochloride; fazarabine; a retinoid amine; floxuridine; fludarabine phosphate; fluorouracil; (iii) flucitabine; a phosphorus quinolone; fostrexasin sodium; gemcitabine; gemcitabine hydrochloride; a hydroxyurea; idarubicin hydrochloride; ifosfamide; ilofovir dipivoxil; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprorelin acetate; liazole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; (ii) maxopropic; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; (ii) a melanoril; mercaptopurine; methotrexate; methotrexate sodium; chlorpheniramine; meltupipide; mitodomide; mitokacin; mitorubin; a serimycin; mitosin; mitomycin; mitospirane culturing; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; a noggin; omastaxine; ormaplatin; oshuzuren; paclitaxel; paclitaxel protein-bound particles (albumin-bound type) for injectable suspensions; a pemetrexed; a pelithromycin; pentazocine; pellomycin sulfate; hyperphosphamide; pipobroman; piposulfan; piroxicam hydrochloride; (ii) a plicamycin; pramipexole; porfimer sodium; porphyrins; deltemustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazole furan rhzomorph; (ii) lybodenosine; safrog; safrog hydrochloride; semustine; octreozine; sorafenib; sodium phosphono-aspartate; sparsomycin; helical germanium hydrochloride; spiromustine; spiroplatinum; streptonigrin; streptozotocin; a sulfochlorophenylurea; talimox; sodium tegafur; docetaxel; tegafur; tioxanolone hydrochloride; temoporphine; (ii) teniposide; a tiroxiron; a testosterone ester; azathioprine; thioguanine; thiotepa; (ii) a thiazole carboxamide nucleoside; tirapazamine; toremifene citrate; triton acetate; triciribine phosphate; trimetrexate; trittrexate glucuronate; triptorelin; tobramzole hydrochloride; uracil mustard; a urethane imine; vapreotide; vemurafenib; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinblastine sulfate; vinorelbine tartrate; vinblastine sulfate; vinzolidine sulfate; (ii) vorozole; zeniplatin; 1, neat setastine; and zorubicin hydrochloride.

Other anti-cancer agents to be included in the methods or compositions include, but are not limited to: 20-epi-1, 25 dihydroxy vitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; an acylfulvene; adenosylpentanol; (ii) Alexanox; aldesleukin; ALL-TK antagonist; altretamine; amifostine; 2, much of the Eimeria; amifostine; (ii) aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; androstanolide; an angiogenesis inhibitor; an antagonist D; an antagonist G; anrlex; anti-dorsal morphogenetic protein-1; an antiandrogen; an antiestrogen; an antineoplastic ketone; an antisense oligonucleotide; myxomycetin glycine; an apoptosis gene modulator; a modulator of apoptosis; a purine acid; ara-CDP-DL-PTBA; arginine deaminase; aoshanaNing (asularnine); atamestan; amoxicillin; 1, apistatin; apistatin 2; apistatin 3; azasetron; azatoxin; diazotyrosine; a baccatin III derivative; banlanuo; batimastat; a BCR/ABL antagonist; benzo chlorin; benzoyl staurosporine; beta lactam derivatives; beta-alicine; betamycin B; betulinic acid; a bFGF inhibitor; bicalutamide; a bisantrene group; bis-aziridinyl spermine; a bis-naphthalene method; bistetrate (bistetralene) a; bizelesin; bit (breve); briprimine; butootitanium; buthionine sulfoximine; calcipotriol; calpain C; a camptothecin derivative; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; a cartilage derived inhibitor; folding to get new; casein kinase Inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins (chlorins); chloroquinoxaline sulfonamide; (ii) cicaprost; a cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; clarithromycin A; clarithromycin B; cobutramine a 4; combretastatin analogs; kanaignin (connagenin); canabexetine (crambescidin) 816; krestist; nostoc 8; a nostoc a derivative; karatin (curve) a; cyclopentaquinone; cycloplatin (cycloplatam); hypophysin (cypemycin); cytarabine phosphodiester (Ara-C ocfosfate); a cytolytic factor; hexestrol phosphate (cytostatin); daclizumab; decitabine; dehydromembrane ecteinascidin B; deslorelin; dexamethasone; (ii) dexifosfamide; dexrazoxane; (ii) verapamil; a sulphinoquinone; a sphingosine B; doxycycline (didox); diethyl norspermine; dihydro-5-azacytosine nucleosides; 9-dihydropaclitaxel; dioxamycin (dioxamycin); diphenylspiromustine; docetaxel; behenyl alcohol; dolasetron; deoxyfluorouridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; etokomustine; edifulin; epidolumab; eflornithine; elemene; ethirimuron fluoride; epirubicin; epristeride; an estramustine analogue; an estrogen agonist; an estrogen antagonist; etanidazole; etoposide phosphate; exemestane; carrying out fadrozole; fazarabine; a retinoid amine; filgrastim; fina D, male safety; frataxinol (flavopiridol); flutemastine; fluasterone; fludarabine; fluxofenacin hydrochloride; fowler; formestane; fostrexed; fotemustine; gadteksporin; gallium nitrate; galocitabine; ganirelix; (ii) a gelatinase inhibitor; gemcitabine; a glutathione inhibitor; and prosulfam (hepsulfam); and regulin (heregulin); hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; iloperidone; ilofovir dipivoxil; ilomastat; the amount of imatinib (e.g.,) (ii) a Imiquimod; an immunostimulatory peptide; insulin-like growth factor-1 receptor inhibitors; an interferon agonist; an interferon; an interleukin; iodobenzylguanidine; iomycin; 4-sweet potato alcohol; iprop; isradine; isobenzoguanazole; isohigh halichondrin B; itasetron; jesspranklide (jasplakinolide); kahalalide (kahalalide) F; lamellarin triacetate-N; lancet; rapamycin (leinamycin); leguminous kiosks; sulfuric acid lentinan; litterostatin (leptin); letrozole; leukemia inhibitory factor; leukocyte interferon-alpha; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liazole; linear polyamine analogs; a lipophilic glycopeptide; a lipophilic platinum compound; lisocillinamide (lissoclinamide) 7; lobaplatin; earthworm phosphatide; lometrexol; lonidamine; losoxanthraquinone; loxoribine; lurtotecan; lutetium texas porphyrin; lithophylline (lysofylline); a lytic peptide; maytansine; mannosidase (mannostatin) a; marimastat (marimastat); (ii) maxolone; masperf (maspin); a matrilysin inhibitor; a matrix metalloproteinase inhibitor; (ii) a melanoril; malbaruron; 1, meperiline; methioninase; metoclopramide; an inhibitor of MIF; meprobinone; miltefosine; a Millisetil; mitoguazone; dibromodulcitol; mitomycin analogs; mitonaphthylamine; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofagotine; moraxest; cetuximab, human chorionic gonadotropin; monophosphoryl lipid a + mycobacteria A cell wall skeleton; mopidanol; mustard anticancer agent; mecaprost B; a mycobacterial cell wall extract; meyer kernel (myriaperone); n-acetyldinaline; an N-substituted benzamide; nafarelin; nageriti; naloxone + tebuconazole; naproxen vitamin; naphthalene is particularly non; a nartostim; nedaplatin; nemorubicin; neridronic acid; nilutamide; a lixamycin; a nitric oxide modulator; a nitrogen oxide antioxidant; rizhulyn (nitrulyn); olimersen (oblimersen)O⁶-benzylguanine; octreotide; oken; an oligonucleotide; onapristone; ondansetron; ondansetron; olazin; an oral cytokine inducer; ormaplatin; an oxateclone; olmesartan platinum; an enomycin; paclitaxel; a paclitaxel analog; a paclitaxel derivative; paclitaxel protein-bound particles (albumin-bound type) for injectable suspensions; panoming; palmitoyl rhizomycin; pamidronic acid; panaxatriol; panomifen; pranobacillin; pazeliptin; a pemetrexed; dermdesine (peldesine); pentosan polysulfate sodium; gustatostatin; pentadecazole (pentazole); perfluorobromoalkane; cultivating phosphoramide; perillyl alcohol; a phenylazeocin; phenyl acetate; a phosphatase inhibitor; piceatannol; pilocarpine hydrochloride; pirarubicin; pirtroxine; pravastatin a; pravastatin B; inhibitors of plasminogen activator; a platinum complex; a platinum compound; a platinum-triamine complex; porfimer sodium; a podomycin; prednisone; propyl bisacridone; prostaglandin J2; a protease inhibitor; protein a-based immunomodulators; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugates; a raf antagonist; leitiqusai; ramosetron; ras farnesyl protein transferase inhibitors; (ii) a ras inhibitor; ras-GAP inhibitors; demethylated retiiidine; rhenium (Re) 186 etidronate; rhizomycin; a ribozyme; RII retinoamide; roxitukale; romurtide; loquimex; lubiginone B1; lupodos (rubo) xyl); safrog; santoprene (saintopin); samustine; a scafford ftot a; sargrastim; a Sdi 1 mimetic; semustine; senescence-derived inhibitor 1; a sense oligonucleotide; a signal transduction inhibitor; a texaphyrin; sobuconazole; sodium boron carbonate; sodium phenyl acetate; sofospuro; a growth regulator binding protein; sonaming; (ii) ospaphosphoric acid; spicamycin (spicamycin) D; spiromustine; slaratine; spongistatin 1; squalamine; stitiamide (stiiamide); a matrilysin inhibitor; sofoshin; a superactive vasoactive intestinal peptide antagonist; suradista (suradista); suramin; swainsonine; tamustine; tamoxifen iodide; taulomustine; tazarotene; sodium tegafur; tegafur, tegafur; a telomerase inhibitor; temoporphine; (ii) teniposide; tetrachlorodecaoxide; tizolamine; tialisine (thalistatin); tiovorelin; thrombopoietin; a thrombopoietin mimetic; thymalfasin (Thymalfasin); a thymopoietin receptor agonist; thymotreonam; thyroid stimulating hormone; ethyl protoporphyrin tin; tirapazamine; titanocene dichloride; tobipritide; toremifene; translation inhibitors, tretinoin; triacetyl uridine; (iii) triciribine; trimetrexate; triptorelin; tropisetron; toleromide; tyrosine kinase inhibitors; a tyrosine phosphorylation inhibitor; an UBC inhibitor; ubenimex; urogenital sinus derived growth inhibitory factor; a urokinase receptor antagonist; vapreotide; vardelin B; vilareol; vaselamine; pyridine; verteporfin; vildagliptin; vitamin A is; vorozole; zanoteron; zeniplatin; benzalvitamin c (zilascorb); and neat stastatin ester.

Other third active agents that may be used in the methods or compositions include, but are not limited to, rituximab, olimersonInfliximab (remicade), docetaxel (docetaxel), celecoxib, melphalan, dexamethasoneSteroids, gemcitabine, cisPlatinum, temozolomide, etoposide, cyclophosphamide, temozolomide (temodar), carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, gefitinibPaclitaxel, taxotere (taxotere), fluorouracil, leucovorin, irinotecan, receptacle (xelodA), interferon alphA, pegylated interferon alphA (e.g., PEG intran-A), capecitabine, cisplatin, thiotepA, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, docetaxel (doxetaxol), paclitaxel, vinblastine, interleukin 2, granulocyte-macrophage colony stimulating factor, dacarbazine, vinorelbine, zoledronic acid, phosphinic acid, pamidronate (palmitronate), clarithromycin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin, irinotecan, and so forthPaclitaxel, paclitaxel protein-binding particles for injectable suspension (albumin-bound type), ganciclovir, doxorubicin, estramustine sodium phosphate Sulindac and etoposide.

Other specific third active agents that may be used in the methods or compositions include, but are not limited to, sorafenib, dabrafenib, vemurafenib, trametinib, cobitinib, bimetinib (binimetinib), semetinib, PD-325901, CI-1040(PD184352), TAK-733, AT7867, AZD8055, BX-912, silmitastinib, pirtilinib (piculisib), MK-2206, plalarinib (pilalisib), gefitinib, erlotinib, lapatinib, oxitinib, OSI-027, AZD8055, saparsertib (saparitifiib), dapulisib (daculisib), BGT226, voxtalisib, apilisib (apilosiib), omiclib (omicliib), omiclinib (omipriapilisib), lewisib-04691502, blepharisib (dapisib), magalimide, PP242, or dofetilimide.

Medical kit

Also provided herein are medical kits. In certain embodiments, provided herein is a medical kit comprising compound a or a pharmaceutically acceptable salt thereof.

In certain embodiments, the kit comprises compound a or a pharmaceutically acceptable salt thereof and a second therapeutic agent as described herein in suitable packaging, along with written material that may include instructions for use, a discussion of clinical studies, a list of side effects, and the like. In certain embodiments, such kits may further include information indicating or establishing the activity and/or advantages of the compositions and/or describing the administration, side effects, drug interactions, or other information useful to the healthcare provider, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these, and the like. In certain embodiments, such information may be based on the results of various studies, such as studies using experimental animals involving in vivo models and studies based on human clinical trials. In certain embodiments, the kit may further comprise another agent. In certain embodiments, compound a of the present disclosure, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are provided as separate compositions in separate containers within a kit. In certain embodiments, compound a of the present disclosure, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are provided as a single composition within a container of a kit. Suitable packaging and other items of use (e.g., measuring cups for liquid formulations, foil packaging with minimal exposure to air, etc.) are known in the art and may be included in the kit. The kits described herein can be offered, sold, and/or promoted to healthcare providers, including doctors, nurses, pharmacists, prescribing personnel, and the like. In some embodiments, the kit may also be sold directly to the consumer.

Examples

Example 1: inferences and interrelationships between adult and pediatric populations

Since no pediatric clinical PK data are currently available for bugatinib, the pediatric clinical PK of bugatinib is extrapolated from adult PKs using a dyskinetic protocol. Key aspects of this analysis are summarized below.

The use of the allometric regimen was supported by knowledge of the clearance mechanism that occurs with bugatinib and its corresponding individuals, indicating that clearance is mature in pediatric patients >1 year old. Therefore, simulations based on previously developed population PK models have been performed to guide the dose selection of a pediatric phase 1 dose confirmation study in view of the dosing regimen for ALK + NSCLC in adults. The proposed study is open label phase 1 dose escalation in patients ≧ 2 years of age and suffering from measurable or evaluable ALK + solid or CNS tumors or therapy refractory ALCL and no known curative treatment is available.

In a critical phase 2 study in adults with ALK + NSCLC, 2 dose regimens were evaluated: (1)90mg QD; (2) 90mg QDs at week 1, followed by an increment to 180mg QDs for those patients who tolerated 90mg QD introduction for 7 days. Based on showing longer PFS at 180mg QDs, the recommended clinical dose of brigatinib in adults is 90mg QDs orally administered for the first 7 days, then dose is increased to 180mg QDs based on patient tolerance. This 7 day introduction regimen at lower doses reduces the risk of EOPE. Therefore, a similar dosing regimen is recommended in pediatric development, using a 7 day introduction period. To reduce the risk of developing EOPE in pediatric patients, the dose of bugatinib selected at treatment week 1 should be known from adult clinical experience and designed to achieve systemic exposure at a daily dose of not more than 90mg in adults.

Adult population PK model the 3-compartment model with transport uptake compartment model was used to describe the bocatinib PK. The final covariate model included a linear function relating body weight to clearance and volume parameters. In addition, age and albumin concentration are considered as statistically significant covariates of clearance.

For the purpose of simulating pediatric PK, a linear covariate function relating body weight to clearance and volume parameters was replaced with a dissimilarity function using a proportionality coefficient (i.e., exponential) of clearance of 0.75 and a proportionality coefficient of volume parameter of 1. The improved model was used to derive a dosimetry in pediatric patients by simulation, which achieved exposures similar to those observed in adult patients after a 90mg QD reference dose. In the National Health and Nutrition Survey (NHANES) dataset provided by the Centers for Disease Control and Prevention (CDC), virtual pediatric patients were simulated based on body-type versus age distribution. The pediatric patient population is stratified by age (1000 patients per month; 1 to 18 years) and gender (50: 50; male: female).

Based on a cross-study comparison of bucindotinib exposure from oral solution (study AP26113-13-104) and tablet PK (study AP26113-16-110) administered in human radioactive mass balance studies in adults, the relative bioavailability of oral bucindotinib solution was expected to be approximately 42% higher in AUC relative to the tablets. Thus, the relative bioavailability factor (oral solution/tablet AUC ratio of 1.42) was incorporated into the pediatric simulation.

Simulations using the modified model showed that pediatric patients aged 1 to less than 18 years were administered 40mg/m in oral solution²The bocatinib exposure after bocatinib would correspond to the exposure achieved in an adult patient receiving 90mg QD in the form of an oral tablet (figure 1).

Based on these simulations, it is expected to receive 40mg/m² QD→80mg/m²The systemic exposure in pediatric patients at QD doses is equivalent to that achieved at the 90mg QD → 180mg QD recommended adult clinical dose. In the planned pediatric phase 1 study, the initial dose level (30 mg/m) was selected² QD→60mg/m²QD; dose level 1) to achieve a model predicted pediatric exposure (AUC) that is no more than 80% of the exposure achieved by adults at clinical doses (90mg QD → 180mg QD), consistent with the protocol commonly used in pediatric phase 1 studies. Expected planned subsequent dose level (40 mg/m) ² QD→80mg/m²QD; dose level 2) achieved 100% of adult exposure. If 40mg/m² QD→80mg/m²The QD dose is tolerated, and an additional dose level is planned. To reduce the risk of EOPE, dose level 3(40 mg/m)² QD→100mg/m²QD) the 1 st Bugatinib dose was 40mg/m²QDs (i.e., expected to provide 90mg QDs equivalent to those in adults)Dose level of systemic exposure achieved at the introduced dose). Selecting 100mg/m²The maximum planned dose of QDs to achieve a systemic exposure approximately equivalent to that of a human in study AP26113-11-101 at the highest acceptable tolerated dose of 240mg QDs.

The rationale for continuing to escalate beyond dose level 2 in the pediatric population is known from the following considerations:

adult experience with bugatinib in ALK + NSCLC, where longer PFS were observed at 90mg QD → 180mg QD versus 90mg QD dose, suggesting that it cannot be assumed that exposure associated with 180mg QD would maximize efficacy in ALK + pediatric cancers.

Pediatric clinical experience with the ALK inhibitor crizotinib, which achieved 280mg/m²MTD/RP2D, wherein the associated systemic exposure is about 50% higher than the adult clinical exposure at 250mg BID.

For these reasons, no direct extrapolation has been proposed for pediatric development of brigatinib. Instead, the clinical experience of adults and available pediatric and adult data on the ALK inhibitor crizotinib have been exploited, with the dose selection for the pediatric phase 1 plan being known through population PK modeling and simulation. Similarly, population PK modeling of pediatric phase 1 PK data will be used to guide dose selection for subsequent efficacy and safety studies for pediatric patient populations.

Example 2: pediatric clinical study

General policy

Two clinical studies were performed on brigatinib in patients with ALCL or IMT at 2 years of age and older: (a) open label, 1/2 phase dose escalation and extension study (study 1) and (b) phase 2 randomization study (study 2).

During phase 1 part of study 1, dose escalation of brigatinib monotherapy was performed in subjects with any advanced ALK + solid tumor or ALK + ALCL with prior standard of care treatment failure according to any Rolling-6 design (part a-1). Following determination of RP2D for the brigatinib monotherapy, an extended cohort of phase 2 specific diseases was opened and patients with unresectable or relapsed ALK + IMT (cohort B-1) or relapsed/refractory ALK + ALCL (cohort B-2) were recruited. At this time, in newly diagnosed ALK + ALCL patients at high risk of relapse, dose escalation was also initiated using a combination of bocatinib with a standard chemotherapy regimen (ALCL99 regimen) to determine RP2D of bocatinib when used in combination with ALCL99 (section a-2).

The sample size for study 1 cohort B-1 was approximately 28 subjects.

Study 2 was initiated if sufficient safety, tolerability, and primary efficacy were observed in ALCL patients in sections a-2 and B of study 1. The patient population enrolled in study 2 included pediatric patients with previously untreated ALK + ALCL and at high risk of recurrence, defined as MDD + status at diagnosis and low anti-ALK antibody titers (< 1/750). This subgroup showed the highest unmet needs and responses to existing treatments, as evidenced by the 28% and 72% 5-year PFS and OS, respectively, and could benefit from a more aggressive or different first-line intervention driving deeper responses, with the goal of preventing or arresting relapse. In contrast, patients with low and moderate risk showed better response to current therapy with PFS/OS of 93%/98% and 68%/84, respectively, for 5 years. Mussolin et al, 2013. The design incorporating randomized comparator control was studied to allow a strict assessment of the safety and efficacy of ALCL99 in combination with bucatinib versus ALCL99 alone.

The phase 2 study sample size of previously untreated high risk ALCL was approximately 104 patients randomized in a 1:1 fashion to receive either bugatinib in combination with ALCL99 or ALCL99 alone.

The design of two clinical studies is shown in figure 2.

Pediatric PK/PD study

Serial plasma samples were collected during the phase 1 portion of the initial trial (study 1) to characterize the PK of bugatinib in the pediatric population. Due to potential blood volume limitations, sparse sampling schemes are used in young children. The data from the phase 1 trial was combined with PK data previously obtained in healthy adult subjects and patients with NSCLC using a comprehensive population PK modeling protocol. The dissimilarity function was incorporated to evaluate the effect of body size measurements (e.g., body surface area [ BSA ], body weight) on clearance and volume parameters. Explore the sources of variation (i.e., covariates) for the bocatinib PK and update the previously evaluated adult covariate effects based on the merged pediatric and adult datasets. Model performance was assessed by a graphical evaluation of goodness-of-fit, statistical criteria, and visual predictive examination. The model was used to derive exposure parameters for each pediatric subject and compared to adult exposure metrics to guide further dose selection.

Bugatinib is administered as an oral solution to patients in a pediatric phase 1 study. In subsequent studies, oral tablet formulations were available for patients who were able to swallow solid oral dosage forms. The dosing regimen (e.g., split dosing) of the tablet formulation is known by performing a comprehensive population PK analysis using available adult and pediatric data collected during the phase 1 study. The population PK analysis provides a more recent estimate of the relative bioavailability of the oral solution formulation versus the tablet formulation.

PK data were obtained in the phase 2 extended cohort of IMT and ALCL patients from the initial study (study 1) and in phase 2 study alone of ALCL patients (study 2). Sparse PK data was collected through a sampling protocol known from the results of modeling phase 1 pediatric PK data. Comprehensive population PK analyses were performed on data collected throughout the pediatric clinical development plan to confirm whether the proposed dosimetry was adequate within the pediatric age range evaluated. The model was used to derive exposure parameters for each pediatric patient and to help assess exposure-efficacy and exposure-safety relationships of brigatinib in pediatric populations.

Clinical efficacy and safety studies

Study 1: phase 1/2 study of bugatinib in patients 2 years of age and older with malignancy with Anaplastic Lymphoma Kinase (ALK) gene alteration

Main object of

The MTD/RP2D regimen of brigatinib monotherapy administered in liquid formulation PO QD was evaluated in a pediatric patient population.

Assessment of MTD/RP2D regimen of brigatinib administered in liquid formulation form PO QD in combination with ALCL99 treatment regimen in pediatric patients with newly diagnosed high risk ALK + ALCL.

Assessing the safety and tolerability of brigatinib administered as monotherapy and in combination with ALCL99 in a pediatric patient population.

Characterize the PK of brigatinib administered as monotherapy and in combination with ALCL99 treatment regimen in a pediatric patient population.

Secondary target

Definition of antitumor Activity of Bugatinib within the extended cohort of specific diseases (IMT and relapsed/refractory ALCL)

Primary endpoint

Part A-1: determination of bucatinib RP2D in monotherapy.

Part A-2: assay of bucatinib RP2D in combination with ALCL 99.

Part B group B-1: ORR.

Part B group B-2: ORR.

Secondary endpoint

Parts A-1 and A-2: MTD, DLT, security and tolerability, and PK.

Part B groups B-1 and B-2: DOR, PFS, OS, security and tolerability.

Major inclusion criteria

For all patients (parts a and B):

The patient must have histologically or cytologically confirmed advanced solid tumors or lymphomas.

Prior to screening, patients were asked to have abnormalities in their tumors of activated ALK detected by a certified assay, i.e., the Clinical Laboratory Improvement Amendments (CLIA). A report of this test needs to be submitted to qualify. ALK immunohistochemistry may be used as a surrogate for Fluorescence In Situ Hybridization (FISH) or Next Generation Sequencing (NGS) in patients with IMT or ALCL.

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

The patient must meet the organ and system functional requirements set forth in the protocol.

For part A-1:

since the likelihood of an early pulmonary adverse reaction in a pediatric patient population is unknown, and it is desirable to monitor that patients may report symptoms such as dyspnea, patients must be ≧ 4 years (the lower age limit will be reduced to 2 years in subsequent cohorts after review of safety and tolerability data).

The patient must have at least one of the following: (1) relapsed/progressive disease at any time prior to study recruitment, (2) refractory disease, (3) persistent disease.

All available standard therapies are refractory or intolerant.

Before entering this study, patients must recover completely from the acute toxic effects of all previous chemotherapy, immunotherapy or radiotherapy.

At the time of entry into the study or during the study, the patient is not allowed to receive any other anti-cancer agents or radiation therapy.

For part a-2:

the patient must be ≧ 2 years and <22 years old.

The patient must have a high risk of ALK + ALCL.

Patients were not allowed to receive any prior systemic chemotherapy.

For part B group B-1:

the patient must be ≧ 2 years old.

Patients with non-resectable or recurrent ALK + IMT.

For part B group B-2:

the patient must be ≧ 2 years and <22 years old.

Patients with relapsed or refractory ALK + ALCL.

Major exclusion criteria

Patients with neurological instability or symptomatic CNS transfer requiring increased corticosteroid dosage.

Patients receiving a strong or moderate CYP3A inhibitor or inducer within 14 days prior to the first dose of study drug.

Previous acceptance of ALK inhibitors (part A-2 and part B only).

Sample size

Part A-1: up to 18 patients with advanced ALK + solid tumors or ALCL with prior standard of care failure were evaluated at 4 years old. At least 15 patients with age less than or equal to 18 years old.

Part A-2: up to 12 patients with newly diagnosed high risk ALCL are rated > 2 years old and <22 years old. At least 9 patients with age less than or equal to 18 years old.

Part B group B-1: 28 patients > 2 years old with unresectable/recurrent IMT. At least 15 patients with age less than or equal to 18 years old.

Part B group B-2: 10 patients with relapsed/refractory ALCL ≧ 2 and <22 years of age. At least 8 subjects ≦ 18 years old.

Duration of follow-up visit

After agreement between the sponsor and the investigator, patients experiencing PR or stable disease will continue to receive a single dose form of bucinib for up to 1 year until disease progression or unacceptable toxicity occurs.

Treatment of

BSA-based administration of bucatinib was used to normalize systemic exposure over the planned age range. A paradigm of 1 week introduction (90mg QDs for 7 days followed by 180mg QDs consecutively) was used that was suggested for adult patients with ALK + NSCLC. The starting dose level is selected to achieve a pediatric exposure (AUC) that does not exceed 80% of the exposure achieved at an adult clinical dose. Selecting 100mg/m²QD maximum planned dose to achieve a systemic exposure approximately equivalent to exposure at the maximum tolerated dose of 240mg QDs in adults.

Figure 3 shows the proposed doses for each stage of the study.

The treatments to be administered in study 1 were as follows:

part A-1:

brigatinib monotherapy (oral solution for all patients).

Part A-2:

ALCL99 +/-Bugatinib followed by six cycles of Bugatinib monotherapy.

And part B:

brigatinib monotherapy. Oral solutions and tablets (tablet dosage for patients able to swallow solid oral dosage forms; tablet dosage determined by PK data collected in section a-1 and relative bioavailability considerations).

Duration of treatment:

for part A-1 and part B: treatment is continued until the disease progresses or unacceptable toxicity occurs.

Part A-2: a total of 6 ALCL99 +/-bugatinib cycles were administered. Patients in either group who experienced CR or CRu after 2 treatment cycles can continue transplantation at the discretion of the investigator.

Patients who experience PR or stable disease continue to receive a single dose form of bucinib for up to 1 year after agreement between the sponsor and investigator until disease progression or unacceptable toxicity occurs.

Statistical considerations

Part A-1: part A-1 of the study followed the Rolling-6 design. While two to 6 patients cumulatively reach a dose level. The decision regarding the dose level at which patients are recruited is based on the number of patients experiencing DLT and the number of patients still at risk of developing DLT when new patients are admitted. Patients were evaluated for DLT 28 days prior to treatment. A non-compartmental analysis of the PK of brigatinib was performed. PK parameters are summarized descriptively by summary statistics. PK data additionally facilitates performing population PK analyses.

In addition to the determination of MTD, a descriptive summary of toxicity was reported.

Part A-2: part A-2 of the study followed the Rolling-6 design. While two to 6 patients cumulatively reached the dose level of bucatinib administered using ALCL99 regimen. The decision regarding the dose level at which patients are recruited is based on the number of patients experiencing DLT and the number of patients still at risk of developing DLT when new patients are admitted. Patients were evaluated for DLT 28 days prior to treatment. A non-compartmental analysis of the PK of brigatinib was performed. PK parameters are summarized descriptively by summary statistics. PK data additionally facilitates performing population PK analyses.

In addition to the determination of MTD, a descriptive summary of toxicity was reported.

Part B group B-1: study group B-1 used an ORR identified with RECIST v1.1 as the primary endpoint. All patients receiving at least 1 dose of brigatinib were analyzed. Twenty-eight patients provide approximately 90% confidence to rule out 20% of the uninteresting rate if the true response rate is 50% and the 1-sided alpha is 0.025. Interim analyses of ineffectiveness were performed on the first 14 patients enrolled in the study. If the conditional power to exclude 20% uninteresting is low, the study may be shut down for invalidity. PK data collected in this cohort was helpful for performing population PK analyses.

Part B group B-2: group B-2 of the study used ORR identified with RECIST v1.1 as the primary endpoint and EFS at 2 years as the critical secondary endpoint. Approximately 10 patients were enrolled in the study. PK data collected in this cohort was helpful for performing population PK analyses.

D.4.3.2 study 2: randomized phase 2 study of the combination of bocatinib with dexamethasone, ifosfamide, methotrexate, etoposide and cytarabine followed by the combination of bocatinib with dexamethasone, methotrexate, cyclophosphamide and doxorubicin (ALCL99 regimen) versus ALCL99 regimen alone in previously untreated patients with high risk ALK + ALCL

Main object of

Assess the efficacy of the combination of bucatinib with ALCL99 in ≧ 2-year-old patients with high risk of previously untreated ALCL.

Assess the safety and tolerability of the combination of bucatinib with ALCL 99.

PK targets

Collect plasma concentration-time data that aids in population PK analysis.

Primary endpoint

EFS at 2 years.

Secondary endpoint

ORR, DOR, reaction time and OS.

Mainly come into

The patient must be ≧ 2 years and <22 years old.

Patients must have a high risk of ALK + ALCL-MDD + and antibody titers at diagnosis ≦ 1/750.

Patients were required to have an abnormality in activated ALK detected by a certification assay (i.e., CLIA in the united states) prior to screening. A report of this test needs to be submitted to qualify. ALK immunohistochemistry may be used as a substitute for FISH or NGS.

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

The patient must meet the organ and system functional requirements set forth in the protocol.

Main exclusion

Patients with neurological instability or symptomatic CNS transfer requiring increased corticosteroid dosage.

Patients receiving a strong or moderate CYP3A inhibitor or inducer within 14 days prior to the first dose of study drug.

Previous acceptance of ALK inhibitors.

The patient received any prior systemic chemotherapy for ALCL.

Sample size

Approximately 104 patients from 2 to <22 years old were randomly assigned in a 1:1 manner to receive either Bugatinib in combination with ALCL99 or ALCL99 alone. (85 to 97 patients ≦ 18 years old.)

Duration of follow-up visit

Patients were followed up to 3 years since random assignment.

Treatment of

Brigatinib is provided to a patient capable of swallowing an oral dosage form in the form of an oral solution or tablet. The therapeutic regimen of bulgatinib + ALCL99 used in study 2 followed the protocol discussed in section a-2 of study 1.

Statistical considerations:

assuming a 2-sidedness of 0.05, 24% 2-year EFS in patients treated with ALCL99 alone, and 50% in patients treated with the combination of bugatinib and ALCL99, the study required the observation of 74 events with 80% confidence at the time of final analysis. After the first 29 events were observed, one interim analysis of invalidity was planned. If the degree of certainty of the condition of interim analysis is less than 20%, the test for invalidity is stopped. This confidence prediction was based on a 2-side log rank test and was controlled at a 2-side 0.05 level, adjusted for the proposed interim analysis plan. The number of events was fixed, but the recruiter (N-104) may vary based on an assessment of the overall event incidence aggregated across treatment groups (before recruitment ended).

The following table provides a tabular summary of all planned clinical studies.

The embodiments described herein are intended to be merely exemplary and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of this disclosure.

All patents, patent applications, and publications cited herein are incorporated by reference in their entirety. Citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present application. The full scope of the disclosure will be better understood with reference to the appended claims.

Claims (36)

1. A method for treating cancer in a pediatric patient having cancer comprising administering to the patient a therapeutically effective amount of compound a having the formula:

or a pharmaceutically acceptable salt thereof, wherein the cancer is Inflammatory Myofibroblastoma (IMT), Anaplastic Large Cell Lymphoma (ALCL), or neuroblastoma.

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

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

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

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

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

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

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

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

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

11. The method of claim 10, wherein the high risk of relapse is characterized by a positive for a disseminated disease at diagnosis (MDD +) or an anti-ALK antibody titer at diagnosis ≤ 1/750.

12. The method of any one of claims 1-11, wherein compound a or a pharmaceutically acceptable salt thereof is administered orally.

13. The method of any one of claims 1 to 12, wherein compound a or a pharmaceutically acceptable salt thereof is administered once daily (QD).

14. The method of any one of claims 1-13, wherein compound a or a pharmaceutically acceptable salt thereof is at about 30mg/m²To about 100mg/m²The dosage of (a).

15. The method of claim 14, wherein compound a or a pharmaceutically acceptable salt thereof is present at about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100mg/m²The dosage of (a).

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

17. The method of claim 16, wherein the second therapeutic agent is cyclophosphamide, doxorubicin, vincristine, a corticosteroid, ifosfamide, etoposide, methotrexate, or cytarabine, or a combination thereof.

18. The method of claim 17, wherein the corticosteroid is dexamethasone or hydrocortisone or a combination thereof.

19. The method of any one of claims 16 to 18, wherein the second therapeutic agent comprises dexamethasone at about 5mg/m²To about 10mg/m²The dosage of (a).

20. The method of any one of claims 16-19, wherein the second therapeutic agent comprises cyclophosphamide, in combinationAbout 200mg/m²The dosage of (a).

21. The method of any one of claims 16-20, wherein the second therapeutic agent comprises ifosfamide at about 800mg/m²The dosage of (a).

22. The method of any one of claims 16-21, wherein the second therapeutic agent comprises methotrexate at about 3g/m²The dosage of (a).

23. The method of any one of claims 16-22, wherein the second therapeutic agent comprises etoposide at about 100mg/m²The dosage of (a).

24. The method of any one of claims 16 to 23, wherein the second therapeutic agent comprises cytarabine at about 150mg/m²And administered twice daily.

25. The method of any one of claims 16-24, wherein the second therapeutic agent comprises doxorubicin at about 25mg/m ²The dosage of (a).

26. The method of any one of claims 16 to 25, wherein compound a or a pharmaceutically acceptable salt thereof and the second therapeutic agent are administered for one or more 21-day cycles.

27. The method of claim 26, wherein compound a or a pharmaceutically acceptable salt thereof is administered on days 1 to 21 of the 21-day cycle.

28. The method of claim 26 or 27, wherein the second therapeutic agent comprises dexamethasone administered on days 1 to 5 of the 21-day cycle.

29. The method of any one of claims 26-28, wherein the second therapeutic agent comprises cyclophosphamide, administered on days 1 and 2 of the 21-day cycle.

30. The method of any one of claims 26-28, wherein the second therapeutic agent comprises cyclophosphamide, administered on days 1-5 of the 21-day cycle.

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

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

33. The method of any one of claims 26-32, wherein the second therapeutic agent comprises methotrexate that is administered on day 1 of the 21-day cycle.

34. The method of any one of claims 26-33, wherein the second therapeutic agent comprises etoposide, which is administered on days 4 and 5 of the 21-day cycle.

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

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