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WO2025104045A1 - Alectinib pour le traitement de tumeurs solides ou du snc positives à la fusion d'alk - Google Patents

Alectinib pour le traitement de tumeurs solides ou du snc positives à la fusion d'alk Download PDF

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Publication number
WO2025104045A1
WO2025104045A1 PCT/EP2024/082092 EP2024082092W WO2025104045A1 WO 2025104045 A1 WO2025104045 A1 WO 2025104045A1 EP 2024082092 W EP2024082092 W EP 2024082092W WO 2025104045 A1 WO2025104045 A1 WO 2025104045A1
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WIPO (PCT)
Prior art keywords
alectinib
daily dose
total daily
pharmaceutically acceptable
subject
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PCT/EP2024/082092
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English (en)
Inventor
Guillaume Jacques BERGTHOLD
Hubertus Nicolaas Caron
Clare Elizabeth DEVLIN
Nassim DJEBLI
Elena GUERINI
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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Publication of WO2025104045A1 publication Critical patent/WO2025104045A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to method of treating an anaplastic lymphoma kinase (ALK) fusion-positive solid tumour or central nervous system tumour in paediatric subjects.
  • ALK anaplastic lymphoma kinase
  • Anaplastic lymphoma kinase is a transmembrane receptor tyrosine kinase, which belongs to the insulin receptor superfamily.
  • the ALK protein has an extracellular ligandbinding domain, a transmembrane region and an intracellular kinase domain. Liganddependent activation leads to dimerization and autophosphorylation resulting in the activation of the ALK pathway cascade and other signalling pathways, which affect cell growth, transformation, and anti-apoptotic signalling.
  • Wild-type ALK is expressed at very low levels in most normal human tissues but is expressed at higher levels in a few limited types of tissue, such as developing and mature nervous system tissue.
  • Dysregulated ALK signalling results from various genetic aberrations, rearrangements, mutations, fusions, and amplification. Translocations in the ALK gene may lead to the production of constitutively activated ALK fusion proteins, which can activate downstream signalling pathways and lead to cell survival, proliferation and migration.
  • ALK fusion As a prominent initiator of carcinogenesis has been extensively demonstrated in in vivo, in vitro, and in clinical studies (Soda et al., 2007, Nature, 448:561-6; Inamura et al., 2008, Thorac Oncol, 3:13-7; Inamura et al., 20009, Mod Pathol, 22:508-15; Wong et al., 2009, Cancer, 15:1723-33; Clarke et al., 2020, Cancer Discov, 10(7): 942-963).
  • ALK inhibition as a therapeutic intervention has been most extensively investigated in adult non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • SOC standard of care
  • Alectinib is a CNS penetrant molecule (Peters et al., 2017, N Engl J Med; 377:829-38) and is considered as the best in class ALK inhibitor for the first-line treatment of ALK fusion-positive NSCLC according to National Comprehensive Cancer Network (NCCN)® and European Society for Medical Oncology (ESMO) guidelines based on the outcome of the ALEX study (Camidge et al., 2019, J Thorac Oncol, 14:1233-43).
  • ALK fusions are identified in a variety of solid tumours, such as inflammatory myofibroblastic tumour (IMT) and bone and soft tissue sarcoma, and in primary CNS tumours, such as high-grade glioma (HGG). These fusions are described as oncogenic drivers (Mosse et al. 2016, Clin Cancer Res, 22:546-52; Ross et al. 2017, Oncologist, 22:1444- 50; Takita, 2017, Cancer Sci, 108:1913-20). More than 50% of IMTs and 25% of HGGs are ALK fusion-positive (Guerreiro Stucklin et al.
  • tumours harbouring ALK-fusions including infantile high grade gliomas and inflammatory myofibroblastic tumours at diagnosis and relapse.
  • alectinib is surprisingly effective at treating anaplastic lymphoma kinase (ALK) fusion-positive solid tumours or central nervous system tumours in the paediatric population.
  • ALK anaplastic lymphoma kinase
  • the invention provides a method of treating an ALK fusion-positive solid tumour or central nervous system tumour, comprising administering to a subject in need of such treatment a therapeutically effective amount of alectinib, or a pharmaceutically acceptable salt thereof, wherein the subject is aged ⁇ 18 years.
  • the ALK fusion-positive central nervous system tumour is a non- metastatic or primary central nervous system tumour.
  • the ALK fusion-positive solid tumour or central nervous system tumour is a neuroblastoma, renal cell carcinoma, papillary or medullary thyroid cancer, skin tumour, such as Spitz tumour or melanoma, inflammatory myofibroblastic tumour, soft tissue sarcoma, such as undifferentiated or rhabdomyosarcoma, osteosarcoma, malignant peripheral nerve sheath tumour, anaplastic large cell lymphoma, ganglioglioma, or glioma (low- or high-grade).
  • the ALK fusion-positive solid tumour or central nervous system tumour is an inflammatory myofibroblastic tumour, high-grade glioma, renal cell carcinoma, or anaplastic large cell lymphoma.
  • the ALK fusion-positive solid tumour or central nervous system tumour may comprise a mutation wherein ALK is fused to KIFC, TPM3, CLTC, PLEKHA7, DCTN1 or HNRNPA3.
  • the subject is aged ⁇ 2 years.
  • the subject is aged ⁇ 6 years.
  • the subject is aged ⁇ 12 years.
  • the subject is aged >2 to ⁇ 6 years.
  • the subject is aged >6 to ⁇ 12 years.
  • the subject is aged >12 to ⁇ 18 years.
  • the subject does not comprise a mutation conferring resistance to ALK inhibitors.
  • the subject has not had prior exposure to an ALK inhibitor.
  • the subject has had prior treatment for an ALK fusion-positive solid tumour or central nervous system tumour.
  • the subject may have a relapsed or refractory tumour.
  • the alectinib, or a pharmaceutically acceptable salt thereof may be administered orally.
  • the alectinib, or a pharmaceutically acceptable salt thereof may be administered twice daily.
  • the total daily dose of alectinib, or a pharmaceutically acceptable salt thereof may be between 50 and 1500 mg, preferably wherein: i. the subject is >40 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 600 and 1500 mg; ii. the subject is >35 to ⁇ 40 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 400 and 1000 mg; iii. the subject is >30 to ⁇ 35 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 300 and 800 mg; iv.
  • the subject is >25 to ⁇ 30 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 300 and 700 mg; v. the subject is >20 to ⁇ 25 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 250 and 600 mg; vi. the subject is >15 to ⁇ 20 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 200 and 500 mg; vii. the subject is >10 to ⁇ 15 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 150 and 400 mg; viii.
  • the subject is >7.5 to ⁇ 10 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 100 and 300 mg; ix. the subject is >5 to ⁇ 7.5 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 75 and 250 mg; or x. the subject is >3.5 to ⁇ 5 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 50 and 200 mg.
  • the alectinib, or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.
  • the pharmaceutical composition comprises alectinib hydrochloride.
  • the pharmaceutical composition is formulated as a capsule, preferably a hard capsule.
  • the capsule may comprise alectinib hydrochloride equivalent to 20 mg or 150 mg alectinib as free base.
  • the pharmaceutical composition may be formulated as a suspension.
  • the pharmaceutical composition is formulated as a capsule and: i. the subject is >40 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 1000 and 1400 mg, preferably the total daily dose is 1200 mg, more preferably 600 mg BID; ii. the subject is >35 to ⁇ 40 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 700 and 900 mg, preferably the total daily dose is 760 mg, even more preferably 380 mg BID; iii.
  • the subject is >30 to ⁇ 35 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 600 and 800 mg, preferably the total daily dose is 680 mg, even more preferably 340 mg BID; iv. the subject is >25 to ⁇ 30 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 500 and 700 mg, preferably the total daily dose is 600 mg, even more preferably 300 mg BID; v. the subject is >20 to ⁇ 25 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 500 and 600 mg, preferably the total daily dose is 540 mg, even more preferably 270 mg BID; vi.
  • the subject is >15 to ⁇ 20 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 400 and 500 mg, preferably the total daily dose is 460 mg, even more preferably 230 mg BID; vii. the subject is >10 to ⁇ 15 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 300 and 400 mg, preferably the total daily dose is 380 mg, even more preferably 190 mg BID; viii. the subject is >7.5 to ⁇ 10 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 200 and 300 mg, preferably the total daily dose is 280 mg, even more preferably 140 mg BID; ix.
  • the subject is >5 to ⁇ 7.5 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 150 and 250 mg total, preferably the total daily dose is 200 mg, even more preferably 100 mg BID; or x.
  • the subject is >3.5 to ⁇ 5 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 100 and 200 mg, preferably the total daily dose is 160 mg, even more preferably 80 mg BID.
  • the pharmaceutical composition is formulated as a capsule and: i. the subject is >40 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 600 and 800 mg, preferably the total daily dose is 718 mg, even more preferably 359 mg BID; ii. the subject is >35 to ⁇ 40 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 400 and 500 mg, preferably the total daily dose is 456 mg, even more preferably 228 mg BID; iii.
  • the subject is >30 to ⁇ 35 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 350 and 450 mg, preferably the total daily dose is 408 mg, even more preferably 204 mg BID; iv. the subject is >25 to ⁇ 30 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 300 and 400 mg, preferably the total daily dose is 360 mg, even more preferably 180 mg BID; v. the subject is >20 to ⁇ 25 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 280 and 380 mg, preferably the total daily dose is 324 mg, even more preferably 162 mg BID; vi.
  • the subject is >15 to ⁇ 20 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 220 and 320 mg, preferably the total daily dose is 276 mg, even more preferably 138 mg BID; vii. the subject is >10 to ⁇ 15 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 180 and 280 mg, preferably the total daily dose is 228 mg, even more preferably 114 mg BID; viii. the subject is >7.5 to ⁇ 10 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 100 and 200 mg, preferably the total daily dose is 168 mg, even more preferably 84 mg BID; ix.
  • the subject is >5 to ⁇ 7.5 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 80 and 180 mg, preferably the total daily dose is 120 mg total, even more preferably 60 mg BID; or x.
  • the subject is >3.5 to ⁇ 5 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 50 and 150 mg, preferably the total daily dose is 96 mg, even more preferably 48 mg BID.
  • the invention provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of treating an ALK fusion-positive solid tumour or central nervous system tumour in a subject, wherein the subject is aged ⁇ 18 years.
  • the invention provides for use of a therapeutically effective amount of alectinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating an ALK fusion-positive solid tumour or central nervous system tumour in a subject, wherein the subject is aged ⁇ 18 years.
  • Alectinib is a tetracyclic compound represented by the following formula (I):
  • Alectinib, and salts thereof can be produced by methods commonly known in the art, for example, the general methodology described in WO 2010/143664 (see, in particular, Example 366, Compound “F6-20”). See also WO 2012/023597 (see, in particular, Production Example 30, Compound “F6-20”).
  • Alectinib is approved for use in the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA- approved test.
  • ALK anaplastic lymphoma kinase
  • NSCLC metastatic non-small cell lung cancer
  • the approval covers patients with previously untreated metastatic lung cancer whose tumours have a cancer-causing alteration in the ALK gene (also called ALK positive).
  • alectinib can be used in free base form, or alternatively can be in the form of a pharmaceutically acceptable salt.
  • salts include suitable acid addition or base salts thereof.
  • suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g.
  • hydrohalic acids such as hydrochloride, hydrobromide and hydroiodide, sulphuric acid, phosphoric acid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate and sulphonic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C4)-alkyl- or aryl-sulfonic acids
  • Examples of preferred salts include hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, bisulphate, hemisulphate, sulfonate such as methanesulfonate and p- toluene sulfonate; carboxylate such as an acetate, trifluoroacetate, citrate, malate, maleate, tartrate, succinate and salicylate; alkali metal salts such as a sodium salt, a potassium salt; an alkaline earth metal salt such as a magnesium salt, a calcium salt; and ammonium salts such as an ammonium salt (NH4 X: X is a monovalent acid group), an alkylammonium salt, a dialkylammonium salt, a trialkylammonium salt and a tetraalkylammonium salt.
  • carboxylate such as an acetate, trifluoroacetate, citrate, malate, maleate, tartrate
  • the alectinib is in the form of a hydrochloride salt, more preferably a monohydrochloride salt.
  • the present invention also includes solvate forms of alectinib.
  • the solvate is a hydrate.
  • the alectinib is in the form of a hydrate of a monohydrochloride salt, more preferably, a monohydrate.
  • the alectinib, or pharmaceutically acceptable salt thereof may be in amorphous form or crystalline form.
  • the invention encompasses the use of various crystalline forms, polymorphic forms and (an)hydrous forms of alectinib. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds.
  • the alectinib is in amorphous form.
  • An amorphous monohydrochloride form of alectinib can be produced in accordance with the teachings of WO 2016/021707.
  • the alectinib is in crystalline form, preferably a crystalline form of a monohydrochloride salt. Suitable crystalline forms are known in the art, and are taught, for example, in WO 2015/163448 and WO 2015/163447.
  • the invention includes all enantiomers and tautomers of alecitnib and pharmaceutically acceptable salts thereof.
  • alecitnib possesses a chiral carbon atom.
  • the corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art. Enantiomers are characterised by the absolute configuration of their chiral centres and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Such conventions are well known in the art (e.g. see ‘Advanced Organic Chemistry’, 3 rd edition, ed. March, J., John Wiley and Sons, New York, 1985). Compounds containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • the alectinib, or pharmaceutically acceptable salt thereof is generally formulated with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • excipients for the various different forms of pharmaceutical compositions described herein may be found in the “Handbook of Pharmaceutical Excipients, 2 nd Edition, (1994), Edited by A Wade and PJ Weller.
  • the carrier, or, if more than one be present, each of the carriers, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and water.
  • compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including antioxidants) and the like, disintegrating agents, dissolution aids, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • suitable binder(s) lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including antioxidants) and the like, disintegrating agents, dissolution aids, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • suitable binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose methylcellulose, povidone (polyvinylpyrrolidone), macrogol, powdered acacia, starch, gelatin, natural sugars such as glucose, anhydrous lactose, freeflow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, and polyethylene glycol.
  • a preferred binder is hydroxypropylcellulose.
  • Suitable lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester and sodium stearyl fumarate.
  • magnesium stearate may be mentioned.
  • Suitable stabilizers include paraoxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride, phenols such as phenol and cresol, thimerosal, dehydroacetic acid and sorbic acid.
  • suitable flavoring agents include a sweetener, an acidulant and a fragrance.
  • suitable disintegrating agents include sodium starch glycolate, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium (carmellose calcium), sodium hydrogen carbonate, pregelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride, carmellose, etc.
  • Suitable dissolution aids include a surfactant, an organic polymer, and a pH adjusting agent, etc.
  • Preferred examples thereof include casein, sodium caseinate, skimmed milk powder, sodium lauryl sulfate (herein below, also referred to as SLS), dioctyl sodium sulfosuccinate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, sodium lauroylsarcosine, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, and sodium dodecylbenzene sulfonate
  • Suitable solubilizing agents include surfactants, organic polymers and pH modifiers.
  • surfactants include ionic surfactants and nonionic surfactants. Ionic surfactants are further classified into anionic surfactants, cationic surfactants and amphoteric surfactants depending upon the charge of the ion to be produced.
  • nonionic surfactants include sugar ester surfactants such as a sorbitan fatty acid ester (C12-18), a POE sorbitan fatty acid ester (C12-18) and sucrose fatty acid ester; fatty acid ester surfactants such as a POE fatty acid ester (C12-18), a POE resin acid ester and a POE fatty acid diester (C12-18); alcohol based surfactants such as a POE alkyl ether (012-18); alkyl phenol surfactants such as a POE alkyl (08-12) phenyl ether, a POE dialkyl (08-12) phenyl ether and a POE alkyl (08- 12) phenyl ether formal
  • monoalkyl sulfates such as sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate, dioctylsodium sulfosuccinate, sodium lauroyl sarcosinate and sodium dodecylbenzenesulfonate are mentioned.
  • Sodium lauryl sulfate is a particularly preferred surfactant.
  • sodium lauryl sulfate when sodium lauryl sulfate is used, it is more preferable to obtain a crystal thereof by crystallization rather than spray dry.
  • a crystal polymorphism of sodium lauryl sulfate a monohydrate, a 1/2 hydrate, a 1/8 hydrate and a non-solvate are known (Journal of Crystal Growth 263 (2004) 480-490). Any of the crystals can be used.
  • the alectinib or pharmaceutically acceptable salt thereof is formulated in accordance with the teachings of WO 2012/023597.
  • the composition comprises alectinib, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and a dissolution aid.
  • alectininib, or pharmaceutically acceptable salt thereof is formulated in accordance with the teachings of WO 2015/163448.
  • the pharmaceutical composition comprises (i) a granule containing alectinib, or a pharmaceutically acceptable salt thereof, and (ii) a disintegrating agent.
  • the "disintegrating agent” is a component facilitating rapid disintegration of a solid formulation taken orally. Suitable examples are described above.
  • the disintegrating agent can be contained in the granules or added to the granules as an external additive. Other additives such as a lubricant and a fluidizer may be further optionally added as external additives, or contained in the granules.
  • the granule (i) contains alectinib, or a pharmaceutically acceptable salt thereof, a disintegrating agent, a solubilizing agent, an excipient and a binder.
  • the granule may further contain one or more additives selected from a lubricant, a coating agent, a stabilizer, a flavoring agent and a diluent.
  • the alectinib, or pharmaceutically acceptable salt thereof is formulated for oral administration, i.e. the composition is an oral formulation.
  • the composition is formulated as a tablet.
  • An appropriate coating agent can be further applied to tablets to obtain sugar coated tablets or film coated tablets. Suitable coating agents will be familiar to the person skilled in the art.
  • the pharmaceutical composition comprises alectinib, or a pharmaceutically acceptable salt thereof, lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate and carmellose calcium.
  • the pharmaceutical composition is in the form of a capsule, more preferably a hard capsule.
  • composition is provided in a capsule shell comprising hypromellose, carrageenan, potassium chloride, titanium dioxide (E171 ), maize starch and carnauba wax.
  • the pharmaceutical composition is in the form of a suspension.
  • a correction factor of 1.67 may be applied to an intact capsule dose in order to obtain an oral suspension dose that ensures a similar exposure.
  • the formulation of the present invention preferably contains alectinib, or a pharmaceutically acceptable salt thereof, in an amount of, for example, about 20 to about 70 wt%, preferably, about 30 to about 60 wt%, and especially preferably, about 35 to about 60 wt% in terms of free base alectinib based on the total amount of the formulation.
  • the alectinib or pharmaceutically acceptable salt thereof is preferably contained in an amount of, for example, about 20 to about 70 wt%, preferably, about 30 to about 60 wt%, and especially preferably, about 35 to about 60 wt% in terms of free base alecinib based on the total amount of the components to be put in a capsule.
  • the composition is in the form of a unit dosage form comprising alectinib or a pharmaceutically acceptable salt thereof in an amount of, for example, 20 to 240 mg, preferably, 100 to 200 mg, and especially preferably, 140 mg to 190 mg in terms of free base alectinib per unit dosage form.
  • the composition is in the form of a unit dosage form comprising alectinib hydrochloride equivalent to about 150 mg alectinib in free base form.
  • the formulation is in a dosage form comprising alectinib hydrochloride equivalent to about 150 mg alectinib in free base form, about 33.7 mg lactose (as monohydrate) and about 6 mg sodium (as sodium lauryl sulfate) per dosage form.
  • the composition is in the form of a unit dosage form comprising alectinib hydrochloride equivalent to about 20 mg alectinib in free base form.
  • compositions as described above can be prepared by a process which comprises bringing the active compound into association with the carrier, for example by admixture.
  • the formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • the composition may be administered orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically and locally (intravenous drip, powder, ointment, gel or cream) and through inhalation (oral or nose spray).
  • parenterally intravenously, intramuscularly, subcutaneously
  • intracisternally intravaginally, intraperitoneally, intravesically and locally (intravenous drip, powder, ointment, gel or cream) and through inhalation (oral or nose spray).
  • oral or nose spray oral or nose spray
  • Examples of the dosage form thereof include tablet, capsule, granule, powder, pill, aqueous and nonaqueous oral solution and suspension, and parenteral solution put in small containers for a unit dose.
  • the dosage form may be designed so as to adapt to various methods for administrating a formulation including a controlled release formulation to be subcutaneously grafted.
  • the dosage form is preferably for oral administration by tablets, capsules, granules, suspension or powder formulation.
  • the dosage form is a capsule or oral suspension.
  • the "oral formulation” refers to a formulation that can be orally administered.
  • the oral administration refers to swallowing a formulation so as to enter the gastrointestinal tract and an active ingredient is mainly absorbed through the intestinal tract.
  • the oral formulation include solid formulations such as a tablet, a capsule, a solution, a powder, a lozenge, a chewable agent, a granule, a gel, a film agent and a spray and liquid formulations.
  • the liquid formulation include a suspension, a solution, syrup and an elixir. Such a formulation can be used as filler in soft or hard capsules.
  • a carrier for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or appropriate oil, and one or more emulsifiers and/or a suspending agent are used.
  • a liquid formulation can be also prepared by dissolving a unit-dose solid medicinal agent, for example, dissolving a pharmaceutical composition in a package into a carrier such as water.
  • the dosage of the active ingredient may vary depending upon the symptom, age, body weight, relative health condition, other medication, administering method, etc.
  • a generally effective amount of active ingredient (the compound or a salt thereof of the present invention represented by formula (I)) to a patient (a warm-blooded animal, particularly a human) orally administered is preferably 0.001 to 1000 mg and further preferably 0.01 to 300 mg per body weight (1 kg) per day.
  • the dosage thereof used per day preferably falls within the range of 1 to 1500 mg per adult patient having an ordinary body weight.
  • the amount thereof used is preferably 0.001 to 1000 mg and further preferably 0.01 to 300 mg per body weight (1 kg) per day. It is desirable that the amount thereof used is administered once per day or administered depending upon the symptom by dividing the amount used into several portions.
  • the alectinib, or pharmaceutically acceptable salt thereof is administered twice a day.
  • the total daily dose of alectinib is preferably from 1 to 1500 mg, 100 to 1400 mg, 200 to 1300 mg, 400 to 1200 mg, 600 to 1500 mg, 700 to 1500 mg, 800 to 1500 mg, 900 to 1500 mg, 600 to 1200 mg, 700 to 1200 mg, 800 to 1200 mg, 900 to 1200 mg, 1000 to 1200 mg.
  • the total daily dose of alectinib may be adjusted based on the body weight of the subject.
  • the subject is >40 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 600 and 1500 mg.
  • the subject is >35 to ⁇ 40 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 400 and 1000 mg.
  • the subject is >30 to ⁇ 35 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 300 and 800 mg.
  • the subject is >25 to ⁇ 30 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 300 and 700 mg.
  • the subject is >20 to ⁇ 25 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 250 and 600 mg.
  • the subject is >15 to ⁇ 20 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 200 and 500 mg.
  • the subject is >10 to ⁇ 15 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 150 and 400 mg.
  • the subject is >7.5 to ⁇ 10 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 100 and 300 mg.
  • the subject is >5 to ⁇ 7.5 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 75 and 250 mg.
  • the subject is >3.5 to ⁇ 5 kg and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 50 and 200 mg.
  • the total daily dose of alectinib may be adjusted based on the formulation of the pharmaceutical composition. For example, a correction factor of 1 .67 may be applied to an intact capsule dose in order to obtain an oral suspension dose that ensures a similar exposure.
  • the pharmaceutical composition is formulated as a capsule and the subject is >40 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 1000 and 1400 mg, preferably 1200 mg total, even more preferably 600 mg BID.
  • the pharmaceutical composition is formulated as a capsule and the subject is >35 to ⁇ 40 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 700 and 900 mg, preferably 760 mg total, even more preferably 380 mg BID.
  • the pharmaceutical composition is formulated as a capsule and the subject is >30 to ⁇ 35 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 600 and 800 mg, preferably 680 mg total, even more preferably 340 mg BID.
  • the pharmaceutical composition is formulated as a capsule and the subject is >25 to ⁇ 30 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 500 and 700 mg, preferably 600 mg total, even more preferably 300 mg BID.
  • the pharmaceutical composition is formulated as a capsule and the subject is >20 to ⁇ 25 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 500 and 600 mg, preferably 540 mg total, even more preferably 270 mg BID.
  • the pharmaceutical composition is formulated as a capsule and the subject is >15 to ⁇ 20 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 400 and 500 mg, preferably 460 mg total, even more preferably 230 mg BID.
  • the pharmaceutical composition is formulated as a capsule and the subject is >10 to ⁇ 15 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 300 and 400 mg, preferably 380 mg total, even more preferably 190 mg BID.
  • the pharmaceutical composition is formulated as a capsule and the subject is >7.5 to ⁇ 10 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 200 and 300 mg, preferably 280 mg total, even more preferably 140 mg BID.
  • the pharmaceutical composition is formulated as a capsule and the subject is >5 to ⁇ 7.5 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 150 and 250 mg, preferably 200 mg total, even more preferably 100 mg BID.
  • the pharmaceutical composition is formulated as a capsule and the subject is >3.5 to ⁇ 5 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 100 and 200 mg, preferably 160 mg total, even more preferably 80 mg BID.
  • the pharmaceutical composition is formulated as a suspension and the subject is >40 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 600 and 800 mg, preferably 718 mg total, even more preferably 359 mg BID.
  • the pharmaceutical composition is formulated as a suspension and the subject is >35 to ⁇ 40 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 400 and 500 mg, preferably 456 mg total, even more preferably 228 mg BID.
  • the pharmaceutical composition is formulated as a suspension and the subject is >30 to ⁇ 35 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 350 and 450 mg, preferably 408 mg total, even more preferably 204 mg BID.
  • the pharmaceutical composition is formulated as a suspension and the subject is >25 to ⁇ 30 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 300 and 400 mg, preferably 360 mg total, even more preferably 180 mg BID.
  • the pharmaceutical composition is formulated as a suspension and the subject is >20 to ⁇ 25 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 280 and 380 mg preferably 324 mg total, even more preferably 162 mg BID.
  • the pharmaceutical composition is formulated as a suspension and the subject is >15 to ⁇ 20 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 220 and 320 mg, preferably 276 mg total, even more preferably 138 mg BID.
  • the pharmaceutical composition is formulated as a suspension and the subject is >10 to ⁇ 15 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 180 and 280 mg, preferably 228 mg total, even more preferably 114 mg BID.
  • the pharmaceutical composition is formulated as a suspension and the subject is >7.5 to ⁇ 10 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 100 and 200 mg, preferably 168 mg total, even more preferably 84 mg BID.
  • the pharmaceutical composition is formulated as a suspension and the subject is >5 to ⁇ 7.5 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 80 and 180 mg, preferably 120 mg total, even more preferably 60 mg BID.
  • the pharmaceutical composition is formulated as a suspension and the subject is >3.5 to ⁇ 5 kg, and the total daily dose of alectinib, or pharmaceutically acceptable salt thereof, is between 50 and 150 mg, preferably 96 mg total, even more preferably 48 mg BID.
  • the alectinib dosage can be reduced in increments in order to mitigate side effects.
  • side effects can include any of the following or a combination thereof: pneumonitis, pneumonia, appendicitis, acute myocardial infarction, nausea, malaise, asthenia, fatigue, tinnitus, vomiting, weight increase, decreased appetite, diarrhoea, constipation, headache, cough, rash, anaemia, dyspnoea, oedema peripheral, dysgeusia, blood creatinine increase, neutropenia, neutrophil count decrease, white blood cell count decrease, blood creatine phosphokinase increase, aspartate aminotransferase increase, alanine aminotransferase increase, hyperbilirubinaemia, COVID-19, myalgia, blood alkaline phosphatase increase, and/or product dose omission issue.
  • the dose may be reduced by approximately 25% of the starting dose.
  • a starting dose of 600 mg BID may be reduced to 450 mg BID.
  • the dose may be further reduced by approximately 33%.
  • a total daily dose of 600 mg BID may be initially reduced to 450 mg BID, and may be further reduced to 300 mg BID.
  • Treatment may continue until completion of treatment period, disease recurrence, unacceptable toxicity, withdrawal of consent, or death.
  • the treatment period may be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 17, 19, 20, 21 , 22, 23, 24, 36, 48, or 60 months. In one embodiment, the treatment period is 6 months or 12 months or 18 months or 24 months.
  • tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer cancer
  • cancer cancerous
  • tumor tumor necrosis factor
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Included in this definition are benign and malignant cancers.
  • eye stage cancer or “early stage tumour” is meant a cancer that is not invasive or metastatic or is classified as a Stage 0, I, or II cancer.
  • cancer examples include, but are not limited to, carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumours (including carcinoid tumours, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies.
  • carcinoma lymphoma
  • blastoma including medulloblastoma and retinoblastoma
  • sarcoma including liposarcoma and synovial cell sarcoma
  • neuroendocrine tumours including carcinoid tumours, gastrinoma, and islet cell cancer
  • mesothelioma including schwannoma (including acous
  • squamous cell cancer e.g., epithelial squamous cell cancer
  • lung cancer including small-cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer (including metastatic breast cancer), colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, Merkel cell cancer, mycoses fungoids, testicular cancer, esophageal cancer, tumours of the biliary tract, as well as head and neck cancer and hematological malignancies.
  • SCLC small-cell lung
  • NSCLC includes squamous NSCLC and non-squamous NSCLC, adenocarcinoma, and large cell carcinoma.
  • the cancer is ALK-positive.
  • ALK-positive or “ALK+” is meant that the cancer expresses anaplastic lymphoma kinase.
  • expression is caused by gene rearrangements leading to fusion of ALK with other genes, such as EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A, and BIRC6.
  • the cancer is an anaplastic lymphoma kinase (ALK) fusionpositive solid tumour or central nervous system tumour.
  • ALK anaplastic lymphoma kinase
  • Determination of ALK positivity may be performed at sites by an FDA-approved and CE- marked test or by central Ventana ALK IHC.
  • ALK positivity e.g., reverse transcription-PCR
  • ALK positivity for fusions may be determined in tissue samples using assays such as fluorescence in situ hybridization, IHC, PCR, and sequencing. As tissue sampling is difficult and tissue biopsy sample sizes from cancer patients are very small, testing of several important biomarkers is challenging. Plasma ALK assays analysing circulating tumour nucleic acids will enable more patients with cancer to be tested for ALK fusions and may also be used to monitor changes in ALK rearrangements during ALK inhibitor treatment.
  • the Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Arlington, AZ, USA) is used to determine ALK positivity.
  • the subject does not demonstrate resistance to ALK inhibitors.
  • the subject does not comprise a mutation conferring resistance to ALK inhibitors.
  • the subject does not exhibit a biomarker associated with resistance to ALK inhibitors.
  • Molecular mechanisms (including mutations and associated biomarkers) of resistance to ALK inhibitors may include: secondary mutations in the ALK gene (e.g., gatekeeper mutation), increased copy number of the ALK gene, increased expression of ALK mRNA, and ALK- independent resistance mechanisms through activation of other oncogenic genes and pathways such as EGFR, cKIT, MET or KRAS.
  • the ALK fusion-positive tumour is an ALK fusion-positive solid tumour.
  • the ALK fusion-positive tumour is an ALK fusion-positive CNS tumour.
  • the ALK fusion-positive solid tumour or central nervous system tumour is a neuroblastoma, renal cell carcinoma, papillary or medullary thyroid cancer, skin tumour, such as Spitz tumour or melanoma, inflammatory myofibroblastic tumour, soft tissue sarcoma, such as undifferentiated or rhabdomyosarcoma, osteosarcoma, malignant peripheral nerve sheath tumour, anaplastic large cell lymphoma, ganglioglioma, or glioma (low- or high-grade).
  • the ALK fusion-positive solid tumour or central nervous system tumour is an inflammatory myofibroblastic tumour, high-grade glioma, renal cell carcinoma, or anaplastic large cell lymphoma.
  • the ALK fusion-positive solid tumour or central nervous system tumour is an inflammatory myofibroblastic tumour or high-grade glioma.
  • the ALK fusion-positive solid tumour or central nervous system tumour comprises a mutation wherein ALK is fused to KIFC, TPM3, CLTC, PLEKHA7, DCTN1 or HNRNPA3.
  • the ALK fusion-positive solid tumour is a non-metastatic (i.e. primary) tumour. In some embodiments, the ALK fusion-positive solid tumour is a metastatic tumour.
  • the ALK fusion-positive central nervous system tumour is a non- metastatic (i.e. primary) or metastatic tumour.
  • the ALK fusion-positive central nervous system tumour is a non-metastatic tumour.
  • the subject has a histologically confirmed diagnosis of CNS or solid tumours harbouring ALK gene fusions as determined locally by an appropriately validated assay performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalently-accredited diagnostic laboratory.
  • CLIA Clinical Laboratory Improvement Amendments
  • tissueologically confirmed refers to determination by microscopic examination of tissue that has been excised by biopsy or surgical resection.
  • the alectinib, or pharmaceutically acceptable salt thereof is administered as adjuvant therapy.
  • adjuvant and/or “adjuvant setting” refers to a therapy given in addition to the primary or initial therapy, for example following resection of a tumour.
  • tumour refers to the surgical removal of all or part of a tumour.
  • the tumour may be removed with a surrounding amount of normal, healthy tissue (surgical margin).
  • surgical margin Preferably, the subject has a negative surgical margin.
  • resection is by lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.
  • resection is not by segmentectomy or wedge resection.
  • the subject has not undergone prior adjuvant radiotherapy. In some embodiments, the subject has not undergone prior adjuvant therapy.
  • alectinib is administered as adjuvant therapy following complete resection of a tumour.
  • alectinib is administered as adjuvant treatment following tumour resection in patients with ALK+ tumours as detected by an FDA-approved test.
  • tumour-adjuvant refers to treatment delivered before resection of tumour, such as to help reduce the size of a tumour.
  • alectinib is not administered in the neo-adjuvant setting.
  • the subject has not been administered alectinib prior to resection of a tumour.
  • the subject has not had prior exposure to ALK inhibitors.
  • the subject has received radiotherapy prior to resection of a tumour.
  • resection occurs between 1 to 16 weeks prior to treatment with alectinib, such as 4 to 12 weeks, 6 to 10 weeks, 4 to 6 weeks, 6 to 8 weeks, or 8 to 12 weeks prior to treatment with alectinib.
  • resection may occur at 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, or 16 weeks prior to treatment with alectinib.
  • resection occurs between 4 to 12 weeks prior to treatment with alectinib.
  • the invention provides a method of treating a subject suffering from an ALK fusion-positive solid tumour or central nervous system tumour, the method comprising administering to the subject a therapeutically effective amount of alectinib, wherein the subject is aged ⁇ 18 years.
  • the invention provides methods for treating or delaying progression of an ALK fusion-positive solid tumour or central nervous system tumour in a subject comprising administering to the subject a therapeutically effective amount of alectinib, wherein the subject is aged ⁇ 18 years.
  • the invention provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of treating an ALK fusion-positive solid tumour or central nervous system tumour in a subject, wherein the subject is aged ⁇ 18 years.
  • the invention provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of treating or delaying progression of an ALK fusion-positive solid tumour or central nervous system tumour in a subject, wherein the subject is aged ⁇ 18 years.
  • the invention provides a method of preventing ALK fusion-positive solid tumour or central nervous system tumour recurrence in a subject, comprising administering to a subject a therapeutically effective amount of alectinib, or a pharmaceutically acceptable salt thereof, wherein the subject is aged ⁇ 18 years.
  • the invention provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of preventing ALK-positive solid tumour or central nervous system tumour recurrence in a subject, wherein the subject is aged ⁇ 18 years.
  • the alectinib is administered as adjuvant therapy following complete resection of tumour.
  • resection refers to a surgery taking place before alectinib treatment.
  • the present invention does not relate to methods of surgery performed on the human body.
  • alectinib is for use in the treatment of ALK fusion-positive solid or CNS tumours in a subject for whom prior treatment has proven to be ineffective (i.e. , relapsed or refractory), or for whom there is no satisfactory treatment, wherein the subject is aged ⁇ 18 years.
  • the subject has had prior treatment for an ALK fusion-positive solid tumour or central nervous system tumour.
  • the terms "patient” or “subject” are used interchangeably and refer to any single animal, more preferably a mammal (including such non-human animals as, for example, dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates) for which treatment is desired.
  • the patient herein is a human.
  • the subject is pediatric.
  • the subject is adolescent.
  • the subject is aged less than 18 years.
  • the subject is aged less than 12 years.
  • the subject is aged less than 6 years.
  • the subject is aged less than 2 years.
  • the subject is aged >2 to ⁇ 6 years.
  • the subject is aged >6 to ⁇ 12 years.
  • the subject is aged >12 to ⁇ 18 years.
  • the subject is aged ⁇ 18 years, such as ⁇ 2 years, >2 to ⁇ 6 years, >6 to ⁇ 12 years or >12 to ⁇ 18 years, at the start of treatment.
  • treatment refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • compositions of the present invention are used to delay development of a disease or to slow the progression of a disease.
  • “Individual response” or “response” can be assessed using any endpoint indicating a benefit to the individual, including, without limitation, (1) inhibition, to some extent, of disease progression (e.g., cancer progression), including slowing down and complete arrest; (2) a reduction in tumour size; (3) inhibition (i.e. , reduction, slowing down or complete stopping) of cancer cell infiltration into adjacent peripheral organs and/or tissues; (4) inhibition (i.e.
  • metatasis metatasis
  • relief, to some extent, of one or more symptoms associated with the disease or disorder e.g., cancer
  • decreased mortality at a given point of time following treatment
  • an “effective response” of a patient or a patient’s “responsiveness” to treatment with a medicament and similar wording refers to the clinical or therapeutic benefit imparted to a patient at risk for, or suffering from, a disease or disorder, such as cancer.
  • a disease or disorder such as cancer.
  • such benefit includes any one or more of: extending survival (including overall survival, progression-free survival and disease-free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.
  • An “objective response” refers to a measurable response, including complete response (CR) or partial response (PR).
  • the “objective response rate (ORR)” refers to the proportion of patients with a complete response (CR) or partial response (PR) on two consecutive occasions > 4 weeks apart, as determined by the blinded independent central review (BICR) according to Response Assessment in Neuro-Oncology (RANO) for patients with primary CNS tumors, RECIST v1.1 for patients with extracranial tumors, and International Neuroblastoma Response Criteria (INRC) for patients with neuroblastoma.
  • partial response refers to a decrease in the size of one or more tumours or lesions, or in the extent of cancer in the body, in response to treatment and is defined according to RECIST v1.1 , INRC or RANO criteria set out below (see Examples).
  • PR refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD.
  • “Sustained response” refers to the sustained effect on reducing tumour growth after cessation of a treatment.
  • the tumour size may remain to be the same or smaller as compared to the size at the beginning of the administration phase.
  • the sustained response has a duration at least the same as the treatment duration, at least 1.5X, 2. OX, 2.5X, or 3. OX length of the treatment duration, or longer.
  • “reducing or inhibiting cancer relapse” means to reduce or inhibit tumour or cancer relapse or tumour or cancer progression.
  • cancer relapse and/or cancer progression include, without limitation, cancer metastasis.
  • stable disease or “SD” refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started.
  • DOR duration of response
  • time to response is defined as the time from the first dose of alectinib to the first documentation of objective response (either a CR or a PR), as determined by BICR and the investigator according to RANO for patients with primary CNS tumours, RECIST v1.1 for extra cranial tumors, and INRC for neuroblastoma.
  • CBR clinical benefit rate
  • progression-free survival refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse. Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.
  • PFS is defined as defined as the time from first dose of alectinib to the first occurrence of disease progression or death from any cause whichever occurs first, as determined by blinded independent central review and the investigator according to RANO for patients with primary CNS tumors, RECIST v1.1 scale for extracranial tumors, and INRC for neuroblastoma.
  • DFS disease-free survival
  • overall survival refers to defined as the time from the first dose of alectinib to the date of death due to any cause.
  • extending survival is meant increasing overall or progression -free survival in a treated patient relative to an untreated patient (i.e. relative to a patient not treated with the medicament), and/or relative to a patient treated with an approved anti-tumour agent.
  • delay progression of a disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.
  • preventing means to reduce the likelihood of disease recurrence as compared to treatment with platinum-based chemotherapy.
  • the “hazard ratio” is the probability of an event in a treatment group relative to the control group probability over a unit of time. For example, a hazard ratio of 0.16 means that alectinib provides 84% risk reduction in terms of a particular event compared to the control group.
  • administration of alectinib increases the subject's likelihood of having an objective response (e.g., a CR), extends the subject's PFS, extends the subjects DFS, extends the subject's OS, and/or extends the subject's DOR as compared to no treatment or treatment without alectinib.
  • alectinib increases the subject's likelihood of having an objective response as compared to no treatment or treatment without alectinib.
  • alectinib increases the subject's likelihood of having a CR as compared to no treatment or treatment without alectinib.
  • alectinib extends the subject's PFS as compared to no treatment or treatment without alectinib. In some embodiments, alectinib extends the subject's DFS as compared to no treatment or treatment without alectinib. In some embodiments, alectinib extends the subject's OS as compared to no treatment or treatment without alectinib. In some embodiments, alectinib extends the subject's DOR as compared to no treatment or treatment without alectinib. In some embodiments, administration of alectinib to the subject extends the subject's ORR as compared to no treatment or treatment without alectinib.
  • benefit from treatment with alectinib includes an increase in OS. In some embodiments, benefit from treatment with alectinib includes an increase in DFS.
  • administration of alectinib to the subject extends the subject's DFS as compared to no treatment or treatment without alectinib.
  • administration of alectinib to the subject may extend the subject's DFS by from about 1 month to about 5 months, by from about 2 months to about 4 months, by from about 2.1 months to about 3.9 months, by from about 2.5 months to about 3.5 months, or by from about 2.8 months to about 3.4 months as compared to administration of the platinum-based chemotherapy without alectinib (e.g., by about 1 month, 1.1 months, 1.2 months, 1.3 months, 1.4 months, 1.5 months, 1.6 months, 1.7 months, 1.8 months, 1.9 months, 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3. 7 months, 3.8
  • administration of alectinib to the subject reduces the subject’s likelihood of disease recurrence as compared to no treatment or treatment without alectinib.
  • administration of alectinib to the subject reduces the subject’s likelihood of disease recurrence by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100% as compared to no treatment or treatment without alectinib.
  • administration of alectinib to the subject reduces the subject’s likelihood of disease recurrence by about 60 to 90%, such as 75% to 85% as compared to no treatment or treatment without alectinib.
  • the method further includes administering to the patient an effective amount of a second therapeutic agent.
  • the second therapeutic agent is selected from the group comprising chemotherapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, molecular targeting agents, or the like.
  • chemotherapeutic agents include an alkylating agent, a platinum formulation, a metabolic antagonist, a topoisomerase inhibitor, an anticancer antibiotic substance, and an anticancer agent derived from plant, etc.
  • alkylating agent include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustin hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustin, estramustin sodium phosphate, triethylene melamine, carmustin, lomustin, streptozocin, pipobroman, etoglucid, altretamin, ambamustin, dibrospidium hydrochloride, fotemustin, prednimustin, pumitepa, rib
  • platinum formulation examples include carboplatin, cisplatin, miboplatin, nedaplatin, and oxaliplatin.
  • examples of the "metabolic antagonist” include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabin, cytarabin, cytarabin ocfosfate, ancitabin hydrochloride, 5-Fll based pharmaceuticals (for example, fluorouracil, tegafur, UFT, doxifluridin, carmofur, galocitabin, and emitefur, etc.), aminopterin, calcium leucovorin, tabloid, butocin, calcium folinate, calcium levofolinate, cladribin, emitefur, fludarabin, gemcitabin, hydrocycarbamide, pentostatin, piritrexim, idoxuridin, mitoguazon, ti
  • Topoisomerase I inhibitor for example, irinotecan and topotecan, etc.
  • topoisomerase II inhibitor for example, sobuzoxan, etc.
  • anticancer antiobiotic material examples include anthracycline-based anticancer agent (doxorubicin hydrochloride, daunorubicin hydrochloride, acrarubicin hydrochloride, pirarubicin hydrochloride, and epirubicin hydrochloride, etc.), actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, neocarzinostatin, mitramycin, sarcomycin, carzinophyllin, mitotam, zorubicin hydrochloride, mitoxantrone hydrochloride, and idarubicin hydrochloride, etc.
  • anticancer agent derived from a plant examples include vincalkaloid anticancer agent (vinblatin sulfate, vincristin sulfate, andêtin sulfate), taxan anticancer agent (paclitaxel and docetaxel, etc), etoposide, etoposide phosphate, teniposide, and vinorelbin.
  • hormones examples include adrenocortical hormone-based pharmaceuticals (for example, dexamethasone, prednisolone, betamethasone, and triamcinolone, etc.). Of these, prednisolone is preferable.
  • immunotherapeutic agents examples include picibanil, krestin, sizofiran, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, and procodazole.
  • the “molecular targeting agents” include a “pharmaceutical which inhibits the function of a cell proliferation factor and its receptor," or the like.
  • the "cell proliferation factor” can be any substance if only it can promote proliferation of a cell, and the included are a peptide having molecular weight of 20,000 or less which exhibits its activity at low concentration via binding to a receptor. Specific examples thereof include (1) EGF (epidermal growth factor) or a substance which has substantially the same activity [e.g., EGF, heregulin (HER2 ligand) etc.], (2) insulin or a substance which has substantially the same activity [e.g., insulin, IGF (insulin-like growth factor)-"!
  • FGF fibroblast growth factor
  • FGF fibroblast growth factor
  • a substance which has substantially the same activity e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10 etc.
  • VEGF vascular endothelial growth factor
  • CSF colony stimulating factor
  • EPO erythropoietin
  • IL-2 interleukin-2
  • NGF nerve growth factor
  • TGFp transforming growth factor P
  • HGF hepatocyte growth factor
  • the "receptor for cell proliferation factor” can be any receptor if only it has an ability of binding to the cell proliferation factor described above. Specific examples thereof include EGF receptor, heregulin receptor (HER2), insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2, HGF receptor (c-met), VEGF receptor, and SCF receptor (c-kit). Examples of the "pharmaceuticals which inhibit the activity of cell proliferation factor” include herceptin (HER2 antibody), GLEEVEC (c-kit, abl inhibitor), and Iressa (EGF receptor inhibitor).
  • a pharmaceutical which inhibits the activity of a plurality of cell proliferation factors even as a single formulation, or a pharmaceutical which blocks cellular signal produced by cell proliferation factor are also included.
  • L-asparaginase, aceglaton, procarbazine hydrochloride, protoporphyrin ⁇ cobalt complex, mercury hematoporphyrin ⁇ sodium, differentiation-promoting agent (e.g. retinoid, vitamin D, etc.), angiogenesis inhibitor, and a- blocker (e.g., tamsulosin hydrochloride, etc.), etc. can be also used.
  • the study consists of three parts, all enrolling paediatric participants with solid or CNS tumours with known ALK fusion for whom prior treatment has proven to be ineffective or for whom there is no satisfactory treatment available:
  • Part 1 dose confirmation and safety run-in: to identify the RP2D for paediatric participants, achieving the exposure observed in the adult population o
  • This portion will consist of a safety run-in with a minimum of 6 participants (up to approximately 18 participants) to assess the safety, tolerability, and pharmacokinetics of alectinib in the paediatric population.
  • the initial paediatric dose will be assessed and refined by modelling and simulation prospectively.
  • Alectinib will be administered orally or via feeding tube to participants BID on Days 1 -28 of each 28-day cycle. All participants will be closely monitored for adverse events (regardless of relationship to study drug) throughout the study and for at least 28 days after the final dose of study treatment or until initiation of a new anti-cancer therapy, whichever occurs first.
  • tumour tissue acquired at diagnosis or at the time of relapse (regardless of the number of lines of treatment) is required prior to participant enrolment either by local testing or central testing at Foundation Medicine, Inc.
  • Local testing of tumour tissue must be performed using a Sponsor-approved test (e.g., nextgeneration sequencing [NGS] assay) at a Clinical Laboratory Improvement Amendments (CLIA) or equivalently certified laboratory.
  • NGS nextgeneration sequencing
  • CLIA Clinical Laboratory Improvement Amendments
  • an archival tumour tissue from diagnosis or, preferably, from relapsed disease preferably from the same tissue block and unless medically contraindicated
  • Exceptions for retrospective central testing may be granted at the discretion of the Medical Monitor.
  • Participants who do not meet the criteria for participation in this study may qualify for one re-screening opportunity (for a total of two screenings per participant) at the investigator's discretion. Participants are not required to re-sign the consent form if they are re-screened within 28 days after previously signing the consent form. The investigator will record reasons for screen failure in the screening log.
  • An iDMC will be established for safety monitoring at predefined study milestones and approximately every 6 months.
  • the dose confirmation portion of the study will consist of a safety run-in assessment combined with prospective PK assessment.
  • the starting dose is determined by popPK model to achieve the target exposure in the adults. It is anticipated that a minimum of approximately 6 participants up to approximately 18 participants will be enrolled in Part 1. Participants will receive fixed doses of alectinib based on body weight ranges).
  • the investigator Owing to the limitations of predicting exposure in children who are ⁇ 2 years old, before enrolment of participants ⁇ 2 years old, the investigator must discuss a participant’s case with the Medical Monitor until at least 3 participants who are > 2-6 years old have completed one cycle of treatment.
  • the first participant enrolled must complete at least 8 days of treatment without a DLT before subsequent participants can enrol. If a dose adjustment is required because of toxicity, the same approach will be taken for the first participant at the new dose level. Participants will be closely monitored for adverse events during a DLT assessment window of one cycle (28 days).
  • DLT non-evaluable participants Participants who discontinue from the study prior to completing the DLT assessment window or who complete ⁇ 80% (i.e., ⁇ 44 doses) of the prescribed therapy for that cycle for reasons other than a DLT will be considered non-evaluable. DLT non-evaluable participants will be replaced, unless the Medical Monitor determines that replacement is not necessary for a dose adjustment decision. The Medical Monitor will review all participants who take prohibited therapies, foods, or supplements or who receive supportive care during the DLT assessment window that would confound the evaluation of DLTs (not including supportive care described below as part of the DLT definition) to determine DLT evaluability and whether such participants will be replaced.
  • Participants who experience a DLT during the assessment window are not permitted to continue study drug at their current dose.
  • the investigator should use guidance provided to determine whether a participant should permanently discontinue study drug or withhold study drug until adequate resolution of the toxicity.
  • Alectinib pharmacokinetics will be monitored prospectively to ensure that the observed exposures of alectinib are within the predicted range.
  • the popPK model (and ultimately PBPK when sufficient data become available) will be continuously updated with the emerging PK data from all enrolled paediatric participants, and the dose will be adjusted if required to ensure exposures reach the target range.
  • Dose level escalation or de-escalation (if required) will be decided following retrospective review of PK and safety data at the end of the DLT assessment window
  • the paediatric RP2D for each body weight category will be confirmed if the following occur:
  • the exposure observed at steady state is in compliance with the exposure ranges of 3150-12800 ng*h/mL for alectinib and 1490-5300 ng*h/mL for M4 (its active metabolite) in at least 6 paediatric participants enrolled, including a minimum of 3 participants who are ⁇ 2 years old. These 3 participants can be counted as part of the total 6 paediatric participants if enrolment allows or can be enrolled at a later time point when RP2D is assessed in participants > 2 years old. More than 3 participants who are ⁇ 2 years old may be required depending on the close monitoring of the PK profiles.
  • the enrolment of children > 2 years old in the initial expansion portion of the study may commence on the basis of the established RP2D for children > 2 years old. No more than one (>1) DLT is observed in the first 3 participants enrolled treated at the same dose level (> 2 years old), and in the additional 3 participants subsequently enrolled and treated at the same dose level (including a minimum of 3 participants ⁇ 2 years old). If more than one DLT occurs among the first 6 participants, a revised dose level will be decided in light of available PK data.
  • the maximum dose administered will be 600 mg BID (regardless of dose level or participant body weight), corresponding to the adult recommended dose. Following the first cycle, participants will undergo DLT assessment.
  • any one of the following events will be considered a DLT if it occurs during the DLT assessment window and is assessed by the investigator to be related or possibly related to alectinib (rules for attributing causality are defined below in ‘Adverse events’).
  • Adverse events identified as DLTs, as defined below, must be reported to the Sponsor within 24 hours.
  • Grade 4 neutropenia (ANC ⁇ 500 cells/mm 3 which is equivalent to ANC ⁇ 0.5 x 10 9 /L) lasting at least 7 days
  • Febrile neutropenia ANC ⁇ 1000 cells/mm 3 (which is equivalent to ANC ⁇ 1 x 10 9 /L) with a single temperature of > 38.3°C (101 °F) or a sustained temperature of >38°C (100.4°F) for more than 1 hour Grade 4 anaemia
  • Grade 4 thrombocytopenia i.e., platelet count ⁇ 25.0 x 10 9 /L
  • Grade 3 thrombocytopenia associated with clinically significant bleeding or any thrombocytopenia requiring platelet transfusion.
  • the post-surgical platelet threshold for platelets transfusion could be higher. In that case, the investigator should contact and discuss with the Medical Monitor prior to reporting.
  • Grade > 3 non-hematologic toxicity with the following exceptions: o Grade 3 nausea, vomiting, or diarrhoea that responds to SOO therapy in ⁇ 3 days o Grade 3 fatigue lasting ⁇ 3 days o Grade 3 laboratory abnormalities that are asymptomatic and are considered by the investigator not to be clinically significant
  • Participants who experience a DLT during the assessment window are not permitted to continue drug at their current dose.
  • the investigator should use guidance provided to determine whether a participant should permanently discontinue study drug or withhold study drug until adequate toxicity resolution. If a participant resumes treatment, the starting dose will be at a reduced dose.
  • CNS central nervous system
  • INRC International Neuroblastoma Response Criteria
  • RANO Response Assessment in Neuro-Oncology
  • RECIST v1. 1 Response Evaluation Criteria in Solid Tumours, Version 1.1.
  • the decision to expand in Part 3 will take into account the safety and tolerability of the regimen in addition to the number of responders, as defined above.
  • a temporary dosing halt and enrolment pause will be applied if any Grade 5 toxicities attributable to study drug occur during the initial dose confirmation and expansion phases of the study. All participants must stop dosing unless evidence of clinical benefit is demonstrated (e.g., decreased tumour-related symptoms, reduced tumour burden, or evidence of stable disease) and has already been observed in the investigator’s opinion.
  • Dosing and enrolment may not resume in the participants until the iDMC recommends resumption of dosing and enrolment after review of the adverse event(s).
  • the end of this study is defined as the date when the last participant, last visit occurs (LPLV) or 5 years after the last participant is enrolled and treated with study drug, whichever occurs first.
  • LPLV last visit occurs
  • the completion of the study i.e. , the last visit
  • the primary analysis will be conducted after a minimum of 30 paediatric participants treated at the RP2D across Parts 1 , 2 and 3 and a minimum of 10 children with primary CNS tumours and 10 children with solid tumours, treated at the RP2D have been enrolled and followed for at least 6 months. Participants
  • Participant eligibility will be assessed during a 28-day screening period. Signed informed consent and assent must be obtained prior to enrolment.
  • Disease status prior treatment proven to be ineffective (i.e., relapsed or refractory), or for whom there is no satisfactory treatment available. Disease should be measurable and evaluable as defined by RECIST v1.1 for solid tumours, or RANO ⁇ bone marrow criteria for primary CNS tumours or INRC criteria (as appropriate, see below).
  • - Available tumour tissue for submission to the Sponsor from active disease, obtained subsequent to last anti-cancer therapy regimen administered and obtained prior to study enrolment, or willingness to undergo a core or excisional biopsy sample collection prior to enrolment o Participants must submit a tissue block or 5-10 slides containing unstained, freshly cut, serial sections available for submission (preferably from the same tissue block as used for local testing if ALK status was determined locally). o Fine-needle aspirations, brush biopsies, bone metastasis samples, and lavage samples are not acceptable. o Participants with ⁇ 5 slides available, or whose tumour tissue does not otherwise meet criteria above, may be eligible for study entry at the discretion of the investigator following advice from the Medical Monitor.
  • Bone marrow metastatic disease as defined by the following laboratory parameters obtained within 28 days prior to initiation of study drug: o Hemoglobin > 8 g/dL (transfusion allowed) o Peripheral ANC > 1 .00 x 10 9 /L and no granulocyte colony-stimulating factor (G- CSF) support for at least a duration of > 5 half-lives of the G-CSF product from last injection o Platelet count > 75 x 10 9 /L (unsupported for 72 hours) o If bone marrow metastatic disease:
  • Platelets not known to be refractory to platelets transfusions Willingness and ability (participant and/or caregiver) to complete clinical outcome assessments throughout the study using either electronic, paper, or interviewer methods
  • Females of childbearing potential agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined below: o
  • a female is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (> 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e.
  • Childbearing potential may be adapted for alignment with local guidelines or regulations.
  • Females of childbearing potential must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation.
  • Examples of contraceptive methods with a failure rate of ⁇ 1 % per year include bilateral tubal ligation, male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
  • a barrier method may be used as the second contraceptive method with the use of spermicide.
  • males who are not surgically sterile agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm, as defined below: o
  • males who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of > 1 % per year during the treatment period and for at least 3 months after the final dose of alectinib. Males must refrain from donating sperm during this same period.
  • Allogeneic (non-autologous) bone marrow or stem cell transplant or any stem cell infusion including donor leukocyte infusion or boost infusion: ⁇ 84 days after infusion and/or on chronic immunosuppressive drug.
  • ALT or AST > 3 x ULN (> 5 x ULN for participants with concurrent liver metastasis)
  • Bilirubin > 1.5 x ULN for age (or > 2.5 x ULN if liver infiltrated or metastases)
  • Creatinine > 1.5 ULN for age or an estimated glomerular filtration rate (GFR) ⁇ 60 mL/min/1.73m 2 GFR based on the Schwartz equation (Mian and Schwartz 2017) or as per institutional guidelines
  • GFR estimated glomerular filtration rate
  • NCI CTCAE v5.0 Grade > 3 toxicities attributed to any prior therapy such as radiotherapy (excluding alopecia), which have not shown improvement and are strictly considered to interfere with alectinib o
  • Co-administration of anti-cancer therapies other than those administered in this study o Active hepatitis B or C virus (HBV, HBC) or known HIV positivity or AIDS- related illness o Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of
  • Neutropenic fever considered infection-related within 72 hours prior to dosing o Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of alectinib
  • the investigational medicinal product (IMP) for this study is alectinib.
  • the alectinib drug substance used for the manufacture of the drug product is milled hydrochloride salt (designated as R05424802-002) existing as a crystalline form (Form I).
  • Alectinib capsules should be administered orally BID, with body weight adjusted/adapted dosage, with food in the morning and evening.
  • Alectinib is available in 20-mg and 150-mg hard capsules and should be administered orally BID with food in the morning and evening.
  • Alectinib can be administered orally or by means of a feeding tube as a suspension.
  • a participant misses a dose it can be taken within 6 hours of the scheduled time. If the time is greater than 6 hours, or if the participant vomits all or part of the dose, the participant should wait until the next scheduled time and take the next scheduled dose. Participants should not take two doses at the same time to make up for a missed dose.
  • Participants will receive a daily dose of alectinib by range of body weight and the following adjustment may be done.
  • Anticoagulants and antithrombotic agents i.e., Coumadin-derived anticoagulants, unfractionated heparin or low-molecular-weight heparins, and paediatric doses of aspirin as per local recommendations
  • Hormone-replacement therapy Local therapy (e.g., surgery, stereotactic radiosurgery, radiofrequency ablation) as outlined below: o Participants experiencing a mixed response requiring local therapy for control of three or fewer lesions may still be eligible to continue study treatment at the investigator’s discretion following advice from the Medical Monitor. Participants who receive local therapy directed at a target lesion will no longer be evaluable for radiographic response but will remain evaluable for progression. o Alectinib has no inhibitory activity on FGFR2; however, there is a known negative chronotropic effect of alectinib that may result in bradycardia. This may be of relevance for major elective surgeries involving general anaesthesia, and the anaesthesiologist should be informed of this.
  • Local therapy e.g., surgery, stereotactic radiosurgery, radiofrequency ablation
  • alectinib treatment should be stopped approximately 5 days prior to the planned surgery involving general anesthesia. Postoperatively, the decision to reinitiate treatment with alectinib should be based on clinical assessment of a participant’s satisfactory recovery from surgery. For participants who need general anesthesia for tumour assessments or other radiological interventions, it is not necessary to hold alectinib; however, the anesthesiologist should be informed of the risk of bradycardia caused by the drug.
  • Premedication with antihistamines, antipyretics, and/or analgesics may be administered at the discretion of the investigator.
  • investigators should manage a participant's care with supportive therapies as clinically indicated, per local standard practice.
  • Participants who experience study drug-associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local standard practice.
  • palliative radiotherapy may start within 24 hours of the last dose of alectinib, unless, in the judgment of the investigator, participant safety will require a longer washout period prior to palliative radiotherapy. Dosing of alectinib may resume with the resolution of any radiation toxicity to ⁇ Grade 1 or better.
  • Participants should be assessed for toxicity at each study visit; dosing will occur only if the clinical assessment and local laboratory test values are acceptable.
  • Medical history including clinically significant diseases, surgeries, dental history, cancer history (including prior cancer therapies and procedures), menstrual history, fertility history, and puberty history, smoking history, and use of alcohol and drugs of abuse, will be recorded at baseline.
  • all medications e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements
  • an interval medical history should be obtained and any changes in medications and allergies should be recorded.
  • Demographic data will include age, sex, and self-reported race/ethnicity (only where permitted by local regulations).
  • a complete physical examination, performed at screening and other specified visits, should include an evaluation of the head, eyes, ears, nose, throat, and teeth, and the cardiovascular, dermatologic, musculoskeletal, respiratory, Gl, genitourinary, and neurologic systems. Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.
  • weight will be measured at the beginning of each cycle.
  • weight should be measured every 3 months.
  • Tanner staging should be performed until the participant has reached Tanner Stage V or the end of the study.
  • a complete physical examination, performed at screening, at the study discontinuation visit and other specified visits should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary examinations may be performed if clinically indicated.
  • a complete neurologic examination should be completed Day 1 of each cycle, including at baseline. Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.
  • Vital signs will include measurements of respiratory rate, pulse rate, systolic and diastolic blood pressures, oxygen saturation by pulse oximetry, and temperature.
  • Baseline tumour assessments should be performed within 28 days prior to initiation of study drug (Day 1 of Cycle 1); subsequent tumour assessments should be performed in accordance with the schedule of activities. At the investigator's discretion, unscheduled tumour assessments may be performed at any time if progressive disease is suspected.
  • Tumour assessment imaging should include all areas of known disease.
  • assessments > 4 weeks after initial documentation The same radiographic procedure used to assess disease sites at screening should be used throughout the study (e.g., the same contrast protocol for CT scans). To the extent that is feasible, assessments should be performed by the same evaluator to ensure internal consistency across visits.
  • Bone marrow examinations should include biopsy and aspirate for morphology (flow studies are optional) and are required at screening for staging purposes unless a bone marrow examination has been performed within 3 months prior to Day 1 . If positive at screening, a subsequent bone marrow examination is required only to confirm a CR.
  • BMAs bone marrow aspirations
  • Participants who have documented bone marrow involvement at screening should have subsequent bone marrow evaluations performed at each response assessment until the first negative bone marrow evaluation.
  • Extracranial tumours will be evaluated for disease response and progressive disease with RECIST v1.1 (see below)
  • Neuroblastoma will be evaluated for disease response and progressive disease with INRC (see below).
  • tumour lesions/lymph nodes will be categorized as measurable or nonmeasurable- as described below. All measurable and non-measurable lesions should be assessed at screening and at subsequent protocol -specified tumour assessment timepoints. Additional assessments may be performed as clinically indicated for suspicion of progression.
  • Tumour lesions must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size as follows:
  • CT computed tomography
  • MRI magnetic resonance imaging
  • a lymph node must be > 15 mm in the short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and follow-up, only the short axis will be measured and followed. See also notes below on "Baseline Documentation of Target and Non-Target Lesions" for information on lymph node measurement.
  • Non-measurable tumour legions encompass small lesions (longest diameter ⁇ 10 mm or pathological lymph nodes with short axis > 10 but ⁇ 15 mm) as well as truly nonmeasurable lesions. Lesions considered truly non- measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal mass/abdominal organomegaly-identified by physical examination that is not measurable by reproducible imaging techniques.
  • Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular comment, as outlined below: o Bone Lesions: ⁇ Bone scan, positron emission tomography (PET) scan, or plain films are not considered adequate imaging techniques for measuring bone lesions. However, these techniques can be used to confirm the presence or disappearance of bone lesions.
  • PET positron emission tomography
  • ⁇ Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered as measurable lesions if the soft tissue component meets the definition of measurability described above.
  • ⁇ Blastic bone lesions are non-measurable.
  • o Cystic Lesions Lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same participant, these are preferred for selection as target lesions.
  • o Lesions with Prior Local Treatment Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion. Study protocols should detail the conditions under which such lesions would be considered measurable.
  • Clinical Lesions will only be considered measurable when they are superficial and > 10 mm in diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, documentation by colour photography including a ruler to estimate the size of the lesion is suggested.
  • Chest X-Ray Chest X-Ray. Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung.
  • CT Magnetic resonance Imaging
  • MRI Magnetic resonance Imaging
  • the decision as to whether a non-contrast CT or MRI will be used to evaluate the participant at baseline and during the study should be guided by the tumor type under investigation and the anatomic location of the disease.
  • the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should also be based on the tumour type and the anatomic location of the disease, and should be optimized to allow for comparison with the prior studies if possible.
  • Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement.
  • Measurable disease is defined by the presence of at least one measurable lesion, as detailed above.
  • target lesions When more than one measurable lesion is present at baseline, all lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline. This means that, for instances in which participants have only one or two organ sites involved, a maximum of two lesions (one site) and four lesions (two sites), respectively, will be recorded. Other lesions (albeit measurable) in those organs will be recorded as non-measurable lesions (even if the size is > 10 mm by CT scan).
  • Target lesions should be selected on the basis of their size (lesions with the longest diameter) and be representative of all involved organs, but in addition should lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement, in which circumstance the next largest lesion that can be measured reproducibly should be selected.
  • Lymph nodes merit special mention since they are normal anatomical structures that may be visible by imaging even if not involved by tumour.
  • pathological nodes that are defined as measurable and may be identified as target lesions must meet the criterion of a short axis of > 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum.
  • the short axis of the node is the diameter normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image is obtained (for CT this is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short axis.
  • an abdominal node that is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node.
  • 20 mm should be recorded as the node measurement.
  • All other pathological nodes (those with short axis > 10 mm but ⁇ 15 mm) should be considered non-target lesions. Nodes that have a short axis of ⁇ 10 mm are considered non-pathological and should not be recorded or followed.
  • a sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be included in the sum, then, as noted above, only the short axis is added into the sum.
  • the baseline sum of diameters will be used as a reference to further characterize any objective tumour regression in the measurable dimension of the disease.
  • All other lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required and these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal progression.”
  • CRF Case Report Form
  • Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to ⁇ 10 mm.
  • Partial response At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters
  • PD Progressive disease
  • the appearance of one or more new lesions is also considered progression.
  • Lymph nodes identified as target lesions should always have the actual short axis measurement recorded (measured in the same anatomical plane as the baseline examination), even if the nodes regress to ⁇ 10 mm on study. This means that when lymph nodes are included as target lesions, the sum of lesions may not be zero even if CR criteria are met, since a normal lymph node is defined as having a short axis of ⁇ 10 mm.
  • BML below measurable limit
  • the longest diameters of the fragmented portions should be added together to calculate the target lesion sum.
  • a plane between them may be maintained that would aid in obtaining maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such that they are no longer separable, the vector of the longest diameter in this instance should be the maximum longest diameter for the coalesced lesion.
  • This section provides the definitions of the criteria used to determine the tumor response for the group of non-target lesions. While some non-target lesions may actually be measurable, they need not be measured and instead should be assessed only qualitatively at the timepoints specified in the protocol.
  • All lymph nodes must be non-pathological in size ( ⁇ 10 mm short axis).
  • Non-CR/Non-PD Persistence of one or more non-target lesions and/or (if applicable) maintenance of tumor marker level above the normal limits
  • the appearance of one or more new lesions is also considered progression.
  • Examples include an increase in a pleural effusion from “trace” to “large” or an increase in lymphangitic disease from localized to widespread, or may be described in protocols as “sufficient to require a change in therapy.” If unequivocal progression is seen, the participant should be considered to have had overall PD at that point. While it would be ideal to have objective criteria to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; therefore, the increase must be substantial.
  • a lesion identified during the study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression.
  • Table A provides a summary of the overall response status calculation at each timepoint for participants who have measurable disease at baseline. When participants have non- measurable (therefore non-target) disease only, Table B is to be used.
  • Timepoint Response Participants with Target Lesions (with or without NonTarget Lesions)
  • CR complete response
  • NE not evaluable
  • PD progressive disease
  • PR partial response
  • SD stable disease
  • NED Non Evaluable Disease.
  • NED a No target lesions identified at Baseline
  • NED b No non-target lesions identified at Baseline Table B.
  • Timepoint Response Participants with Non-Target Lesions Only
  • CR complete response
  • NE not evaluable
  • PD progressive disease.
  • a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, assigning “stable disease” when no lesions can be measured is not advised.
  • the participant When no imaging/measurement is done at all at a particular timepoint, the participant is not evaluable at that timepoint (see T able C). If only a subset of lesion measurements are made at an assessment, usually the case is also considered not evaluable at that timepoint, unless a convincing argument can be made that the contribution of the individual missing lesion(s) would not change the assigned timepoint response. This would be most likely to happen in the case of PD. For example, if a participant had a baseline sum of 50 mm with three measured lesions and during the study only two lesions were assessed, but those gave a sum of 80 mm, the participant will have achieved PD status, regardless of the contribution of the missing lesion.
  • the response for target lesions should be “unable to assess” since the participant is not evaluable.
  • the response for non-target lesions should be “unable to assess” except where there is clear progression.
  • Overall response would be “unable to assess” if either the target response or the non-target response is “unable to assess” except where this is clear evidence of progression, as this equates with the case being not evaluable at that timepoint.
  • Symptomatic deterioration is not a descriptor of an objective response; it is a reason for stopping study therapy.
  • the objective response status of such participants is to be determined by evaluation of target and non-target lesions as shown in Table A.
  • treatment may continue until the next scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of progression should be the earlier date of when progression was suspected.
  • FDG-PET is not VALIDATED for the use in clinical trials to determine the response but can identify new lesions (Table C) and benefit clinical decisions.
  • CT computed tomography
  • FDG-PET fluorodeoxyglucose-positron emission tomography
  • MRI magnetic resonance imaging
  • PD progressive disease.
  • CR complete response
  • NE not evaluable
  • PD progressive disease
  • PR partial response
  • SD stable disease.
  • nodal disease When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” size ( ⁇ 10 mm), they may still have a measurement reported on scans. This measurement should be recorded even though the nodes are normal in order not to overstate progression should it be based on increase in size of the nodes. As noted earlier, this means that participants with CR may not have a total sum of “zero” on the CRF.
  • Symptomatic deterioration is not a descriptor of an objective response; it is a reason for stopping study therapy.
  • the objective response status of such participants is to be determined by evaluation of target and non-target disease as shown in Tables A-D.
  • treatment may continue until the next scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of progression should be the earlier date when progression was suspected.
  • the primary tumor should also be captured as a target or non- target lesion, as appropriate. This is to avoid an incorrect assessment of CR if the primary tumor is still present, but not evaluated as a target or non-target lesion.
  • Antitumor activity will be assessed based on clinical and radiographic evidence as described by the INRC (Park et al. 2017, Clin Oncol; 35:2580-7).
  • tumor lesions/lymph nodes will be categorized as measurable or non-measurable as described below. All measurable and non-measurable lesions should be assessed at screening and at subsequent protocol-specified tumor assessment timepoints. Additional assessments may be performed as clinically indicated for suspicion of progression.
  • Bone marrow will be assessed by histology or immunohistochemistry and cytology or immunocytology. Bone marrow with ⁇ 5% tumor involvement will be classified as minimal disease.
  • Target Lesions At baseline, one primary target lesion (or two in the case of bilateral adrenal disease unless biopsy proves one to be ganglioneuroma) will be selected based on anatomic imaging and radionuclide scans, and will be > 10 mm in the Longest Diameter (LD) on CT or MRI and have MIBG uptake for MIBG-avid lesions as shown by the Curie score, or FDG uptake for lesions that are not MIBG-avid.
  • LD Longest Diameter
  • MIBG or FDG
  • Non-Target Lesions MIBG (or FDG) avid or biopsy proven disease not selected as target disease will be followed as non-target disease and may include disease meeting the size criteria for target disease, in excess of the allowed maximum numbers, non-nodal lesions ⁇ 10 mm in LD, nodal lesions ⁇ 15 mm short axis diameter, or non-measurable disease such as leptomeningeal tumor, tumor in cerebrospinal fluid, ascites, or pleural effusion.
  • MIBG or FDG
  • a score for osteomedullary lesions will be assessed in nine different body regions. Paired segments are considered a single segment (e.g. , two femurs make one segment).
  • CR complete response
  • FDG-PET fluorodeoxyglucose-positron emission tomography
  • MIBG metaiodobenzylguanidine
  • PD progressive disease
  • PR partial response
  • SD stable disease.
  • CR complete response
  • CT computed tomography
  • FDG-PET fluorodeoxyglucose-positron emission tomography
  • INRC International Neuroblastoma Response Criteria
  • MIBG metaiodobenzylguanidine
  • MR! magnetic resonance imaging
  • PD progressive disease
  • PR partial response
  • SD stable disease.
  • b Sum of diameters is defined as the sum of the short axis of discrete lymph nodes (i.e., cervical, axillary nodes) added to the sum of the longest diameters of nonu lymph node soft tissue metastases. Masses of conglomerate non-discrete lymph nodes will be measured using longest diameter.
  • Relative MIBG score is the absolute score for bone lesions at time of response assessment divided by the absolute score for bone lesions at baseline before therapeutic interventions.
  • the same scoring method e.g., INRC
  • MIBG single photon-emission computed tomography (SPECT) or MIBG-SPECT/CT may be used for scoring purposes, but the same imaging methodology should be used for all evaluations.
  • CR complete response
  • MD minimal disease
  • PD progressive disease
  • SD stable disease.
  • a Response will be compared with baseline disease evaluation at study enrollment.
  • b Accompanied by immunocytology (recommended, not mandatory).
  • c Accompanied by immunohistochemistry; specific recommendations by Burchill et al., Cancer (2016).
  • CR complete response
  • MD minimal disease
  • Nl not involved
  • PD progressive disease
  • PR partial response
  • SD stable disease.
  • RANG terminology characterizes lesions as measurable versus non-measurable and target versus non-target in the brain.
  • Measurable lesions are the ones that can be assessed quantitatively. From among the measurable lesions, up to 5 target lesions will be selected at baseline (to be followed through the participant's treatment course). Once a lesion is recorded as a target lesion, it is always a target lesion, even if it falls below the size limits for what is considered measurable at baseline. The remaining lesions (additional measurable and/or non- measurable lesions) are categorized as non-target lesions and do not require measurement, only qualitative assessment. With primary CNS disease, any metastases outside the brain are extremely rare. If this does happen, it will be assessed using RECIST 1.1 (as a non-target lesion at baseline or new lesion post-baseline).
  • Antitumor activity will be assessed based on clinical and radiographic evidence as described by the RANO criteria.
  • All measurable and non-measurable lesions should be assessed using the same techniques as at baseline. Ideally, participants should be imaged on the same MRI scanner, or at least with the same magnet strength, for the duration of the study to reduce difficulties in interpreting changes.
  • Measurable disease is defined as contrast enhancing lesions with clearly defined margins by MRI scan, with two perpendicular diameters of at least 10 mm, visible on two or more axial slices that are preferably, at most, 5 mm apart with 0-mm skip. If there are multiple contrastenhancing lesions, up to five of the largest lesions that are suitable for reproducible measurements should be selected as target lesions, and the sum of the products of the perpendicular diameters of these lesions should be determined. If the MRI is performed with thicker slices (> 5 mm), the minimum size of a measurable lesion at baseline should be two times the slice thickness.
  • perpendicular diameters must be at least two times the sum of the slice thickness and inter-slice gap for lesions to be considered measurable at baseline. Measurement of tumor around a cyst or surgical cavity represents a particularly difficult challenge. In general, such lesions should be considered non-measurable unless there is a nodular component measuring > 10 mm in diameter. The cystic or surgical cavity should not be measured in determining response.
  • Lesions with a necrotic component can be selected as target if they are the only lesion(s) present, otherwise they should be selected as non-target.
  • Non-measurable disease is defined as either other enhancing measurable lesions, masses with margins not clearly defined (non-enhancing Flair/T2 lesions), or enhancing lesions with maximal perpendicular diameters less than the minimum size for measurability, e.g., 10 mm.
  • Radiographic response should be determined in comparison with the tumor measurements obtained at pretreatment baseline. The smallest tumor measurements at either pretreatment baseline or after initiation of therapy should be used for determination of progression.
  • Target lesion response categories are defined by changes in enhancing tumor measurements; non- target lesions are assessed qualitatively.
  • Target lesion, non-target lesion (both enhancing and non-enhancing), and new lesion status are combined as the radiologic (MRI) timepoint response.
  • the MRI timepoint response is combined with clinical status and corticosteroid use to derive the overall response per RANO criteria.
  • CR Complete Response
  • NE Not Evaluable
  • SD Stable Disease
  • SPD sum of the product
  • PD Progressive Disease
  • PR Partial Response Radiology Lesion Time Point Response Categories
  • 0-mm skip will also be considered to have experienced progression.
  • the transition from a non-measurable lesion to a measurable lesion resulting in progression can theoretically occur with relatively small increases in tumor size (e.g., a 9 x 9 mm lesion [non-measurable] increasing to a 10 x 11 mm lesion [measurable]).
  • the change should be significant (> 5 mm increase in maximal diameter or > 25% increase in the sum of the products of perpendicular diameters of enhancing lesions).
  • CR Complete Response
  • FLAIR fluid-attenuated inversion recovery
  • MRI magnetic resonance imaging
  • PR Partial Response
  • SD Stable Disease
  • PD Progressive Disease
  • Plasma concentrations of alectinib, and its metabolite M4 will be collected. Samples for the following biomarker assessments will be collected. Exploratory biomarker research may include, but will not be limited to, analysis of somatic mutations and gene signatures associated with disease type (i.e. , ALK fusion-positive solid or CNS tumours), as well as evaluation of candidate biomarkers of response to alectininb (i.e., ALK).
  • Biomarkers of bone formation and resorption and biomarkers of calcium metabolism and skeletal homeostasis will be measured from blood (subject to blood volume limitations). These biomarkers include: bone-specific ALP, Vitamin D, and parathyroid hormone.
  • Bone markers will be analyzed at baseline (up to two baseline assessments due to variability), 6 weeks (on Day 15 of Cycle 2), after Cycle 6 (Day 1 of Cycle 7) and every 6 cycles thereafter (paired with the DXA scan at 12 cycles if possible) until the follow-up visit.
  • Serial DXA scans will be performed in participants at baseline, after Cycle 6 (Day 1 of Cycle 7), every 12 cycles until the end of treatment, and 30 days after the final dose, whichever occurs last.
  • Serial X-rays will be performed in participants on treatment at baseline, at 6 weeks, Cycle 6 and, every 6 months until the end of treatment.
  • PRO Patient-reported outcome
  • ObsRO observer-reported outcome
  • PRO data will be collected through use of the following instruments: Paediatric PRO-CTCAE and medication Acceptability Survey. ObsRO data will be collected through use of the Caregiver (Proxy) PRO-CTCAE.
  • the Bayley or Wechsler scale (adapted for age) should be administered by a neuropsychologist or appropriately qualified professional and according to local practice.
  • the adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for assessing adverse event severity.
  • Table 6 will be used for assessing severity for adverse events that are not specifically listed in the NCI CTCAE.
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events.
  • Presence of risk factors in the participant or use of concomitant medications known to increase the occurrence of the event Presence of non-treatment-related factors that are known to be associated with the occurrence of the event
  • the intent-to-treat (ITT) population is defined as all enrolled participants regardless of whether they were dosed.
  • the efficacy-evaluable population is defined as all participants enrolled at the paediatric RP2D with measurable disease who have received at least one dose of study drug and have tumours with confirmed ALK fusion.
  • the safety-evaluable population is defined as all enrolled participants who have received any amount of study treatment.
  • DLT-evaluable population is defined as all participants enrolled in Part 1 who either have completed at least 80% of the prescribed dose of alectinib in Cycle 1 or have experienced a DLT in Cycle 1 .
  • PK-evaluable population is defined as all participants who were administered alectinib and have at least one timepoint with a measurable concentration; data from this population will be included in the PK analysis dataset. Participants will be excluded from the PK analysis population if they significantly violate the inclusion or exclusion criteria, deviate significantly from the protocol or if data are unavailable or incomplete which may influence the PK analysis. Excluded cases will be documented together with the reason for exclusion.
  • PRO-evaluable population is defined as all participants who have received at least one dose of study drug and have one baseline and at least one post-baseline measurement.
  • the safety run-in phase of this study will enrol a minimum of 6 participants and until approximately 12 participants to confirm the paediatric RP2D. Explicit power and type I error considerations are not factored into the design of the paediatric RP2D determination, as this phase is designed to obtain preliminary safety and PK information on the study drug.
  • Part 3 will enrol a minimum of an additional 14 participants. Participants included in the safety run-in phase will not be included in the initial response assessment of the participants in Part 2.
  • the primary efficacy analysis will include all participants enrolled at the paediatric RP2D who receive any amount of study drug with confirmed ALK-fusion. The primary efficacy analysis will occur after these participants have been followed for at least 6 months. A minimum number of 10 participants with solid tumours and 10 participants with CNS tumours will be enrolled in this trial. With at least 30 participants (i.e., at least 6 participants enrolled at the paediatric RP2D in the safety run-in phase and a total of 24 participants enrolled in the initial and additional response assessment) and, if expanded to Part 3, this trial will be able to detect a large benefit conferred by alectinib in terms of the ORR.
  • an observed response rate of 50% in 30 participants (i.e., 15 responders) with ALK-fusion positive solid or CNS tumours will have a 95% Cl, excluding an ORR of 30% with 90% power if the true ORR is 60%.
  • the primary efficacy analysis will require centrally confirmed blinded tumour assessments by the BICR.
  • Demographic and baseline characteristics (including age, sex, and disease characteristics) will be summarized in the ITT population using means, standard deviations, medians, and ranges for continuous variables and proportions for categorical variables, as appropriate.
  • Safety will be characterized by incidence of adverse events and DLTs, as well as change from baseline in laboratory test results, vital signs and ECGs.
  • Study treatment exposure (such as treatment duration, total dose received, and number of cycles and dose modifications) will be summarized with descriptive statistics.
  • DLT analyses will be based on the DLT-evaluable population. Exploratory Analyses of PRO-CTCAE Data
  • Paediatric and Caregiver (Proxy) PRO-CTCAE analyses will be primarily descriptive, with a focus on characterizing the pattern of symptomatic treatment toxicities over the course of the study. Results from these exploratory analyses will be presented separately from the other safety analyses.
  • Paediatric and Caregiver (Proxy) PRO-CTCAE data will be analyzed at the item level consistent with current NCI recommendations for data handling (Basch et al. 2014). The analysis population will be the safety-evaluable population.
  • Plasma pharmacokinetics of alectinib and M4 will be summarized ⁇ e.g., area under the concentration-time curve [AUC]), C max, Tmax, and Ctrough 3S appropriate), and if permitted for data collected, grouped according to treatment received.
  • Alectinib and M4 PK parameters will also be tabulated and summarized (mean, standard deviation, coefficient of variation, median, minimum, and maximum as applicable). Interparticipant variability and drug accumulation will be evaluated if permitted.
  • Non-linear mixed effects modeling (software NONMEM®) will be used to analyze the PK concentrations.
  • Population and individual PK parameters will be estimated and the influence of various covariates (e.g., age, gender and body weight) on these parameters will be investigated in an exploratory way.
  • Data may be pooled with data from other studies with alectinib in order to improve the parameter estimates from the model.
  • Secondary PK parameters (e.g., C ma x and AUC) may be derived from the model for each individual included in the PK analysis and will be presented descriptively.
  • the analysis population for the efficacy analyses will be efficacy evaluable participants defined as all participants enrolled at the paediatric RP2D with measurable disease who have received at least one dose of study drug and have tumours with confirmed ALK fusion, unless otherwise specified.
  • the primary efficacy endpoint is ORR in participants treated at the paediatric RP2D, as assessed by BICR, defined as the proportion of participants with an objective response.
  • the objective response for individual participants will be assessed per RECIST v1.1 for participants with extracranial tumours, and per RANO for participants with primary CNS tumours, and INRC for neuroblastoma.
  • An objective response is defined as a CR or PR per disease-specific response criteria, confirmed > 4 weeks apart in two separate tumour assessments. Participants not meeting these criteria (including participants without a postbaseline tumour assessment) will be considered non-responders.
  • the secondary efficacy endpoints for all participants, as assessed by BICR and investigators, are defined above, including TTR, CBR, PFS, OS and investigator-assessed ORR in the paediatric RP2D population; DOR in participants who achieve an objective response.
  • the Kaplan-Meier approach will be used to estimate median for all time-to-event endpoints including PFS, TTR, DOR and OS.
  • the 95% Cl of the median will be estimated using Brookmeyer and Crowley method.
  • DOR will be calculated in participants who achieve an objective response, data for participants without disease progression or death by the date of data cutoff for analysis will be censored at the date of the last tumour assessment. If no tumour assessments were performed after the date of the first occurrence of objective response, DOR will be censored at the date of the first occurrence of objective response plus 1 day.
  • ORR, CBR, TTR, OS, and DOR in these subgroups will be examined.
  • ORR and its 95% Cl will be summarized (where applicable) and listed for participants with solid tumours and participants with CNS tumours.
  • DOR will be listed for the responders in the two subgroups.
  • ORR To assess the consistency of study results in subgroups defined by tumour types ORR, CBR, TTR, OS, and DOR in these subgroups will be examined. ORR and its 95% Cl will be summarized and listed for participants for participants with each tumour type. DOR will be listed for the responders in the available tumour types.
  • ALK fusion partners were KIF5C in 2 patients and TPM3, CLTC, PLEKHA7, DCTN1 and HNRNPA3 in 1 patient each (Table 11).
  • Median treatment duration was 12 months (range 1 -21).
  • Alectinib was generally well tolerated in paediatric patients with ALK-fusion positive solid or CNS tumours. In this hard-to-treat population, efficacy results are promising with the majority of patients experiencing a response, demonstrating a favourable benefit-risk profile.

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Abstract

La présente invention concerne une méthode de traitement d'une tumeur solide ou d'une tumeur du système nerveux central, positives à la fusion de kinase du lymphome anaplasique (ALK), comprenant l'administration à un sujet ayant besoin d'un tel traitement d'une quantité thérapeutiquement efficace d'alectinib, ou d'un sel pharmaceutiquement acceptable de celui-ci, le sujet étant âgé < 18 ans.
PCT/EP2024/082092 2023-11-15 2024-11-13 Alectinib pour le traitement de tumeurs solides ou du snc positives à la fusion d'alk Pending WO2025104045A1 (fr)

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