[go: up one dir, main page]

WO2025045901A1 - Traitement du cancer du poumon non à petites cellules avec de l'alectinib - Google Patents

Traitement du cancer du poumon non à petites cellules avec de l'alectinib Download PDF

Info

Publication number
WO2025045901A1
WO2025045901A1 PCT/EP2024/073974 EP2024073974W WO2025045901A1 WO 2025045901 A1 WO2025045901 A1 WO 2025045901A1 EP 2024073974 W EP2024073974 W EP 2024073974W WO 2025045901 A1 WO2025045901 A1 WO 2025045901A1
Authority
WO
WIPO (PCT)
Prior art keywords
alectinib
alk
subject
pharmaceutical composition
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/073974
Other languages
English (en)
Inventor
Venice Rosalie ARCHER
Walter Bordogna
Andres CARDONA GAVALDON
Sophie Maude Alice GOLDING
Magalie MAUDIRE ÉPOUSE HILTON
Johannes Alexander NOÉ
Tania Helena OCHI LOHMANN
Thorsten Ruf
Tingting Xu
Ali ZEAITER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Publication of WO2025045901A1 publication Critical patent/WO2025045901A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 a method of treating anaplastic lymphoma kinase (ALUpositive non-small cell lung cancer (NSCLC), 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 has resected early-stage ALK-positive NSCLC.
  • ALUpositive non-small cell lung cancer NSCLC
  • NSCLC non-small-cell lung cancer
  • NSCLC cases Approximately 4-5% of NSCLC cases have been shown to harbour the echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) fusion gene a result of a chromosomal inversion at 2p21 and 2p23.
  • EML4 echinoderm microtubule-associated protein-like 4
  • ALK anaplastic lymphoma kinase
  • Anaplastic Lymphoma Kinase is a receptor tyrosine kinase belonging to an insulin receptor family.
  • Crizotinib was the first ALK inhibitor approved and registered for the treatment of advanced and metastatic ALK-positive NSCLC. Since then, second-generation ALK inhibitors like alectinib, ceritinib, and brigatinib have been granted marketing authorization as first- or second-line treatment for advanced and metastatic ALK-positive NSCLC. Alectinib is described in WO 2010/143664, WO 2012/023597 and WO 2015/163448. Despite advancements in the treatment of NSCLC, improved therapies are still being sought, particularly in the adjuvant setting and in respect of early stage NSCLC.
  • the present inventors have shown that alectinib adjuvant therapy is surprisingly effective at preventing disease recurrence for early-stage ALK-positive NSCLC.
  • the invention provides a method of treating anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer (NSCLC), 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 has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.
  • ALK anaplastic lymphoma kinase
  • NSCLC nonsmall cell lung cancer
  • the invention further provides a method of preventing ALK-positive NSCLC recurrence in a subject, comprising administering to a subject a therapeutically effective amount of alectinib, or a pharmaceutically acceptable salt thereof, wherein the subject has resected stage lb ALK- positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.
  • the subject has resected stage II to stage 111 A ALK-positive NSCLC.
  • the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage lib ALK-positive NSCLC.
  • the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm.
  • the subject has resected stage II ALK-positive NSCLC.
  • the subject has resected stage Illa ALK-positive NSCLC.
  • the stage of ALK-positive NSCLC is histologically confirmed.
  • the subject does not have metastatic ALK-positive NSCLC.
  • the alectinib, or pharmaceutically acceptable salt thereof is administered as adjuvant therapy.
  • the subject may have completely resected ALK-positive NSCLC with negative margins.
  • the resection may be by lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.
  • the subject does not comprise a mutation conferring resistance to ALK inhibitors. In some embodiments, the subject has not had prior exposure to an ALK inhibitor. In some embodiments, the subject has not had prior adjuvant radiotherapy.
  • 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 600 and 1500 mg, preferably 1200 mg, more preferably 600 mg two times per day (BID).
  • the alectinib, or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.
  • the pharmaceutical composition comprises alectinib hydrochloride.
  • the pharmaceutical composition may comprise lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate and carboxymethylcellulose calcium.
  • the pharmaceutical composition may be formulated as a capsule, preferably a hard capsule.
  • the capsule comprises alectinib hydrochloride equivalent to 150 mg alectinib as free base.
  • the capsule comprises 33.7 mg lactose monohydrate and 6 mg sodium lauryl sulfate.
  • the method further comprises administering a therapeutically effective amount of a second therapeutic agent.
  • the second therapeutic agent may be selected from the group comprising chemotherapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, molecular targeting agents.
  • the invention also provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of treating ALK-positive NSCLC in a subject, wherein the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.
  • the invention provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of preventing ALK-positive NSCLC recurrence in a subject, wherein the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.
  • 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 ALK-positive NSCLC in a subject, wherein the subject has resected stage lb ALK- positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC. DESCRIPTION OF THE DRAWINGS
  • Figure 1 Primary Endpoint: Kaplan-Meier plot of Investigator-assessed Disease-Free Survival (DFS) in the stage II to I HA population.
  • DFS Investigator-assessed Disease-Free Survival
  • Figure 2 - Primary Endpoint Kaplan-Meier Plot of plot of Investigator-assessed DFS in Intent- to-Treat patients.
  • Figure 4 Exploratory Endpoint: Kaplan-Meier plot of CNS-Disease Free Survival in Intent- to-Treat patients.
  • Alectinib is a tetracyclic compound represented by the following formula (I): having the compound name 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo- 6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (CAS Nos. 1256580-46-7 and 1256589-74- 8 as hydrochloride).
  • 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 tumors 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 (012-18); 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 formalin
  • 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 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, 60 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 pharmaceutical 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 oral administration by tablets, capsules, granules or powder formulation.
  • the dosage form is a capsule.
  • 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 is 900 mg of alectinib (free base equivalent).
  • 450 mg is administered twice per day.
  • the total daily dose is 1200 mg of alectinib (free base equivalent).
  • 600 mg is administered twice per day.
  • the alectinib is administered as four 150 mg capsules twice per day.
  • an alectinib dosage of 600 mg BID can be reduced in 150 mg increments to 450 mg BID or 300 mg BID respectively, 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.
  • 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.
  • head stage cancer or “early stage tumor” 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 tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies.
  • carcinoma including lymphoma, blastoma (including medulloblastoma and retinoblastoma)
  • sarcoma including liposarcoma and synovial cell sarcoma
  • neuroendocrine tumors including carcinoid tumors, gastrinoma, and islet cell cancer
  • mesothelioma including schwannoma (including a
  • 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, tumors 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.
  • the cancer is ALK-positive NSCLC.
  • 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.
  • 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 lung cancer patients are very small, testing of several important biomarkers is challenging. Plasma ALK assays analysing circulating tumor nucleic acids will enable more patients with NSCLC 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 T staging is determined by the size of primary tumour in long axis, or direct extent of the tumour into adjacent structures such as mediastinum or chest wall: TX, primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy; TO, no evidence of primary tumour; Tis, carcinoma in situ, T 1 , tumour 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (T1 a if 2 cm or less, T1 b if more than 2 cm but 3 cm); T2, tumour more than 3 cm but 7 cm or less or tumour with any of the following features: involves main bronchus, 2 cm or more distal to the carina, invades visceral pleura, associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung (T2a
  • the N staging describes the degree of spread to regional lymph nodes: NX, regional lymph nodes cannot be assessed; NO, no regional lymph node metastases; N1 , metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension; N2, metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s); and N3, metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).
  • the M staging defines the presence of metastases beyond regional lymph node: MO, no distant metastasis; M1 , distant metastasis (M1a, separate tumor nodule(s) in a contralateral lobe, tumour with pleural nodules or malignant pleural (or pericardial) effusion; M1b, distant metastasis (in extrathoracic organs)).
  • MO no distant metastasis
  • M1a distant metastasis
  • M1a separate tumor nodule(s) in a contralateral lobe, tumour with pleural nodules or malignant pleural (or pericardial) effusion
  • M1b distant metastasis (in extrathoracic organs)).
  • Disease stage classifications include occult carcinoma (TX, NO), stage 0 (Tis, NO), stage la (T1 , NO), stage lb (T2a, NO), stage Ila (T2b, NO; T1 , N1 ; T2a, N1), stage lib (T2b, N1 ; T3, NO), stage Illa (T1-2, N2; T3, N1-2; T4, NO-1), stage I lib (T1-3, N3; T4, N2-3), or stage IV (any T, any N, M1).
  • TX occult carcinoma
  • stage 0 Tis, NO
  • stage la T1 , NO
  • stage lb T2a, NO
  • stage Ila T2b, NO; T1 , N1 ; T2a, N1
  • stage lib T2b, N1 ; T3, NO
  • stage Illa T1-2, N2; T3, N1-2; T4, NO-1
  • stage I lib T1-3, N3; T4, N2-3)
  • the subject has completely resected, histologically confirmed stage lb with a tumour greater or equal to 4cm in greatest dimension (tumour > 4 cm) to stage Illa NSCLC.
  • the subject has completely resected, histologically confirmed stage lb (tumour > 4 cm) to stage lib NSCLC. In some embodiments, the subject has completely resected, histologically confirmed stage lb (tumour > 4 cm) to stage Ila NSCLC.
  • the subject has completely resected, histologically confirmed stage lb (tumour > 4 cm) NSCLC.
  • the subject has completely resected, histologically confirmed stage Ila to stage Illa NSCLC.
  • the subject has completely resected, histologically confirmed stage lib to stage Illa NSCLC.
  • the subject has completely resected, histologically confirmed stage Illa NSCLC.
  • the subject has completely resected, histologically confirmed stage II NSCLC.
  • the subject has completely resected, histologically confirmed stage Ila NSCLC.
  • the subject has completely resected, histologically confirmed stage lib NSCLC.
  • the subject has a TNM classification of T2-4 NO, T1-4 N1 , or T1-3 N2.
  • the subject does not have a TNM classification of N3 or M1.
  • the subject does not have metastatic or stage IV ALK-positive NSCLC.
  • tissueologically confirmed refers to determination by microscopic examination of tissue that has been excised by biopsy or surgical resection.
  • 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.
  • 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.
  • the subject has not undergone prior adjuvant radiotherapy.
  • 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 tumor resection in patients with ALK+ NSCLC 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 ALK-positive non-small cell lung cancer, the method comprising administering to the subject a therapeutically effective amount of alectinib.
  • the invention provides methods for treating or delaying progression of non-small cell lung cancer in a subject comprising administering to the subject a therapeutically effective amount of alectinib.
  • the invention provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of treating ALK-positive NSCLC in a subject, wherein the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.
  • the invention provides alectinib, or a pharmaceutically acceptable salt thereof, for use in a method of preventing ALK-positive NSCLC recurrence in a subject, wherein the subject has resected stage lb ALK-positive NSCLC with a tumour greater or equal to 4cm to stage Illa ALK-positive NSCLC.
  • the subject is suffering from stage lb (tumours > 4 cm) to stage Illa, ALK-positive NSCLC.
  • 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 indicated for adjuvant treatment following tumour resection for adult patients with ALK+ NSCLC.
  • alectinib is indicated for adjuvant treatment following tumour resection for adult patients with Stage IB (> 4cm) - 1 HA ALK+ NSCLC.
  • alectinib is indicated for adjuvant treatment following tumour resection for adult patients with Stage ll-IIIA ALK+ NSCLC.
  • 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 patient is non-Asian.
  • 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 tumor 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 sum of complete response (CR) rate and partial response (PR) rate.
  • “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.
  • partial response refers to a decrease in the size of one or more tumors or lesions, or in the extent of cancer in the body, in response to treatment.
  • 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.
  • 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.
  • 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.
  • DFS disease-free survival
  • 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-tumor agent.
  • delaying progression of a disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer (e.g., NSCLC, such as squamous or non-squamous NSCLC)).
  • This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated.
  • a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • 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.
  • the hazard ratio may relate to the probability of a DFS-related event in the alectinib-treated group versus the chemotherapy-treated group.
  • a hazard ratio of 0.16 means that alectinib provides 84% risk reduction in terms of DFS-related events compared to the chemotherapy- treated (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 treatment with the platinum-based chemotherapy without alectinib.
  • an objective response e.g., a CR
  • alectinib increases the subject's likelihood of having an objective response as compared to treatment with the platinum-based chemotherapy without alectinib. In some embodiments, alectinib increases the subject's likelihood of having a CR as compared to treatment with the platinum-based chemotherapy without alectinib. In some embodiments, alectinib extends the subject's PFS as compared to treatment with the platinum-based chemotherapy without alectinib. In some embodiments, alectinib extends the subject's DFS as compared to treatment with the platinum-based chemotherapy without alectinib.
  • alectinib extends the subject's OS as compared to treatment with the platinumbased chemotherapy without alectinib. In some embodiments, alectinib extends the subject's DOR as compared to treatment with the platinum-based chemotherapy without alectinib. In some embodiments, administration of alectinib to the subject extends the subject's ORR as compared to administration of the platinum-based chemotherapy 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 administration of the platinum-based chemotherapy 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 platinumbased 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,
  • administration of alectinib to the subject reduces the subject’s likelihood of disease recurrence as compared to administration of the platinum-based chemotherapy 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 administration of the platinum-based chemotherapy 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 administration of the platinum-based chemotherapy without alectinib.
  • alectinib has an improved safety profile as compared to the platinumbased chemotherapy without alectinib.
  • alectinib may reduce the number of adverse events leading to withdrawal from treatment, improve neutrophil and/or white blood cell counts, and/or reduce incidence of asthenia, nausea, vomiting, decreased appetite, malaise, neutropenia, fatigue and/or tinnitus relative to treatment with platinum-based chemotherapy.
  • the platinum-based chemotherapy comprises a platinum-based chemotherapeutic agent and a nucleoside analog.
  • the platinum-based chemotherapeutic agent is cisplatin, carboplatin, or oxaliplatin.
  • the platinum-based chemotherapeutic agent is cisplatin.
  • the nucleoside analog is gemcitabine.
  • the platinum-based chemotherapy comprises cisplatin and gemcitabine.
  • the platinum-based chemotherapy comprises cisplatin and premetrexed.
  • the platinum-based chemotherapy comprises cisplatin and vinorelbine.
  • the platinum-based chemotherapy is selected from:
  • platinum-based chemotherapy is provided for 4 cycles, with each cycle lasting 21 days.
  • 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.
  • This randomized, active-controlled, multicenter, open-label, Phase III study is designed to investigate the efficacy and safety of alectinib compared with platinum-based chemotherapy in the adjuvant setting.
  • the primary endpoint of the study is DFS as assessed by investigator, while OS is a secondary endpoint.
  • This study will comprise approximately 200 centers in around 30 countries worldwide. Central randomization will be performed via an interactive voice or Web-based response system (IxRS). Randomized patients will be stratified by extent of disease (Stage lb [tumors >4 cm] vs. Stage II vs. Stage Illa) and ethnicity (Asian vs. non-Asian). Relevant instruction will be provided to each study site by the IxRS provider.
  • IxRS interactive voice or Web-based response system
  • Staging must occur in accordance with the UICC/AJCC 7th edition and not the 8th edition.
  • Patients with Stage lb NSCLC with tumors >4 cm per the 7th edition classification have been shown to experience more modest benefit from adjuvant chemotherapy treatment than patients with Stage Il-Illa NSCLC, and this has been taken into consideration for recruitment capping, stratification, and statistical analysis of the primary endpoint.
  • Protocol-defined platinum-based chemotherapy regimens include:
  • Platinum-based chemotherapy will be provided for 4 cycles, with each cycle lasting 21 days.
  • carboplatin can be administered instead of cisplatin in one of the above combinations.
  • Post-operative radiation therapy is not allowed as a treatment option. Therefore, patients with Stage Illa N2 NSCLC who, in the investigator's opinion, should receive PORT, are excluded from the study.
  • Study drug (alectinib or platinum-based chemotherapy) will be administered until completion of treatment period (24 months for alectinib and 4 cycles for chemotherapy), recurrence of disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.
  • Patients who complete a study treatment regimen or discontinue treatment prior to disease recurrence e.g., due to unacceptable toxicity
  • After disease recurrence, patients will be treated at the discretion of the investigator according to local clinical practice. No crossover in the adjuvant setting will be allowed between the 2 arms.
  • iDMC Data Monitoring Committee
  • Stage lb (tumor > 4 cm) to Stage Illa (T2-3 NO, T1-3 N1 , T1-3 N2, T4 NO-1) NSCLC as per UICC/AJCC, 7th edition, with negative margins, at 4-12 weeks before enrolment
  • o Accepted types of resection include any of the following: lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy. o Resection by segmentectomy or wedge resection is not allowed. o N3 disease is not allowed.
  • MLND mediastinal lymph node dissection
  • This study is event-driven with a recruitment period of approximately 3 years.
  • the required number of events for the primary analysis of the primary endpoint is expected to occur approximately 60 months after the first patient has been enrolled. Patients are to be treated until completion of the treatment period (24 months for alectinib and 4 cycles [21 -day cycles] of platinum-based chemotherapy), recurrence of disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.
  • the final survival follow-up analysis will be conducted at approximately 5 years after the last patient is enrolled. The study will formally end once the final survival follow-up analysis has been completed.
  • IMPs investigational medicinal products
  • platinum-based chemotherapies The investigational medicinal products (IMPs) for this study are alectinib and platinum-based chemotherapies.
  • Alectinib comes in a capsule dosage form containing the following active ingredient:
  • Each capsule contains alectinib hydrochloride equivalent to 150 mg alectinib (as free base) along with lactose monohydrate, carboxymethylcellulose calcium, hydroxypropyl cellulose, sodium lauryl sulfate (SLS), and magnesium stearate as excipients.
  • alectinib hydrochloride equivalent to 150 mg alectinib (as free base) along with lactose monohydrate, carboxymethylcellulose calcium, hydroxypropyl cellulose, sodium lauryl sulfate (SLS), and magnesium stearate as excipients.
  • Alectinib 600 mg (four 150-mg capsules) should be administered orally BID with food in the morning and evening.
  • First dose of study drug should be administered as soon as possible after randomization and no later than 7 days after randomization. Treatment will continue until completion of treatment period (24 months), disease recurrence, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.
  • a planned dose of alectinib is missed, patients can make up that dose unless the next dose is due within 6 hours. If vomiting occurs after taking a dose of alectinib, patients should take the next dose at the scheduled time. Patients should not take two doses at the same time to make up for a missed dose.
  • the patient will record their daily dose and time in a diary (Patient Dosing Diary).
  • Platinum-based chemotherapy will be provided for 4 cycles, with each cycle lasting 21 days.
  • Investigators can choose one of the permitted platinum-based chemotherapy regimens, which include the following:
  • First dose of study drug should be administered as soon as possible after randomization, taking required premedication into account, and no later than 7 days after randomization. Treatment will continue until completion of treatment period (4 cycles), recurrence of disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.
  • Institutions should follow their standard administration regiments (e.g., administration sequence or time) for the chemotherapy treatment. Patients must receive adequate premeditations, anti-emetic treatments, and IV hydration for platinum-based treatments according to the local standard of care and prescribing information.
  • administration regiments e.g., administration sequence or time
  • the selected cisplatin-based chemotherapy regimen should remain the same for all cycles.
  • carboplatin can be used.
  • the investigator should inform the Medical Monitor of the switch from a cisplatin-based regimen to a carboplatin-based regimen.
  • the primary and secondary efficacy analyses will be performed for all randomized patients (ITT population) and for the Stage Il-Illa subpopulation. The same analysis methods will be applied for both the ITT population and the Stage Il-Illa subpopulation.
  • Safety analyses will be performed on all randomized patients who received at least 1 dose of study medication.
  • Stage lb patients Approximately 255 patients are expected to be randomized into the study.
  • the number of Stage lb patients will be capped at 25% to ensure that at least 75% of all randomized patients will have Stage Il-Illa disease.
  • the resulting ITT population of all patients randomized will include a minimum of 191 patients in the Stage Il-Illa subpopulation.
  • Months 1-2 1 patient per month
  • Month 4 3 patients per month
  • Months 5-6 4 patients per month
  • Months 7-9 5 patients per month Months 10-12: 7 patients per month Month 13 onwards: 8 patients per month
  • the primary DFS analysis will be conducted after approximately 89 DFS events in the Stage Il-Illa subpopulation have been observed. This is predicted to occur approximately 60 months (5 years) after the first patient is randomized.
  • DFS Disease-free survival
  • the stopping boundaries for the DFS interim and primary analyses are to be computed with use of the Lan-DeMets approximation to the O'Brien-Fleming boundaries.
  • the stopping boundary for early rejection of the null hypothesis for an overall 2-sided 5% significance level is HR ⁇ 0.52 (p ⁇ 0.0118).
  • the stopping boundary for early rejection of the null hypothesis for an overall 2-sided 5% significance level is HR ⁇ 0.55 (p ⁇ 0.0121).
  • the stopping boundaries will be adjusted depending on the actual number of DFS events observed in the ITT population.
  • the ITT interim analysis would only take place in the case of early rejection of the null hypothesis in the Stage Il-Illa subpopulation.
  • An external iDMC will evaluate safety data on an ongoing basis and review the data from the interim analysis. All summaries and analyses by treatment arm for the iDMC's review will be prepared by an external independent data coordinating center. Members of the iDMC will be external to the Sponsor and will follow a charter that outlines their roles and responsibilities. Any outcomes of these reviews that affect study conduct will be communicated in a timely manner to the investigators for notification of the Institutional Review Board (IRB)/Ethics Committee (EC). A detailed plan will be included in the iDMC Charter. Positive efficacy results at the interim analysis will not change the conduct of the study and timing of disease assessments.
  • IRS Institutional Review Board
  • EC Institutional Review Board
  • a detailed plan will be included in the iDMC Charter. Positive efficacy results at the interim analysis will not change the conduct of the study and timing of disease assessments.
  • the primary efficacy objective for this study is to evaluate the efficacy of alectinib compared with platinum-based chemotherapy on the basis of DFS.
  • Disease-free survival is defined as the time from randomization to the first documented recurrence of disease or new primary NSCLC - as determined by the investigator through use of an integrated assessment of radiographic data, biopsy sample results (if clinically feasible), and clinical status - or death from any cause, whichever occurs first.
  • the null (HO) and alternative (HA) hypotheses regarding DFS in each population can be phrased in terms of the DFS survival distribution function (SDF) in the alectinib arm and SDF in the control arm, respectively:
  • the HR in the Stage Il-Illa subpopulation will be estimated with use of a stratified Cox regression model with race as stratification factor, including 95% Cis.
  • stratification factor including 95% Cis.
  • All stratification factors specified for randomization will be used for the stratified Cox regression model.
  • Strata with less than 20 patients will be pooled for analysis in the stratified Cox regression model.
  • the unstratified HR will also be presented.
  • Kaplan-Meier methodology will be used to estimate the median DFS for each treatment arm, and the Kaplan-Meier curve will be constructed to provide a visual description of the difference between the treatment and control arms. Brookmeyer-Crowley methodology will be used to construct the 95% Cl for the median DFS for each treatment arm.
  • the impact of loss to follow-up on DFS will be assessed depending on the number of patients who are lost to follow-up. If more than 5% of patients are lost to follow-up for DFS in either treatment arm, a sensitivity analysis (“worst-case” analysis) will be performed in which patients who are lost to follow-up will be considered to have recurrent disease at the date of the last disease assessment.
  • Alectinib compared with platinum-based chemotherapy, demonstrated a statistically significant and clinically meaningful improvement in DFS as adjuvant therapy in patients with completely resected stage IB to IIIA (UICC/AJCC 7th edition) anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).
  • ALK anaplastic lymphoma kinase
  • stage IB tumors >4 cm] to stage IIIA
  • treatment with alectinib resulted in an excellent 76% reduction in disease recurrence or new primary NSCLC compared to chemotherapy (hazard ratio of 0.24).
  • hazard ratio of 0.24 The results are show in Table 2 and Figure
  • Alectinib resulted in an excellent and surprising 84% reduction (hazard ratio: 0.16) in disease recurrence or new primary NSCLC compared to standard platinum-based chemotherapy in the non-Asian population.
  • a 64% reduction (hazard ratio: 0.36) was achieved in the Asian population.
  • CNS-disease free survival was assessed in the intent-to-treat population (Table 4 and Figure 4). Treatment with alectinib resulted in a clinically meaningful prolongation of CNS-disease free survival compared to chemotherapy (hazard ratio: 0.22).
  • Alectinib demonstrated improvements versus chemotherapy in the number of adverse events leading to withdrawal from treatment, neutrophil and white blood cell counts, and incidence of asthenia, nausea, vomiting, decreased appetite, malaise, neutropenia, fatigue and tinnitus.
  • alectinib is the first and only ALK inhibitor to demonstrate a reduction in the risk of disease recurrence or death for people with early-stage ALK-positive NSCLC in a Phase III trial.
  • ALK inhibitors for early-stage ALK-positive disease to treat cancer before it has spread.
  • Health-related quality of life is an important clinical consideration for adjuvant treatment in resected ALK+ NSCLC and was assessed using SF- 36v2, which is a well-established, validated health status assessment tool.
  • SF- 36v2 is a well-established, validated health status assessment tool.
  • Mental as well as physical Health-related quality of life improvement was shown for Alectinib treatment.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une méthode de traitement du cancer du poumon non à petites cellules (NSCLC) positif à la 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 ayant un NSCLC ALK-positif de stade Ib réséqué avec une tumeur supérieure ou égale à 4 cm par rapport à un NSCLC ALK-positif de IIIa.
PCT/EP2024/073974 2023-08-31 2024-08-28 Traitement du cancer du poumon non à petites cellules avec de l'alectinib Pending WO2025045901A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP23194748.2 2023-08-31
EP23194748 2023-08-31
EP23200990.2 2023-09-29
EP23200990 2023-09-29

Publications (1)

Publication Number Publication Date
WO2025045901A1 true WO2025045901A1 (fr) 2025-03-06

Family

ID=92583356

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/073974 Pending WO2025045901A1 (fr) 2023-08-31 2024-08-28 Traitement du cancer du poumon non à petites cellules avec de l'alectinib

Country Status (2)

Country Link
TW (1) TW202513075A (fr)
WO (1) WO2025045901A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010143664A1 (fr) 2009-06-10 2010-12-16 中外製薬株式会社 Composé tétracyclique
WO2012023597A1 (fr) 2010-08-20 2012-02-23 中外製薬株式会社 Composition contenant un composé tétracyclique
WO2015163448A1 (fr) 2014-04-25 2015-10-29 中外製薬株式会社 Préparation contenant un composé tétracyclique à haute dose
WO2015163447A1 (fr) 2014-04-25 2015-10-29 中外製薬株式会社 Nouveau cristal de composé tétracyclique
WO2016021707A1 (fr) 2014-08-08 2016-02-11 中外製薬株式会社 Forme amorphe de composé tétracyclique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010143664A1 (fr) 2009-06-10 2010-12-16 中外製薬株式会社 Composé tétracyclique
WO2012023597A1 (fr) 2010-08-20 2012-02-23 中外製薬株式会社 Composition contenant un composé tétracyclique
WO2015163448A1 (fr) 2014-04-25 2015-10-29 中外製薬株式会社 Préparation contenant un composé tétracyclique à haute dose
WO2015163447A1 (fr) 2014-04-25 2015-10-29 中外製薬株式会社 Nouveau cristal de composé tétracyclique
WO2016021707A1 (fr) 2014-08-08 2016-02-11 中外製薬株式会社 Forme amorphe de composé tétracyclique

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Excipients", 1994
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING CO.
BERGE ET AL., J PHARM SCI, vol. 66, no. 1256589-74-8, 1977, pages 1 - 19
JOURNAL OF CRYSTAL GROWTH, vol. 263, 2004, pages 480 - 490
KAWAMURA TAKAHISA ET AL: "Leptomeningeal recurrence after long-term alectinib therapy for non-small cell lung cancer harboring an EML4-ALK fusion protein", INVESTIGATIONAL NEW DRUGS, SPRINGER US, NEW YORK, vol. 37, no. 1, 3 July 2018 (2018-07-03), pages 184 - 187, XP036722445, ISSN: 0167-6997, [retrieved on 20180703], DOI: 10.1007/S10637-018-0633-6 *
KUBO SHINSUKE ET AL: "Complete resection following alectinib administration for stage IIIA-N2 ALK-translocated non-small cell lung cancer", JAPANESE JOURNAL OF LUNG CANCER, 20 October 2017 (2017-10-20), pages 752 - 757, XP093218414, Retrieved from the Internet <URL:https://www.jstage.jst.go.jp/article/haigan/57/6/57_752/_pdf/-char/ja> *
LEONETTI ALESSANDRO ET AL: "Phase II, Open-label, Single-arm, Multicenter Study to Assess the Activity and Safety of Alectinib as Neoadjuvant Treatment in Surgically Resectable Stage III ALK-positive NSCLC: ALNEO Trial", CLINICAL LUNG CANCER, vol. 22, no. 5, 1 September 2021 (2021-09-01), US, pages 473 - 477, XP093218412, ISSN: 1525-7304, Retrieved from the Internet <URL:https://pdf.sciencedirectassets.com/280645/1-s2.0-S1525730421X00058/1-s2.0-S1525730421000498/main.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEJn//////////wEaCXVzLWVhc3QtMSJGMEQCIEhXO4tunqkfyKUbDe0tCDgvtS50c8jUAuvYpme5buzUAiBo6mJzjzoNY8Trv5tVPEM3JR9NV0AJaID9b63vq9IlTSqyBQgSEAUaDDA1OTAwMzU0Njg2NSIMtP32c> DOI: 10.1016/j.cllc.2021.02.014 *
LIANG QI ET AL: "Coexistence of a novel NBEA-ALK, EML4-ALK double-fusion in a lung adenocarcinoma patient and response to alectinib: A case report", LUNG CANCER, ELSEVIER, AMSTERDAM, NL, vol. 162, 5 November 2021 (2021-11-05), pages 86 - 89, XP086884866, ISSN: 0169-5002, [retrieved on 20211105], DOI: 10.1016/J.LUNGCAN.2021.10.015 *
PÉROL MAURICE ET AL: "Patient-reported outcomes from the randomized phase III ALEX study of alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer", LUNG CANCER, ELSEVIER, AMSTERDAM, NL, vol. 138, 11 October 2019 (2019-10-11), pages 79 - 87, XP085937511, ISSN: 0169-5002, [retrieved on 20191011], DOI: 10.1016/J.LUNGCAN.2019.10.002 *
SOLOMON BENJAMIN J. ET AL: "ALINA: A phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB-IIIA anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). | Journal of Clinical Oncology", JOURNAL OF CLINICAL ONCOLOGY, vol. 37, no. 15_suppl, 20 May 2019 (2019-05-20), pages TPS8569 - TPS8569, XP093218387, ISSN: 0732-183X, Retrieved from the Internet <URL:https://ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.TPS8569> DOI: 10.1200/JCO.2019.37.15_suppl.TPS8569 *

Also Published As

Publication number Publication date
TW202513075A (zh) 2025-04-01

Similar Documents

Publication Publication Date Title
US10888559B2 (en) Quinoline derivatives for non-small cell lung cancer
TWI607754B (zh) 醫藥組合
US20170312233A1 (en) Potentiation of anti-cancer activity through combination therapy with ber pathway inhibitors
WO2017013160A1 (fr) Composé 4-amino-6-(2,6-dichlorophényl)-8-méhyle-2-(phénylamino)-pyrido[2,3-d] pyrimidin-7(8h)-one pour le traitement des cancers solides
CN107835687A (zh) 癌症治疗
JP2021502415A (ja) 癌の処置のためのアパチニブを用いる併用療法
CN104582706A (zh) 辅助癌症治疗的方法
CN114652723A (zh) 治疗非小细胞肺癌的喹啉衍生物
WO2018214925A1 (fr) Dérivé de quinoléine pour le traitement du cancer colorectal
US11571437B2 (en) Methods of treating cancer using PRMT5 inhibitors
US11439625B2 (en) Combination therapy for proliferative diseases
US11207319B2 (en) Method for the treatment of bladder cancer
WO2025045901A1 (fr) Traitement du cancer du poumon non à petites cellules avec de l&#39;alectinib
WO2020057539A1 (fr) Dérivé de quinoléine utilisé pour le traitement du cancer du poumon à petites cellules
CN116098894A (zh) Mitochornic acid 5在治疗肿瘤中的应用
WO2020083187A1 (fr) Utilisation d&#39;une association d&#39;un antagoniste d&#39;ar et d&#39;un inhibiteur de parp dans la préparation d&#39;un médicament destiné au traitement du cancer de la prostate
KR102528732B1 (ko) 포지오티닙 및 칼슘채널 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물
JP2015515476A (ja) Ｐｉ３ｋ阻害剤及びｍｅｋ阻害剤を使用する癌の治療方法
WO2025104045A1 (fr) Alectinib pour le traitement de tumeurs solides ou du snc positives à la fusion d&#39;alk
WO2022191870A1 (fr) Traitement du cancer chez un patient présentant une altération génétique concomitante dans le gène fgfr2 et un gène promoteur de cancer
KR20240138069A (ko) 프탈라지논 유도체를 포함하는 항암제와의 병용 투여용 약학적 조성물
US20190231801A1 (en) Methods of treating ovarian cancer
HK40079036A (en) Quinoline derivative for treating non-small cell lung cancer
JPWO2017030146A1 (ja) 胆道癌治療剤
HK40080863A (en) Quinoline derivative for treating non-small cell lung cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24762306

Country of ref document: EP

Kind code of ref document: A1