WO2022074011A1 - Association d'encorafénib et de binimétinib comme traitement adjuvant pour un mélanome de stade ii réséqué - Google Patents

Association d'encorafénib et de binimétinib comme traitement adjuvant pour un mélanome de stade ii réséqué Download PDF

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WO2022074011A1
WO2022074011A1 PCT/EP2021/077466 EP2021077466W WO2022074011A1 WO 2022074011 A1 WO2022074011 A1 WO 2022074011A1 EP 2021077466 W EP2021077466 W EP 2021077466W WO 2022074011 A1 WO2022074011 A1 WO 2022074011A1
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melanoma
encorafenib
binimetinib
stage
treatment
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PCT/EP2021/077466
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English (en)
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Jean-Claude VEDOVATO
Jeanne SUISSA
Olivier PROVENDIER
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Pierre Fabre Medicament
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Priority to MX2023003867A priority Critical patent/MX2023003867A/es
Priority to AU2021358394A priority patent/AU2021358394A1/en
Priority to EP21789664.6A priority patent/EP4225307A1/fr
Publication of WO2022074011A1 publication Critical patent/WO2022074011A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • Melanoma is one of the most aggressive skin cancers. Epidemiologic data reveals the increasing incidence of melanoma over time in both United States (USA) and Europe with more than 100.000 new cases expected in 2020 in both USA and Europe. The increase in incidence of melanoma has led to an increased number of patients with early stage being diagnosed each year, across the globe, but especially in the western world (Ref. 1 -3).
  • stage 0 melanoma progression from an early stage lesion, confined to the epidermis (stage 0) followed by a series of early stages of local invasion (I and II) before moving to the regional lymph nodes (stage III) and finally metastasising to distal sites (stage IV).
  • High-risk cancers are usually considered those that are ulcerated, involve lymph nodes, demonstrate microsatellitosis, or in-transit disease (stage III).
  • Immunotherapy (immune checkpoint inhibitors) and several BRAF and MEK inhibitor combinations (encorafenib plus binimetinib, dabrafenib plus trametinib, vemurafenib plus cobimetinib) have been approved for treating metastatic melanoma (Ref. 5).
  • melanoma specific survival (MSS) at 5 and 10 years for N0M0 is 93% and 88% for pT2b, 94% and 88% for pT3a, 86% and 81% for pT3b, 90% and 83% for pT4a, 82% and 75% for pT4b, respectively (Ref. 4).
  • MSS melanoma specific survival
  • Surgical resection is the treatment of choice for localised melanoma.
  • WLE wide local excision
  • SN sentinel node
  • stage IIB-IIC melanoma After surgical removal of melanoma, some patients will relapse; then, the goal of adjuvant systemic therapy is to minimise that risk of relapse.
  • stage IIB-IIC melanoma There are currently two phase 3 trials examining adjuvant systemic therapy with immunotherapy in stage IIB-IIC melanoma.
  • Previous studies with the BRAF inhibitor vemurafenib singleagent did not yield a significant result in stage IIC-IIIB.
  • the present description provides a method of providing adjuvant treatment to a patient after resection of a melanoma, wherein the melanoma which has been resected is stage II melanoma.
  • This method comprises the administration to the patient of a pharmaceutical combination, wherein the pharmaceutical combination comprises therapeutically effective amounts, independently, of: a) encorafenib or a pharmaceutically acceptable salt thereof and b) binimetinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination may also optionally comprise at least one pharmaceutically acceptable carrier.
  • the present description relates to a pharmaceutical combination for use as adjuvant treatment after resection of a melanoma, wherein the melanoma which has been resected is stage II melanoma, and wherein the pharmaceutical combination comprises therapeutically effective amounts, independently, of: a) encorafenib or a pharmaceutically acceptable salt thereof; b) binimetinib or a pharmaceutically acceptable salt thereof; and optionally at least one pharmaceutically acceptable carrier.
  • the present description relates also to the use of a pharmaceutical combination for the manufacture of a medicinal product intended to be used as adjuvant treatment after resection of a melanoma, wherein the melanoma which has been resected is stage II melanoma, and wherein the pharmaceutical combination comprises therapeutically effective amounts, independently, of: a) encorafenib or a pharmaceutically acceptable salt thereof; b) binimetinib or a pharmaceutically acceptable salt thereof; and optionally at least one pharmaceutically acceptable carrier.
  • the present description relates to a pharmaceutical combination for use in preventing melanoma recurrence after melanoma resection, wherein the melanoma which has been resected is stage II melanoma, and wherein the pharmaceutical combination comprises therapeutically effective amounts, independently, of: a) encorafenib or a pharmaceutically acceptable salt thereof; b) binimetinib or a pharmaceutically acceptable salt thereof; and optionally at least one pharmaceutically acceptable carrier.
  • the present description also relates to a method of preventing melanoma recurrence after melanoma resection, the method comprising administering a pharmaceutical combination to a patient in need thereof, wherein the melanoma which has been resected is stage II melanoma, and wherein the pharmaceutical combination comprises therapeutically effective amounts, independently, of: a) encorafenib or a pharmaceutically acceptable salt thereof; b) binimetinib or a pharmaceutically acceptable salt thereof; and optionally at least one pharmaceutically acceptable carrier.
  • the present description relates also to the use of a pharmaceutical combination for the manufacture of a medicinal product intended to prevent melanoma recurrence after melanoma resection, wherein the melanoma which has been resected is stage II melanoma, and wherein the pharmaceutical combination comprises therapeutically effective amounts, independently, of: a) encorafenib or a pharmaceutically acceptable salt thereof; b) binimetinib or a pharmaceutically acceptable salt thereof; and optionally at least one pharmaceutically acceptable carrier.
  • the stage II melanoma is a BRAF-V600 positive melanoma. More preferably, the melanoma is a BRAF V600E positive melanoma or a BRAF V600K positive melanoma. Even more preferably, the BRAF genotype is determined after resection.
  • the stage II melanoma is a stage HA (i.e. pT2b or pT3a), IIB (i.e. pT3b or pT4a) or IIC (i.e. pT4b) melanoma, preferably with a BRAF V600 mutation, and more preferably with a BRAF V600K or BRAF V600E mutation. Even more preferably, the BRAF genotype is determined after resection.
  • the stage II melanoma is a stage HA (i.e. pT2b or pT3a) melanoma, preferably with a BRAF V600 mutation, and more preferably with a BRAF V600K or BRAF V600E mutation. Even more preferably, the BRAF genotype is determined after resection.
  • the stage II melanoma is a IIB (i.e. pT3b or pT4a) or IIC (i.e. pT4b) melanoma, preferably with a BRAF V600 mutation, and more preferably with a BRAF V600K or BRAF V600E mutation. Even more preferably, the BRAF genotype is determined after resection.
  • encorafenib and binimetinib are formulated as separate unit dosages for simultaneous, separate or sequential administration.
  • encorafenib, or a pharmaceutically acceptable salt thereof, and binimetinib, or a pharmaceutically acceptable salt thereof are administered simultaneously, separately or sequentially over time.
  • encorafenib is administered at an amount of 450 mg once a day.
  • binimetinib is administered at an amount of 45 mg twice a day.
  • encorafenib is administered at an amount of 450 mg once a day and binimetinib is administered at an amount of 45 mg twice a day.
  • encorafenib, or a pharmaceutically acceptable salt thereof, and binimetinib, or a pharmaceutically acceptable salt thereof are administered during 6 months.
  • encorafenib, or a pharmaceutically acceptable salt thereof, and binimetinib, or a pharmaceutically acceptable salt thereof are administered during 6 months, the treatment being renewable once of 6 months.
  • encorafenib, or a pharmaceutically acceptable salt thereof, and binimetinib, or a pharmaceutically acceptable salt thereof are administered during 12 months.
  • the stage II melanoma is a stage HA (i.e. pT2b or pT3a), IIB (i.e. pT3b or pT4a) or IIC (i.e. pT4b) melanoma, preferably with a BRAF V600 mutation, and more preferably with a BRAF V600K or BRAF V600E mutation; and encorafenib, or a pharmaceutically acceptable salt thereof, and binimetinib, or a pharmaceutically acceptable salt thereof, are administered during 6 months; 6 months with a possible prolongation of 6 months; or 12 months. Even more preferably, the BRAF genotype is determined after resection.
  • the stage II melanoma is a stage HA (i.e. pT2b or pT3a) melanoma, preferably with a BRAF V600 mutation, and more preferably with a BRAF V600K or BRAF V600E mutation; and encorafenib, or a pharmaceutically acceptable salt thereof, and binimetinib, or a pharmaceutically acceptable salt thereof, are administered during 6 months; 6 months with a possible prolongation of 6 months; or 12 months. Even more preferably, the BRAF genotype is determined after resection.
  • the stage II melanoma is a stage IIB (i.e. pT3b or pT4a) or IIC (i.e. pT4b) melanoma, preferably with a BRAF V600 mutation, and more preferably with a BRAF V600K or BRAF V600E mutation; and encorafenib, or a pharmaceutically acceptable salt thereof, and binimetinib, or a pharmaceutically acceptable salt thereof, are administered during 6 months; 6 months with a possible prolongation of 6 months; or 12 months. Even more preferably, the BRAF genotype is determined after resection.
  • the stage II melanoma is a stage HA (i.e. pT2b or pT3a) melanoma, preferably with a BRAF V600 mutation, and more preferably with a BRAF V600K or BRAF V600E mutation; and encorafenib, or a pharmaceutically acceptable salt thereof, and binimetinib, or a pharmaceutically acceptable salt thereof, are administered during 6 months.
  • the BRAF genotype is determined after resection.
  • the methods described herein result in increasing relapse-free survival (RFS) (also called recurrence free survival) compare to no treatment.
  • RFS relapse-free survival
  • BRAF V600 mutations The essential role and the position of RAF in many signalling pathways has been demonstrated from studies using deregulated and dominant inhibitory RAF mutants in mammalian cells as well as from studies employing biochemical and genetic techniques to model organisms.
  • the frequency of BRAF V600 mutations is approximately 40-50% in melanomas (Ref. 7).
  • the most commonly observed BRAFV600 mutation is the BRAF V600E mutation representing over 90% of the mutations.
  • the second most common mutation is BRAF V600K representing ⁇ 5%-6% of the mutations.
  • Encorafenib is an ATP-competitive BRAF serine and threonine kinase inhibitor selectively exhibiting anti-proliferative effects in BRAF V600-mutated cells, and in particular in BRAF V600E-mutated cells, and inhibiting signalling of RAS/MEK/ERK pathway.
  • encorafenib is characterised by a significantly increased dissociation half-life of more than 30 hours, as compared with the 2 and 0.5 hours reported for dabrafenib and vemurafenib, respectively. This results in increased efficacy and reduced toxicity, thereby improving the overall benefit-risk ratio of the drug (Ref. 8).
  • Binimetinib is a reversible inhibitor of the activation of protein kinases MEK1 and MEK2, which are responsible for phosphorylating the ERK1 and ERK2 proteins. Activated ERKs interact with and phosphorylate numerous cytoplasmic substrates and ultimately modulate transcription factors, thereby activating involved in one of the main proliferation pathways of cell survival.
  • encorafenib and binimetinib in combination show enhanced efficacy and reduced toxicity against BRAF-dependent tumours, such as unresectable or metastatic melanoma.
  • BRAF-dependent tumours such as unresectable or metastatic melanoma.
  • the rapid onset and sustained efficacy observed in these settings shows that the pharmaceutical combination of encorafenib and binimetinib is particularly advantageous over the combinations of BRAF and MEK inhibitors of the prior art (Ref. 9-12).
  • the specific combination of encorafenib and binimetinib allows for a shorter adjuvant treatment duration than comparable combinations of RAF and MAK inhibitors.
  • the term “pharmaceutically acceptable” is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use.
  • pharmaceutically acceptable salt is intended to mean, in the framework of the present invention, a salt of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.
  • the pharmaceutically acceptable salts comprise:
  • Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.
  • Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • Encorafenib is also known as methyl N-[(2S)-1 -( ⁇ 4-[3-(2-chloro-5-fluoro-3- methanesulfonamidophenyl)-1 -(propan-2-yl)-1 H-pyrazol-4-yl]pyrimidin-2- yl ⁇ amino)propan-2-yl]carbamate, LGX818 or NVP-LGX818.
  • Encorafenib and methods of preparation thereof are described in e.g., PCT application No. WO 2011 /025927.
  • the synthesis of encorafenib is described in Examples 5 and 6 of PCT application No. WO 2011 /025927.
  • encorafenib is in an amorphous form.
  • salt or “salts” is understood to be a salt of encorafenib that can be present alone or in mixture with the free compound of Formula (I) and are preferably pharmaceutically acceptable salts.
  • Such salts are formed, for example, as acid addition salts by reacting the free base form of encorafenib with a pharmaceutically acceptable inorganic acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric or phosphoric acid and the like; or with a pharmaceutically acceptable organic acid such as formic, acetic, benzoic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphthoic, 2-hydroxyethanesulfonic, lactic, maleic, malic, mandelic, oxalic, salicylic, methanesulfonic, muconic, 2-naphthalenesulfonic, propionic, succinic, dibenzoyl-L-citric, tartaric, tartaric, p-toluenesulfonic, tri methylacetic, or trifluoroacetic acid and the like.
  • Binimetinib is described in e.g., PCT application No. WO 2003/077914A1 . This PCT application describes methods for its preparation, for example, in Example 18 (compound 29111). Binimetinib is also known as 5-[(4-bromo-2-fluorophenyl)amino]-4- fluoro-N-(2-hydroxyethoxy)-1 -methyl-1H-benzimidazole-6-carboxamide, ARRY-162, and MEK 162.
  • 6-(4-bromo-2-fluoro-phenylamino)-7-fluoro-3- methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy) -amide is crystallised 6-(4-bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy) -amide.
  • Crystallised 6-(4-bromo-2-fluoro-phenylamino)-7- fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide and methods of preparing crystallised 6-(4-bromo-2-fluoro-phenylamino)-7-fluoro-3- methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy) -amide are described in PCT Publication No. WO 2014/063024.
  • salt or “salts”, unless otherwise indicated, includes salts of acidic and basic groups which may be present in the compounds of the present invention.
  • it can be a pharmaceutically salt as defined above formed with an organic or inorganic acid or formed with an organic or inorganic base.
  • binimetinib is capable of forming salts with various inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric or phosphoric acid and the like; and with various organic acids such as formic, acetic, benzoic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphthoic, 2-hydroxyethanesulfonic, lactic, maleic, malic, mandelic, oxalic, salicylic, methanesulfonic, muconic, 2-naphthalenesulfonic, propionic, succinic, dibenzoyl-L-citric, tartaric, tartaric, p-toluenesulfonic, tri methylacetic, or trifluoroacetic acid and the like.
  • inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, ni
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of binimetinib are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the acetate, benzoate, citrate, fumarate, hydrobromide, hydrochloride, hydroiodide, lactate, maleate, mandelate, nitrate, oxalate, salicylate, succinate, and tartrate salts.
  • An example of a salt of this type is a hydrochloride or sulfate salt of binimetinib as described herein.
  • Additional pharmaceutically acceptable salts of binimetinib suitable for the present invention include the salts disclosed in PCT Application No. WO 03/077914.
  • the terms “subject” or “patient,” used interchangeably, refer to any animal, including mammals such as humans, primates, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep and horses.
  • the subject is a human.
  • the subject has been identified or diagnosed as having stage II melanoma with dysregulation of a BRAF gene, a BRAF protein, or expression or activity, or level of the same (e.g., as determined using a validated assay or kit or a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject has a stage II melanoma that is positive for dysregulation of a BRAF gene, a BRAF protein, or expression or activity, or level of the same (e.g., as determined using a validated assay or kit or a regulatory agency- approved assay or kit).
  • the subject has a stage II melanoma that is positive for a BRAF mutation which results in dysregulation of a BRAF gene, a BRAF protein, or expression or activity, or level of the same (e.g., as determined using a validated assay or kit or a regulatory agency-approved assay or kit).
  • this mutation is a BRAF V600 mutation, preferably V600K or V600E.
  • the genotype of the stage II melanoma has been determined after this melanoma has been resected.
  • resection is used herein to refer to the surgical removal of a tissue or part or all of an organ. More specifically, in the context of the present disclosure, resection consists in the surgical removal of malignant tissue characteristic of melanoma from the patient. Preferably, after resection, the presence of remaining malignant tissue is undetectable with the available methods. In another preferred embodiment, after resection, the presence of remaining melanoma disease is undetectable with the available methods.
  • surrounding healthy tissue is removed in addition to malignant tissue by resection.
  • surrounding non-cancerous tissue is removed in addition to melanoma by resection. For example, stage II melanoma are usually removed by wide local excision (WLE), i.e., a margin of healthy tissue is removed in addition to the melanoma.
  • WLE wide local excision
  • treating refers to administering or the administration of a drug or drugs (e.g. a pharmaceutical combination described herein) in an amount, manner, and/or mode effective to improve a condition, symptom, or parameter associated with a disorder or to prevent progression or exacerbation of the disorder (including secondary damage caused by the disorder) to either a statistically significant degree or to a degree detectable to one skilled in the art.
  • a drug or drugs e.g. a pharmaceutical combination described herein
  • adjuvant therapy refers to therapy given after surgery, where no evidence of residual disease can be detected, so as to reduce the risk of disease recurrence or to delay the onset of the biological, radiological or clinical manifestations of the reoccurrence of the disease.
  • the goal of adjuvant therapy is to prevent recurrence of the cancer, and therefore to reduce the risk of cancer-related death. More specifically, the goal of adjuvant therapy is to prevent recurrence of melanoma, and therefore to reduce the risk of melanoma-related death. In other words, the goal of adjuvant therapy is to increase relapse-free survival (RFS).
  • RFS relapse-free survival
  • One particular advantage of the present pharmaceutical combination disclosed herein is that such an increase in RFS is obtained with a shorter treatment duration than for other targeted therapy.
  • Another advantage of the present pharmaceutical combination disclosed herein is that its safety profile confers a favourable benefit-risk ratio compared to other targeted therapies available.
  • Recurrence herein refers to a local recurrence, a regional recurrence, a distant metastasis, a new melanoma which is ulcerated, or thick (Breslow thickness > 1 mm), or which requires a treatment other than surgery, or a combination thereof.
  • a “local cutaneous recurrence” is a regrowth of melanoma occuring in close proximity to the anatomic site from which the primary tumor was excised, in particular within 2 cm of the tumor bed.
  • a “regional recurrence” is either a nodal recurrence defined as regrowth of melanoma into lymph nodes at the periphery of the prior surgical procedure, or an occurrence of “in transit metastases” defined as any skin or subcutaneous metastases that are more than 2 cm from the primary lesion but are not beyond the regional nodal basin.
  • the local and regional recurrences are also named locoregional recurrences.
  • a “distant metastasis” is once melanoma spreads to distant locations: non-visceral (as the skin, subcutaneous tissue, and lymph nodes), or visceral locations (lung, brain, liver, gastrointestinal tract), or bone.
  • an “effective amount” refers to an amount of a drug or a pharmaceutical agent which is effective, at dosages and for periods of time necessary, to achieve the result desired by a researcher or a clinician.
  • a “therapeutically effective amount” means an amount sufficient to influence the therapeutic course of a particular disease state.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the agent are outweighed by the therapeutically beneficial effects.
  • the present disclosure also relates to one or more pharmaceutical composition
  • carriers i.e., buffering agents, stabilising agents, preservatives, isotonifiers, non-ionic detergents, antioxidants, and other miscellaneous additives.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredient(s) of the composition and not deleterious to the recipient thereof.
  • the type of carrier can be selected based upon the intended route of administration. The amount of each carriers used may vary within ranges conventional in the art.
  • Encorafenib and binimetinib or their pharmaceutically acceptable salts may be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • encorafenib and binimetinib or their pharmaceutically acceptable salts are administered, as pharmaceutical compositions, enterally, e.g., orally, e.g., in the form of tablets or capsules.
  • compositions comprising encorafenib and/or binimetinib in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods.
  • oral compositions can be tablets or gelatine capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminium silicate, starch paste, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavours and sweeteners.
  • diluents e.g., lactose, dextrose
  • compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • the compositions may be sterilised and/or contain adjuvants, such as preserving, stabilising, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • adjuvants such as preserving, stabilising, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • they may also contain other therapeutically valuable substances.
  • the preferred route may vary with, for example, the condition of the subject receiving the combination disclosed herein.
  • each of the agents administered may be administered by the same or different routes and that the compounds may be formulated separately or compounded together in a pharmaceutical composition.
  • encorafenib is formulated for oral administration.
  • encorafenib is formulated as a tablet or capsule, e.g. a capsule.
  • Methods of preparing oral formulations of encorafenib are described in PCT publication No. WO 2013/078264.
  • Binimetinib is preferably formulated for oral administration.
  • the binimetinib is formulated as a tablet or capsule.
  • binimetinib is formulated as a tablet, e.g. a coated tablet. Methods of preparing oral formulations of binimetinib are described in PCT publication No. WO 2014/063024.
  • the administration of encorafenib is performed with binimetinib, either simultaneously, separately or sequentially over time.
  • the two active principles may be combined in a single pharmaceutical composition, comprising the two compositions, such as a tablet or a hard capsule.
  • the two active principles may, whether or not they are administered simultaneously, be present in separate pharmaceutical compositions.
  • the two compounds may be administered by the same or different routes, e.g., they can be both administered enterally, e.g., orally, or one can be administered enterally and the other parenterally or topically.
  • both encorafenib and binimetinib are administered enterally, more preferably orally.
  • one or more doses of encorafenib is administered simultaneously, separately or sequentially over time with one or more doses of binimetinib.
  • the effective dosage of each of the compounds employed in the present pharmaceutical combination may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, and the severity of the condition being treated.
  • the optimum ratios, individual and combined dosages, and concentrations of the combination partners (encorafenib and binimetinib) of a pharmaceutical combination that yield efficacy without toxicity are based on the kinetics of the therapeutic agents' availability to target sites, and may be determined using methods known to those of skill in the art.
  • Encorafenib may be administered to a suitable subject daily in single or divided doses at an effective dosage in the range of about 0.05 to about 50 mg per kg body weight per day, (e.g., about 0.10 mg/kg/day, 0.30 mg/kg/day, 0.50 mg/kg/day, 0.80 mg/kg/day, 1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 15 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 30 mg/kg/day, 35 mg/kg/day, 40 mg/kg/day, 50 mg/kg/day, 0.1 -25 mg/kg/day, or 0.5-10 mg/kg/day).
  • an effective dosage in the range of about 0.05 to about 50 mg per kg body weight per day, (e.g., about 0.10 mg/kg/day, 0.30 mg/kg/day, 0.50 mg/kg/day, 0.80 mg/kg/day, 1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/
  • doses may be about 35 mg to about 700 mg (e.g., about 50 mg, about 75 mg, about 100 mg, about 120 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 650 mg), in single or divided doses.
  • encorafenib is orally administered.
  • encorafenib is in a capsule form.
  • a capsule formulation of encorafenib comprises 50 mg of encorafenib.
  • a capsule formulation of encorafenib comprises 75 mg of encorafenib. In one embodiment, a capsule formulation of encorafenib comprises 100 mg of encorafenib. In one embodiment, a capsule formulation of encorafenib comprises amorphous encorafenib.
  • 450 mg of encorafenib is orally administered once daily, In one embodiment, 375 mg of encorafenib is orally administered once daily, In one embodiment, 300 mg of encorafenib is orally administered once daily, In one embodiment, 225 mg of encorafenib is orally administered once daily, In one embodiment, 150 mg of encorafenib is orally administered once daily.
  • Binimetinib may be administered to a suitable subject daily in single or divided doses at an effective dosage in the range of about 0.001 to about 100 mg per kg body weight per day, (e.g., about 0.01 mg/kg/day, about 0.10 mg/kg/day, 0.30 mg/kg/day, 0.50 mg/kg/day, 0.80 mg/kg/day, 1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 15 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 30 mg/kg/day, 35 mg/kg/day, 40 mg/kg/day, 50 mg/kg/day, 60 mg/kg/day, 70 mg/kg/day, 80 mg/kg/day, 90 mg/kg/day, 100 mg/kg/day, 0.1 -25 mg/kg/day, 0.5-10 mg/kg/day, or 1 -35 mg/kg/day).
  • an effective dosage in the range of about 0.001 to about 100 mg per kg body weight per day, (e.
  • doses may be about 10 mg to about 85 mg (e.g., about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, or about 85 mg).
  • this would amount to a preferable dosage range of about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day, notably 0.9 g/day.
  • binimetinib is orally administered.
  • binimetinib is formulated as a tablet.
  • a tablet formulation of binimetinib comprises 15 mg of binimetinib.
  • binimetinib is orally administered twice daily. In one embodiment, binimetinib is orally administered twice daily, wherein the second dose of binimetinib is administered about 12 hours after the first dose of binimetinib. In one embodiment, 45 mg of binimetinib is orally administered twice daily. In one embodiment, binimetinib is 6- (4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy) -amide or a pharmaceutically acceptable salt thereof.
  • binimetinib is crystallised 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3- methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy) -amide.
  • a tablet formulation of binimetinib comprises 15 mg of crystallised 6-(4- bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2- hydroxyethoxy) -amide.
  • BRAF V600E/K mutation Approximately 45% of the patients are expected to have a BRAF V600E/K mutation. In addition, some BRAF-positive patients may eventually not be randomised, for example due to a lack of consent or a disease recurrence in the period of time between surgery and randomisation. Hence, approximately 2400 patients need to be screened in order to randomise 900 patients.
  • the primary objective of the study is to prospectively assess whether treatment with encorafenib and binimetinib prolongs recurrence-free survival (RFS) as compared to placebo in resected pT2b-4bN0 (corresponding to stage HA, B and C melanoma) BRAF V600E/K melanoma patients.
  • Secondary efficacy objectives include:
  • the goal of adjuvant therapy is to reduce the rate of recurrent melanoma and therefore to prolong overall survival (OS).
  • OS overall survival
  • pT2b-pT4b melanoma patients are chosen because they have a large risk of relapse and considerably high 5-year death rate due to melanoma. Therefore, assuming a similar relative risk reduction with adjuvant therapy as seen in stage III melanoma, the absolute benefit of adjuvant therapies is justifiable versus the associated costs in terms of toxicity and the cost of the treatment.
  • encorafenib and binimetinib have been proven to be safe and effective treatment for unresectable or metastatic BRAF V600-mutated melanomas.
  • Sentinel node SN: staged node negative (pNO) and within 12 weeks from SN biopsy surgery;
  • FFPE Form-Fixed, Paraffin-Embedded tumor tissue block or a minimum of 10 slides, optimally up to 15 slides;
  • Adequate bone marrow function i. Absolute neutrophil count (ANC) > 1.5 x 10 9 /L ii. Platelets > 100 x 10 9 /L iii. Hemoglobin > 9.0 g/dL
  • Adequate hepatic function i. Serum total bilirubin ⁇ 1 .5 x ULN and ⁇ 2 mg/dL ii. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ⁇ 2.5 x ULN
  • Adequate cardiac function i. Left ventricular ejection fraction (LVEF) > 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram (ECHO) ii. Mean triplicate QT interval corrected for heart rate according to Fridericia’s formula (QTcF) value ⁇ 480 msec and no history of QT syndrome
  • Negative serum B-HCG human chorionic gonadotropin
  • SNB sentinel node biopsy
  • RVO retinal vein occlusion
  • current risk factors for RVO e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes
  • thromboembolic or cerebrovascular events ⁇ 12 weeks prior to starting study treatment, including stroke, transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or sub- massive) deep vein thrombosis, pulmonary emboli, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis (Note: Patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled); Previous or concurrent malignancy for the past 5 years (must be free from disease for at least 5 years). Except for non-melanoma skin cancer (Basal Cell Carcinomas or Squamous Cell Carcinomas) and any in situ cancer;
  • Impaired cardiovascular function or clinically significant cardiovascular diseases including any of the following:
  • Uncontrolled hypertension defined as persistent systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg despite optimal therapy;
  • CK creatine kinase
  • ULN e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy
  • Impaired gastrointestinal function or disease e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection
  • Impaired gastrointestinal function or disease e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection
  • Impaired gastrointestinal function or disease e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection
  • Impaired gastrointestinal function or disease e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection
  • the experimental arm will receive encorafenib 450 mg (6 x 75 mg oral capsule) QD (daily) per os and binimetinib 45 mg (3 x 15 mg oral tablet) BID (twice a day) per os for 26 weeks.
  • the control arm will receive the relevant placebos of encorafenib and binimetinib, respectively.
  • Patients will regularly undergo clinical examination (including dermatological skin assessment) and imaging (such as chest/abdomen/pelvis computed tomography and/or Magnetic Resonance Imaging (MRI)) while treatment is ongoing, at the end of treatment, and during follow up in order to detect a possible disease recurrence.
  • clinical examination including dermatological skin assessment
  • imaging such as chest/abdomen/pelvis computed tomography and/or Magnetic Resonance Imaging (MRI)
  • MRI Magnetic Resonance Imaging
  • Frequency for evaluation is about every 3 months during the treatment period, then about every 6 months until occurrence of relapse.
  • the study treatment can be discontinued during the treatment period in the case of an unacceptable toxicity or a recurrence of disease.
  • the study can be discontinued in the following cases: consent withdrawal, loss of follow up, or death.
  • stage HA i.e., pT2b or pT3a
  • stage IIB i.e., pT3b or pT4a
  • stage IIC i.e., pT4b
  • RFS Recurrence Free Survival
  • a target HR (hazard ratio) of 0.55 was used for the power calculations.
  • the hazard ratio stratified by the stratification factor stage will be used to describe the treatment effect and the log-rank stratified by stage will be used for statistical testing.
  • the secondary endpoints are:
  • DMFS Distant metastasis-free survival
  • DMFS Distant metastasis-free survival
  • 162 DMFS events are needed to have a power of 90% to detect a HR of 0.60 in the whole study population with a one-sided alpha of 0.025 using the non-stratified log-rank test.
  • the clinical cut-off time for the DMFS analysis will be 5 years from the accrual end, irrespective of the number of DMFS events present at that time.
  • the objective of the HRQoL component is twofold: Assess the difference between the two treatment groups during the treatment duration: it is expected that, while on treatment, patients in the experimental arm will have slightly poorer HRQoL due to the additional toxicities;
  • HRQoL questionnaires will consist of the QLQ-C30 complemented with selected questions to cover any additional relevant issues (such as arthralgia). The questionnaires will be collected at baseline, week 6, 12, 24, 36, 48, and 60 regardless of treatment status or progression status.
  • Observed differences will be compared to the relevant MID magnitude in order to asses clinical relevance on top of statistical significance.
  • Descriptive statistics for all scales will include estimates at each time point and overall graphical profiles, adjusted for missing data.
  • the exploratory endpoints are: • Overall survival (OS), defined as the time from random assignment until death due to any cause.
  • OS Overall survival
  • PFS2 Progression/recurrence-free survival 2
  • BRAF V600E/K mutation Approximately 45% of the patients are expected to have a BRAF V600E/K mutation. In addition, some BRAF-positive patients may eventually not be randomised, for example due to a lack of consent or a disease recurrence in the period of time between surgery and randomisation. Hence, approximately 2200 patients need to be screened in order to randomise about 815 patients.
  • the primary objective of the study is to prospectively assess whether treatment with encorafenib and binimetinib prolongs recurrence-free survival (RFS) as compared to placebo in resected stage II melanoma (especially in melanoma of (1 ) stage pT3b, pT4a, or pT4b, or of (2) stage pT2b or pT3a or of (3) stage pT2b, pT3a, pT3b, pT4a, or pT4b depending on the selected patients) BRAF V600E/K melanoma patients.
  • Secondary efficacy objectives include:
  • the goal of adjuvant therapy is to reduce the rate of recurrent melanoma and therefore to prolong overall survival (OS).
  • pT2b-pT4b e.g. pT2b-pT3a and/or pT3b-pT4b
  • melanoma patients are chosen because they have a high risk of relapse and considerably high 5-year death rate due to melanoma. Therefore, assuming a similar relative risk reduction with adjuvant therapy as seen in stage III melanoma, the absolute benefit of adjuvant therapies is justifiable versus the associated costs in terms of toxicity and the cost of the treatment.
  • encorafenib and binimetinib have been proven to be safe and effective treatment for unresectable or metastatic BRAF V600-mutated melanomas.
  • About 800-900 patients (e.g. about 815 patients) with a BRAF V600E/K mutation will be randomised 1 :1 to receive either treatment with encorafenib and binimetinib or placebo).
  • SNB Sentinel node biopsy
  • FFPE Form-Fixed, Paraffin-Embedded tumor tissue block or a minimum of 10 slides, optimally up to 20 slides;
  • Adequate bone marrow function i. Absolute neutrophil count (ANC) > 1.5 x 10 9 /L ii. Platelets > 100 x 10 9 /L iii. Hemoglobin > 9.0 g/dL
  • Adequate electrolytes defined as serum potassium and magnesium levels within institutional normal limits.
  • Adequate hepatic function i. Serum total bilirubin ⁇ 1 .5 x ULN and ⁇ 2 mg/dL ii. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ⁇ 2.5 x ULN
  • Adequate cardiac function i. Left ventricular ejection fraction (LVEF) > 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram (ECHO)
  • LVEF Left ventricular ejection fraction
  • MUGA multigated acquisition
  • ECHO echocardiogram
  • Adequate coagulation function defined as International Normalized Ratio (INR) ⁇ 1.5x ULN unless the patient is receiving anticoagulant therapy as long as Partial Thromboplastin Time (PTT) and activated Partial Thromboplastin Time (aPTT) is within the therapeutic range;
  • Negative serum B-HCG human chorionic gonadotropin
  • RVO retinal vein occlusion
  • current risk factors for RVO e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes
  • thromboembolic or cerebrovascular events ⁇ 12 weeks prior to starting study treatment, including stroke, transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or sub- massive) deep vein thrombosis, pulmonary emboli, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis (Note: Patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled);
  • Impaired cardiovascular function or clinically significant cardiovascular diseases including any of the following: History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ⁇ 6 months prior to randomization;
  • Uncontrolled hypertension defined as persistent systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg despite optimal therapy;
  • CK creatine kinase
  • ULN e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy
  • Patients with active bacterial, fungal, or viral infection including, but not limited to: HBV, HCV, and known HIV or AIDS-related illness, or an infection requiring systemic therapeutic treatment within 2 weeks prior to randomization;
  • Impaired gastrointestinal function or disease e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection
  • Impaired gastrointestinal function or disease e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection
  • Impaired gastrointestinal function or disease e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection
  • the experimental arm will receive encorafenib 450 mg (6 x 75 mg oral capsule) QD (daily) per os and binimetinib 45 mg (3 x 15 mg oral tablet) BID (twice a day) per os for a maximum of 12 months, e.g. for 26 weeks or for 12 months.
  • the control arm will receive the relevant placebos of encorafenib and binimetinib, respectively.
  • Patients will regularly undergo clinical examination (including dermatological skin assessment) and imaging (such as chest/abdomen/pelvis computed tomography and/or Magnetic Resonance Imaging (MRI)) while treatment is ongoing, at the end of treatment, and during follow up in order to detect a possible disease recurrence.
  • clinical examination including dermatological skin assessment
  • imaging such as chest/abdomen/pelvis computed tomography and/or Magnetic Resonance Imaging (MRI)
  • MRI Magnetic Resonance Imaging
  • Frequency for clinical examination is about every 1 months during the treatment period, then about every 3 months until year 3 from the time of random assignment, then about every 6 months until year 5 from the time of random assignment, then about every year until year 10 from the time of random assignment.
  • Frequency for imaging is about every 6 months for the first 3 years from the time of random assignment, and thereafter about every year until 10 years from the time of random assignment.
  • the study treatment can be discontinued during the treatment period in the case of an unacceptable toxicity or a recurrence of disease (defined as any local, loco- regional recurrence; new melanoma which is ulcerated or thick (Breslow thickness > 1 mm) or which requires a treatment other than surgery; or distant metastases).
  • an unacceptable toxicity or a recurrence of disease defined as any local, loco- regional recurrence; new melanoma which is ulcerated or thick (Breslow thickness > 1 mm) or which requires a treatment other than surgery; or distant metastases).
  • the study can be discontinued in the following cases: consent withdrawal, loss of follow up, or death.
  • stage HA i.e., pT2b or pT3a
  • stage IIB i.e., pT3b or pT4a
  • stage IIC i.e., pT4b
  • RFS Recurrence Free Survival
  • a target HR (hazard ratio) of 0.55 was used for the power calculations.
  • the hazard ratio stratified by the stratification factor stage will be used to describe the treatment effect and the log-rank stratified by stage will be used for statistical testing.
  • the secondary endpoints are:
  • DMFS Distant metastasis-free survival
  • OS Overall survival
  • DMFS Distant metastasis-free survival
  • 162 DMFS events are needed to have a power of 90% to detect a HR of 0.60 in the whole study population with a one-sided alpha of 0.025 using the non-stratified log-rank test.
  • the clinical cut-off time for the DMFS analysis will be 5 years from the accrual end, irrespective of the number of DMFS events present at that time.
  • AEs The incidence and severity of advert events (AEs) and serious advert events (SAEs) are graded according to the NCI CTCAE V5.0 and aim to assess the safety and tolerability of the treatment.
  • HRQoL questionnaires will consist of the QLQ-C30 complemented with selected questions to cover any additional relevant issues (such as arthralgia).
  • the questionnaires will be collected at baseline, and months 3, 6, 9, 12, 18, 24 and 30 (+/- 7 days) regardless of treatment status or progression status.
  • Analysis of the difference between the two study intervention arms during the treatment period For each patient, the change from baseline to the average of the scores between randomization and last dose of treatment will be calculated. In the main analysis, the mean of this summary statistic will be compared between the two treatment groups. The difference between the treatment arms in the mean change from baseline will be calculated for each imputed dataset and the Rubin’s rules will be used to combine the estimates.
  • a non-inferiority test will be performed for the hypothesis that the difference between the treatment arms is smaller than the threshold of clinical relevance, using a one-sided significance level of 0.025.

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Abstract

La présente invention concerne une association pharmaceutique destinée à être utilisée comme traitement adjuvant après résection d'un mélanome, le mélanome qui a été réséqué étant un mélanome de stade II, et l'association pharmaceutique comprenant des quantités thérapeutiquement efficaces, indépendamment, a) d'encorafénib ou d'un sel pharmaceutiquement acceptable de celui-ci, b) de binimétinib ou d'un sel pharmaceutiquement acceptable de celui-ci et éventuellement au moins un support pharmaceutiquement acceptable.
PCT/EP2021/077466 2020-10-05 2021-10-05 Association d'encorafénib et de binimétinib comme traitement adjuvant pour un mélanome de stade ii réséqué WO2022074011A1 (fr)

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