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WO2014066745A1 - Compositions comprenant du polyéthylèneglycol dans le traitement du carcinome malpighien de la tête et du cou - Google Patents

Compositions comprenant du polyéthylèneglycol dans le traitement du carcinome malpighien de la tête et du cou Download PDF

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Publication number
WO2014066745A1
WO2014066745A1 PCT/US2013/066784 US2013066784W WO2014066745A1 WO 2014066745 A1 WO2014066745 A1 WO 2014066745A1 US 2013066784 W US2013066784 W US 2013066784W WO 2014066745 A1 WO2014066745 A1 WO 2014066745A1
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Prior art keywords
composition
peg
thereabout
hnscc
subject
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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.)
Ceased
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PCT/US2013/066784
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English (en)
Inventor
Ian David Cox
Christopher Alexander HEWSON
Hemand K. ROY
Ramesh K. WALI
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Norgine BV
NorthShore University HealthSystem
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Norgine BV
NorthShore University HealthSystem
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Publication of WO2014066745A1 publication Critical patent/WO2014066745A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • compositions comprising polyethylene glycol in the therapy of Head and Neck
  • the present invention concerns compositions for use in the prophylaxis and/or treatment of Head and Neck Squamous Cell Carcinoma (HNSCC).
  • HNSCC Head and Neck Squamous Cell Carcinoma
  • the present invention also concerns methods for preventing and/or treating such carcinomas.
  • Other aspects, objects and advantages of the present invention will be apparent from the description below.
  • Head and neck cancer is estimated to have caused approximately 7900 deaths in the U.S. in 2010 (Pfister D.G et al; J. Natl. Compr. Cane. Netw. 2011 ; 9:596-650).
  • Common risk factors for developing this disease include the smoking or chewing of tobacco, consumption of alcohol, chewing of betel nut and/or infection with human papillomavirus (HPV).
  • Head and neck squamous cell carcinoma accounts for approximately 3 percent of all cancers in the United States.
  • HNSCC includes any cancer of the head and neck that begins in squamous cells.
  • HNSCC ulcerative colitis .
  • This aggressive epithelial malignancy implicates the mucosal lining of the upper aerodigestive track including the oral cavity, oropharynx and larynx.
  • HNSCC retinoic acid
  • beta-carotene have to-date demonstrated minimal efficacy and are marred with toxicity.
  • 5-year survival rate for HNSCC has not greatly improved over the last 4 to 5 decades.
  • HNSCC patients have a worsening quality of life due to debilitating changes in facial appearance, speech, swallowing and breathing.
  • the present invention concerns compositions and methods for preventing and/or treating HNSCC.
  • compositions for use in preventing and/or treating HNSCC in a subject comprising polyethylene glycol (PEG) at a concentration of 30mg/ml or greater wherein the PEG has a weight average molecular weight (M w ) of about 800 daltons or greater.
  • PEG polyethylene glycol
  • compositions for use in such a method are also provided.
  • the composition of the invention comprises (or consists essentially of) PEG at a concentration of 30mg/ml or greater, wherein the PEG has a M w preferably of 800 daltons or thereabout to 20,000 daltons or thereabout, for example 2000 daltons or thereabout to 15,000 daltons or thereabout, more preferably 3000 or thereabout to 12,000 or thereabout, for example, 3000 or thereabout to 10000 or thereabout, most preferably 3200 or thereabout to 9000 or thereabout (e.g.
  • PEG has a M w of 3350 or thereabout, 4000 or thereabout, 8000 or thereabout, 10000 or thereabout, 15000 to 20000 or thereabout. Of these, PEG having a M w of 8000 or thereabout or 10000 or thereabout is particularly preferred.
  • the invention provides a composition for use in the prophylaxis and/or treatment of HNSCC as described in various aspects and embodiments of the invention herein, the composition comprising (e.g. as its sole therapeutically active constituent) PEG having a M w as described herein at a concentration of 30mg/ml or greater.
  • the present invention provides a method for preventing and/or treating HNSCC in a subject comprising topically administering to said subject an effective amount of the composition of the invention.
  • Compositions for use in such a method are also provided.
  • the present invention provides a method for reducing or suppressing HNSCC initiation and/or proliferation in a subject comprising topically administering to the region of the subject afflicted with pre-existing HNSCC and/or a pre-malignant lesion and/or oral leukoplakia, an effective amount of the composition of the invention.
  • Compositions for use in such a method are also provided.
  • the present invention provides a method for preventing and/or treating HNSCC in a subject comprising locoregionally administering to the subject an effective amount of the composition of the invention.
  • Compositions for use in such a method are also provided.
  • the present invention further provides a composition for locoregional use in the prevention and/or treatment of HNSCC in a subject afflicted with said disease wherein the composition comprises PEG as described herein.
  • a method for preventing and/or treating HNSCC in a subject wherein an effective amount of the composition of the invention is administered to the subject from 1 to 5 time(s) a day, preferably 2 to 4 times a day, more preferably 3 times a day.
  • Compositions for use in such a method are also provided.
  • the present invention provides a method for reducing or suppressing HNSCC proliferation in the head and neck of a subject comprising administering to the subject (preferably topically administering) an effective amount of the composition of the invention to one or more of: the lip, oral cavity (including the tongue, buccal mucosa, alveolar ridge, retromolar trigone, gums, floor of mouth, hard palate), salivary glands, nasal cavity (including nasopharynx), paranasal sinuses, pharynx (including oropharynx such as the base of tongue, soft palate, tonsillar pillar and fossa) hypopharynx (including pyriform sinus, lateral pharyngeal wall, posterior pharyngeal wall, postcricoid pharynx), and larynx
  • supraglottis e.g. false cords, arytenoids, epiglottis, arytenoepiflottic fold
  • glottis subglottis of the subject.
  • the present invention further provides methods for preventing and/or treating HNSCC in a subject as described in various aspects and embodiments of the invention herein, wherein the HNSCC has afflicted one or more of: the lip, oral cavity (including the tongue, buccal mucosa, alveolar ridge, retromolar trigone, gums, floor of mouth, hard palate), salivary glands, nasal cavity (including nasopharynx), paranasal sinuses, pharynx (including oropharnyx such as the base of tongue, soft palate, tonsillar pillar and fossa) hypopharnyx (including pyriform sinus, lateral pharyngeal wall, posterior pharyngeal wall, postcricoid pharynx), and larynx (including supraglottis (e.g.
  • a preferred embodiment of the invention is a method for preventing and/or treating HNSCC in a subject wherein the HNSCC has afflicted the oral cavity (or anatomical site thereof) comprising administering (for example locoregionally and/or topically administering) to the oral cavity an effective amount of the composition of the invention.
  • Compositions for use in such a method are also provided.
  • the present invention provides a method for reducing or inhibiting Epidermal Growth Factor Receptor (EGFR) surface expression and/or phosphorylation of the receptor in the squamous cells of the head and/or neck of a subject, the method comprising administering to the subject an effective amount of the composition of the invention.
  • EGFR Epidermal Growth Factor Receptor
  • the present invention comprises a method for preventing and/or treating HNSCC in a subject which method comprises co-administering to the subject an effective amount of the composition of the invention with an effective amount of one or more additional therapeutic agent(s).
  • compositions for use in this method optionally further comprising the one or more additional therapeutic agent(s) are also provided.
  • an effective amount of a therapeutic agent such as an anti-EGFR agent (for example an anti-EGFR antibody such as cetixumab);
  • step (b) an effective amount of a composition of the invention.
  • step (a) occurs before step (b).
  • step (a) occurs after step (b).
  • step (a) and step (b) occur concurrently.
  • a method for preventing and/or treating HNSCC in a subject in remission of HNSCC comprising administering to the subject an effective amount of the composition of the invention.
  • the subject may be in partial or complete remission.
  • Compositions for use in such a method are also provided.
  • a method for ameliorating (such as preventing) the recurrence of HNSCC in a subject in remission of that disease comprising administering to the subject an effective amount of the composition of the invention.
  • Compositions for use in such a method are also provided.
  • compositions for use in such a method are also provided.
  • compositions for use in such a method are also provided.
  • a method for regressing a HNSCC carcinoma in a subject comprises (a) administering an effective amount of a composition of the invention.
  • compositions for use in such a method, such as described herein, are also provided.
  • the HNSCC carcinoma over-expresses EGFR.
  • the EGFR expression status of the HNSCC carcinoma may be determined according to standard methods, techniques and kits such as described herein.
  • the method further comprises (b) resecting and/or ablating the HNSCC carcinoma and/or administering an effective amount of a therapeutic agent.
  • step (b) may occur after step (a).
  • the present invention may reduce the degree of trauma or treatment related adverse events to the subject resulting from subsequent therapeutic procedures.
  • a method for preventing and/or treating HNSCC in a subject comprising
  • step (b) administering to the subject an effective amount of the composition of the invention.
  • step (a) occurs before step (b).
  • the composition of the invention is administered to the resected/ablated region of the subject.
  • step (b) occurs before step (a).
  • step (a) and step (b) occur concurrently.
  • the invention further provides the use of the PEG having a M w of 800 or greater and a concentration of 30mg/ml or greater in the manufacture of a medicament for the treatment and/or prophylaxis of HNSCC, as described in various aspects and embodiments herein.
  • the invention further provides the use of PEG having a M w of 800 or greater and a concentration of 30mg/ml as described in various aspects and embodiments herein in the manufacture of a medicament, for regressing a squamous cell carcinoma such as HNSCC.
  • Figure 6 Inhibition of cellular proliferation in the human SCC-9 cell-line after 72 hours incubation with (A) PEG-3350, (B) PEG-8000 run 1 and 2, (C) PEG-8000 run 3, (D) PEG-10000 run 1 and 3 and (E) PEG-10000 run 2.
  • compositions of the Invention are Compositions of the Invention.
  • compositions of the invention may comprise PEG as its sole therapeutically active constituent or may contain one or more therapeutic agents (particularly anti-cancer agents) as described in more detail below.
  • compositions of the present invention are aqueous compositions.
  • Compositions of the present invention depending, in particular, on the intended preparation (described in more detail below), may be in the form of a solid, semi-solid (e.g. slurry or paste) or liquid.
  • polyethylene glycol generally known as poly(oxyethylene) or poly(ethylene oxide) (PEO), refers to a polymer of ethylene oxide as well known to those skilled in the art.
  • the polyethylene glycol (PEG) used in the invention typically has the general formula H-(OCH 2 CH 2 ) n OH.
  • other polyethylene glycol compounds may be used such as end-capped structures and polyoxyethylenes that include minor amounts of alkylene oxide units other than ethylene oxide.
  • PEG used in compositions of the invention preferably has a weight average molecular weight (M w ) in a range wherein the lower limit of the range is selected from the group consisting of: 800,1000, 2000, 3000, 4000, 6000; and an upper limit of the range is, selected independently, from the group consisting of: 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12,000, 15,000, 20,000.
  • Preferred ranges are wherein the lower limit is 3000 or 4000 and the upper limit is, selected independently, 5000, 6000, 7000, 8000, 9000, 10000, 12000.
  • the PEG may be 'PEG 3350', 'PEG 4000', 'PEG 8000', 'PEG 10000' as defined in some national or regional pharmacopeias.
  • suitable PEGs recognized in some national or regional pharmacopoeias include Macrogols, for example Macrogol 3350, Macrogol 4000, Macrogol 8000, Macrogol 10000.
  • Macrogol 8000 is particularly preferred.
  • the PEG is not systemically absorbed to any significant extent when topically administered to the subject.
  • compositions of the present invention comprise PEG at a concentration of 30mg/ml or greater.
  • compositions of the present invention comprise PEG at a concentration in the range of 30mg/ml up to, and including, the maximum solubility available in that composition, e.g. an aqueous solution (for example, at 25°c) for the PEG concerned (having regard, amongst other things, to its M w ).
  • the maximum solubility available of PEG may be affected by factors such as the prevailing temperature when the composition is prepared, what other constituents (such as described herein) are present in the composition, pH and the like. Such matters are routine considerations for the skilled artisan.
  • compositions of the present invention comprise PEG at a high concentration with respect to the maximum solubility available, i.e. 0.5 fold or greater, 0.6 fold or greater,0.7 fold or greater,0.8 fold or greater, or 0.9 fold or greater of the maximum solubility available for the PEG concerned in that composition (having regard to the matters described herein).
  • compositions of the present invention comprise PEG having a concentration of at least l lOmg/ml or greater, at least 120mg/ml or greater, preferably, at least 130mg/ml or greater, e.g. 140mg/ml or greater such as at least 150mg/ml or greater, at least 200mg/ml or greater or 300mg/ml or greater; having regard to the maximum solubility available for the PEG concerned in the composition.
  • concentration of PEG is referred to in units of mg/ml. It is well within the purview of the skilled artisan to convert this unit into equivalent molarity (such as mM).
  • compositions of the present invention comprise (or consist essentially of) PEG having a concentration in a range wherein the lower limit is 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200mg/ml and the upper limit, selected independently, is 100,110, 120, 130, 140, 150, 160, 170,180,190, 200, 300, 350, 400mg/ml, or the upper limit is the maximum solubility available for the PEG concerned in the composition, having regard to the matters described herein.
  • compositions of the present invention may comprise PEG at 120mg/ml to 200 or 300mg/ml, 130mg/ml to 200 or 300mg/ml, 140mg/ml to 200 or 300mg/ml, 150mg/ml to 200 or 300mg/ml, 160mg/ml to 200 or 300mg/ml, or 160mg/ml up to, and including the maximum solubility available for the PEG concerned in the composition.
  • Preferred ranges for PEGs having a particular M w are set forth below.
  • compositions of the present invention comprise (or consist essentially of) PEG having a weight average molecular weight (M w ) in a range wherein the lower limit of the range is selected from the group consisting of: 800,1000, 2000, 3000, 4000, 6000; and an upper limit of the range is, selected independently, from the group consisting of: 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12,000, 15,000, 20,000.
  • M w weight average molecular weight
  • Preferred ranges are wherein the lower limit is 3000 or 4000 and the upper limit is, selected independently, 5000, 6000, 7000, 8000, 9000, 10000, 12000, the composition having a PEG concentration in a range wherein the lower limit is 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200mg/ml and the upper limit, selected independently, is 100,
  • compositions of the present invention may comprise PEG having a Mw of 3000 to 12,000, preferably 3000 to 10000, such as 3350, 4000, 8000 or 10000 and a concentration of 120mg/ml to 200 or 300mg/ml, 130mg/ml to 200 or 300mg/ml, 140mg/ml to 200 or 300mg/ml, 150mg/ml to 200 or 300mg/ml, 160mg/ml to 200 or
  • compositions of the present invention may comprise PEG having a M w of 3350 ('PEG 3350') at a concentration of 30mg/ml to 670mg/ml.
  • Preferred concentration ranges of PEG 3350 are wherein the lower limit is 30, 40, 50, 60, 70,80,90, 100, 120, 150, 200mg/ml and the upper limit, selected independently, is 150, 200, 250,300, 400,500,600 or 670mg/ml.
  • More preferred ranges are 150mg/ml to 670mg/ml, for example, 167.5mg/ml to 335mg/ml or 167.5mg/ml to 670mg/ml or 335mg/ml to 670mgl/ml.
  • Particularly preferred concentrations are 167.5mg/ml, 200mg/ml 335mg/ml and 670mg/ml or thereabout.
  • Compositions of the invention comprising (or consisting essentially of) PEG 3350 at a concentration of 200mg/ml is particularly preferred.
  • compositions of the present invention may comprise PEG having a M w of 10000 ('PEG 10000') at a concentration of 30mg/ml to 300mg/ml.
  • Preferred concentration ranges of PEG 10000 are wherein the lower limit is 30, 40, 50, 60, 70, 80, 90, 100, 150mg/ml and the upper limit, selected independently, is 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300mg/ml.
  • Particularly preferred PEG 10000 ranges are 70 to 400mg/ml, 100 to 300mg/ml, 150 to 300mg/ml.
  • compositions of the invention comprising (or consisting essentially of) PEG 10000, at a concentration of
  • 300mg/ml or thereabout is a particularly preferred embodiment of the invention as it combines favorable efficacy and formulation properties.
  • compositions of the present invention may comprise PEG having a M w of 8000 ('PEG 8000') at a concentration of 30mg/ml to 400mg/ml.
  • Preferred concentration ranges of PEG 8000 are wherein the lower limit is 30, 40, 50, 60, 70, 80, 90, 100, 150mg/ml and the upper limit, selected independently, is 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390 or 400mg/ml.
  • Particularly preferred PEG 8000 concentrations are 50,100, 200 and 400mg/ml or thereabout.
  • Compositions of the invention comprising (or consisting essentially of) PEG 8000, at a concentration of 200mg/ml or thereabout is also a particularly preferred embodiment of the invention as it combines favorable efficacy and formulation properties.
  • compositions of the present invention may further comprise other constituents such as another therapeutic agent (see below), and one or more excipients.
  • excipients include one or more electrolytes such as sodium chloride, potassium chloride, sodium bicarbonate, sulphate such as sodium sulphate.
  • compositions of the invention comprise sodium chloride and potassium chloride and optionally sodium bicarbonate.
  • compositions of the invention may comprise one or more sweetener(s) (such as aspartame, acesulfame potassium (acesulfame K), sucralose and saccharine and combinations thereof) and one or more flavouring(s) (such as orange, lemon-lime, lemon, citrus, chocolate, tropical fruit, aloe vera, tea, strawberry, grapefruit, blackcurrant, pineapple and vanilla).
  • Compositions may further comprise ascorbate and/or citrate.
  • Compositions of the invention may further comprise preservatives and other additives such as, for example, antimicrobials, anti-oxidants, pharmaceutically acceptable carriers, chelating agents, and inert gases and the like as known and called for by acceptable pharmaceutical practice.
  • compositions of the invention may be presented in a variety of preparations.
  • compositions of the invention may be prepared in the form of an aqueous solution or suspension (for example a mouthwash), emulsion, paste (e.g. toothpaste), cream, balm (e.g. lip balm), ointment, foam, paint, sponge, gel, chewing gum, spray, lozenge, troche, syrup (e.g. viscous syrup), linctus, slurry, film (e.g. orodispersible film), tablet (e.g. orodispersible tablet), capsule (e.g. liquid-gel capsule), granule, caplet, buccal patch.
  • Particularly preferred preparations of compositions of the invention include solutions, suspensions, linctus and paints.
  • compositions of the invention may be particularly apt.
  • the composition may be prepared as a lip balm or cream.
  • a mouthwash, spray or lozenge may be particularly appropriate.
  • the preparation is a mouthwash, it maybe gargled or swirled around the mouth before swallowing or expelling.
  • Compositions of the invention may be prepared as an aerosol preparation, particularly for administration to the nasal, buccal and oropharynx.
  • Compositions of the invention may also be prepared as non-pressured preparations, such as in a nebulizer or an atomizer.
  • composition of the invention may be a linctus preparation, a preparation form well known to those skilled in the art. This form may assist in increasing the contact time between PEG and the target tissue such as the pharynx and/or larynx mucosa and may be particularly appropriate in the prophylaxis and/or treatment of HNSCC at these anatomical sites.
  • compositions of the invention are administered topically to the subject. Topical administration, in the context of the present invention, refers to the application of a composition of the invention to a surface of the subject's body. Topical administration includes application to an internal surface of the subject, for example the buccal mucosa. Compositions of the present invention may be administered to the target area (e.g.
  • compositions of the present invention are applied to a region of the carcinoma that is accessible at the surface of subject's body, for example, surface exposed HNSCC that has afflicted the lip, tongue, buccal mucosa (e.g. buccal floor and/or roof), nasal cavity, pharynx, larynx and anatomical sites thereof.
  • administration may include per os administration of compositions of the invention.
  • topical administration may include swallowing a composition of the invention. Accordingly, contact between the composition of the invention and the surface exposed region of the carcinoma (if present) is enabled as the composition passes into the stomach via the pharynx.
  • composition of the invention to be employed therapeutically will depend, for example, upon the therapeutic and treatment objectives (e.g. prophylaxis or treatment, or both), the route of administration, the age, body mass, condition of the subject undergoing treatment or therapy (for example, by assessing the subject's performance status and/or other co-morbidities ), stage and/or aggressiveness (e.g. TNM score) of the carcinoma (if present), any auxiliary or adjuvant therapies being provided to the subject, and on the subjects previous response (if appropriate) to therapy with compositions of the invention.
  • the duration of therapy with compositions of the invention depends, in part, on the considerations given above. Such considerations are within the purview of the attending physician or healthcare professional.
  • An effective amount of the composition of the invention may be determined, at least in part, by the desired reduction in EGFR surface expression in the target tissue (for example, a HNSCC carcinoma).
  • An effective amount of the composition of the present invention may produce in the target tissue a reduction in EGFR expression of at least 30% (or thereabout), for example, at least 40%, compared to the expression observed prior to contact with the composition.
  • the degree of EGFR reduction may be determined using methods described in the examples herein.
  • the degree of EGFR reduction may be determined using flow cytometry, as described, for example, in PCT/US2012/035434 or otherwise well known to the skilled artisan.
  • the EGFR expression status of a target tissue may be determined using standard methods and kits (for example EGFR pharmDxTM, available from Dako Denmark A/S, Glostrup,
  • the composition of the invention is topically administered to the subject so as to coat the target tissue (e.g. the surface exposed region of a HNSCC carcinoma, and preferably the local tissue region thereof).
  • Compositions of the present invention may be repeatedly administered to the target tissue of the subject to maintain or renew the coating of the target tissue.
  • the present invention provides a method of preventing and/or treating HNSCC in a subject as described in various aspects and embodiments described herein, the method comprises coating the target tissue of the subject with the composition of the invention.
  • the method comprises coating the target tissue so as to produce a PEG concentration at the target tissue/composition interface of greater than 30mg/ml, preferably greater than 50mg/ml, more preferably greater than lOOmg/ml such as 150mg/ml or greater, e.g. 200mg/ml or greater. Since PEG at the M w described herein is known to be generally well tolerated, even at relatively high concentrations, with a low risk of any serious adverse events, the subject, attending physician or healthcare professional can readily administer an effective amount of the composition of the invention to meet or exceed the PEG concentration at the target tissue/composition interface as set forth herein.
  • the method comprises coating the target tissue (e.g. surface exposed carcinoma and preferably the local region thereof) with a composition comprising PEG 8000 or PEG 10000 having a concentration of 150mg/ml to 300mg/ml, preferably 200mg/ml to 300mg/ml.
  • a composition comprising PEG 8000 or PEG 10000 having a concentration of 150mg/ml to 300mg/ml, preferably 200mg/ml to 300mg/ml.
  • Particular examples of compositions of the invention comprise PEG 8000 at a concentration of 200mg/ml or thereabout, or PEG 10000 at a concentration of 300mg/ml.
  • An effective amount of PEG for use in the prophylaxis of HNSCC may differ from an effective amount of PEG for use in the treatment of HNSCC.
  • a lower amount of PEG is required than typically used in a treatment setting.
  • compositions of present invention may be used in conjunction with one or more therapeutic agents for the prophylaxis and/or treatment of HNSCC.
  • compositions of the invention may be co-administered with the one or more therapeutic agent(s).
  • coadministered means the coordinated administration of compositions of the invention with one or more therapeutic agents to prevent and/or treat HNSCC.
  • Such coordinated administration between compositions of the invention and one or more therapeutic agent(s) may be simultaneous, sequential or separate.
  • compositions of the invention examples include radiation therapy and anti-cancer agents.
  • anti-cancer agent means a therapeutic agent that is capable of inhibiting the initiation and/or proliferation of cancer and/or promoting cell death (e.g. by apoptosis) in cancer cells such as squamous cell carcinomas, particularly those of the head and neck.
  • Such therapeutic agents include those approved by national or regional regulatory authorities for such use.
  • anti-cancer agents include agents that target EGFR expression and/or function (for example by inhibiting functional signaling of the EGFR), herein referred to as "anti- EGFR" agents".
  • anti-EGFR agents include anti-EGFR antibodies such as cetixumab, panitumumab, zalutumab, nimotuzumab.
  • Other anti-EGFR agents include Erlotinib, Gefitinib, Lapatinib, BIBW-2992.
  • anti-cancer agents include agents that target VEGFR expression and/or function ("anti-VEGFR agents").
  • anti-VEGFR agents include bevacizumab, sorafenib, sunitinib, vandetanib.
  • anti-cancer agents include agents that target IGF-IR expression and/or function (“anti-IGF-lR agents”).
  • anti-IGF-lR agents include figitumumab and cixtumumab.
  • anti-cancer agents include agents that inhibit the mammalian target of rapamycin ("mTOR agents").
  • mTOR agents include Temsirolimus, Everolimus.
  • anti-cancer agents include platinating agents such as cisplatin and carboplatin; taxanes such as paclitaxel and docetaxel; folate anti-metabolites such as pemetrexed; fluorouracil, methotrexate.
  • anti-cancer agents examples include Dasatinib, Ionafarnib and Bortezomib.
  • compositions of the present invention comprise the PEG as described herein together (for example in intimate physical admixture) with an effective amount of one or more therapeutic agents, e.g. anti-cancer agents, such as described above.
  • the composition comprises PEG that is not conjugated to the therapeutic agent such as an anticancer agent.
  • an "effective amount" of one or more therapeutic agent(s) need not necessarily be the same weight amount as an effective amount of PEG. It will also be apparent that when considering the term “effective amount” in relation to radiation therapy, an appropriate dose unit (for example gray (gy) or rad) should be deployed.
  • an appropriate dose unit for example gray (gy) or rad
  • a kit comprising a composition of the invention together with at least one composition of one or more anti-cancer agents such as described above, optionally together with instructions for use.
  • the present invention provides a method for preventing and/or treating HNSCC in a subject comprising (or consisting essentially of) administering an effective amount of the composition of the invention.
  • the present invention also provides compositions for use in the prophylaxis and/or treatment of HNSCC in a subject.
  • compositions of the present invention may be of particular use in treating HNSCC that over- express surface EGFR.
  • the EGFR expression status of a squamous cell carcinoma in a subject may be determined according to standard methods and kits (for example EGFR pharmDxTM, available from Dako Denmark A/S, Glostrup, Denmark).
  • the method is for preventing HNSCC. In another embodiment, the method is for treating HNSCC. In a further embodiment, the method is for preventing and treating HNSCC.
  • prophylaxis and “preventing” and grammatical variations thereof means inhibiting the initiation of HNSCC and/or inhibiting the progression of a pre- malignant pathology of the epithelium (such as oral leukoplakia) and/or early stage carcinoma to a later stage carcinoma.
  • prophylaxis methods of the invention are performed prior to a positive diagnosis of HNSCC.
  • treat and grammatical variations thereof means inhibiting the proliferation of HNSCC and/or promoting cell death in HNSCC.
  • treat includes "cure", although the term cure does not necessarily mean the complete restoration of health with respect to the malignancy. Those skilled in the art recognize that a treatment may have varying degrees of curative effect and as such are encompassed by the term "treat”.
  • the present invention further provides a method for preventing HNSCC in a subject in remission of that disease comprising (or consisting essentially of) administering to the subject an effective amount of a composition of the invention.
  • the remission may be total or partial.
  • Compositions for use in such a method are also provided.
  • the present invention further provides a method for treating locally advanced and/or metastatic HNSCC in a subject comprising (or consisting essentially of) administering to the subject an effective amount of the composition of the invention.
  • a method for preventing and/or treating HNSCC in a subject susceptible to developing HNSCC comprising (or consisting essentially of) administering to the subject an effective amount of the composition of the invention.
  • Such subjects include those with a history and/or concurrent use of: tobacco (smoking and/or chewing), excessive alcohol intake, betel nut chewing.
  • Such subjects include those that are infected with HPV (particularly with serotype HPV 16) and/or immunocompromised and/or with a prior or familial history of (or predisposition to) developing HNSCC.
  • the invention further provides a method for preventing and/or treating HNSCC in a subject that is HPV negative comprising (or consisting essentially of) administering to the subject an effective amount of the composition of the invention.
  • compositions for use in such methods are also provided.
  • a method for preventing HNSCC in a subject afflicted with oral leukoplakia and/or erythroplakia comprising (or consisting essentially of) administering to the subject an effective amount of the composition of the invention.
  • compositions for use in such a method are also provided.
  • a method for preventing HNSCC in a subject afflicted with pre-malignant alterations to the epithelium of the upper aerodigestive tract comprising (or consisting essentially of) administering to the subject an effective amount of a composition of the invention.
  • Pre-malignant alterations may arise as a result of "field cancerization".
  • Field cancerization refers to a process whereby the epithelium undergoes alterations (which may be multiple and independent of one another) that primes the epithelium for transformation. These alterations may be evident in subtle changes to the epithelium vasculature, cellular dysplasia and other molecular changes to the epithelium.
  • This embodiment may be particularly apt in preventing HNSCC in subjects with a prior history of (or predisposition to) HNSCC.
  • a method for preventing and/or treating HNSCC in a subject which method comprises (or consists essentially of):
  • a therapeutic agent such as radiation therapy and/or an anti-cancer agent, e.g. an anti-EGFR agent (for example an anti-EGFR antibody such as cetixumab);
  • an anti-EGFR agent for example an anti-EGFR antibody such as cetixumab
  • step (b) and step (a) occur concurrently.
  • step (b) occurs after step (a).
  • step (b) occurs before step (a).
  • the method further comprises (or further consists essentially of) the step of (c) administering an effective amount of a therapeutic agent e.g. radiation therapy and/or an anti-cancer agent such as an anti-EGFR agent (for example, an anti-EGFR antibody such as cetixumab).
  • step (b) may occur after step (a) and before step (c). Therefore, an effective amount of the composition of the invention may be administered between cycles of treatment with other therapeutic agents, particularly radiation and/or anti-cancer agents.
  • the therapeutic agents of step (a) and step (c) need not necessarily be the same. Where the therapeutic agents of step (a) and step (c) are the same, the posology followed in step (a) and step (c) need not necessarily be the same.
  • an effective amount of the composition of the invention may be used to treat HNSCC in a subject in conjunction with resection and/or ablation of a HNSCC carcinoma. Accordingly, there is provided a method for treating HNSCC in a subject comprising (or consisting essentially of) the steps of:
  • Step (b) administering to the subject an effective amount of the composition of the invention.
  • Step (a) may occur either before step (b) or after step (b).
  • step (c) comprising the step of administering an effective amount of a therapeutic agent as described herein.
  • Step (c) may occur after step (a) and before, after or concurrently with step (b). Where step (b) occurs after step (a), it is preferred that the composition of the invention is administered to the resected/ablated region of the subject.
  • an effective amount of PEG may be administered at the site(s) and local region of the surgical resection/ablation e.g. locoregional administration.
  • an effective amount of the composition of the invention may be administered (e.g. locoregionally administered) to a lesion of the head and neck suspected of being afflicted with HNSCC.
  • the present invention further provides methods for the multi-modal treatment of HNSCC
  • the method comprising administering an effective amount of the composition of the invention.
  • the present invention provides a method for reducing or inhibiting EGFR expression and/or phosphorylation in the squamous cells of the head and neck of a subject, by administering to the subject an effective amount of the composition of the invention.
  • the dosages and duration of use is dependent on the amount of reduction of EGFR expression or phosphorylation desired.
  • the composition of the invention is administered to the subject at least 1 to 14 days, however PEG can be administered for a longer period, or until the reduction of expression and/or phosphorylation of EGFR in the target tissue is achieved.
  • a method for reducing the tumor burden i.e. tumor number and/or volume
  • administering an effective amount of the composition of the invention.
  • compositions for use in such as method are also provided.
  • the subject referred to in this specification is preferably a mammal and more preferably human.
  • SCC-25 cells (CRL- 1628; American Type Tissue Culture, Rockville, MD, USA) were cultured in DMEM/F-12 media (containing 2.5 mM L-glutamine, 15 mM HEPES, 0.5 mM sodium pyruvate and 1200 mg/L sodium bicarbonate) supplemented with 400 ng/mL of hydrocortisone (Sigma/Aldrich Inc.,St.Louis, MO), 10% v/v fetal bovine serum (FBS), and 0.5% v/v Penicillin/Streptomycin (ATCC).
  • DMEM/F-12 media containing 2.5 mM L-glutamine, 15 mM HEPES, 0.5 mM sodium pyruvate and 1200 mg/L sodium bicarbonate
  • hydrocortisone Sigma/Aldrich Inc.,St.Louis, MO
  • FBS v/v fetal bovine serum
  • Penicillin/Streptomycin ATCC
  • PEG-BPA (catalogue number P2263, Sigma-Aldrich, PEG-BPA is PEG bisphenol A Epichlorohydrin copolymer, PEG 15000-20000).
  • Cell proliferation was assessed by measuring the cleavage of the tetrazolium salt WST-1 (4- [3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-l, 3-benzene disulfonate) to formosan according to the manufacturer's instructions (Roche Diagnostics, Indianapolis, IN, USA). Briefly, cells were grown in 96 well plates in a final volume of 100 ⁇ and then incubated with 10 ⁇ of the WST-1 reagent at 37 °C for 30 minutes in a humidified 5% C0 2 incubator. Conversion of tetrazolium salt into formosan was determined spectrophotometrically at 440 nm absorbance (Molecular Devices, Sunnyvale, CA, USA).
  • the results present the effective concentration range of each PEG formulation molecular weight and identifies specific concentration that causes maximum inhibition of cellular proliferation in SCC-25 cells.
  • SCC-9 cells (CRL-1629; ATCC), a human HNSCC cell line, were cultured in DMEM/F12 (1:1) medium (Thermo Scientific, Rockford, IL) supplemented with 10% FBS (Life trademark of DMEM/F12 (1:1) medium (Thermo Scientific, Rockford, IL) supplemented with 10% FBS (Life trademark of DMEM/F12 (1:1) medium (Thermo Scientific, Rockford, IL) supplemented with 10% FBS (Life).
  • the cells were cultured at 37°C and 5% C0 2 in a humidified incubator.
  • Healthy cell number was assessed using the alamarBlue reagent (Invitrogen, Carlsbad, CA) and quantification of the metabolic cleavage from non-fluorescent resorufin to the fluorescent resorufin, following manufacturer's instruction. Briefly, cells were incubated with 12.5 ⁇ alamarBlue reagent (10% [v/v]) for 20 minutes (24 hour PEG treatment) or 60 minutes (72 hour PEG treatment) at 37°C and 5% C0 2 in a humidified incubator. Fluorescence was determined by excitation at 540 nm and emission at 590 nm using a TECAN infinite M200 instrument (Tecan Group Ltd., Mannedorf, CH).
  • HNSCC head and neck cancer
  • PEG-3350 50 mM
  • PEG-8000 25 mM
  • PEG- 10,000 30 mM

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Abstract

La présente invention concerne des compositions comprenant du polyéthylène glycol (PEG) ayant un poids moléculaire moyen en poids de 800 ou plus et une concentration de 30 mg/ml ou plus pour une utilisation dans la prévention et/ou le traitement du carcinome malpighien de la tête et du cou (HNSCC). La présente invention concerne en outre des procédés de prévention et/ou de traitement du HNSCC.
PCT/US2013/066784 2012-10-26 2013-10-25 Compositions comprenant du polyéthylèneglycol dans le traitement du carcinome malpighien de la tête et du cou Ceased WO2014066745A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012059725A1 (fr) * 2010-11-04 2012-05-10 Norgine Bv Polyéthylène glycol ou copolymères séquencés de polyéthylène glycol pour le traitement du cancer colorectal

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012059725A1 (fr) * 2010-11-04 2012-05-10 Norgine Bv Polyéthylène glycol ou copolymères séquencés de polyéthylène glycol pour le traitement du cancer colorectal

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WALI ET AL.: "Topical Polyethylene Glycol as a Novel Chemopreventive Agent for Oral Cancer via Targeting of Epidermal Growth Factor Response", PLOS ONE, vol. 7, no. 6, 4 June 2012 (2012-06-04) *

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