(19) TZZ _T

(11) EP 2 488 642 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/519 (2006.01) A61K 45/06 (2006.01) 11.03.2015 Bulletin 2015/11 A61P 17/00 (2006.01) C12N 15/09 (2006.01)

(21) Application number: 10824160.5 (86) International application number: PCT/US2010/052836 (22) Date of filing: 15.10.2010 (87) International publication number: WO 2011/047256 (21.04.2011 Gazette 2011/16)

(54) COMPOSITIONS AND METHODS FOR THE TREATMENT OF DRUG-INDUCED HAND-FOOT SYNDROME ZUSAMMENSETZUNGEN UND VERFAHREN ZUR BEHANDLUNG DES ARZNEIMITTELINDUZIERTEN HAND-FUSS-SYNDROMS COMPOSITIONS ET PROCÉDÉS POUR TRAITER L’ÉRYTHRODYSESTHÉSIE PALMO- PLANTAIRE INDUIT PAR LES MÉDICAMENTS

(84) Designated Contracting States: • MOFFAT A C ET AL: "Inhibition in vitro of cyclic AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 3’,5’ nucleotide phosphodiesterase activity by GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO drugs", EUR. J. TOXICOL. 1972, vol. 5, no. 3, 1972, PL PT RO RS SE SI SK SM TR pages 160-162, XP008159611, • PUSZTAI LAJOS ET AL: "Phase I and II study of (30) Priority: 16.10.2009 US 279091 P exisulind in combination with in patients with metastatic .", (43) Date of publication of application: JOURNAL OF CLINICAL ONCOLOGY : OFFICIAL 22.08.2012 Bulletin 2012/34 JOURNAL OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY 15 SEP 2003, vol. 21, no. (73) Proprietor: Duke University 18, 15 September 2003 (2003-09-15), pages Durham, NC 27708-0083 (US) 3454-3461, XP002690937, ISSN: 0732-183X • LIPWORTH ADAM D ET AL: "Hand-Foot (72) Inventor: HURWITZ, Herbert Syndrome (Hand-Foot Skin Reaction, Palmar- Hillsborough, North Carolina 27278 (US) PlantarErythrodysesthesia): Focus on Sorafenib andSunitinib", ONCOLOGY, S. KARGER, BASEL, (74) Representative: Markham, Lisouschka et al CH, vol. 77, no. 5, 1 January 2009 (2009-01-01), HGF Limited pages 257-271, XP009134272, ISSN: 0030-2414 Belgrave Hall • GOMBERG-MAITLAND M ET AL: "A dosing/ Belgrave Street cross-development study of the multikinase Leeds LS2 8DD (GB) inhibitor sorafenib in patients with pulmonary arterial hypertension", CLINICAL (56) References cited: PHARMACOLOGY AND THERAPEUTICS 2010 US-A1- 2002 028 237 US-A1- 2007 225 217 NATURE PUBLISHING GROUP GBR, vol. 87, no. US-A1- 2008 188 480 US-A1- 2009 048 179 3, March 2010 (2010-03), pages 303-310, US-A1- 2009 197 922 XP008159564, ISSN: 0009-9236

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 488 642 B1

Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 488 642 B1

• LEE K W ET AL: "Sildenafil attenuates renal injury in an experimental model of rat - induced nephrotoxicity", TOXICOLOGY, LIMERICK, IR, vol. 257, no. 3, 29 March 2009 (2009-03-29), pages 137-143, XP025952987, ISSN: 0300-483X, DOI: 10.1016/J.TOX.2008.12.017 [retrieved on 2008-12-30]

2 1 EP 2 488 642 B1 2

Description rase inhibitor, thereby treating PPE in the subject. [0009] Another aspect of the present invention pro- PRIORITY STATEMENT vides a composition for ameliorating PPE in a subject (e.g., a subject in need thereof), comprising, consisting [0001] The present invention claims the benefit, under 5 or, or consisting essentially of an effective amount of a 35 U.S.C. § 119(e), of U.S. Provisional Application Serial phosphodiesterase inhibitor, thereby ameliorating PPE No. 61/279,091, filed October 16, 2009. in the subject. [0010] Another aspect of the present invention pro- FIELD OF THE INVENTION vides a composition for preventing PPE in a subject (e.g., 10 a subject in need thereof), comprising, consisting of, or [0002] The present invention is directed to composi- consisting essentially of an effective amount of a phos- tions for the treatment of drug-induced hand/foot syn- phodiesterase inhibitor, thereby preventing PPE in the drome using phosphodiesterase inhibitors. subject. [0011] In certain embodiments of this invention, the BACKGROUND OF THE INVENTION 15 PPE is drug-induced. [0012] Additionally provided herein is the use of a [0003] Palmar-plantar erythrodysesthesia (PPE), also phosphodiesterase inhibitor in the treatment, ameliora- known as hand-foot syndrome (HFS), is a frequent der- tion and/or prevention of PPE in a subject (e.g., a subject matologic toxicity wherein the tissues of the palms and in need thereof). soles become red, painful and thickened, with possible 20 [0013] Further provided herein is the use of a phos- blistering and peeling of the skin. phodiesterase inhibitor in the manufacture of a medica- [0004] PPE is associated with many commonly used ment for the treatment, amelioration and/or prevention anticancer agents, particularly the VEGF-kinase inhibi- of PPE in a subject (e.g., a subject in need thereof). tors sorafenib (Nexevar™) and sunitinib (Sutent™), in- fusional 5-fluoracil (5-FU), capecitabine (Xeloda™), and 25 DETAILED DESCRIPTION OF THE INVENTION liposomal (Doxil™). Over 400,000 patients worldwide are treated with these agents each year. PPE [0014] For the purposes of promoting an understand- is among the most common reasons for dose holding, ing of the principles of the present invention, reference dose reduction and/or treatment discontinuation for willnow be made to exemplaryembodiments and specific these anti-cancer agents. The frequency of any grade 30 language will be used to describe the same. (grade 1-3) PPE is up to 21% for sunitinib, 30% for sor- [0015] Articles "a," "an" and "the" are used herein to afenib, 54% for capecitabine, and 51 % for liposomal refer to one or to more than one ( i.e., at least one) of the doxorubicin (1-4). The frequency of severe (grade 3) PPE grammatical object of the article. By way of example, "an is seen in up to 5% of patients for sunitinib, 8% for sor- element" means at least one element and can include afenib, 17% for capecitabine and 24% for liposomal dox- 35 more than one element (e.g., a multiplicity or plurality of orubicin(1-7). Thus, PPE represents an importanttoxicity elements). not only because of the suffering it causes directly, but [0016] As used herein, the term "and/or" refers to and also because this toxicity often limits the potential bene- encompasses any and all possible combinations of one fits of otherwise effective anti-cancer therapies. or more of the associated listed items, as well as the lack [0005] The standard of care for the management of 40 of combinations when interpreted in the alternative ("or"). PPE currently includes only the use of emollients and [0017] As used herein, the term "about," when used in discontinuation or dose reduction of the relevant anti- reference to a measurable value such as an amount of cancer treatment. More effective, mechanism based mass, dose, time, temperature, and the like, is meant to treatments for PPE are urgently needed. encompass variations of 20%, 10%, 5%, 1%, 0.5%, or [0006] The present invention overcomes previous45 even 0.1 % of the specified amount. shortcomings in the art by providing compositions for [0018] As used herein, "one or more" can mean one, treating PPE in a subject. two, three, four, five, six, seven, eight, nine, ten or more, up to any number. SUMMARY OF THE INVENTION [0019] Unless otherwise defined, all technical terms 50 used herein have the same meaning as commonly un- [0007] The present invention provides compositions derstood by one of ordinary skill in the art to which this for the treatment, amelioration, and/or prevention of con- disclosure belongs. ditions characterized by PPE (e.g., drug-induced PPE) [0020] As used herein, the term "subject" and "patient" in a subject. are used interchangeably herein and refer to both human [0008] One aspect of the present invention provides a 55 and nonhuman animals. The term "nonhuman animals" composition for treating PPE in a subject (e.g., a subject includes all vertebrates, e.g., mammals and non-mam- in need thereof), comprising, consisting of, or consisting mals, such as nonhuman primates, sheep, dog, pig, cat, essentially of an effective amount of a phosphodieste- horse, cow, chickens, amphibians, reptiles, rodents (e.g.,

3 3 EP 2 488 642 B1 4 mice, rats, etc.) and the like. In particular embodiments, cristine, , and , as well as any other the subject of this invention is a human subject. drug now known or later identified to be associated with [0021] A drug of this invention can be a chemothera- PPE, including any combination thereof. Examples of peutic drug, an anti-cancer drug, an anti-neoplastic drug, combinations of this invention include 1) bevacizumab an anti-angiogenesis drug, an anti-vascular drug, an anti- 5 and 5-, 2) bevacizamub and capecitabine, infective drug, a liposomal drug, a liposomal antifungal and 3) and 5-fluorouracil. drug, an anti-vascular epithelial growth factor (anti- [0026] The phosphodiesterase inhibitor of this inven- VEGF) drug, a drug associated with PPE, and/or any tion is a phosphodiesterase type 5 (PDE-5) inhibitor se- other drug now known or later identified that is known or lected from sildenafil, sildenafil citrate, lodenafil, mirode- believed to be associated with PPE and/or with a reac- 10 nafil, avanafil, tadalafil, vardenafil, udenafil and any com- tion, condition, disorder and/or symptom of drug toxicity, bination thereof. and any combinations thereof. A drug "associated with [0027] The phosphodiesterase inhibitor can be admin- PPE" can be any drug that is known or believed to pro- istered to the subject by any suitable means, such as duce and/or exacerbate the symptoms of PPE, alone e.g., topically, orally and/or parenterally. Topical admin- and/or in combination with other drugs, as described15 istration can be employed to treat or prevent PPE. Oral herein. and/or potential (e.g., intravenous) administration can al- [0022] In some embodiments, a drug of this invention so be employed not only to treat or prevent PPE but also can be a drug that may not be associated with PPE when in some embodiments to treat or prevent systemic toxic given at lower doses and/or when given by other than reactions and/or related symptoms associated with use intravenous infusion and/or when given in the absence 20 of the drugs of this invention. of other drugs that are associated with PPE, but becomes [0028] For topical administration of the phosphodieste- associated with PPE when given at higher doses and/or rase inhibitor, a dose in the range of about 0.0001% to when given by intravenous infusion (e.g., continuous in- about 20% can be used. For example, in some embod- travenous infusion) and/or when given with other drugs iments, a dose in the range of about 0.005% to about 5% that are associated with PPE. 25 can be used and in some embodiments, a dose in the [0023] The clinical symptoms of PPE and methods of range of about 0.05% to about 2% can be used. For oral diagnosing PPE are known in the art. Symptoms of PPE or parenteral administration of the phosphodiesterase in- include the appearance, onset, development and/or hibitor, a dose in the range of about 1 mg to about 500 worsening (e.g., exacerbation) of redness, tenderness, mg can be used. For example, in some embodiments, a dryness, burning, sores, ulcers, swelling, peeling, crack- 30 dose in the range of about 0.5 mg to about 100 mg can ing, blistering, numbness, tingling, thickening, hardening be used and in some embodiments, a dose in the range and pain. of about 1 mg to about 50 mg can be used. Administration [0024] The reactions, disorders and symptoms de- canbe one or more times daily, one ormore times weekly, scribed herein can be the result of radiation therapy, one or more times monthly, as indicated according to alone or in conjunction with or other drug 35 clinical parameters known in the art. therapy, as is known in the art. Thus, the phosphodieste- [0029] Various topical formulations are possible. The rase inhibitors of this invention can be employed in the formulations may include creams and ointments of vari- methods described herein to treat, ameliorate and/or pre- ous concentrations. Topical formulations may be applied vent such radiation associated reactions, disorders using drug embedded into patches and /or other cover- and/or symptoms. 40 ings. Examples of a cream of this invention include [0025] Examples of a drug of this invention associated amantyl cream and cold cream (e.g., an emulsion of oil, with PPE include sorafenib, sunitinib, pazopanib, lini- wax and water). fanib, bevacizumab, 5-fluorouracil, capecitabine, floxuri- [0030] In representative embodiments, one applica- dine, araC, liposomal araC, doxorubin, , tion is for dermatologic vascular toxicities associated with , liposomal doxorubicin, irniotecan, , 45 a drug of this invention (e.g., chemotherapy and/or anti- liposomal amphotericin B (e.g., AmBisome; Fungisome, angiogenic agents). A direct extension of this approach Amphotec, Abelcet, Ampholip), interleukin -2 (IL-2), ida- is the treatment of short and long term radiation induced rubicin and any combination thereof. Further examples toxicities, which are thought to be related to radiation of a drug of this invention include abraxane, anti-estro- induced vascular injury. Treatment of mucositis (includ- gens, anthracyclins, , azathioprine, bleomy- 50 ing proctitis, vaginitis, cystitis) may also be possible with cin, , carbexataxel, , cisplatin, chlo- other local delivery approaches, including locally admin- rambucil, , , , istered solutions or pastes. , , , , etopo- [0031] A "subject in need thereof" or "a subject in need side, , hydroxyurea, imatinib, interferons, of" is a subject known to be, or suspected of having or mechlorethamine, , , meth- 55 developing PPE or at risk of developing PPE. In repre- otrexate, mitomycin C, , oxaliplatin, paclit- sentative embodiments, a subject of this invention can axel, , retinoic acid, taxotere, tamoxifen, ten- also include a subject not previously known or suspected iposide, , , , , vin- to have PPE or in need of treatment for PPE.

4 5 EP 2 488 642 B1 6

[0032] A subject of this invention is also a subject refers to oral, sublingual, buccal, transnasal, transder- known to have PPE or believed to be at risk of having or mal, rectal, intramascular, intravenous, intraventricular, developing PPE. In particular embodiments, a subject in intrathecal, and subcutaneous routes. In particular em- need thereof according to the present invention is a sub- bodiments, the term "administering" refers to topical (i.e., ject who is receiving a drug or drugs that are associated 5 application of the compound to the skin/dermal surface with PPE, as such drugs are known in the art and as of a patient). The use of topical administration would allow described herein. In certain embodiments of this inven- a potentially higher local concentration, thereby improv- tion, a subject is a subject diagnosed with or suspected ing activity and/or reducing the risk of systemic toxicity. of having cancer, as well as a subject undergoing treat- In accordance with good clinical practice, the instant ment for cancer. In some embodiments, the subject is a 10 compounds can be administered at a dose that will pro- subject diagnosed with or suspected of having a disorder duce effective beneficial effects without causing undue or condition for which treatment with a drug associated harmful or untoward side effects, i.e., the benefits asso- with PPE is indicated, as well as a subject to whom such ciated with administration outweigh the detrimental ef- a drug of this invention is being or is going to be admin- fects. istered. The subject of this invention can also be a subject 15 [0038] Also as used herein, the terms "treat," "treating" diagnosed with or suspected of having a disorder for or "treatment" refer to any type of action that imparts a whichradiation treatment is indicated,as well as asubject modulating effect, which, for example, can be a beneficial about to or already undergoing radiation treatment. and/or therapeutic effect, to a subject afflicted with a con- [0033] In particular embodiments, a subject of this in- dition, disorder, disease or illness, including, for example, vention can be administered the compositions of this in- 20 improvement in the condition of the subject ( e.g., in one vention even if it is not known or suspected that the sub- or more symptoms), delay in the progression of the dis- ject has PPE (e.g., prophylactically). order, diseaseor illness, delayof the onset of the disease, [0034] Administration of one or more phosphodieste- disorder, or illness, and/or change in clinical parameters rase inhibitors of this invention to the subject can be by of the condition, disorder, disease or illness, as would be any suitable route (e.g., orally to treat systemic reactions, 25 well known in the art. disorders and/or symptoms and/or locally (e.g., topically [0039] An "effective amount" or "therapeutically effec- to treat mucosal surfaces such as in the mouth, bladder, tive amount" refers to an amount of a compound or com- vagina, bowel, etc.). For example, one or more phos- position of this invention that is sufficient to produce a phodiesterase inhibitors can be administered to a subject desired effect, which can be a therapeutic and/or bene- both topically and systemically (e.g., orally) to treat, amel- 30 ficial effect. The effective amount will vary with the age, iorate and/or prevent PPE in the subject. general condition of the subject, the severity of the con- [0035] As used herein, the term "condition" or "condi- dition being treated, the particular agent administered, tion of interest" refers to those conditions involving in- theduration of thetreatment, the natureof any concurrent flammatory and/orvascular pathologies. Insome embod- treatment, the pharmaceutically acceptable carrier used, iments, the condition comprises inflammatory and/or35 and like factors within the knowledge and expertise of vascular disorders associated with drugs such as chem- those skilled in the art. As appropriate, an effective otherapy drugs, anti-angiogenesis drugs and/or other amount or therapeutically effective amount in any indi- drugs that have anti-vascular side effects. Such disorder vidual case can be determined by one of ordinary skill in is PPE. the art by reference to the pertinent texts and literature [0036] The term "administering" or "administered" as 40 and/or by using routine experimentation. ( See, for exam- used herein is meant to include topical, parenteral and/or ple, Remington, The Science and Practice of Pharmacy oral administration, all of which are described herein. (latest edition)). Parenteral administration includes, without limitation, in- [0040] As used herein, the term "ameliorate" refers to travenous, subcutaneous and/or intramuscular adminis- the ability to make better, or more tolerable, PPE. The tration (e.g., skeletal muscle administration). The phos- 45 term "prevent" refers to the ability to keep PPE from hap- phodiesterase inhibitor of this invention may be admin- pening or existing, as well as to delay or diminish onset. istered alone and/or simultaneously with one or more oth- [0041] The compounds of the present invention, and er compounds. In some embodiments, the compounds pharmaceutical compositions thereof, can be adminis- may be administered sequentially, in any order. It will be tered to subjects as described herein for prophylactic appreciated that the actual order of administration will 50 and/or therapeutic purposes. vary according to, inter alia, the particular preparation of [0042] In therapeutic applications, the phosphodieste- compound(s) being utilized, the particular formulation(s) rase inhibitor is administered to a subject that already of the one or more other compounds being utilized. The has PPE. Those subjects in the incubation phase or the optimal order of administration of the compounds of the acute phase of the reaction or disorder may be treated invention for a given set of conditions can be ascertained 55 with one or more phosphodiesterase inhibitors separate- by those skilled in the art using conventional techniques ly or in conjunction with other treatments, as appropriate and in view of the information set out herein. and as would be known to one of skill in the art. [0037] The term "administering" or "administered" also [0043] Furthermore, in therapeutic applications, a

5 7 EP 2 488 642 B1 8 phosphodiesterase inhibitor is administered to a subject ter, 0.9% saline, 0.3% glycine, hyaluronic acid. These in an amount sufficient to effectively treat, or at least par- compositions may-be sterilized by conventional, well tially arrest, diminish and/or reduce, symptoms and/or known sterilization techniques, or may be sterile filtered. complications of PPE. An amount adequate to accom- The resulting compositions may be packaged for use as plish this is defined as an "effective dose" or "therapeu- 5 is, or lyophilized, the lyophilized preparation being com- tically effective dose." Amounts effective for this use will bined with a sterile solution prior to administration. The depend in part on the compound used, the manner of compositions may contain pharmaceutically acceptable administration, the stage and severity of the disease be- auxiliary substances as required to approximate physio- ing treated, the weight and general state of health of the logical conditions, such as buffering agents, tonicity ad- subject, and the judgment of the prescribing physician. 10 justing agents, wetting agents, for example, sodium ac- [0044] Further, the compositions of this invention can etate, sodium lactate, sodium chloride, potassium chlo- be used prophylactically to prevent, treat, reduce, and/or ride, calcium chloride, sorbitan monolaurate, trieth- ameliorate conditions associated with drug-induced anolamine oleate.Alternatively, the pharmaceutical com- PPE. Effective amounts are as described herein. Addi- positions according the present disclosure may also be tionally, one of ordinary skill in the art would also know 15 in dry powder formulations. how to adjust or modify prophylactic treatments, as ap- propriate. EXAMPLES [0045] Therapeutic administration may begin at the first sign of disease or detection of symptoms of PPE [0049] Four patients were treated with topical sildenafil (e.g., redness, swelling, pain, etc. of the hand(s) and/or 20 for PPE, two with PPE related to capecitabine and two foot/feet). Prophylactic administration may begin prior to with PPE related to sunitinib. In all three patients, their any signs or symptoms of PPE. Such prophylactic ad- PPE-related symptoms significantly improved as a result ministration would be for a subject in need thereof, e.g., of topical sildenafil treatment. This initial clinical experi- a subject to whom one or more drugs associated with encewas outside thecontext of formal clinical trials, since PPE is to be administered. Thus, the phosphodiesterase 25 no such trials were available. This treatment was also inhibitor can be administered prior to and/or concurrently initiated because these patients had no therapeutic al- with the administration of a drug associated with PPE, ternatives for their cancer and were deriving robust clin- but prior to the onset of symptoms of PPE. ical benefit that would have likely been jeopardized by [0046] The pharmaceutical compositions for therapeu- stopping or further reducing their anti-cancer treatment. tic and/or prophylactic treatment are intended for mucos- 30 [0050] The first patient had both metastatic pancreatic al (oral, nasal, rectal, urethral, vaginal, tracheal),cancer and a history of mild Raynaud’s syndrome. Treat- parenteral, topical, or local administration (Note that mu- ment with capecitabine resulted in a minor response but cosal administration is different from topical administra- was complicated by grade 2-3 PPE and a flare of her tion, as mucosal administration refers to application of Raynaud’s syndrome, leading to painful ulcers in several the compound to a mucosal surface such as a surface 35 finger tips. After failure of calcium channel blockers, top- of the respiratory tract, gastrointestinal tract, reproduc- ical 2% sildenafil was applied to the ulcers and within a tive tract). weekthere was marked improvement in thepatient’s pain [0047] In particular embodiments, the pharmaceutical and in the size and depth of the digital ulcers. Importantly, compositions are administered topically, e.g., applied to the PPE adjacent to the ulcers also improved. Topical the affected area on the skin (e.g., palms of hands and/or 40 sildenafil was then applied to the full palm of one hand soles of feet). Other topical administrations may be to an with significant improvement in PPE. Similar improve- airway surface, such as by droplet administration to a ments were then seen when the other palm and the soles nasal surface or by inhalation administration of aero- were treated. solized particles to a nasal surface or the surfaces of [0051] The second patient was a woman with meta- other airway passages; or to skin such as for the treat- 45 static colon cancer, who had a dramatic anti-tumor re- ment of wounds or scarring as described herein. Thus, sponse with capecitabine, oxaliplatin and bevacizuamb. the invention provides compositions for topical (mucosal However, her treatment was complicated by grade 2-3 or non-mucosal) or parenteral administration which can PPE that persisted despite dose holdings and reductions. comprise a compound of the present invention (a phos- The patient was switched to a regimen of infusional 5FU phodiesterase inhibitor) dissolved or suspended in a50 plus irniotecan and bevacizumab, which also was asso- pharmaceuticallyacceptable carrier, such as an aqueous ciated with grade 2-3 PPE in this patient. Administration carrier as a pharmaceutical composition. In some em- of 5FU was held due to the severity and persistence of bodiments, a pharmaceutical composition can comprise the hand-foot syndrome. Topical sildenafil was applied albumin, liposomes, nanoparticles, as are known in the to only the left hand. The patient noted improvement in art. 55 the pain and redness of the left hand as noted by day 8. [0048] In some embodiments, the pharmaceutical By day 72, the hand-foot syndrome had resolved in both composition can be administered topically. A variety of hands. aqueous carriers may be used, e.g., water, buffered wa- [0052] The third patient was a man with a gastro-intes-

6 9 EP 2 488 642 B1 10 tinal stromal tumor (GIST) refractory to imatinib, who was PPE and these four cases indicate that topical sildenafil beingtreated with sunitinib. Despitea gratifyingresponse may ameliorate the severity of PPE. Oral administration to sunitinib, he experienced grade 3 sunitinib-related also resulted in improvement of systemic toxicities. PPE that required frequent dose holding and reduction. Hewas treated with topical2% sildenafil threetimes daily. 5 REFERENCES To ensure activity in the setting of potentially significant costs for custom formulation, this patient applied topical [0056] sildenafil to only his left hand. He experienced no side effects, such as headache, chest pain, lightheadedness, 1. Bayer HealthCare Pharmaceuticals. Sorafenib and no spontaneous erections during this month of treat- 10 Prescribing Information. 2009. ment. After only 3 doses (1 day) he noticed an improve- 2. Hoffman La Roche Laboratories Inc. Capecitabine ment on the tenderness and redness of his hands. By Prescribing Information. 2006. one week, pain, redness and blisters were markedly im- 3. Ortho Biotech. Doxil Prescribing Information. proved. After 4 weeks, redness was markedly better; pain 2007. had resolved; multiple blisters, cracks, and callousness 15 4. Pfizer Labs. Sunitinib malate Prescribing Informa- had all resolved essentially completely. The improve- tion. 2009. ment was "like day and night." The right hand had all of 5. Lorusso D, Di Stefano A, Carone V, Fagotti A, these complications. These were severe enough that the Pisconti S, Scambia G. "Pegylated liposomal doxo- patient had difficulty physically closing his hand more rubicin-related palmar-plantar erythrodysesthesia than halfway due to skin thickening as well as pain. His 20 (’hand-foot’ syndrome)" Ann Oncol. 2007; left hand was completely flexible. After administration to 18(7):1159-64. both hands, he was able for the first time in many months 6. Walko CM, Lindley C. "Capecitabine: a review" to shake hands and make a fist without difficulty or pain Clin Ther. 2005; 27(1):23-44. and he restarted playing his guitar in his church choir. 7. Lacouture ME, Wu S, Robert C, Atkins MB, Kong This patient later was dosed with 1% topical sildenafil 25 HH, Guitart J, et al. "Evolving strategies for the man- once per week. In addition, this patient experienced su- agement of hand-foot skin reaction associated with nitinib-induced gastrointestinal toxicities (enteritis, di- the multitargeted kinase inhibitors sorafenib and su- arrhea), which were treated with oral sildenafil to allow nitinib" Oncologist 2008;13 (9):1001-11. systemic absorption. The initial dose was 50mg oral sildenafil daily. This rapidly improved his gastrointestinal 30 toxicities and his hand-foot syndrome, within 1 day. Claims Thereafter lower doses were used on an as needed ba- sis, including a quarter tablet (50mg size) given once or 1. A phosphodiesterase type 5 (PDE-5) inhibitor select- twice per week. ed from the group consisting of sildenafil, sildenafil [0053] A fourth patient was a woman with metastatic 35 citrate, lodenafil, mirodenafil, avanafil, tadalafil, var- angiosarcoma, who was treated with sunitinib for over denafil,udenafil and anycombination thereof, for use four years. Her treatment was complicated by grade 3 in treating palmar-plantar erythrodysesthesia (PPE). PPE that required reduction of her sunitinib from 50mg given daily to 12.5mg given every other day (i.e., three 2. A phosphodiesterase type 5 (PDE-5) inhibitor select- times per week; e.g., Monday-Wednesday-Friday). Due 40 ed from the group consisting of sildenafil, sildenafil to tumor progression on low does sunitinib, her dose of citrate, lodenafil, mirodenafil, avanafil, tadalafil, var- sunitinib was increased to 37.5 mg per day (7 days per denafil,udenafil and anycombination thereof, for use week), which caused her PPE to return. Her hand-foot in ameliorating PPE. syndrome was grade 1 when she started treatment with topical sildenafil 2% (with a cold cream base) to only her 45 3. A phosphodiesterase type 5 (PDE-5) inhibitor select- right hand and right foot. The right hand and foot im- ed from the group consisting of sildenafil, sildenafil proved markedly within 1-2 weeks. The untreated hand citrate, lodenafil, mirodenafil, avanafil, tadalafil, var- and foot continued to worsen. Of note, the patient’s tumor denafil,udenafil and anycombination thereof, for use showed signs of response to the higher dose of sunitinib in preventing PPE. after only 1 month at the higher dose. 50 [0054] Since each of these patients initially had only 4. A PDE-5 inhibitor for use according to any of claims one affected skin region treated, followed by treatment 1-3, wherein the PPE is associated with drug intake. of the other similarly affected regions, each patient was able to serve as her/his own control. No local or systemic 5. A PDE-5 inhibitor for use according to any preceding side effects were experienced in any of these patients. 55 claim, wherein the PPE is as a result of a toxic side Furthermore, no patient had any suggestion of an ad- effect of a drug selected from the group consisting verse impact on their cancer’s response to treatment. of a chemotherapeutic drug, an anti-cancer drug, an [0055] Taken together, the known pathophysiology of anti-neoplastic drug, an anti-angiogenesis drug, an

7 11 EP 2 488 642 B1 12

anti-vascular drug, an anti-infective drug, an anti- menhang mit PPE und einer beliebigen Kombination VEGF drug, a drug associated with PPE, and any dieser stammt. combination thereof. 6. Ein PDE-5-Hemmer zur Anwendung gemäß An- 6. A PDE-5 inhibitor for use according to claim 55 , spruch 5, wobei das Medikament aus der Gruppe wherein the drug is selected from the group consist- bestehend aus Sorafenib, Sunitinib, Pazopanib, Li- ing of sorafenib, sunitinib, pazopanib, linifanib, bev- nifanib, Bevacizumab, 5-Fluorouracil, Capecitabin, acizumab, 5-fluorouracil, capecitabine, , Floxuridin, AraC, Liposomalem AraC, Doxorubin, araC, liposomal araC, doxorubin, daunorubicin, ida- Daunorubicin, Idarubicin, Liposomalem Doxorubi- rubicin, liposomal doxorubicin, irniotecan, topote- 10 cin, Irniotecan, Topotecan, Liposomalem Amphote- can, liposomal amphotericin B, interleukin -2, idaru- ricin B, Interleukin-2, Idarubicin und einer beliebigen bicin and any combination thereof. Kombination dieser stammt.

7. A PDE-5 inhibitor for use according to any preceding 7. Ein PDE-5-Hemmer zur Anwendung gemäß eines claim, that is administered topically to a subject. 15 beliebigen vorstehenden Anspruchs, der einem Pro- banden topisch verabreicht wird. 8. A PDE-5 inhibitor for use according to any one of claims 1 to 6, that is administered orally to a subject. 8. Ein PDE-5-Hemmer zur Anwendung gemäß eines beliebigen Anspruchs 1 bis 6, der einem Probanden 20 oral verabreicht wird. Patentansprüche

1. Ein Phosphodiesterase-5-Hemmer (PDE-5), der Revendications aus der Gruppe bestehend aus Sildenafil, Sildena- filcitrat, Lodenafil, Mirodenafil, Avanafil, Tadalafil, 25 1. Inhibiteur de phosphodiestérase de type 5 (PDE-5) Vardenafil, Udenafil und einer beliebigen Kombina- choisi parmi le groupe constitué par le sildénafil, le tion dieser stammt und zur Behandlung von Palmar- citrate de sildénafil, le lodénafil, le mirodénafil, l’ava- Plantarer Erythrodysästhesie (PPE) dient. nafil, le vardénafil, l’udénafil et toute combinaison de ceux-ci, destiné à être utilisé pour le traitement de 2. Ein Phosphodiesterase-5-Hemmer (PDE-5), der30 l’érythrodysesthésie palmo-plantaire (PPE). aus der Gruppe bestehend aus Sildenafil, Sildena- filcitrat, Lodenafil, Mirodenafil, Avanafil, Tadalafil, 2. Inhibiteur de phosphodiestérase de type 5 (PDE-5) Vardenafil, Udenafil und einer beliebigen Kombina- choisi parmi le groupe constitué par le sildénafil, le tion dieser stammt und zur Verbesserung von PPE citrate de sildénafil, le lodénafil, le mirodénafil, l’ava- dient. 35 nafil, le tadalafil, le vardénafil, l’udénafil et toute com- binaison de ceux-ci, destiné à être utilisé pour faire 3. Ein Phosphodiesterase-5-Hemmer (PDE-5), der régresser la PPE. aus der Gruppe bestehend aus Sildenafil, Sildena- filcitrat, Lodenafil, Mirodenafil, Avanafil, Tadalafil, 3. Inhibiteur de phosphodiestérase de type 5 (PDE-5) Vardenafil, Udenafil und einer beliebigen Kombina- 40 choisi parmi le groupe constitué par le sildénafil, le tion dieser stammt und zur Vorbeugung gegen PPE citrate de sildénafil, le lodénafil, le mirodénafil, l’ava- dient. nafil, le tadalafil, le vardénafil, l’udénafil et toute com- binaison de ceux-ci, destiné à être utilisé pour pré- 4. Ein PDE-5-Hemmer zur Anwendung gemäß eines venir la PPE. beliebigen Anspruchs 1 bis 3, wobei PPE mit der 45 Einnahme von Medikamenten in Verbindung ge- 4. Inhibiteur de PDE-5 destiné à être utilisé selon l’une bracht wird. quelconque des revendications 1 à 3, ladite PPE étant associée à la prise d’un médicament. 5. Ein PDE-5-Hemmer zur Anwendung gemäß eines beliebigenvorstehenden Anspruchs, wobeiPPE das 50 5. Inhibiteur de PDE-5 destiné à être utilisé selon l’une Ergebnis einer toxischen Nebenwirkung eines Me- quelconque revendication précédente, ladite PPE dikamentes ist, das aus der Gruppe bestehend aus résultant d’un effet secondaire toxique d’un médica- einem chemotherapeutischem Medikament, einem ment choisi dans le groupe constitué par un médi- Anti-Krebs-Medikament, einem Anti-neoplasti- cament chimiothérapeutique, un médicament anti- schem Medikament, einem Anti-Angiogenese-Me- 55 cancer, un médicament anti-néoplastique, un médi- dikament, einem Anti-vaskulärem Medikament, ei- cament anti-angiogenèse, un médicament anti-vas- nem Anti-infektiösem Medikament, einem Anti- culaire, un médicament anti-infectieux, un médica- VEGF-Medikament, einem Medikament im Zusam- ment anti-VEGF, un médicament associé à la PPE

8 13 EP 2 488 642 B1 14

et toute combinaison de ceux-ci.

6. Inhibiteur de PDE-5 destiné à être utilisé selon la revendication 5, ledit médicament étant sélectionné dansle groupe constitué par lesorafénib, le sunitinib, 5 le pazopanib, le linifanib, le bévacizumab, le 5-fluo- rouracile, la capécitabine, la floxuridine, l’araC, l’araC liposomale, la doxorubine, la daunorubicine, l’idarubicine, la doxorubicine liposomale, l’irniotéca- ne, la topotécane, l’amphotéricine B liposomale, l’in- 10 terleukine-2, l’idarubicine et toute combinaison de ceux-ci.

7. Inhibiteur de PDE-5 destiné à être utilisé selon l’une quelconque revendication précédente qui est admi- 15 nistré par voie topique à un sujet.

8. Inhibiteur de PDE-5 destiné à être utilisé selon l’une quelconque des revendications 1 à 6 qui est admi- nistré par voie orale à un sujet. 20

25

30

35

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45

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 61279091 A [0001]

Non-patent literature cited in the description

• REMINGTON. The Science and Practice of Pharma- • LORUSSO D ; DI STEFANO A ;CARONE V ; cy [0039] FAGOTTI A ; PISCONTI S ; SCAMBIA G. Pegylated • Bayer HealthCare Pharmaceuticals. Sorafenib Pre- liposomal doxorubicin-related palmar-plantar eryth- scribing Information, 2009 [0056] rodysesthesia (’hand-foot’ syndrome). Ann Oncol., • Capecitabine Prescribing Information, 2006 [0056] 2007, vol. 18 (7), 1159-64 [0056] • Ortho Biotech. Doxil Prescribing Information, 2007 • WALKO CM ; LINDLEY C. Capecitabine: a review. [0056] Clin Ther., 2005, vol. 27 (1), 23-44 [0056] • Sunitinib malate Prescribing Information, 2009 • LACOUTURE ME ; WU S ; ROBERT C ; ATKINS [0056] MB ; KONG HH ; GUITART J et al. Evolving strate- gies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist, 2008, vol. 13 (9), 1001-11 [0056]

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