BACKGROUND OF THE INVENTION
5 Breast cancer i s the most frequently diagnosed malignancy in women and one of the top
two causm of cancer-related deaths in women worldwide. The incidence ofbreast cancer in the
world rs maeasw and it is estimated that the disease will affect 5 mllion women in the next
decade. Treatments permit control of symptoms, prolongation of survival, and maintenance of
quality of life. However, m about 40% to 50% of all patients treated with curative intent,
10 incurable metastatic diseae WIU develop. Since there is no cure fox metastatic breast cancer,
current therapeut~cg oals are palliative
111 several cancer types, deregulation of growth factor signaling is obaemed, associated
,math a hyperactivation of the ErbB receptors. The ErbB receptor family includes ErbB-1 (also
known as HER-1, epidermal growth factor receptor (EGFR)), ErbB-2 (ak.a nvu or HER-2),
15 HER-3 (a k a ErbB-31, and HER-4 (ak a. ErbB-4). Overexpression of ErbB-1 is observed in
non-small oell lung cancer (NSCLC) (40%-80%), breast cancer (14%-91%), and pancreatic
cancer (30%-89%). In NSCLC, actmation by mutation of mpEcation of ErbB-1 also occurs in
10% to 30% of patients.
Overexpression of ErbB-2, usually resultitkg from erbB-2 gene amplification, is observed
20 in tumor lissue in 25% to 30% of patrents of patients with metastatic breast cancer @BC) and is
associated with malignant transfmation. ErbB-2 overexpression is! usually associated with a
more aggressive tumor phenotype, worse overall prognosis, and faster relapse times at all stages
of cancer development. In women with MBC, this overexpression confers a relative resistance to
treatment with either anthracyclinelabkylator- or taxane-based chemotherapy. ErbB-2
25 overexpression in tumongenesis has been mainly studied in breast cancers but is also observed in
other cancers.
Among current therapeutics for cancers, specifically those characterized by
overexpression of ErbB-2, are vinorelbine. trastummb and HKI-272. Vinorelbine, a
semisynthetic vinca alkaloid having broad antitumor activity, acts throqgh microtubule
30 disruphon Vrnorelbine presents a lower neurotoxicity profile than vincristine or vinblastine.
Vinorelbine has been shown to be less toxic to axonal microtubules than vincristine or
vinblastme at therape- concentrations In studiea conducted on subjects with advanced breast
cancer, treatment with vinorelbine as a single agent is at least as efficient as other
chemotherap~ebs ut with a lower risk of toxicity. However, the risk of toxicity increases in
parallel \nth the number of previous anticancer treatments.
5 Trasluzumab (HERCEPTIN@ dmg) 1s a humanized monoclonal antibody specific for the
extracellular domam of ErbB-2. It presents s~gnificanct linical benefit and sigruficant antitumor
activ~tyw hen used alone or m combination with taxanes in metastatic breast cancer in first-line
treatment or in patlents whb have tumor progression after chemotherapy. Because of the
improvement in survival, trastuzumab-based therapies have become standard of care for women
10 wth ErbB-2-positive RIBC. For women with advanced or metastatic disease, brwt canwr
eventually recurs despite trastuzumab treatment. Trastuzumab-based therapy is also associated
w~thpo tentla1 carbac toxicity. Certain breast cancer cells are resistant to trastunrmab due to the
occurrence of secondaq~E rbB-2 mutations, such as trun~tionof extracellular domain ErbB-2
receptor Such mutations can resull in cancer cells which are not recognized by the antibody.
15 In recent studies, trastuzumab in combination with either vinorelbine or taxane (paclitaxel
with or without carboplatin, or docetaxel) was utilized to treat subjects with ErbB-2-
overexpressing MBC. As expected, the most frequent grade toxicity observed with the
combination of trartuzumab and vinorelhie was neutropenia
HKI-272 o a small molecule, irreversible pan-ErbB receptor inhibitor specific for
20 ep~dermagl rowth factor receptor WbB-1 or EGFR), ErbB-2 (HER-2), and ErbB-4 (HER-4).
HRI-272 blocks W e activity of the receptor through bindii to the intracellular adenosine
tiphosphate (ATP) blndmg site ofthe receptor. HKI-272 blocks ErbB receptor
autophosphorylat~onin cells at doses consistent wthinhibition of cell proliferation. In v~tro,
HW-272 alone mnh~b~ktsln ase activity of ErbB-1, ErbB-2, and HER-4, inhibits tumor cell growth
25 wth breast and lung bmor cell lines, and presents a potent growth inhibition of lung cancer cells
resistant to gefitlnib or erlotinib. In vivo, HKI-272 blocks tumor growth in xmo@ animal
models. Overall, HKI-272 is less potent against ErbB-1-dependeat !amom thanErbB-2-
dependent tumors in vivo, even though it has equvalent activity against the 2 kinases in vrtro.
There remans a need m the art for therapeutic methods, regimens, compositions, and kitr
30 whlch are useful m treating metastatic breast cancer and solid tumors.
SUMMARY OF THE INVENTION
This invention addresses the need in the art by providing regimens, compositions and
methods using aHKI-272 compound and a vinoreIbine compound for the treatmat of cancers,
such as solid tumors and metastatic breast cancer
5 In one aspectn regimens for treating a neoplasm in a subject are provided aad include
admnustering a vinorelbine compound and administering a HKI-272 compound. Des~rablyt,h e
vinorelbine compound 1s vinorelbine and the HKI-272 compound is HKI-272. In one
embo&ment, the neoplasm is breast cancer.
In another aspect, aregimen for treating a solid tumor associated with overexpression or
10 ampllficabon of HER-2 in a subject is provided, wherein one cycle of the regimen includes 21
days. The regimen includes orally W s t e r i n g at least one unit dose of HKI-272 starting on day
1 of the cycle and inlTavenousty administering at least one unit dose of vinorelbine on days 1 and
8 of the cycle
m a further aspect, a regimen for treating a metastatic cancer associated with
15 overexpression or amplification of HER-2 m a subject is provided. One cycle of the regimen
includes 21 days and the regimen includes orally administering at least one unit dose of HRI-272
starting on day 2 of the cycle and intravenously administering at least one unit dose of vinorelbine
on days 1 and 8 of the cycle.
In still another aspect, a product comprising avinorelbine compound andHKI-272
20 compound is provided as a combined preparation for simultaneous, separate or sequential use in
lreating a neoplasm in a mammal
In ! cr, a fuaher aspect, a pharmaceutical pack for treating a neoplasm in one individual
mammal is provided and includes (a) at least one unit dose of vinorelbiie; and (b) at least one unit
dose of HKI-272
25 In another aspect, a pharmaceutical composition is described and contains vinorelbine,
HKI-272, and at least one pharmaceutically acceptable carrier.
In sail another aspect, a method or treating aneoplasm assodated with overexpression or
amplifi~cationo f HmR-2 in a mammal in need thereof is provided and includes administering a
unit dose of a vinorelbine compound and administering aunit dose of aHKI-272 compound.
30 Other aspects and advantages of the invention will be readily apparent from the following
detruled descripaon of the invention
DESCRIPTION OF THE INVENTION
This invent~onp rovides compositions, methods, and regimens using a combination of a
HKI-272 compound and a vinorelbine compound for the treatment of cancers. This invention
5 provides m one embodiment composrtions comprising HKI-272 and vinorelbine for the
treatment of neoplasms Also provided are products containing HKI-272 and vinorelbine
formdated for simdtyeous, separate or sequential use in treating neoplasms in amamrnal. The
invenfion is also usefui as an adjuvant andlor neoadjuvant therapy of earlier stages of breast
cancer The inventLon provides, in another embodiment, methods for the combined use or
10 administration of a HKI-272 compound and vinorelbhie compound.
The Therapeutic Regimen and Its Components
Without wishing to be bound by theoiy, the inventors hypothesize that the combination of
HKI-272 and vinorelbine for treating a neoplasm is desirable because HKI-272 targets the
15 intracellular ErbB-2 kinase rather than the extracellular domain Thus, this combination has
d~fferenmt echanisms of sensitivtty and resistance and then presents an advantage over the
therapeutic combination of trastmmab and vinorelbine. Further, the combination of HKI-272
and vinorelbine is anbc~patedto be more effective than combinations of vinorelbine with other
pan-ErbB ihbltors due to the tyrosine b a s e inhibition activity ofHKI-272 through an
20 irreversible binding at a targeted cysteine residue hi the ATP bmding pocket of the receptor.
Tbese methods, ccmbmahons and produets are useful in the treatment of a variety of
neoplasms, partioularly those associated with overexpression or amplification of HER-2. In one
embodiment, the neoplasm is a solid tumor or an advanced solid tumor. In a further
embod~mentt,h e neoplasm is metastatic. In another embodiment, neoplasms that may be treated
25 as described herein include, e g , lung cancers (such as bronchioalveolar carcinoma and non
small cell lung cancer), breast cancers (such as metastatic breast cancer andHER-2 -positive
breast cancer), prostate cancers, myeloma, head and neck cancer, transitional cell carcinoma,
small cell and large cell neuroendow~nec arcinoma of the uterine cervix In still another
embohment, the neoplasm is resistant to trastuzumab.
The regimens, methods, and compositions described herem include the concment,
simultaneous, sequential or separate administration of the components, i.e., a m - 2 7 2 compound
and a vinorelbme compound The term "composition" as used herein is mtended to cover both
4
pharmaceutical compositions in which 2 or more components are mixed, wmpositions of matter
such as pharmaeeufical kits and packs in which the components are individually packaged for
concurrent, simultaneous, sequentml, or separate administration. In one aspect of the invention,
"acombination" includes simultaneous adminkation of theHKI-272 and vinorelbiie
5 compounds. In a further aspect ofthe mvention, "a combination" indudes sequential
admnistration of the HKI-272 8nd vlnorelbine compounds. In one embodiment the HKI-272 is
admuustered before the vinorelbine compound In another embodiment the vinorelbine
compound is admimstered before them-272 wmpouud In another aspect, "a combination"
includes separate administration of the HKI-272 and vinorelbine compounds in a particular
10 therapeutic regimen In which the two components of the combination are administered at specific
bmea and amounts with respect to each other. In one embodiment, the combination of the HIU-
272 and vinorelbine compounds produces a more beneficial therapeutic effect tban that
achievable by the administration of either aHKI-272 compound alone or a vinorelbiie compound
alone. Where the admirustration of those agents is sequential or separate, the delay in
15 adnnnistering the second component should not be such as to lose the benefits provided the
combination therapy.
In one embodiment, the combination of the HKI-272 and vinorelbine compounds is
particularly well suted for treatment of metastatic breast cancer. In another embodiment, the
combination of the HKI-272 and vinorelbine compounds are well suited for treatment of breast,
20 kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, and lung), and polycystic
kidney disease
& wed herein a ~edxc ept wherenoted, the terms "individual", "subject" and "patient" are
used interchangeably, and refer to any anitnal, including mammals, preferably doe, rats, other
rodents, rabbits, dog, cats, swine, cattle, sheep, horses, non-human primates, and humans.
25 Desirably, the term "individual", "subject!' or "patient" refers to a human. In certain
circumstances, these terms refer to experimental animals such as rabbits, rats, md mice, and other
mmals In most embo&mants, the subjects or patients are in need of the therapeutic treatment.
Accordingly, the term "subject" or "patient" as used herein means any mammalian patient or
subject to \vhlch the HKI-272 and vmorelbine compounds can be adminiswed. In one
30 embodiment, to ident~fys ubject patients for treatment according to the methods of the invention,
accepted screening methods are employed to d e t m e risk factors associated with a targeted or
suspected dlsease or conhtion or to determine the status of an existing disease or condition in a
5
subject These screening methods include, e.g., conventional work-ups to determine risk factors
that are associated with the targeted or suspected disease or condition. These and other routine
methods allow the clmcian to select patients in need of therapy using the methods and
formulations of the present inventton. In one embodiment, the "individual", "subject" or "patient"
5 may have had no previously chemotherapeutic treatment. In another embodiment, the
"individual", "subject" or "patient" may have previously undexgone chemotherapeutic treatment.
In another embodiment, the "individual", "subject" or "patient" may have previously been
administered an aniloquinwoline class inhibrtor In a further embodiment, the "individual",
"subject" or "patient" may have previously been admitustered lapatinib orgeftinib as the
10 an~loqwnazolmec lass i&bitor Desirably, the blood count of the patient prior to treatment with
the descnbed combmabons is stable enough to permit administration of the combinations
descnbed herern In one embodiment, the neufrophil count of the patient prior to administratyon
of the vlnorelbine and HKI-272 compounds is at least 1500. In another embodiment, the platelet
count of the patient prior to administration of the vinorelbine and HgI-272 compounds is at least
15 100,000/1.
As used herein, "am-272 compound'' refers, in one embodiment, to a compound
having the following core structure'
or a derivative or pharmaceutically acceptable salt thereof. Suitable derivatives may include,
20 e g., an ester, ether, or carbamate The core structure represented above is a particularly HKI-
272 compound, called HKI-272, whch has the chemical name (E)-N-{4-[3-~hloro4{2-
pyridinylmethoxy) anilino] -3-cyano-7-ethoxydquinolirr,1}-4-(dime~lamino)-2-butenamide.
In one embodtment, the HKI-272 compound useful in the compositions and methods described
herein is HKI-272.
2.5 In another enlbod~menta, n HKI-272 compound has the structure;
6
wherein:
R' is halogen;
R2 is pyr~dlnyl,%uophenyl, pyrirmdmyl, thiazolyl, or phenyl, whereinI? is optionally
5 substituted with up to three subshtuents;
R~ is 0 or S;
R4 is CH3 or CHZCROCH~;
R' is CH3 or CHaCH3, and
nls 0011
The tm "halogen" as used herern refers to el, Br, I, and P.
These HKI-272 compounds, of which HKI-272 is a species, are characterized by the
ability Lo act as potent HER-2 mhibitors. &ee @.g.U, S Patent Nos. 6,288,082 and 6,297,258 and
US Patent Application PublicztionNo. 2007/0104721, which are hereby incorporated by
rehrence These compounds and their prepmation are described in detail in US Patent
15 Application Publication No 200510059678, which is hereby incorporated by reference. For
convenience, "am-272 compound" is used throughout this specification However, any
compound of the structure(s) provided above can be substituted for HKI-272 in the combinations
described m detail below.
HW-27% other HKI-272 compounds, and methods of making and farmdating same have
20 been described See, e g , US Patent Apphcation PublicationNo. 2005/0059678 and US Patent
No 6,002,008, which are hereby incorporated by reference. The methods described in these
documenb can also be used to prepare the substituted 3-quinoline compounds used herein and
are hereby incorporated by reference. In add~tlonto the methods describedin these documents,
International P&nt Publ~cationN os. W0-96/33978 and WO-96f33980, which are hereby
25 incorporated by reference, describe methods that are usell for tlle preparation of these HKI-272
compounds Although these methods descnbe the preparation of certainquinazolines, they are
also applicable to the preparation of correspondingly substiluted 3-cyanoquindines and are
hereby incorporated by reference.
As used herem, the term"a vinorelbine compound" means vinwelbme or a
5 pharmaceubcally acceptable salt thereof, which has broad antitumor activity and that acts
through szuc~tubuled isruption See, Widakowlch et al., Anticancer Agents Mad. Chem.,
8(5) 488-406 (hule 20(18) and Wissner et al., Arch. Phm. (Weinhe*), (May 20,2008 epublicaaon)
The term rncludes the neutral vrnorelbine compound, r.e., 4-(acetyloxy)-6,7-
~dehydro-l5-((2R,6~S)-4-ethyl-1,3,G~7,K,9-hexohydro-8-(~tho~carbonyl)-2,6-m&ano-
10 2H-aze~ino~4,3-b)indol-8-yl)-3-hydroxy-16-methoxy-1-m&mye1t~h yl ester, (28,3j3,48,5a,
12R, 1%)-aspidosperrmdme-3-carboxplic acid (vinorelbine; tradename: Navelbine).
V~norelhinea nd its pharmaceuticaIly acceptable salts are available from commercial vendors
incluang AdvenhdSD Pharmaceuticals (SDP-O12@ drugdrug), Hana (ALOCREST@ drug), and
Inex Pharmaceuticals Corp. (INX-0125TM drug), and other viaorelhine compounds, including
15 those discussed in US Patent No 7,235,564, which is hereby incorporated by reference. In one
emhodtment, a vmorelbine compound includes a compound with a s t m c t d similarity to the
tnorelbine compound structure below, e.g , compounds with a similar alkaloid structure that
ha^ e been mohfied to enhance therapeutic benefit.
The preparation of vinorelbine compounds are described by Langlois et al., in J. Am.
Chem SOC 98,7017-7024 (1976); and by Mangeney et al.,in Tetrahedron, 35:2175-2179
(1979)
The HKI-272 and ~lnorelbmnec ompounds and corresponding pharmaceutically
acceptable salts or esters thereofinclude isomers either individually or as amixtme, such as
enantiomers, diastereomers, and pcslQonal isomers.
"Pharmaceutically acceptable salts and esters" refers to salts and esters that are
5 pharmaceutically acceptable and have the desued pharmacological properties. Such salts include,
e.g., salts that can be formed where acikc protons present in the compounds are capable of
reacting with inorganic or organic bases Suitable inorganic salts include, e.g., those formed with
the alkali metals or alkaline earth metals, e.g. sodium and potasslum, magnesium, calcium, and
a l m m Suttable organlc salts include, e g , those formed with organic bas= such as the
10 amine bases, e.g ethanolamine, dlethanolamine, triethanolamine, trom&bdne, Nmeihylglucmncne,
and the like. Pharmaceutically acceptable salts can also include acid addition
saIts formed from the reachon of basic moieties, such as amines, in the parent compound with
morgaulc aids (e g. hydrochloric and hydrabromic acids) and organic acids (e.g. acetic acid,
citnc acid* maieic acid, md the alkane-and arene-sulfonic acids such as methanesulfb~ca cid
15 and benzrnesulfonic aad)
Pharmaceutically acceptable esters include esters formed from carboxy, sulfonyloxy, and
phosphonoxy groups present in the compounds of the invention, e.g., C1.6akyl esters. When
there are two acidic groups present, apharmaceutically acceptable salt or ester can be amonoacid-
mono-salt or ester or a di-salt or ester; and similarly where there are more than two aeidii
20 groups present, some or all of such groups can be salified or esterified. Compolmds d i d
herem may be present in unsaltfied or unesterified form, or in salified andlor esterified form, and
the naming of such compounds is intended to include both the original (unsalified and
uoester~fied)c ompound and its pharmaceutically acceptable salts and esters. Also, one w more
compounds utllized herein may be present in more than one stereoisomeric form, and the naming
25 of such compounds is intended to include dl single stereoisomers and all mixtures (whether
racemic or otherw~se)o f such stereolsomers.
Pharmaceutically acceptable salts of the HKI-272 and vmorelbie compounds with an
acidic mo~etym ay be formed from organic and inorganic bases mcluding e.g., salts with alkali
metals or allraline earth metals such as sodium, potassium, litbium, calcium, or magnesium or
30 organic bases and N- tetraalloilammonium salts such as N-tetrabutylemmoniumabuoum salts.
Similarly, when one or more compound utilized herein contains a basic moiety, salts mrry
be formed from organic and inorganic acids. For example, salts may be formed from acids such
9
as acetic, propionic, lacuc, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, aalic,
phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic,
naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known
acceptable acids when a compound of this lnvenhon contains a basic functional group. Other
5 slutable exalyles olpharmaceu~callya cceptable salts mclude, but are not limited, to sulfate;
atrate, acetate, oxdate; chloride; bromide; iodide; nitrate; bisulfate; phosphate; acid phosphate;
isonicotinate; lactate; salicylate; acid citrate; tartrate; oleate; tamate; pantothenate; bitartrate;
ascorbate, sucanate; malea*; gentsinate; fumarate; gluconata; gluoaronatq saccharate; formate;
benzoate; glutamate; methanesulfonate; ethanesulfonate; betlzenesulfonate; p-toluenesulfanate;
l o pamoate (1.e , 1,1'-m&ylene-bis-(2-hydro~3-naphthoa~; and salts of fatty acids such as
caproate, laurate. wristate, palmitate, stearate, oleate, linoleate, and linolenate salts. In one
embodiment, the vinorelbiie compound is vinorelbime tarttate.
The compounds can dso be used in the form of esters, carbarnates and other conventional
ester forms, also referred to herein as prodrug forms, which when administered in suchfwm,
15 convert to the active moiety I??-wwE. xemplary ester forms of the compounds of this invention
mclude, but are not limited to, straight chain alkyl esten having from 1 to 6 carbon atoms or
branched cham alkyl gmups containing 1 to 6 carbon atoms, including methyl, ethyl, propyl,
butyl, 2-methylpropyl and 1,l-dimethylethyl esters, cycloalkyl esters, akylaryl esters, benzyl
esters, and the like.
Accordmgly, a pharmaceutical composition is provided and contains effective amounts of
the HKI-272 and vinorelbine compounds in combination or association with one or more
phamawu~callyac ceptable carrier. Suitable examples of pharmaceutical carriers used herein
include, but are not limited to, excipients, dituents, fillers, disintegrants, lubricants and other
agents that can function as a carrier. The term "pharmawutically acceptable excipient" me~ns8 n
25 excipient that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic,
and desirable, and mcludes excipients that aze acceptable for veterinary use as well as for
human pharmaceutical use. Such excipients can be solid, liquid, semisolid, or, in the case of an
aerosol composlhon, gaseous. Pharmaceutical compositions are prepared In accordance with
acceptable pharmaceutical procedures, such as described in Remingtons Phamaceutical
30 Scienm, 17th edition, ed. Alfonoso R Gennaro, Mack Publishing Company, Easton, Pa (1985).
Pharmace&cally acceptable carriers are those that are compatible with the other ingredients in
the formulation and biologically acceptable. Suitable pharmaceutically-acceptable excipients or
10
carriers for a tablet or caplet formulalxon include, e g., inert excipienls such as lactose, sodium
carbonate, calcium phosphate or calctum carbonate, granulating and disintegrating agents such as
com starch or a l g t ~acc ~db; mding agents such as gelatin or starch; lubricatmg agents such as
magnesium slearate, stearic acid or talc; preservative agents such as ethyl or propyl4-
5 liy drox) benzoate, and anti-oxidants, such as ascorbtc acld. Tablet or caplet formulations may be
uncoated or coaled either to mod@ their msintegration and the subsequent absorption of the
actme ingredient wittun the gastrointestinal tract, or to improve their stability and/or appearance
uslng con~fent~oncaola ting agents and procedures well known in the art. In one embodiment, the
we~ghot f the tablet 1s at least about 20,30,40,50, 60, or 70 mg.
10
Optional Components of the Regimens
The regimens described herein may also include the administration of other agents. In
one embodiment, the regmen further includes administration of a tawane, e.g., docetaxel and
paclitaxel [a g , a suspension of paclitaxel bound to albumen nanoparticles, which is available as
15 the ABRAXANEBfi reagent]. Paditaxel may also be administered on a weekly schedule at doses
60-1 00 mg/mz administered over 1 hour, weekly, or 2-3 weekly doses followed by a one week
rest In one embodiment, paclitaxel is administered intravenously over 3 hours at a dose of 175
mg/m2, optionally followed by cisplatin at a dose of 75 mg/mZ; or paclitaxel administered
~ntravenouslyo ver 24 hours at a dose of 135 mg/m2, optionally followed by cisplatin at a dose of
20 75 mglm2. In patlents previously treated with therapy for carcinom paclitaxel can be injected
at several doses and schedules. However, the optimal regimen is not yet clear. The recommended
reglmen 1s pahtaxel 135 mdm2 or 175 mg/m2 administered intravenously over 3 hours every 3
weeks These doses may be altered as needed or desired.
In another embodiment, other active agents may be included in a combination with an
25 HKI-272 oompound and vinorelbine compound and include, e.g., chemotherapeutic agents, such
as allcylating agents or mTOR irhbitors (rapamycin and derivatives thereof); hormonal agents
(LC., estramustine, tamoxifen, toremifene, anastrozole, or letrozole); antibiotics (i.e., plicamycin,
bleomyctn, rmlowantrone, idarubicin, dactinomycin, mitomycin, or daunorubicin); other
antimitotic agents ( I e , vinblastine, vincristine, teniposide); topoisomerase inhibitors (i.e..
30 topotecan, irinotecan, etoposide, or doxorubicin, e.g., CAELYX" or DOXILIB reagents,
pegylated I~posomaId oxombicm hydrochloride); and other agents (i.e., hydroxyurea,
aleetmne, ntuxlmab, paclitaxel, doeetaxel, L-aspmginase, or gemtuzumab ozogamicin);
11
b~ochermcaml odulatmg agents, unatib, EGFR inhib~torsu ch as EKB-569o r other multi-base
inhibitors e g , those that targets serine/threonine and receptor tyrosine kinases in both the tumor
cell and tumor vasculature, or immunomodulatom (i.e., mterferons, IL-2, or BCG). Examples of
sultable interferons include interferon a, interferon P, interon y, and mixtures thereof.
5 Desuably, the combination of the HKI-272 compound and vinorelbine compound may be
further combined wth antineoplastic alkylating agents, e.g., those described in US Patent
Application PublicationNo. 2002-0198137, which is hereby incorporated by reference.
Antlneoplastic alkylating agents are roughly classified, accordmg to thdr structure or reactive
molety, into several categories which includemtrogen mustards, such as MUSTARGEN@ drug
10 (meclorethmne), cyclophosphamide, ifosfamide, melphalan, and chlorambucil; azidines and
epoxldes, such as thiotepa, mttomycin C, dianhydrogalactitol, and dibromodulcitol; alkyl
sulfmates, such as busulfaqnitrosoureas, such as bischloroe~lnitrosourea(B CNU),
cyclohexyl-chloroethyInitrosourea (CCNU), and methylcyclohexyl~oroethy~nitrosourea
(MeCCNUJ, hydrazine and triazine derivatives, such as procarbazine, dawbazine, and
15 temozolomide; streptazom, melphalan, chlorambucil, camwheq methclorethamine,
1omushne)and platmum compounds. Platinum compomds are platinum containing agents that
react preferentially at theN7 yosiaon of guanine and adenine residues to form a variety of
monofunctional and biictional adduets, [Johnson S W, Stevenson J P, O'Dwyer P J. Cisplatin
and Ifs Analogues. In Cancer Princ~ples& Practice of Oncology 6'~dition. ed. DeVitaV T,
20 Hellman S, Rosenberg S A. Lippincolt Williams & Wilkins. Ph~ladelphia2 001. p. 378.) These
compounds include c~splahnc, arboplatin, platinum IV compounds, and multinuclear platinum
complexes Representative examples of alkylatmg agents including meclorethamine (injectable;
MUSTARGENB drug), cyclophosphamide (injectable; cyclophosphamide, lyophilized
CYTOXANCC drug, or NEOSAR5 drug; oral tablets cyclophosphamide or CYTOXAN@ drug),
25 ifosfamide (injectable; JFEX), melphalan (injectable, ALKERANB drug and oral tablets,
ALKERAN@ drug), chlorambucil (oral tablets, LEUKERAN@ drug), thiotepa (injectable,
thiotepa or THIOPLEXQ drug), mitomycin (injectable, mitomycin or MUTAMYCIN@ drug),
bmulfan (injectable, BUSULFEX@ drug; oral tablets, MYLERANB drug), lomustine (oral
capsules, CEENU), carmusbne (mtracranial implant, GLIADEL), injectable (BICNU),
30 procarbazine (oral capsules, MATULANEm w)te,m ozolomide (oral capsules, TEMODm@
drug), cisplatin (injectable, usplalln, PLATINOLB drug, or PLATINOLaAQ)., carboplatin
(injectable, PARAPLATIN@ drug)? and oxaliplatin (ELOXATIN@ drug).
12
In another embodiment, a combination described herein may further include an
antmeoplaac antimetabohte, as descnbed in US Patent Application PublicationNos.
200510187184 or 200210183239, which are hereby incorporated by reference. As used herein
accordance, the tern "mtimetabolite" means a substance which is lit~ct~ralsliym ilar to a critical
5 natural interndate (metabolite) m a biochemical pathway leading to DNA or RNA synthesis
which is used by the host in that pathway, but acts to inhibit the completion ofthat pathway (i.e.,
synthesis of DNA or RNA). More specifically, antimetabolites typically function by (1)
camp+ with metabolites for the catalytic or regulatory site of a key enzyme in DNA or RNA
synthesis, or (2) substitute for ametabolite that is normally incorporated into DNA or RNA, and
10 thereby producmg aDNA or RNA that cannot support replication. Major categories of
antimetabolites include (1) folic acid analogs, which are inhibitors of dihydrofolate reductase
(DHFR); (2) purine d o g s , which rmrmc the natural purines (adenine or guanine) but are
structudly different so they competitiveIy or irreversibly inhibit nuclear proces~ingo f DNA or
FWA; and (3) pynmidiie analogs, which mimic the natural pyrimidines (cytosine, thymidine,
15 and uracil), but are structurally different so thy competitively or irreversibly inhibit nuclear
processing of DNA or RNA Representative examples of antimetabolites include, without
limtallon, 5-Fluorouracil(5-FU; 5-fluoro-2,4(1H,3H)-pyrimidinedione; topical cfeam,
FLUOROPLEXB or EFUDEXm drugs; topical solution, PLUOROPLEX@ or EFUDEX@
drugs; injectable, ADRUCILm drug orflurou~acil))fl,o xwadine (2'-deoxy-5-fluorouridine;
20 bjectable, FUDR or floxuradine), thiogwnme (2-armno-1,7-d1hydro-6-H-punne-6-thi(moera l
tablets, thiogpmne), cytarabine (4-amino-l-(~)-D-arabinofuranosyl-2(1H)-~timidinone;
liposomal injectable, DEPOCYT@ reagent, liquid injectable, cytarabine or CYTOSAR-U@
drug), fludarabme (9-H-Purin-6-amine~-fluoro-9-(5-O-phosphono-@~D-a-rabino~msyI;
liqwd injectable, FLUDARA), 6-Mercaptopdne (1,7-dihydro-6H-purin66-thime; oral tabIets,
25 PURINETHOL)., methotrexate (MTX, N-14-[[[2,4-diamino-6-
pterid~nyl)methyl]methylarmno]benzoyl]-lc acid; liquid injectable, methotrexate
sod~umor FOLEX; oral tablets, methutrexrrte sodium), gemcitabiie (2'-deoxy-2',2'-
d~fluorocyhdmem onohydrochlonde ((j3)-isomer); liquid injectable, GEMZAR), capedtabine (5'-
deoxy-5-fluoro-N-[(pentyloxy)mbonyl]-cytidineo ral tablet, XELODA), pentostatin ((R)-3-(2-
30 deoxy-(beta)-D-erythro-pentofuranosyl)-3,6,7,8-t&~dro~~o[4,5-d][l,3]&~~-8-01;
hqu~dul j ectable, NIPENT). eetrexate (Z4-diamino-5-methy1-6-[(3,4,5-
Inmethoxymlino)methyl]qu~nazoline mono-D-glucuronate; liqurd injectable, NEUTREXIN),
cladribine (2-chlo~o-6-amino-9-(Z-deoxy-(~)-D-e~openko-furanopsuyri1n)e ; liquid injectable,
LEUSTATIN)
The term "biochemcal lnodulahng agent" is well known and understood to those skilled
5 m the art as an agent given as an adjunct to anti-cancer therapy, which serves to potentate its
antineoplastic activity, as well as cotmteract the side effects of the active agent, e.g., an
antrmetabolite. Leucovonn and levofol~natea re typically used as biochemical modulating agents
for methotrexate and 5-FU therapy. Leucovorin (5-fonnyl-5,6,7,8-tetrahydrofolic &ld) is
commetc~allya vailable as an injectable liquid (leucovorin calcium or WELLGOVORIN) and as
10 oral tablets Oeucnvorin caIcium). I.evofolinate (pharmacologically acme isomer of 5-
formyltetrahydroLolic acid) is commercially available as an injectable containing (ISOVORCN)
01 as oral tablets (ISOVORIN)
In stdl another embodiment, the combination further includes a kinase inhibitor.
Partml arly desirable h a s e Inhibitors include multi-kinase inhibitors target serinelthreonine and
15 receptor tyrosint; kinases in both the tumor cell and tumor vasculature. Examples of suitable
kinase inhibitors include, without limitation, sorafenib (BAY 43-9006, commercially available as
NEXAVAR), whch has been granted Fast Track status by the FDA for metastatic renal cell
cancer, zamestra (R115777, tipifornib), suntinib (SUTENT), and other campounds that farget
Ras/Raf/MEK and/or MAP lanases mcludtng, e.g., avastin, ISIS 5132, and MEK inhibitors such
20 as CI-1040 or PD 0325901 Alternabvely, the kinase inhibitor may be administered to the
pabent pnor lo or subsequent to treatment \nth the vinorelbine compound and/or HKI-272
compound
In stdl filrther embodiment, the combination may include an anti diarrheal. One of skill
in the art would readiiy be able to select a suitable antidimheal for use herein including, mthout
25 limitation, loperamide or diphenoxylate hydrochloride and atropine sulfate. Alternatively, the
anti-diarrheal may be admmistered to the patient prior to or subsequent to treatment with the
vinorelblne compound and/or HKI-272 compound.
In a f d w embodiment, the combination further contains an antiemetic agent. Examples
of antiemetic agents mclude, w~thoulti mitation, metoclopramide, Dolasetron, Granisetron,
30 Ondansel~onT, ropisekon, and Palonosetron, among oIhers. Alternatively, the antiemetic may be
adrmntstered to the paSlent prior to or subsequent to treatment with the vinorelbine compound
and/or HKT-272 compound.
In ye1 a further embod~mentt,h e combiition also contains an antihistamine. Examples
oC antihistamu~esm clude, *out limitation, Cyclizine, Diphenhydramine, Dimenhydrinate
5 (Gravel), Mechzme, Promethaztne pentazine, Phenergan, Promacot), or Hydroxyzine, among
others. Alternatively, the ant~h~staminmea y be administered to the patient prior to or subsequent
to treatment with the vinoreibme compound andfor HKI-272 wmpovnd
In yet another embodiment, the wmbinatio~ml ay include a growth factor to prevent
and/or treat neutropenia Such growth factors may readily be selec5ed by those skill in the art
10 according to practice guidelines from the American Society of Cluiical Oncology (ASCO, 2006).
Alternatively, the growth factor may be administered to the patient prior to or subsequent to
treatment with the vinorelbine compound andlor HKI-272 compound.
Administration of the CompositionslCombinations
15 As used herein, the term "effective amount" or "pharmaceutically effective amount"
refers to the amounl of achve compound or phamaceical agent that elicits the biological or
medicinal response in a tissue, system, animal, individd or human that is being sought by a
researcher, veterinarian, medical doctor or other clinician, which includes one or more of the
following (1) preventing the disease; e.g., preventing a disease, condition or disorder in an
20 inlvrdual that may be predisposed to the disease, condition or disorder but doe$ not yet
expmence or d~splayth e pathology or syrnplomatology of the disease; (2) &biting the disease;
e g , inhibitmg a dlsease, wnd~t~orn d isorder in an individual that is experiencing or displaying
the pathology or symptomatology of the disease, condition or disorder Q.e., arresting or slowing
further development of the pathology andlor symptomatology); and (3) ameliorating the disease;
25 e.g., ameliorating a disease, condition or disorder in au individd that is experiencing or
displaying the patholow or symptomatology of the disease, condition or disorder (i.e., reversing
the pathology and/or syrnptomatology). For example, an effective amount," when administered
to a subect to treat cancer, is sufficient to Inhibit slow, reduce, or eliminate tumor growth in a
subject havlng cancer
30 Use of a combinahon dthe HKI-272 compound and vinorelbine compound also provides
for the use of combmations of each of the agents in which one or both agent is used at
subtherapeutically effectrve dosages. Subtherapeutically effective dosages may be readily
15
determined by one of skill in the art, in vlew of the teachings herein. In one embodiment, the
subtherapeutically effective dosage is a dosage which is effective at a lower dosage when used in
the combinattan regimen described herein, as compared to the dosage that is effective when used
alone Also provided are one or more of the active agents in the combinations herein to he used
5 in a supratherapeuhc amount, c.e., at a higher dosage in the combination than when used alone.
In this embodiment, the other active agent(s) may be used in atherapeutic or subtherapeutic
amount.
The term "treating" or "treatment" refers to any indicia of success in amelioration of an
mjury, pathology, or condition, including any objective or subjective parameter such as
10 abatement; remission, drmimshmg of symptoms or making @e injury, pathology, or condition
more tolerable to the patient, slowng the rate of degeneration or decline; making the final point
of degeneration less debilitating; or improving asubjeot's physical or mental well-being. The
treatment or amelioration of symptoms can be based on objective or subjective parameters;
including the results of a physical exarmnation, neurological examination, andlor psychiatric
15 evaluation. Accordingly, the term "treating" mcludes the administration of the HKI-272 and
vinorelbine compounds to a subject to prevent or delay, to alleviate, or to anesf or inhibit
development of the symptoms or con&tions associated with cancers, mcludmg tumor growfh
assoc~atedw ith cancer A skllled rnedmal pramhoner will know how to use standard methods to
d e t e m ew hether apai~enits suffering from a disease sssociated with cancer by examining the
20 patlent and detennuung whether the patient is suffering from cancer.
As used herein, the term "providing with respect to prowding a HKI-272 compound and
a vinorelbine compound, means either directly administering the HKI-272 compound and
vinorelbine compound, or administering aprodrug, derivative, or analog which will form an
effective amount ofthe HEU-272 compound andor Yinorelbme compound within the body.
25 The invention therefore includes administering an HKI-272 compound and vinorelbine
compound to a patient for the treatment of aneoplasmin apatient. In one embodiment, the HW-
272 compound is adm~msteredse parately fromthe vinorelbine compound In a further
embodinienl, the HKI-272 compound is administered prior to the vinorelbine compound. In
another embodiment, the HKI-272 compound is administered subsequent to the vinorelbine
30 compound, In still another embodimentt the HKI-272 compound and the vinorelbine compound
are admltustered simultaneously, but separately. In one embodiment, the HKI-272 compound and
the vinorelblne compound are administered together as a combinedpreparation
16
In one embodiment, a product contam an HKI-272 compound and vinorelbine
compound as a comblned preparation for simultaneous, separate or sequential use in treating a
neoplasm in a mammal in need thereof. In one embodiment, the EW-272 compound is
separately formulated from the vlnorelblne compound. In another embodunenf a product
5 contains the HKI-272 compund and the vlnorelbine compound as acombined preparation for
sim~taneouss, eparate or sequential use in a neoplasm in a mammal in need thereof.
In one embodiment, a pharmaceutical pack contains a course of treatment of aneoplasm
for one individual mammal, where~nth e pack contains units of an W-272 compound in unit
dosage form and units of a vinorelbine compound in unit dosage farm. In another embodiment, a
10 pharmaceutical pack contains a course of treatment of a neoplasm for one individual mammal,
whernn the pack contains unlts of an HKI-272 compound in unit dosage form and units of a
vlnorelblne compound in untt dosage form. In yet another embodiment, a pharmaceutical pack
as described herein contains a come of treatment of metastatic breast cancer for one individual
m d .
Adm~nistrationo f the individual components or a composition containing two or more of
the indiv~dualc omponents may employ any suitable mute. Such routes may be selected fiom,
e.g., oral, mnixamnous (i.v.), respiratory (e g , nasal or intrabronchial), infusion, parentera1 (aside
from1 v ,s uch ns intral~ional~, ntraperitoneaal nd subcutaneous injections), intraperitoneal,
transdermal (including all administration across the surface of the body and the inner linings of
20 bodily passages includmg epithelial and mucosal tissues), and vaginal (including intrauterine
administration) Other routes of administration are also feasible and include, without limitation,
I~posome-mediatedd ellvety, topical, nasal, sublingual, metheral, intrathecal, ocular or otic
delivery, implant, rectal, or mntranasal.
W l e the components may be dehered viathe same route, a ptoduct or pack described
25 herem may co~ltiuna vmorelb~nec ompound for deliveg by a diierent route than that of an HKI-
272 compound, e.g., one or more of the components may be delivered orallyYw hile one or more
of the others are administered intravenously. In one embodiment, the HKI-272 compound is
prepared for oral delivery and the vinorelbine compound is prepared for intravenous delivery. In
another embedment, both the HKI-272 and vinorelbine compounds are prepared for intravenous
30 delivery. In still another embodiment, both the HKI-272 and vinorelbine compounds are
prepared for oral deliven. Optionally, other active components may be delivered by'the same or
different routes as the HKI-272 andlor vinorelbine compounds. Ofher variations would be
apparent to one sktlled in the art
111 s~il la nother embodiment, the compounds or components of the therapeutic regimen
are adrmlvstered once aweek In certain situahons, dosing with the HRI-272 compound may be
5 delayed or disconhnued for a brief period [e.g., 1,2 or three weeks) during the come of
treatment Such a delay or discontinuation may occur once, or more, during the course of
treatmant. The effective amount is known to one of skill in the art; it will also be dependent
upon the form ofthe HKI-272 compound. One of skill in the art could routinely perform
empirical ackvity tests Lo determine the bioacti~ityo f them-272 compound in bioassays and
10 thus determine a suitable dosage to administer.
The HKI-272 and vlnorelblne compounds or other optional compounds used in the
combm&on and produots described hereinmay be formulated in any suitablemanner.
However, the amounts of each compound in theunit dose can vary widely depending on thetype
of wmposikon, regimen, size of a unit dosage, kind of excipients, and other factors well known
15 to those of ordinq skill in the art In one embodiment, the unit dose can contain, e.g., 0.000001
percent by weight (% w) to 10% w of either compound In another embodiment the unit dose
can contain about 0 00001 Oia w to 1% w, with the remainder being the exeipient or excipients.
The compositions described herein may be in a form suitable for oral adrmnistrafion, e.g.,
tablet, caplet, capsllle. buccal forms, troches, lozenges and oral liquids, suspensions or solutions:
20 pasenteral injecoon (ineludmg intravenous, subcutaneous, intramuscular, intravascular or
snfus~on)e, .g., as a sterile solution, suspension or emulsion; topical administration, e.g, an
omtment or cream; rectal admimstration, e g., a suppository, or the route of m a t i o n may
be by direct Injection into the twnor or by regional delivery or by local delivay. In other
embodiments, one or both components of the combination treatment may be delivered
25 endoscopicall~. ~ntratrachedlyi,n tralesimally, percutmeously, intravenously, subcutaneously,
lntrapentoneally or intratumorally. In general the compositions described herein may be prepared
m a conventlona1 man& usmg conventional excipients or carriers that are well knownin the att.
Pharmaceutid compositions for oral use may also be in the form of hard gelatin capsules in
whrch the active ingredient is mured with an inert solid excipient, e.g,, calcium carbonate,
30 calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed
with water or an oil, such as peanut oil, liquid paraffin or olive oil. In one embodiment, one or
bolh of said vlnorelbine compound and saidHKI-272 compound are delivered orally to said
subject
Capsules may contain mtures of the active compound(s) with inert fillers andlor
diluents such a the phar~naceuticallyac ceptable starches (e.g, corn, potato or tapioca starch),
5 sugars, arhficlal sweetening agents, powdered celluloses, such as crystalline and microcrystalline
celluloses, flours, gelabns, gums, etc.
Useful tablet ot caplet formulations may be made by conventional compression, wet
granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding
agents, lubricants, disinteptants, surface modifyig agents (including surfactants), suspending or
10 stab~l~zinagge nts, including, but not limited to, magnesium stearate, stearic acid, talc, sodium
lawyl sulfate, microcrystalline cellulose, carboxymethylceUdose calcium, polyvinylpyrrolidone,
gelatin, algihic acid, acaciagum, xanthan gm~s,o dium citrate, complex calcium
carbonate, giycme, dex(ri11. sucrose, sorbltol, dicalcium phosphate, calcium sulfate, lactose,
kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Preferred surface
15 mowing agents include nonionic and anionic surface mowing agents. Representative
examples of surface modiiying agents mclude, but arenot limited to, poloxamer 188,
benvllkonium chlonde, calcium stearate, cetosteasyl alcohol, cetomacrogol emulsi&ing WFS,
sorbitan esters, colloidal s i l i c ~d~ oxldep, hosphates, sodium dodecylsulfate, magnesium
alunitnum silicate, and tnethanolamine.
20 Oral SormulaUons herem. e g , tablets, caplets, or capsules described above, may utillze
standard delay or time release formulabons to alter the absorption ofthe active compound(s).
The oral formulabon may also consist of admimstenng the acbve ingredient in water or a fruit
jmce, contaming appropriate solubilizers or emulsifiers as needed
In some cases it may be desirable to administer the compolmds directly to the airways in
25 the form of an aerosol.
The pharmaceutical forms slutable for injectable use include stenle aqueous solutions or
dispersions and sterile powders for the extemporaneous preparation of sterileinjectable solutions
or dispers~ons In all cases, the form mwt be sterile and must be fluid to the extent that easy
syringab~l~etxyr sts It must be stable under the cmditions of manufacture and storage and must
30 be preserved agmnst the contaminating acbon of microorganisms such as bacteria and fungi.
The curler can be a solvent or dispersion medium containing, e.g., water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and
19
vegetable oils. Prefered mjectable fomulations containing vinorelbine are described in the art.
In one embodiment, the compounds may be administered parenterally or in!zaperitonedly.
Solutions or suspensions of these active compounds as aftee base or pharmacologically
acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-
5 propylcellulose. Dispersions can also be prepared in glycerol, liqlud polyethylene glycols and
mixtures thereof in oils Under ordinary conditions of storage and use, these preparations may
contam a preenatwe to prevent the growth of mcroorganisms. In one embodiment, one or
both of the vinorelblne and HKI-272 compounds ate delivered intravenously.
For use herem, transdermal administrations include all administrations across the surface
10 of the body and the inner linings of bodily passages including ep~theliaal nd mucosal tissues.
Such administrations may be performed using the present compoundsdso r pharmaceutically
acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and
supposltones (rectal and vaginal) Transdermal administration may be accomplished through the
use of a transdermal patch containing the active compound and a carrier that is inert to the active
15 compound, is nontoxic to the skin, and allows dehvery of the agent for systemic absorption into
the blood stream via the skin. The carrier may take any number of fotms such as creams and
ointments, pastes, gels, and occlusive devices. The creams and otnttnents may be viscous liquid
or semisolid emulsions of either the oil-in-water or water-in-oil type Pastes comprised of
absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active
20 ingredient my also be suitable. A variety of occlusive devices may be used to releae the active
lngredtent into the blood stream such as asemi-permeable membrane covering a reservoir
contammg the active lugreclient with or without a carrier, or amatrix containing the active
ingredient Other occlus~ved evices are known in the literature,
Suppository formulations may be made from traditional materials, including cocoa butter,
25 with or w~thoutth e addition of waxes to alter the suppository's melting point, and glycerin.
Water soluble suppository bases, such m polyethylene glycols of various molecular weights, may
also be used.
In another embodiment, one or both of the HKI-272 and vinorelbine wmpounds can be
delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed,
30 re , by employing ligands attached to the liposome, or attached directly to the oligonucleotide,
thzt bind to surface membrane protein receptors of the cell resulting in endocytosis. By using
liposomes, particularly where the liposome surface cames ligands specific for target cellss,o r are
20
otherwise prererenhally dmcted to a specific organ, one can focus the delivery of one or more
compound Into the target cells in vim. (See, e.g., Al-Muhammod, J. Micmencapsul. 13:293-306,
1996; Chonn, Curr Op~n Blotechnol. 6 698-708,1995; Ostro, Am J. Hosp. P h m 46:1576-
1587, 1989). Zn other cases, the preferred preparation of one or more of the components can be a
5 lyoph~lizedp owder.
Encapsulating materials can also be employed with one or more of the compounds and
the ten11 "composition" can include the active ingredient in combination with an encapsulating
material as a formulation, with or without other carriers. For example, the compounds crm also
be delivered as microspheres for slow release in the body. In one embodiment, microspheres can
10 be administered via intradermal injection of drbg-contaitiing microspheres, which slowly release
subcutaneously (see Rao, J. Biomater SCIP. olym Ed. 7.623-645,1995; as biodegradable and
mjectable gel formulations (see, e.g . Gao, Pharm Res. 12:857-863,1995); or, as microspheres
for oral adrmtllstrakon (see, e.g., Eyles, J. Pharm. Phannacol. 49.669-674,1997). Both
transdermal and mntradermal routes afford constant delivery for weeks or months. Cachets can
15 also be used in the delivery of the compounds of the present invention, e.g., anti-atherosclerotic
med~caments.
Dosages of the HM-272 Compound and Vinorelbme Compound
20 As is typical with oncology treatments, dosage regimens are closely monitored by the
treating physician, based on numerous factors including the severity of the disease, response to
the disease, any treatment related toxicities, age, and health of the patient. Dosage regimens are
expected to vary according to the route of adminimation.
The dosages and schedules described herelubefore may be varied according to the
25 particular disease state and the overall condition of the paent. For example, it may be necessary
or des~rableto reduce the above-mentioned dosa of the components of the combination
treatment in ordel to reduce toxlcrty Dosages and ~cbedulesm ay also vary 5 in addition to a
combination of an HKI-272 compound and avinorelbine, one or more additional
chemotherapeutic agents are used. Scheduling can be determined by the practitioner who is
30 treating any particular patient using his professional skill and knowledge.
For the HKI-272 compound andlor vinorelbine compound, it is desired each compound of
the combina&on of compounds is in the form of a unit dose. The term "unit dose" or "unit dose
21
form" as used herem describes a single dose form including, without limitation, tablets, caplets,
capsules, powders in sachets or vials, saliae infusion bags, as described above.
Un~dt ose forms contan &om about 0.1 to about 300 mg of a m - 2 7 2c ompound. In
another embodimenf the unit dose form contains about5 to about 300 mg of the HKI-272
5 compound. In another embodiment, the m t dose form contains about 50 to about 300 mg of the
HK1-272 compound. In a further embodiment, the unit dose form contains about 75 to about 300
mg of the be-272 compound In still a fmther embodiment, the unit dose form contains about
100 lo about 300 mg of the HKI-272 compound In yet another embodiment, the unit dose form
contains about 120 to about 300 mg of the HKI-272 compound. In yet a further embodiment, the
10 unlt dose form contains about 160 to about 300 mg of the HKI-272 compound In another
embomment. the unit dose form contains about 200 to about 300 mg of the HKI-272 compound.
In yet another embodiment, the unit dose form contains about 240 to abovt 300 mg of the HKI-
272 compound. In a further embodiment, the unit dose form contains about at least about 120
mg. In still a father ehbodiment, the wit dose f m contains at least about 160 mg. In another
15 embodiment, the unit dose form contans at least about 240 mg.
The HIU-272 compound can be administered, e.g., orally, at a dose range of about 0.01 to
100 &g. In one embedment, the HKI-272 compound is administered at a dose range of about
0 I lo about 90 mglkg. In another embodiment, the HKI-272 compound is administered at a dose
range of about 1 to about 80 mglkg. In afurther embodiment, the HKI-272 compound is
20 adrmnistered at a dose range of about 10 to about 70 mgkg. In yet another embodiment, &e HKI-
272 compound is adnvnistered at a dose range of about 15 to about 60 mgbg. In still afurthm
embobment, the be-272 compound is adrmnisteted at a dose range of about 20 to about 50
mg/kg. In another embodiment, the HKI-272 compound is administered at a dose range of about
30 to about SO mgikg. One of skill in the art could routinely perform empirical activity tests to
25 determine the bioactivity of the compound in bioassays and thus determine what dosage to
administer.
In one embodiment, the oral dosage of the HKI-272 compomdis at least about 700
=/week. In another embodiment, the oral dosage of the HKI-272 compound is about 800
mglweek to at Least to about 1700 mg/week In another embodiment, the oral dosage of the HKI-
30 272 compound is about 840 mg/week to about 1680 &week In another embodiment, the oral
dosage of the HKI-272 compound is about 900 mg/week to about 1600 mgheek. In a further
embodiment, the oral dosage of the HKI-272 compound is about 1000 mg/week to about 1500
22
mglweek In yet another embodmmt, the oral dosage of the HKI-272 compound is about 1100
mg/week to about 1400 mg/week In In a arther embodiment, the oral dosage of the HKI-272
compound is about 1200 mglweek to about 1300 mg/week Precise dosages are determined by
the administering physician based on experience with the individual subject to be treated. Other
5 dosage regimens and variazlons are foreseeable, and are determined through physician guidance.
Desirably, the patient is administered about 0.1 to about 50 mgkg of the vinorelbine
compound In one embodiment, the patient is administered about 1 to about 30 mgikg of the
vinmelbine compound. In another embodiment, the patient is administered about 5 to about 25
mgkg of the vinorelbine compound. In a further embodiment, the patient is admmistered about '
10 10 to about 20 mgkg of the vinorelbine compound. In still a further embodiment, the patient is
admnrstered about 20 mglkg of the vinorelbiie compound.
Unit dose fonns contam about 0.1 to about 100 mg of a vinorelbine compound. In another
embod~mentt,h e unit dose fom~co ntains about 1 to about 70 mg of the vinorelbiie compound. In
another embohment, the unit dose form contains about 5 to about 500 mg of the vinorelbine
15 compound Jn a arther embodiment, the unit dose form contains about 10 to about250 mg of the
vmorelbine compound. In still a further embodunen1, the unit dose form con* about 15 to
about I00 nlg of the vinorelbine compound In yet another embodiment, the unit dose form
contains about 20 to about 75 mg of the vinorelbiie compound. In yet a further embodiment, the
unit dose form contains about 25 to about 50 mg of the vinorelbime compound. In another
20 embodiment, the unit dose form contak about 31) to about 40 mg of the vinorelbine compound.
In yet another embohment, the unit dose form contains about 240 to about 300 mg of the
vmorelbine compound. In a further embodiment, the unit dose formcontains about at least about
120 mg. In still a further embodiment, the unit dose form contains at least abut 160 mg. In
another embodiment, the unit dose form contains at Ieast about 240 mg.
25 In one embodiment, i.v. infusion dosages of the vinorelbine compound are from about 5 to
about 25 mgL. The initial infusion dosage of the vinarelbine compound may be more or less, as
determined by the treating physician. In one embodiment, the i.v. infusion dosage ofthe
vinmelbm compound is about 10 to about 20 m&. In a further embodiment, the i.v. infusion
dosage of the vinorelbine compound is about 20 to about 25 mgL. In yet another embodiment,
30 the 1.v. infusion dosage of the vinorelbine compound is at least about 10 mg/L. In another
embodiment, the i.v infUsion dosage of the mnorelbine compound is at least about 15 mg/L. In
yet another embodiment, the 1.v. rnfusion dosage of the vinorelbine compound is at least about 20
23
mgL. In yet another ernbodiment,the i.v infusion dosage of the vinorelbine compound is at least
about 25 mg/L Precise dosages are determined by the administemg physician based on
experlence wth theindividual subject to be treated Other dosage regimens and variations are
foreseeable, and are deteimined through physician guidance. In one embodiment, the vinorelbine
5 compound is admuustered by 1.v. infusion or orally, preferably in the form of tablets or capsules.
As described herein, subtherapeuticaUy effective amounts of the HKI-272 compound and
v~norebll ne compound ma) be used to achieve atherapeutic effect when administered in
cornbinahon In one embodiment, the HKI-272 compound is provided 4t dosages of 5 to 50%
lower when provlded dong with the vinorelbine compound. In another embodiment, the HKI-
10 272 compound is provided at dosages of 10 to 25% lower when providedalong with the
vinorelbine compound. In a further embodiment, the HKI-272 compound is provided at dosages
of 15 to 20% lower when provided along with the vinorelbme compound. In one embodiment, a
resulting HICI-272 compound dwage is about 8 to 40 mg. In another embodiment, a resulting
HKI-272 compound dosage is about 8 to 30 mg In a further embodimenf a resulting HKI-272
15 compound dosage is about 8 to 25 mg. Subtherapeutically effective amounts of the HKI-272
compound and vmorelb~nec ompound are expected to redvce the side-effects of treatment.
Alternatively, one or more ofthe active agents in the combination described herein is to
be used in a suprathsrc+peutic amount, i.e., at a higher dosage in the combination than when used
alone In th~se mbodiment, the other active agent(s) are used in a therapeutic or subtherapeutic
20 amount.
Regimen Using the HECI-272 Compound and Vinorelbhe Compound
As used herem, the components ofthe therapeutic "combined" regimen, is., the HKI-272
compound and the vinorelbine compound, can be administered simultaneously. Alternatively,
25 the two components can be administered in a staggered regimen, r.e., with theHKI-272
compound being given at a different bme during the course of chemotherapy than the vinorelbine
compound This time differential may range from several minutes, hours, days, weeks, or longer
between admirustratlon of the at least two agents. Therefore, the term combination (or
combined) does not necessarily mean administered al the same bme or as a unitary dose or single
30 composition, but that each of the components are administered during a desired treatment period.
The agents may also be administered by different routes. As used herein in one embodiment, 1
"cycle" includm 3 weeks
24
These regmens or cycles may be repeated, or alternated, as desired. Other dosage
regimens and vanations are foreseeable, and we determined through physician guidance. The
regimen mav Include ''non-treatment" steps/visits including screening periods aad post-treatment
per~ods In one embodimen$ the regimen continues at least about 2 weeks, at least about 6 weeks,
5 at least about 12 weeks, at least about 24 weeks, at least about 33 weeks, at least about 40 weeks,
and at least about 46 weeks. Additional screening weeks and final monitoring weeks may also be
included. For example, the regmen may include 4 weeks of screening and 6 week for final visit.
Smgle doses and multiple doses are contemplated. In one embodiment, the vinorelbi
andlor HKI-272 compound is administered only once in the treatment. In another embodiment,
10 the heinorelbine andlor HKI-272 compound is administered at least once over a period of 21 days.
In a further embodiment, the vinorelbine andfor HKI-272 compound is administered at least twice
over a per~odo f 21 days. In still another embodiment, the vinorelbine a d o rH KI-272 compound
is administered on days 1, 2, 3,4, 5,6,7, 8, 9, 10, 11, 12,13,14, 15,16, 17, 18, 19,20,Bndlor21
of the cycle In a further embodiment, the vinorelbine and/or HKI-272 compound is administered
15 on days 1 and 8 of the cycle. In still a M e r embodiment, the vinorelbine and/orHKI-272
compound is administered at least once daily In yet another embodiment, the vinom1bine andlor
HW-272 compound HKI-272 compound is administered on day 1. Desirably, theHKI-272
compound is admimstered on day 1 if the neoplasm is non-metastatic. In afurther embodiment,
the vinorelbine andlor HKI-272 compound is administered on day 2 of said regimen. Desirably,
20 the HW-272 compound is administered on day 2 if theneoplasm is metastatic. In still afurther
embodiment, the HKI-272 compound is administered orally at least once a day. b mother
embodrment, the M-272 compound is administered at least 1,2,3,4,5, or 6 times a day. In a
further embodiment theHKI-272 compound is administered 1 to 4 times aday.
In one embodiment, a smgle loading dose of the vinorelbine compound and/or HKI-272
25 compound 1s administered. The single loading dose of the vinoreIbine compound and/or the
HW-272 compound may be the same dose as the subsequent doses or the single loading dose
may be greater than the dose admmistered to the patient throughout the remaining treatment. In
a further embodiment, the vinorelbiie compound /or the HKI-272 compound may be
administered at a larger dose only once per cycle, t e., one day per cycle.
30 If certainsubjects do not tolerate one or more of the components of the composition, te.,
the HKI-272 compound or ~inorelbinec ompound or if the subject does not recover ftom
treatment-related toxicity after more than 3 consecuime weeks, or if any grade 4 nonhematologic
25
toxtclty occurs that is treatment related, a dose reduction may be performed. In one embodiment,
administration of one or both of the HKI-272 compound and the vinorelbine compound is
&sconQnued if patent acquires one or more of a symptom including, without limitation, selected
from the group consisting of neuropathy, neutropenia, thrombocytopenia, nausea, vomiting,
5 decreased platelet count, and increased bilirubin count. In another embodiment, administration of
one or both of the HKI-272 compound and the vinorelblne compound is discontinued or
intermpted if the patient's neutrophil count of is less than about 1000L. In a further
embodiment, adminurattion of one or both of theHKI-272 compound and the vinorelbiie
compound is discontinued or intermpted if the patient's platelet count is less than 75,000L.
10 Altemahsely, for those subjects do not tolerate one or more of the components of the
composition, i e , the HKI-272 compound or vinorelbiie compound, dose reductions may be
performed In one embodiment, 1 or 2 dose reductions are performed. More desirably, only 1
dose reduction is performed
For subjects who not recover from vinorelbine or HKI-272-related toxicity after more than
15 3 consecuhve weeks, treatment with vinorelbme or HKI-272, respectively, may be discontinued
However, administration of the other agent i.e., HKI-272 or vinorelbine, respectively, may be
contmued
The regimen is typically continued for at least about 2 weeks. In one embodiment, the
regimen is continued for no more than 46 weeks. In another embodiment, the regiment is
20 continued for about 6 weeks. The length of parheipationis dependent on a subject's tolerance of
the treatment and status of his or her disease. However, the treating physician may determine that
shorter or longer treatment can be pursued For example, subjects may receive more than 12
cycles of treatment if it is well tolerated, if the neoplasm has not progressed, if the subject is
cllnicdly stable, and if the subject has received an overall benefit.
25 In addition, the vlnorelbine compound lor the HKI-272 compound may also be
administered after completion of chemotherapy as maintenance therapy.
Pharmaceutical Packs and Kits
Also included is a product or pharmaceutical pack contamng a come of an anti-
30 neoplastic treatment for one mdlvidual mammal comprising one or more container(s) having
one, one to four, or more unit($ of the HKI-272 oompound in unit dosage form an4 optionally,
one, one lo four, or more unit(s) of the HKI-272 and vinorelbine compouods, and optionally,
another active agent. The combinations may be in the form of a kit of parts.
In one embodiment a kit includes a first container with a suitable composition containing
aHKI-272 compound and a second contamer with a suitable composition containing a
5 vtnorelbtne compound. Accordingly, there is promded a kit for use m the treatment or
prophylaxis of cancer Th~kst t includes comprising, a) HKI-272 compound together with a
phammceuhcally-acceptable exclpient or carrier, ina fmt unit dosage fonn; b) a vinorelbine
compound together with a pharmacemcally-acceptable excipient or carrier, in a second unit
dosage form, and c) a container for containing sad first and second dosage form.
10 In another embodiment, pharmaceutical packs contain a course of anti-neoplastic
treatment for one individual mammal comprising a container having a uait of a HKI-272
compound in unit dosage form, a containiig having a unit of avinorelbine compound, and
optionally, a contruner wlh another active agent
In some embodiments, the compositions are in packs in aformready for administration.
15 In other embodiments, the compositions are in concentrated fotmin packs, oflonally with the
dlluent required to make a fhal solution for administration. In still other embodiments, the
product contams a compound described herein in solid formand, optionally, a separate container
with a suitable solvent or camier.
In shll other embodunents, the above packs/kits include other components, e.5,
20 ~nstructlonsf or dtluhon, m i n ga nd/or administrahon of the product, other containers, syringes,
needles, elc. Other such packkit components are readily apparwt to one of skill in the art.
Concurrent Treatments
In addttion to the optional chemotherapeutic agents and optional compounds noted above,
25 the reglmens and methods described herein can be performed prior to, concurrently with, or
subsequent to other non-medication procedures. In one embodiment, radiation may be performed
pnor to, concurrently wi~o,r s ubsequent to treatment with the HKI-272 and vinorelbiie
compounds
30 Preferred Embodiments
In one embobmenf a regimen for treating a solid tumor associated with overexpr~ssiono r
amplification of HER-;! in a subject is provided. One cycle of the regimen includes 21 days and
27
the regmen includes orally administering alleast one unit dose of HKI-272 starting on day 1 of
the cycle and intravenously admirstenng at least one a unit dose of vinorelbine on days 1 and 8
of the cycle
In mother embodiment, a regimen for treating a mematic cancer associated with
5 overexpression or ampl~ficationo f HER-2 in a subject is provided One cycle of the regmen
icludes 21 days and the regimen includes orally administering at least one unit dose of HKI-272
starting on day 2 of the cycle and ~ntraver~ousalyd ministering at least one unit dose of vinorelbine
on days 1 nnd 8 of the cycle.
In a further embodiment, aproduct con- vino~elbiiea nd HIU-272 is provided. The
10 product is usem as a combmed preparation for simultaneous, separate or sequential use in
treating a neoplasm in ammmal.
In .Ml a further embodiment, a phmceuhcal pack for treating a neoplasm in one
indtv~d ual mammal is provided. The pbmaceutical pack contains at least one unit of vinorelbine
and at Leist one a t of HKI-272.
15 In another embod~menta, pharmaceuacal composition is provided and contains
vinorelbine, HIU-272, and at least one pharmaceutically acceptable carrier. Desirably, the
pharmaceu~cal composition is useful for treating aneoplasm in a ma&
In still another embodiment, a method of treating aneoplasm associated with
overexpression or amplification of HER-2 in a mammal in need thereof is provided The method
20 ~ncludesa dministering a umt dose of a vinorelbine compound and administe~ga unit dose of a
HKI-272 compound.
The followmg examples illustrate of the ususes of the combinations of the invention It will
be readily understood that alterations or modifications, e.g., in the formulation of the
25 components, the routes of delivery, and the dosing, can be made for reasons known to those of
skill m the art.
EXAMPLE 1 COMBINATION REGIMEN OF HKI-272 AND VINORELBINEIN LUNG
CANCER CELL PROLIFERATION ASSAYS
30 A standard cell proliferation assay was ut~l~zteod i ndependently analyze the response of
lung cell hnes NCI-H1666, NCI-H1650, and NCI-HI975 to various dilutions of HKI-272 and
vinorelbiie in combinat~on. Briefly, fetal bovine senun (FBS) RPMI-1640 (Media) was added
28
to each well of 96 well plates contai~xryo ne of the cell lines. Each column of wells contained a
different dilution of HKI-272 and solutions of vinorelbine were added to each well at a variety of
d~lui~owns11 1 respect to the HKI-272 dilutions (thehighest final concentration of HKI-272 was 1
pM for the HI650 andH1666 cell luies; the highest final concentration of HKI-272 was 9 phi
5 for the Hl975 cell line; and the highest final ooncentration of vinorelbine was 0.1 pM for dl of
the cell lines) Following incubaon of the cell plates at 37 'C, 5% C02 for 72 hours, cell
proltferation was assessed.
Cell proliferabon was reduced after incubation with HKI-272 and vinorelbine.
10 =AMPLE 2. GOMBINATION REGIMEN OF HKI-272 AND VINORELBINE IN
TREATMENT OF NON-METASTATIC BREAST CANCERS
Patients having diagnosed non-metastatic breast cancers are mated using a regimen of
HKI-272 and vinorelb~ne Pabents are administeredHK1-272 at either dose level 1 or 2. Dosing
of HKI-272 begins at cycle 1, day 1 with daily oral administration of HKI-272 at the dosages in
5 Table 3 HKI-272 1s taken orally on the remaining days of the each cycle. On those days that
HKI-272 and vinorelbine are admtnistered on the same day, i.e., days 1 and 8 of the cycle, HKI-
272 is ah~n~slerpendo r to the vmorelbme mfuslon.
Table 3
Dose Hyl-272 Dose Vinorelbint Dose
Level [ms) (mglm 1
1 160
2 240 25
V~norelbmeis administered on days 1 and 8 of each 21-day cycle, provided that the
combination of HKI-272 and vinorelbine is well tolerated and there is no evidence of disease
progression. Vinorelbrne 1s administered intravenously using preferentially a central venous
route, through a free-flowing IV Sine over approximately 10 minutes, followed by 125 mZ, of
25 saline solubon Infused over approximately 30 minutes.
If the patlent has any senous side-effwts during the treatment, dose adjustments of HKI-
272 andlor vinorelbine are permitted. See, Tables 4 and 5.
Table 4
Dose Adjustment HKI-2
-1 6.0-
I L I 240
The -1 dose level is used only if dose reduction 1s required.
b The dose 1 level is to be used as first level of dose reduction in case the
deiined max~mumioleratedd ose is 240 mg.
Table 5
I 1 I
a. The -1 dose level is to be used only if dose reduction is needed.
It is predicted that a decrease in tumor @;row& will be observed.
EXAMPLE 3' COMJ3INATION REGIMEN OF HKI-272 AND VONORELBINE IN
TREATMENT OF NETASTATIC BREAST CANCERS
15 Paents having diagnosed metastatic breast cancers are treated using aregimen ofHKI-
272 and vinorelbine
Vinorelbme is administered on day 1 and day 8 of the cycle using the dosages described
in Example 2 Table 3 or 5. The vinorelbine is administered over a 30-minute period using an inline
filter and an automatic dispensing pump Optionally, antihistamine (diphenhydramine, 25 to
20 50 mg IV or the equivalent) 1s ahn~steredab out 30 minutes prior to vinorelbine Man.
Dosing of HKT-272 begins at cyde 1, day 2 with daily oral administration of HKI-272 at
the dosages provlded m Example 2, Table 3 or 4. HKI-272 is taken orally on the remaining days
of the each cycle. 04 those days that HKI-272 and vinorelbine are administered on the same
day, i e., day 8 of the cl cle, HW-272 is administered prior to the vinorelbine infusion. If the
25 patient has any serious side-effects duringthe treatment, the dose adjustments of HKI-272 andlor
~rmorelbinea re pentted.
30
It is predicted that a decrease in tumor growth will be observed.
All patents, patent publications, articles, and other documents teferenced herein are
incorporated by reference It will be clear to one of skill in the art that modifications can be
5 made to the speclfic embedments descnbed herem without depatting from the scope of the
invention.

We Claim:
1. A pharmaceutical pack, comprising:
i) a unit dose of vinorelbine or a pharmaceutically acceptable salt ereo of; and
ii) 50-300 mg of ~)-N-(4-[3-chloro-4-(2-pyridinylmethoxy)anilin0]-3-cymo-7-ethoxy-6-
quinoliny1)-4-(dimethylamino)-2-butenamide ("HKI-272") or a pharmaceutically
acceptable salt thereof,
wherein the pharmaceutical pack further comprises instructions for dilution, mixing and/or
administration, syringes, or needles.
2. The pharmaceutical pack as claimed in claim 1, wherein said HKI-272 or a
pharmaceutically acceptable salt thereof is at least about 120 mg, at least about 160 mg, or at
least about 240 mg.
3. The pharmaceutical pack as claimed in any one of claims 1-2, wherein the unit dose
amount of said vinorelbine or a pharmaceutically acceptable salt thereof is between 5-500 mg,
20-250 mg, or at least 240 mg.
4. The pharmaceutical pack as claimed in any one of claims 1-3, wherein the
pharmaceutical composition is delivered intravenously.
5. The pharmaceutical pack as claimed in any one of claims 1-3, wherein one or both of said
vinorelbine or a pharmaceutically acceptable salt thereof and said HKI-272 or a pharmaceutically
acceptable sall thereof are delivered intravenously.
6. The pharmaceutical pack as claimed in any one of claims 1-4, wherein the unit dose
amount of said vinorelbine or a pharmaceutically acceptable salt thereof is about 20 to about 25
mpn.
7. The pharmaceutical pack as claimed in any one of claim 1-3, wherein the
pharmaceutical composition is delivered orally.
33
8. The pharmaceutical pack as claimed in any one of claims 1-3, wherein one or both of said
vinorelbine or a pharmaceutically acceptable salt thereof and said HKI-272 or a pharmaceutically
acceptable salt thereof are delivered orally.
9. The pharmaceutical pack as claimed in any one of claims 1-3 or 7-8, wherein the unit
dose is a tablet.
10. The pharmaceutical pack as claimed in any one of claims 1-9, wherein said
pharmaceutical composition is usehl in treating a neoplasm associated with overexpression or
amplification of HER-2.
1 1. The pharmaceutical pack as claimed in claim 10, wherein the neoplasm is selected from
the group consisting of a lung cancer, breast cancer, myeloma, prostate cancer, head and neck
cancer, transitional cell carcinoma, small cell neuroendocrine carcinoma of the uterine cervix,
and large cell neuroendocrine carcinoma of the uterine cervix.
12. The pharmaceutical pack as claimed in claim 11, wherein the neoplasm is a breast cancer.
13. The pharmaceutical pack as claimed in claim 12, wherein the neoplasm is metastatic.
14. The pharmaceutical pack as claimed rn claim 13, wherein the neoprasm is an advanced
solid tumor.
15. The pharmaceutical pack as claimed in any one of claims 1-9, wherein said
pharmaceutical composition is useful in treating a metastatic, HER-2-positive breast cancer.