U.S. patent application number 12/486153 was filed with the patent office on 2009-12-17 for antineoplastic combinations containing hki-272 and vinorelbine.
This patent application is currently assigned to Wyeth. Invention is credited to Charles Michael Zacharchuk.
Application Number | 20090312360 12/486153 |
Document ID | / |
Family ID | 41415366 |
Filed Date | 2009-12-17 |
United States Patent
Application |
20090312360 |
Kind Code |
A1 |
Zacharchuk; Charles
Michael |
December 17, 2009 |
Antineoplastic Combinations Containing HKI-272 and Vinorelbine
Abstract
A combination of HKI-272 compound and a vinorelbine compound in
the treatment of a neoplasm is provided. Regimens, kits, and
methods for treatment of neoplasm, including breast cancer
including metastatic breast cancer, and lung cancer, using this
combination, optionally in combination with other anti-neoplastic
agents, or immune modulators are also described.
Inventors: |
Zacharchuk; Charles Michael;
(Westford, MA) |
Correspondence
Address: |
WYETH;PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
41415366 |
Appl. No.: |
12/486153 |
Filed: |
June 17, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61073330 |
Jun 17, 2008 |
|
|
|
Current U.S.
Class: |
514/285 |
Current CPC
Class: |
A61K 9/20 20130101; A61K
31/437 20130101; A61N 5/10 20130101; A61P 35/00 20180101; A61K
31/4709 20130101; A61K 31/475 20130101; A61K 31/436 20130101; A61P
43/00 20180101; A61P 35/04 20180101; A61P 15/00 20180101; A61K
31/4745 20130101; A61K 31/436 20130101; A61K 2300/00 20130101; A61K
31/4745 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/285 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61P 35/00 20060101 A61P035/00 |
Claims
1. A regimen for treating a neoplasm in a subject, said regimen
comprising: administering a vinorelbine compound; and administering
a HKI-272 compound.
2. The regimen according to claim 1, wherein the administering
steps occur concurrently, sequentially, simultaneously, in a
specified order, or according to a specific temporal
relationship.
3. The regimen according to claim 1, wherein said vinorelbine
compound is administered in a unit dose.
4. The regimen according to claim 1, wherein said HKI-272 compound
is administered in a unit dose.
5. The regimen according to claim 1, wherein said vinorelbine
compound is vinorelbine.
6. The regimen according to claim 1, wherein said HKI-272 compound
is HKI-272.
7. The regimen according to claim 1, wherein one or both of said
vinorelbine compound and said HKI-272 compound are delivered
intravenously to said subject.
8. The regimen according to claim 1, wherein one or both of said
vinorelbine compound and said HKI-272 compound are delivered orally
to said subject.
9. The regimen according to claim 1, wherein said neoplasm is
associated with overexpression or amplification of HER-2.
10. The regimen according to claim 1, wherein said neoplasm is
metastatic.
11. The regimen according to claim 1, wherein said 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 regimen according to claim 11, wherein said neoplasm is a
breast cancer.
13. The regimen according to claim 12, wherein said breast cancer
is a metastatic, HER-2-positive breast cancer.
14. The regimen according to claim 1, wherein said neoplasm is an
advanced solid tumor.
15. The regimen according to claim 1, wherein said vinorelbine
compound is administered in an amount of at least about 20
mg/L.
16. The regimen according to claim 15, wherein said vinorelbine
compound is administered in an amount of about 20 to about 25
mg/L.
17. The regimen according to claim 16, wherein said vinorelbine
compound is administered in an amount of about 25 mg/L.
18. The regimen according to claim 1, wherein said HKI-272 compound
is administered in an amount of at least about 120 mg.
19. The regimen according to claim 18, wherein said HKI-272
compound is administered in an amount of at least about 160 mg.
20. The regimen according to claim 19, wherein said HKI-272
compound is administered in an amount of at least about 240 mg.
21. The regimen according to claim 4, wherein said unit dose is a
tablet.
22. The regimen according to claim 1, wherein said HKI-272 compound
is administered daily.
23. The regimen according to claim 1, wherein said HKI-272 compound
is administered at least once daily.
24. The regimen according to claim 1, wherein said HKI-272 compound
is administered on day 1 of said regimen.
25. The regimen according to claim 10, wherein said HKI-272
compound is administered on day 2 of said regimen.
26. The regimen according to claim 1, wherein said HKI-272 compound
is administered for at least 2 continuous weeks.
27. A pharmaceutical composition according to claim 1, further
comprising at least one pharmaceutically acceptable carrier.
28. The regimen according to claim 1, further comprising radiation.
Description
BACKGROUND OF THE INVENTION
[0001] Breast cancer is the most frequently diagnosed malignancy in
women and one of the top two causes of cancer-related deaths in
women worldwide. The incidence of breast cancer in the world is
increasing, and it is estimated that the disease will affect 5
million women in the next decade. Treatments permit control of
symptoms, prolongation of survival, and maintenance of quality of
life. However, in about 40% to 50% of all patients treated with
curative intent, incurable metastatic disease will develop. Since
there is no cure for metastatic breast cancer, current therapeutic
goals are palliative.
[0002] In several cancer types, deregulation of growth factor
signaling is observed, associated with 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
(a.k.a. neu or HER-2), HER-3 (a.k.a. ErbB-3), and HER-4 (a.k.a.
ErbB-4). Overexpression of ErbB-1 is observed in non-small cell
lung cancer (NSCLC) (40%-80%), breast cancer (14%-91%), and
pancreatic cancer (30%-89%). In NSCLC, activation by mutation of
amplification of ErbB-1 also occurs in 10% to 30% of patients.
[0003] Overexpression of ErbB-2, usually resulting from erbB-2 gene
amplification, is observed in tumor tissue in 25% to 30% of
patients of patients with metastatic breast cancer (MBC) and is
associated with malignant transformation. 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
anthracycline/alkylator- or taxane-based chemotherapy. ErbB-2
overexpression in tumorigenesis has been mainly studied in breast
cancers but is also observed in other cancers.
[0004] Among current therapeutics for cancers, specifically those
characterized by overexpression of ErbB-2, are vinorelbine,
trastuzumab and HKI-272. Vinorelbine, a semisynthetic vinca
alkaloid having broad antitumor activity, acts through microtubule
disruption. Vinorelbine presents a lower neurotoxicity profile than
vincristine or vinblastine. Vinorelbine has been shown to be less
toxic to axonal microtubules than vincristine or vinblastine at
therapeutic concentrations. In studies conducted on subjects with
advanced breast cancer, treatment with vinorelbine as a single
agent is at least as efficient as other chemotherapies but with a
lower risk of toxicity. However, the risk of toxicity increases in
parallel with the number of previous anticancer treatments.
[0005] Trastuzumab (HERCEPTIN.RTM. drug) is a humanized monoclonal
antibody specific for the extracellular domain of ErbB-2. It
presents significant clinical benefit and significant antitumor
activity when used alone or in combination with taxanes in
metastatic breast cancer in first-line treatment or in patients who
have tumor progression after chemotherapy. Because of the
improvement in survival, trastuzumab-based therapies have become
standard of care for women with ErbB-2-positive MBC. For women with
advanced or metastatic disease, breast cancer eventually recurs
despite trastuzumab treatment. Trastuzumab-based therapy is also
associated with potential cardiac toxicity. Certain breast cancer
cells are resistant to trastuzumab due to the occurrence of
secondary ErbB-2 mutations, such as truncation of extracellular
domain ErbB-2 receptor. Such mutations can result in cancer cells
which are not recognized by the antibody.
[0006] 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 trastuzumab and
vinorelbine was neutropenia.
[0007] HKI-272 is a small molecule, irreversible pan-ErbB receptor
inhibitor specific for epidermal growth factor receptor (ErbB-1 or
EGFR), ErbB-2 (HER-2), and ErbB-4 (HER-4). HKI-272 blocks kinase
activity of the receptor through binding to the intracellular
adenosine triphosphate (ATP) binding site of the receptor. HKI-272
blocks ErbB receptor autophosphorylation in cells at doses
consistent with inhibition of cell proliferation. In vitro, HKI-272
alone inhibits kinase activity of ErbB-1, ErbB-2, and HER-4,
inhibits tumor cell growth with breast and lung tumor cell lines,
and presents a potent growth inhibition of lung cancer cells
resistant to gefitinib or erlotinib. In vivo, HKI-272 blocks tumor
growth in xenograft animal models. Overall, HKI-272 is less potent
against ErbB-1-dependent tumors than ErbB-2-dependent tumors in
vivo, even though it has equivalent activity against the 2 kinases
in vitro.
[0008] There remains a need in the art for therapeutic methods,
regimens, compositions, and kits which are useful in treating
metastatic breast cancer and solid tumors.
SUMMARY OF THE INVENTION
[0009] This invention addresses the need in the art by providing
regimens, compositions and methods using a HKI-272 compound and a
vinorelbine compound for the treatment of cancers, such as solid
tumors and metastatic breast cancer.
[0010] In one aspect, regimens for treating a neoplasm in a subject
are provided and include administering a vinorelbine compound and
administering a HKI-272 compound. Desirably, the vinorelbine
compound is vinorelbine and the HKI-272 compound is HKI-272. In one
embodiment, the neoplasm is breast cancer.
[0011] In another aspect, a regimen for treating a solid tumor
associated with overexpression or amplification of HER-2 in a
subject is provided, wherein one cycle of the regimen includes 21
days. The regimen includes orally administering at least one unit
dose of HKI-272 starting on day 1 of the cycle and intravenously
administering at least one unit dose of vinorelbine on days 1 and 8
of the cycle.
[0012] In a further aspect, a regimen for treating a metastatic
cancer associated with overexpression or amplification of HER-2 in
a subject is provided. One cycle of the regimen includes 21 days
and the regimen includes orally administering at least one unit
dose of HKI-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.
[0013] In still another aspect, a product comprising a vinorelbine
compound and HKI-272 compound is provided as a combined preparation
for simultaneous, separate or sequential use in treating a neoplasm
in a mammal.
[0014] In yet a further aspect, a pharmaceutical pack for treating
a neoplasm in one individual mammal is provided and includes (a) at
least one unit dose of vinorelbine; and (b) at least one unit dose
of HKI-272.
[0015] In another aspect, a pharmaceutical composition is described
and contains vinorelbine, HKI-272, and at least one
pharmaceutically acceptable carrier.
[0016] In still another aspect, a method of treating a neoplasm
associated with overexpression or amplification of HER-2 in a
mammal in need thereof is provided and includes administering a
unit dose of a vinorelbine compound and administering a unit dose
of a HKI-272 compound.
[0017] Other aspects and advantages of the invention will be
readily apparent from the following detailed description of the
invention.
DESCRIPTION OF THE INVENTION
[0018] This invention provides compositions, methods, and regimens
using a combination of a HKI-272 compound and a vinorelbine
compound for the treatment of cancers. This invention provides in
one embodiment compositions comprising HKI-272 and vinorelbine for
the treatment of neoplasms. Also provided are products containing
HKI-272 and vinorelbine formulated for simultaneous, separate or
sequential use in treating neoplasms in a mammal. The invention is
also useful as an adjuvant and/or neoadjuvant therapy of earlier
stages of breast cancer. The invention provides, in another
embodiment, methods for the combined use or administration of a
HKI-272 compound and vinorelbine compound.
The Therapeutic Regimen and Its Components
[0019] Without wishing to be bound by theory, the inventors
hypothesize that the combination of HKI-272 and vinorelbine for
treating a neoplasm is desirable because HKI-272 targets the
intracellular ErbB-2 kinase rather than the extracellular domain.
Thus, this combination has different mechanisms of sensitivity and
resistance, and then presents an advantage over the therapeutic
combination of trastuzumab and vinorelbine. Further, the
combination of HKI-272 and vinorelbine is anticipated to be more
effective than combinations of vinorelbine with other pan-ErbB
inhibitors due to the tyrosine kinase inhibition activity of
HKI-272 through an irreversible binding at a targeted cysteine
residue in the ATP binding pocket of the receptor.
[0020] These methods, combinations and products are useful in the
treatment of a variety of neoplasms, particularly 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 embodiment, the neoplasm is metastatic. In another
embodiment, neoplasms that may be treated 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 and HER-2-positive breast cancer), prostate cancers,
myeloma, head and neck cancer, transitional cell carcinoma, small
cell and large cell neuroendocrine carcinoma of the uterine cervix.
In still another embodiment, the neoplasm is resistant to
trastuzumab.
[0021] The regimens, methods, and compositions described herein
include the concurrent, simultaneous, sequential or separate
administration of the components, i.e., a HKI-272 compound and a
vinorelbine compound. The term "composition" as used herein is
intended to cover both pharmaceutical compositions in which 2 or
more components are mixed, compositions of matter such as
pharmaceutical kits and packs in which the components are
individually packaged for concurrent, simultaneous, sequential, or
separate administration. In one aspect of the invention, "a
combination" includes simultaneous administration of the HKI-272
and vinorelbine compounds. In a further aspect of the invention, "a
combination" includes sequential administration of the HKI-272 and
vinorelbine compounds. In one embodiment the HKI-272 is
administered before the vinorelbine compound. In another embodiment
the vinorelbine compound is administered before the HKI-272
compound. In another aspect, "a combination" includes separate
administration of the HKI-272 and vinorelbine compounds in a
particular therapeutic regimen in which the two components of the
combination are administered at specific times and amounts with
respect to each other. In one embodiment, the combination of the
HKI-272 and vinorelbine compounds produces a more beneficial
therapeutic effect than that achievable by the administration of
either a HKI-272 compound alone or a vinorelbine compound alone.
Where the administration of those agents is sequential or separate,
the delay in administering the second component should not be such
as to lose the benefits provided the combination therapy.
[0022] In one embodiment, the combination of the HKI-272 and
vinorelbine compounds is particularly well suited 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, kidney, bladder, mouth, larynx, esophagus, stomach,
colon, ovary, and lung), and polycystic kidney disease.
[0023] As used herein and except where noted, the terms
"individual", "subject" and "patient" are used interchangeably, and
refer to any animal, including mammals, preferably mice, rats,
other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses,
non-human primates, and humans. Desirably, the term "individual",
"subject" or "patient" refers to a human. In certain circumstances,
these terms refer to experimental animals such as rabbits, rats,
and mice, and other animals. In most embodiments, 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 which the HKI-272 and vinorelbine compounds
can be administered. In one embodiment, to identify subject
patients for treatment according to the methods of the invention,
accepted screening methods are employed to determine risk factors
associated with a targeted or suspected disease or condition or to
determine the status of an existing disease or condition in a
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 clinician to select patients in need of therapy
using the methods and formulations of the present invention. In one
embodiment, the "individual", "subject" or "patient" may have had
no previously chemotherapeutic treatment. In another embodiment,
the "individual", "subject" or "patient" may have previously
undergone chemotherapeutic treatment. In another embodiment, the
"individual", "subject" or "patient" may have previously been
administered an aniloquinazoline class inhibitor. In a further
embodiment, the "individual", "subject" or "patient" may have
previously been administered lapatinib or geftinib as the
aniloquinazoline class inhibitor. Desirably, the blood count of the
patient prior to treatment with the described combinations is
stable enough to permit administration of the combinations
described herein. In one embodiment, the neutrophil count of the
patient prior to administration of the vinorelbine and HKI-272
compounds is at least 1500. In another embodiment, the platelet
count of the patient prior to administration of the vinorelbine and
HKI-272 compounds is at least 100,000/L.
[0024] As used herein, "a HKI-272 compound" refers, in one
embodiment, to a compound having the following core structure:
##STR00001##
or a derivative or pharmaceutically acceptable salt thereof.
Suitable derivatives may include, e.g., an ester, ether, or
carbamate. The core structure represented above is a particularly
HKI-272 compound, called HKI-272, which has the chemical name
(E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quin-
olinyl}-4-(dimethylamino)-2-butenamide. In one embodiment, the
HKI-272 compound useful in the compositions and methods described
herein is HKI-272.
[0025] In another embodiment, an HKI-272 compound has the
structure:
##STR00002##
wherein:
[0026] R.sup.1 is halogen;
[0027] R.sup.2 is pyridinyl, thiophenyl, pyrimidinyl, thiazolyl, or
phenyl, wherein R.sup.2 is optionally substituted with up to three
substituents;
[0028] R.sup.3 is O or S;
[0029] R.sup.4 is CH.sub.3 or CH.sub.2CH.sub.2OCH.sub.3;
[0030] R.sup.5 is CH.sub.3 or CH.sub.2CH.sub.3; and
[0031] n is 0 or 1.
[0032] The term "halogen" as used herein refers to Cl, Br, I, and
F.
[0033] These HKI-272 compounds, of which HKI-272 is a species, are
characterized by the ability to act as potent HER-2 inhibitors.
See, e.g., U.S. Pat. Nos. 6,288,082 and 6,297,258 and US Patent
Application Publication No. 2007/0104721, which are hereby
incorporated by reference. These compounds and their preparation
are described in detail in US Patent Application Publication No.
2005/0059678, which is hereby incorporated by reference. For
convenience, "a HKI-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
in detail below.
[0034] HKI-272, other HKI-272 compounds, and methods of making and
formulating same have been described. See, e.g., US Patent
Application Publication No. 2005/0059678 and U.S. Pat. No.
6,002,008, which are hereby incorporated by reference. The methods
described in these documents can also be used to prepare the
substituted 3-quinoline compounds used herein and are hereby
incorporated by reference. In addition to the methods described in
these documents, International Patent Publication Nos. WO-96/33978
and WO-96/33980, which are hereby incorporated by reference,
describe methods that are useful for the preparation of these
HKI-272 compounds. Although these methods describe the preparation
of certain quinazolines, they are also applicable to the
preparation of correspondingly substituted 3-cyanoquinolines and
are hereby incorporated by reference.
[0035] As used herein, the term "a vinorelbine compound" means
vinorelbine or a pharmaceutically acceptable salt thereof, which
has broad antitumor activity and that acts through microtubule
disruption. See, Widakowich et al., Anticancer Agents Med. Chem.,
8(5):488-496 (June 2008) and Wissner et al., Arch. Pharm.
(Weinheim), (May 20, 2008 e-publication). The term includes the
neutral vinorelbine compound, i.e.,
4-(acetyloxy)-6,7-didehydro-15-((2R,6R,8S)-4-ethyl-1,3,6,7,8,9-hexohydro--
8-(methoxycarbonyl)-2,6-methano-2H-azecino(4,3-b)indol-8-yl)-3-hydroxy-16--
methoxy-1-methyl, methyl ester, (2.beta., 3.beta., 4.beta.,
5.alpha., 12R, 19.alpha.)-aspidospermidine-3-carboxylic acid
(vinorelbine; tradename: Navelbine). Vinorelbine and its
pharmaceutically acceptable salts are available from commercial
vendors including Adventrx/SD Pharmaceuticals (SDP-012.RTM. drug),
Hana (ALOCREST.RTM. drug), and Inex Pharmaceuticals Corp.
(INX-0125.TM. drug), and other vinorelbine compounds, including
those discussed in U.S. Pat. No. 7,235,564, which is hereby
incorporated by reference. In one embodiment, a vinorelbine
compound includes a compound with a structural similarity to the
vinorelbine compound structure below, e.g., compounds with a
similar alkaloid structure that have been modified to enhance
therapeutic benefit.
##STR00003##
[0036] 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).
[0037] The HKI-272 and vinorelbine compounds and corresponding
pharmaceutically acceptable salts or esters thereof include isomers
either individually or as a mixture, such as enantiomers,
diastereomers, and positional isomers.
[0038] "Pharmaceutically acceptable salts and esters" refers to
salts and esters that are pharmaceutically acceptable and have the
desired pharmacological properties. Such salts include, e.g., salts
that can be formed where acidic 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 potassium, magnesium,
calcium, and aluminum. Suitable organic salts include, e.g., those
formed with organic bases such as the amine bases, e.g.
ethanolamine, diethanolamine, triethanolamine, tromethamine,
N-methylglucamine, and the like. Pharmaceutically acceptable salts
can also include acid addition salts formed from the reaction of
basic moieties, such as amines, in the parent compound with
inorganic acids (e.g. hydrochloric and hydrobromic acids) and
organic acids (e.g. acetic acid, citric acid, maleic acid, and the
alkane- and arene-sulfonic acids such as methanesulfonic acid and
benzenesulfonic acid).
[0039] Pharmaceutically acceptable esters include esters formed
from carboxy, sulfonyloxy, and phosphonoxy groups present in the
compounds of the invention, e.g., C.sub.1-6 alkyl esters. When
there are two acidic groups present, a pharmaceutically acceptable
salt or ester can be a mono-acid-mono-salt or ester or a di-salt or
ester; and similarly where there are more than two acidic groups
present, some or all of such groups can be salified or esterified.
Compounds utilized herein may be present in unsalified or
unesterified form, or in salified and/or esterified form, and the
naming of such compounds is intended to include both the original
(unsalified and unesterified) compound and its pharmaceutically
acceptable salts and esters. Also, one or more compounds utilized
herein may be present in more than one stereoisomeric form, and the
naming of such compounds is intended to include all single
stereoisomers and all mixtures (whether racemic or otherwise) of
such stereoisomers.
[0040] Pharmaceutically acceptable salts of the HKI-272 and
vinorelbine compounds with an acidic moiety may be formed from
organic and inorganic bases including, e.g., salts with alkali
metals or alkaline earth metals such as sodium, potassium, lithium,
calcium, or magnesium or organic bases and N-tetraalkylammonium
salts such as N-tetrabutylammonium salts.
[0041] Similarly, when one or more compound utilized herein
contains a basic moiety, salts may be formed from organic and
inorganic acids. For example, salts may be formed from acids such
as acetic, propionic, lactic, citric, tartaric, succinic, fumaric,
maleic, malonic, mandelic, malic, phthalic, hydrochloric,
hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic,
naphthalenesulfonic, benzenesulfonic, toluenesulfonic,
camphorsulfonic, and similarly known acceptable acids when a
compound of this invention contains a basic functional group. Other
suitable examples of pharmaceutically acceptable salts include, but
are not limited, to sulfate; citrate, acetate; oxalate; chloride;
bromide; iodide; nitrate; bisulfate; phosphate; acid phosphate;
isonicotinate; lactate; salicylate; acid citrate; tartrate; oleate;
tannate; pantothenate; bitartrate; ascorbate; succinate; maleate;
gentisinate; fumarate; gluconate; glucaronate; saccharate; formate;
benzoate; glutamate; methanesulfonate; ethanesulfonate;
benzenesulfonate; p-toluenesulfonate; pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)); and salts of fatty
acids such as caproate, laurate, myristate, palmitate, stearate,
oleate, linoleate, and linolenate salts. In one embodiment, the
vinorelbine compound is vinorelbine tartrate.
[0042] The compounds can also be used in the form of esters,
carbamates and other conventional ester forms, also referred to
herein as prodrug forms, which when administered in such form,
convert to the active moiety in-vivo. Exemplary ester forms of the
compounds of this invention include, but are not limited to,
straight chain alkyl esters having from 1 to 6 carbon atoms or
branched chain alkyl groups containing 1 to 6 carbon atoms,
including methyl, ethyl, propyl, butyl, 2-methylpropyl and
1,1-dimethylethyl esters, cycloalkyl esters, alkylaryl esters,
benzyl esters, and the like.
[0043] Accordingly, a pharmaceutical composition is provided and
contains effective amounts of the HKI-272 and vinorelbine compounds
in combination or association with one or more pharmaceutically
acceptable carrier. Suitable examples of pharmaceutical carriers
used herein include, but are not limited to, excipients, diluents,
fillers, disintegrants, lubricants and other agents that can
function as a carrier. The term "pharmaceutically acceptable
excipient" means an excipient that is useful in preparing a
pharmaceutical composition that is generally safe, non-toxic, and
desirable, and includes excipients that are 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 composition, gaseous. Pharmaceutical compositions are
prepared in accordance with acceptable pharmaceutical procedures,
such as described in Remingtons Pharmaceutical Sciences, 17th
edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton,
Pa. (1985). Pharmaceutically acceptable carriers are those that are
compatible with the other ingredients in the formulation and
biologically acceptable. Suitable pharmaceutically-acceptable
excipients or carriers for a tablet or caplet formulation include,
e.g., inert excipients such as lactose, sodium carbonate, calcium
phosphate or calcium carbonate, granulating and disintegrating
agents such as corn starch or alginic acid; binding agents such as
gelatin or starch; lubricating agents such as magnesium stearate,
stearic acid or talc; preservative agents such as ethyl or propyl
4-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet
or caplet formulations may be uncoated or coated either to modify
their disintegration and the subsequent absorption of the active
ingredient within the gastrointestinal tract, or to improve their
stability and/or appearance using conventional coating agents and
procedures well known in the art. In one embodiment, the weight of
the tablet is at least about 20, 30, 40, 50, 60, or 70 mg.
Optional Components of the Regimens
[0044] The regimens described herein may also include the
administration of other agents. In one embodiment, the regimen
further includes administration of a taxane, e.g., docetaxel and
paclitaxel [e.g., a suspension of paclitaxel bound to albumen
nanoparticles, which is available as the ABRAXANEL.RTM. reagent].
Paclitaxel may also be administered on a weekly schedule at doses
60-100 mg/m.sup.2 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/m.sup.2, optionally followed by cisplatin at a dose of 75
mg/m.sup.2; or paclitaxel administered intravenously over 24 hours
at a dose of 135 mg/m.sup.2, optionally followed by cisplatin at a
dose of 75 mg/m.sup.2. In patients previously treated with therapy
for carcinoma, paclitaxel can be injected at several doses and
schedules. However, the optimal regimen is not yet clear. The
recommended regimen is paclitaxel 135 mg/m.sup.2 or 175 mg/m.sup.2
administered intravenously over 3 hours every 3 weeks. These doses
may be altered as needed or desired.
[0045] In another embodiment, other active agents may be included
in a combination with an HKI-272 compound and vinorelbine compound
and include, e.g., chemotherapeutic agents, such as alkylating
agents or mTOR inhibitors (rapamycin and derivatives thereof);
hormonal agents (i.e., estramustine, tamoxifen, toremifene,
anastrozole, or letrozole); antibiotics (i.e., plicamycin,
bleomycin, mitoxantrone, idarubicin, dactinomycin, mitomycin, or
daunorubicin); other antimitotic agents (i.e., vinblastine,
vincristine, teniposide); topoisomerase inhibitors (i.e.,
topotecan, irinotecan, etoposide, or doxorubicin, e.g., CAELYX.TM.
or DOXIL.RTM. reagents, pegylated liposomal doxorubicin
hydrochloride); and other agents (i.e., hydroxyurea, altretamine,
rituximab, paclitaxel, docetaxel, L-asparaginase, or gemtuzumab
ozogamicin); biochemical modulating agents, imatib, EGFR inhibitors
such as EKB-569 or other multi-kinase inhibitors, e.g., those that
targets serine/threonine and receptor tyrosine kinases in both the
tumor cell and tumor vasculature, or immunomodulators (i.e.,
interferons, IL-2, or BCG). Examples of suitable interferons
include interferon .alpha., interferon .beta., interferon .gamma.,
and mixtures thereof.
[0046] Desirably, the combination of the HKI-272 compound and
vinorelbine compound may be further combined with antineoplastic
alkylating agents, e.g., those described in US Patent Application
Publication No. 2002-0198137, which is hereby incorporated by
reference. Antineoplastic alkylating agents are roughly classified,
according to their structure or reactive moiety, into several
categories which include nitrogen mustards, such as MUSTARGEN.RTM.
drug (meclorethamine), cyclophosphamide, ifosfamide, melphalan, and
chlorambucil; azidines and epoxides, such as thiotepa, mitomycin C,
dianhydrogalactitol, and dibromodulcitol; alkyl sulfinates, such as
busulfan; nitrosoureas, such as bischloroethylnitrosourea (BCNU),
cyclohexyl-chloroethylnitrosourea (CCNU), and
methylcyclohexylchloroethylnitrosourea (MeCCNU); hydrazine and
triazine derivatives, such as procarbazine, dacarbazine, and
temozolomide; streptazoin, melphalan, chlorambucil, carmustine,
methclorethamine, lomustine) and platinum compounds. Platinum
compounds are platinum containing agents that react preferentially
at the N7 position of guanine and adenine residues to form a
variety of monofunctional and bifunctional adducts. (Johnson S W,
Stevenson J P, O'Dwyer P J. Cisplatin and Its Analogues. In Cancer
Principles & Practice of Oncology 6.sup.th Edition. ed. DeVita
V T, Hellman S, Rosenberg S A. Lippincott Williams & Wilkins.
Philadelphia 2001. p. 378.) These compounds include cisplatin,
carboplatin, platinum IV compounds, and multinuclear platinum
complexes. Representative examples of alkylating agents including
meclorethamine (injectable; MUSTARGEN.RTM. drug), cyclophosphamide
(injectable; cyclophosphamide, lyophilized CYTOXAN.RTM. drug, or
NEOSAR.RTM. drug; oral tablets cyclophosphamide or CYTOXAN.RTM.
drug), ifosfamide (injectable; IFEX), melphalan (injectable,
ALKERAN.RTM. drug; and oral tablets, ALKERAN.RTM. drug),
chlorambucil (oral tablets, LEUKERAN.RTM. drug), thiotepa
(injectable, thiotepa or THIOPLEX.RTM. drug), mitomycin
(injectable, mitomycin or MUTAMYCIN.RTM. drug), busulfan
(injectable, BUSULFEX.RTM. drug; oral tablets, MYLERAN.RTM. drug),
lomustine (oral capsules; CEENU), carmustine (intracranial implant,
GLIADEL); injectable (BICNU), procarbazine (oral capsules,
MATULANEL.RTM. drug), temozolomide (oral capsules, TEMODAR.RTM.
drug), cisplatin (injectable, cisplatin, PLATINOL.RTM. drug, or
PLATINOL.RTM.-AQ)., carboplatin (injectable, PARAPLATIN.RTM. drug),
and oxaliplatin (ELOXATIN.RTM. drug).
[0047] In another embodiment, a combination described herein may
further include an antineoplastic antimetabolite, as described in
US Patent Application Publication Nos. 2005/0187184 or
2002/0183239, which are hereby incorporated by reference. As used
herein accordance, the term "antimetabolite" means a substance
which is structurally similar to a critical natural intermediate
(metabolite) in a biochemical pathway leading to DNA or RNA
synthesis which is used by the host in that pathway, but acts to
inhibit the completion of that pathway (i.e., synthesis of DNA or
RNA). More specifically, antimetabolites typically function by (1)
competing with metabolites for the catalytic or regulatory site of
a key enzyme in DNA or RNA synthesis, or (2) substitute for a
metabolite that is normally incorporated into DNA or RNA, and
thereby producing a DNA or RNA that cannot support replication.
Major categories of antimetabolites include (1) folic acid analogs,
which are inhibitors of dihydrofolate reductase (DHFR); (2) purine
analogs, which mimic the natural purines (adenine or guanine) but
are structurally different so they competitively or irreversibly
inhibit nuclear processing of DNA or RNA; and (3) pyrimidine
analogs, which mimic the natural pyrimidines (cytosine, thymidine,
and uracil), but are structurally different so thy competitively or
irreversibly inhibit nuclear processing of DNA or RNA.
Representative examples of antimetabolites include, without
limitation, 5-Fluorouracil (5-FU;
5-fluoro-2,4(1H,3H)-pyrimidinedione; topical cream, FLUOROPLEX.RTM.
or EFUDEX.RTM. drugs; topical solution, FLUOROPLEX.RTM. or
EFUDEX.RTM. drugs; injectable, ADRUCIL.RTM. drug or fluorouracil),
floxuradine (2'-deoxy-5-fluorouridine; injectable, FUDR or
floxuradine), thioguanine (2-amino-1,7-dihydro-6-H-purine-6-thione
(oral tablets, thioguanine), cytarabine
(4-amino-1-(.beta.)-D-arabinofuranosyl-2(1H)-pyrimidinone;
liposomal injectable, DEPOCYT.RTM. reagent; liquid injectable,
cytarabine or CYTOSAR-U.RTM. drug), fludarabine
(9-H-Purin-6-amine,2-fluoro-9-(5-O-phosphono-(.beta.)-D-a-rabinofuranosyl-
; liquid injectable, FLUDARA), 6-Mercaptopurine
(1,7-dihydro-6H-purine-6-thione; oral tablets, PURINETHOL).,
methotrexate (MTX;
N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glut-
amic acid; liquid injectable, methotrexate sodium or FOLEX; oral
tablets, methotrexate sodium), gemcitabine
(2'-deoxy-2',2'-difluorocytidine monohydrochloride
((.beta.)-isomer); liquid injectable, GEMZAR), capecitabine
(5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine; oral tablet,
XELODA), pentostatin
((R)-3-(2-deoxy-(beta)-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidaz-
o[4,5-d][1,3]diazepin-8-ol; liquid injectable, NIPENT),
trimetrexate
(2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline
mono-D-glucuronate; liquid injectable, NEUTREXIN), cladribine
(2-chloro-6-amino-9-(2-deoxy-(.beta.)-D-erythropento-furanosyl)
purine; liquid injectable, LEUSTATIN).
[0048] The term "biochemical modulating agent" is well known and
understood to those skilled in the art as an agent given as an
adjunct to anti-cancer therapy, which serves to potentate its
antineoplastic activity, as well as counteract the side effects of
the active agent, e.g., an antimetabolite. Leucovorin and
levofolinate are typically used as biochemical modulating agents
for methotrexate and 5-FU therapy. Leucovorin
(5-formyl-5,6,7,8-tetrahydrofolic acid) is commercially available
as an injectable liquid (leucovorin calcium or WELLCOVORIN) and as
oral tablets (leucovorin calcium). Levofolinate (pharmacologically
active isomer of 5-formyltetrahydrofolic acid) is commercially
available as an injectable containing (ISOVORIN) or as oral tablets
(ISOVORIN).
[0049] In still another embodiment, the combination further
includes a kinase inhibitor. Particularly desirable kinase
inhibitors include multi-kinase inhibitors target serine/threonine
and receptor tyrosine 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), which has been granted Fast Track status by the FDA
for metastatic renal cell cancer, zarnestra (R115777, tipifarnib),
suntinib (SUTENT), and other compounds that target Ras/Raf/MEK
and/or MAP kinases including, e.g., avastin, ISIS 5132, and MEK
inhibitors such as CI-1040 or PD 0325901. Alternatively, the kinase
inhibitor may be administered to the patient prior to or subsequent
to treatment with the vinorelbine compound and/or HKI-272
compound.
[0050] In still further embodiment, the combination may include an
anti diarrheal. One of skill in the art would readily be able to
select a suitable antidiarrheal for use herein including, without
limitation, loperamide or diphenoxylate hydrochloride and atropine
sulfate. Alternatively, the anti-diarrheal may be administered to
the patient prior to or subsequent to treatment with the
vinorelbine compound and/or HKI-272 compound.
[0051] In a further embodiment, the combination further contains an
antiemetic agent. Examples of antiemetic agents include, without
limitation, metoclopramide, Dolasetron, Granisetron, Ondansetron,
Tropisetron, and Palonosetron, among others. Alternatively, the
antiemetic may be administered to the patient prior to or
subsequent to treatment with the vinorelbine compound and/or
HKI-272 compound.
[0052] In yet a further embodiment, the combination also contains
an antihistamine. Examples of antihistamines include, without
limitation, Cyclizine, Diphenhydramine, Dimenhydrinate (Gravol),
Meclizine, Promethazine (Pentazine, Phenergan, Promacot), or
Hydroxyzine, among others. Alternatively, the antihistamine may be
administered to the patient prior to or subsequent to treatment
with the vinorelbine compound and/or HKI-272 compound.
[0053] In yet another embodiment, the combination may include a
growth factor to prevent and/or treat neutropenia. Such growth
factors may readily be selected by those skill in the art according
to practice guidelines from the American Society of Clinical
Oncology (ASCO; 2006). Alternatively, the growth factor may be
administered to the patient prior to or subsequent to treatment
with the vinorelbine compound and/or HKI-272 compound.
Administration of the Compositions/Combinations
[0054] As used herein, the term "effective amount" or
"pharmaceutically effective amount" refers to the amount of active
compound or pharmaceutical agent that elicits the biological or
medicinal response in a tissue, system, animal, individual 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 individual that may be predisposed to the
disease, condition or disorder but does not yet experience or
display the pathology or symptomatology of the disease; (2)
inhibiting the disease; e.g., inhibiting a disease, condition or
disorder in an individual that is experiencing or displaying the
pathology or symptomatology of the disease, condition or disorder
(i.e., arresting or slowing further development of the pathology
and/or symptomatology); and (3) ameliorating the disease; e.g.,
ameliorating a disease, condition or disorder in an individual that
is experiencing or displaying the pathology or symptomatology of
the disease, condition or disorder (i.e., reversing the pathology
and/or symptomatology). For example, an effective amount," when
administered to a subject to treat cancer, is sufficient to
inhibit, slow, reduce, or eliminate tumor growth in a subject
having cancer.
[0055] Use of a combination of the HKI-272 compound and vinorelbine
compound also provides for the use of combinations of each of the
agents in which one or both agent is used at subtherapeutically
effective dosages. Subtherapeutically effective dosages may be
readily determined by one of skill in the art, in view 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 combination 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 be
used in a supratherapeutic amount, i.e., at a higher dosage in the
combination than when used alone. In this embodiment, the other
active agent(s) may be used in a therapeutic or subtherapeutic
amount.
[0056] The term "treating" or "treatment" refers to any indicia of
success in amelioration of an injury, pathology, or condition,
including any objective or subjective parameter such as abatement;
remission; diminishing of symptoms or making the injury, pathology,
or condition more tolerable to the patient; slowing the rate of
degeneration or decline; making the final point of degeneration
less debilitating; or improving a subject'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 examination, neurological examination, and/or psychiatric
evaluation. Accordingly, the term "treating" includes the
administration of the HKI-272 and vinorelbine compounds to a
subject to prevent or delay, to alleviate, or to arrest or inhibit
development of the symptoms or conditions associated with cancers,
including tumor growth associated with cancer. A skilled medical
practitioner will know how to use standard methods to determine
whether a patient is suffering from a disease associated with
cancer by examining the patient and determining whether the patient
is suffering from cancer.
[0057] As used herein, the term "providing" with respect to
providing a HKI-272 compound and a vinorelbine compound, means
either directly administering the HKI-272 compound and vinorelbine
compound, or administering a prodrug, derivative, or analog which
will form an effective amount of the HKI-272 compound and/or
vinorelbine compound within the body.
[0058] The invention therefore includes administering an HKI-272
compound and vinorelbine compound to a patient for the treatment of
a neoplasm in a patient. In one embodiment, the HKI-272 compound is
administered separately from the vinorelbine compound. In a further
embodiment, the HKI-272 compound is administered prior to the
vinorelbine compound. In another embodiment, the HKI-272 compound
is administered subsequent to the vinorelbine compound. In still
another embodiment, the HKI-272 compound and the vinorelbine
compound are administered simultaneously, but separately. In one
embodiment, the HKI-272 compound and the vinorelbine compound are
administered together as a combined preparation.
[0059] In one embodiment, a product contains an HKI-272 compound
and vinorelbine compound as a combined preparation for
simultaneous, separate or sequential use in treating a neoplasm in
a mammal in need thereof. In one embodiment, the HKI-272 compound
is separately formulated from the vinorelbine compound. In another
embodiment, a product contains the HKI-272 compound and the
vinorelbine compound as a combined preparation for simultaneous,
separate or sequential use in a neoplasm in a mammal in need
thereof.
[0060] In one embodiment, a pharmaceutical pack contains a course
of treatment of a neoplasm for one individual mammal, wherein the
pack contains units of an HKI-272 compound in unit dosage form and
units of a vinorelbine compound in unit dosage form. In another
embodiment, a pharmaceutical pack contains a course of treatment of
a neoplasm for one individual mammal, wherein the pack contains
units of an HKI-272 compound in unit dosage form and units of a
vinorelbine compound in unit dosage form. In yet another
embodiment, a pharmaceutical pack as described herein contains a
course of treatment of metastatic breast cancer for one individual
mammal.
[0061] Administration of the individual components or a composition
containing two or more of the individual components may employ any
suitable route. Such routes may be selected from, e.g., oral,
intravenous (i.v.), respiratory (e.g., nasal or intrabronchial),
infusion, parenteral (aside from i.v., such as intralesional,
intraperitoneal and subcutaneous injections), intraperitoneal,
transdermal (including all administration across the surface of the
body and the inner linings of bodily passages including epithelial
and mucosal tissues), and vaginal (including intrauterine
administration). Other routes of administration are also feasible
and include, without limitation, liposome-mediated delivery,
topical, nasal, sublingual, uretheral, intrathecal, ocular or otic
delivery, implant, rectal, or intranasal.
[0062] While the components may be delivered via the same route, a
product or pack described herein may contain a vinorelbine compound
for delivery by a different route than that of an HKI-272 compound,
e.g., one or more of the components may be delivered orally, while
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 embodiment, both the HKI-272 and vinorelbine compounds are
prepared for intravenous delivery. In still another embodiment,
both the HKI-272 and vinorelbine compounds are prepared for oral
delivery. Optionally, other active components may be delivered by
the same or different routes as the HKI-272 and/or vinorelbine
compounds. Other variations would be apparent to one skilled in the
art.
[0063] In still another embodiment, the compounds or components of
the therapeutic regimen are administered once a week. In certain
situations, dosing with the HKI-272 compound may be delayed or
discontinued for a brief period (e.g., 1, 2 or three weeks) during
the course of treatment. Such a delay or discontinuation may occur
once, or more, during the course of treatment. The effective amount
is known to one of skill in the art; it will also be dependent upon
the form of the HKI-272 compound. One of skill in the art could
routinely perform empirical activity tests to determine the
bioactivity of the HKI-272 compound in bioassays and thus determine
a suitable dosage to administer.
[0064] The HKI-272 and vinorelbine compounds or other optional
compounds used in the combination and products described herein may
be formulated in any suitable manner. However, the amounts of each
compound in the unit dose can vary widely depending on the type of
composition, regimen, size of a unit dosage, kind of excipients,
and other factors well known to those of ordinary 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% w to 1% w, with
the remainder being the excipient or excipients.
[0065] The compositions described herein may be in a form suitable
for oral administration, e.g., tablet, caplet, capsule, buccal
forms, troches, lozenges and oral liquids, suspensions or
solutions; parenteral injection (including intravenous,
subcutaneous, intramuscular, intravascular or infusion), e.g., as a
sterile solution, suspension or emulsion; topical administration,
e.g., an ointment or cream; rectal administration, e.g., a
suppository; or the route of administration may be by direct
injection into the tumor or by regional delivery or by local
delivery. In other embodiments, one or both components of the
combination treatment may be delivered endoscopically,
intratracheally, intralesionally, percutaneously, intravenously,
subcutaneously, intraperitoneally or intratumorally. In general the
compositions described herein may be prepared in a conventional
manner using conventional excipients or carriers that are well
known in the art. Pharmaceutical compositions for oral use may also
be in the form of hard gelatin capsules in which the active
ingredient is mixed with an inert solid excipient, e.g., calcium
carbonate, 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 both of said vinorelbine compound and said HKI-272 compound are
delivered orally to said subject.
[0066] Capsules may contain mixtures of the active compound(s) with
inert fillers and/or diluents such as the pharmaceutically
acceptable starches (e.g. corn, potato or tapioca starch), sugars,
artificial sweetening agents, powdered celluloses, such as
crystalline and microcrystalline celluloses, flours, gelatins,
gums, etc.
[0067] Useful tablet or caplet formulations may be made by
conventional compression, wet granulation or dry granulation
methods and utilize pharmaceutically acceptable diluents, binding
agents, lubricants, disintegrants, surface modifying agents
(including surfactants), suspending or stabilizing agents,
including, but not limited to, magnesium stearate, stearic acid,
talc, sodium lauryl sulfate, microcrystalline cellulose,
carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin,
alginic acid, acacia gum, xanthan gum, sodium citrate, complex
silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol,
dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol,
sodium chloride, talc, dry starches and powdered sugar. Preferred
surface modifying agents include nonionic and anionic surface
modifying agents. Representative examples of surface modifying
agents include, but are not limited to, poloxamer 188, benzalkonium
chloride, calcium stearate, cetostearyl alcohol, cetomacrogol
emulsifying wax, sorbitan esters, colloidal silicon dioxide,
phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and
triethanolamine.
[0068] Oral formulations herein, e.g., tablets, caplets, or
capsules described above, may utilize standard delay or time
release formulations to alter the absorption of the active
compound(s). The oral formulation may also consist of administering
the active ingredient in water or a fruit juice, containing
appropriate solubilizers or emulsifiers as needed.
[0069] In some cases it may be desirable to administer the
compounds directly to the airways in the form of an aerosol.
[0070] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier 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 vegetable oils. Preferred injectable formulations
containing vinorelbine are described in the art. In one embodiment,
the compounds may be administered parenterally or
intraperitoneally. Solutions or suspensions of these active
compounds as a free base or pharmacologically acceptable salt can
be prepared in water suitably mixed with a surfactant such as
hydroxy-propylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols and mixtures thereof in oils.
Under ordinary conditions of storage and use, these preparations
may contain a preservative to prevent the growth of microorganisms.
In one embodiment, one or both of the vinorelbine and HKI-272
compounds are delivered intravenously.
[0071] For use herein, transdermal administrations include all
administrations across the surface of the body and the inner
linings of bodily passages including epithelial and mucosal
tissues. Such administrations may be performed using the present
compounds, or pharmaceutically acceptable salts thereof, in
lotions, creams, foams, patches, suspensions, solutions, and
suppositories (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
compound, is non toxic to the skin, and allows delivery of the
agent for systemic absorption into the blood stream via the skin.
The carrier may take any number of forms such as creams and
ointments, pastes, gels, and occlusive devices. The creams and
ointments 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 ingredient may also be suitable. A variety of
occlusive devices may be used to release the active ingredient into
the blood stream such as a semi-permeable membrane covering a
reservoir containing the active ingredient with or without a
carrier, or a matrix containing the active ingredient. Other
occlusive devices are known in the literature.
[0072] Suppository formulations may be made from traditional
materials, including cocoa butter, with or without the addition of
waxes to alter the suppository's melting point, and glycerin. Water
soluble suppository bases, such as polyethylene glycols of various
molecular weights, may also be used.
[0073] In another embodiment, one or both of the HKI-272 and
vinorelbine compounds can be delivered by the use of liposomes
which fuse with the cellular membrane or are endocytosed, i.e., by
employing ligands attached to the liposome, or attached directly to
the oligonucleotide, that bind to surface membrane protein
receptors of the cell resulting in endocytosis. By using liposomes,
particularly where the liposome surface carries ligands specific
for target cells, or are otherwise preferentially directed to a
specific organ, one can focus the delivery of one or more compound
into the target cells in vivo. (See, e.g., Al-Muhammed, J.
Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol.
6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). In
other cases, the preferred preparation of one or more of the
components can be a lyophilized powder.
[0074] Encapsulating materials can also be employed with one or
more of the compounds and the term "composition" can include the
active ingredient in combination with an encapsulating material as
a formulation, with or without other carriers. For example, the
compounds can also be delivered as microspheres for slow release in
the body. In one embodiment, microspheres can be administered via
intradermal injection of drug-containing microspheres, which slowly
release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed.
7:623-645, 1995; as biodegradable and injectable gel formulations
(see, e.g., Gao, Pharm. Res. 12:857-863, 1995); or, as microspheres
for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol.
49:669-674, 1997). Both transdermal and intradermal routes afford
constant delivery for weeks or months. Cachets can also be used in
the delivery of the compounds of the present invention, e.g.,
anti-atherosclerotic medicaments.
Dosages of the HKI-272 Compound and Vinorelbine Compound
[0075] 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 administration.
[0076] The dosages and schedules described hereinbefore may be
varied according to the particular disease state and the overall
condition of the patient. For example, it may be necessary or
desirable to reduce the above-mentioned doses of the components of
the combination treatment in order to reduce toxicity. Dosages and
schedules may also vary if, in addition to a combination of an
HKI-272 compound and a vinorelbine, one or more additional
chemotherapeutic agents are used. Scheduling can be determined by
the practitioner who is treating any particular patient using his
professional skill and knowledge.
[0077] For the HKI-272 compound and/or vinorelbine compound, it is
desired each compound of the combination of compounds is in the
form of a unit dose. The term "unit dose" or "unit dose form" as
used herein describes a single dose form including, without
limitation, tablets, caplets, capsules, powders in sachets or
vials, saline infusion bags, as described above.
[0078] Unit dose forms contain from about 0.1 to about 300 mg of a
HKI-272 compound. In another embodiment, the unit dose form
contains about 5 to about 300 mg of the HKI-272 compound. In
another embodiment, the unit dose form contains about 50 to about
300 mg of the HKI-272 compound. In a further embodiment, the unit
dose form contains about 75 to about 300 mg of the HKI-272
compound. In still a further embodiment, the unit dose form
contains about 100 to 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
unit dose form contains about 160 to about 300 mg of the HKI-272
compound. In another embodiment, 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 about 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 further
embodiment, the unit dose form contains at least about 160 mg. In
another embodiment, the unit dose form contains at least about 240
mg.
[0079] The HKI-272 compound can be administered, e.g., orally, at a
dose range of about 0.01 to 100 mg/kg. In one embodiment, the
HKI-272 compound is administered at a dose range of about 0.1 to
about 90 mg/kg. In another embodiment, the HKI-272 compound is
administered at a dose range of about 1 to about 80 mg/kg. In a
further embodiment, the HKI-272 compound is administered at a dose
range of about 10 to about 70 mg/kg. In yet another embodiment, the
HKI-272 compound is administered at a dose range of about 15 to
about 60 mg/kg. In still a further embodiment, the HKI-272 compound
is administered 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 50 mg/kg. One of skill in the art could
routinely perform empirical activity tests to determine the
bioactivity of the compound in bioassays and thus determine what
dosage to administer.
[0080] In one embodiment, the oral dosage of the HKI-272 compound
is at least about 700 mg/week. In another embodiment, the oral
dosage of the HKI-272 compound is about 800 mg/week to at least to
about 1700 mg/week. In another embodiment, the oral dosage of the
HKI-272 compound is about 840 mg/week to about 1680 mg/week. In
another embodiment, the oral dosage of the HKI-272 compound is
about 900 mg/week to about 1600 mg/week. In a further embodiment,
the oral dosage of the HKI-272 compound is about 1000 mg/week to
about 1500 mg/week. In yet another embodiment, the oral dosage of
the HKI-272 compound is about 1100 mg/week to about 1400 mg/week.
In still a further embodiment, the oral dosage of the HKI-272
compound is about 1200 mg/week to about 1300 mg/week. Precise
dosages are determined by the administering physician based on
experience with the individual subject to be treated. Other dosage
regimens and variations are foreseeable, and are determined through
physician guidance.
[0081] Desirably, the patient is administered about 0.1 to about 50
mg/kg of the vinorelbine compound. In one embodiment, the patient
is administered about 1 to about 30 mg/kg of the vinorelbine
compound. In another embodiment, the patient is administered about
5 to about 25 mg/kg of the vinorelbine compound. In a further
embodiment, the patient is administered about 10 to about 20 mg/kg
of the vinorelbine compound. In still a further embodiment, the
patient is administered about 20 mg/kg of the vinorelbine
compound.
[0082] Unit dose forms contain about 0.1 to about 100 mg of a
vinorelbine compound. In another embodiment, the unit dose form
contains about 1 to about 70 mg of the vinorelbine compound. In
another embodiment, the unit dose form contains about 5 to about
500 mg of the vinorelbine compound. In a further embodiment, the
unit dose form contains about 10 to about 250 mg of the vinorelbine
compound. In still a further embodiment, the unit dose form
contains about 15 to about 100 mg of the vinorelbine compound. In
yet another embodiment, the unit dose form contains about 20 to
about 75 mg of the vinorelbine compound. In yet a further
embodiment, the unit dose form contains about 25 to about 50 mg of
the vinorelbine compound. In another embodiment, the unit dose form
contains about 30 to about 40 mg of the vinorelbine compound. In
yet another embodiment, the unit dose form contains about 240 to
about 300 mg of the vinorelbine compound. In a further embodiment,
the unit dose form contains about at least about 120 mg. In still a
further embodiment, the unit dose form contains at least about 160
mg. In another embodiment, the unit dose form contains at least
about 240 mg.
[0083] In one embodiment, i.v. infusion dosages of the vinorelbine
compound are from about 5 to about 25 mg/L. The initial infusion
dosage of the vinorelbine compound may be more or less, as
determined by the treating physician. In one embodiment, the i.v.
infusion dosage of the vinorelbine compound is about 10 to about 20
mg/L. In a further embodiment, the i.v. infusion dosage of the
vinorelbine compound is about 20 to about 25 mg/L. In yet another
embodiment, the i.v. infusion dosage of the vinorelbine compound is
at least about 10 mg/L. In another embodiment, the i.v. infusion
dosage of the vinorelbine compound is at least about 15 mg/L. In
yet another embodiment, the i.v. infusion dosage of the vinorelbine
compound is at least about 20 mg/L. In yet another embodiment, the
i.v. infusion dosage of the vinorelbine compound is at least about
25 mg/L. Precise dosages are determined by the administering
physician based on experience with the individual subject to be
treated. Other dosage regimens and variations are foreseeable, and
are determined through physician guidance. In one embodiment, the
vinorelbine compound is administered by i.v. infusion or orally,
preferably in the form of tablets or capsules.
[0084] As described herein, subtherapeutically effective amounts of
the HKI-272 compound and vinorelbine compound may be used to
achieve a therapeutic effect when administered in combination. In
one embodiment, the HKI-272 compound is provided at dosages of 5 to
50% lower when provided along with the vinorelbine compound. In
another embodiment, the HKI-272 compound is provided at dosages of
10 to 25% lower when provided along 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 vinorelbine
compound. In one embodiment, a resulting HKI-272 compound dosage is
about 8 to 40 mg. In another embodiment, a resulting HKI-272
compound dosage is about 8 to 30 mg. In a further embodiment, a
resulting HKI-272 compound dosage is about 8 to 25 mg.
Subtherapeutically effective amounts of the HKI-272 compound and
vinorelbine compound are expected to reduce the side-effects of
treatment.
[0085] Alternatively, one or more of the active agents in the
combination described herein is to be used in a supratherapeutic
amount, i.e., at a higher dosage in the combination than when used
alone. In this embodiment, the other active agent(s) are used in a
therapeutic or subtherapeutic amount.
Regimen Using the HKI-272 Compound and Vinorelbine Compound
[0086] As used herein, the components of the therapeutic "combined"
regimen, i.e., the HKI-272 compound and the vinorelbine compound,
can be administered simultaneously. Alternatively, the two
components can be administered in a staggered regimen, i.e., with
the HKI-272 compound being given at a different time during the
course of chemotherapy than the vinorelbine compound. This time
differential may range from several minutes, hours, days, weeks, or
longer between administration of the at least two agents.
Therefore, the term combination (or combined) does not necessarily
mean administered at the same time or as a unitary dose or single
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" includes 3 weeks.
[0087] These regimens or cycles may be repeated, or alternated, as
desired. Other dosage regimens and variations are foreseeable, and
are determined through physician guidance. The regimen may include
"non-treatment" steps/visits including screening periods and
post-treatment periods. In one embodiment, the regimen continues at
least about 2 weeks, at least about 6 weeks, 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 regimen may include 4 weeks of screening and 6 weeks for final
visit.
[0088] Single doses and multiple doses are contemplated. In one
embodiment, the vinorelbine and/or HKI-272 compound is administered
only once in the treatment. In another embodiment, the vinorelbine
and/or HKI-272 compound is administered at least once over a period
of 21 days. In a further embodiment, the vinorelbine and/or HKI-272
compound is administered at least twice over a period of 21 days.
In still another embodiment, the vinorelbine and/or HKI-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, and/or 21 of the cycle. In a
further embodiment, the vinorelbine and/or HKI-272 compound is
administered on days 1 and 8 of the cycle. In still a further
embodiment, the vinorelbine and/or HKI-272 compound is administered
at least once daily. In yet another embodiment, the vinorelbine
and/or HKI-272 compound HKI-272 compound is administered on day 1.
Desirably, the HKI-272 compound is administered on day 1 if the
neoplasm is non-metastatic. In a further embodiment, the
vinorelbine and/or HKI-272 compound is administered on day 2 of
said regimen. Desirably, the HKI-272 compound is administered on
day 2 if the neoplasm is metastatic. In still a further embodiment,
the HKI-272 compound is administered orally at least once a day. In
another embodiment, the HKI-272 compound is administered at least
1, 2, 3, 4, 5, or 6 times a day. In a further embodiment the
HKI-272 compound is administered 1 to 4 times a day.
[0089] In one embodiment, a single loading dose of the vinorelbine
compound and/or HKI-272 compound is administered. The single
loading dose of the vinorelbine compound and/or the HKI-272
compound may be the same dose as the subsequent doses or the single
loading dose may be greater than the dose administered to the
patient throughout the remaining treatment. In a further
embodiment, the vinorelbine compound/or the HKI-272 compound may be
administered at a larger dose only once per cycle, i.e., one day
per cycle.
[0090] If certain subjects do not tolerate one or more of the
components of the composition, i.e., the HKI-272 compound or
vinorelbine compound, or if the subject does not recover from
treatment-related toxicity after more than 3 consecutive weeks, or
if any grade 4 nonhematologic toxicity 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 discontinued if patent acquires one or more
of a symptom including, without limitation, selected from the group
consisting of neuropathy, neutropenia, thrombocytopenia, nausea,
vomiting, decreased platelet count, and increased bilirubin count.
In another embodiment, administration of one or both of the HKI-272
compound and the vinorelbine compound is discontinued or
interrupted if the patient's neutrophil count of is less than about
1000/L. In a further embodiment, administration of one or both of
the HKI-272 compound and the vinorelbine compound is discontinued
or interrupted if the patient's platelet count is less than
75,000/L.
[0091] Alternatively, for those subjects do not tolerate one or
more of the components of the composition, i.e., the HKI-272
compound or vinorelbine compound, dose reductions may be performed.
In one embodiment, 1 or 2 dose reductions are performed. More
desirably, only 1 dose reduction is performed.
[0092] For subjects who not recover from vinorelbine or
HKI-272-related toxicity after more than 3 consecutive weeks,
treatment with vinorelbine or HKI-272, respectively, may be
discontinued. However, administration of the other agent, i.e.,
HKI-272 or vinorelbine, respectively, may be continued.
[0093] 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 continued for
about 6 weeks. The length of participation is 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 clinically
stable, and if the subject has received an overall benefit.
[0094] In addition, the vinorelbine compound/or the HKI-272
compound may also be administered after completion of chemotherapy
as maintenance therapy.
Pharmaceutical Packs and Kits
[0095] Also included is a product or pharmaceutical pack containing
a course of an anti-neoplastic treatment for one individual mammal
comprising one or more container(s) having one, one to four, or
more unit(s) of the HKI-272 compound in unit dosage form and,
optionally, one, one to four, or more unit(s) of the HKI-272 and
vinorelbine compounds, and optionally, another active agent. The
combinations may be in the form of a kit of parts.
[0096] In one embodiment a kit includes a first container with a
suitable composition containing a HKI-272 compound and a second
container with a suitable composition containing a vinorelbine
compound. Accordingly, there is provided a kit for use in the
treatment or prophylaxis of cancer. This kit includes comprising:
a) HKI-272 compound together with a pharmaceutically-acceptable
excipient or carrier, in a first unit dosage form; b) a vinorelbine
compound together with a pharmaceutically-acceptable excipient or
carrier, in a second unit dosage form; and c) a container for
containing said first and second dosage forms.
[0097] In another embodiment, pharmaceutical packs contain a course
of anti-neoplastic treatment for one individual mammal comprising a
container having a unit of a HKI-272 compound in unit dosage form,
a containing having a unit of a vinorelbine compound, and
optionally, a container with another active agent.
[0098] In some embodiments, the compositions are in packs in a form
ready for administration. In other embodiments, the compositions
are in concentrated form in packs, optionally with the diluent
required to make a final solution for administration. In still
other embodiments, the product contains a compound described herein
in solid form and, optionally, a separate container with a suitable
solvent or carrier.
[0099] In still other embodiments, the above packs/kits include
other components, e.g., instructions for dilution, mixing and/or
administration of the product, other containers, syringes, needles,
etc. Other such pack/kit components are readily apparent to one of
skill in the art.
Concurrent Treatments
[0100] In addition to the optional chemotherapeutic agents and
optional compounds noted above, the regimens 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 prior to, concurrently with, or subsequent to
treatment with the HKI-272 and vinorelbine compounds.
Preferred Embodiments
[0101] In one embodiment, a regimen for treating a solid tumor
associated with overexpression or amplification of HER-2 in a
subject is provided. One cycle of the regimen includes 21 days and
the regimen includes orally administering at least one unit dose of
HKI-272 starting on day 1 of the cycle and intravenously
administering at least one a unit dose of vinorelbine on days 1 and
8 of the cycle.
[0102] In another embodiment, a regimen for treating a metastatic
cancer associated with overexpression or amplification of HER-2 in
a subject is provided. One cycle of the regimen includes 21 days
and the regimen includes orally administering at least one unit
dose of HKI-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.
[0103] In a further embodiment, a product containing vinorelbine
and HKI-272 is provided. The product is useful as a combined
preparation for simultaneous, separate or sequential use in
treating a neoplasm in a mammal.
[0104] In still a further embodiment, a pharmaceutical pack for
treating a neoplasm in one individual mammal is provided. The
pharmaceutical pack contains at least one unit of vinorelbine and
at least one unit of HKI-272.
[0105] In another embodiment, a pharmaceutical composition is
provided and contains vinorelbine, HKI-272, and at least one
pharmaceutically acceptable carrier. Desirably, the pharmaceutical
composition is useful for treating a neoplasm in a mammal.
[0106] In still another embodiment, a method of treating a neoplasm
associated with overexpression or amplification of HER-2 in a
mammal in need thereof is provided. The method includes
administering a unit dose of a vinorelbine compound and
administering a unit dose of a HKI-272 compound.
[0107] The following examples illustrate of the uses of the
combinations of the invention. It will be readily understood that
alterations or modifications, e.g., in the formulation of the
components, the routes of delivery, and the dosing, can be made for
reasons known to those of skill in the art.
Example 1
Combination Regimen of HKI-272 and Vinorelbine in Lung Cancer Cell
Proliferation Assays
[0108] A standard cell proliferation assay was utilized to
independently analyze the response of lung cell lines NC1-H1666,
NC1-H1650, and NC1-H1975 to various dilutions of HKI-272 and
vinorelbine in combination. Briefly, fetal bovine serum (FBS)
RPM1-1640 (Media) was added to each well of 96 well plates
containing one 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 dilutions with respect to the
HKI-272 dilutions (the highest final concentration of HKI-272 was 1
.mu.M for the H1650 and H1666 cell lines; the highest final
concentration of HKI-272 was 9 .mu.M for the H1975 cell line; and
the highest final concentration of vinorelbine was 0.1 .mu.M for
all of the cell lines). Following incubation of the cell plates at
37.degree. C., 5% CO.sub.2 for 72 hours, cell proliferation was
assessed.
[0109] Cell proliferation was reduced after incubation with HKI-272
and vinorelbine.
Example 2
Combination Regimen of HKI-272 and Vinorelbine in Treatment of
Non-Metastatic Breast Cancers
[0110] Patients having diagnosed non-metastatic breast cancers are
treated using a regimen of HKI-272 and vinorelbine. Patients are
administered HKI-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 Table 3. HKI-272 is taken orally on the remaining
days of the each cycle. On those days that HKI-272 and vinorelbine
are administered on the same day, i.e., days 1 and 8 of the cycle,
HKI-272 is administered prior to the vinorelbine infusion.
TABLE-US-00001 TABLE 3 Dose Level HKI-272 Dose (mg) Vinorelbine
Dose (mg/m.sup.2) 1 160 25 2 240
[0111] Vinorelbine is 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.
Vinorelbine is administered intravenously using preferentially a
central venous route, through a free-flowing IV line over
approximately 10 minutes, followed by 125 mL of saline solution
infused over approximately 30 minutes.
[0112] If the patient has any serious side-effects during the
treatment, dose adjustments of HKI-272 and/or vinorelbine are
permitted. See, Tables 4 and 5.
TABLE-US-00002 TABLE 4 Dose Adjustment HKI-272 (mg) -1.sup.a 120
1.sup.b 160 2.sup. 240 .sup.aThe -1 dose level is used only if dose
reduction is required. .sup.bThe dose 1 level is to be used as
first level of dose reduction in case the defined maximum tolerated
dose is 240 mg.
TABLE-US-00003 TABLE 5 Dose Adjustment Vinorelbine (mg/m.sup.2)
-1.sup.a 20 .sup. 1 25 .sup.aThe -1 dose level is to be used only
if dose reduction is needed.
[0113] It is predicted that a decrease in tumor growth will be
observed.
Example 3
Combination Regimen of HKI-272 and Vonorelbine in Treatment of
Metastatic Breast Cancers
[0114] Patients having diagnosed metastatic breast cancers are
treated using a regimen of HKI-272 and vinorelbine.
[0115] Vinorelbine 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
in-line filter and an automatic dispensing pump. Optionally,
antihistamine (diphenhydramine, 25 to 50 mg IV or the equivalent)
is administered about 30 minutes prior to vinorelbine infusion.
[0116] Dosing of HKI-272 begins at cycle 1, day 2 with daily oral
administration of HKI-272 at the dosages provided in Example 2,
Table 3 or 4. HKI-272 is taken orally on the remaining days of the
each cycle. On those days that HKI-272 and vinorelbine are
administered on the same day, i.e., day 8 of the cycle, HKI-272 is
administered prior to the vinorelbine infusion. If the patient has
any serious side-effects during the treatment, the dose adjustments
of HKI-272 and/or vinorelbine are permitted.
[0117] It is predicted that a decrease in tumor growth will be
observed.
[0118] All patents, patent publications, articles, and other
documents referenced herein are incorporated by reference. It will
be clear to one of skill in the art that modifications can be made
to the specific embodiments described herein without departing from
the scope of the invention.
* * * * *