U.S. patent application number 11/592066 was filed with the patent office on 2007-05-10 for antineoplastic combinations with mtor inhibitor,herceptin, and/or hki-272.
This patent application is currently assigned to Wyeth. Invention is credited to Laurence Moore, Sridhar K. Rabindran, Charles Zacharchuk.
Application Number | 20070104721 11/592066 |
Document ID | / |
Family ID | 37845244 |
Filed Date | 2007-05-10 |
United States Patent
Application |
20070104721 |
Kind Code |
A1 |
Moore; Laurence ; et
al. |
May 10, 2007 |
Antineoplastic combinations with mTOR inhibitor,herceptin, and/or
hki-272
Abstract
A combination of temsirolimus and herceptin in the treatment of
cancer is provided. A combination of temsirolimus and HKI-272 is
provided. A combination of herceptin and HKI-272 is also provided.
Regimens and kits for treatment of metastatic breast cancer,
containing herceptin, temsirolimus and/or HKI-272, optionally in
combination with other anti-neoplastic agents, or immune modulators
are described.
Inventors: |
Moore; Laurence; (Newton,
MA) ; Zacharchuk; Charles; (Westford, MA) ;
Rabindran; Sridhar K.; (Chestnut Ridge, NY) |
Correspondence
Address: |
HOWSON AND HOWSON;CATHY A. KODROFF
SUITE 210
501 OFFICE CENTER DRIVE
FT WASHINGTON
PA
19034
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
37845244 |
Appl. No.: |
11/592066 |
Filed: |
November 2, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60837509 |
Aug 14, 2006 |
|
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60733562 |
Nov 4, 2005 |
|
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Current U.S.
Class: |
424/155.1 ;
514/291; 514/314 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 39/39558 20130101; A61K 45/06 20130101; A61P 25/00 20180101;
A61P 43/00 20180101; A61P 7/00 20180101; A61P 11/00 20180101; A61P
5/00 20180101; A61P 3/00 20180101; A61P 19/00 20180101; A61K 31/436
20130101; A61K 31/337 20130101; A61P 35/02 20180101; A61P 15/00
20180101; A61P 17/00 20180101; A61K 31/4709 20130101; A61P 35/04
20180101; A61P 13/08 20180101; A61K 31/4745 20130101; A61K 31/436
20130101; A61K 2300/00 20130101; A61K 39/39558 20130101; A61K
2300/00 20130101; A61K 31/4709 20130101; A61K 2300/00 20130101;
A61K 31/4745 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/155.1 ;
514/291; 514/314 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 31/4745 20060101 A61K031/4745; A61K 31/4709
20060101 A61K031/4709 |
Claims
1. A method of treating a neoplasm associated with overexpression
or amplification of HER2 in a mammal in need thereof, which
comprises providing to said mammal an effective amount of a
combination of active components comprising a herceptin and an mTOR
inhibitor and/or HKI-272.
2. The method according to claim 1, wherein the combination
comprises HKI-272.
3. The method according to claim 1 or 2, wherein one or more of the
active components is provided in subtherapeutically effective
amounts.
4. A method of treating a neoplasm associated with overexpression
or amplification of HER2 in a mammal in need thereof, which
comprises providing to said mammal an effective amount of a
combination comprising a rapamycin and an HKI-272.
5. The method according to any one of claims 1 to 4, wherein the
neoplasm is selected from the group consisting of lung cancers,
including bronchioalveolar carcinoma and non small cell lung
cancer, breast cancers, myeloma, prostate cancers, head and neck
cancer, or transitional cell carcinoma; small cell and large cell
neuroendocrine carcinoma of the uterine cervix.
6. The method according to any one of claims 1 to 5, wherein said
combination further comprises another active component selected
from the group consisting of one or more antineoplastic alkylating
agent, one or more antimetabolite antineoplastic agents, one or
more biochemical immune modulators, imatinib, one or more EGFR
inhibitors, a multi-kinase inhibitor that targets serine/threonine
and receptor tyrosine kinases in both the tumor cell and tumor
vasculature or an interferon.
7. The method according to claim 6, wherein said antineoplastic
agents are selected from the group consisting of meclorethamine,
cyclophosphamide, ifosfamide, melphalan, chlorambucil, thiotepa,
mitomycin, busulfan, lomustine, carmustine, procarbazine,
temozolomide, oxaliplatin, cisplatin, and carboplatin.
8. The method according to claim 7, wherein the antimetabolite
antineoplastic agent is selected from the group consisting of:
5-fluorouracil; floxuradine; thioguanine; cytarabine; fludarabine;
6-mercaptopurine; methotrexate; gemcitabine; capecitabine; taxanes;
pentostatin; trimetrexatel; and cladribine.
9. The method according to claim 7, wherein the biochemical
modulating agent is selected from the group consisting of
leucovorin and levofolinate.
10. The method according to claim 9, wherein the combination
further comprises a taxane.
11. The method according to any one of claims 1 to 10, wherein the
rapamycin is rapamycin.
12. The method according to any one of claims 1 to 10, wherein the
rapamycin is 42-O-(2-hydroxy)ethyl rapamycin.
13. The method according to any one of claims 1 to 12, wherein the
neoplasm is metastatic breast cancer.
14. A regimen for treatment of breast cancer associated with
overexpression or amplification of HER2, said method comprising:
delivering a dosage amount amount of a herceptin; and delivering a
dose of at least one additional compound selected from the group
consisting of an mTOR inhibitor and a HKI-272.
15. The regimen according to claim 14, wherein the rapamycin mTOR
inhibitor and/or the herceptin is delivered intravenously.
16. The regimen according to claim 14, wherein the rapamycin and/or
the herceptin is delivered weekly.
17. The regimen according to claim 14, wherein the rapamycin and/or
the herceptin is delivered orally.
18. The regimen according to claim 14, wherein the herceptin is
delivered for at least two weeks following at least one week
off.
19. The regimen according to claim 14, wherein the herceptin is
delivered for a period of four weeks followed by two weeks off.
20. The regimen according to claim 14, wherein the herceptin is
delivered once every three to four weeks.
21. The regimen according to claim 14, wherein the rapamycin is
selected from the group consisting of rapamycin and
temsirolimus.
22. The regimen according to claim 14, wherein the HKI-272 is
delivered orally.
23. A product containing temsirolimus and a herceptin as a combined
preparation for simultaneous, separate or sequential use in
treating a neoplasm in a mammal.
24. A product containing a rapamycin and an HKI-272 as a combined
preparation for simultaneous, separate or sequential use in
treating a neoplasm in a mammal.
25. A product containing a herceptin and an HKI-272 as a combined
preparation for simultaneous, separate or sequential use in
treating a neoplasm in a mammal.
26. A pharmaceutical pack containing a course of an anti-neoplastic
treatment for one individual mammal, wherein the pack contains (a)
at least one unit of temsirolimus and (b) at least one unit of
herceptin in unit dosage form.
27. A pharmaceutical pack containing a course of an anti-neoplastic
treatment for one individual mammal, wherein the pack contains (a)
at least one unit of a rapamycin and (b) at least one unit of
HKI-272 in unit dosage form.
28. A pharmaceutical pack containing a course of an anti-neoplastic
treatment for one individual mammal, wherein the pack contains (a)
at least one unit of herceptin and (b) at least one unit of HKI-272
in unit dosage form.
29. A pharmaceutical composition useful in treating a neoplasm in a
mammal, the composition comprising (a) at least one unit of
temsirolimus and (b) at least one unit of a herceptin in unit
dosage form, and at least one pharmaceutically acceptable
carrier.
30. A pharmaceutical composition useful in treating a neoplasm in a
mammal, the composition comprising (a) at least one unit of a
rapamycin and (b) at least one unit of an HKI-272 in unit dosage
form, and at least one pharmaceutically acceptable carrier.
31. A pharmaceutical composition useful in treating a neoplasin in
a mammal, the composition comprising (a) at least one unit of a
herceptin and (b) at least one unit of an HKI-272 in unit dosage
form, and at least one pharmaceutically acceptable carrier.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 USC 119(e) of
US Provisional Patent Application No. 60/837,509, filed Aug. 14,
2005 and US Provisional Patent Application No. 60/733,562, filed
Nov. 4, 2005.
BACKGROUND OF THE INVENTION
[0002] This invention relates to the use of combinations of
herceptin with an mTOR inhibitor and/or HKI-272, for the treatment
of neoplasms associated with overexpression or amplification of
HER2.
[0003] CCI-779, is rapamycin 42-ester with
3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, an ester of
rapamycin which has demonstrated significant inhibitory effects on
tumor growth in both in vitro and in vivo models. This compound is
now known generically under the name temsirolimus. The preparation
and use of hydroxyesters of rapamycin, including temsirolimus, are
described in U.S. Pat. Nos. 5,362,718 and 6,277,983.
[0004] Temsirolimus exhibits cytostatic, as opposed to cytotoxic
properties, and may delay the time to progression of tumors or time
to tumor recurrence. Temsirolimus is considered to have a mechanism
of action that is similar to that of sirolimus. Temsirolimus binds
to and forms a complex with the cytoplasmic protein FKBP, which
inhibits an enzyme, mTOR (mammalian target of rapamycin, also known
as FKBP12-rapamycin associated protein [FRAP]). Inhibition of
mTOR's kinase activity inhibits a variety of signal transduction
pathways, including cytokine-stimulated cell proliferation,
translation of mRNAs for several key proteins that regulate the G1
phase of the cell cycle, and IL-2-induced transcription, leading to
inhibition of progression of the cell cycle from G1 to S. The
mechanism of action of temsirolimus that results in the G1 -S phase
block is novel for an anticancer drug.
[0005] Metastatic breast cancer (MBC) is essentially incurable with
standard therapy, and patients with MBC have a median survival of
about 2 years after documentation of metastasis. As a consequence,
the goals of treatment are to improve patients' symptoms while
trying to maintain (or improve, in certain cases) quality of life.
Prolonging survival remains a clear goal, particularly in breast
cancer that has overexpression or amplification of the her-2
oncogene.
[0006] Hercepting.RTM. (Trastuzumab) is an FDA-approved therapeutic
monoclonal antibody for HER2 protein overexpressing metastatic
breast cancer. A murine monoclonal antibody was described [see,
U.S. Pat. No. 5,705,151]. The murine MAb4D5 molecule described in
that document has been humanized in an attempt to improve its
clinical efficacy by reducing immunogenicity and allowing it to
support human effector functions. WO 92/22653. Later documents
describe the development of a lyophilized formulation comprising
full length humanized antibody huMAb4D5-8 described in WO 92/22653.
Herceptin is currently approved by the FDA for the treatment of
metastatic breast cancer that overexpresses HER2, (1) as a single
agent after previous treatment of the metastatic breast cancer with
one or more chemotherapy regimens and (2) in combination with
paclitaxel in such patients without prior chemotherapy for their
metastatic breast cancer. Moreover, there is evidence that the
addition of herceptin to taxane adjuvant or neoadjuvant
chemotherapy improves to patients with earlier stage breast
cancer.
[0007] HKI-272, (E)-N-{4-[3-chloro-4-(2-pyridinyl methoxy)
anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide,
has been described as a promising anticancer drug candidate for the
treatment of breast cancers and other HER-2-dependent cancers.
Because it also inhibits the EGFR kinase with similar potency,
HKI-272 may be useful to treat tumors that overexpress both HER-2
and EGFR and be more efficacious than a specific EGFR or HER-2
antagonist. S. K. Rabindran et al, "Antitumor Activity of HKI-272,
an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine
Kinase", Cancer Research 64, 3958-3965, Jun. 1, 2004. See, U.S.
Pat. No. 6,288,082; U.S. Pat. No. 6,297,258.
[0008] What is needed is an improved antineoplastic therapy.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 is a 3-dimensional contour plot with the plane at 0%
representing additive interaction, and peaks and valleys
representing areas of synergy or antagonism, respectively, between
the herceptin and HKI-272 in BT474 [HER-2+ (amplified); ATCC
HTB-20] cells.
[0010] FIG. 2 is a 3-dimensional contour plot with the plane at 0%
representing additive interaction, and peaks and valleys
representing areas of synergy or antagonism between the herceptin
and HKI-272 in MCF-7 [HER-2.sup.-, EGFR-; adenocarcinoma; ATCC
HTB22] cells.
[0011] FIG. 3 is a 3-dimensional contour plot with the plane at 0%
representing additive interaction, and peaks and valleys
representing areas of synergy or antagonism between the herceptin
and HKI-272 in MDA-MB-361 [HER-2.sup.+ (non-amplified);
adenocarcinoma; ATCC HTB 27] cells.
DETAILED DESCRIPTION OF THE INVENTION
[0012] This invention provides the use of combinations comprising
herceptin, an mTOR inhibitor and/or HKI-272 in the treatment of
neoplasms. Thus, the invention provides for the combined use of a
herceptin with an mTOR inhibitor, the combined use of herceptin
with an HKI-272, the combined use of an mTOR inhibitor with
HKI-272, or the combined use of a herceptin with mTOR inhibitor and
an HKI-272. The invention further provides products containing a
herceptin in combination with an mTOR inhibitor and/or HKI-272
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
following detailed description illustrates temsirolimus. However,
other mTOR inhibitors may be substituted for temsirolimus in the
methods, combinations and products described herein.
[0013] These methods, combinations and products are useful in the
treatment of a variety of neoplasms associated with overexpression
or amplification of HER2, including, for example, lung cancers,
including bronchioalveolar carcinoma and non small cell lung
cancer, breast cancers, prostate cancers, myeloma, head and neck
cancer, or transitional cell carcinoma; small cell and large cell
neuroendocrine carcinoma of the uterine cervix.
[0014] In one embodiment, the combination of temsirolimus and
herceptin is particularly well suited for treatment of metastatic
breast cancer. In another embodiment, the combination of herceptin
and a mTOR inhibitor and/or an HKI-272, are well suited for
treatment of breast, kidney, bladder, mouth, larynx, esophagus,
stomach, colon, ovary, and lung), and polycystic kidney
disease.
[0015] As used herein, the term mTOR inhibitor means a compound or
ligand, or a pharmaceutically acceptable salt thereof, that
inhibits cell replication by blocking the progression of the cell
cycle from G1 to S. The term includes the neutral tricyclic
compound rapamycin (sirolimus) and other rapamycin compounds,
including, e.g., rapamycin derivatives, rapamycin analogues, other
macrolide compounds that inhibit mTOR activity, and all compounds
included within the definition below of the term "a rapamycin".
These include compounds with a structural similarity to "a
rapamycin", e.g., compounds with a similar macrocyclic structure
that have been modified to enhance therapeutic benefit. FK-506 can
also be used in the method of the invention.
[0016] As used herein, the term a rapamycin defines a class of
immunosuppressive compounds that contain the basic rapamycin
nucleus as shown below. ##STR1## The rapamycins of this invention
include compounds that are chemically or biologically modified as
derivatives of the rapamycin nucleus, while still retaining
immunosuppressive properties. Accordingly, the term a rapamycin
includes rapamycin, and esters, ethers, carbamates, oximes,
hydrazones, and hydroxylamines of rapamycin, as well as rapamycins
in which functional groups on the rapamycin nucleus have been
modified, for example through reduction or oxidation. Also included
in the term a rapamycin are pharmaceutically acceptable salts of
rapamycins.
[0017] The term a rapamycin also includes 42- and/or 31 -esters and
ethers of rapamycin as described in the following patents, which
are all hereby incorporated by reference: alkyl esters (U.S. Pat.
No. 4,316,885); aminoalkyl esters (U.S. Pat. No. 4,650,803);
fluorinated esters (U.S. Pat. No. 5,100,883); amide esters (U.S.
Pat. No. 5,118,677); carbamate esters (U.S. Pat. No. 5,118,678);
silyl esters (U.S. Pat. No. 5,120,842); aminodiesters (U.S. Pat.
No. 5,162,333); sulfonate and sulfate esters (U.S. Pat. No.
5,177,203); esters (U.S. Pat. No. 5,221,670); alkoxyesters (U.S.
Pat. No. 5,233,036); O-aryl, -alkyl, -alkenyl, and -alkynyl ethers
(U.S. Pat. No. 5,258,389); carbonate esters (U.S. Pat. No.
5,260,300); arylcarbonyl and alkoxycarbonyl carbamates (U.S. Pat.
No. 5,262,423); carbamates (U.S. Pat. No. 5,302,584); hydroxyesters
(U.S. Pat. No. 5,362,718); hindered esters (U.S. Pat. No.
5,385,908); heterocyclic esters (U.S. Pat. No. 5,385,909);
gem-disubstituted esters (U.S. Pat. No. 5,385,910); amino alkanoic
esters (U.S. Pat. No. 5,389,639); phosphorylcarbamate esters (U.S.
Pat. No. 5,391,730); carbamate esters (U.S. Pat. No. 5,411,967);
carbamate esters (U.S. Pat. No. 5,434,260); amidino carbamate
esters (U.S. Pat. No.5,463,048); carbamate esters (U.S. Pat. No.
5,480,988); carbamate esters (U.S. Pat. No. 5,480,989); carbamate
esters (U.S. Pat. No. 5,489,680); hindered N-oxide esters (U.S.
Pat. No. 5,491,231); biotin esters (U.S. Pat. No.5,504,091);
O-alkyl ethers (U.S. Pat. No. 5,665,772); and PEG esters of
rapamycin (U.S. Pat. No. 5,780,462). The preparation of these
esters and ethers is disclosed in the patents listed above.
[0018] Further included within the definition of the term a
rapamycin are 27-esters and ethers of rapamycin, which are
disclosed in U.S. Pat. No. 5,256,790. Also described are C-27
ketone rapamycins which are reduced to the corresponding alcohol,
which is in turn converted to the corresponding ester or ether. The
preparation of these esters and ethers is disclosed in the patent
listed above. Also included are oximes, hydrazones, and
hydroxylamines of rapamycin are disclosed in U.S. Pat. Nos.
5,373,014, 5,378,836, 5,023,264, and 5,563,145. The preparation of
these oximes, hydrazones, and hydroxylamines is disclosed in the
above-listed patents. The preparation of 42-oxorapamycin is
disclosed in 5,023,263.
[0019] As used herein, the term a CCI-779 means rapamycin 42-ester
with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid
(temsirolimus), and encompasses prodrugs, derivatives,
pharmaceutically acceptable salts, or analogs thereof.
[0020] Examples of a rapamycin include, e.g., rapamycin,
32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin,
16-pent-2-ylyloxy-32(S)-dihydro-rapamycin,
16-pent-2-ylyloxy-32(S)-dihydr-o-40-O-(2-hydroxyethyl)-rapamycin,
40-O-(2-hydroxyethyl)-rapamycin, rapamycin 42-ester with
3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779),
40-[3-hydroxy-2-(hydroxymethyl)-2-meth-ylpropanoate]-rapamycin, or
a pharmaceutically acceptable salt thereof, as disclosed in U.S.
Pat. No. 5,362,718, ABT578, or 40-(tetrazolyl)-rapamycin,
40-epi-(tetrazolyl)-rapamycin, e.g., as disclosed in International
Patent Publication No. WO 99/15530, or rapamycin analogs as
disclosed in International Patent Publication No. WO 98/02441 and
WO 01/14387, e.g., AP23573. In another embodiment, the compound is
Certican.TM. (everolimus, 2-O-(2-hydroxy)ethyl rapamycin, Novartis,
U.S. Pat. No. 5,665,772).
[0021] As used herein, "an HKI-272" refers to a compound having the
following core, ##STR2## or a derivative or pharmaceutically
acceptable salt thereof. Suitable derivatives may include, e.g., an
ester, ether, or carbamate. The core structure, HKI-272, has the
chemical name (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)
anilino]-3-cyano-7-ethoxy-6-quinolinyl }-4-(dimethylam
ino)-2-butenamide.
[0022] In one embodiment, the invention also provides for use of
substituted 3-cyano quinolines having structure: ##STR3## [0023]
where R.sub.1 is halogen; [0024] R.sub.2 is pyridinyl, thiophene,
pyrimidine, thiazole, or phenyl optionally substituted with up to
three substituents; [0025] R.sub.3 is --O-- or --S--; [0026]
R.sub.4 is methyl or CH.sub.2CH.sub.2OCH.sub.3; [0027] R.sub.5 is
ethyl or methyl; and [0028] n is O or 1. These 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. 6,288,082 and U.S.
Pat. 6,297,258. These compounds and their preparation are described
in detail in US Published Patent Application No. 2005/0059678. For
convenience, HKI-272 is used throughout this specification.
However, it will be understood that the compound of the structure
provided above can be substituted for HKI-272 in the combinations
with an mTOR inhibitor and/or herceptin which are described in
detail below.
[0029] The following standard pharmacological test procedure can be
used to determine whether a compound is an mTOR inhibitor, as
defined herein. Treatment of growth factor stimulated cells with an
mTOR inhibitor like rapamycin completely blocks phosphorylation of
serine 389 as evidenced by Western blot and as such constitutes a
good assay for mTOR inhibition. Thus, whole cell lysates from cells
stimulated by a growth factor (e.g. IGF1) in culture in the
presence of an mTOR inhibitor should fail to show a band on an
acrylamide gel capable of being labeled with an antibody specific
for serine 389 of p70s6K.
[0030] It is preferred that the mTOR inhibitor used in the
antineoplastic combinations of this invention is a rapamycin, and
more preferred that the mTOR inhibitor is rapamycin, temsirolimus,
or 42-O-(2-hydroxy)ethyl rapamycin. The preparation of
42-O-(2-hydroxy)ethyl rapamycin is described in U.S. Pat.
5,665,772.
[0031] The preparation of temsirolimus is described in U.S. Pat.
5,362,718. A regiospecific synthesis of temsirolimus is described
in U.S. Pat. 6,277,983, which is hereby incorporated by reference.
Still another regiospecific method for synthesis of temsirolimus is
described in US Patent Publication No. 2005-0033046-A 1, published
Feb. 10, 2005 (Application Ser. No. 10/903,062, filed Jul. 30,
2004), and its counterpart, International Patent Publication No. WO
2005/016935, published Apr. 7, 2005.
[0032] Herceptin, and methods of making and formulating same have
been described. See, e.g., U.S. Pat. 6,821,515; U.S. Pat. No.
6,399,063 and U.S. Pat. No. 6,387,371. Herceptin is available
commercially from Genentech. As used herein, the term "a herceptin"
includes includes trastuzumab and altered forms of, and derivatives
of, trastuzumab. The term "a herceptin" includes agents that target
the same epitope on the Her-2 receptor as targeted by trastuzumab.
The epitope is known from H. S. Cho et al., Structure of the
extracellular region of HER2 alone and in complex with the
Herceptin Fab, Nature 421 (2003), pp. 756-760.
[0033] HKI-272 and methods of making and formulating same have been
described. See, e.g., US Published Patent Application
No.2005/0059678; U.S. Pat. No. 6,002,008, can also be used to
prepare the substituted 3-quinoline compounds used this invention
and are hereby incorporated by reference. In addition to the
methods described in these documents, WO-9633978 and WO-9633980
describe methods that are useful for the preparation of these
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.
[0034] As used in accordance with this invention, the term
"treatment" means treating a mammal having a neoplasm by providing
said mammal an effective amount of a combination of a two or
three-way combination of the components selected from an mTOR
inhibitor, a herceptin and/or HKI-272 with the purpose of
inhibiting progression of the neoplastic disease, growth of a tumor
in such mammal, eradication of the neoplastic disease, prolonging
survival ofthe mammal and/or palliation of the mammal.
[0035] As used in accordance with this invention, the term
"providing," with respect to providing an mTOR inhibitor with
herceptin and/or HKI-272, means either directly administering the
mTOR inhibitor, or administering a prodrug, derivative, or analog
which will form an effective amount of the mTOR inhibitor within
the body, along with herceptin and/or HKI-272 directly, or
administering a prodrug, derivative, or analog which will form an
effective amount of herceptin or HKI-272 in the body.
[0036] Use of a combination of an mTOR inhibitor (e.g.,
temsirolimus), a herceptin and/or HKI-272 also provides for the use
of combinations of each of the agents in which one, two, or all
three agents is used at subtherapeutically effective dosages.
Subtherapeutically effective dosages may be readily determined by
one of skill in the art, in view ofthe 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 of the invention, as compared to the dosage that is
effective when used alone. The invention further provides for one
or more of the active agents in the combination of the invention 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.
[0037] The combinations of the invention may be in the form of a
kit of parts. The invention therefore includes a product containing
an mTOR inhibitor, a herceptin and/or HKI-272 as a combined
preparation for simultaneous, separate or sequential delivery for
the treatment of a neoplasm in a mammal in need thereof. In one
embodiment, a product contains temsirolimus and a herceptin as a
combined preparation for simultaneous, separate or sequential use
in treating a neoplasm in a mammal in need thereof. Optionally, the
product further contains an HKI-272. HKI-272 may be separately
formulated, e.g., for oral delivery. In another embodiment, a
product contains temsirolimus and an HKI-272 as a combined
preparation for simultaneous, separate or sequential use in a
neoplasm in a mammal in need thereof. Optionally, the product
further contains herceptin. In yet another embodiment, the product
contains a herceptin and an HKI-272. Optionally, the product
further contains an mTOR inhibitor. In one embodiment, the neoplasm
is metastatic breast cancer.
[0038] 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 mTOR inhibitor in unit dosage form and
units of herceptin in unit dosage form, optionally further in
combination with units of an HKI-272 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 mTOR inhibitor in unit dosage form and units
of HKI-272 in unit dosage form, optionally further in combination
with units of herceptin in unit dosage form. In yet another
embodiment, a pharmaceutical pack contains a course of treatment of
a neoplasm for one individual mammal, wherein the pack contains
units of a herceptin in unit dosage form and units of HKI-272 in
unit dosage form, optionally further in combination with units of
an mTOR inhibitor in unit dosage form. In one embodiment, a
pharmaceutical pack as described herein contains a course of
treatment of metastatic breast cancer for one individual
mammal.
[0039] Administration of the compositions may be oral, intravenous,
respiratory (e.g., nasal or intrabronchial), infusion, parenteral
(besides 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, such as via
liposome-mediated delivery; topical, nasal, sublingual, uretheral,
intrathecal, ocular or otic delivery, implants, rectally,
intranasally.
[0040] While the components of the invention may be delivered via
the same route, a product or pack according to the invention may
contain a rapamycin, such as temsirolimus, for delivery by a
different route than that of the herceptin or the HKI-272, e.g.,
one or more ofthe components may be delivered orally, while one or
more of the others are administered intravenously. In one
embodiment, temsirolimus is prepared for oral delivery, HKI-272 is
prepared for oral delivery and herceptin is prepared for
intravenous delivery. In another embodiment, both temsirolimus and
herceptin are prepared for intravenous delivery. In still another
embodiment, all of the components are prepared for oral delivery.
Optionally, other active components may be delivered by the same or
different routes as the mTOR inhibitor (e.g., temsirolimus) or
herceptin. Other variations would be apparent to one skilled in the
art and are contemplated within the scope of the invention.
[0041] The mTOR inhibitor plus herceptin combination may be
administered in the absence of HKI-272. In one embodiment, these
are the sole active antineoplastic agents utilized in the regimen.
In another embodiment, the mTOR inhibitor/herceptin combination is
administered in combination with HKI-272.
[0042] The mTOR inhibitor plus HKI-272 combination may be
administered in the absence of herceptin. In another embodiment,
the mTOR inhibitor/HKI-272 combination is administered in
combination with herceptin. In one embodiment, these two and
three-way combinations are the sole active antineoplastic agents
utilized in the regimen. In another embodiment, these two and
three-way combinations may be utilized in further combination with
other active agents.
[0043] The herceptin plus HKI-272 combination may be administered
in the absence of an mTOR inhibitor. In another embodiment, the
herceptin/HKI-272 combination is administered in combination with
an mTOR inhibitor. In one embodiment, these two and three-way
combinations are the sole active antineoplastic agents utilized in
the regimen. In another embodiment, these two and three-way
combinations may be utilized in further combination with other
active agents.
[0044] 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.
[0045] It is projected that initial i.v. infusion dosages of the
mTOR inhibitor (e.g., temsirolimus) will be from about 5 to about
175 mg, or about 5 to about 25 mg, when administered on a weekly
dosage regimen. It is projected that the oral dosage of an mTOR
useful in the invention will be 10 mg/ week to 250 mg/week, about
20 mg/week to about 150 mg/week, about 25 mg/week to about 100
mg/week, or about 30 mg/week to about 75 mg/week. For rapamycin,
the projected oral dosage will be between 0.1 mg/day to 25 mg/day.
Precise dosages will be determined by the administering physician
based on experience with the individual subject to be treated.
[0046] Other dosage regimens and variations are foreseeable, and
will be determined through physician guidance. It is preferred that
the mTOR inhibitor is administered by i.v. infusion or orally,
preferably in the form of tablets or capsules.
[0047] For herceptin, single doses and multiple doses are
contemplated. In one embodiment, a single loading dose of herceptin
is administered as a 90-minute intravenous infusion in a range of
about 4-5 mg/kg on day 1, followed by about 2 mg/kg per week
starting on day 8. Typically, 3 weeks is 1 cycle. From 1, to 2 to
3, weeks may be provided between cycles. Herceptin may also be
given at a dose of 6 mg/kg once every 3-4 weeks. In addition,
herceptin may also be given after completion of chemotherapy as
maintenance therapy.
[0048] For an HKI-272, it is desired that a compound of the
invention is in the form of a unit dose. Suitable unit dose forms
include tablets, capsules and powders in sachets or vials. Such
unit dose forms may contain from 0.1 to 300 mg of a compound of the
invention and preferably from 2 to 100 mg. Still further preferred
unit dosage forms contain 5 to 50 mg of a compound of the present
invention. The compounds of the present invention can be
administered at a dose range of about 0.01 to 100 mg/kg or
preferably at a dose range of 0.1 to 10 mg/kg. In one embodiment,
the compounds are administered orally from 1 to 6 times a day, more
usually from I to 4 times a day. Alternatively, the compounds may
be administered through another suitable route, e.g., intravenous.
In still another embodiment, the compounds are administered once a
week. In certain situations, dosing with the HKI-272 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 will be known to one of skill in the art; it will also be
dependent upon the form of the compound. 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.
[0049] These regimens may be repeated, or alternated, as desired.
Other dosage regimens and variations are foreseeable, and will be
determined through physician guidance.
[0050] For example, in one embodiment, the regimen further
comprises administration of a taxane, e.g., docetaxel and
paclitaxel [e.g., a suspension of paclitaxel bound to albumen
nanoparticles, which is available as Abraxane]. Paclitaxel may also
be administered on a weekly schedule, at doses 60-100 mg/m2
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.
[0051] Still other active agents may be included in a combination
with an mTOR inhibitor and herceptin, including, e.g.,
chemotherapeutic agents, such as alkylating agents; hormonal agents
(i.e., estramustine, tamoxifen, toremifene, anastrozole, or
letrozole); antibiotics (i.e., plicamycin, bleomycin, mitoxantrone,
idarubicin, dactinomycin, mitomycin, or daunorubicin); antimitotic
agents (i.e., vinblastine, vincristine, teniposide, or vinorelbine,
available as Navelbine); topoisomerase inhibitors (i.e., topotecan,
irinotecan, etoposide, or doxorubicin, e.g., CAELYX or Doxil,
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.
[0052] In one embodiment, the combination of an mTOR inhibitor and
herceptin may be further combined with antineoplastic alkylating
agents, e.g., those described in US 2002-0198137A 1. Antineoplastic
alkylating agents are roughly classified, according to their
structure or reactive moiety, into several categories which include
nitrogen mustards, such as MUSTARGEN (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.
[0053] The following are representative examples of alkylating
agents of this invention. Meclorethamine is commercially available
as an injectable (MUSTARGEN). Cyclophosphamide is commercially
available as an injectable (cyclophosphamide, lyophilized CYTOXAN,
or NEOSAR) and in oral tablets (cyclophosphamide or CYTOXAN).
Ifosfamide is commercially available as an injectable (IFEX).
Melphalan is commercially available as an injectable (ALKERAN) and
in oral tablets (ALKERAN). Chlorambucil is commercially available
in oral tablets (LEUKERAN). Thiotepa is commercially available as
an injectable (thiotepa or THIOPLEX). Mitomycin is commercially
available as an injectable (mitomycin or MUTAMYCIN). Busulfan is
commercially available as an injectable (BUSULFEX) and in oral
tablets (MYLERAN). Lomustine (CCNU) is commercially available in
oral capsules (CEENU). Carmustine (BCNU) is commercially available
as an intracranial implant (GLIADEL) and as an injectable (BICNU).
Procarbazine is commercially available in oral capsules (MATULANE).
Temozolomide is commercially available in oral capsules (TEMODAR).
Cisplatin is commercially available as an injectable (cisplatin,
PLATINOL, or PLATINOL-AQ). Carboplatin is commercially available as
an injectable (PARAPLATIN). Oxiplatin is commercially available as
ELOXATIN.
[0054] In another embodiment, a combination of the invention may
further include treatment with an antineoplastic antimetabolite,
such as is described in U.S. Patent Publication No. US
2005-0187184A1 or US 2002-0183239 A1. As used in accordance with
this invention, 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.
[0055] The following are representative examples of antimetabolites
of this invention. 5-Fluorouracil (5-FU;
5-fluoro-2,4(1H,3H)-pyrimidinedione) is commercially available in a
topical cream (FLUOROPLEX or EFUDEX), a topical solution
(FLUOROPLEX or EFUDEX), and as an injectable containing 50 mg/mL
5-fluorouracil (ADRUCIL or flurouracil). Floxuradine
(2'-deoxy-5-fluorouridine) is commercially available as an
injectable containing 500 mg/vial of floxuradine (FUDR or
floxuradine). Thioguanine (2-amino-1,7-dihydro-6-H-purine-6-thione)
is commercially available in 40 mg oral tablets (thioguanine).
Cytarabine (4-amino-1-(beta)-D-arabinofuranosyl-2(1
H)-pyrimidinone) is commercially available as a liposomal
injectable containing 10 mg/mL cytarabine (DEPOCYT) or as a liquid
injectable containing between1 mg-1 g/vial or 20 mg/mL (cytarabine
or CYTOSAR-U). Fludarabine
(9-H-Purin-6-amine,2-fluoro-9-(5-O-phosphono-(beta)-D-a-rabinofuranosyl)
is commercially available as a liquid injectable containing 50
mg/vial (FLUDARA). 6-Mercaptopurine
(1,7-dihydro-6H-purine-6-thione) is commercially available in 50 mg
oral tablets (PURINETHOL). Methotrexate (MTX;
N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glut-
amic acid) is commercially available as a liquid injectable
containing between 2.5-25 mg/mL and 20 mg-1 g/vial (methotrexate
sodium or FOLEX) and in 2.5 mg oral tablets (methotrexate sodium).
Gemcitabine (2'-deoxy-2',2'-difluorocytidine monohydrochloride
((beta)-isomer)), is commercially available as a liquid injectable
containing between 200mg -1 g/vial (GEMZAR). Capecitabine
(5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine) is
commercially available as a 150 or 500 mg oral tablet (XELODA).
Pentostatin
((R)-3-(2-deoxy-(beta)-D-erythro-pentofuranosyl)-3,6,7,-8-tetrahydroimida-
zo[4,5-d][1,3]diazepin-8-ol) is commercially available as a liquid
injectable containing 10 mg/vial (NIPENT). Trimetrexate
(2,4-diamino-5-methyl-6-[(3,4,5
-trimethoxyanilino)methyl]quinazoline mono-D-glucuronate) is
commercially available as a liquid injectable containing between
25-200 mg/vial (NEUTREXIN). Cladribine
(2-chloro-6-amino-9-(2-deoxy-(beta)-D-erythropento-furanosyl)
purine) is commercially available as a liquid injectable containing
1 mg/mL (LEUSTATIN).
[0056] 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 containing between 5-10 mg/mL or 50-350
mg/vial (leucovorin calcium or WELLCOVORIN) and as 5-25 mg oral
tablets (leucovorin calcium). Levofolinate (pharmacologically
active isomer of 5-formyltetrahydrofolic acid) is commercially
available as an injectable containing 25-75 mg levofolinate
(ISOVORIN) or as 2.5-7.5 mg oral tablets (ISOVORIN).
[0057] In another embodiment, the combination of the invention
further includes an active agent selected from among a kinase
inhibitor. Particularly desirable are multi-kinase inhibitors
target serine/threonine and receptor tyrosine kinases in both the
tumor cell and tumor vasculature. Examples of suitable kinase
inhibitors are Sorafenib (BAY 43-9006, Bayer, commercially
available as NEXAVAR), which has been granted Fast Track status by
the FDA for metastatic renal cell cancer. Another suitable
farnesyltransferase inhibitor is Zarnestra (R115777, tipifarnib).
Yet another compound is suntinib (SUTENT). Still other suitable
compounds that target Ras/Raf/MEK and/or MAP kinases include, e.g.,
avastin, ISIS 5132, and MEK inhibitors such as CI-1040 or PD
0325901.
[0058] As described herein, subtherapeutically effective amounts of
herceptin and temsirolimus may be used to achieve a therapeutic
effect when administered in combination. For example, herceptin may
be provided at dosages of 5 to 50% lower, 10 to 25% lower, or 15 to
20% lower, when provided along with temsirolimus. For example, a
resulting herceptin dosage can be from about 8 to 40 mg, or about 8
to 30 mg, or 8 to 25 mg. Subtherapeutically effective amounts of
herceptin are expected to reduce the side-effects of herceptin
treatment. The invention further provides for one or more of the
active agents in the combination of the invention 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.
[0059] The mTOR inhibitor, herceptin, HKI-272 or other active
compounds used in the combination and products of the invention may
be formulated in any suitable manner. For example, oral
formulations containing the mTOR inhibitor (and optionally, other
active compounds) useful in combination and products of this
invention may comprise any conventionally used oral forms,
including tablets, capsules, buccal forms, troches, lozenges and
oral liquids, suspensions or solutions. 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. Useful
tablet 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. Oral formulations herein 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.
Preferred oral formulations for rapamycin 42-ester with
3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid are described in
US Patent Publication No. 2004/0077677 A1, published Apr. 22,
2004.
[0060] In some cases it may be desirable to administer the
compounds directly to the airways in the form of an aerosol.
[0061] The compounds may also 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
contain a preservative to prevent the growth of microorganisms.
[0062] 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, for example, water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils. Preferred injectable
formulations for rapamycin 42-ester with
3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid are described in
U.S. Patent Publication No. 2004/0167152 A1, published Aug. 26,
2004.
[0063] For the purposes of this disclosure, transdermal
administrations are understood to 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 carried out using the present compounds, or
pharmaceutically acceptable salts thereof, in lotions, creams,
foams, patches, suspensions, solutions, and suppositories (rectal
and vaginal).
[0064] 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.
[0065] 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.
[0066] As used in this invention, the combination regimen can be
given simultaneously or can be given in a staggered regimen, with
the mTOR inhibitor being given at a different time during the
course of chemotherapy than the herceptin. 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, but that each
of the components are administered during a desired treatment
period. The agents may also be administered by different
routes.
Pharmaceutical Packs/Kits.
[0067] The invention includes 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 an mTOR inhibitor (e.g.,
temsirolimus) in unit dosage form and, optionally, one, one to
four, or more unit(s) of herceptin, and optionally, another active
agent.
[0068] In another embodiment, pharmaceutical packs contain a course
of anti-neoplastic treatment for one individual mammal comprising a
container having a unit of a rapamycin in unit dosage form, a
containing having a unit of herceptin, and optionally, a container
with another active agent. In other embodiments, the rapamycin is
rapamycin, an ester (including a 42-ester, ether (including a
42-ether), oxime, hydrazone, or hydroxylamine of rapamycin. In
another embodiment, the rapamycin is 42-O-(2-hydroxy)ethyl
rapamycin.
[0069] In another embodiment, the rapamycin is temsirolimus, and
the pack contains one or more container(s) comprising one, one to
four, or more unit(s) of temsirolimus with the components described
herein.
[0070] In some embodiments, the compositions of the invention are
in packs in a form ready for administration. In other embodiments,
the compositions of the invention 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 useful in the invention in solid form
and, optionally, a separate container with a suitable solvent or
carrier for the compound useful in the invention.
[0071] 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 will be readily apparent to one
of skill in the art.
[0072] The following examples illustrate of the uses ofthe
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 Temsirolimus (CCI-779) and Herceptin in
Trearment of Noeplasms
[0073] Dosing begins at month 1, day 1 with weekly intravenous (IV)
temsirolimus and herceptin (IV) at the dosages provided below.
[0074] Temsirolimus and herceptin can be administered
simultaneously, consecutively, or on alternative days.
[0075] Temsirolimus is administered IV weekly 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 temsirolimus
infusion.
[0076] A herceptin loading dose is administered IV weekly over a 90
minute period. Weekly doses are administered, which are typically
half the amount of the loading dose. For example, a 4 mg/kg loading
dose is typically followed by 2 mg/kg weekly doses. These amounts
may be adjusted. In one embodiment, no loading dose is required and
the same dose is administered throughout the course of treatment.
TABLE-US-00001 HERCEPTIN Temsirolimus Dose (mg/kg) (mg) 2 15 4 25 6
50
[0077] Dose adjustments and/or delays for temsirolimus, and/or
herceptin are permitted. For example, treatment may continue as
described herein for six months, with weekly doses of temsirolimus.
The herceptin may be provided on a weekly basis for a cycle, e.g.,
three weeks. Typically, 2 to 3 weeks is provided between
cycles.
[0078] In certain situations, dosing with the temsirolimus may be
delayed or discontinued for a brief period (e.g., 1, 2 or three
weeks) during the regimen. Similarly, a cycle of treatment with
herceptin may be shortened by one or more weeks, lengthened by one
or more weeks, or the period between cycles delayed or eliminated.
Such a delay or discontinuation may occur once, or more, during the
course of treatment.
EXAMPLE 2
Use of a Combination Regimen of HKI-272 and Temsirolimus (CCI-779)
in Treatment of Neoplasms
[0079] Dosing begins at month 1, day 1 with daily HKI-272 and
weekly intravenous (IV) temsirolimus at the dosages provided
below.
[0080] On month 1, day 1, HKI-272 is administered orally prior to
temsirolimus. Temsirolimus is administered following HKI-272,
preferably within 30 minutes.
[0081] Temsirolimus is administered IV weekly 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 temsirolimus
infusion.
[0082] Thereafter, HKI-272 is taken orally once daily with food,
preferably in the morning. TABLE-US-00002 HKI-272 Temsirolimus Dose
(mg) (mg) 80 15 160 25 240 50
[0083] Dose adjustments and/or delays for HKI-272 and temsirolimus
are permitted. For example, treatment may continue as described
herein for six months, with daily doses of HKI-272 and weekly doses
of temsirolimus. However, in certain situations, dosing with one or
both drugs may be delayed or discontinued for a brief period (e.g.,
1, 2 or three weeks) during the regimen course of treatment. Such a
delay or discontinuation may occur once, or more, during the course
of treatment.
EXAMPLE 3
Use of a Combination Regimen of HKI-272, Temsirolimus (CCI-779),
and Herceptin in Trearment of NEOPLASMS
[0084] Dosing begins at month 1, day1 with daily HKI-272 and weekly
intravenous (IV) temsirolimus and herceptin (IV) at the dosages
provided below.
[0085] On month 1, day 1, HKI-272 is administered orally prior to
temsirolimus. Temsirolimus and herceptin are administered following
HKI-272, preferably within 30 minutes.
[0086] Temsirolimus is administered IV weekly 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 temsirolimus
infusion.
[0087] A herceptin loading dose is administered IV weekly over a 90
minute period. Weekly doses are administered, which are typically
half the amount of the loading dose. For example, a 4 mg/kg loading
dose is typically followed by 2 mg/kg weekly doses. These amounts
may be adjusted. In one embodiment, no loading dose is required and
the same dose is administered throughout the course of
treatment.
[0088] Thereafter, HKI-272 is taken orally once daily with food,
preferably in the morning. TABLE-US-00003 HKI-272 HERCEPTIN
Temsirolimus Dose (mg) (mg/kg) (mg) 80 2 15 160 4 25 240 6 50
[0089] Dose adjustments and/or delays for HKI-272, temsirolimus,
and/or herceptin are permitted. For example, treatment may continue
as described herein for six months, with daily doses of HKI-272 and
a weekly dose of temsirolimus. The herceptin may be provided on a
weekly basis for a cycle, e.g., three weeks. Typically, 2 to 3
weeks is provided between cycles. However, in certain situations,
dosing with the HKI-272 and/or temsirolimus may be delayed or
discontinued for a brief period (e.g., 1, 2 or three weeks) during
the regimen or course of treatment. Such a delay or discontinuation
may occur once, or more, during the course of treatment.
[0090] Similarly, a cycle of treatment with herceptin may be
shortened by one or more weeks, lengthened by one or more weeks, or
the period between cycles delayed or eliminated. Such a delay or
discontinuation may occur once, or more, during the course of
treatment.
EXAMPLE 4
Use of a Combination Regimen of HKI-272 and Herceptin in Trearment
of Neoplasms
[0091] The antineoplastic activity of the HKI-272 plus herceptin
combination was confirmed in in vitro standard pharmacological test
procedure. The following briefly describes the procedure used and
the results obtained.
[0092] The combination was tested in three breast cancer cell lines
of differing genotypes. More particularly, BT474 [HER-2+
(amplified); ATCC HTB-20] and is highly sensitive to both HKI-272
and Herceptin. MDA-MB-361 [HER-2.sup.+ (non-amplified);
adenocarcinoma; ATCC HTB 27] has lower levels of HER-2 without
amplification and less sensitive to both herceptin and HKI-272.
MCF-7 [HER-2.sup.-, EGFR-; adenocarcinoma; ATCC HTB22] has no HER-2
and is resistant to both Herceptin and HKI-272.
[0093] Cells from each of these cell lines were incubated in the
presence of a range of concentrations (0.0041, 0.012, 0.037, 0.11,
0.33, 0.1, 3 .mu.g/mg) for each drug. The cells were maintained in
RPMI 1640 medium (Life Technologies, Inc., Gaithersburg, Md.)
supplemented with 10% fetal bovine serum (FBS, Life Technologies)
and 50 .mu.g/ml gentamicin (Life Technologies) under 7% CO.sub.2 at
37.degree. C. Cells were plated in 96-well microtiter dishes
(12,000 cells/well for BT474 Cells, 6000 cells/well MCF-7 Cells and
10,000 cells/well for MDA-MB-361 Cells) in 100 .mu.l RPMI 1640
medium containing 5% FBS and 50 .mu.g/ml gentamicin and incubated
overnight at 37.degree. C. Compound dilutions were prepared in the
same medium, at 2.times. final concentration, and 100 .mu.l of the
drug dilution was added to the cell-containing wells.
[0094] Serial dilutions of one compound were prepared in the
presence of a fixed dose of a second compound. Alternatively, a
checkerboard dilution series was employed. Cells were cultured for
three days in the presence of the drugs. Untreated cells were
included as controls. The percentage of surviving cells was
determined using sulforhodamine B (SRB, Sigma-Aldrich, St Louis,
Mo.), a protein binding dye. Cellular protein was precipitated in
each well by the addition of 50 .mu.l 50% cold trichloroacetic
acid. After 1 hour, the plates were washed extensively in water and
dried. SRB dye reagent (0.4% SRB in 1% acetic acid, 80 .mu.l per
well) was added and plates were kept at room temperature for ten
minutes. Plates were then washed thoroughly in 1% acetic acid and
dried. Cell-associated dye was dissolved in 10 mM Tris (150 .mu.l)
and the absorbance was read at 540 nm in a microtiter plate reader.
The concentration of compound that caused a fixed percentage
inhibition of growth was determined by plotting cell survival
(relative to untreated cells) against the compound dose.
[0095] A model for studying drug interactions has been described by
Prichard and Shipman [Antiviral Research. 14:181-206 (1990);
Prichard, Minn., et al., 1993. MacSynergy II. Version 1.0. User's
manual. University of Michigan, Ann Arbor.] This is a 3-dimensional
model: one for each drug and the third for the biological effect.
Theoretical additive interactions are calculated from the
individual dose-response curves, based on a dissimilar sites model
of additivity (Bliss independence). The calculated additive
surface, representing predicted cytotoxicity is subtracted from the
experimental surface to reveal areas of enhanced toxicity (synergy)
or reduced toxicity (antagonism). The resulting surface appears as
a horizontal plane at 0% inhibition above the calculated additive
surface, if the interaction is additive. Peaks and valleys
deviating from this plane are indicative of synergy and antagonism,
respectively. MacSynergy II, a Microsoft Excel-based software was
used to perform all calculations automatically. This spreadsheet
calculates the theoretical additive interactions, and locates and
quantifies synergistic or antagonistic interactions that are
significant at the 95% confidence levels. The results were plotted
as a 3-dimensional plot, or as a contour plot with the plane at 0%
representing additive interaction, and peaks and valleys
representing areas of synergy or antagonism, respectively, between
the two drugs.
[0096] For purposes of this study, the Pritchard and Shipman method
was modified to allow determination of the combination effects at
different levels of statistical significance (p-values 0.05, 0.01,
0.001). A p-value of 0.05 is considered significant. The method of
estimating statistical variability within each experiment was also
modified. Variability was determined across all compound
combinations, whereas in the original version, variability was
estimated separately for each compound combination. It is believed
that better estimates of the variability are obtained with the
modified approach. In general, single points of synergy or
antagonism are not considered representative of either synergistic
or antagonistic activity. Thus, single point peaks or valleys are
disregarded in the analysis. Furthermore, peaks or valleys that
occur only along single concentration of one of the compounds are
also disregarded, if no synergy or antagonism is observed at the
adjacent, flanking concentrations. Finally, all experiments are
repeated at least twice and determinations of synergy and
antagonism are made by examination of all the data.
[0097] FIGS. 1-3 provide the results from a single set of
experiments. In MDA-MB-361 cells, there is an area of antagonism at
0.11-3 .mu.g/mL herceptin for at a concentration of 0.012 .mu.g/mL
HKI-272 at the 95% confidence level. In MCF7 cells, there is an
area of synergy at 0.037-0.33 .mu.g/mL herceptin for at a
concentration of 0.11 .mu.g/mL HKI-272 at the 95% confidence level.
For the BT474 cells, there is an area of antagonism at 0.33-1
.mu.g/mL herceptin for at a concentration of 0.11 .mu.g/mL HKI-272
at the 95% confidence level. When repeated at the 99% confidence
level, no statistically significant areas of antagonism or synergy
were found. Based on the above criteria, the combination of
herceptin and HKI-272 is considered additive across all
concentrations.
[0098] The results of these standard pharmacological test
procedures derived from multiple independent experiments, indicate
that combinations of HKI-272 are not significantly antagonistic or
synergistic, but are additive over a range of concentrations. These
data support the use of the combinations in the treatment of HER2+
cancers. As these combinations contain at least two active
antineoplastic agents, the use of such combinations also provides
for the use of combinations of each of the agents in which one or
both of the agents is used at subtherapeutically effective dosages,
thereby lessening toxicity associated with the individual
chemotherapeutic agent.
[0099] 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.
* * * * *