This appliacation is divided out of Indian patent application
No. 1810/kolnp/2005
BACKGROUND OF THE INVENTION
This invention relates to the treatment of neoplasms.
Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces
hygroscopicus, which was found to have antifungal activity, particularly against
Candida albicans, both in vitro and in vivo [C. Vezina et al.. J. Antibiot. 28, 721
(1975); S.N. Sehgal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot.
31, 539 (1978); US Patent 3,929,992; and US Patent 3,993,749]. Additionally,
rapamycin alone [US Patent 4,885,171] or in combination with picibanil [US Patent
4,401,653] has been shown to have antitumor activity.
The immunosuppressive effects of rapamycin have been disclosed in FASEB
3, 3411 (1989). Cyclosporin A and FK-506, other macrocyclic molecules, also have
been shown to be effective as immunosuppressive agents, therefore useful in
preventing transplant rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); R.
Y. Calne et al., Lancet 1183 (1978); and US Patent 5,100,899]. R. Martel et al. [Can.
J. Physiol. Pharmacol. 55,48 (1977)] disclosed that rapamycin is effective in the
experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the
adjuvant arthritis model, a model for rheumatoid arthritis; and effectively inhibited
the formation of IgE-like antibodies.
Rapamycin is also useful in preventing or treating systemic lupus
erythematosus [US Patent 5,078,999], pulmonary inflammation [US Patent
5,080,899], insulin dependent diabetes mellitus [US Patent 5,321,009], skin
disorders, such as psoriasis [US Patent 5,286,730], bowel disorders [US Patent
5,286,731], smooth muscle cell proliferation and intimal thickening following
vascular injury [US Patents 5,288,711 and 5,516,781], adult T-cell
leukemia/lymphoma [European Patent Application 525,960 Al], ocular inflammation
[US Patent 5,387,589], malignant carcinomas [US Patent 5,206,018], cardiac
inflammatory disease [US Patent 5,496,832], and anemia [US Patent 5,561,138].

Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-rnethylpiopionic
acid (CCI-779) is an ester of rapamycin which has demonstrated significant
inhibitory effects on tumor growth in both in vitro and in vivo models. The
preparation and use of hydroxyesters of rapamycin, including CCI-779, are disclosed
in US Patents 5,362,718 and 6,277,983.
CCI-779 exhibits cytostatic, as opposed to cytotoxic properties, and may
delay the time to progression of tumors or tin\e to rumor recurrence. CCI-779 is
considered to have a mechanism of action that is similar to that of sirolimus. CCI-
779 binds to and forms a complex with the cytoplasmic protein FKBP, which inhibits
an enzyme, mTOR (mammalian targei 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
poliferation, 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 CCI-779 that
results in the G1-S phase block is novel for an anticancer drug.
In vitro, CCI-779 has been shown to inhibit the growth of a number of
histologically diverse tumor cells. Central nervous system (CNS) cancer, leukemia
(T-cell), breast cancer, prostate cancer, and melanoma lines were among the most
sensitive to CCI-779. The compound arrested cells in the Gl phase of the cell cycle.
In vivo studies in nude mice have demonstrated that CCI-779 has activity
against human tumor xenografts of diverse histological types. Gliomas were
particularly sensitive to CCI-779 and the compound was active in an orthotopic
glioma model in nude mice. Growth factor (platelet-derived)-induced stimulation of
a human glioblastoma cell line in vitro was markedly suppressed by CCI-779. The
growth of several human pancreatic tumors in nude mice as well as one of two breast
cancer lines studied in vivo also was inhibited by CCI-779.

DETAILED DESCRIPTION OF THE INVENTION
This invention provides the use of combinations of CCI-779 and an aromatase
inhibitor as antineoplastic combination chemotherapy. In particular, these
combinations are useful in the treatment of renal cancer, soft tissue cancer, breast
cancer, neuroendocrine tumor of the lung, cervical cancer, uterine cancer, head and
neck cancer, glioma, non-small lung cell cancer, prostate cancer, pancreatic cancer,
lymphoma, melanoma, small cell lung cancer, ovarian cancer, colon cancer,
esophageal cancer, gastric cancer, leukemia, colorectal cancer, and unknown primary
cancer. This invention also provides combinations of CCI-779 and an aromatase
inhibitor for use as antineoplastic combination chemotherapy, in which the dosage of
either CCI-779 or the aromatase inhibitor or both are used in subtherapeutically
effective dosages. Letrozole is the preferred aromatase inhibitor.
This invention also provides use of combinations of 42-O-(2-hydroxy)ethyi
rapamycin and an aromatase inhibitor as antineoplastic combination chemotherapy.
The preparation of 42-O-(2-hydroxy)ethyl rapamycin is described in US Patent
5,665,772, which is hereby incorporated by reference.
As used in accordance with this invention, the term "treatment" means
treating a mammal having a neoplastic disease by providing said mammal an
effective amount of a combination of CCI-779 and an aromatase inhibitor with the
purpose of inhibiting growth of the neoplasm in such mammal, eradication of the
neoplasm, or palliation of the mammal.
A.s used in accordance with this invention, the term "providing," with respect
to providing the combination (including simultaneous, separate or sequential
administration of the components of the combination), means either directly
administering the combination, or administering a prodrug, derivative, or analog of
one or both of the components of the combination which will form an effective
amount of the combination within the body.
Aromatase is an enzyme which converts androgens to estrone. Estrone can
subsequently be converted to estradiol, which has been linked to increased growth or
proliferation of estrogen receptor positive carcinoma. As used in accordance with
this invention, the term "aromatase inhibitor" means compounds or substances which

inhibit the activity of the enzyme aromatase. Thus the goal of using aromatase
inhibitors in chemotherapy is typically to reduce the levels of circulating estradiol, to
ultimately inhibit the growth of neoplasms that are estrogen receptor positive. There
are two types of aromatase inhibitors; steroidal (type I inhibitors) and non-steroidal
inhibitors (type II inhibitors). Examples of steroidal aromatase inhibitors include
exemestane, formestane, and atamestane, and the like. Examples of non-steroidal
aromatase inhibitors include fadrozole, letrozole, vorozole, anastrozole, YM511
[Susaki et al, J. Steroid Biochem Molec Biol, 58:89-194 (1996) and the like. When
used with CCI-779 or 42-O-(2-hydroxy)ethyl rapamycin, letrozoie is the preferred
aromatase inhibitor.
It is also preferred that the combination of CCI-779 and an aromatase
inhibitor be used in an treating estrogen receptor positive carcinoma, particularly
estrogen receptor positive breast or ovarian cancer.
The preparation of CCI-779 is described in US Patent 5,362,718, which is
hereby incorporated by reference. A regiospecific synthesis of CCI-779 is described
in US Patent 6,277,983, which is hereby incorporated by reference. Letrozole is
commercially available [e.g., as Femara® (Novartis), CGS 20267 ].
As used in this invention, the combination regimen can be given
simultaneously or can be given in a staggered regimen, with CCI-779 being given at a
different time during the course of chemotherapy than an aromatase inhibitor. This
time differential may range from several minutes, hours, days, weeks, or longer
between administration of the two agents. Therefore, the term combination 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
be administered by the same or different routes. For example, one component may be
administered orally, while the other parenterally. These combination can be
administered daily, weekly, or even once monthly. As typical for chemotherapeutic
regimens, a course of chemotherapy may be repeated several weeks later, and may
follow the same timeframe for administration of the two agents, or may be modified
based on patient response.

The combinations of the invention may be in the form of a kit of parts. The
invention therefore includes a product containing (a) CCI-779 or 42-O-(2-
hydroxy)ethyl rapamycin and (b) an aromatase inhibitor as a combined preparation
for simultaneous, separate or sequential use in treating a neoplasm in a mammal in
need thereof. The invention also includes a pharmaceutical pack containing a course
of treatment of a neoplasm for one individual mammal, wherein the pack contains (a)
units of CCI-779 or 42-O-(2-hydroxy)ethyl rapamycin in unit dosage form and (b)
units of an aromatase inhibitor in unit dosage form.
For the combination of CCI-779 and letrozole, it is preferred that both
components are provided orally, and that the initial oral dosage of CCI-779 will in the
range of about 2 to about 100 mg/day, 5 mg/day to 75 mg/day, 10 mg/day to 50
mg/day, 15 mg/day to 35 mg/day, or about 20 mg/day to 25 mg/day (on days thai ii is
provided) and the initial oral dose of letrozole will be about 0. 1 to 10 mg daily, 0.5
mg to 5 mg, or 1 to 3 mg, or about 2.5 mg (on days that it is provided).
When the combination of CCI-779 and letrozole are provided orally, it is
preferred that the CCI-779 and letrozole are provided daily, or that the CCI-779 is
provided 5 times every two weeks, while the letrozole is provided daily.
As typical with chemotherapy, 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, health of the patient, and
other concomitant disorders or treatments. After one or more treatment cycles, the
dosages can be adjusted upwards or downwards depending on the results obtained
and the side effects observed.
In providing chemotherapy, multiple agents having different modalities of
action are typically used as part of a chemotherapy "cocktail." It is anticipated that
the combinations of this invention will be used as part of a chemotherapy cocktail
that may contain one or more additional antineoplastic agents depending on the
nature of the neoplasia to be treated.
Oral formulations containing the active compounds 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, micfocrystailine cellulose, carboxymeihylcellulose calcium,
polyvinylpyrrolidone, gelatin, aiginic 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.
Particularly suitable oral formulations for rapamycin 42-ester with 3-hydroxy-
2-(hydroxymethyl)-2-methylpropionic acid are disclosed in USSN 60/411,264 and
PCT/US03/29228, which are hereby incorporated by reference. Such an oral
formulation contains a granulation prepared using a wet granulation process. The
granulation contains CCI-779, a water soluble polymer, a pH modifying agent, a
surfactant, and an antioxidant. In one embodiment, the formulation contains from 0.1
to 30%, from 0.5 to 25%, from 1 to 20%, from 5 to 15%, or from 7 to 12% (wt/wt)
CCI-779, from 0.5 to 50%, from 1 to 40%, from 5 to 35%, from 10 to 25%, or from
15 to 20% (wt/wt) water soluble polymer, from 0.5 to 10%, 1 to 8%, or 3 to 5%
(wt/wt) surfactant, and from 0.001% to 1%, 0.01% to 1%, or 0.1% to 0.5% (wt/wt)

antioxidant. However, other embodiments may contain more, or less, of these
components.
The oral formulation may also contain suitable chelating agents, fillers,
binders, surfactants, and the like to facilitate the granulation and tableting process. It
is preferred that the wet granulation be performed with a hydroalcoholic solvent
system comprising water and an alcohol, with ethanol being the preferred alcoholic
component.
Typical water soluble polymers include, but are not limited to,
polyvinylpyrrolidone (PVF), hydroxypropylmethyicellulose (HPMC), polyethylene
glycol (PEG), and cyclodextrin or mixtures thereof. It is preferred that the water-
soluble polymer is PVP, and having a molecular weight of between 2.5 and 60
kilodaltons. Any given oral formulation useful in the invention may contain multiple
ingredients of each class of component. For example, an orai formulation containing
an antioxidant may contain one or more antioxidants as the antioxidant component.
Acceptable pH modifying agents include, but are not limited to citric acid,
sodium citrate, dilute HC1, and other mild acids or bases capable of buffering a
solution containing CCI-779 to a pH in the range of about 4 to about 6. Acceptable
antioxidants include, but are not limited to, citric acid, d,1--tocopherol, BHA, BHT,
monothioglycerol, ascorbic acid, and propyl gallate. It is expected that the
antioxidants of the oral formulations used in this invention will be used in
concentrations ranging from 0.001% to 3% wt/wt Chelating agents, and other
materials capable of binding metal ions, such as ethylene diamine tetra acetic acid
(EDTA) and its salts are capable of enhancing the stability of CCI-779. Surfactants
may include polysorbate 80, sodium lauryl sulfate, sodium dodecyl sulfate, salts of
bile acids (taurocholate, glycocholate, cholate, deoxycholate, etc.) that may be
combined with lecithin. Alternatively, ethoxylated vegetable oils, such as Cremophor
EL, vitamin E tocopherol propylene glycol succinate (Vitamin E TGPS),
polyoxyethylene-polyoxypropylene block copolymers, and poloxamers. Binders,
fillers, and disintegrants such as sucrose, lactose, microcrystalline cellulose,
croscarmellose sodium, magnesium stearate, gum acacia, cholesterol, tragacanth,
stearic acid, gelatin, casein, lecithin (phosphatides), carboxymethylcellulose calcium,

carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxypropylmethycellulose phthaiate, noncrystalline
cellulose, cetosteaiyl alcohol, cetyl alcohol, cetyl esters wax, dextrates, dextrin,
lactose, dextrose, glyceryl monooleate, glyceryl monostearate, glyceryl
palmitostearate, polyoxyethylene alkyl ethers, polyethylene glycols, polyoxyethylene
castor oil derivatives, polyoxyethylene stearates, and polyvinyl alcohol, and the like
may also be incorporated into the oral formulation.
The oral formulation useful in the method of the invention can be prepared by
preparing an alcoholic solution comprising CCI-779 and an antioxidaut, and an
aqueous solution comprising a water-soluble polymer, a surfactant, and a pH
modifier, in sufficient quantity to adjust the pH of the aqueous solution to 4 to 6.
Suitable alcohols include methanol ethanol isonrnpanol, and the like, where ethanol
is the preferred alcohol. The solutions were mixed and added to a mixer containing
intragranular excipients. Alternatively, the alcoholic and aqueous solutions can be
added separately without mixing with each other. Such intragranular excipients
comprise binders and fillers to promote dissolution enhancement. Typical
intragranular excipients may include, but are not limited to, microcrystalline
cellulose, lactose, and croscarmellose sodium. The solid intragranular excipients are
granulated with the solutions in the mixer until a uniform granulation is achieved.
The mixer can be a blender with intensifying bar, a low shear granulator or a high
shear granulator. The granulation is dried in a fluid bed dryer at approximately 50°C,
and milled using a suitable milling device, such as a Fitz mill. The wet granulation
and drying can be done in a fluid bed granulator/dryer. The wet granulation can be
dried using a tray drying oven. If desired, the dried granulation can be further blended
with extragranular fillers and binders, such as microcrystalline cellulose,
croscarmellose sodium, and magnesium stearate in a blender, such as a V-blender,
before compression into tablets.
Alternatively, some of the water-soluble polymer can be contained in the
intragranular excipients, and the aqueous and alcoholic solutions added to the mixer
containing the intragranular excipients stepwise. For example, the order of addition
to the mixer may be one half of the aqueous solution, followed by the entire alcoholic

solution, and then the remainder of the aqueous solution. Other sequences of
addition are possible and permissible in these solid oral formulations.
In some cases it maybe desirable to administer the compounds directly to the
airways in the form of an aerosol.
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
glyceroi, liquid polyethylene giycols and mixtures thereof in oils. Under ordinary
conditions of storage and use, these preparations contain a preservative to prevent the
growth of microorganisms.
Ths pharmaceutical forms suitable for injectable use include sterile aqueous
solutions or dispersions and sterile powders for the extemporancous 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., glyceroi, propylene glycol and liquid polyethylene glycol), suitable mixtures
thereof, and vegetable oils.
Particularly suitable injectable formulations for rapamycin 42-ester with 3-
hydroxy-2-(hydroxymethyl)-2-methylpropionic acid are disclosed in US Patent
Application No. 10/626,943 and PCT/US03/223276, which are hereby incorporated
by reference. In this embodiment, the injectable formulation useful in the invention
provides a CCI-779 cosolvent concentrate containing an parenterally acceptable
solvent and an antioxidant as described above and a parenteral formulation
containing CCI-779, composed of CCI-779, an parenterally acceptable cosolvent, an
antioxidant, a diluent solvent, and a surfactant. Any given formulation useful in this
invention may contain multiple ingredients of each class of component. For example,
a parenterally acceptable solvent can include a non-alcoholic solvent, an alcoholic
solvent, or mixtures thereof. Examples of suitable non-alcoholic solvents include,

eg., dimethylacetamide, dimethylsulfoxide or acetonitrile, or mixtures thereof. "An
alcoholic solvent," may contain one or more alcohols as the alcoholic solvent
component of the formulation. Examples of solvents useful in the formulations
invention include, without limitation, ethanol, propylene glycol, polyethylene glycol
300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, or
mixtures thereof. These cosolvents are particularly desirable because degradation via
oxidation and lactone cleavage occurs to a lower extent for these cosolvents. Further,
ethanol and propylene glycol can be combined to produce a less flammable product,
but larger amounts of ethanol in the mixture generally result in better chemical
stability. A concentration of 30 to 100%v/v of ethanol in the mixture is preferred.
In this embodiment, the stability of CCI-779 in parenterally acceptable
alchoholic cosolvents in enhanced by addition of an antioxident to the formulation
Acceptable antioxidants include, but are not limited to, citric acid, d,1--tocopherol,
BHA, BHT, monothioglycerol, ascorbic acid, propyl gallate, and mixtures thereof.
Generally, the parenteral formulations useful in this embodiment of the invention will
contain an antioxidant component(s) in a concentration ranging from 0.001% to 1%
w/v, or 0.01% to 0.5% w/v, of the cosolvent concentrate, although lower or higher
concentrations may be desired. Of the antioxidants, d,l--tocopherol is particularly
desirable and is used at a concentration of 0.01 to 0.1% w/v with a preferred
concentration of 0.075% w/v of the cosolvent concentrate.
In certain embodiments, the antioxidant component of the formulation of the
invention also exhibits chelating activity. Examples of such chelating agents include,
e.g., citric acid, acetic acid, and ascorbic acid (which may function as both a classic
antioxidant and a chelating agent in the present formulations). Other chelating agents
include such materials as are capable of binding metal ions in solution, such as
ethylene diamine tetra acetic acid (EDTA), its salts, or amino acids such as glycine
are capable of enhancing the stability of CCI-779. In some embodiments,
components with chelating activity are included in the formulations of the invention
as the sole "antioxidant component". Typically, such metal-binding components,
when acting as chelating agents are used in the lower end of the range of
concentrations for the antioxidant component provided herein. In one example, citric

acid enhanced the stability of CCI-779 when used at a concentration of less than
0.01% w/v. Higher concentrations are less stable solutions and thus, less desirable
for products to be subject to long-term storage in liquid form. Additionally, such
chelating agents may be used in combination with other antioxidants as part of the
antioxidant component of the invention. For example, an acceptable formulation
may contain both citric acid and d,1--tocopherol. Optimal concentrations for the
selected antioxidant(s) can be readily determined by one of skill in the art, based
upon the information provided herein.
Advantageously, in certain embodiments of the parenteral formulations useful
in the invention, precipitation of CCI-779 upon dilution with aqueous infusion
solutions or blood is prevented through the use of a surfactant contained in the
diluent solution. The most important component of the diluent is a parenteraily
acceptable surfactant. One particularly desirable surfactant is polysorbate 20 or
polysorbate 80. However, one of skill in the art may readily select other suitable
surfactants from among salts of bile acids (taurocholate, glycocholate, cholate,
deoxycholate, etc.) which are optionally combined with lecithin. Alternatively,
ethoxylated vegetable oils, such as a pegylated castor oil [e.g., such as PEG-35 castor
oil which is sold, e.g., under the name Cremophor EL, BASF], vitamin E tocopherol
propylene glycol succinate (Vitamin E TGPS), and polyoxyethylene-
polyoxypropylene block copolymers can be used in the diluent as a surfactant, as well
as other members of the polysorbate family such as polysorbate 20 or 60 Other
components of the diluent may include water, ethanol, polyethylene glycol 300,
polyethylene 400, polyethylene 600, polyethylene 1000, or blends containing one or
more of these polyethylene glycols, propylene glycol and other parenteraily
acceptable cosolvents or agents to adjust solution osmolarity such as sodium chloride,
lactose, mannitol or other parenteraily acceptable sugars, polyols and electrolytes. It
is expected that the surfactant will comprise 2 to 100% w/v of the diluent solution, 5
to 80% w/v, 10 to 75% w/v, 15 to 60 % w/v, and preferably, at least 5% w/v, or at
least 10% w/v, of the diluent solution.
A parenteral formulation useful in the invention can be prepared as a single
solution, or preferably can be prepared as a cosolvent concentrate containing CCI-

779, an alcoholic solvent,, and an antioxidant, which is subsequently combined with a
diluent that contains a diluent solvent and suitable surfactant. Prior to use, the
cosolvent concentrate is mixed with a diluent comprising a diluent solvent, and a
surfactant. When CCI-779 is prepared as a cosolvent concentrate according to this
invention, the concentrate can contain concentrations of CCI-779 from 0.05 mg/mL,
from 2.5 mg/mL, from 5 mg/mL, from 10 mg/mL or from 25 mg/mL up to
approximately 50 mg/ml. The concentrate can be mixed with the diluent up to
approximately 1 part concentrate to 1 part diluent, to give parenteral formulations
having concentrations of CCI-779 from 1 mg/mL, from 5 mg/mL, from 10 mg/mL,
from 20 mg/mL, up to approximately 25 mg/ml. For example the concentration of
CCI-779 in the parenteral formulation may be from about 2.5 to 10 mg/mL. This
invention also covers the use of formulations having lesser concentrations of CCI-
779 in the cosolvent concentrate, and formulations in which one part of the
concentrate is mixed with greater than 1 part of the diluent, e.g., concentrate: diluent
in a ratio of about 1:1.5,1:2, 1:3, 1:4 ,1:5, or 1:9 v/v and so on, to CCI-779 parenteral
formulations having a CCI-779 concentration down to the lowest levels of detection.
Typically the antioxidant may comprise from about 0.0005 to 0.5% w/v of the
formulation. The surfactant may for example comprise from about 0.5% to about
10% w/v of the formulation. The alcoholic solvent may for example comprise from
about 10% to about 90% w/v of the formulation.
The parenteral formulations useful in this invention can be used to produce a
dosage form that is suitable for administration by either direct injection or by addition
to sterile infusion fluids for intravenous infusion.
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 carriedout 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.
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.
The following examples are illustrative of the present invention, but are not a
limitation thereof.
Example 1 - CCI-779 in combination with an aromatase inhibitor in a neoplasm
The combination of CCI-779 and letrozole in postmenopausal women with
locally advanced or metastatic breast cancer is being evaluated in this clinical trial.
Fifty-five patients (pts) were enrolled. Randomization is in a 1:1:1 ratio (-30
evaluable pts/arm), letrozole alone: letrozole with CCI daily (CCI daily arm):
letrozole with CCI daily for 5 days every 2 weeks (CCI intermittent arm). All pts
receive 2.5 mg letrozole daily.
Initially, 6 patients each were enrolled at high dose (HD) schedules, 25 mg
CCI daily and 75 mg CCI intermittent; 3 patients in each arm had toxicity that
resulted in dose delay/reduction or discontinuation. Thus, the protocol was amended
and doses were reduced to low dose (LD) schedules, 10 mg CCI daily and 30 mg CCI
intermittent. As of 01 Dec 2003, 12 and 23 patients were enrolled in the HD and LD
schedules, respectively. The median age was 60 yrs (range, 42-81). Safety data are

available for 12 pts treated with the HD schedules (25 mg, 6 pts; 75 mg, 6 pts), 11 pts
treated with the LD schedules (10 mg, 4 pts; 30 mg, 7 pts), and 12 pts treated with
letrozole alone. The most frequently occurring grade 3-4 CCI related toxicity was
stomatitis for the HD schedules (2/6 pts, 1/6 pts) and diarrhea for the LD schedules (0
pts, 1/7 pts). No grade 3-4 toxicities were reported for pts treated with letrozole
alone. Of 55 pts, 7 have been on study for 40+ wk. Preliminary tumor responses
(RECIST) are available for 19 evaluable pts. CCI pts (n=13) had 1 complete response
(HD schedule), 3 partial responses (HD schedules), 9 stable disease (6 pts on HD
schedules. 3 on LD schedules, incl 4 pts on HD schedules with SD >24 wk).
Letrozole-alone pts (n=6) had 2 PR and 4 SD (including 1 pt with SD >24 wk)
The combination of 10 mg CCI daily or 30 mg CCI intermittent with letrozole
showed favorable results for tolerability.
Example 2
Tablets each containg 2.5 mg of letrozole and also tablets each containing a dose of
CCI-779 as mentioned in Example 1 are packaged in a container to provide a course
of treatment for a patient.
All patents, patent applications, 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.

We Claim:
1. An antineoplastic combination comprising an antineoplastic effective amount
of a combination of CCI-779 and an aromatase inhibitor.
2. A product containing (a) CCI-779 or 42-O-(2-hydroxy)ethyl rapamycin and (b)
an aromatase inhibitor as a combined preparation for silmultaneous, separate or
sequential use in treating a neoplasm in a mammal in need thereof.
3. The product as claimed in claim 2, wherein the aromatase inhibitor is selected
from the group consisting of exemestane, formestane, atamestane, atamestane, fadrozole,
letrozole, vorozole, and anastrozole.
4. The product as claimed in claim 3, wherein the aromatase inhibitor is letrozole.
5. A pharmaceutical pack containing a course of treatment of a neoplasm for one
individual mammal, wherein the pack contains (a) units of CCI-779 or 42-O-(2-
hydroxy)ethyl rapamycin in unit dosage from and (b) units of an aromatase inhibitor in
unit dosage form.
6. A pharmaceutical pack as claimed in claim 5, wherein the aromatase inhibitor
is selected from the group consisting of exemestane, formestane, atamestane, fadrozole,
letrozole, vorozole, and anastrozole.
7. A pharmaceutical pack as claimed in claim 5, wherein the aromatase inhibitors
is letrozole.
8. A pharmaceutical composition useful in treating a neoplasm in a mammal in
need thereof, the composition comprising (a) CCI-779 or 42-O-(2-hydroxy)ethyl
rapamycin and (b) an aromatase inhibitor in combination or association with a
pharmaceutically acceptable carrier.

9. The pharmaceutical composition as claimed in claim 8, wherein the aromatase
inhibitor is selected from the group consisting of exemestane, formestane, atamestane,
fadrozole, letrozole, vorozole, and anastozole.
10. The pharmaceutical composition as claimed in claim 9, wherein the aromatase
inhibitor is letrozole.
11. An antineoplastic combination comprising an antineoplastic effective amount
of a combination of 42-O-(2-hydroxy)ethyl rapamycin and an aromatase inhibitor.
12. A pharmaceutical composition substantially as herein described particularly
with reference to the examples.

This invention discloses an antineoplastic combination comprising an antineoplastic
effective amount of a combination of CCI-779 and an aromatase inhibitor.