U.S. patent application number 13/403474 was filed with the patent office on 2013-03-07 for treatment of solid tumors with rapamycin derivatives.
The applicant listed for this patent is Heidi Lane, Terence O'Reilly, Jeanette Marjorie Wood. Invention is credited to Heidi Lane, Terence O'Reilly, Jeanette Marjorie Wood.
Application Number | 20130059877 13/403474 |
Document ID | / |
Family ID | 26245731 |
Filed Date | 2013-03-07 |
United States Patent
Application |
20130059877 |
Kind Code |
A1 |
Lane; Heidi ; et
al. |
March 7, 2013 |
TREATMENT OF SOLID TUMORS WITH RAPAMYCIN DERIVATIVES
Abstract
Rapamycin derivatives have interesting effects in the treatment
of solid tumours, optionally in combination with a chemotherapeutic
agent.
Inventors: |
Lane; Heidi; (Basel, CH)
; O'Reilly; Terence; (Basel, CH) ; Wood; Jeanette
Marjorie; (Biel-Benken, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lane; Heidi
O'Reilly; Terence
Wood; Jeanette Marjorie |
Basel
Basel
Biel-Benken |
|
CH
CH
CH |
|
|
Family ID: |
26245731 |
Appl. No.: |
13/403474 |
Filed: |
February 23, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10468520 |
Jan 27, 2004 |
|
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|
PCT/EP02/01714 |
Feb 18, 2002 |
|
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13403474 |
|
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Current U.S.
Class: |
514/291 |
Current CPC
Class: |
A61P 15/14 20180101;
A61P 35/04 20180101; A61P 11/04 20180101; A61K 33/24 20130101; A61K
45/06 20130101; A61K 33/243 20190101; A61P 17/00 20180101; A61K
31/439 20130101; A61K 31/502 20130101; A61K 31/337 20130101; A61K
31/704 20130101; A61K 39/39558 20130101; A61P 1/18 20180101; A61P
5/00 20180101; A61P 13/02 20180101; A61P 43/00 20180101; A61P 5/32
20180101; A61P 35/02 20180101; A61P 27/02 20180101; A61K 31/475
20130101; A61K 31/4545 20130101; A61P 15/00 20180101; A61P 1/04
20180101; A61P 5/28 20180101; A61P 11/00 20180101; A61P 21/00
20180101; A61K 39/3955 20130101; A61P 13/12 20180101; A61P 9/00
20180101; A61P 25/00 20180101; A61K 31/555 20130101; A61K 31/7068
20130101; A61P 1/02 20180101; A61P 13/00 20180101; A61K 31/4196
20130101; A61P 3/00 20180101; A61P 19/00 20180101; A61P 1/16
20180101; A61P 25/02 20180101; A61P 35/00 20180101; A61P 13/10
20180101; A61K 31/436 20130101; A61K 31/451 20130101; A61P 11/02
20180101; A61K 31/5685 20130101; A61K 31/366 20130101; A61K 31/4745
20130101; A61P 27/16 20180101; A61K 31/58 20130101; A61K 31/436
20130101; A61K 2300/00 20130101; A61K 31/436 20130101; A61K 31/4196
20130101; A61K 31/475 20130101; A61K 2300/00 20130101; A61K 33/24
20130101; A61K 2300/00 20130101; A61K 31/337 20130101; A61K 2300/00
20130101; A61K 31/7068 20130101; A61K 2300/00 20130101; A61K 31/704
20130101; A61K 2300/00 20130101; A61K 31/502 20130101; A61K 2300/00
20130101; A61K 31/555 20130101; A61K 2300/00 20130101; A61K 31/5685
20130101; A61K 2300/00 20130101; A61K 31/4545 20130101; A61K
2300/00 20130101; A61K 31/4196 20130101; A61K 2300/00 20130101;
A61K 31/451 20130101; A61K 2300/00 20130101; A61K 31/366 20130101;
A61K 2300/00 20130101; A61K 31/58 20130101; A61K 2300/00 20130101;
A61K 33/243 20190101; A61K 2300/00 20130101 |
Class at
Publication: |
514/291 |
International
Class: |
A61K 31/436 20060101
A61K031/436; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 19, 2001 |
GB |
0104072.4 |
Oct 17, 2001 |
GB |
0124957.2 |
Claims
1-10. (canceled)
11. A method for inhibiting growth of solid tumors of the pancreas
in a subject, said method consisting of administering to said
subject a therapeutically effective amount of a compound of formula
I ##STR00002## wherein R.sub.1 is CH.sub.3, R.sub.2 is
--CH.sub.2--CH.sub.2--OH, and X is .dbd.O.
12. The method of claim 11 wherein the solid tumor of the pancreas
has metastasized.
13. The method of claim 11 wherein the compound of formula I is
administered orally.
14. The method of claim 11 wherein the compound of formula I is
administered at a daily dose range of from about 0.1 to 25 mg, as a
single dose or in divided doses.
15. The method of claim 11 wherein the compound of formula I is
administered in a unit dosage form of from about 0.05 to 12.5
mg.
16. The method of claim 11 wherein the compound of formula I is
administered in a unit dosage form of from about 0.25 to 10 mg.
17. The method of claim 11 wherein the compound of formula I is
administered in a unit dosage form of 10 mg.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 10/468,520, filed Jan. 27, 2004, which is a 371 application of
PCT/EP2002/01714, filed Feb. 18, 2002, which in its entirety is
herein incorporated by reference.
[0002] The present invention relates to a new use, in particular a
new use for a compound group comprising rapamycin and derivatives
thereof.
[0003] Rapamycin is a known macrolide antibiotic produced by
Streptomyces hygroscopicus. Suitable derivatives of rapamycin
include e.g. compounds of
##STR00001##
wherein R.sub.1 is CH.sub.3 or C.sub.3-6alkynyl,
R.sub.2 is H or --CH.sub.2--CH.sub.2--OH, and
X is .dbd.O, (H,H) or (H.sub.2OH)
[0004] provided that R.sub.2 is other than H when X is .dbd.O and
R.sub.1 is CH.sub.3.
[0005] Compounds of formula I are disclosed e.g. in U.S. Pat. Nos.
5,665,772; 6,440,990; 5,985,890; and 6,200,985, which are
incorporated herein by reference. They may be prepared as disclosed
or by analogy to the procedures described in these references.
[0006] Preferred compounds are 32-deoxorapamycin,
16-pent-2-ynyloxy-32-deoxorapamycin,
16-pent-2-ynyloxy-32(S)-dihydro-rapamycin,
16-pent-2-ynyloxy-32(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin
and, more preferably, 40-O-(2-hydroxyethyl)-rapamycin (referred
thereafter as Compound A), disclosed as Example 8 in U.S. Pat. Nos.
5,665,772 and 6,440,990.
[0007] Compounds of formula I have, on the basis of observed
activity, e.g. binding to macrophilin-12 (also known as FK-506
binding protein or FKBP-12), e.g. as described in WO 94/09010, WO
95/16691 or WO 96/41807, been found to be useful e.g. as
immunosuppressant, e.g. in the treatment of acute allograft
rejection. It has now been found that Compounds of formula I have
potent antiproliferative properties which make them useful for
cancer chemotherapy, particularly of solid tumors, especially of
advanced solid tumors. There is still the need to expand the
armamentarium of cancer treatment of solid tumors, especially in
cases where treatment with anticancer compounds is not associated
with disease regression or stabilization.
[0008] In accordance with the particular findings of the present
invention, there is provided: [0009] 1.1 A method for treating
solid tumors in a subject in need thereof, comprising administering
to said subject a therapeutically effective amount of a compound of
formula I. [0010] 1.2 A method for inhibiting growth of solid
tumors in a subject in need thereof, comprising administering to
said subject a therapeutically effective amount of a compound of
formula I. [0011] 1.3 A method for inducing tumor regression, e.g.
tumor mass reduction, in a subject in need thereof, comprising
administering to said subject a therapeutically effective amount of
a compound of formula I. [0012] 1.4 A method for treating solid
tumor invasiveness or symptoms associated with such tumor growth in
a subject in need thereof, comprising administering to said subject
a therapeutically effective amount of a compound of formula I.
[0013] 1.5 A method for preventing metastatic spread of tumours or
for preventing or inhibiting growth of micrometastasis in a subject
in need thereof, comprising administering to said subject a
therapeutically effective amount of a compound of formula I.
[0014] By "solid tumors" are meant tumors and/or metastasis
(whereever located) other than lymphatic cancer, e.g. brain and
other central nervous system tumors (eg. tumors of the meninges,
brain, spinal cord, cranial nerves and other parts of central
nervous system, e.g. glioblastomas or medulla blastomas); head
and/or neck cancer; breast tumors; circulatory system tumors (e.g.
heart, mediastinum and pleura, and other intrathoracic organs,
vascular tumors and tumor-associated vascular tissue); excretory
system tumors (e.g. kidney, renal pelvis, ureter, bladder, other
and unspecified urinary organs); gastrointestinal tract tumors
(e.g. oesophagus, stomach, small intestine, colon, colorectal,
rectosigmoid junction, rectum, anus and anal canal), tumors
involving the liver and intrahepatic bile ducts, gall bladder,
other and unspecified parts of biliary tract, pancreas, other and
digestive organs); head and neck; oral cavity (lip, tongue, gum,
floor of mouth, palate, and other parts of mouth, parotid gland,
and other parts of the salivary glands, tonsil, oropharynx,
nasopharynx, pyriform sinus, hypopharynx, and other sites in the
lip, oral cavity and pharynx); reproductive system tumors (e.g.
vulva, vagina, Cervix uteri, Corpus uteri, uterus, ovary, and other
sites associated with female genital organs, placenta, penis,
prostate, testis, and other sites associated with male genital
organs); respiratory tract tumors (e.g. nasal cavity and middle
ear, accessory sinuses, larynx, trachea, bronchus and lung, e.g.
small cell lung cancer or non-small cell lung cancer); skeletal
system tumors (e.g. bone and articular cartilage of limbs, bone
articular cartilage and other sites); skin tumors (e.g. malignant
melanoma of the skin, non-melanoma skin cancer, basal cell
carcinoma of skin, squamous cell carcinoma of skin, mesothelioma,
Kaposi's sarcoma); and tumors involving other tissues incluing
peripheral nerves and autonomic nervous system, connective and soft
tissue, retroperitoneum and peritoneum, eye and adnexa, thyroid,
adrenal gland and other endocrine glands and related structures,
secondary and unspecified malignant neoplasm of lymph nodes,
secondary malignant neoplasm of respiratory and digestive systems
and secondary malignant neoplasm of other sites.
[0015] Where hereinbefore and subsequently a tumor, a tumor
disease, a carcinoma or a cancer is mentioned, also metastasis in
the original organ or tissue and/or in any other location are
implied alternatively or in addition, whatever the location of the
tumor and/or metastasis is.
[0016] In a series of further specific or alternative embodiments,
the present invention also provides [0017] 1.6 A method for the
treatment of a disease associated with deregulated angiogenesis in
a subject in need thereof, comprising administering to said subject
a therapeutically effective amount of rapamycin or a derivative
thereof, e.g. CCI779, ABT578 or a compound of formula I. [0018] 1.7
A method for inhibiting or controlling deregulated angiogenesis in
a subject in need thereof, comprising administering to said subject
a therapeutically effective amount of rapamycin or a derivative
thereof, e.g. CCI779, ABT578 or a compound of formula I. [0019] 1.8
A method for enhancing the activity of a chemotherapeutic agent or
for overcoming resistance to a chemotherapeutic agent in a subject
in need thereof, comprising administering to said subject a
therapeutically effective amount of rapamycin or a derivative
thereof, e.g. CCI779, ABT578 or a compound of formula I, either
concomitantly or sequentially with said chemotherapeutic agent.
[0020] 1.9 A method according to 1.8 wherein the chemotherapeutic
agent is an inhibitor of signal transduction pathways directed
either against host cells or processes involved in tumor formation
and/or metastases formation or utilised by tumour cells for
proliferation, survival, differentiation or development of drug
resistance. [0021] 1.10 A method as indicated above, wherein
rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a
compound of formula I is administered intermittently.
[0022] CCI779 is a rapamycin derivative, i.e.
40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin or a
pharmaceutically acceptable salt thereof, and is disclosed e.g. in
U.S. Pat. No. 5,362,718. ABT578 is a 40-substituted rapamycin
derivative further comprising a diene reduction.
[0023] Examples of diseases associated with deregulated
angiogenesis include without limitation e.g. neoplastic diseases,
e.g. solid tumors. Angiogenesis is regarded as a prerequisite for
those tumors which grow beyond a certain diameter, e.g. about 1-2
mm.
[0024] In a series of further specific or alternative embodiments,
the present invention also provides: [0025] 2.1 A compound of
formula I for use in any method as defined under 1.1 to 1.5 above.
[0026] 2.2 Rapamycin or a derivative thereof, e.g. CCI779, ABT578
or a compound of formula I for use in any method as defined under
1.6 to 1.10 above or 7 below. [0027] 3.1 A compound of formula I
for use in the preparation of a pharmaceutical composition for use
in any method as defined under 1.1 to 1.5 above. [0028] 3.2
Rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a
compound of formula I for use in the preparation of a
pharmaceutical composition for use in any method as defined under
1.6 to 1.10 above or 7 below. [0029] 4.1 A pharmaceutical
composition for use in any method as defined under 1.1 to 1.5 above
comprising a compound of formula I together with one or more
pharmaceutically acceptable diluents or carriers therefor. [0030]
4.2 A pharmaceutical composition for use in any method as defined
under 1.6 to 1.10 above or 7 below comprising rapamycin or a
derivative thereof, e.g. CCI779, ABT578 or a compound of formula I,
e.g. Compound A, together with one or more pharmaceutically
acceptable diluents or carriers therefor. [0031] 5.1 A
pharmaceutical combination comprising a) a first agent which is
rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a
compound of formula I, e.g. Compound A, and b) a co-agent which is
a chemotherapeutic agent, e.g. as defined hereinafter. [0032] 5.2 A
pharmaceutical combination comprising an amount of a) a first agent
which is rapamycin or a derivative thereof, e.g. CCI779, ABT578 or
a compound of formula I, e.g. Compound A, and b) a co-agent which
is a chemotherapeutic agent selected from the compounds defined
under paragraph (iv) or (v) below, to produce a synergistic
therapeutic effect. [0033] 6. A method as defined above comprising
co-administration, e.g. concomitantly or in sequence, of a
therapeutically effective amount of rapamycin or a derivative
thereof, e.g. CCI779, ABT578 or a compound of formula I, e.g.
Compound A, and a second drug substance, said second drug substance
being a chemotherapeutic agent, e.g. as indicated hereinafter.
[0034] 7. A method for treating post-transplant lymphoproliferative
disorders or a lymphatic cancer, e.g. for treating tumor
invasiveness or symptoms associated with such tumor growth in a
subject in need thereof, comprising co-administering to said
subject, e.g. concomitantly or in sequence, of rapamycin or a
derivative thereof, e.g. CCI779, ABT578 or a compound of formula I,
e.g. Compound A, and a second drug substance, said second drug
substance being a chemotherapeutic agent, e.g. as indicated
hereinafter.
[0035] By "lymphatic cancer" are meant e.g. tumors of blood and
lymphatic system (e.g. Hodgkin's disease, Non-Hodgkin's lymphoma,
Burkitt's lymphoma, AIDS-related lymphomas, malignant
immunoproliferative diseases, multiple myeloma and malignant plasma
cell neoplasms, lymphoid leukemia, myeloid leukemia, acute or
chronic lymphocytic leukemia, monocytic leukemia, other leukemias
of specified cell type, leukemia of unspecified cell type, other
and unspecified malignant neoplasms of lymphoid, haematopoietic and
related tissues, for example diffuse large cell lymphoma, T-cell
lymphoma or cutaneous T-cell lymphoma).
[0036] By the term "chemotherapeutic agent" is meant especially any
chemotherapeutic agent other than rapamycin or a derivative
thereof. It includes but is not limited to, [0037] i. an aromatase
inhibitor, [0038] ii. an antiestrogen, an anti-androgen (especially
in the case of prostate cancer) or a gonadorelin agonist, [0039]
iii. a topoisomerase I inhibitor or a topoisomerase II inhibitor,
[0040] iv. a microtubule active agent, an alkylating agent, an
antineoplastic antimetabolite or a platin compound, [0041] v. a
compound targeting/decreasing a protein or lipid kinase activity or
a protein or lipid phosphatase activity, a further anti-angiogenic
compound or a compound which induces cell differentiation
processes, [0042] vi. a bradykinin 1 receptor or an angiotensin II
antagonist, [0043] vii. a cyclooxygenase inhibitor, a
bisphosphonate, a histone deacetylase inhibitor, a heparanase
inhibitor (prevents heparan sulphate degradation), e.g. PI-88, a
biological response modifier, preferably a lymphokine or
interferons, e.g. interferon .gamma., an ubiquitination inhibitor,
or an inhibitor which blocks anti-apoptotic pathways, [0044] viii.
an inhibitor of Ras oncogenic isoforms, e.g. H-Ras, K-Ras or N-Ras,
or a farnesyl transferase inhibitor, e.g. L-744,832 or DK8G557,
[0045] ix. a telomerase inhibitor, e.g. telomestatin, [0046] x. a
protease inhibitor, a matrix metalloproteinase inhibitor, a
methionine aminopeptidase inhibitor, e.g. bengamide or a derivative
thereof, or a proteosome inhibitor, e.g. PS-341.
[0047] The term "aromatase inhibitor" as used herein relates to a
compound which inhibits the estrogen production, i.e. the
conversion of the substrates androstenedione and testosterone to
estrone and estradiol, respectively. The term includes, but is not
limited to steroids, especially atamestane, exemestane and
formestane and, in particular, non-steroids, especially
aminoglutethimide, roglethimide, pyridoglutethimide, trilostane,
testolactone, ketokonazole, vorozole, fadrozole, anastrozole and
letrozole. Exemestane can be administered, e.g., in the form as it
is marketed, e.g. under the trademark AROMASIN.TM.. Formestane can
be administered, e.g., in the form as it is marketed, e.g. under
the trademark LENTARON.TM.. Fadrozole can be administered, e.g., in
the form as it is marketed, e.g. under the trademark AFEMA.TM..
Anastrozole can be administered, e.g., in the form as it is
marketed, e.g. under the trademark ARIMIDEX.TM.. Letrozole can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark FEMARA.TM. or FEMAR.TM. Aminoglutethimide can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark ORIMETEN.TM.. A combination of the invention comprising a
chemotherapeutic agent which is an aromatase inhibitor is
particularly useful for the treatment of hormone receptor positive
tumors, e.g. breast tumors.
[0048] The term "antiestrogen" as used herein relates to a compound
which antagonizes the effect of estrogens at the estrogen receptor
level. The term includes, but is not limited to tamoxifen,
fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can
be administered, e.g., in the form as it is marketed, e.g. under
the trademark NOLVADEX.TM.. Raloxifene hydrochloride can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark EVISTA.TM.. Fulvestrant can be formulated as disclosed in
U.S. Pat. No. 4,659,516 or it can be administered, e.g., in the
form as it is marketed, e.g. under the trademark FASLODEX.TM.. A
combination of the invention comprising a chemotherapeutic agent
which is an antiestrogen is particularly useful for the treatment
of estrogen receptor positive tumors, e.g. breast tumors.
[0049] The term "anti-androgen" as used herein relates to any
substance which is capable of inhibiting the biological effects of
androgenic hormones and includes, but is not limited to,
bicalutamide (CASODEX.TM.), which can be formulated, e.g. as
disclosed in U.S. Pat. No. 4,636,505.
[0050] The term "gonadorelin agonist" as used herein includes, but
is not limited to abarelix, goserelin and goserelin acetate.
Goserelin is disclosed in U.S. Pat. No. 4,100,274 and can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark ZOLADEX.TM.. Abarelix can be formulated, eg. as disclosed
in U.S. Pat. No. 5,843,901.
[0051] The term "topoisomerase I inhibitor" as used herein
includes, but is not limited to topotecan, irinotecan,
9-nitrocamptothecin and the macromolecular camptothecin conjugate
PNU-166148 (compound A1 in WO99/17804). Irinotecan can be
administered, e.g. in the form as it is marketed, e.g. under the
trademark CAMPTOSAR.TM.. Topotecan can be administered, e.g., in
the form as it is marketed, e.g. under the trademark
HYCAMTIN.TM..
[0052] The term "topoisomerase II inhibitor" as used herein
includes, but is not limited to the anthracyclines such as
doxorubicin (including liposomal formulation, e.g. CAELYX.TM.),
daunorubicin, epirubicin, idarubicin and nemorubicin, the
anthraquinones mitoxantrone and losoxantrone, and the
podophillotoxines etoposide and teniposide. Etoposide can be
administered, e.g. in the form as it is marketed, e.g. under the
trademark ETOPOPHOS.TM.. Teniposide can be administered, e.g. in
the form as it is marketed, e.g. under the trademark VM
26-BRISTOL.TM. Doxorubicin can be administered, e.g. in the form as
it is marketed, e.g. under the trademark ADRIBLASTIN.TM..
Epirubicin can be administered, e.g. in the form as it is marketed,
e.g. under the trademark FARMORUBICIN.TM.. Idarubicin can be
administered, e.g. in the form as it is marketed, e.g. under the
trademark ZAVEDOS.TM.. Mitoxantrone can be administered, e.g. in
the form as it is marketed, e.g. under the trademark
NOVANTRON.TM..
[0053] The term "microtubule active agent" relates to microtubule
stabilizing and microtubule destabilizing agents including, but not
limited to taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids,
e.g., vinblastine, especially vinblastine sulfate, vincristine
especially vincristine sulfate, and vinorelbine, discodermolides
and epothilones and derivatives thereof, e.g. epothilone B or a
derivative thereof. Paclitaxel may be administered e.g. in the form
as it is marketed, e.g. TAXOL.TM.. Docetaxel can be administered,
e.g., in the form as it is marketed, e.g. under the trademark
TAXOTERE.TM.. Vinblastine sulfate can be administered, e.g., in the
form as it is marketed, e.g. under the trademark VINBLASTIN R.P.TM.
Vincristine sulfate can be administered, e.g., in the form as it is
marketed, e.g. under the trademark FARMISTIN.TM.. Discodermolide
can be obtained, e.g., as disclosed in U.S. Pat. No. 5,010,099.
[0054] The term "alkylating agent" as used herein includes, but is
not limited to cyclophosphamide, ifosfamide, melphalan or
nitrosourea (BCNU or Gliadel.TM.). Cyclophosphamide can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark CYCLOSTIN.TM.. Ifosfamide can be administered, e.g., in
the form as it is marketed, e.g. under the trademark
HOLOXAN.TM..
[0055] The term "antineoplastic antimetabolite" includes, but is
not limited to 5-fluorouracil, capecitabine, gemcitabine,
methotrexate and edatrexate. Capecitabine can be administered,
e.g., in the form as it is marketed, e.g. under the trademark
XELODA.TM.. Gemcitabine can be administered, e.g., in the form as
it is marketed, e.g. under the trademark GEMZAR.TM..
[0056] The term "platin compound" as used herein includes, but is
not limited to carboplatin, cis-platin and oxaliplatin. Carboplatin
can be administered, e.g., in the form as it is marketed, e.g.
under the trademark CARBOPLAT.TM.. Oxaliplatin can be administered,
e.g., in the form as it is marketed, e.g. under the trademark
ELOXATIN.TM..
[0057] The term "compounds targeting/decreasing a protein or lipid
kinase activity or further anti-angiogenic compounds" as used
herein includes, but is not limited to protein tyrosine kinase
and/or serine and/or threonine kinase inhibitors or lipid kinase
inhibitors, e.g. compounds targeting, decreasing or inhibiting the
activity of the epidermal growth factor family of receptor tyrosine
kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers), the
vascular endothelial growth factor family of receptor tyrosine
kinases (VEGFR), the platelet-derived growth factor-receptors
(PDGFR), the fibroblast growth factor-receptors (FGFR), the
insulin-like growth factor receptor 1 (IGF-1R), the Trk receptor
tyrosine kinase family, the Axl receptor tyrosine kinase family,
the Ret receptor tyrosine kinase, the Kit/SCFR receptor tyrosine
kinase, members of the c-Abl family and their gene-fusion products
(e.g. BCR-Abl), members of the protein kinase C (PKC) and Raf
family of serine/threonine kinases, members of the MEK, SRC, JAK,
FAK, PDK or PI(3) kinase family, or of the PI(3)-kinase-related
kinase family, and/or members of the cyclin-dependent kinase family
(CDK) and anti-angiogenic compounds having another mechanism for
their activity, e.g. unrelated to protein or lipid kinase
inhibition.
[0058] Compounds which target, decrease or inhibit the activity of
VEGFR are especially compounds, proteins or antibodies which
inhibit the VEGF receptor tyrosine kinase, inhibit a VEGF receptor
or bind to VEGF, and are in particular those compounds, proteins or
monoclonal antibodies generically and specifically disclosed in WO
98/35958, e.g. 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine
or a pharmaceutically acceptable salt thereof, e.g. the succinate,
or in WO 00109495, WO 00/27820, WO 00/59509, WO 98/11223, WO
00/27819 and EP 0 769 947; those as described by M. Prewett et al
in Cancer Research 59 (1999) 5209-5218, by F. Yuan et al in Proc.
Natl. Acad. Sci. USA, vol. 93, pp. 14765-14770, December 1996, by
Z. Zhu et al in Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti
et al in Toxicologic Pathology, Vol. 27, no. 1, pp 14-21, 1999; in
WO 00/37502 and WO 94/10202; Angiostatin.TM., described by M. S.
O'Reilly et al, Cell 79, 1994, 315-328; Endostatin.TM., described
by M. S. O'Reilly et al, Cell 88, 1997, 277-285; anthranilic acid
amides; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF antibodies or
anti-VEGF receptor antibodies, e.g. RhuMab.
[0059] By antibody is meant intact monoclonal antibodies,
polyclonal antibodies, multispecific antibodies formed from at
least 2 intact antibodies, and antibodies fragments so long as they
exhibit the desired biological activity.
[0060] Compounds which target, decrease or inhibit the activity of
the epidermal growth factor receptor family are especially
compounds, proteins or antibodies which inhibit members of the EGF
receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3
and ErbB4 or bind to EGF or EGF related ligands, and are in
particular those compounds, proteins or monoclonal antibodies
generically and specifically disclosed in WO 97/02266, e.g. the
compound of ex. 39, or in EP 0 564 409, WO 99/03854, EP 0520722, EP
0 566 226, EP 0 787 722, EP 0 837 063, U.S. Pat. No. 5,747,498, WO
98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO
96/30347 (e.g. compound known as CP 358774), WO 96/33980 (e.g.
compound ZD 1839) and WO 95/03283 (e.g. compound ZM105180); e.g.
trastuzumab (Herpetin.RTM.), cetuximab, Iressa, OSI-774, CI-1033,
EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or
E7.6.3.
[0061] Compounds which target, decrease or inhibit the activity of
PDGFR are especially compounds which inhibit the PDGF receptor,
e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib.
[0062] Compounds which target, decrease or inhibit the activity of
c-Abl family members and their gene fusion products, e.g. a
N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib; PD180970;
AG957; or NSC 680410.
[0063] Compounds which target, decrease or inhibit the activity of
protein kinase C, Raf, MEK, SRC, JAK, FAK and PDK family members,
or PI(3) kinase or PI(3) kinase-related family members, and/or
members of the cyclin-dependent kinase family (CDK) are especially
those staurosporine derivatives disclosed in EP 0 296 110, e.g.
midostaurin; examples of further compounds include e.g. UCN-01,
safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO
318220 and RO 320432; GO 6976; Isis 3521; or LY333531/LY379196.
[0064] Further anti-angiogenic compounds are e.g. thalidomide
(THALOMID) and TNP-470.
[0065] Compounds which target, decrease or inhibit the activity of
a protein or lipid phosphatase are e.g. inhibitors of phosphatase
1, phosphatase 2A, PTEN or CDC25, e.g. okadaic acid or a derivative
thereof.
[0066] Compounds which induce cell differentiation processes are
e.g. retinoic acid, .alpha.-, .gamma.- or .delta.-tocopherol or
.alpha.-, .gamma.- or .delta.-tocotrienol.
[0067] The term cyclooxygenase inhibitor as used herein includes,
but is not limited to, e.g. celecoxib (Celebrex.RTM.), rofecoxib
(Vioxx.RTM.), etoricoxib, valdecoxib or a
5-alkyl-2-arylaminophenylacetic acid, e.g.
5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid.
[0068] The term "histone deacetylase inhibitor" as used herein
includes, but is not limited to MS-27-275, SAHA, pyroxamide,
FR-901228 or valproic acid.
[0069] The term "bisphosphonates" as used herein includes, but is
not limited to, etridonic, clodronic, tiludronic, pamidronic,
alendronic, ibandronic, risedronic and zoledronic acid. "Etridonic
acid" can be administered, e.g., in the form as it is marketed,
e.g. under the trademark DIDRONEL.TM.. "Clodronic acid" can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark BONEFOS.TM.. "Tiludronic acid" can be administered, e.g.,
in the form as it is marketed, e.g. under the trademark SKELID.TM..
"Pamidronic acid" can be administered, e.g. in the form as it is
marketed, e.g. under the trademark AREDIA.TM.. "Alendronic acid"
can be administered, e.g., in the form as it is marketed, e.g.
under the trademark FOSAMAX.TM.. "Ibandronic acid" can be
administered, e.g., in the form as it is marketed, e.g. under the
trademark BONDRANAT.TM.. "Risedronic acid" can be administered,
e.g., in the form as it is marketed, e.g. under the trademark
ACTONEL.TM.. "Zoledronic acid" can be administered, e.g. in the
form as it is marketed, e.g. under the trademark ZOMETA.TM.
[0070] The term "matrix metalloproteinase inhibitor" as used herein
includes, but is not limited to collagen peptidomimetic and
nonpetidomimetic inhibitors, tetracycline derivatives, e.g.
hydroxamate peptidomimetic inhibitor batimastat and its orally
bioavailable analogue marimastat, prinomastat, BMS-279251, BAY
12-9566, TAA211 or AAJ996.
[0071] In each case where citations of patent applications or
scientific publications are given, the subject-matter relating to
the compounds is hereby incorporated into the present application
by reference. Comprised are likewise the pharmaceutically
acceptable salts thereof, the corresponding racemates,
diastereoisomers, enantiomers, tautomers as well as the
corresponding crystal modifications of above disclosed compounds
where present, e.g. solvates, hydrates and polymorphs, which are
disclosed therein. The compounds used as active ingredients in the
combinations of the invention can be prepared and administered as
described in the cited documents, respectively. Also within the
scope of this invention is the combination of more than two
separate active ingredients as set forth above, i.e. a
pharmaceutical combination within the scope of this invention could
include three active ingredients or more. Further both the first
agent and the co-agent are not the identical ingredient.
[0072] Utility of the compounds of formula I in treating solid
tumors as hereinabove specified, may be demonstrated in animal test
methods as well as in clinic, for example in accordance with the
methods hereinafter described.
A. In Vitro
[0073] A.1 Antiproliferative Activity in Combination with Other
Agents
[0074] A cell line, e.g. the compound A resistant A549 line
(IC.sub.50 in low nM range) versus the comparative Compound A
resistant KB-31 and HCT116 lines (IC.sub.50 in the .mu.M range), is
added to 96-well plates (1,500 cells/well in 100 .mu.l medium) and
incubated for 24 hr. Subsequently, a two-fold dilution series of
each compound (Compound of formula I or a known chemotherapeutic
agent) is made in separate tubes (starting at 8.times. the
IC.sub.50 of each compound) either alone or in paired combinations,
and the dilutions are added to the wells. The cells are then
re-incubated for 3 days. Methylene blue staining is performed on
day 4 and the amount of bound dye (proportional to the number of
surviving cells that bind the dye) determined. IC.sub.50s are
subsequently determined using the Calcusyn program, which provides
a measure of the interaction, namely the so-called non-exclusive
combination index (CI), where: CI.about.1=the interaction is nearly
additive; 0.85-0.9=slight synergism; <0.85=synergy. In this
assay, the compounds of formula I show interesting
antiproliferative activity in combination with another
chemotherapeutic agent. For example the following CI values are
obtained with a combination of Compound A and cisplatinum,
paclitaxel, gemcitabine and doxorubicin, showing synergistic
effects.
TABLE-US-00001 CI Cell line Cisplatinum Paclitaxel Gemcitabine
Doxorubicin KB-31 0.74 0.9 0.79 0.7 A549 0.47 0.74 0.76 0.64 HCT116
0.47 0.3 0.9 0.52
Furthermore, in this assay, Compound A potentiates the loss of A549
cell viability and cell death when it is used in combination with
gemcitabine.
A.2 Antiangiogenic Activity
[0075] In vitro assay of the antiproliferative activity of
rapamycin or a derivative thereof, e.g. Compound A, against human
umbilical vein endothelial cells (HUVECs) demonstrates IC.sub.50
values of 120.+-.22 pM and 841.+-.396, and >10 000 pM for VEGF-
and bFGF- and FBS-stimulated proliferation, respectively.
Additionally, no significant effects of Compound A on
bFGF-stimulated normal human dermal fibroblast (NHDF) proliferation
are observed over the same concentration range. These results
indicate that Compound A inhibits the proliferation of HUVECs,
being particularly potent against the VEGF-induced proliferation,
VEGF being a key pro-angiogenic factor.
B. In Vivo
[0076] In the following assays, antitumor activity is expressed as
T/C % (mean increase in tumor volumes of treated animals divided by
the mean increase of tumor volumes of control animals multiplied by
100) and % regressions (tumor volume minus initial tumor volume
divided by the initial tumor volume and multiplied by 100).
B.1 Activity in A549 Human Lung Tumor Xenografts
[0077] Fragments of A549 tumors (approx. 25 mg; derived from Cell
line CCL 185, ATCC, Rockville Md., USA) are transplanted
subcutaneously into the left flank of BALB/c nude mice. Treatment
is started on day 7 or day 12 following tumor transplantation. The
compound to be tested is administered p.o. once per day from day
7/12 to day 38/55, respectively. In this assay, when administered
at a daily dose ranging from 0.1 mg/kg to 2.5 mg/kg, the compounds
of formula I exhibit dose-dependent inhibition of tumor growth; for
example in one representative experiment Compound A when
administered at a dose of 2.5 mg/kg results in persisting
regressions (41%); a dose of 0.5 mg/kg results in transient
regressions (38% on day 17), with a final T/C of 16%, and a dose of
0.1 mg/kg slows tumor growth resulting in a final T/C of 43% (T/C
for control animals is 100%).
B.2 Activity in KB-31 Human Epidermoid Tumor Xenografts
[0078] Fragments of KB-31 tumors (approx. 25 mg; derived from the
cell lines obtained from Roswell Park Memorial Institute Buffalo,
N.Y., USA) are transplanted subcutaneously into the left flank of
BALB/c nude mice. Treatment is started on day 7 or on day 10
following tumor transplantation. The compound to be tested is
administered p.o. once per day from day 7/10 to day 25/35,
respectively. Antitumor activity is expressed as T/C % as indicated
above. In this assay, when administered at a daily dose ranging
from 0.5 mg/kg to 2.5 mg/kg, the compounds of formula I inhibit
tumor growth; for example in one representative experiment Compound
A when administered at a dose of 2.5 mg/kg/day results in a final
T/C value of 25% (T/C for control animals is 100%).
B.3 Activity in CA20948 Rat Pancreatic Tumors
[0079] Tumors are established in male Lewis rats by subcutaneous
injection of CA20948 tumor cell suspension derived from donor rats
into the left flank. Treatment is started on day 4 post
inoculation. The compound to be tested is administered p.o. once
per day (6 days a week) from day 4 to day 9-15 post inoculation.
Antitumor activity is expressed as T/C % as indicated above. In
this assay, when administered at a daily dose of 0.5 mg/kg to 2.5
mg/kg, the compounds of formula I inhibit tumor growth; for example
in a representative experiment Compound A when administered p.o. at
a daily dose of 2.5 mg/kg results in a final T/C value of 23%. In
the same experiment, intermittent administration of Compound A, 5
mg/kg twice per week, results in a final T/C value of 32%. Compound
A significantly and consistently decreases in these assays the rate
of CA20948 pancreatic tumor growth when compared to vehicle
controls (T/C for control animals is defined as 100%). Compounds of
formula I, e.g. Compound A, have been tested in further tumor
models in accordance with the procedure as disclosed above. For
example, a daily dosage of 2.5 mg/kg or 5 mg/kg Compound A produces
final T/Cs of 18% and 9% when administered to the human NCI H-596
lung tumor model and the human MEXF 989 melanoma tumor model,
respectively; 5 mg/kg produces final T/Cs of 20% (primary tumor)
and 36% (cervical lymph node metastases) when administered to the
orthotopic mouse B16/BL6 melanoma tumor model and 24% when
administered to the human AR42J pancreatic tumor model; 2.5 mg/kg
produces a final TIC of 28% when administered to the multi-drug
resistant (MDR) human KB-8511 epidermoid tumor model. Good
antitumor responses are also obtained when compounds of formula I,
e.g. Compound A, are administered intermittently, e.g. 2 subsequent
days per week or twice a week, to mice transplanted with human
AR42J pancreatic tumors.
B.4 Combination with Doxorubicin
[0080] Mice transplanted with human KB-31 epidermoid tumors are
treated for 21 days with doxorubicin at a dose of 5 mg/kg i.v. once
per week, a compound of formula I, e.g. Compound A, at a dose of
2.5 mg/kg p.o once per day, or a combination of both. Thereafter
compound of formula I treatment alone is continued in the
combination group in order to determine if the compound of formula
I can suppress the outgrowth of tumors that respond to conventional
agents. Antitumor activity is expressed as T/C % or % regressions
as indicated above. For example, the combination of Compound A and
doxorubicin produces greater antitumor effect (74% regressions) as
compared to either agent alone (Compound A, T/C 32%; doxorubicin
44% regressions). No exacerbation of the body weight losses caused
by doxorubicin occurrs when Compound A treatment is added.
Continuing Compound A treatment in the combination group, after
ceasing doxorubicin, inhibits tumor outgrowth such that the tumor
volumes of the doxorubicin monotherapy group are significantly
larger than those of the combination group. Morever the combination
appears to produce a greater cure rate (8/8 tumors) at 14 days post
end of treatment than doxorubicin alone (3/8 tumors).
[0081] B.5 Combination with Cisplatinum
[0082] Mice transplanted with human NCI H-596 lung tumors are
treated for 21 days with cisplatinum at a dose of 2.5 mg/kg i.v.
once per week, a compound of formula I, e.g. Compound A, at a dose
of 2.5 mg/kg p.o. once per day, or a combination of both. Antitumor
activity is expressed as T/C % or % regressions as indicated above.
A combination of Compound A and cisplatinum produces a greater
antitumor effect (5% regressions) as compared to either agent alone
(Compound A, TIC 26%; cisplatinum, TIC 26%). The combination did
not lead to worsened tolerability.
B.6 Antiangiogenic Activity
[0083] B16/BL6 cells (5.times.10.sup.4) are injected intradermally
into the ear of C57BU6 mice. Seven days later treatment with
rapamycin or a derivative thereof e.g. Compound A, or vehicle is
initiated. Primary tumor and cervical lymph nodes are collected
after two weeks of daily treatment for measurement of vessel
density. Endothelium of perfused vessels in the tumors is
visualized using a nuclear staining dye (Hoechst 33342, 20 mg/kg)
that is injected i.v. shortly before killing the mice. Tumors and
metastases are snap frozen and sections examined under a light
microscope equipped with an epifluorescent source. The fluorescence
H33342-labelled endothelium cells is used to measure vessel number
and size over the whole tumor section. Vessels are assigned to
groups of 10 .mu.m-size range. Distribution of vessel size is
assessed using a histogram frequency analysis. At a dose of 5 mg/kg
p.o., rapamycin or a derivative thereof reduces vessel density in
both the primary tumor (e.g. T/C 50% for Compound A) and the
metastases (e.g. T/C 40% for Compound A) as compared to controls.
Rapamycin or a derivative thereof, e.g. Compound A, also changes
vessel size distribution in the metastases.
B.7 Combination with an Antiangiogenic Agent
[0084] B16/BL6 cells (5.times.10.sup.4) are injected intradermally
into the ear of C57BU6 mice. Seven days later treatment with
rapamycin or a derivative thereof, e.g. Compound A, a VEGF receptor
tyrosine kinase inhibitor, e.g.
1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a salt
thereof, e.g. the succinate, or a combination of both is initiated
and effects on the growth and weight of the primary tumor and
cervical lymph node metastases are monitored, respectively. Daily
administration of the antiangiogenic agent (100 mg/kg p.o.) or of
rapamycin or a derivative thereof, e.g. Compound A, (1 mg/kg p.o.)
alone, reduces the size of the primary tumor (final T/C: 65% and
74%, respectively), whereas the combination of these two agents is
synergistic (T/C 12%). Rapamycin or a derivative thereof, e.g.
Compound A and the antiangiogenic agent treatment alone reduces
cervical lymph node weights (related to regional metastases) (T/C:
75% and 34%, respectively), and the combination further reduces
lymph node weights (T/C 13%). The treatments significantly promote
body weight gains as compared to controls. For the primary tumors,
analysis of possible interaction shows synergy with Compound A and
antiangiogenic agent as antiangiogenic agent/controls=0.66;
Compound A/controls=0.77; Compound A and antiangiogenic
agent/controls=0.135. As Compound A and antiangiogenic
agent/controls <Compound A/controls.times.antiangiogenic
agent/controls (0.51), this is defined as synergy. For the
metastases, analysis also shows synergy with Compound A and the
antiangiogenic agent as antiangiogenic agent/controls=0.337;
Compound A/controls=0.75; Compound A and antiangiogenic
agent/controls=0.122. As Compound A and antiangiogenic
agent/controls<Compound A/controls.times.antiangiogenic
agent/controls (0.252), this is also defined as synergy (Clark,
Breast Cancer Research Treatment 1997; 46:255).
C. Clinical Trial
[0085] C.1 Investigation of Clinical Benefit of a Compound of
Formula I, e.g. Compound A as Monotherapy in Solid Tumours [0086]
Aim of the study: To identify the optimal dose of said compound,
given orally once weekly, in a dose escalating study and the
efficacy of the optimal dosage in solid tumours. [0087] The study
is divided into 2 parts:
Part 1:
[0087] [0088] Primary Aim: Identify the optimal dose of a compound
of formula I, e.g. Compound A, given p.o. once weekly, assuming
this should be the minimum dose associated with prolonged
inhibition of mTOR and blood levels of said compound at least
equivalent to those achieving an anti-tumor effect in in-vivo
preclinical levels. [0089] Secondary Aim: Assess safety of said
compound when given alone to cancer patients and assess changes in
tumor metabolic activity. [0090] Design: Successive groups of 4
patients with advanced malignant solid tumors, refractory or
resistant to standard therapies to receive a compound of formula I,
e.g. Compound A, every 7 days different doses (group 1 to receive 5
mg; group 2 to receive 10 mg, group 3 to receive 20 mg) for 4
weeks. In week 4, establish the pharmacokinetic profile and the
profile of mTOR inhibition as reflected by the inhibition of p70s6
kinase in peripheral lymphocytes. Carry out comparative
18-fluorodeoxyglucose (FDG) positron-emission tomography (FDG-PET)
imaging (before 1.sup.st dose, after 3.sup.rd dose) to explore the
change in tumor metabolism. [0091] Patients main selection
criteria: Adults with advanced-stage (III-V) solid tumors,
resistant or refractory to standard therapies. At least one tumoral
lesion should be measurable (>20 mm in one dimension). [0092]
Main variables for evaluation: Safety (adverse events), standard
serum biochemistry and haematology, blood levels of the compound to
be tested, lymphocyte p70-s6kinase activity, changes in tumor
glucose uptake by FDG-PET.
Part 2:
[0092] [0093] Primary Aim: Explore the efficacy of a compound of
formula I, e.g. Compound A, in patients with advanced solid tumors
when given once a week at the optimal dosage, as identified in Part
1 as shown by tumor response. [0094] Secondary Aim: Assess the
safety of said compound at this dosage. [0095] Design: 20 patients
with progressing, advanced-stage solid tumors, resistant or
refractory to standard therapies, to receive said compound at the
dosage recommended as a result of Part 1. The general clinical
state of the patient is investigated weekly by physical and
laboratory examination. Changes in tumor burden are assessed every
2 months by radiological examination. Initially patients receive
treatment for 2 months. Thereafter, they remain on treatment for as
long as their disease does not progress and the drug is
satisfactorily tolerated. [0096] Main variables for evaluation:
Safety (adverse events), standard serum biochemistry and
haematology, tumor dimensions by computerised tomographic (CT) scan
or magnetic resonance imaging (MRI).
C.2 Combined Treatment
[0097] Suitable clinical studies are, for example, open label
non-randomized, dose escalation studies in patients with advanced
solid tumors. Such studies prove in particular the synergism of the
active ingredients of the combination of the invention. The
beneficial effects on proliferative diseases can be determined
directly through the results of these studies or by changes in the
study design which are known as such to a person skilled in the
art. Such studies are, in particular, suitable to compare the
effects of a monotherapy using the active ingredients and a
combination of the invention. Preferably, the dose of agent (a) is
escalated until the Maximum Tolerated Dosage is reached, and the
co-agent (b) is administered with a fixed dose. Alternatively, the
agent (a) is administered in a fixed dose and the dose of co-agent
(b) is escalated. Each patient receives doses of the agent (a)
either daily or intermittent. The efficacy of the treatment can be
determined in such studies, e.g., after 12, 18 or 24 weeks by
radiologic evaluation of the tumors every 6 weeks.
[0098] Alternatively, a placebo-controlled, double blind study can
be used in order to prove the benefits of the combination of the
invention mentioned herein.
[0099] Daily dosages required in practicing the method of the
present invention when a compound of formula I alone is used will
vary depending upon, for example, the compound used, the host, the
mode of administration and the severity of the condition to be
treated. A preferred daily dosage range is about from 0.1 to 25 mg
as a single dose or in divided doses. Suitable daily dosages for
patients are on the order of from e.g. 0.1 to 25 mg p.o. Compound A
may be administered by any conventional route, in particular
enterally, e.g. orally, e.g. in the form of tablets, capsules,
drink solutions, nasally, pulmonary (by inhalation) or
parenterally, e.g. in the form of injectable solutions or
suspensions. Suitable unit dosage forms for oral administration
comprise from ca. 0.05 to 12.5 mg, usually 0.25 to 10 mg Compound
A, together with one or more pharmaceutically acceptable diluents
or carriers therefor.
[0100] The combination of the invention can also be applied in
combination with surgical intervention, mild prolonged whole body
hyperthermia and/or irradiation therapy.
[0101] The administration of a pharmaceutical combination of the
invention results not only in a beneficial effect, e.g. a
synergistic therapeutic effect, e.g. with regard to slowing down,
arresting or reversing the neoplasm formation or a longer duration
of tumor response, but also in further surprising beneficial
effects, e.g. less side-effects, an improved quality of life or a
decreased mortality and morbidity, compared to a monotherapy
applying only one of the pharmaceutically active ingredients used
in the combination of the invention, in particular in the treatment
of a tumor that is refractory to other chemotherapeutics known as
anti-cancer agents. In particular, an increased up-take of the
co-agent (b) in tumor tissue and tumor cells is observed, when
applied in combination with the first agent (a).
[0102] A further benefit is that lower doses of the active
ingredients of the combination of the invention can be used, for
example, that the dosages need not only often be smaller but are
also applied less frequently, or can be used in order to diminish
the incidence of side-effects, while controlling the growth of
neoplasm formation. This is in accordance with the desires and
requirements of the patients to be treated.
[0103] According to one embodiment of the invention, a preferred
pharmaceutical combination comprises
a) a compound of formula I, e.g. Compound A, and b) as co-agent,
one or more compounds as indicated in paragraphs (ii), (iii) or
(iv) above, e.g. carboplatin, cisplatinum, paclitaxel, docetaxel,
gemcitabine or doxorubicin.
[0104] A synergistic combination of a compound of formula I, e.g.
Compound A, with carboplatin, cisplatinum, paclitaxel, docetaxel,
gemcitabine or doxorubicin is particularly preferred.
[0105] A further preferred pharmaceutical combination is e.g. a
combination comprising
a) rapamycin or a derivative thereof, e.g. CCI-779, ABT578 or
Compound A, and b) as co-agent, one or more compounds as indicated
under paragraphs (i) and (v) to (x) above, preferably one or more
compounds as specified in paragraph (v) above.
[0106] Preferred is e.g. a synergistic combination of rapamycin or
a derivative thereof, e.g. CCI-779, ABT578 or Compound A, with a
compound which target, decrease or inhibit the activity of VEGFR,
EGFR family, PDGFR, c-ABI family members or protein kinase C, e.g.
as disclosed above.
[0107] One specific embodiment of the invention relates to the use
of a combination of the invention for the prevention, delay of
progression or treatment of or for the preparation of a medicament
for the prevention, delay of progression or treatment of breast
cancer. Preferably, in such embodiment the combination comprises as
co-agent b) an aromatase inhibitor, e.g. the aromatase inhibitor
letrozole, an anti-estrogen, e.g. tamoxifen, a topoisomerase II
inhibitor, e.g. doxorubicin, or a microtubule active agent, e.g.
paclitaxel.
[0108] Another embodiment of the invention relates to the use of a
combination of the invention for the prevention, delay of
progression or treatment of or for the preparation of a medicament
for the prevention, delay of progression or treatment of lung
cancer. Preferably, in such embodiment the combination of the
invention comprises as co-agent b) a platin compound, e.g.
carboplatin, or a microtubule active agent, e.g. paclitaxel.
[0109] Another embodiment of the invention relates to the use of a
combination of the invention for the prevention, delay of
progression or treatment of or for the preparation of a medicament
for the prevention, delay of progression or treatment of pancreatic
cancer. Preferably, in such embodiment the combination of the
invention comprises as co-agent b) an antineoplastic
antimetabolite, e.g. gemcitabine.
[0110] Another embodiment of the invention relates to the use of a
combination of the invention for the prevention, delay of
progression or treatment of or for the preparation of a medicament
for the prevention, delay of progression or treatment of
glioblastomas. Preferably, in such embodiment the combination of
the invention comprises as co-agent b) an alkylating agent, e.g.
BCNU.
[0111] A further embodiment of the invention relates to the use of
rapamycin or a derivative thereof in combination with a
chemotherapeutic agent in the treatment of a lymphatic cancer, e.g.
as disclosed above. The combination may additionally comprise as
co-agent b) busulfan, cytarabine, 6-thioguanine, fludarabine,
hydroxyurea, procarbazine, bleomycin or methotrexate. Topoisomerase
II inhibitors e.g. daunorubicin or, particularly, compounds which
target, decrease or inhibit the activity of PDGFR or of c-Abl
family members and their gene fusion products, e.g. imatinib are
preferred as co-agent (b).
[0112] The terms "co-administration" or "combined administration"
or the like as utilized herein are meant to encompass
administration of the selected therapeutic agents to a single
patient, and are intended to include treatment regimens in which
the agents are not necessarily administered by the same route of
administration or at the same time.
[0113] It is one objective of this invention to provide a
pharmaceutical composition comprising a quantity, which is jointly
therapeutically effective against a proliferative malignant disease
comprising a combination of the invention. In this composition, the
first agent a) and co-agent (b) can be administered together, one
after the other or separately in one combined unit dosage form or
in two separate unit dosage forms. The unit dosage form may also be
a fixed combination.
[0114] The pharmaceutical compositions for separate administration
of the first agent a) and co-agent b) and for the administration in
a fixed combination, i.e. a single galenical composition comprising
at least two combination partners a) and b), according to the
invention can be prepared in a manner known per se and are those
suitable for enteral, such as oral or rectal, and parenteral
administration to mammals (warm-blooded animals), including humans,
comprising a therapeutically effective amount of at least one
pharmacologically active combination partner alone, e.g. as
indicated above, or in combination with one or more
pharmaceutically acceptable carriers or diluents, especially
suitable for enteral or parenteral application.
[0115] Suitable pharmaceutical compositions contain, for example,
from about 0.1% to about 99.9%, preferably from about 1% to about
60%, of the active ingredient(s). Pharmaceutical preparations for
the combination therapy for enteral or parenteral administration
are, for example, those in unit dosage forms, such as sugar-coated
tablets, tablets, capsules or suppositories, or ampoules. If not
indicated otherwise, these are prepared in a manner known per se,
for example by means of conventional mixing, granulating,
sugar-coating, dissolving or lyophilizing processes. It will be
appreciated that the unit content of a combination partner
contained in an individual dose of each dosage form need not in
itself constitute an effective amount since the necessary effective
amount can be reached by administration of a plurality of dosage
units.
[0116] In particular, a therapeutically effective amount of each of
the combination partner of the combination of the invention may be
administered simultaneously or sequentially and in any order, and
the components may be administered separately or as a fixed
combination. For example, the method of delay of progression or
treatment of a proliferative malignant disease according to the
invention may comprise (i) administration of the first agent a) in
free or pharmaceutically acceptable salt form and (ii)
administration of a co-agent b) in free or pharmaceutically
acceptable salt form, simultaneously or sequentially in any order,
in jointly therapeutically effective amounts, preferably in
synergistically effective amounts, e.g. in daily or intermittently
dosages corresponding to the amounts described herein. The
individual combination partners of the combination of the invention
may be administered separately at different times during the course
of therapy or concurrently in divided or single combination forms.
Furthermore, the term administering also encompasses the use of a
pro-drug of a combination partner that convert in vivo to the
combination partner as such. The instant invention is therefore to
be understood as embracing all such regimens of simultaneous or
alternating treatment and the term "administering" is to be
interpreted accordingly.
[0117] The effective dosage of each of the combination partners
employed in the combination of the invention may vary depending on
the particular compound or pharmaceutical composition employed, the
mode of administration, the condition being treated, the severity
of the condition being treated. Thus, the dosage regimen of the
combination of the invention is selected in accordance with a
variety of factors including the route of administration and the
renal and hepatic function of the patient. A physician, clinician
or veterinarian of ordinary skill can readily determine and
prescribe the effective amount of the single active ingredients
required to prevent, counter or arrest the progress of the
condition. Optimal precision in achieving concentration of the
active ingredients within the range that yields efficacy without
toxicity requires a regimen based on the kinetics of the active
ingredients' availability to target sites.
[0118] Daily dosages for the first agent a) will, of course, vary
depending on a variety of factors, for example the compound chosen,
the particular condition to be treated and the desired effect. In
general, however, satisfactory results are achieved on
administration of rapamycin or a derivative thereof at daily dosage
rates of the order of ca. 0.1 to 25 mg as a single dose or in
divided doses. Rapamycin or a derivative thereof, e.g. a compound
of formula I, may be administered by any conventional route, in
particular enterally, e.g. orally, e.g. in the form of tablets,
capsules, drink solutions or parenterally, e.g. in the form of
injectable solutions or suspensions. Suitable unit dosage forms for
oral administration comprise from ca. 0.05 to 10 mg active
ingredient, e.g. Compound A, together with one or more
pharmaceutically acceptable diluents or carriers therefor.
[0119] Fadrozole may be administered orally to a human in a dosage
range varying from about 0.5 to about 10 mg/day, preferably from
about 1 to about 2.5 mg/day. Exemestane may be administered orally
to a human in a dosage range varying from about 5 to about 200
mg/day, preferably from about 10 to about 25 mg/day, or
parenterally from about 50 to 500 mg/day, preferably from about 100
to about 250 mg/day. If the drug shall be administered in a
separate pharmaceutical composition, it can be administered in the
form disclosed in GB 2,177,700. Formestane may be administered
parenterally to a human in a dosage range varying from about 100 to
500 mg/day, preferably from about 250 to about 300 mg/day.
Anastrozole may be administered orallly to a human in a dosage
range varying from about 0.25 to 20 mg/day, preferably from about
0.5 to about 2.5 mg/day. Aminogluthemide may be administered to a
human in a dosage range varying from about 200 to 500 mg/day.
[0120] Tamoxifen citrate may be administered to a human in a dosage
range varying from about 10 to 40 mg/day.
[0121] Vinblastine may be administered to a human in a dosage range
varying from about 1.5 to 10 mg/m.sup.2 day. Vincristine sulfate
may be administered parenterally to a human in a dosage range
varying from about 0.025 to 0.05 mg/kg body weight*week.
Vinorelbine may be administered to a human in a dosage range
varying from about 10 to 50 mg/m.sup.2 day. Etoposide phosphate may
be administered to a human in a dosage range varying from about 25
to 115 mg/m.sup.2 day, e.g. 56.8 or 113.6 mg/m.sup.2 day.
[0122] Teniposide may be administered to a human in a dosage range
varying from about 75 to 150 mg about every two weeks. Doxorubicin
may be administered to a human in a dosage range varying from about
10 to 100 mg/m.sup.2 day, e.g. 25 or 50 mg/m.sup.2 day. Epirubicin
may be administered to a human in a dosage range varying from about
10 to 200 mg/m.sup.2 day. Idarubicin may be administered to a human
in a dosage range varying from about 0.5 to 50 mg/m.sup.2 day.
Mitoxantrone may be administered to a human in a dosage range
varying from about 2.5 to 25 mg/m.sup.2 day.
[0123] Paclitaxel may be administered to a human in a dosage range
varying from about 50 to 300 mg/m.sup.2 day. Docetaxel may be
administered to a human in a dosage range varying from about 25 to
100 mg/m.sup.2 day.
[0124] Cyclophosphamide may be administered to a human in a dosage
range varying from about 50 to 1500 mg/m.sup.2 day. Melphalan may
be administered to a human in a dosage range varying from about 0.5
to 10 mg/m.sup.2 day.
[0125] 5-Fluorouracil may be administered to a human in a dosage
range varying from about 50 to 1000 mg/m.sup.2 day, e.g. 500
mg/m.sup.2 day. Capecitabine may be administered to a human in a
dosage range varying from about 10 to 1000 mg/m.sup.2 day.
Gemcitabine hydrochloride may be administered to a human in a
dosage range varying from about 1000 mg/m.sup.2/week. Methotrexate
may be administered to a human in a dosage range varying from about
5 to 500 mg/m.sup.2 day.
[0126] Topotecan may be administered to a human in a dosage range
varying from about 1 to 5 mg/m.sup.2 day. Irinotecan may be
administered to a human in a dosage range varying from about 50 to
350 mg/m.sup.2 day.
[0127] Carboplatin may be administered to a human in a dosage range
varying from about 200 to 400 mg/m.sup.2 about every four weeks.
Cisplatin may be administered to a human in a dosage range varying
from about 25 to 75 mg/m.sup.2 about every three weeks. Oxaliplatin
may be administered to a human in a dosage range varying from about
50 to 85 mg/m.sup.2 every two weeks.
[0128] Imatinib may be administered to a human in a dosage in the
range of about 2.5 to 850 mg/day, more preferably 5 to 600 mg/day
and most preferably 20 to 300 mg/day.
[0129] Alendronic acid may be administered to a human in a dosage
range varying from about 5 to 10 mg/day. Clodronic acid may be
administered to a human e.g. in a dosage range varying from about
750 to 1500 mg/day. Etridonic acid may be administered to a human
in a dosage range varying from about 200 to 400 mg/day. Ibandronic
acid may be administered to a human in a dosage range varying from
about 1 to 4 mg every three to four weeks. Risedronic acid may be
administered to a human in a dosage range varying from about 20 to
30 mg/day. Pamidronic acid may be administered to a human in a
dosage range varying from about 15 to 90 mg every three to four
weeks. Tiludronic acid may be administered to a human in a dosage
range varying from about 200 to 400 mg/day.
[0130] Trastuzumab may be administered to a human in a dosage range
varying from about 1 to 4 mg/m.sup.2/week.
[0131] Bicalutamide may be administered to a human in a dosage
range varying from about 25 to 50 mg/m.sup.2 day.
[0132] 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or salt
thereof, e.g. succinate, may be administered to a human in a dosage
range of about 50 to 1500, more preferably about 100 to 750, and
most preferably 250 to 500, mg/day.
[0133] Rapamycin or derivatives thereof are well tolerated at
dosages required for use in accordance with the present invention.
For example, the NTEL for Compound A in a 4-week toxicity study is
0.5 mg/kg/day in rats and 1.5 mg/kg/day in monkeys.
* * * * *