U.S. patent application number 13/003581 was filed with the patent office on 2011-05-05 for combination of (a) a phosphoinositide 3-kinase inhibitor and (b) a modulator of ras/raf/mek pathway.
This patent application is currently assigned to NOVARTIS AG. Invention is credited to Christine Fritsch, Carlos Garcia-Echeverria, Sauveur-Michel Maira, Tobi Nagel, Darrin Stuart, Susan Wee.
Application Number | 20110105521 13/003581 |
Document ID | / |
Family ID | 39739487 |
Filed Date | 2011-05-05 |
United States Patent
Application |
20110105521 |
Kind Code |
A1 |
Garcia-Echeverria; Carlos ;
et al. |
May 5, 2011 |
COMBINATION OF (A) A PHOSPHOINOSITIDE 3-KINASE INHIBITOR AND (B) A
MODULATOR OF RAS/RAF/MEK PATHWAY
Abstract
The invention relates to a pharmaceutical combination which
comprises (a) a phosphoinositide 3-kinase inhibitor compound and
(b) a compound which modulates the Ras/Raf/Mek pathway for the
treatment of a proliferative disease, especially a solid tumor
disease; a pharmaceutical composition comprising such a
combination; the use of such a combination for the preparation of a
medicament for the treatment of a proliferative disease; a
commercial package or product comprising such a combination as a
combined preparation for simultaneous, separate or sequential use;
and to a method of treatment of a warm-blooded animal, especially a
human.
Inventors: |
Garcia-Echeverria; Carlos;
(Basel, CH) ; Maira; Sauveur-Michel; (Habsheim,
FR) ; Stuart; Darrin; (Pleasant Hill, CA) ;
Wee; Susan; (Skillman, NJ) ; Fritsch; Christine;
(Ranspach-le-bas, FR) ; Nagel; Tobi; (Oakland,
CA) |
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
39739487 |
Appl. No.: |
13/003581 |
Filed: |
July 10, 2009 |
PCT Filed: |
July 10, 2009 |
PCT NO: |
PCT/US2009/050192 |
371 Date: |
January 11, 2011 |
Current U.S.
Class: |
514/253.03 ;
514/293 |
Current CPC
Class: |
A61P 35/02 20180101;
A61K 31/5377 20130101; A61K 31/4188 20130101; A61P 35/00 20180101;
A61K 31/4188 20130101; A61K 31/437 20130101; A61K 31/4439 20130101;
A61K 45/06 20130101; A61K 31/166 20130101; A61P 1/18 20180101; A61K
31/4745 20130101; A61K 2300/00 20130101; A61P 43/00 20180101 |
Class at
Publication: |
514/253.03 ;
514/293 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/4745 20060101 A61K031/4745; A61P 35/00
20060101 A61P035/00; A61P 35/02 20060101 A61P035/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 11, 2008 |
EP |
08160218.7 |
Claims
1. A combination which comprises (a) a phosphoinositide 3-kinase
inhibitor compound inhibitor and (b) a compound which modulates the
Ras/Raf/Mek pathway, wherein the active ingredients are present in
each case in free form or in the form of a pharmaceutically
acceptable salt or any hydrate thereof, and optionally at least one
pharmaceutically acceptable carrier; for simultaneous, separate or
sequential use.
2. A combination according to claim 1, wherein said combination
comprises an amount of (a) a phosphoinositide 3-kinase inhibitor
compound inhibitor and (b) a compound which modulates the
Ras/Raf/Mek pathway in free form or in the form of a
pharmaceutically acceptable salt or any hydrate thereof in a
synergistic ratio.
3. A combination according to claim 1 wherein the phosphoinositide
3-kinase inhibitor compound is COMPOUND A, COMPOUND B or COMPOUND
C.
4. A combination according to claim 1 wherein the compound which
modulates the Ras/Raf/Mek pathway modulates Raf kinase
activity.
5. A combination according to claim 1 wherein the compound which
modulates the Ras/Raf/Mek pathway modulates Mek kinase
activity.
6. A combination according to claim 4 wherein the compound which
modulates Raf kinase activity is Sorafenib, Raf265, SB590885, XL281
or PLX4032.
7. A combination according to claim 5 wherein the compound which
modulates Mek kinase activity is PD325901, PD-181461,
ARRY142886/AZD6244, ARRY-509, XL518, JTP-74057, AS-701255,
AS-701173, AZD8330, ARRY162, ARRY300, RDEA436, E6201,
RO4987655/R-7167, GSK1120212 or AS703026.
8. A pharmaceutical composition comprising a quantity which is
jointly therapeutically effective against a proliferative disease
of a combination according to claim 1 and at least one
pharmaceutically acceptable carrier.
9. A combination as defined in claim 1 for the treatment of a
proliferative disease.
10. A combination according to claim 9 wherein the proliferative
disease is a solid tumor.
11. A combination according to claim 9 wherein the proliferative
disease is melanoma, lung cancer, colorectal cancer (CRC), breast
cancer, kidney cancer such as e.g. renal cell carcinoma (RCC),
liver cancer, acute myelogenous leukemia (AML), myelodysplastic
Syndromes (MDS), non-small-cell lung cancer (NSCLC), thyroid
cancer, pancreatic cancer, neurofibromatosis or hepatocellular
carcinoma.
12. A combined preparation, which comprises (a) one or more unit
dosage forms of phosphoinositide-3 kinase inhibitor and (b) one or
more unit dosage forms of a compound which modulates the
Ras/Raf/Mek pathway.
13. A synergistic combination for human administration comprising a
PI3K inhibitor compound and a compound which modulates the
Ras/Raf/Mek pathway, in free form or in the form of a
pharmaceutically acceptable salt or any hydrate thereof, in a w/w
combination range which corresponds to a synergistic combination
range of 10:1 to 1:1 parts by weight in the BN472 tumor model or
pancreatic tumor models PANC1 and MiaPaCa2.
14. A synergistic combination for human administration comprising a
PI3K inhibitor compound and a compound which modulates the
Ras/Raf/Mek pathway, in free form or in the form of a
pharmaceutically acceptable salt or any hydrate thereof, in a w/w
combination range which corresponds to a synergistic combination
range of 1-50 mg/kg and 1-30 mg/kg respectively, in the BN472 tumor
model or pancreatic tumor models PANC1 and MiaPaCa2.
15. A combination according to claim 1 for human administration
comprising a synergistic amount of a PI3K inhibitor compound at
about MTD and a compound which modulates the Ras/Raf/Mek at
50%-100% of the MTD.
Description
[0001] The invention relates to a pharmaceutical combination which
comprises (a) a phosphoinositide 3-kinase (PI3K) inhibitor compound
and (b) a compound which modulates the Ras/Raf/Mek pathway and
optionally at least one pharmaceutically acceptable carrier for
simultaneous, separate or sequential use, in particular for the
treatment of a proliferative disease, especially a proliferative
disease in which the Ras/Raf/MeK and PI3K/Akt pathways are
concomitantly dysregulated; a pharmaceutical composition comprising
such a combination; the use of such a combination for the
preparation of a medicament for the treatment of a proliferative
disease; a commercial package or product comprising such a
combination as a combined preparation for simultaneous, separate or
sequential use; and to a method of treatment of a warm-blooded
animal, especially a human.
[0002] WO2006/122806 describes imidazoquinoline derivatives, which
have been described to inhibit the activity of lipid kinases, such
as PI3-kinases. Specific imidazoquinoline derivatives which are
suitable for the present invention, their preparation and suitable
pharmaceutical formulations containing the same are described in
WO2006/122806 and include compounds of formula I
##STR00001##
wherein
[0003] R.sub.1 is naphthyl or phenyl wherein said phenyl is
substituted by one or two substituents independently selected from
the group consisting of Halogen; lower alkyl unsubstituted or
substituted by halogen, cyano, imidazolyl or triazolyl; cycloalkyl;
amino substituted by one or two substituents independently selected
from the group consisting of lower alkyl, lower alkyl sulfonyl,
lower alkoxy and lower alkoxy lower alkylamino; piperazinyl
unsubstituted or substituted by one or two substituents
independently selected from the group consisting of lower alkyl and
lower alkyl sulfonyl; 2-oxo-pyrrolidinyl; lower alkoxy lower alkyl;
imidazolyl; pyrazolyl; and triazolyl;
[0004] R.sub.2 is O or S;
[0005] R.sub.3 is lower alkyl;
[0006] R.sub.4 is pyridyl unsubstituted or substituted by halogen,
cyano, lower alkyl, lower alkoxy or piperazinyl unsubstituted or
substituted by lower alkyl; pyrimidinyl unsubstituted or
substituted by lower alkoxy; quinolinyl unsubstituted or
substituted by halogen; quinoxalinyl; or phenyl substituted with
alkoxy
[0007] R.sub.5 is hydrogen or halogen;
[0008] n is 0 or 1;
[0009] R.sub.6 is oxido;
[0010] with the proviso that if n=1, the N-atom bearing the radical
R.sub.6 has a positive charge;
[0011] R.sub.7 is hydrogen or amino;
[0012] or a tautomer thereof, or a pharmaceutically acceptable
salt, or a hydrate or solvate thereof.
[0013] The radicals and symbols as used in the definition of a
compound of formula I have the meanings as disclosed in
WO2006/122806 which publication is hereby incorporated into the
present application by reference.
[0014] A preferred compound of the present invention is a compound
which is specifically described in WO2006/122806. A very preferred
compound of the present invention is
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile and its monotosylate salt
(COMPOUND A). The synthesis of
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]q-
uinolin-1-yl)-phenyl]-propionitrile is for instance described in
WO2006/122806 as Example 1. Another very preferred compound of the
present invention is
8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-
-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (COMPOUND B). The
synthesis of
8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-
-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one is for instance
described in WO2006/122806 as Example 86.
[0015] WO07/084,786 describes pyrimidine derivatives, which have
been found the activity of lipid kinases, such as PI3-kinases.
Specific pyrimidine derivatives which are suitable for the present
invention, their preparation and suitable pharmaceutical
formulations containing the same are described in WO07/084,786 and
include compounds of formula I
##STR00002## [0016] or a stereoisomer, tautomer, or
pharmaceutically acceptable salt thereof, wherein, W is CR.sub.w or
N, wherein R.sub.w is selected from the group consisting of [0017]
(1) hydrogen, [0018] (2) cyano, [0019] (3) halogen, [0020] (4)
methyl, [0021] (5) trifluoromethyl, [0022] (6) sulfonamido; [0023]
R.sub.1 is selected from the group consisting of [0024] (1)
hydrogen, [0025] (2) cyano, [0026] (3) nitro, [0027] (4) halogen,
[0028] (5) substituted and unsubstituted alkyl, [0029] (6)
substituted and unsubstituted alkenyl, [0030] (7) substituted and
unsubstituted alkynyl, [0031] (8) substituted and unsubstituted
aryl, [0032] (9) substituted and unsubstituted heteroaryl, [0033]
(10) substituted and unsubstituted heterocyclyl, [0034] (11)
substituted and unsubstituted cycloalkyl, [0035] (12) --COR.sub.1a,
[0036] (13) --CO.sub.2R.sub.1a, [0037] (14) --CONR.sub.1aR.sub.1b,
[0038] (15) --NR.sub.1aR.sub.1b, [0039] (16) --NR.sub.1aCOR.sub.1b,
[0040] (17) --NR.sub.1aSO.sub.2R.sub.1b, [0041] (18) --OCOR.sub.1a,
[0042] (19) --OR.sub.1a, [0043] (20) --SR.sub.1a, [0044] (21)
--SOR.sub.1a, [0045] (22) --SO.sub.2R.sub.1a, and [0046] (23)
--SO.sub.2NR.sub.1aR.sub.1b, [0047] wherein R.sub.1a, and R.sub.1b
are independently selected from the group consisting of [0048] (a)
hydrogen, [0049] (b) substituted or unsubstituted alkyl, [0050] (c)
substituted and unsubstituted aryl, [0051] (d) substituted and
unsubstituted heteroaryl, [0052] (e) substituted and unsubstituted
heterocyclyl, and [0053] (f) substituted and unsubstituted
cycloalkyl; [0054] R.sub.2 is selected from the group consisting
[0055] (1) hydrogen, [0056] (2) cyano, [0057] (3) nitro, [0058] (4)
halogen, [0059] (5) hydroxy, [0060] (6) amino, [0061] (7)
substituted and unsubstituted alkyl, [0062] (8) --COR.sub.2a, and
[0063] (9) --NR.sub.2aCOR.sub.2b, [0064] wherein R.sub.2a, and
R.sub.2b are independently selected from the group consisting of
[0065] (a) hydrogen, and [0066] (b) substituted or unsubstituted
alkyl; [0067] R.sub.3 is selected from the group consisting of
[0068] (1) hydrogen, [0069] (2) cyano, [0070] (3) nitro, [0071] (4)
halogen, [0072] (5) substituted and unsubstituted alkyl, [0073] (6)
substituted and unsubstituted alkenyl, [0074] (7) substituted and
unsubstituted alkynyl, [0075] (8) substituted and unsubstituted
aryl, [0076] (9) substituted and unsubstituted heteroaryl, [0077]
(10) substituted and unsubstituted heterocyclyl, [0078] (11)
substituted and unsubstituted cycloalkyl, [0079] (12) --COR.sub.3a,
[0080] (13) --NR.sub.3aR.sub.3b, [0081] (14) --NR.sub.3aCOR.sub.3b,
[0082] (15) --NR.sub.3aSO.sub.2R.sub.3b, [0083] (16) --OR.sub.3a,
[0084] (17) --SR.sub.3a, [0085] (18) --SOR.sub.3a, [0086] (19)
--SO.sub.2R.sub.3a, and [0087] (20) --SO.sub.2NR.sub.3aR.sub.3b,
[0088] wherein R.sub.3a, and R.sub.3b are independently selected
from the group consisting of [0089] (a) hydrogen, [0090] (b)
substituted or unsubstituted alkyl, [0091] (c) substituted and
unsubstituted aryl, [0092] (d) substituted and unsubstituted
heteroaryl, [0093] (e) substituted and unsubstituted heterocyclyl,
and [0094] (f) substituted and unsubstituted cycloalkyl; and [0095]
R.sub.4 is selected from the group consisting of [0096] (1)
hydrogen, and [0097] (2) halogen.
[0098] The radicals and symbols as used in the definition of a
compound of formula I have the meanings as disclosed in
WO07/084,786 which publication is hereby incorporated into the
present application by reference.
[0099] A preferred compound of the present invention is a compound
which is specifically described in WO07/084,786. A very preferred
compound of the present invention is
5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylam-
ine (COMPOUND C). The synthesis of
5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylam-
ine is described in WO07/084,786 as Example 10.
[0100] The Ras/Raf/Mek signal transduction pathway is activated
through the initial extracellular binding and stimulation of RTKs
by their respective cognate ligands. Upon autophosphorylation of
specifc tyrosine residues in the cytosolic domain of RTKs, the
Grb2-Sos complex translocates to the plasma membrane, and converts
the inactive RasGDP to active RasGTP. The interaction between Grb2
and the activated kinases or the phosphorylated receptor associated
proteins is mediated by the SH2 domain of the signalling protein
that recognizes specific phosphotyrosine sequences. Ras undergoes a
conformational changes upon GTP binding and causes the recruitment
of Raf-1 to the cytoplasmic membrane where is phosphorylated by
several kinases and simultaneous disphosphorylated at key residues
by protein phosphatase-2B. Activated Raf phosphorylates Mek on two
serine residues in the activation loop, which results in the
activation of this protein kinase. Mek then phosphorylates and
activates Erk, allowing its translocation to the nucleus where it
phosphorylates transcriptional factors permitting the expression of
a variety of genes. As shown in this section, several components of
the Raf/Mek/Erk cascade represent unique opportunities for cancer
treatment, e.g. genetic alterations such as HRAS, KRAS, NRAS or
BRAF mutations or gene amplifications.
[0101] Sorafenib, also known as Nexavar.TM. or BAY 43-9006, has
been the first Raf kinase modulator to receive marketing approval
for treatment of advanced renal cell carcinoma (RCC). Sorafenib is
a bi-aryl urea derivative of the following structure:
##STR00003##
[0102] Sorafenib and methods for its preparation have been
described e.g. in U.S. Pat. No. 7,235,576 or U.S. Pat. No.
7,351,834.
[0103] RAF265 (previously known as CHIR-265) is another orally
bioavailable Raf modulator of following structure:
##STR00004##
[0104] RAF265 and methods for its preparation for are for instance
described in WO07/030,377.
[0105] Further Raf kinase modulators include for instance SB590885,
XL281, PLX4032.
[0106] Mek kinase modulators include compounds described in
WO02/06213, in particular compound PD-0325901 which has following
structure:
##STR00005##
[0107] Another related Mek kinase inhibitor is compound
PD-181461.
[0108] Further Mek kinase modulators include compounds described in
WO03/077914, in particular compound ARRY1428861/AZD6244 of
structure
##STR00006##
and ARRY-509 and the compounds described in WO05/051906,
WO05/023251, WO03/077855 and US20050049419 covering N3-alkylated
benzimidazoles and other similar heterocyclic derivatives as MEK
inhibitors for the treatment of hyperproliferative diseases.
[0109] Further Mek kinase modulators include for instance XL518,
JTP-74057, AS-701255, AS-701173.
[0110] Hence, the present invention also pertains to a combination
such as a combined preparation or a pharmaceutical composition
which comprises (a) a phosphoinositide 3-kinase (PI3K) inhibitor
compound and (b) a compound which modulates the Ras/Raf/Mek
pathway. More particularly, in a first embodiment, the present
invention relates to a combination which comprises (a) a
phosphoinositide 3-kinase (PI3K) inhibitor compound and (b) a Raf
kinase modulator or Mek kinase modulator.
[0111] The term "a combined preparation", as used herein defines
especially a "kit of parts" in the sense that the combination
partners (a) and (b) as defined above can be dosed independently or
by use of different fixed combinations with distinguished amounts
of the combination partners (a) and (b), i.e. simultaneously or at
different time points. The parts of the kit of parts can then,
e.g., be administered simultaneously or chronologically staggered,
that is at different time points and with equal or different time
intervals for any part of the kit of parts. The ratio of the total
amounts of the combination partner (a) to the combination partner
(b) to be administered in the combined preparation can be varied,
e.g. in order to cope with the needs of a patient sub-population to
be treated or the needs of the single.
[0112] It has been found that combination therapy with an PI3K
inhibitor and a raf-kinase or mek-kinase inhibitor results in
unexpected improvement in the treatment of tumor diseases. When
administered simultaneously, sequentially or separately, the PI3K
inhibitor and the raf-kinase or mek-kinase inhibitor interact in a
synergistic manner to inhibit cell proliferation. This unexpected
synergy allows a reduction in the dose required of each compound,
leading to a reduction in the side effects and enhancement of the
clinical effectiveness of the compounds and treatment.
[0113] Determining a synergistic interaction between one or more
components, the optimum range for the effect and absolute dose
ranges of each component for the effect may be definitively
measured by administration of the components over different w/w
ratio ranges and doses to patients in need of treatment. For
humans, the complexity and cost of carrying out clinical studies on
patients renders impractical the use of this form of testing as a
primary model for synergy. However, the observation of synergy in
one species can be predictive of the effect in other species and
animal models exist, as described herein, to measure a synergistic
effect and the results of such studies can also be used to predict
effective dose and plasma concentration ratio ranges and the
absolute doses and plasma concentrations required in other species
by the application of pharmacokinetic/pharmacodynamic methods.
Established correlations between tumor models and effects seen in
man suggest that synergy in animals may e.g. be demonstrated in the
BN472 tumor model or pancreatic PANC1 and MiaPaCa2 tumor models as
described in the Examples below.
[0114] In one aspect the present invention provides a synergistic
combination for human administration comprising (a) PI3K inhibitor
compound and (b) a compound which modulates the Ras/Raf/Mek
pathway, or pharmaceutically acceptable salts or solvates thereof,
in a combination range (w/w) which corresponds to the ranges
observed in a tumor model, e.g. as described in the Examples below,
used to identify a synergistic interaction. Suitably, the ratio
range in humans corresponds to a non-human range selected from
between 50:1 to 1:50 parts by weight, 50:1 to 1:20, 50:1 to 1:10,
50:1 to 1:1, 20:1 to 1:50, 20:1 to 1:20, 20:1 to 1:10, 20:1 to 1:1,
10:1 to 1:50, 10:1 to 1:20, 10:1 to 1:10, 10:1 to 1:1, 1:1 to 1:50,
1.1 to 1:20 and 1:1 to 1:10. More suitably, the human range
corresponds to a non-human range of the order of 10:1 to 1:1 or 5:1
to 1:1 or 2:1 to 1:1 parts by weight.
[0115] According to a further aspect, the present invention
provides a synergistic combination for administration to humans
comprising an (a) a PI3K inhibitor compound and (b) a compound
which modulates the Ras/Raf/Mek pathway or pharmaceutically
acceptable salts thereof, where the dose range of each component
corresponds to the synergistic ranges observed in a suitable tumor
model, e.g. the tumor models described in the Examples below,
primarily used to identify a synergistic interaction. Suitably, the
dose range of the PI3K inhibitor compound in human corresponds to a
dose range of 1-50 mg/kg, more suitably 1-30 mg/kg (e.g. 1-35 mg/kg
or 1-10 mg/kg for Compound A, 1-25 mg/kg for Compound B) in a
suitable tumor model, e.g. a rat or mouse model as described in the
Examples below.
[0116] For the compound which modulates the Ras/Raf/Mek pathway,
the dose range in the human suitably corresponds to a synergistic
range of 1-50 mg/kg or 1-30 mg/kg (e.g. 1-25 mg/kg, 1-10 mg/kg or
1-2.5 mg/kg) in a suitable tumor model, e.g. a rat or mouse model
as described in the Examples below.
[0117] Suitably, the dose of PI3K inhibitor compound for use in a
human is in a range selected from 1-1200 mg, 1-500 mg, 1-100 mg,
1-50 mg, 1-25 mg, 500-1200 mg, 100-1200 mg, 100-500 mg, 50-1200 mg,
50-500 mg, or 50-100 mg, suitably 50-100 mg, once daily or twice
daily (b.i.d.) or three times per day (t.i.d.), and the dose of
compound which modulates the Ras/Raf/Mek pathway is in a range
selected from 1-1000 mg, 1-500 mg, 1-200 mg, 1-100 mg, 1-50 mg,
1-25 mg, 10-100 mg, 10-200 mg, 50-200 mg or 100-500 mg once daily,
b.i.d or t.i.d.
[0118] In accordance with a further aspect the present invention
provides a synergistic combination for administration to humans
comprising an (a) a PI3K inhibitor compound at 10%-100%, preferably
50%-100% or more preferably 70%-100%, 80%-100% or 90%-100% of the
maximal tolerable dose (MTD) and (b) a compound which modulates the
Ras/Raf/Mek pathway at 10%-100%, preferably 50%-100% or more
preferably 70%-100%, 80%-100% or 90%-100% of the MTD. In a
preferred embodiment one of the compounds, preferably the PI3K
inhibitor compound, is dosed at the MTD and the other compound,
preferably the compound which modulates the Ras/Raf/Mek pathway, is
dosed at 50%-100% of the MTD, preferably at 60%-90% of the MTD. The
MTD corresponds to the highest dose of a medicine that can be given
without unacceptable side effects. It is within the art to
determine the MTD. For instance the MTD can suitably be determined
in a Phase I study including a dose escalation to characterize dose
limiting toxicities and determination of biologically active
tolerated dose level.
[0119] In one embodiment of the invention, (a) the phosphoinositide
3-kinase (PI3K) inhibitor compound inhibitor is selected from the
group consisting of COMPOUND A, COMPOUND B or COMPOUND C.
[0120] In one embodiment of the invention, (b) the Raf kinase
modulator is selected from the group consisting of Sorafenib,
Raf265, SB590885, XL281 and PLX4032. In another embodiment, (b) the
Mek kinase modulator is selected from the group consisting of
PD325901, PD-181461, ARRY142886/AZD6244, ARRY-509, XL518,
JTP-74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300,
RDEA436, E6201, RO4987655/R-7167, GSK1120212 and AS703026.
[0121] The term "treating" or "treatment" as used herein comprises
the a treatment effecting a delay of progression of a disease. The
term "delay of progression" as used herein means administration of
the combination to patients being in a pre-stage or in an early
phase of the proliferative disease to be treated, in which patients
for example a pre-form of the corresponding disease is diagnosed or
which patients are in a condition, e.g. during a medical treatment
or a condition resulting from an accident, under which it is likely
that a corresponding disease will develop.
[0122] In one embodiment of the present invention, the
proliferative disease is melanoma, lung cancer, colorectal cancer
(CRC), breast cancer, kidney cancer such as e.g. renal cell
carcinoma (RCC), liver cancer, acute myelogenous leukemia (AML),
myelodysplastic Syndromes (MDS), non-small-cell lung cancer
(NSCLC), thyroid cancer, pancreatic cancer, neurofibromatosis or
hepatocellular carcinoma.
[0123] In another embodiment of the present invention, the
proliferative disease is a solid tumor. The term "solid tumor"
especially means breast cancer, ovarian cancer, cancer of the colon
and generally the GI (gastro-intestinal) tract, cervix cancer, lung
cancer, in particular small-cell lung cancer, and non-small-cell
lung cancer, head and neck cancer, bladder cancer, cancer of the
prostate or Kaposi's sarcoma. The present combination inhibits the
growth of solid tumors, but also liquid tumors. Furthermore,
depending on the tumor type and the particular combination used a
decrease of the tumor volume can be obtained. The combinations
disclosed herein are also suited to prevent the metastatic spread
of tumors and the growth or development of micrometastases. The
combinations disclosed herein are in particular suitable for the
treatment of poor prognosis patients, especially such poor
prognosis patients having metastatic melanome or pancreatic
cancer.
[0124] The cancer to be treated can have a genetic alteration in
the Ras/Raf/Mek signal transduction pathway such as e.g. a HRAS,
KRAS, NRAS or BRAF mutation or gene amplification. In one
embodiment the cancer to be treated has a KRAS mutation, e.g. KRAS
mutated pancreas cancer, colon cancer, lung cancer (e.g. NSCLC) or
leukemias.
[0125] The structure of the active agents identified by code nos.,
generic or trade names may be taken from the actual edition of the
standard compendium "The Merck Index" or from databases, e.g.
Patents International (e.g. IMS World Publications). The
corresponding content thereof is hereby incorporated by
reference.
[0126] It will be understood that references to the combination
partners (a) and (b) are meant to also include the pharmaceutically
acceptable salts. If these combination partners (a) and (b) have,
for example, at least one basic center, they can form acid addition
salts. Corresponding acid addition salts can also be formed having,
if desired, an additionally present basic center. The combination
partners (a) and (b) having an acid group (for example COOH) can
also form salts with bases. The combination partner (a) or (b) or a
pharmaceutically acceptable salt thereof may also be used in form
of a hydrate or include other solvents used for
crystallization.
[0127] A combination which comprises (a) a phosphoinositide
3-kinase inhibitor compound and (b) a compound which modulates the
Ras/Raf/Mek pathway, in which the active ingredients are present in
each case in free form or in the form of a pharmaceutically
acceptable salt and optionally at least one pharmaceutically
acceptable carrier, will be referred to hereinafter as a
COMBINATION OF THE INVENTION.
[0128] The COMBINATION OF THE INVENTION are both synergistic and
additive advantages, both for efficacy and safety. Therapeutic
effects of combinations of a phosphoinositide 3-kinase inhibitor
compound with a compound which modulates the Ras/Raf/Mek pathway
can result in lower safe dosages ranges of each component in the
combination.
[0129] The pharmacological activity of a COMBINATION OF THE
INVENTION may, for example, be demonstrated in a clinical study or
in a test procedure as essentially described hereinafter. Suitable
clinical studies are, for example, open label non-randomized, dose
escalation studies in patients with advanced solid tumors. Such
studies can prove the additive or synergism of the active
ingredients of the COMBINATIONS 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 combination partner (a) is administered
with a fixed dose and the dose of the combination partner (b) is
escalated until the Maximum Tolerated Dosage is reached.
[0130] It is one objective of this invention to provide a
pharmaceutical composition comprising a quantity, which is
therapeutically effective against a proliferative disease
comprising the COMBINATION OF THE INVENTION. In this composition,
the combination partners (a) and (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.
[0131] The pharmaceutical compositions 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 man. Alternatively, when
the agents are administered separately, one can be an enteral
formulation and the other can be administered parenterally.
[0132] The novel pharmaceutical composition contain, for example,
from about 10% to about 100%, preferably from about 20% to about
60%, of the active ingredients. 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, and furthermore
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.
[0133] In preparing the compositions for oral dosage form, any of
the usual pharmaceutical media may be employed, such as, for
example, water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents; or carriers such as starches,
sugars, microcrystalline cellulose, diluents, granulating agents,
lubricants, binders, disintegrating agents and the like in the case
of oral solid preparations such as, for example, powders, capsules
and tablets, with the solid oral preparations being preferred over
the liquid preparations. Because of their ease of administration,
tablets and capsules represent the most advantageous oral dosage
unit form in which case solid pharmaceutical carriers are obviously
employed.
[0134] 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 disease according to the invention may
comprise (i) administration of the first combination partner in
free or pharmaceutically acceptable salt form and (ii)
administration of the second combination partner in free or
pharmaceutically acceptable salt form, simultaneously or
sequentially in any order, in jointly therapeutically effective
amounts, preferably in synergistically effective amounts. The
individual combination partners of the COMBINATION OF THE INVENTION
can 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 regimes of simultaneous or
alternating treatment and the term "administering" is to be
interpreted accordingly.
[0135] The COMBINATION OF THE INVENTION can be a combined
preparation or a pharmaceutical composition.
[0136] Moreover, the present invention relates to a method of
treating a warm-blooded animal having a proliferative disease
comprising administering to the animal a COMBINATION OF THE
INVENTION in a quantity which is therapeutically effective against
said proliferative disease.
[0137] Furthermore, the present invention pertains to the use of a
COMBINATION OF THE INVENTION for the treatment of a proliferative
disease and for the preparation of a medicament for the treatment
of a proliferative disease.
[0138] Moreover, the present invention provides a commercial
package comprising as active ingredients COMBINATION OF THE
INVENTION, together with instructions for simultaneous, separate or
sequential use thereof in the delay of progression or treatment of
a proliferative disease.
[0139] Preferred embodiments of the invention are represented by
combinations comprising [0140] COMPOUND A, COMPOUND B or COMPOUND C
and Sorafenib, [0141] COMPOUND A, COMPOUND B or COMPOUND C and
RAF265
[0142] In another preferred embodiment, the invention provides
combinations comprising [0143] COMPOUND A and Sorafenib, Raf265,
SB590885, XL281 or PLX4032. [0144] COMPOUND B and Sorafenib,
Raf265, SB590885, XL281 or PLX4032. [0145] COMPOUND C and
Sorafenib, Raf265, SB590885, XL281 or PLX4032. [0146] COMPOUND A
and PD325901, PD-181461, ARRY142886/AZD6244, ARRY-509, XL518,
JTP-74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300,
RDEA436, E6201, RO4987655/R-7167, GSK1120212 or AS703026. [0147]
COMPOUND B and PD325901, PD-181461, ARRY142886/AZD6244, ARRY-509,
XL518, JTP-74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300,
RDEA436, E6201, RO4987655/R-7167, GSK1120212 or AS703026. [0148]
COMPOUND C and PD325901, PD-181461, ARRY142886/AZD6244, ARRY-509,
XL518, JTP-74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300,
RDEA436, E6201, RO4987655/R-7167, GSK1120212 or AS703026.
[0149] In further aspects, the present inventions provides [0150] a
combination which comprises (a) a COMBINATION OF THE INVENTION,
wherein the active ingredients are present in each case in free
form or in the form of a pharmaceutically acceptable salt or any
hydrate thereof, and optionally at least one pharmaceutically
acceptable carrier; for simultaneous, separate or sequential use;
[0151] a pharmaceutical composition comprising a quantity which is
jointly therapeutically effective against a proliferative disease
of a COMBINATION OF THE INVENTION and at least one pharmaceutically
acceptable carrier; [0152] the use of a COMBINATION OF THE
INVENTION for the treatment of a proliferative disease; [0153] the
use of a COMBINATION OF THE INVENTION for the preparation of a
medicament for the treatment of a proliferative disease; [0154] the
use of a combination COMBINATION OF THE INVENTION wherein the PI3K
inhibitor is selected from COMPOUND A, COMPOUND B or COMPOUND C;
[0155] the use of a COMBINATION OF THE INVENTION wherein the
compound which modulates the Ras/Raf/Mek pathway is compound which
modulates Raf kinase activity, e.g. Sorafenib, RAF265, SB590885,
XL281, PLX4032; and [0156] the use of COMBINATION OF THE INVENTION
wherein the compound which modulates the Ras/Raf/Mek pathway is a
compound which modulates Mek kinase activity, e.g. PD-0325901,
PD-181461, ARRY142886/AZD6244, ARRY-509, XL518, JTP-74057,
AS-701255, AS-701173, AZD8330, ARRY162, ARRY300, RDEA436, E6201,
RO4987655/R-7167, GSK1120212 or AS703026.
[0157] Moreover, in particular, the present invention relates to a
combined preparation, which comprises (a) one or more unit dosage
forms of a phosphoinositide 3-kinase inhibitor compound and (b) a
compound which modulates the Ras/Raf/Mek pathway.
[0158] Furthermore, in particular, the present invention pertains
to the use of a combination comprising (a) a phosphoinositide
3-kinase inhibitor compound and (b) a compound which modulates the
Ras/Raf/Mek pathway for the preparation of a medicament for the
treatment of a proliferative disease.
[0159] 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 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.
[0160] When the combination partners employed in the COMBINATION OF
THE INVENTION are applied in the form as marketed as single drugs,
their dosage and mode of administration can take place in
accordance with the information provided on the package insert of
the respective marketed drug in order to result in the beneficial
effect described herein, if not mentioned herein otherwise.
[0161] COMPOUND A may be administered to a human in a dosage range
varying from about 50 to 800 mg/day.
[0162] COMPOUND B may be administered to a human in a dosage range
varying from about 25 to 800 mg/day.
[0163] COMPOUND C may be administered to a human in a dosage range
varying from about 25 to 800 mg/day.
[0164] Sorafenib may be administered to a human in a dosage range
varying from about 75 to 800 mg/day, more preferable 400 mg taken
twice daily.
[0165] The following Examples illustrate the invention described
above; they are not, however, intended to limit the scope of the
invention in any way. The beneficial effects of the COMBINATION OF
THE INVENTION can also be determined by other test models known as
such to the person skilled in the pertinent art.
FIGURE LEGEND
[0166] FIG. 1: A549 cells were incubated either with compound A,
PD03251901 (250 nM) alone or in combination for 30 min. Cells were
then harvested and estimation of phosphorylated levels of either
Akt; p70S6K or ERK done by regular Western-blotting.
[0167] FIG. 2: Rat bearing BN472 tumors were treated with the
indicated compound at the indicated dose and schedule, either alone
or in combination. Evolution of tumor growth were followed by
callipering throughout the course of the study. *, P<0.05
(Dunnett's).
[0168] FIG. 3: Rat bearing BN472 tumors were treated with the
indicated compound at the indicated dose and schedule, either alone
or in combination. Evolution of body weight were followed
throughout the course of the study. *, P<0.05 (Dunnett's).
[0169] FIG. 4: KRAS mutant PANC1 cells were grown subcutaneously on
the flank of Harlan nude mice and treated with either compound A,
AZD6244 alone or in combination for 12 days. Evolutions of Tumor
volume (A) and body weight (B) were measured throughout the course
of the study. *, p<0.05 (Dunnett's).
[0170] FIG. 5: KRAS mutant MiaPaCa2 cells were grown subcutaneously
on the flank of Harlan nude mice and treated with either compound
A, AZD6244 alone or in combination for 12 days. Evolutions of Tumor
volume (A) and body weight (B) were measured throughout the course
of the study. *, p<0.05 (Dunnett's).
[0171] FIG. 6: KRAS mutant MiaPaCa2 cells were grown subcutaneously
on the flank of Harlan nude mice and treated with either
5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylam-
ine (COMPOUND C, termed here cpd B), AZD6244 alone or in
combination for 12 days. Evolutions of Tumor volume (A) and body
weight (B) were measured throughout the course of the study. *,
p<0.05 (Dunnett's).
EXAMPLES
Example 1
[0172] the MEK inhibitor PD0325901 synergizes with compound A in an
antiproliferative assay. The KRAS mutant NSCLC cell line was used
in a standard methylene blue proliferation assay. In this assay,
compound A and PD0325901 inhibited the proliferation with a GI50
(that is the concentration for which 50% of growth inhibition is
observed) of 9.41 and 36.8 nM respectively (Table 1). When tested
in combination, the GI50 for BEZ235 decrease to 3.2 nM, that is to
say to say that in presence of PD0325901, 3 times less BEZ235 is
required to observe a similar decrease in proliferation.
Conversely, the GI50 for PD0325901 decreased to 11.5 nM in presence
of compound A. The combination Index obtained is of 0.718, which
correspond to a moderate synergism (Table 2).
TABLE-US-00001 TABLE 1 GI50 (in nM) GI50 (in nM) Combination
Compound alone in combination Index (CI) Compound A 9.41 4.46 0.718
NVP-LBW624 36.8 11.5
[0173] A549 cells were incubated with increasing amount of either
compound A or PD0325901 (NVP-LBW624) alone or in combination, for
72 h and proliferation assessed with a standard methylene blue
assay. The GI50 were determined and Cl quantified with the CalcuSyn
software.
TABLE-US-00002 TABLE 2 CI Value Phenotypical response 1.1 to 10
antagonism 0.9 to 1.1 Nearly additive 0.85 to 0.9 Slight synergism
0.7 to 0.85 Moderate synergism 0.3 to 0.7 synergim 0.1 to 0.3
Strong synergism
Example 2
[0174] the MEK inhibitor and compound A when incubated in cells
alone do block their respective downstream effectors (ERK and Akt).
When A549 cells are incubated in the presence of both inhibitors,
then both pathway are effectively and simultaneously blocked (FIG.
1).
Example 3
[0175] In the BN472 tumor model administration of compound A at a
dose of 10 mg/kg (p.o., 1 q24 h) or the Raf inhibitor Raf265 (at a
dose of 2.5 mg/kg, po, &q24 h) produced a weak and not
significant antitumor activity (expressed as T/C) of either 83 and
76. The combination of compound A (10 mg/kg) with RAF265, however,
produced a strong and statistically significant antitumor activity
with a TIC of 34% (FIG. 2). The combination was well tolerated as
no effect on body weight could be measured (FIG. 3).
Example 4
[0176] KRAS mutant PANC1 cells were grown subcutaneously on the
flank of Harlan nude mice. Tumor bearing animals were then treated
with the indicated compounds and dosage regimen in FIG. 4.
Evolutions of Tumor volume (A) and body weight (B) were measured
throughout the course of the study, until day 12 at which time the
animals were sacrificed. *, p<0.05, One way ANOVA followed by
Tukey post hoc test, showing that the antitumor activity obtained
in the combo group is significantly different from the control and
single agent treated groups (synergistic activity between the two
compounds).
Example 5
[0177] KRAS mutant MiaPaCa2 cells were grown subcutaneously on the
flank of Harlan nude mice. Tumor bearing animals were then treated
with the indicated compounds and dosage regimen in FIGS. 5 and 6.
Evolutions of Tumor volume (A) and body weight (B) were measured
throughout the course of the study, until day 12 at which time the
animals were sacrificed. *, p<0.05, One way ANOVA followed by
Tukey post hoc test, showing that the antitumor activity obtained
in the combo group is significantly different from the control and
single agent treated groups (synergistic activity between the two
compounds).
* * * * *