U.S. patent application number 13/389266 was filed with the patent office on 2012-11-08 for methods of using c-met modulators.
This patent application is currently assigned to Exelixis, Inc.. Invention is credited to Dana T. Aftab, Jaymes Holland, Thomas Mueller, Aaron Weitzman.
Application Number | 20120282179 13/389266 |
Document ID | / |
Family ID | 42668075 |
Filed Date | 2012-11-08 |
United States Patent
Application |
20120282179 |
Kind Code |
A1 |
Aftab; Dana T. ; et
al. |
November 8, 2012 |
Methods of Using C-Met Modulators
Abstract
Methods of treating cancer by administering a compound of
Formula I, ##STR00001## or a pharmaceutically acceptable salt or
solvate thereof, in combination with other cancer treatments are
described, wherein R.sup.1 is halo; R.sup.2 is halo; and Q is CH or
N.
Inventors: |
Aftab; Dana T.; (San Rafael,
CA) ; Mueller; Thomas; (San Francisco, CA) ;
Weitzman; Aaron; (Los Altos, CA) ; Holland;
Jaymes; (South San Francisco, CA) |
Assignee: |
Exelixis, Inc.
South San Francisco
CA
|
Family ID: |
42668075 |
Appl. No.: |
13/389266 |
Filed: |
August 6, 2010 |
PCT Filed: |
August 6, 2010 |
PCT NO: |
PCT/US10/44749 |
371 Date: |
July 12, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61232382 |
Aug 7, 2009 |
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Current U.S.
Class: |
424/1.61 ;
424/130.1; 514/312; 514/393; 600/1 |
Current CPC
Class: |
A61K 31/4188 20130101;
A61K 45/06 20130101; A61N 5/10 20130101; A61P 35/00 20180101; A61K
31/47 20130101; A61P 43/00 20180101; A61K 31/495 20130101; A61K
31/4706 20130101; A61K 41/00 20130101; A61K 31/015 20130101; A61K
31/495 20130101; A61K 2300/00 20130101; A61K 31/4706 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/1.61 ;
514/312; 424/130.1; 514/393; 600/1 |
International
Class: |
A61K 31/47 20060101
A61K031/47; A61M 37/00 20060101 A61M037/00; A61K 51/02 20060101
A61K051/02; A61K 31/4188 20060101 A61K031/4188; A61P 35/00 20060101
A61P035/00; A61K 39/395 20060101 A61K039/395 |
Claims
1. A method of treating cancer, wherein the method comprises
administering to a patient in need of the treatment a compound of
Formula I: ##STR00016## or a pharmaceutically acceptable salt
thereof, in combination with temozolomide (TMZ) or radiation
therapy wherein: R.sup.1 is halo; R.sup.2 is halo; and Q is CH or
N.
2. A method of treating cancer, wherein the method comprises
administering to a patient in need of the treatment a compound of
Formula I: ##STR00017## or a pharmaceutically acceptable salt
thereof, in combination with radiation therapy (RT) wherein:
R.sup.1 is halo; R.sup.2 is halo; and Q is CH or N.
3. The method according to claim 1, wherein the compound of Formula
I is represented by the following structure: ##STR00018## or a
pharmaceutically acceptable salt thereof.
4. The method according to claim 1, wherein the compound of Formula
I is represented by the following structure: ##STR00019##
5. The method according to claim 1, wherein the compound of Formula
I, or a pharmaceutically acceptable salt thereof, further comprises
a pharmaceutically acceptable carrier, excipient, or diluent.
6. The method according to according to claim 1, further comprising
one or more additional treatment(s) selected from (1) surgery, (2)
one or more additional chemotherapeutic agent(s), (3) one or more
hormone therapy(s), (4) one or more antibody(s), (5) one or more
immunotherapy(ies), (6) radioactive iodine therapy, and (7)
radiation.
7. The method according to claim 1, wherein the compound of formula
I is administered with radiation therapy.
8. The method according to claim 1 comprising administering a
therapeutically effective dose of compound (I) or a
pharmaceutically acceptable salt thereof.
9. The method according to claim 1, comprising administering a
therapeutically effective dose of TMZ.
10. The method according to claim 2 comprising administering a
therapeutically effective dose of radiation.
11. The method according to claim 1, where the cancer is brain
cancer.
12. The method according to claim 1, where the cancer is selected
from astrocytoma, glioblastoma, giant cell glioblastoma,
gliosarcoma, and glioblastoma with oligodendroglial components.
13. The method according to claim 1, wherein the method comprises
(1) a concurrent phase, (2) a rest phase and (3) a maintenance
phase, wherein: the concurrent phase comprises administering
radiation and the compound of Formula I to the patient; the rest
phase comprises not administering the compound of Formula I or
radiation to the patient; and the maintenance phase comprises
administering the compound of Formula I to the patient.
14. The method according to claim 1, wherein the concurrent phase
is 7-8 weeks in duration, and the rest phase is about 4 weeks in
duration; and the maintenance phase is of a duration sufficient
slow down the cancer growth.
15. The method according to claim 1, wherein the compound of
Formula I is administered to the patient in 25-125 mg dosages daily
during the concurrent phase; TMZ is administered to the patient in
5-180 mg dosages daily to the patient during the concurrent phase;
RT is administered to the patient during the concurrent phase using
1.8-2 Gy/fraction, daily for 5 days/week for a total dose of up to
60 Gy; the compound of Formula I is administered to the patient in
25-125 mg dosages daily during the maintenance phase; and TMZ is
administered to the patient in 5-180 mg dosages for 5 consecutive
days and repeated every 28 days until the cancer growth is slowed
down.
Description
FIELD OF THE INVENTION
[0001] This invention relates to methods of using c-Met modulators,
and specifically c-Met modulators in combination with other
anti-cancer agents and/or radiation, which can be useful for the
modulation of various cellular activities and for the treatment of
various diseases as described in the specification.
BACKGROUND OF THE INVENTION
[0002] Traditionally, dramatic improvements in the treatment of
cancer are associated with identification of therapeutic agents
acting through novel mechanisms. One mechanism that can be
exploited in cancer treatment is the modulation of protein kinase
activity because signal transduction through protein kinase
activation is responsible for many of the characteristics of tumor
cells. Protein kinase signal transduction is of particular
relevance in, for example, thyroid, gastric, head and neck, lung,
breast, prostate, and colorectal cancers, as well as in the growth
and proliferation of brain tumor cells.
[0003] Protein kinases can be categorized as receptor type or
non-receptor type. Receptor-type tyrosine kinases are comprised of
a large number of transmembrane receptors with diverse biological
activity. For a detailed discussion of the receptor-type tyrosine
kinases, see Plowman et al., DN&P 7(6): 334-339, 1994. Since
protein kinases and their ligands play critical roles in various
cellular activities, deregulation of protein kinase enzymatic
activity can lead to altered cellular properties, such as
uncontrolled cell growth associated with cancer. In addition to
oncological indications, altered kinase signaling is implicated in
numerous other pathological diseases, including, for example,
immunological disorders, cardiovascular diseases, inflammatory
diseases, and degenerative diseases. Therefore, protein kinases are
attractive targets for small molecule drug discovery. Particularly
attractive targets for small-molecule modulation with respect to
antiangiogenic and antiproliferative activity include receptor type
tyrosine kinases Ret, c-Met, and VEGFR2.
[0004] The kinase c-Met is the prototypic member of a subfamily of
heterodimeric receptor tyrosine kinases (RTKs) which include Met,
Ron and Sea. The endogenous ligand for c-Met is the hepatocyte
growth factor (HGF), a potent inducer of angiogenisis. Binding of
HGF to c-Met induces activation of the receptor via
autophosphorylation resulting in an increase of receptor dependent
signaling, which promotes cell growth and invasion. Anti-HGF
antibodies or HGF antagonists have been shown to inhibit tumor
metastasis in vivo (See: Maulik et al Cytokine & Growth Factor
Reviews 2002 13, 41-59). c-Met, VEGFR2 and/or Ret overexpression
has been demonstrated on a wide variety of tumor types including
breast, colon, renal, lung, squamous cell myeloid leukemia,
hemangiomas, melanomas, astrocytomas, and glioblastomas. The Ret
protein is a transmembrane receptor with tyrosine kinase activity.
Ret is mutated in most familial forms of medullary thyroid cancer.
These mutations activate the kinase function of Ret and covert it
into an oncogene product.
[0005] Inhibition of EGF, VEGF and ephrin signal transduction will
prevent cell proliferation and angiogenesis, two key cellular
processes needed for tumor growth and survival (Matter A. Drug
Disc. Technol. 20016, 1005-1024). Kinase KDR (refers to kinase
insert domain receptor tyrosine kinase) and flt-4 (fms-like
tyrosine kinase-4) are both vascular endothelial growth factor
(VEGF) receptors. Inhibition of EGF, VEGF and ephrin signal
transduction will prevent cell proliferation and angiogenesis, two
key cellular processes needed for tumor growth and survival (Matter
A. Drug Disc. Technol. 20016, 1005-1024). EGF and VEGF receptors
are desirable targets for small molecule inhibition.
[0006] Glioblastoma is the most aggressive form of primary brain
tumor, with an incidence of 2.3 per 100,000 persons per year in the
United Sates. The median survival time following diagnosis is 12-15
months with current standard of care involving surgery followed by
radiation. It has been reported that targeting the MET pathway
potentiates GBM response to gamma-radiation (Lal et al, 2005). It
has also been report that MET expression correlate with high grade
GBM tumors (Hirose et al, 1998) and expression of HGF and MET
correlate with malignancy (Koochekpour et al, 1995; Abounader et
al, 2001, Uchinokura et al, 2006). It has also been reported that
the glioma derived stem cell factor induces angiogenesis within the
brain. SCF and VEGF may have complementary roles in the robust
angiogenic response in GBM (Sun et al, 2006).
[0007] Accordingly, small-molecule compounds that specifically
inhibit, regulate and/or modulate the signal transduction of
kinases, particularly including Ret, c-Met and VEGFR2 described
above, are particularly desirable as a means to treat or prevent
disease states associated with abnormal cell proliferation and
angiogenesis. One such small-molecule is
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, which has the chemical structure:
##STR00002##
[0008] WO 2005/030140 describes the synthesis of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide (Examples 25, 37, 38, and 48) and also
discloses the therapeutic activity of this molecule to inhibit,
regulate and/or modulate the signal transduction of kinases,
(Assays, Table 4, entry 289). Compound (I) has been measured to
have an c-Met IC.sub.50 value of 1.3 nanomolar (nM) and a Ret
IC.sub.50 value of 5.2 nanomolar (nM).
[0009] Thus, finding new uses of compounds for treating diseases by
using new combination therapies is desirable.
SUMMARY OF THE INVENTION
[0010] The summary of the invention only summarizes certain aspects
of the invention and is not intended to be limiting in nature.
These aspects and other aspects and embodiments are described more
fully below. All references cited in this specification are hereby
incorporated by reference in their entirety. In the event of a
discrepancy between the express disclosure of this specification
and the references incorporated by reference, the express
disclosure of this specification shall control.
[0011] One aspect of this disclosure relates to methods of treating
diseases, as defined in the detailed description herein below.
These methods of treatment include administering a Compound of
Formula I, wherein the compound of Formula I is as define in the
detailed description of the invention, to a patient in need of the
treatment, in combination with either temozolomide (TMZ) and/or
radiation therapy (RT) and optionally one or more additional
treatment(s), wherein the one or more additional treatment(s) are
as described in the detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0012] Aspect (I) of this disclosure relates to a method of
treating a disease comprising administering to a patient in need of
the treatment a compound of Formula I:
##STR00003##
or a pharmaceutically acceptable salt thereof, in combination with
temozolomide (TMZ) wherein: R' is halo; R.sup.2 is halo; and
Q is CH or N.
[0013] Aspect (II) of this disclosure relates to a method of
treating a disease comprising administering to a patient in need of
the treatment a compound of Formula I:
##STR00004##
or a pharmaceutically acceptable salt thereof, in combination with
radiation therapy (RT) wherein: R.sup.1 is halo; R.sup.2 is halo;
and
Q is CH or N.
[0014] In other embodiments of aspect (I) and Aspect (II) of this
disclosure the compound of Formula I, or a pharmaceutically
acceptable salt thereof, is a pharmaceutical composition which
further comprises a pharmaceutically acceptable carrier, excipient,
or diluent.
[0015] In other embodiments of Aspect (I), the method further
comprises administereing to the patient one or more additional
treatment(s), wherein the one or more treatment(s) are selected
from (1) surgery, (2) one or more additional chemotherapeutic
agent(s), (3) one or more hormone therapy(s), (4) one or more
antibody(s), and (5) one or more immunotherapy(ies), (6)
radioactive iodine therapy, and (7) radiation.
[0016] In other embodiments of Aspect (II), the method further
comprises administereing to the patient one or more additional
treatment(s), wherein the one or more treatment(s) are selected
from (1) surgery, (2) one or more additional chemotherapeutic
agent(s), (3) one or more hormone therapy(s), (4) one or more
antibody(s), and (5) one or more immunotherapy(ies).
[0017] In other embodiments of Aspect (I) and Aspect (II), the
compound of Formula I in any of the above embodiments is the
following compound:
##STR00005##
or a pharmaceutical salt thereof.
[0018] In other embodiments of Aspect (I) and Aspect (II), the
compound of Formula I in any of the above embodiments is the
following compound:
##STR00006##
[0019] The compound of Formula (I), and all of the embodiments of
the compound of Formula (I) as described herein, includes both the
recited compounds as well as individual isomers and mixtures of
isomers. In each instance, the compound of Formula (I) includes the
pharmaceutically acceptable salts, hydrates, and/or solvates of the
recited compounds and any individual isomers or mixture of isomers
thereof.
ABBREVIATIONS AND DEFINITIONS
[0020] The following abbreviations and terms have the indicated
meanings throughout:
TABLE-US-00001 Abbreviation Meaning Ac acetyl Br broad .degree. C.
degrees Celsius c- cyclo CBZ CarboBenZoxy = benzyloxycarbonyl d
doublet dd doublet of doublet dt doublet of triplet DCM
dichloromethane DME 1,2-dimethoxyethane DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphano)ferrocene
EI Electron Impact ionization
TABLE-US-00002 Abbreviation Meaning g gram(s) Gy Gray unit h or hr
hour(s) HPLC high pressure liquid chromatography L liter(s) M molar
or molarity m Multiplet mg milligram(s) MGMT O.sup.6-Methylguanine
methyltransferase MHz megahertz (frequency) Min minute(s) mL
milliliter(s) .mu.L microliter(s) .mu.M Micromole(s) or micromolar
mM Millimolar mmol millimole(s) mol mole(s) MS mass spectral
analysis N normal or normality nM Nanomolar NMR nuclear magnetic
resonance spectroscopy q Quartet RT Radiation Therapy s Singlet t
or tr Triplet TFA trifluoroacetic acid THF tetrahydrofuran TLC thin
layer chromatography
[0021] The symbol "-" means a single bond, "=" means a double
bond.
[0022] When chemical structures are depicted or described, unless
explicitly stated otherwise, all carbons are assumed to have
hydrogen substitution to conform to a valence of four. For example,
in the structure on the left-hand side of the schematic below there
are nine hydrogens implied. The nine hydrogens are depicted in the
right-hand structure. Sometimes a particular atom in a structure is
described in textual formula as having a hydrogen or hydrogens as
substitution (expressly defined hydrogen), for example,
--CH.sub.2CH.sub.2--. It is understood by one of ordinary skill in
the art that the aforementioned descriptive techniques are common
in the chemical arts to provide brevity and simplicity to
description of otherwise complex structures.
##STR00007##
[0023] If a group "R" is depicted as "floating" on a ring system,
as for example in the formula:
##STR00008##
then, unless otherwise defined, a substituent "R" may reside on any
atom of the ring system, assuming replacement of a depicted,
implied, or expressly defined hydrogen from one of the ring atoms,
so long as a stable structure is formed.
[0024] If a group "R" is depicted as floating on a fused ring
system, as for example in the formulae:
##STR00009##
then, unless otherwise defined, a substituent "R" may reside on any
atom of the fused ring system, assuming replacement of a depicted
hydrogen (for example the --NH-- in the formula above), implied
hydrogen (for example as in the formula above, where the hydrogens
are not shown but understood to be present), or expressly defined
hydrogen (for example where in the formula above, "Z" equals
.dbd.CH--) from one of the ring atoms, so long as a stable
structure is formed. In the example depicted, the "R" group may
reside on either the 5-membered or the 6-membered ring of the fused
ring system. In the formulas depicted above, there may more than
one R group (R.sub.y), wherein y is an integer of 1 or more. When y
is 2, for example, then the two "R's" may reside on any two atoms
of the ring system, again assuming each replaces a depicted,
implied, or expressly defined hydrogen on the ring.
[0025] When a group "R" is depicted as existing on a ring system
containing saturated carbons, as for example in the formula:
##STR00010##
where, in this example, "y" can be more than one, assuming each
replaces a currently depicted, implied, or expressly defined
hydrogen on the ring; then, unless otherwise defined, where the
resulting structure is stable, two "R's" may reside on the same
carbon. A simple example is when R is a methyl group; there can
exist a geminal dimethyl on a carbon of the depicted ring (an
"annular" carbon). In another example, two R's on the same carbon,
including that carbon, may form a ring, thus creating a spirocyclic
ring (a "spirocyclyl" group) structure with the depicted ring as
for example in the formula:
##STR00011##
[0026] "Halogen" or "halo" refers to fluorine, chlorine, bromine or
iodine.
[0027] "Yield" for each of the reactions described herein is
expressed as a percentage of the theoretical yield.
[0028] "Cancer" refers to cellular-proliferative disease states,
including but not limited to: Cardiac: sarcoma (angiosarcoma,
fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma,
fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma
(squamous cell, undifferentiated small cell, undifferentiated large
cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial
adenoma, sarcoma, lymphoma, chondromatous hanlartoma,
inesothelioma; Gastrointestinal: esophagus (squamous cell
carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach
(carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal
adenocarcinoma, insulinorna, glucagonoma, gastrinoma, carcinoid
tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid
tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma,
neurofibroma, fibroma), large bowel (adenocarcinoma, tubular
adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary
tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma],
lymphoma, leukemia), bladder and urethra (squamous cell carcinoma,
transitional cell carcinoma, adenocarcinoma), prostate
(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal
carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial
cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);
Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,
hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant
fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant
lymphoma (reticulum cell sarcoma), multiple myeloma, malignant
giant cell tumor chordoma, osteochronfroma (osteocartilaginous
exostoses), benign chondroma, chondroblastoma, chondromyxofibroma,
osteoid osteoma and giant cell tumors; Nervous system: skull
(osteoma, hemangioma, granuloma, xanthoma, osteitis deformians),
meninges (meningioma, meningiosarcoma, gliomatosis), brain
(astrocytoma, medulloblastoma, glioma, ependymoma, germinoma
[pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma,
retinoblastoma, congenital tumors), spinal cord neurofibroma,
meningioma, glioma, sarcoma); Gynecological: uterus (endometrial
carcinoma), cervix (cervical carcinoma, pre-tumor cervical
dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,
mucinous cystadenocarcinoma, unclassified carcinoma],
granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,
dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,
intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),
vagina (clear cell carcinoma, squamous cell carcinoma, botryoid
sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma);
Hematologic: blood (myeloid leukemia [acute and chronic], acute
lymphoblastic leukemia, chronic lymphocytic leukemia,
myeloproliferative diseases, multiple myeloma, myelodysplastic
syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant
lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous
cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma,
angioma, dermatofibroma, keloids, psoriasis; Adrenal Glands:
neuroblastoma; and breast cancer. Thus, the term "cancerous cell"
as provided herein, includes a cell afflicted by any one of the
above-identified conditions.
[0029] "Hormone therapy" or "hormonal therapy" includes, for
example, treatment with one or more of the following: steroids
(e.g. dexamethasone), finasteride, tamoxifen, and an aromatase
inhibitor.
[0030] "Patient" for the purposes of the present invention includes
humans and other animals, particularly mammals, and other
organisms. Thus the methods are applicable to both human therapy
and veterinary applications. In another embodiment the patient is a
mammal, and in another embodiment the patient is human.
[0031] A "pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. It is
understood that the pharmaceutically acceptable salts are
non-toxic. Additional information on suitable pharmaceutically
acceptable salts can be found in Remington's Pharmaceutical
Sciences, 17.sup.th ed., Mack Publishing Company, Easton, Pa.,
1985, which is incorporated herein by reference or S. M. Berge, et
al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19 both of
which are incorporated herein by reference.
[0032] Examples of pharmaceutically acceptable acid addition salts
include those formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric
acid, and the like; as well as organic acids such as acetic acid,
trifluoroacetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, oxalic acid, maleic acid, malonic acid, succinic acid,
fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic
acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,
4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,
p-toluenesulfonic acid, and salicylic acid and the like.
[0033] Examples of a pharmaceutically acceptable base addition
salts include those formed when an acidic proton present in the
parent compound is replaced by a metal ion, such as sodium,
potassium, lithium, ammonium, calcium, magnesium, iron, zinc,
copper, manganese, aluminum salts and the like. Specific salts are
the ammonium, potassium, sodium, calcium, and magnesium salts.
Salts derived from pharmaceutically acceptable organic non-toxic
bases include, but are not limited to, salts of primary, secondary,
and tertiary amines, substituted amines including naturally
occurring substituted amines, cyclic amines and basic ion exchange
resins. Examples of organic bases include isopropylamine,
trimethylamine, diethylamine, triethylamine, tripropylamine,
ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, ethylenediamine, glucosamine,
methylglucamine, theobromine, purines, piperazine, piperidine,
N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine
resins, and the like. Exemplary organic bases are isopropylamine,
diethylamine, ethanolamine, trimethylamine, dicyclohexylamine,
choline, and caffeine.
[0034] "Platin(s)," and "platin-containing agent(s)" include, for
example, cisplatin, carboplatin, and oxaliplatin.
[0035] "Prodrug" refers to compounds that are transformed
(typically rapidly) in vivo to yield the parent compound of the
above formulae, for example, by hydrolysis in blood. Common
examples include, but are not limited to, ester and amide forms of
a compound having an active form bearing a carboxylic acid moiety.
Examples of pharmaceutically acceptable esters of the compounds of
this invention include, but are not limited to, alkyl esters (for
example with between about one and about six carbons) the alkyl
group is a straight or branched chain. Acceptable esters also
include cycloalkyl esters and arylalkyl esters such as, but not
limited to benzyl. Examples of pharmaceutically acceptable amides
of the compounds of this invention include, but are not limited to,
primary amides, and secondary and tertiary alkyl amides (for
example with between about one and about six carbons). Amides and
esters of the compounds of the present invention may be prepared
according to conventional methods. A thorough discussion of
prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as
Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and
in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987, both
of which are incorporated herein by reference for all purposes.
[0036] "Taxane(s)" includes, for example, one or more of the
following: Paclitaxel (Taxol.RTM.) and Docetaxel
(Taxotere.RTM.).
[0037] "Therapeutically effective amount" is an amount of a
compound of the invention, that when administered to a patient,
ameliorates a symptom of the disease. A therapeutically effective
amount is intended to include an amount of a compound alone or in
combination with other active ingredients effective to modulate
Ret, c-Met, and/or VEGFR2, or effective to treat or prevent cancer.
The amount of a compound of the invention which constitutes a
"therapeutically effective amount" will vary depending on the
compound, the disease state and its severity, the age of the
patient to be treated, and the like. The therapeutically effective
amount can be determined routinely by one of ordinary skill in the
art having regard to their knowledge and to this disclosure.
[0038] "Topoisomerase inhibitor" includes, for example, one or more
of the following: amsacrine, camptothecin, etoposide, etoposide
phosphate, exatecan, irinotecan, lurtotecan, and teniposide, and
topotecan.
[0039] "Treating" or "treatment" of a disease, disorder, or
syndrome, as used herein, includes (i) preventing the disease,
disorder, or syndrome from occurring in a human, i.e. causing the
clinical symptoms of the disease, disorder, or syndrome not to
develop in an animal that may be exposed to or predisposed to the
disease, disorder, or syndrome but does not yet experience or
display symptoms of the disease, disorder, or syndrome; (ii)
inhibiting the disease, disorder, or syndrome, i.e., arresting its
development; and (iii) relieving the disease, disorder, or
syndrome, i.e., causing regression of the disease, disorder, or
syndrome. As is known in the art, adjustments for systemic versus
localized delivery, age, body weight, general health, sex, diet,
time of administration, drug interaction and the severity of the
condition may be necessary, and will be ascertainable with routine
experimentation by one of ordinary skill in the art.
ADDITIONAL EMBODIMENTS OF THE INVENTION
[0040] In another embodiment of Aspect (I) or Aspect (II) of this
disclosure, the disease being treated is selected from astocytoma,
glioblastoma, giant cell glioblastoma, gliosarcoma, and
glioblastoma with oligodendroglial components.
[0041] In another embodiment of Aspect (I) of this disclosure, the
method further comprises administering radiation therapy to the
patient.
[0042] In another embodiment of Aspect (I) of this disclosure, the
disease is selected from astocytoma, glioblastoma, giant cell
glioblastoma, gliosarcoma, and glioblastoma with oligodendrogilial
components; and the method further comprises administering
radiation therapy to the patient.
[0043] In another embodiment of Aspect (I) or Aspect (II) of this
disclosure, the disease is selected from astocytoma, glioblastoma,
giant cell glioblastoma, gliosarcoma, and glioblastoma with
oligodendrogilial components; and the method further comprises
administering surgury to the patient.
[0044] In another embodiment of Aspect (I) of this disclosure, the
disease is selected from astocytoma, glioblastoma, giant cell
glioblastoma, gliosarcoma, and glioblastoma with oligodendrogilial
components; and the method further comprises administering
radiation therapy and surgery to the patient.
[0045] Non-limiting examples of the additional chemotherapeutic
agent(s) that can be used in any of the above embodiments include
rapamycin, a rapamycin analogue, an alkylating agent(s), a
taxane(s), and a platin(s). In chemotherapeutic agent(s) is
selected from rapamycin, temozolomide, paclitaxel, docetaxel,
carboplatin, cisplatin, oxaliplatin, gefitinib (Iressa.RTM.),
erlotinib (Tarceva.RTM.), Zactima (ZD6474), HKI-272, pelitinib,
canertinib, and lapatinib.
[0046] A non-limiting example of the antibody that can be used as
the one or more additional treatments in Aspect (I) or Aspect (II)
of this disclosure is panitumumab.
[0047] In another embodiment of Aspect (I) or (II) of this
disclosure, the one or more additional treatments is one or more
hormone therapy(s). Non-limiting examples of the hormone therapy(s)
that can be used in this embodiment include tamoxifen, Toremifene
(Fareston), Fulvestrant (Faslodex), Megestrol acetate (Megace),
ovarian ablation, Raloxifene, a luteinizing hormone-releasing
hormone (LHRH) analog (including goserelin and leuprolide),
Megestrol acetate (Megace), and one or more aromatase inhibitor(s);
in another embodiment, one or more of the aromatase inhibitor(s) is
selected from letrozole (Femara), anastrozole (Arimidex), and
exemestane (Aromasin). In another embodiment, one or more of the
hormone therapy(s) is selected from tamoxifen and an aromatase
inhibitor.
[0048] In another embodiment of Aspect (I) or Aspect (II) of this
disclosure, the disease is an astrocytic tumor selected from
astocytoma, glioblastoma, giant cell glioblastoma, gliosarcoma, and
glioblastoma with oligodendroglial components, and the one or more
treatment(s) are selected from (1) surgery, (2) radiation, (3) one
or more additional chemotherapeutic agent(s), (4) one or more
anti-seizure agent(s), and (5) one or more agent(s) to reduce
swelling. Non-limiting examples of the radiation treatment that can
be used in this embodiment include external beam radiation,
interstitial radiotherapy, and stereotactic radiosurgery.
Non-limiting examples of the additional chemotherapeutic agent(s)
that can be used in this embodiment include carmustine (BCNU),
Erlotinib (Tarceva), bevacizumab, gefitinib (Iressa), rapamycin,
cisplatin, BCNU, lomustine, procarbazine, and vincristine. A
non-limiting examples of the antiseizure agent(s) that can be used
in this embodiment is diphenylhydantoin (Dilantin). A non-limiting
example of the agent that can be used to reduce swelling in this
embodiment include dexamethasone (Decadron).
[0049] In another embodiment of Aspect (I) of this disclosure, the
one or more additional treatments are radiation and surgery.
[0050] In another embodiment of Aspect (I) of this disclosure, the
one or more additional treatments are radiation and one or more
additional chemotherapeutic agent(s).
[0051] In another embodiment of Aspect (I) or Aspect (II) of this
disclosure, the one or more additional treatments are surgery and
one or more additional chemotherapeutic agent(s).
[0052] In another embodiment, treatment for patients with GB
comprises a (1) "concurrent phase," which is followed by a (2)
"rest phase," which is followed by a (3) "maintenance phase."
[0053] The concurrent phase is followed by a (2) "rest phase which
can range from about 2 weeks to about 8 weeks in duration. The rest
phase is meant to allow for recovery from delayed toxicity, if
present. In another embodiment, the rest phase can range from about
3 weeks to about 6 weeks in duration. In another embodiment, the
rest phase is about 4 weeks in duration.
[0054] The rest phase is followed by a (3) "maintenance phase,"
during which patients receive active pharmaceutical ingredients for
approximately twelve 28-day cycles, but can vary from about six to
about twenty four 28-day cycles. In various embodiments, patients
receive different amounts of the compound of Formula I at different
times according to the phase of TMZ and radiation therapy.
Concurrent Phase
[0055] During the concurrent phase, the compound of Formula I, in
one embodiment, can be administered to the patient concurrently
with RT and TMZ for 3-12 weeks, or 4-10 weeks, or 6-7 weeks. In
another embodiment, for patients having a mutation in the MGMT
promoter wherein the mutated MGMT promoter is an unmethylated
promoter, the compound of Formula I will be administered to the
patient concurrently with RT for 6-7 weeks in the concurrent phase.
The concurrent phase can range from about 3 weeks to about 12 weeks
in duration. In another embodiment, the concurrent phase ranges
from about 4 weeks to about 10 weeks in duration. In another
embodiment, the concurrent phase ranges from about 6 weeks to about
8 weeks in duration. In another embodiment, the concurrent phase
ranges from about 6 weeks to about 7 weeks in duration. During the
concurrent phase, active pharmaceutical ingredients are given with
(RT). In another embodiment, the active pharmaceutical
ingredient(s) in the concurrent phase are TMZ and the compound of
Formula I. In another embodiment, the active pharmaceutical
ingredient in the concurrent phase is TMZ provided that the
compound of Formula I is at least one of the active pharmaceutical
ingredients in the maintenance phase. In another embodiment, the
active pharmaceutical ingredient in the concurrent phase is the
compound of Formula I.
Rest Phase
[0056] During the rest phase, no RT, compounds of Formula I, or TMZ
is administered to the patient. The rest phase can range from about
2 weeks to about 12 weeks. In another embodiment, the rest phase
can range from about 3 weeks to about 6 weeks in duration. In
another embodiment, the rest phase range is about 4 weeks in
duration.
Maintenance Phase
[0057] In one embodiment of the maintenance phase, the compound of
Formula I is administered to the patient. In another embodiment of
the maintenance phase, temozolomide and the compound of Formula I
are both administered to the patient. In another embodiment of the
maintenance phase, temozolomide and the compound of Formula I are
each administered to the patient for a period of time ranging from
about 4 months to about 10 months. In another embodiment of the
maintenance phase, temozolomide and the compound of Formula I are
each administered to the patient for about 4 months. In another
embodiment of the maintenance phase, temozolomide and the compound
of Formula I are each administered to the patient for about 5
months. In another embodiment of the maintenance phase,
temozolomide and the compound of Formula I are each administered to
the patient for about 6 months. In another embodiment of the
maintenance phase, temozolomide and the compound of Formula I are
each administered to the patient for about 7 months. In another
embodiment of the maintenance phase, temozolomide and the compound
of Formula I are each administered to the patient for about 8
months. In another embodiment of the maintenance phase,
temozolomide and the compound of Formula I are each administered to
the patient for about 9 months. In another embodiment of the
maintenance phase, temozolomide and the compound of Formula I are
each administered to the patient for about 10 months. In another
embodiment of the maintenance phase, the compound of Formula I is
administered to the patient for period of time ranging from about 4
months to about 10 months. In another embodiment of the maintenance
phase, the compound of Formula I is administered for about 4
months. In another embodiment of the maintenance phase, the
compound of Formula I is administered for about 5 months. In
another embodiment of the maintenance phase, the compound of
Formula I is administered for about 6 months. In another embodiment
of the maintenance phase, the compound of Formula I is administered
for about 7 months. In another embodiment of the maintenance phase,
the compound of Formula I is administered for about 8 months. In
another embodiment of the maintenance phase the compound of Formula
I is administered for about 9 months. In another embodiment of the
maintenance phase, the compound of Formula I is administered for 10
months.
[0058] During the maintenance phase, the compound of Formula I can
be administered daily as a single oral agent as a 10-200 mg dosages
(which can be in capsules or tablets). In another embodiment of the
maintenance phase, the compound of Formula I can be administered
daily as a single oral agent as a 25-125 mg dosage, or 25-100 mg
dosage, (which can be in a capsule or tablet). Also during the
maintenance phase, TMZ can be administered for 5 consecutive days
and repeated every 28 days. TMZ, during the maintenance phase, can
be administered to the patient as 5-300 mg dosages (which can be in
capsules or tablets) to the patient.
[0059] For purposes of this disclosure, for all examples that are
disclosed herein that refer to the compound of Formula I or
temozolomide in dosage amounts in milligrams (mg), it is to be read
as mg of the compound in question, and this dosage amount can be
administered in any form, including tablet and capsule form. The
examples of capsule or tablet forms, that are within the
parenthesis after the dosage amounts, are non-limiting examples of
how the dosages can be administered and these examples are meant to
be non-limiting. For example, in the above embodiment, TMZ can be
administered in other modes in addition to capsules or tablets,
which are meant to be only non-limiting examples of how the dosage
amount can be administered.
[0060] In non-limiting examples in all of the above embodiments
(including the concurrent and maintenance phases), the compound of
Formula I can be administered in 5 mg, 10 mg, 15 mg, 20 mg, 25 mg,
30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75
mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120
mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg,
165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg
dosages (which can be in capsules or tablets).
[0061] In non-limiting examples in all of the above embodiments
(including the concurrent and maintenance phases), TMZ can be
administered in 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40
mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg,
90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130
mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg,
175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215
mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg,
260 mg, 265 mg, 260 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, and
300 mg dosages (which can be in capsules or tablets).
[0062] In another embodiment of Aspect (I) or Aspect (II) of this
disclosure, the concurrent phase comprises administereing radiation
and the compound of Formula I to the patient; the rest phase
comprises not administering the compound of Formula I or radiation
to the patient; and the maintenance phase comprises administereing
the compound of Formula I to the patient. In one subembodiment of
this embodiment, the concurrent phase can be 7-8 weeks in duration,
the rest phase can be about 4 weeks in duration; and the
maintenance phase is of a duration sufficient slow down the cancer
growth. In another subembodiment of this embodiment, the compound
of Formula I is administered to the patient in 25-100 mg dosages,
or 25-125 mg dosages, (which can be in capsules or tablets) daily
during the concurrent phase; TMZ is administered to the patient in
5-180 mg dosages (which can be in capsules or tablets) daily to the
patient during the concurrent phase; RT is administered to the
patient during the concurrent phase using 1.8-2 Gy/fraction, daily
for 5 days/week for a total dose of up to 60 Gy; the compound of
Formula I is administered to the patient in 25-100 mg dosages, or
25-125 mg dosages, (which can be in capsules or tablets) daily
during the maintenance phase; and TMZ is administered to the
patient in 5-180 mg dosages (which can be in capsules or tablets)
for 5 consecutive days and repeated every 28 days until the cancer
growth is slowed down.
[0063] In other embodiments of any of the above embodiments of
Aspect (I) and Aspect (II), the Compound of Formula I is the
following compound:
##STR00012##
or a pharmaceutical salt thereof.
[0064] In another embodiment, the compound of Formula I is the
(L)-malate salt form of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide having the following structure:
##STR00013##
General Administration
[0065] In one aspect, the invention provides pharmaceutical
compositions comprising a compound of Formula I as described above
and a pharmaceutically acceptable carrier, excipient, or diluent.
In certain other embodiments, administration is by the oral route.
Administration of the compound of Formula I, or their
pharmaceutically acceptable salts, in pure form or in an
appropriate pharmaceutical composition, can be carried out via any
of the accepted modes of administration or agents for serving
similar utilities. Thus, administration can be, for example,
orally, nasally, parenterally (intravenous, intramuscular, or
subcutaneous), topically, transdermally, intravaginally,
intravesically, intracistemally, or rectally, in the form of solid,
semi-solid, lyophilized powder, or liquid dosage forms, such as for
example, tablets, suppositories, pills, soft elastic and hard
gelatin dosages (which can be in capsules or tablets), powders,
solutions, suspensions, or aerosols, or the like, specifically in
unit dosage forms suitable for simple administration of precise
dosages.
[0066] The compositions will include a conventional pharmaceutical
carrier or excipient and a compound of Formula I as the/an active
agent, and, in addition, may include carriers and adjuvants,
etc.
[0067] Adjuvants include preserving, wetting, suspending,
sweetening, flavoring, perfuming, emulsifying, and dispensing
agents. Prevention of the action of microorganisms can be ensured
by various antibacterial and antifungal agents, for example,
parabens, chlorobutanol, phenol, sorbic acid, and the like. It may
also be desirable to include isotonic agents, for example sugars,
sodium chloride, and the like. Prolonged absorption of the
injectable pharmaceutical form can be brought about by the use of
agents delaying absorption, for example, aluminum monostearate and
gelatin.
[0068] If desired, a pharmaceutical composition of the compound of
Formula I may also contain minor amounts of auxiliary substances
such as wetting or emulsifying agents, pH buffering agents,
antioxidants, and the like, such as, for example, citric acid,
sorbitan monolaurate, triethanolamine oleate, butylated
hydroxytoluene, etc.
[0069] The choice of formulation depends on various factors such as
the mode of drug administration (e.g., for oral administration,
formulations in the form of tablets, pills or capsules) and the
bioavailability of the drug substance. Recently, pharmaceutical
formulations have been developed especially for drugs that show
poor bioavailability based upon the principle that bioavailability
can be increased by increasing the surface area i.e., decreasing
particle size. For example, U.S. Pat. No. 4,107,288 describes a
pharmaceutical formulation having particles in the size range from
10 to 1,000 nm in which the active material is supported on a
crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684
describes the production of a pharmaceutical formulation in which
the drug substance is pulverized to nanoparticles (average particle
size of 400 nm) in the presence of a surface modifier and then
dispersed in a liquid medium to give a pharmaceutical formulation
that exhibits remarkably high bioavailability.
[0070] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents or vehicles include water, ethanol, polyols
(propyleneglycol, polyethyleneglycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions and by the use of surfactants.
[0071] One specific route of administration is oral, using a
convenient daily dosage regimen that can be adjusted according to
the degree of severity of the disease-state to be treated.
[0072] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is admixed with at least one inert customary
excipient (or carrier) such as sodium citrate or dicalcium
phosphate or (a) fillers or extenders, as for example, starches,
lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders,
as for example, cellulose derivatives, starch, alignates, gelatin,
polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as
for example, glycerol, (d) disintegrating agents, as for example,
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, croscarmellose sodium, complex silicates, and sodium
carbonate, (e) solution retarders, as for example paraffin, (f)
absorption accelerators, as for example, quaternary ammonium
compounds, (g) wetting agents, as for example, cetyl alcohol, and
glycerol monostearate, magnesium stearate and the like (h)
adsorbents, as for example, kaolin and bentonite, and (i)
lubricants, as for example, talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, or
mixtures thereof. In the case of capsules, tablets, and pills, the
dosage forms may also comprise buffering agents.
[0073] Solid dosage forms as described above can be prepared with
coatings and shells, such as enteric coatings and others well known
in the art. They may contain pacifying agents, and can also be of
such composition that they release the active compound or compounds
in a certain part of the intestinal tract in a delayed manner.
Examples of embedded compositions that can be used are polymeric
substances and waxes. The active compounds can also be in
microencapsulated form, if appropriate, with one or more of the
above-mentioned excipients.
[0074] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. Such dosage forms are prepared, for example,
by dissolving, dispersing, etc., the compound of Formula I, or a
pharmaceutically acceptable salt thereof, and optional
pharmaceutical adjuvants in a carrier, such as, for example, water,
saline, aqueous dextrose, glycerol, ethanol and the like;
solubilizing agents and emulsifiers, as for example, ethyl alcohol,
isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,
dimethylformamide; oils, in particular, cottonseed oil, groundnut
oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol,
tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid
esters of sorbitan; or mixtures of these substances, and the like,
to thereby form a solution or suspension.
[0075] Suspensions, in addition to the active compounds, may
contain suspending agents, as for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, or mixtures of these substances, and the
like.
[0076] Compositions for rectal administrations are, for example,
suppositories that can be prepared by mixing the compound of
Formula I with, for example, suitable non-irritating excipients or
carriers such as cocoa butter, polyethyleneglycol or a suppository
wax, which are solid at ordinary temperatures but liquid at body
temperature and therefore, melt while in a suitable body cavity and
release the active component therein.
[0077] Dosage forms for topical administration of the compound of
Formula I include ointments, powders, sprays, and inhalants. The
active component is admixed under sterile conditions with a
physiologically acceptable carrier and any preservatives, buffers,
or propellants as may be required. Ophthalmic formulations, eye
ointments, powders, and solutions are also contemplated as being
within the scope of this disclosure.
[0078] Compressed gases may be used to disperse the compound of
Formula I in aerosol form. Inert gases suitable for this purpose
are nitrogen, carbon dioxide, etc.
[0079] Generally, depending on the intended mode of administration,
the pharmaceutically acceptable compositions will contain about 1%
to about 99% by weight of a compound(s) of Formula I, or a
pharmaceutically acceptable salt thereof, and 99% to 1% by weight
of a suitable pharmaceutical excipient. In one example, the
composition will be between about 5% and about 75% by weight of a
compound(s) of Formula I, or a pharmaceutically acceptable salt
thereof, with the rest being suitable pharmaceutical
excipients.
[0080] Actual methods of preparing such dosage forms are known, or
will be apparent, to those skilled in this art; for example, see
Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing
Company, Easton, Pa., 1990). The composition to be administered
will, in any event, contain a therapeutically effective amount of a
compound of Formula I, or a pharmaceutically acceptable salt
thereof, for treatment of a disease-state in accordance with the
teachings of this disclosure.
[0081] The compounds of this disclosure, or their pharmaceutically
acceptable salts or solvates, are administered in a therapeutically
effective amount which will vary depending upon a variety of
factors including the activity of the specific compound employed,
the metabolic stability and length of action of the compound, the
age, body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity
of the particular disease-states, and the host undergoing therapy.
The compound of Formula I can be administered to a patient at
dosage levels in the range of about 0.1 to about 1,000 mg per day.
For a normal human adult having a body weight of about 70
kilograms, a dosage in the range of about 0.01 to about 100 mg per
kilogram of body weight per day is an example. The specific dosage
used, however, can vary. For example, the dosage can depend on a
number of factors including the requirements of the patient, the
severity of the condition being treated, and the pharmacological
activity of the compound being used. The determination of optimum
dosages for a particular patient is well known to one of ordinary
skill in the art.
[0082] If formulated as a fixed dose, such combination products
employ the compound of Formula I within the dosage range described
above and the other pharmaceutically active agent(s) within its
approved dosage range. Compounds of Formula I may alternatively be
used sequentially with known pharmaceutically acceptable agent(s)
when a combination formulation is inappropriate.
General Synthesis
[0083] Compounds of this invention can be made by the synthetic
procedures described below. These procedures are merely
illustrative of some methods by which the compounds of Formula I
can be synthesized, and various modifications to these procedures
can be made. The starting materials and the intermediates of the
reaction may be isolated and purified if desired using conventional
techniques, including but not limited to filtration, distillation,
crystallization, chromatography and the like. Such materials may be
characterized using conventional means, including physical
constants and spectral data.
[0084] The disclosure is further illustrated by the following
examples, which are not to be construed as limiting the disclosure
in scope or spirit to the specific procedures described in
them.
EXAMPLES
Example 1A
Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide and the (L)-malate salt thereof
[0085] A synthetic route that has been used for the preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide and the (L)-malate salt thereof is
depicted in FIG. 1:
##STR00014##
[0086] The process above is described in more detail below.
Preparation of 4-Chloro-6,7-dimethoxy-quinoline
[0087] A reactor was charged sequentially with
6,7-dimethoxy-quinoline-4-ol (10.0 kg) and acetonitrile (64.0 L).
The resulting mixture was heated to approximately 65.degree. C. and
phosphorus oxychloride (POCl.sub.3, 50.0 kg) was added. After the
addition of POCl.sub.3, the temperature of the reaction mixture was
raised to approximately 80.degree. C. The reaction was deemed
complete (approximately 9.0 hours) when <2% of the starting
material remained (in process high-performance liquid
chromotography [HPLC] analysis). The reaction mixture was cooled to
approximately 10.degree. C. and then quenched into a chilled
solution of dichloromethane (DCM, 238.0 kg), 30% NH.sub.4OH (135.0
kg), and ice (440.0 kg). The resulting mixture was warmed to
approximately 14.degree. C., and phases were separated. The organic
phase was washed with water (40.0 kg) and concentrated by vacuum
distillation with the removal of solvent (approximately 190.0 kg).
Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and
the mixture was cooled to approximately 10.degree. C., during which
time the product crystallized out. The solids were recovered by
centrifugation, washed with n heptane (20.0 kg), and dried at
approximately 40.degree. C. to afford the title compound (8.0
kg).
Preparation of 6,7-dimethyl-4-(4-nitro-phenoxy)-quinoline
[0088] A reactor was sequentially charged with
4-chloro-6,7-dimethoxy-quinoline (8.0 kg), 4 nitrophenol (7.0 kg),
4 dimethylaminopyridine (0.9 kg), and 2,6 lutidine (40.0 kg). The
reactor contents were heated to approximately 147.degree. C. When
the reaction was complete (<5% starting material remaining as
determined by in process HPLC analysis, approximately 20 hours),
the reactor contents were allowed to cool to approximately
25.degree. C. Methanol (26.0 kg) was added, followed by potassium
carbonate (3.0 kg) dissolved in water (50.0 kg). The reactor
contents were stirred for approximately 2 hours. The resulting
solid precipitate was filtered, washed with water (67.0 kg), and
dried at 25.degree. C. for approximately 12 hours to afford the
title compound (4.0 kg).
Preparation of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine
[0089] A solution containing potassium formate (5.0 kg), formic
acid (3.0 kg), and water (16.0 kg) was added to a mixture of
6,7-dimethoxy-4-(4 nitro-phenoxy)-quinoline (4.0 kg), 10% palladium
on carbon (50% water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that
had been heated to approximately 60.degree. C. The addition was
carried out such that the temperature of the reaction mixture
remained approximately 60.degree. C. When the reaction was deemed
complete as determined using in-process HPLC analysis (<2%
starting material remaining, typically 15 hours), the reactor
contents were filtered. The filtrate was concentrated by vacuum
distillation at approximately 35.degree. C. to half of its original
volume, which resulted in the precipitation of the product. The
product was recovered by filtration, washed with water (12.0 kg),
and dried under vacuum at approximately 50.degree. C. to afford the
title compound (3.0 kg).
Preparation of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic
acid
[0090] Triethylamine (8.0 kg) was added to a cooled (approximately
4.degree. C.) solution of commercially available
cyclopropane-1,1-dicarboxylic acid (21, 10.0 kg) in THF (63.0 kg)
at a rate such that the batch temperature did not exceed 10.degree.
C. The solution was stirred for approximately 30 minutes, and then
thionyl chloride (9.0 kg) was added, keeping the batch temperature
below 10.degree. C. When the addition was complete, a solution of
4-fluoroaniline (9.0 kg) in THF (25.0 kg) was added at a rate such
that the batch temperature did not exceed 10.degree. C. The mixture
was stirred for approximately 4 hours and then diluted with
isopropyl acetate (87.0 kg). This solution was washed sequentially
with aqueous sodium hydroxide (2.0 kg dissolved in 50.0 L of
water), water (40.0 L), and aqueous sodium chloride (10.0 kg
dissolved in 40.0 L of water). The organic solution was
concentrated by vacuum distillation followed by the addition of
heptane, which resulted in the precipitation of solid. The solid
was recovered by centrifugation and then dried at approximately
35.degree. C. under vacuum to afford the title compound. (10.0
kg).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl
chloride
[0091] Oxalyl chloride (1.0 kg) was added to a solution of
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (2.0 kg)
in a mixture of THF (11 kg) and N,N-dimethylformamide (DMF; 0.02
kg) at a rate such that the batch temperature did not exceed
30.degree. C. This solution was used in the next step without
further processing.
Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide
[0092] The solution from the previous step containing
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was
added to a mixture of
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg) and
potassium carbonate (4.0 kg) in THF (27.0 kg) and water (13.0 kg)
at a rate such that the batch temperature did not exceed 30.degree.
C. When the reaction was complete (in typically 10 minutes), water
(74.0 kg) was added. The mixture was stirred at 15-30.degree. C.
for approximately 10 hours, which resulted in the precipitation of
the product. The product was recovered by filtration, washed with a
pre made solution of THF (11.0 kg) and water (24.0 kg), and dried
at approximately 65.degree. C. under vacuum for approximately 12
hours to afford the title compound (free base, 5.0 kg). .sup.1H NMR
(400 MHz, d.sub.6-DMSO): .delta. 10.2 (s, 1H), 10.05 (s, 1H), 8.4
(s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25
(m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H).
LC/MS: M+H=502.
Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide, (L) malate salt
[0093] A solution of L-malic acid (2.0 kg) in water (2.0 kg) was
added to a solution of cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide
(4-fluoro-phenyl)-amide free base (15, 5.0 kg) in ethanol,
maintaining a batch temperature of approximately 25.degree. C.
Carbon (0.5 kg) and thiol silica (0.1 kg) were then added, and the
resulting mixture was heated to approximately 78.degree. C., at
which point water (6.0 kg) was added. The reaction mixture was then
filtered, followed by the addition of isopropanol (38.0 kg), and
was allowed to cool to approximately 25.degree. C. The product was
recovered by filtration and washed with isopropanol (20.0 kg) and
dried at approximately 65.degree. C. to afford the title compound
(5.0 kg).
Example 1B
Preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide and the (L)-malate salt thereof
[0094] Another synthetic route that has been used for the
preparation of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide and the (L)-malate salt thereof is
depicted in FIG. 2:
##STR00015##
Preparation of 4-Chloro-6,7-dimethoxy-quinoline
[0095] A reactor was charged sequentially with
6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg).
The resulting mixture was heated to approximately 60.degree. C. and
phosphorus oxychloride (POCl.sub.3, 130.6 kg) was added. After the
addition of POCl.sub.3, the temperature of the reaction mixture was
raised to approximately 77.degree. C. The reaction was deemed
complete (approximately 13 hours) when <3% of the starting
material remained (in-process high-performance liquid
chromatography [HPLC] analysis). The reaction mixture was cooled to
approximately 2-7.degree. C. and then quenched into a chilled
solution of dichloromethane (DCM, 482.8 kg), 26% NH.sub.4OH (251.3
kg), and water (900 L). The resulting mixture was warmed to
approximately 20-25.degree. C., and phases were separated. The
organic phase was filtered through a bed of AW hyflo super-cel NF
(Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg).
The combined organic phase was washed with brine (282.9 kg) and
mixed with water (120 L). The phases were separated and the organic
phase was concentrated by vacuum distillation with the removal of
solvent (approximately 95 L residual volume). DCM (686.5 kg) was
charged to the reactor containing organic phase and concentrated by
vacuum distillation with the removal of solvent (approximately 90 L
residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then
charged and the temperature of the mixture was adjusted to -20 to
-25.degree. C. and held for 2.5 hours resulting in solid
precipitate which was then filtered and washed with n-heptane (92.0
kg), and dried on a filter at approximately 25.degree. C. under
nitrogen to afford the title compound. (35.6 kg).
Preparation of 4-(6, 7-Dimethoxy-quinoline-4-yloxy)-phenylamine
[0096] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide
(DMA, 184.3 kg) was charged to a reactor containing
4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-butoxide (21.4
kg) and DMA (167.2 kg) at 20-25.degree. C. This mixture was then
heated to 100-105.degree. C. for approximately 13 hours. After the
reaction was deemed complete as determined using in-process HPLC
analysis (<2% starting material remaining), the reactor contents
were cooled at 15 to 20.degree. C. and water (pre-cooled, 2 to
7.degree. C., 587 L) charged at a rate to maintain 15 to 30.degree.
C. temperature. The resulting solid precipitate was filtered,
washed with a mixture of water (47 L) and DMA (89.1 kg) and finally
with water (214 L). The filter cake was then dried at approximately
25.degree. C. on filter to yield crude
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (59.4 kg wet, 41.6
kg dry calculated based on LOD). Crude
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed
(approximately 75.degree. C.) in a mixture of tetrahydrofuran (THF,
211.4 kg) and DMA (108.8 kg) for approximately 1 h and then cooled
to 0-5.degree. C. and aged for approximately 1 h after which time
the solid was filtered, washed with THF (147.6 kg) and dried on a
filter under vacuum at approximately 25.degree. C. to yield
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic
acid
[0097] Triethylamine (19.5 kg) was added to a cooled (approximately
5 C) solution of cyclopropane-1,1-dicarboxylic acid (24.7 kg) in
THF (89.6 kg) at a rate such that the batch temperature did not
exceed 5.degree. C. The solution was stirred for approximately 1.3
h, and then thionyl chloride (23.1 kg) was added, keeping the batch
temperature below 10 C. When the addition was complete, the
solution was stirred for approximately 4 h keeping the temperature
below 10.degree. C. A solution of 4-fluoroaniline (18.0 kg) in THF
(33.1 kg) was then added at a rate such that the batch temperature
did not exceed 10 C. The mixture was stirred for approximately 10
hours after which the reaction was deemed complete. The reaction
mixture was then diluted with isopropyl acetate (218.1 kg). This
solution was washed sequentially with aqueous sodium hydroxide
(10.4 kg, 50% dissolved in 119 L of water) further diluted with
water (415 L), then with water (100 L) and finally with aqueous
sodium chloride (20.0 kg dissolved in 100 L of water). The organic
solution was concentrated by vacuum distillation (100 L residual
volume) below 40.degree. C. followed by the addition of n-heptane
(171.4 kg), which resulted in the precipitation of solid. The solid
was recovered by filtration and washed with n-Heptane (102.4 kg)
resulting in wet crude,
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg).
The crude, 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid
was dissolved in methanol (139.7 kg) at approximately 25.degree. C.
followed by the addition of water (320 L) resulting in slurry which
was recovered by filtration, washed sequentially with water (20 L)
and n-heptane (103.1 kg) and then dried on the filter at
approximately 25 C under nitrogen to afford the title compound
(25.4 kg).
Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl
chloride
[0098] Oxalyl chloride (12.6 kg) was added to a solution of
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg)
in a mixture of THF (96.1 kg) and N,N-dimethylformamide (DMF; 0.23
kg) at a rate such that the batch temperature did not exceed 25 C.
This solution was used in the next step without further
processing.
Preparation of cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide
[0099] The solution from the previous step containing
1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was
added to a mixture of compound
4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (23.5 kg) and
potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L)
at a rate such that the batch temperature did not exceed 30.degree.
C. When the reaction was complete (in approximately 20 minutes),
water (653 L) was added. The mixture was stirred at 20-25 C for
approximately 10 hours, which resulted in the precipitation of the
product. The product was recovered by filtration, washed with a
pre-made solution of THF (68.6 kg) and water (256 L), and dried
first on a filter under nitrogen at approximately 25.degree. C. and
then at approximately 45 C under vacuum to afford the title
compound (41.0 kg, 38.1 kg, calculated based on LOD).
Preparation of cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide-
, (L) malate salt
[0100] Cyclopropane-1,1-dicarboxylic acid
[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide-
(1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK;
188.6 kg) and water (37.3 kg) were charged to a reactor and the
mixture was heated to reflux (approximately 74.degree. C.) for
approximately 2 h. The reactor temperature was reduced to 50 to
55.degree. C. and the reactor contents were filtered. These
sequential steps described above were repeated two more times
starting with similar amounts of 1-5 (13.3 kg), L-Malic acid (4.96
kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was
azeotropically dried at atmospheric pressure using MEK (1133.2 kg)
(approximate residual volume 711 L; KF<0.5% w/w) at
approximately 74.degree. C. The temperature of the reactor contents
was reduced to 20 to 25.degree. C. and held for approximately 4
hours resulting in solid precipitate which was filtered, washed
with MEK (448 kg) and dried under vacuum at 50.degree. C. to afford
the title compound (45.5 kg).
Example 2
Administration of the compound of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide during the Concurrent Phase to
patients
Example 2A
[0101]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). The concurrent phase is followed by a rest phase that
will last for about 4 weeks. TMZ, when given, is supplied as 5, 20,
100, 250, 140 and 180 mg dosages (which can be in capsules or
tablets). In another embodiment, the starting dose of TMZ is 75
mg/m.sup.2/day with concurrent RT for 6 weeks. For purposes of this
patent application, the term "m.sup.2" refers to body surface area
in patients measured in square meters. Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2B
[0102]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 5 mg dosages (which
can be in capsules or tablets). Patients receive RT consisting of
fractional focal irradiation administered using a 1.8-2
Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total dose
of up to 60 Gy.
Example 2C
[0103]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 50 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 5 mg dosages (which
can be in capsules or tablets). Patients receive RT consisting of
fractional focal irradiation administered using a 1.8-2
Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total dose
of up to 60 Gy.
Example 2D
[0104]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 75 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 5 mg dosages (which
can be in capsules or tablets). Patients receive RT consisting of
fractional focal irradiation administered using a 1.8-2
Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total dose
of up to 60 Gy.
Example 2E
[0105]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). The concurrent phase is followed by a rest phase that
will last for about 4 weeks. TMZ, when given, is supplied as 5 mg
dosages (which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2F
[0106]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 100 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 20 mg dosages (which
can be in capsules or tablets). Patients receive RT consisting of
fractional focal irradiation administered using a 1.8-2
Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total dose
of up to 60 Gy.
Example 2G
[0107]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 50 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 20 mg dosages (which
can be in capsules or tablets). Patients receive RT consisting of
fractional focal irradiation administered using a 1.8-2
Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total dose
of up to 60 Gy.
Example 2H
[0108]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 75 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 20 mg dosages (which
can be in capsules or tablets). Patients receive RT consisting of
fractional focal irradiation administered using a 1.8-2
Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total dose
of up to 60 Gy.
Example 2I
[0109]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). The concurrent phase is followed by a rest phase that
will last for about 4 weeks. TMZ, when given, is supplied as 20 mg
dosages (which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2J
[0110]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 100 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 20 mg dosages (which
can be in capsules or tablets). Patients receive RT consisting of
fractional focal irradiation administered using a 1.8-2
Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total dose
of up to 60 Gy.
Example 2K
[0111]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 100 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2L
[0112]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 50 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 100 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2M
[0113]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 75 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 100 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2N
[0114]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-phenyl)-N'-(4-fluorophe-
nyl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). The concurrent phase is followed by a rest phase that
will last for about 4 weeks. TMZ, when given, is supplied as 100 mg
dosages (which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2O
[0115]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 100 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 100 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2P
[0116]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 140 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2Q
[0117]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 50 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 140 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2R
[0118]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 75 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 140 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2S
[0119]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). The concurrent phase is followed by a rest phase that
will last for about 4 weeks. TMZ, when given, is supplied as 140 mg
dosages (which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2T
[0120]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 100 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 140 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2U
[0121]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 180 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2V
[0122]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 50 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 180 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2W
[0123]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 75 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 180 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2X
[0124]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). The concurrent phase is followed by a rest phase that
will last for about 4 weeks. TMZ, when given, is supplied as 180 mg
dosages (which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2Y
[0125]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 100 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 180 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2Z
[0126]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 250 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2AA
[0127]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 50 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 250 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2AB
[0128]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 75 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 250 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2AC
[0129]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). The concurrent phase is followed by a rest phase that
will last for about 4 weeks. TMZ, when given, is supplied as 250 mg
dosages (which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 2AD
[0130]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is initiated at the start of a
6-7 week concurrent phase of RT and TMZ. Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 100 mg dosages (which can be in capsules or tablets).
The concurrent phase is followed by a rest phase that will last for
about 4 weeks. TMZ, when given, is supplied as 250 mg dosages
(which can be in capsules or tablets). Patients receive RT
consisting of fractional focal irradiation administered using a
1.8-2 Gy/fraction, daily for 5 days/week for 6-7 weeks, for a total
dose of up to 60 Gy.
Example 3
Administration of the compound of
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide during the Concurrent Phase to
patients
Example 3A
[0131]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 25 mg and 100
mg dosages (which can be in capsules or tablets). Some patients
that have a mutation in the MGMT promoter, wherein the mutated MGMT
promoter is an unmethylated promoter, may not receive TMZ and
instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 5, 20, 100, 250, 140,
180, and 200 mg dosages (which can be in capsules or tablets) given
for 5 consecutive days and repeated every 28 days. In another
embodiment, TMZ is administered in the amount of 200 mg/m.sup.2/day
given for 5 consecutive days and repeated every 28 days. For
purposes of this disclosure, the term m2 is meant to mean body
surface area in patients measured in square meters. The maintenance
phase in Example 3A can be combined with the concurrent phase of
any of Examples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M,
2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC
and 2AD.
Example 3B
[0132]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 25 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 5 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3B can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3C
[0133]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 50 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 5 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3C can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3D
[0134]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 75 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 5 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3D can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3E
[0135]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 100 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 5 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3E can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3F
[0136]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 25 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 20 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3F can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3G
[0137]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 50 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 20 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3G can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 82AD.
Example 3H
[0138]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 75 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 20 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3H can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3I
[0139]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 100 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N-(4-fluorophenyl)cycl-
opropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 20 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3I can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3J
[0140]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 25 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 100 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3J can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3K
[0141]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 50 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 100 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3K can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3L
[0142]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 75 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 100 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3L can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3M
[0143]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 100 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 100 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3M can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3N
[0144]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 25 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 140 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3N can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3O
[0145]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 50 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N-(4-fluorophenyl)cycl-
opropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 140 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 30 can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3P
[0146]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 75 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 140 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3P can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3Q
[0147]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 100 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 140 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3Q can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3R
[0148]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 25 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N-(4-fluorophenyl)cycl-
opropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 180 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3R can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3S
[0149]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 50 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 180 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3S can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3T
[0150]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 75 mg dosages
(which can be in a capsule or tablet). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 180 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3T can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3U
[0151]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 100 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 180 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3U can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3V
[0152]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 25 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied in doses of 200
mg/m.sup.2/day given for 5 consecutive days and repeated every 28
days. The maintenance phase in Example 3V can be combined with the
concurrent phase of any of Examples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H,
2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y,
2Z, 2AA, 2AB, 2AC and 2AD.
Example 3W
[0153]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 50 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied in doses of 200
mg/m.sup.2/day given for 5 consecutive days and repeated every 28
days. The maintenance phase in Example 3W can be combined with the
concurrent phase of any of Examples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H,
2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y,
2Z, 2AA, 2AB, 2AC and 2AD.
Example 3X
[0154]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 75 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied in doses of 200
mg/m.sup.2/day given for 5 consecutive days and repeated every 28
days. The maintenance phase in Example 3X can be combined with the
concurrent phase of any of Examples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H,
2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y,
2Z, 2AA, 2AB, 2AC and 2AD.
Example 3Y
[0155]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 100 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied in doses of 200
mg/m.sup.2/day given for 5 consecutive days and repeated every 28
days. The maintenance phase in Example 3Y can be combined with the
concurrent phase of any of Examples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H,
2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y,
2Z, 2AA, 2AB, 2AC and 2AD.
Example 3Z
[0156]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 25 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 250 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3Z can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3AA
[0157]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 50 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 250 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3AA can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
Example 3AB
[0158]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 75 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied in doses of 200
mg/m.sup.2/day given for 5 consecutive days and repeated every 28
days. The maintenance phase in Example 3AB can be combined with the
concurrent phase of any of Examples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H,
2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T, 2U, 2V, 2W, 2X, 2Y,
2Z, 2AA, 2AB, 2AC and 2AD.
Example 3AC
[0159]
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophen-
yl)cyclopropane-1,1-dicarboxamide is administered as 100 mg dosages
(which can be in capsules or tablets). Some patients that have a
mutation in the MGMT promoter, wherein the mutated MGMT promoter is
an unmethylated promoter, may not receive TMZ and instead receive
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide as a single agent in combination with
RT.
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide is administered as a single oral agent
supplied as 25 mg and 100 mg dosages (which can be in capsules or
tablets). TMZ, when given, is supplied as 250 mg dosages (which can
be in capsules or tablets) given for 5 consecutive days and
repeated every 28 days. The maintenance phase in Example 3AC can be
combined with the concurrent phase of any of Examples 2A, 2B, 2C,
2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 2S, 2T,
2U, 2V, 2W, 2X, 2Y, 2Z, 2AA, 2AB, 2AC and 2AD.
[0160] The foregoing disclosure has been described in some detail
by way of illustration and example, for purposes of clarity and
understanding. The invention has been described with reference to
various specific and preferred embodiments and techniques. However,
it should be understood that many variations and modifications can
be made while remaining within the spirit and scope of the
invention. It will be obvious to one of skill in the art that
changes and modifications can be practiced within the scope of the
appended claims. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
* * * * *