U.S. patent application number 17/644211 was filed with the patent office on 2022-04-07 for radiotherapy improvements.
This patent application is currently assigned to NOXOPHARM LIMITED. The applicant listed for this patent is NOXOPHARM LIMITED. Invention is credited to Graham KELLY.
Application Number | 20220105182 17/644211 |
Document ID | / |
Family ID | 1000006027661 |
Filed Date | 2022-04-07 |
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United States Patent
Application |
20220105182 |
Kind Code |
A1 |
KELLY; Graham |
April 7, 2022 |
RADIOTHERAPY IMPROVEMENTS
Abstract
The invention relates to a method for inducing an abscopal
response to radiotherapy in an individual.
Inventors: |
KELLY; Graham; (Turramurra,
AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOXOPHARM LIMITED |
Turramurra |
|
AU |
|
|
Assignee: |
NOXOPHARM LIMITED
Turramurra
AU
|
Family ID: |
1000006027661 |
Appl. No.: |
17/644211 |
Filed: |
December 14, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16091706 |
Oct 5, 2018 |
11229703 |
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PCT/AU2017/050299 |
Apr 6, 2017 |
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17644211 |
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62318946 |
Apr 6, 2016 |
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62461559 |
Feb 21, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/353 20130101;
A61K 41/0038 20130101; A61K 31/382 20130101; A61K 31/352 20130101;
A61P 35/04 20180101; A61K 31/366 20130101; A61K 31/435
20130101 |
International
Class: |
A61K 41/00 20200101
A61K041/00; A61P 35/04 20060101 A61P035/04; A61K 31/435 20060101
A61K031/435; A61K 31/382 20060101 A61K031/382; A61K 31/366 20060101
A61K031/366; A61K 31/352 20060101 A61K031/352; A61K 31/353 20060101
A61K031/353 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 28, 2016 |
AU |
PCT/AU2016/050674 |
Claims
1-33. (canceled)
34. A method for inducing an abscopal response to radiotherapy in
an individual, including: irradiating an individual having a
plurality of tumors, and who has received idronoxil, with a
cytotoxic dose of ionising radiation so that fewer than all of the
plurality of tumors are irradiated, thereby resulting in the
individual having irradiated and non-irradiated tumors, wherein at
least one of the tumors is a primary tumor, and at least one of the
tumors is a metastatic or secondary tumor of a primary tumor;
wherein at least one of the primary, or metastatic or secondary
tumors, is a prostate tumor; wherein idronoxil is administered to
the individual about 12 to 24 hours before irradiating the
individual; wherein one or more non-irradiated tumors regress
following administration of idronoxil and the irradiation of the
individual, thereby inducing an abscopal response to radiotherapy
in the individual.
35. The method of claim 34, wherein the one or more non-irradiated
tumors are tumors that have a diameter of more than 10 mm.
36. The method of claim 34, wherein all non-irradiated tumors
regress.
37. The method of claim 34, wherein one or more non-irradiated
tumors are eliminated.
38. The method of claim 34, wherein all non-irradiated tumors are
eliminated.
39. The method of claim 34, wherein an irradiated tumor is located
in or on the same organ, or in or on the same connective tissue as
a non-irradiated tumor.
40. The method of claim 34, wherein a primary tumor is
irradiated.
41. The method of claim 40, wherein a primary tumor and a
metastatic tumor are irradiated.
42. The method of claim 34, wherein a metastatic tumor is
irradiated and a primary tumor is not irradiated.
43. The method of claim 34 including the steps of: assessing at
least some of the tumors to determine at least one tumor for
irradiation with the cytotoxic dose of ionising radiation; and
selecting at least one of the assessed tumors for irradiation with
the cytotoxic dose of ionising radiation.
44. The method of claim 43, wherein a tumor is assessed according
to the size or diameter of the tumor.
45. The method according to claim 43, wherein the plurality of
tumors is assessed according to the dose of radiotherapy required
to provide cytotoxicity to a tumor of the plurality of tumors.
46. The method according to claim 43, wherein a tumor is assessed
according to anatomical location.
47. The method according to claim 43, wherein the plurality of
tumors are assessed according to the expression of one or more
biomarkers.
48. The method of claim 43, wherein the tumor selected for
irradiation has a longest diameter of at least 10 mm.
49. The method of claim 34, including the further step of:
assessing one or more organs or tissues of an individual who has
received the compound and irradiation, to determine the regression
of a non-irradiated tumor in the individual.
50. The method of claim 34, wherein the compound is administered to
the individual in an amount of about 10 to 30 mg/kg.
51. The method of claim 34, wherein idronoxil is administered to
the individual in a daily amount of about 100 to 900 mg.
52. The method of claim 51, wherein idronoxil is administered to
the individual in a daily amount of about 400 or 800 mg.
53. The method of claim 34, wherein idronoxil is administered to
the individual for a period of up to 14 days before the
commencement of radiotherapy.
54. The method of claim 53, wherein idronoxil is administered to
the individual for a period of 1 to 7 days before the commencement
of radiotherapy.
55. The method of claim 34, wherein idronoxil is administered to
the individual on each day that radiotherapy is given.
56. The method of claim 34, wherein idronoxil is administered to
the individual for a period of up to 3 months post the final
radiotherapy treatment.
57. The method of claim 56, wherein idronoxil is administered to
the individual for about 14 days post the final radiotherapy
treatment.
58. The method of claim 34, wherein idronoxil is administered to
the individual by rectal administration.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/091,706, filed Oct. 5, 2018, which is a
national phase application under 35 U.S.C. .sctn. 371 of
International Application No. PCT/AU2017/050299, filed Apr. 6,
2017, which claims the priority to U.S. Provisional Patent
Application No. 62/318,946, filed Apr. 6, 2016, International
Application No. PCT/AU2016/050674, filed Jul. 28, 2016, and to U.S.
Provisional Patent Application No. 62/461,559, filed Feb. 21, 2017,
the entirety of each are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates to radiotherapy of cancer and to
abscopal responses to radiotherapy.
BACKGROUND OF THE INVENTION
[0003] Reference to any prior art in the specification is not an
acknowledgment or suggestion that this prior art forms part of the
common general knowledge in any jurisdiction or that this prior art
could reasonably be expected to be understood, regarded as
relevant, and/or combined with other pieces of prior art by a
skilled person in the art.
[0004] Ionising radiation is a standard form of therapy in the
management of cancer. Its objective is to induce damage to a cancer
cell's DNA, RNA and cellular proteins to an extent that exceeds the
ability of the cancer cell to repair that damage, leading to death
of the cell.
[0005] When non-irradiated cells respond to radiation, the response
is known as a "bystander effect". According to (Marin A. et al.
2015 Reports Pract Oncol and Radiother 20:12-21), a bystander
effect may apply to cells which neighbour irradiated cells, or
cells which do not neighbour irradiated cells. The latter includes
cells that are located in non-irradiated tumours, and potentially
tumours that are located in a different anatomical compartment to
the tumour that has received radiation.
[0006] In general, the bystander effect observed in non-irradiated
cells mimics the direct effects of radiation including an increased
frequency of apoptosis, micro-nucleation, DNA strand breaks and
mutations, altered levels or activity of regulatory proteins and
enzymes, reduced clonogenic efficiency and oncogenic
transformation.
[0007] Marin et al. supra describes the bystander effect applying
to non-irradiated cells that neighbour irradiated cells as being
"the radiobiological events arising from the radiation effect".
[0008] Where a bystander effect is observed in non-irradiated cells
that are not neighbours of the irradiated cells, the effect is
referred to as an `abscopal effect`, or an `abscopal response` to
irradiation and it has been explained as a "clinical change related
to radiation effect".
[0009] In more detail, the result of radiotherapy at one tumour
site may profoundly influence the biology of tumours at other
locations in the body that have not been irradiated. Mole R et al
1953 J Radiol 26:234-41 described abscopal responses to
radiotherapy some 70 years ago. Since this time, there have been
numerous anecdotal reports of abscopal effects in patients
receiving radiotherapy.
[0010] In one example, an abscopal response was observed in
untreated metastatic disease following local primary
tumour-directed therapy (Orton A. et al. 2016 Cureus 8(10):e821.DOI
10.7759/cureus.821). In another example, an abscopal response was
observed in lung metastases of hepatocellular carcinoma (Okuma K et
al. 2011 J Med Case Rep 5:111). Other examples include an abscopal
effect in a case of toruliform para-aortic lymph node metastasis in
a patient with advance uterine cervical carcinoma (Takaya M et al
2007 Anticancer Res: 27-499-503) and in a patient treated with an
anti-CTLA-4 antibody and radiotherapy for melanoma (Postow et al M
2012 N. Enql. J. Med 366:925-31) and in hepatocellular carcinoma
(Lock M et al. 2015 Cureus 7:e344.10.7759/cureus.344). Other
disease histologies where abscopal effects have been reported are
described in Reynder K et al. 2015 Cancer Treat Rev 41:503-10.
[0011] Given the significant benefit to a patient of having all
tumours within the body responding to the limited irradiation of a
few tumours, it would be useful to increase the likelihood of
formation of an abscopal effect in an individual having metastatic
cancer, or even a condition involving a plurality of primary
tumours, including benign tumours, as this would mean a higher
likelihood that the irradiation of some of the individual's tumours
might lead to a complete or partial response to radiotherapy,
including for example the elimination or at least minimisation of
some or all of the individual's non-irradiated tumours.
[0012] Further, treatment of tumours that are otherwise
anatomically inaccessible to radiotherapy may also be possible.
[0013] Further, an abscopal response of tumours within the brain
where the use of radiotherapy is highly restricted may be
possible.
[0014] Prostate cancer is a disease of particular concern and that
might benefit from an abscopal response, as this disease in
metastatic form has a high mortality rate and sometimes presents in
the form multiple metastatic nodules located in physiologically
sensitive or anatomically inaccessible compartments such as the
vertebrae.
[0015] As mentioned, abscopal responses to radiotherapy have
generally been observed anecdotally. They are also infrequently
reported.
[0016] Attempts to harness the effect, so as to reproducibly cause
regression of non-irradiated tumours have utilised immunotherapy in
combination with radiotherapy. While the CD-8 T cells and
macrophages are considered by some to be an essential component of
the effect in humans, the molecular basis for the effect, whether
an immunological basis, or otherwise, remains unknown.
[0017] There is a need to improve the likelihood of formation of,
or to induce the formation of, an abscopal effect to radiotherapy
in an individual having multiple tumours, especially an individual
having solid tumours, one example being metastatic prostate
cancer.
[0018] There is a need to improve the likelihood of formation of,
or to induce the formation of, a complete or partial response to
radiotherapy in an individual wherein said individual has multiple
tumours and in which some but not all of the tumours of the
individual are irradiated, especially an individual having solid
tumours, one example being metastatic prostate cancer.
SUMMARY OF THE INVENTION
[0019] The invention seeks to provide improvements in radiotherapy
and/or to address one of the above mentioned needs and in one
embodiment provides a method for inducing an abscopal response to
radiotherapy in an individual including: [0020] providing an
individual having a plurality of tumours, [0021] administering a
compound of Formula I or Formula II to the individual,
[0022] wherein Formula (I) is
##STR00001##
[0023] wherein
[0024] R.sub.1 is H, or R.sub.ACO where R.sub.A is C.sub.1-10 alkyl
or an amino acid;
[0025] R.sub.2 is H, OH, or R.sub.B where R.sub.B is an amino acid
or COR.sub.A where R.sub.A is as previously defined;
[0026] A and B together with the atoms between them form a six
membered ring selected from the group
##STR00002##
[0027] wherein
[0028] R.sub.4 is H, COR.sub.D where R.sub.D is H, OH, C.sub.1-10
alkyl or an amino acid, CO.sub.2R.sub.C where R.sub.C is C.sub.1-10
alkyl, COR.sub.E where R.sub.E is H, C.sub.1-10 alkyl or an amino
acid, or CONHR.sub.E where R.sub.E is as previously defined;
[0029] R.sub.5 is H, CO.sub.2R.sub.C where R.sub.C is as previously
defined, or COR.sub.COR.sub.E where R.sub.C and R.sub.E are as
previously defined, and where the two R.sub.5 groups are attached
to the same group they are the same or different;
[0030] X is O, N or S;
[0031] Y is
##STR00003##
[0032] where R.sub.7 is H, or C.sub.1-10 alkyl; and
[0034] wherein Formula II is:
##STR00004##
[0035] wherein
[0036] R.sub.1 is H, or R.sub.ACO where R.sub.A is C.sub.1-10 alkyl
or an amino acid;
[0037] R.sub.2 is H, OH, or R.sub.B where R.sub.B is an amino acid
or COR.sub.A where R.sub.A is as previously defined;
[0038] A and B together with the atoms between them form the
group:
##STR00005##
[0039] wherein
[0040] R.sub.4 is H, COR.sub.D where R.sub.D is H, OH, C.sub.1-10
alkyl or an amino acid, CO.sub.2R.sub.C where R.sub.C is C.sub.1-10
alkyl, COR.sub.E where R.sub.E is H, C.sub.1-10 alkyl or an amino
acid, or CONHR.sub.E where R.sub.E is as previously defined;
[0041] R.sub.5 is substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl;
[0042] X is O, N or S;
[0043] Y is
##STR00006##
[0044] where R.sub.7 is H, or C.sub.1-10 alkyl; and
[0045] [0046] irradiating the individual with a cytotoxic dose of
ionising radiation so that fewer than all of the plurality of
tumours are irradiated, thereby resulting in the individual having
irradiated and non-irradiated tumours,
[0047] wherein one or more non-irradiated tumours regresses
following the administration of the compound and the irradiation of
the individual,
[0048] thereby inducing an abscopal response to radiotherapy in the
individual.
[0049] In another embodiment there is provided a method for
inducing a complete or partial response to radiotherapy in an
individual wherein the individual has multiple tumours and the
radiotherapy involves the irradiation of fewer than all of the
tumours of the individual, including: [0050] providing an
individual having multiple tumours, [0051] administering a compound
of Formula I or Formula II (described above) to the individual,
[0052] irradiating the individual with a cytotoxic dose of ionising
radiation so that fewer than all of the tumours are irradiated,
thereby resulting in the individual having irradiated and
non-irradiated tumours,
[0053] wherein one or more non-irradiated tumours regresses
following the administration of the compound and the irradiation of
the individual,
[0054] thereby inducing a complete or partial response to
radiotherapy in the individual.
[0055] In another embodiment there is provided a method for
inducing a complete or partial response to radiotherapy in an
individual wherein the individual has multiple tumours and the
radiotherapy involves the irradiation of fewer than all of the
tumours of the individual, including: [0056] irradiating an
individual having a plurality of tumours, and who has received a
compound of Formula I or Formula II (described above), with a
cytotoxic dose of ionising radiation so that fewer than all of the
plurality of tumours are irradiated, thereby inducing a complete or
partial response to radiotherapy in the individual.
[0057] In another embodiment there is provided a use of a compound
of Formula I or Formula II (described above) for inducing a
complete or partial response in an individual to radiotherapy of
cancer wherein the individual has multiple tumours and the multiple
tumours include irradiated tumours and at least one non-irradiated
tumour.
[0058] In another embodiment there is provided a compound of
Formula I or Formula II (described above) for use in inducing a
complete or partial response in an individual to radiotherapy of
cancer wherein the individual has multiple tumours and the multiple
tumours include irradiated tumours and at least one non-irradiated
tumour.
[0059] In the above described embodiments the tumours are typically
solid tumours and may be prostate cancer, especially metastatic
prostate cancer.
[0060] In the above described embodiments the compound of Formula I
may be:
##STR00007##
[0061] In the above described embodiments the compound of Formula
I, such as idronoxil, or of Formula II, may be administered
rectally.
[0062] In another embodiment there is provided a kit for use in a
method described above including: [0063] a composition including a
compound of Formula I or Formula II; [0064] written instructions
for use of the kit in a method for inducing an abscopal response to
radiotherapy in an individual as described above.
[0065] Further aspects of the present invention and further
embodiments of the aspects described in the preceding paragraphs
will become apparent from the following description.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0066] Reference will now be made in detail to certain embodiments
of the invention. While the invention will be described in
conjunction with the embodiments, it will be understood that the
intention is not to limit the invention to those embodiments. On
the contrary, the invention is intended to cover all alternatives,
modifications, and equivalents, which may be included within the
scope of the present invention as defined by the claims.
[0067] One skilled in the art will recognize many methods and
materials similar or equivalent to those described herein, which
could be used in the practice of the present invention. The present
invention is in no way limited to the methods and materials
described.
[0068] It will be understood that the invention disclosed and
defined in this specification extends to all alternative
combinations of two or more of the individual features mentioned or
evident from the text. All of these different combinations
constitute various alternative aspects of the invention.
[0069] As used herein, except where the context requires otherwise,
the term "comprise" and variations of the term, such as
"comprising", "comprises" and "comprised", are not intended to
exclude further additives, components, integers or steps.
[0070] As described herein, the invention generally relates to
improvements in radiotherapy that provide for abscopal responses in
patients having multiple tumours. According to the invention,
complete or partial responses of an individual to radiotherapy are
observed in circumstances where some, but not all of the
individual's tumours are irradiated, and especially in
non-irradiated tumours that do not neighbour the irradiated
tumours, for example tumours that are located outside of a field in
which irradiation is given, examples of which include tumours that
are located in the same organ or connective tissue but outside of
the irradiation field, and tumours that are located in different
organs, tissues or anatomical compartments to those tumours that
are irradiated.
[0071] An `irradiated tumour` refers to a tumour that has been
exposed to a beam of ionising radiation for the purpose of causing
regression of the tumour.
[0072] A `non-irradiated tumours` refers to a tumour that (a) has
not been exposed to a beam of ionising radiation and (b) that does
not directly neighbour, or is not adjacent to an irradiated
tumour.
[0073] The effect on non-irradiated tumours appears to derive from
the irradiation of isoflavanoid-treated tumours. While not wanting
to be bound by hypothesis it is believed that non-irradiated
isoflavanoid treated tumours are susceptible to factors released
from isoflavanoid treated irradiated tumours, resulting in the
regression of non-irradiated tumours and observations of partial or
complete responses. Further the abscopal effect leading to partial
or complete response is not simply a function of
radio-sensitisation of tumours to radiotherapy, because, by
definition the effect is observed in non-irradiated tumours.
[0074] `Regression` and `regress` and `regresses` generally refers
to the reduction in tumour size or growth of a tumour, resulting in
the complete or partial involution or elimination of a tumour.
[0075] Thus in one embodiment there is provided a method for
inducing a complete or partial response to radiotherapy in an
individual or for inducing an abscopal response to radiotherapy
wherein the individual has multiple tumours and the radiotherapy
involves the irradiation of fewer than all of the tumours of the
individual, including: [0076] irradiating an individual having a
plurality of tumours, and who has received a compound of Formula I
or Formula II, with a cytotoxic dose of ionising radiation so that
fewer than all of the plurality of tumours are irradiated, thereby
inducing a complete or partial response to radiotherapy in the
individual, or inducing an abscopal response to radiotherapy.
[0077] In another embodiment there is provided a method for
inducing a complete or partial response to radiotherapy in an
individual wherein the individual has multiple tumours and the
radiotherapy involves the irradiation of fewer than all of the
tumours of the individual, including: [0078] providing an
individual having multiple tumours, [0079] administering a compound
of Formula I or Formula II to the individual, [0080] irradiating
the individual with a cytotoxic dose of ionising radiation so that
fewer than all of the tumours are irradiated, thereby resulting in
the individual having irradiated and non-irradiated tumours,
[0081] wherein one or more non-irradiated tumours regresses
following the administration of the compound and the irradiation of
the individual,
[0082] thereby inducing a complete or partial response to
radiotherapy in the individual.
[0083] A. Compounds
[0084] According to the invention, Compounds of Formula I or
Formula II are utilised to provide improvements in radiotherapy and
specifically to provide for regression of tumours that are not
subjected to radiotherapy. These compounds are described by Formula
I
##STR00008##
[0085] wherein
[0086] R.sub.1 is H, or R.sub.ACO where R.sub.A is C.sub.1-10 alkyl
or an amino acid,
[0087] R.sub.2 is H, OH, or R.sub.B where R.sub.B is an amino acid
or COR.sub.A where R.sub.A is as previously defined;
[0088] A and B together with the atoms between them form a six
membered ring selected from the group
##STR00009##
[0089] wherein
[0090] R.sub.4 is H, COR.sub.D where R.sub.D is H, OH, C.sub.1-10
alkyl or an amino acid, CO.sub.2R.sub.C where R.sub.C is C.sub.1-10
alkyl, COR.sub.E where R.sub.E is H, C.sub.1-10 alkyl or an amino
acid, or CONHR.sub.E where R.sub.E is as previously defined;
[0091] R.sub.5 is H, CO.sub.2R.sub.C where R.sub.C is as previously
defined, or COR.sub.COR.sub.E where R.sub.C and R.sub.E are as
previously defined, and where the two R.sub.5 groups are attached
to the same group they are the same or different;
[0092] X is O, Nor S;
[0093] Y is
##STR00010##
[0094] where R.sub.7 is H, or C.sub.1-10 alkyl; and
[0096] Preferably, X is O.
[0097] In preferred embodiments, the compound of formula (I) is
selected from the group consisting of
##STR00011## ##STR00012##
[0098] wherein
[0099] R.sub.8 is H or COR.sub.D where R.sub.D is as previously
defined;
[0100] R.sub.9 is CO.sub.2R.sub.C or COR.sub.E where R.sub.C and
R.sub.E are as previously defined;
[0101] R.sub.10 is COR.sub.C or COR.sub.COR.sub.E where R.sub.C and
R.sub.E are as previously defined;
[0102] R.sub.11 is H or OH;
[0103] R.sub.12 is H, COOH, CO.sub.2R.sub.C where R.sub.C and is as
previously defined, or CONHR.sub.E where R.sub.E is as previously
defined; and
[0105] Some of the compounds discussed above may be referred to by
the names dihydrodaidzein (compound 1 where R.sub.8 is H),
dihydrogenestein (compounds 2 and 5), tetrahydrodaidzein (compound
8) and equol and dehydroequol (compound 10).
[0106] Preferably, the compound of Formula (I) is
##STR00013## [0107] wherein R.sub.11 and R.sub.12 are as defined
above.
[0108] Even more preferably, the compound of Formula (I) is
##STR00014##
[0109] otherwise known as idronoxil (also known as phenoxodiol;
dehydroequol; Haginin E
(2H-1-Benzopyran-7-0,1,3-(4-hydroxyphenyl)).
[0110] In another aspect, the isoflavonoids for use in the methods
of the invention described are shown by Formula II:
##STR00015##
[0111] wherein
[0112] R.sub.1 is H, or R.sub.ACO where R.sub.A is C.sub.1-10 alkyl
or an amino acid;
[0113] R.sub.2 is H, OH, or R.sub.B where R.sub.B is an amino acid
or COR.sub.A where R.sub.A is as previously defined;
[0114] A and B together with the atoms between them form the
group:
##STR00016##
[0115] wherein
[0116] R.sub.4 is H, COR.sub.D where R.sub.D is H, OH, C.sub.1-10
alkyl or an amino acid, CO.sub.2R.sub.C where R.sub.C is C.sub.1-10
alkyl, COR.sub.E where R.sub.E is H, C.sub.1-10 alkyl or an amino
acid, or CONHR.sub.E where R.sub.E is as previously defined;
[0117] R.sub.5 is substituted or unsubstituted aryl or substituted
or unsubstituted heteroaryl;
[0118] X is O, N or S;
[0119] Y is
##STR00017##
[0120] where R.sub.7 is H, or C.sub.1-10 alkyl; and
[0122] In one preferred embodiment, R.sub.5 is aryl substituted
with an alkoxy group.
[0123] Preferably, the alkoxy group is methoxy. In another
preferred embodiment, R.sub.5 is hydroxyl-substituted aryl.
[0124] In preferred embodiments, the compound of Formula II is
##STR00018##
[0125] As used herein the term "alkyl" refers to a straight or
branched chain hydrocarbon radical having from one to ten carbon
atoms, or any range between, i.e. it contains 1, 2, 3, 4, 5, 6, 7,
8, 9 or 10 carbon atoms. The alkyl group is optionally substituted
with substituents, multiple degrees of substitution being allowed.
Examples of "alkyl" as used herein include, but are not limited to,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,
n-pentyl, isopentyl, and the like.
[0126] As used herein, the term "C.sub.1-10 alkyl" refers to an
alkyl group, as defined above, containing at least 1, and at most
10 carbon atoms respectively, or any range in between (e.g. alkyl
groups containing 2-5 carbon atoms are also within the range of
C.sub.1-10).
[0127] Preferably the alkyl groups contain from 1 to 5 carbons and
more preferably are methyl, ethyl or propyl.
[0128] As used herein, the term "aryl" refers to an optionally
substituted benzene ring. The aryl group is optionally substituted
with substituents, multiple degrees of substitution being
allowed.
[0129] As used herein, the term "heteroaryl" refers to a monocyclic
five, six or seven membered aromatic ring containing one or more
nitrogen, sulfur, and/or oxygen heteroatoms, where N-oxides and
sulfur oxides and dioxides are permissible heteroatom substitutions
and may be optionally substituted with up to three members.
Examples of "heteroaryl" groups used herein include furanyl,
thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,
thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl,
thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl,
pyrimidyl and substituted versions thereof.
[0130] A "substituent" as used herein, refers to a molecular moiety
that is covalently bonded to an atom within a molecule of interest.
For example, a "ring substituent" may be a moiety such as a
halogen, alkyl group, or other substituent described herein that is
covalently bonded to an atom, preferably a carbon or nitrogen atom,
that is a ring member. The term "substituted," as used herein,
means that any one or more hydrogens on the designated atom is
replaced with a selection from the indicated substituents, provided
that the designated atom's normal valence is not exceeded, and that
the substitution results in a stable compound, i.e., a compound
that can be isolated, characterised and tested for biological
activity.
[0131] The terms "optionally substituted" or "may be substituted"
and the like, as used throughout the specification, denotes that
the group may or may not be further substituted, with one or more
non-hydrogen substituent groups. Suitable chemically viable
substituents for a particular functional group will be apparent to
those skilled in the art.
[0132] Examples of substituents include but are not limited to:
[0133] C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.3-C.sub.7 heterocyclyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 alkylsulfonylamino, arylsulfonoamino, alkylcarboxy,
alkylcarboxyamide, oxo, hydroxy, mercapto, amino, acyl, carboxy,
carbamoyl, aminosulfonyl, acyloxy, alkoxycarbonyl, nitro, cyano or
halogen.
[0134] The term "isoflavonoid" as used herein is to be taken
broadly and includes isoflavones, isoflavenes, isoflavans,
isoflavanones, isoflavanols and similar or related compounds. Some
non-limiting examples of isoflavonoid core structures are shown
below:
##STR00019##
[0136] Methods for synthesis of the above described compounds are
described in WO1998/008503 and WO2005/049008 and references cited
therein towards the synthesis, the contents of which are
incorporated herein by reference in entirety.
[0137] B. Dosage
[0138] Certain isoflavonoids according to Formula I and Formula II,
and in particular, genestein and idronoxil have been proposed for
use in treatment of cancer, especially metastatic disease involving
solid tumours. However, in various clinical trials these compounds
have been observed to be unable to provide either a complete or
partial response to cancer, and at best they may slow disease
progression. In particular, in a phase Ib/IIa safety and efficacy
study of idronoxil in males with hormone refractory prostate cancer
given idronoxil ranging from 20 to 400 mg, the disease had
progressed in most individuals by 6 months from treatment Alvaro A.
US Oncological Review, 20084(1):39-41. Related observations were
also made in clinical trials of idronoxil on other tumours, clearly
pointing to the inability of the isoflavanoids alone, such as
idronoxil alone, to provide a partial or complete response to
treatment.
[0139] As described herein, the compounds of Formula I or II and
especially idronoxil are provided to increase the likelihood of an
abscopal response to radiotherapy. An `abscopal response` is
generally understood as referring to tumour regression at sites
distant to an irradiated field, and is seen generally in patients
with various types of metastatic tumours receiving palliative
radiotherapy to a single metastasis. The tumour distant to the
irradiated field that is susceptible to an abscopal effect may be
located in the same anatomical compartment i.e. the same organ or
connective tissue as the irradiated tumour.
[0140] A `complete response` to therapy is generally understood as
meaning the disappearance of all detectable signs of cancer in
response to treatment. According to the invention, a complete
response arises from the elimination of tumours by irradiation and
the elimination of tumours (which are not irradiated) by the
abscopal response or effect.
[0141] A `partial response` is generally understood as meaning a
decrease in tumour load in an individual, for example in terms of
tumour number, size and growth rate. A partial response may
increase the time to disease progression. According to the
invention, a partial response may arise from the regression of
tumours by irradiation and the regression of tumours (which are not
irradiated) by the abscopal effect.
[0142] In the embodiments of the invention described herein, a
clinical response, such as a complete response or a partial
response may be defined by RECIST 1.0 criteria (Therasse P, et al.)
2000 J. Natl Cancer Inst 92:2015-16 as described in herein.
[0143] According to the invention a compound of Formula I or II is
provided to the individual in amounts that at least increase the
likelihood of formation of an abscopal response, or that at least
increase the likelihood of creation of an abscopal effect as such a
response or effect is important for providing either a partial or
complete response in circumstances where some, but not all tumours
of the individual are irradiated.
[0144] Typically a compound of Formula I or II, preferably
idronoxil, is provided to the individual in amount of 10 to 30
mg/kg, preferably 15-25 mg/kg.
[0145] The compound of Formula I or II, preferably idronoxil, may
be provided before the commencement of radiotherapy, for example,
for a period of up to 14 days, preferably from 1 to 7 days.
Preferably the compound is provided on a consecutive daily
basis.
[0146] The compound of Formula I or II, preferably idronoxil, may
be provided in a daily amount of about 100 to 900 mg, preferably
400 or 800 mg.
[0147] The compound of Formula I or II, preferably idronoxil, may
be provided on each day that radiotherapy is given.
[0148] The compound of Formula I or II, preferably idronoxil, may
be provided for a period of up to 3 months post the final
radiotherapy treatment, preferably for about 14 days.
[0149] In one embodiment, idronoxil is dosed daily for 13
consecutive days (1 day before radiotherapy, on each day of
radiotherapy (totaling 5 days) and on each day for 7 days following
radiotherapy.
[0150] In certain embodiments, a compound of Formula I or Formula
II, preferably idronoxil is administered to the individual by
rectal administration.
[0151] As described herein, the inventor has found that oleaginous
bases (i.e. hydrophobic or lipophilic bases) enable the therapeutic
effect of an isoflavonoid, whereas hydrophilic bases, such as PEG,
cyclodextrin and the like do not.
[0152] In the disclosure below, `base` may refer to a substance
commonly used as a carrier in a suppository, pessary or
intra-urethral device.
[0153] Generally the base has a solvent power for the isoflavonoid
enabling at least partial, preferably complete dissolution of the
isoflavonoid in the base.
[0154] The base may be comprised of, or consist of an oil or
fat.
[0155] In one embodiment the base includes saturated fatty acids in
an amount of 50 to 65% w/w base. Stearic acid may be included in an
amount of 25 to 40% w/w base. Palmitic acid may be included in an
amount of 25 to 30% w/w base. Longer chain saturated fatty acids
such as myristic, arachidic and lauric acid may be included in an
amount of <2% w/w base.
[0156] In one embodiment the lipophilic suppository base contains
fatty acids and wherein 50 to 100% of the fatty acids of the base
are saturated fatty acids, preferably, 90 to 99% of the fatty acids
of the base are saturated fatty acids. 30 to 60%, preferably about
40% of fatty acids of the base may be stearic acid. 20 to 30%,
preferably about 25% of fatty acids of the base may be palmitic
acid. 15 to 25%, preferably about 20% of fatty acids of the base
may be lauric acid. 5 to 10%, preferably about 8% of fatty acids of
the base may be myristic acid.
[0157] Further described herein, it has been found that oleaginous
bases that are high in unsaturated fatty acids tend to be less
advantageous in the invention. Typically, the oleaginous base
includes unsaturated fatty acids in an amount of 35 to 50% w/w
base. Monounsaturated fatty acid may be included in an amount of 30
to 45% w/w base. Oleic acid may be included in an amount of 30 to
40% w/w base. Polyunsaturated fatty acids such as linoleic and
alpha linolenic acid may be included in an amount of 0 to 5% w/w
base.
[0158] Theobroma oil (cocoa butter) has been a traditional base in
a suppository because of: (a) its non-toxic and non-irritant
nature, and (b) its low melting point, meaning that it readily
dissolves at body temperature when placed within a bodily cavity,
However, it is increasingly being replaced for a number of reasons.
One reason is its variability in composition, a consequence of its
natural origins; Theobroma oil also is polymorphic, meaning it has
the ability to exist in more than one crystal form. Another is that
the formulated product needs to be kept refrigerated because of its
low melting point, rendering it unsuitable in tropical regions.
This has led to a number of substitute products offering a range of
advantages over Theobroma oil such as greater consistency,
decreased potential for rancidity, and greater ability to tailor
phase transitions (melting and solidification) to specific
formulation, processing, and storage requirements.
[0159] Nevertheless, Theobroma oil or a hydrogenated vegetable oil
has been found to be a preferred embodiment of the invention.
[0160] The oleaginous base may comprise a predominance of (>45%
w/w base) of saturated fatty acids. The oleaginous base may be a
Theobroma oil (cocoa butter) or an oil fraction or derivative or
synthetic version thereof (such as a hydrogenated vegetable oil)
having a saturated fatty acid profile substantially the same as, or
identical to the fatty acid profile of Theobroma oil.
[0161] Other examples of oils that may be used to provide or obtain
fatty acids useful as bases include those obtainable from natural
sources such as canola oil, palm oil, soya bean oil, vegetable oil,
and castor oil. Oils derived from these sources may be fractionated
to obtain oil fractions containing saturated fatty acids.
[0162] The base may be formed or derived from a hard fat, butter or
tallow.
[0163] A base may comprise esterified or non-esterified fatty acid
chains. The fatty acid chains may be in the form of mono, di and
triglycerides, preferably comprising saturated fatty acid chains of
C9-20 chain length.
[0164] A suppository base may be formed from synthetic oils or
fats, examples including Fattibase, Wecobee, Witepesoll (Dynamit
Nobel, Germany), Suppocire (Gatefosse, France, Hydrokote and
Dehydag.
[0165] The proportion of the oleaginous suppository base in the
final product is a function of the dosage of active pharmaceutical
ingredient and the presence of other pharmaceutical or inert
ingredient (if any) but may be provided by way of example in an
amount of about 1 to 99% w/w formulation.
[0166] The isoflavonoid compositions may be prepared as follows.
The isoflavonoid is contacted with a suppository base (as described
above) in molten form in conditions enabling at least partial,
preferably complete or substantially complete dissolution of the
isoflavonoid in the base. This solution is then poured into a
suitable mould, such as a PVC, polyethylene, or aluminium mould.
For example, the isoflavonoid may be contacted with the base at a
temperature of from about 35.degree. C. to about 50.degree. C. and
preferably from about 40.degree. C. to about 44.degree. C. The
isoflavonoid can be milled or sieved prior to contact with the
base.
[0167] In one embodiment, the conditions provided for manufacture,
and formulation or device formed from same, enable at least, or
provide at least, 50%, preferably 60%, preferably 70%, preferably
80%, preferably 90%, preferably 95% of the isoflavonoid for a given
dosage unit to be dissolved in the dosage unit. In these
embodiments, no more than 50% of the isoflavonoid for a given
dosage unit, preferably no more than 40%, preferably no more than
30%, preferably no more than 20%, preferably no more than 10%,
preferably no more than 5% of isoflavonoid for a given dosage unit
may be in admixture with, (i.e. undissolved in) the suppository
base of the dosage unit.
[0168] In a preferred embodiment, all of the isoflavonoid added to
a dosage unit is dissolved in the base. In this embodiment, no
isoflavonoid is left in admixture with the suppository base. This
is believed to increase the likelihood of the uptake of all of the
isoflavonoid given in the dosage unit.
[0169] It will be understood that the objective of the manufacture
process is not to admix, or to mingle, or to blend the suppository
base with the isoflavonoid as generally occurs in pharmacy practice
of admixing components, as it is believed that the resulting
admixture would have a lower likelihood of providing therapeutic
benefit. In this context, it is particularly important that any
other excipient, carrier or other pharmaceutical active does not
interfere with the dissolution of the isoflavonoid in the base, for
example as may occur if the isoflavonoid forms a complex with a
charged molecular species (other pharmaceutical active, carrier or
excipient), the result of which would be to decrease the propensity
of the complex, and therefore the isoflavonoid contained in it, to
dissolve in the suppository base.
[0170] Optionally the suppositories, pessaries or intra-urethral
devices may be coated, prior to packing, for example with cetyl
alcohol, macrogol or polyvinyl alcohol and polysorbates to increase
disintegration time or lubrication or to reduce adhesion on
storage.
[0171] One or more sample suppositories, pessaries, or
intra-urethral devices from each batch produced are preferably
tested by the dissolution method of the present invention for
quality control. According to a preferred embodiment, a sample from
each batch is tested to determine whether at least about 75 or 80%
by weight of the base dissolves within 2 hours.
[0172] Typically the suppository, pessary or like device according
to the invention is substantially hydrophobic or lipophilic
throughout and does not contain a hydrophilic substance such as
hydrophilic carrier or pharmaceutical active, or hydrophilic foci
or region formed from the ligation or complexing of the
isoflavonoid to or with another pharmaceutical compound, carrier or
excipient.
[0173] Preferably the formulation for forming the suppository,
pessary and devices for urethral application does not include a
further pharmaceutical active, cytotoxic or chemotherapeutic agent.
In this embodiment, the only active is the isoflavonoid and the
formulation does not include a platin, taxane or other cytotoxic or
chemotherapeutic agent.
[0174] The total weight of the suppository preferably ranges from
about 2250 to about 2700 mg and more preferably from about 2250 to
about 2500 mg. According to one embodiment, the suppository has a
total weight ranging from about 2300 mg to about 2500 mg.
[0175] The suppository or pessary is preferably smooth
torpedo-shaped.
[0176] The melting point of the suppository or pessary is generally
sufficient to melt in the patient's body, and is typically no more
than about 37.degree. C.
[0177] In one particularly preferred embodiment there is provided:
[0178] a kit including: [0179] a plurality of suppositories
sufficient in number to provide an individual with a suppository
once daily, or twice daily, for a period of 30 to 90 days,
preferably 30 to 60 days, preferably 30 days [0180] each
suppository including: [0181] 400 mg or 800 mg of idronoxil; [0182]
a suppository base in the form of cocoa butter; [0183] wherein the
suppository base in provided an amount of 1-99% w/w of the
suppository, [0184] the kit further including: [0185] written
instructions to provide the suppository once daily, or twice daily
for a period of 30 to 90 days, preferably 30 to 60 days, preferably
30 days, preferably for use in a method described herein,
preferably where the cancer is prostate cancer.
[0186] Methods for applying a suppository are well known in the
art. Generally the methods involve inserting the suppository to a
point aligned with the inferior and medial haemorrhoid veins,
thereby enabling the release of the drug to the inferior vena
cavea.
[0187] Methods for applying a pessary, or for urethral application
of a pharmaceutically active ingredient are well known in the
art.
[0188] C. Tumours
[0189] Embodiments of the invention described herein relate to the
treatment of a range of solid tumours, enabling complete or partial
response based on irradiation of certain tumours and abscopal
responses in non-irradiated tumours.
[0190] The individual requiring treatment has at least two
measurable tumours.
[0191] The tumours may include a primary tumour.
[0192] At least one of the tumours may be a metastatic or secondary
tumour of a primary tumour. The secondary cancer may be located in
any organ or tissue, and particularly those organs or tissues
having relatively higher hemodynamic pressures, such as lung,
liver, kidney, pancreas, bowel and brain.
[0193] Other examples of cancer include blastoma (including
medulloblastoma and retinoblastoma), sarcoma (including liposarcoma
and synovial cell sarcoma), neuroendocrine tumors (including
carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma,
schwannoma (including acoustic neuroma), meningioma,
adenocarcinoma, melanoma, leukemia or lymphoid malignancies, lung
cancer including small-cell lung cancer (SGLG), non-small cell lung
cancer (NSGLG), adenocarcinoma of the lung and squamous carcinoma
of the lung, cancer of the peritoneum, hepatocellular cancer,
gastric or stomach cancer including gastrointestinal cancer,
pancreatic cancer, glioblastoma, ovarian cancer, liver cancer,
bladder cancer, hepatoma, breast cancer (including metastatic
breast cancer), colon cancer, rectal cancer, colorectal cancer,
salivary gland carcinoma, kidney or renal cancer, prostate cancer,
thyroid cancer, hepatic carcinoma, anal carcinoma, penile
carcinoma, testicular cancer, oesophageal cancer, tumors of the
biliary tract, as well as head and neck cancer.
[0194] In one particularly preferred embodiment, the cancer is
primary or secondary prostate cancer, the isoflavonoid is idronoxil
and the formulation is in the form of a suppository having a
suppository base formed from, or consisting of Theobroma oil (cocoa
butter). The idronoxil may be contained in the suppository in an
amount of 400 mg or 800 mg. The idronoxil may be given once or
twice daily for a period of 2 to 4 weeks, or for up to 12
months.
[0195] In one embodiment, the treatment provides for an inhibition
of increase in prostate specific antigen (PSA) score, or for
inhibition of tumour growth. In one embodiment the treatment
provides for a reduction in PSA score, preferably a 50%, 60%, 70%,
80%, 90% or 100% reduction in PSA score.
[0196] D. Irradiation
[0197] As described herein, the invention includes the step of
irradiating the individual requiring treatment with a cytotoxic
dose of ionising radiation so that fewer than all of the tumours
are irradiated, thereby resulting in the individual having
irradiated and non-irradiated tumours.
[0198] Methods for the selective irradiation of tumours are very
well known in the art. Methods such as stereotactic radiotherapy
enable the precise focussing and delivery of an ionising beam of
radiation to a particular anatomic or histologic region of tissue
or organ and in particular enabling the irradiation of a tumour in
one tissue or organ but not another tumour in the same tissue or
organ.
[0199] Radiation therapy, radiotherapy, or radiation oncology is
therapy using ionizing radiation, generally as part of cancer
treatment to control or kill malignant cells. Radiation may be
prescribed by a radiation oncologist for curative, adjuvant,
neoadjuvant, therapeutic, or palliative treatment. It is also
common to combine radiation therapy with surgery, chemotherapy,
hormone therapy, immunotherapy or some mixture of the four. Most
common cancer types can be treated with radiation therapy in some
way. The precise treatment intent (curative, adjuvant, neoadjuvant,
therapeutic, or palliative) will depend on the tumor type,
location, and stage, as well as the general health of the patient.
Total body irradiation (TBI) is a radiation therapy technique used
to prepare the body to receive a bone marrow transplant. However,
the disclosed methods generally involve the use of targeted,
localized radiation therapy to promote an abscopal effect.
[0200] The amount of radiation used in photon radiation therapy is
measured in gray (Gy), and varies depending on the type and stage
of cancer being treated. For curative cases, the typical dose for a
solid epithelial tumor ranges from 60 to 80 Gy, while lymphomas are
treated with 20 to 40 Gy. Preventive (adjuvant) doses are typically
around 45-60 Gy in 1.8-2 Gy fractions (for breast, head, and neck
cancers.) Many other factors are considered by radiation
oncologists when selecting a dose, including whether the patient is
receiving chemotherapy, patient comorbidities, whether radiation
therapy is being administered before or after surgery, and the
degree of success of surgery.
[0201] Delivery parameters of a prescribed dose are determined
during treatment planning (part of dosimetry). Treatment planning
is generally performed on dedicated computers using specialized
treatment planning software. Depending on the radiation delivery
method, several angles or sources may be used to sum to the total
necessary dose. The planner will try to design a plan that delivers
a uniform prescription dose to the tumor and minimizes dose to
surrounding healthy tissues.
[0202] The total dose is fractionated (spread out over time) for
several important reasons.
[0203] Fractionation allows normal cells time to recover, while
tumor cells are generally less efficient in repair between
fractions. Fractionation also allows tumor cells that were in a
relatively radioresistant phase of the cell cycle during one
treatment to cycle into a sensitive phase of the cycle before the
next fraction is given. Similarly, tumor cells that were
chronically or acutely hypoxic (and therefore more radioresistant)
may reoxygenate between fractions, improving the tumor cell
kill.
[0204] In North America, Australia, and Europe, the standard
fractionation schedule for adults is 1.8 to 2 Gy per day, five days
a week. In some cancer types, prolongation of the fraction schedule
over too long can allow for the tumor to begin repopulating, and
for these tumor types, including head-and-neck and cervical
squamous cell cancers, radiation treatment is preferably completed
within a certain amount of time. For children, a typical fraction
size may be 1.5 to 1.8 Gy per day, as smaller fraction sizes are
associated with reduced incidence and severity of late-onset side
effects in normal tissues.
[0205] In some cases, two fractions per day are used. This
schedule, known as hyperfractionation, is used on tumors that
regenerate more quickly when they are smaller. In particular,
tumors in the head-and-neck demonstrate this behavior. One
fractionation schedule that is increasingly being used and
continues to be studied is hypofractionation. This is a radiation
treatment in which the total dose of radiation is divided into
large doses. Typical doses vary significantly by cancer type, from
2.2 Gy/fraction to 20 Gy/fraction. The logic behind
hypofractionation is to lessen the possibility of the cancer
returning by not giving the cells enough time to reproduce and also
to exploit the unique biological radiation sensitivity of some
tumors. One commonly treated site where there is very good evidence
for such treatment is in breast cancer.
[0206] One of the best-known alternative fractionation schedules is
Continuous Hyper-fractionated Accelerated Radiation therapy
(CHART). CHART, used to treat lung cancer, consists of three
smaller fractions per day. Although reasonably successful, CHART
can be a strain on radiation therapy departments.
[0207] Another increasingly well-known alternative fractionation
schedule, used to treat breast cancer, is called Accelerated
Partial Breast Irradiation (APBI). APBI can be performed with
either brachytherapy or with external beam radiation. APBI normally
involves two high-dose fractions per day for five days, compared to
whole breast irradiation, in which a single, smaller fraction is
given five times a week over a six-to-seven-week period. An example
of APBI where the entire dose is delivered in a single fraction is
TARGIT.
[0208] The methods provided herein can be performed with any
suitable radiotherapy, including, but not limited to, external beam
radiotherapy, also known as teletherapy; sealed source
radiotherapy, also known as brachytherapy; unsealed source
radiotherapy; radioisotope therapy; and radioimmunotherapy.
[0209] In some embodiments, the radiotherapy is external radiation
therapy. Examples of external radiation therapy include, but are
not limited to, conventional external beam radiotherapy;
three-dimensional conformal radiation therapy (3D-CR.T), which
delivers shaped beams to closely fit the shape of a tumor from
different directions; intensity modulated radiation therapy (IMRT),
e.g., helical tomotherapy, which shapes the radiation beams to
closely fit the shape of a tumor and also alters the radiation dose
according to the shape of the tumor; conformal proton beam
radiation therapy; image-guided radiotherapy (IGRT), which combines
scanning and radiation technologies to provide real time images of
a tumor to guide the radiation treatment; intraoperative radiation
therapy (TORT), which delivers radiation directly to a tumor during
surgery; stereotactic radiosurgery, which delivers a large, precise
radiation dose to a small tumor area in a single session;
hyperfractionated radiotherapy, e.g., continuous hyperfractionated
accelerated radiotherapy (CHART), in which more than one treatment
(fraction) of radiotherapy are given to a subject per day; and
hypofractionated radiotherapy, in which larger doses of
radiotherapy per fraction is given but fewer fractions.
[0210] In another embodiment, the radiotherapy is internal
radiation therapy. Example of internal radiation therapy include,
but are not limited to, interstitial, intracavitary, intraluminal,
intravenously radiation therapy, and implant radiation therapy,
such as implantation of radioactive beads, particles, or seeds. In
some embodiments, the radiotherapy is sealed source radiotherapy.
In another embodiment, the radiotherapy is unsealed source
radiotherapy.
[0211] In yet another embodiment, the radiotherapy is radioisotope
therapy or radioimmunotherapy, where the radiotherapy is performed
by administering a radioisotope parenterally to a subject, e.g., by
injecting to a subject a tumor-specific antibody-radioisotope
conjugate. Suitable radioisotopes for radioisotope therapy or
radioimmunotherapy include, but are not limited to, 72As, i98Au,
206Bi, 77Br, C, i4C, 47Ca, i29Ce, 137Ce, 55Co, 56Co, 57Co, 58Co,
60Co, 51Cr, 6iCu, 16 9Er/t8F, 52Fe, 55Fe, 59Fe, 67Ga, u % u % i %
min, i921r, 8i r, i 77Lu, 52Mg, I, 22Na, 24Na, 57NL 550, 32P,
203Pb, 103Pd, 8 [Rb, 72Se, 7 Se, 75Se, [53Sm, 89Sr, 90Sr, T, "Tc,
201 TI, i 67Tm, 90Y, 62Zn, and I3 Xe. Examples of reagents for
radioisotope therapy and radioimmunotherapy include, but not
limited to, metaiodobenzylguanidine, oral iodine-131, hormone-bound
lutetium-177 and yttrium-90, ibritumomab tiuxetan, tositumomab
iodine-131, radioactive glass or resins, and radioactive
nanoparticles.
[0212] The choice of the radiation therapy can be determined by
taking into consideration various factors, including, e.g., the
type, size, and location of the tumor, the age, weight, and
condition of the subject being treated. It is understood that the
precise dose of the radiation and duration of treatment may vary
with the age, weight, and condition of the subject being treated,
and may be determined empirically using known testing protocols or
by extrapolation from in vivo or in vitro test or diagnostic data.
It is also understood that the total radiation dose required is
often divided into two or more fractions, which are administered
over an extended period of time. It is further understood that for
any particular individual, specific dosage regimens could be
adjusted over time according to the individual need and the
professional judgment of the person administering or supervising
the administration of the radiation.
[0213] In some embodiments, the total dose given in the
radiotherapy is ranging from about 40 Gy to about 80 Gy. In certain
embodiments, the total dose is divided into fractions and each
fraction can be the same or different. Each fraction ranges from
about 0.5 Gy to about 50 Gy.
[0214] In one embodiment the method includes the steps of: [0215]
assessing at least some of the tumours to determine at least one
tumour for irradiation with the cytotoxic dose of ionising
radiation; and [0216] selecting at least one of the assessed
tumours for irradiation with the cytotoxic dose of ionising
radiation.
[0217] In one embodiment a tumour is assessed according to the size
or diameter of the tumour.
[0218] In one embodiment the plurality of tumours is assessed
according to the dose of radiotherapy required to provide
cytoxicity to a tumour of the plurality of tumours.
[0219] In one embodiment a tumour is assessed according to
anatomical location.
[0220] In one embodiment, a tumour selected for irradiation has a
longest diameter of at least 10 mm.
[0221] In one embodiment, the one or more non-irradiated tumours
are tumours that have a diameter of more than 10 mm.
[0222] In one embodiment, an irradiated tumour is located in or on
the same organ, or in or on the same connective tissue as a
non-irradiated tumour.
[0223] In one embodiment a primary tumour is irradiated, or a
primary tumour and a metastatic tumour are irradiated.
[0224] In one embodiment a metastatic tumour is irradiated and a
primary tumour is not irradiated.
[0225] D. Assessment of Treatment
[0226] The invention may include the further step of assessing one
or more organs or tissues of an individual who has received the
compound and irradiation, to determine the regression of a
non-irradiated tumour in the individual. In one embodiment the step
utilises radiological imaging to determine the location and volume
for each of the plurality of tumor lesions in the subject after
irradiation. For example, this can involve three-dimensional
radiological images of the subject registering geographic locations
of each of the plurality of tumor lesions. Non-limiting examples of
radiological images that can be used to determine location and/or
volume of a tumor lesion include positron emission tomography (PET)
scans, x-ray computerized tomography (CT), magnetic resonance
imaging (MRI), nuclear magnetic resonance imaging (NMRI), magnetic
resonance tomography (MRT), or a combination thereof.
[0227] In one embodiment, all non-irradiated tumours regress.
[0228] In another embodiment, one or more non-irradiated tumours
are eliminated.
[0229] In another embodiment, all non-irradiated tumours are
eliminated.
[0230] In certain embodiments, the assessment of treatment follows
the RECIST criteria as follows:
[0231] RECIST 1.0 Criteria
[0232] Definition of Measurable and Non-Measurable Disease
[0233] Measurable disease: The presence of at least one measurable
lesion.
[0234] Measurable lesion: Lesions that can be accurately measured
in at least one dimension, with the longest diameter (LD) being:
[0235] .gtoreq.20 mm with conventional techniques (medical
photograph [skin or oral lesion], palpation, plain X-ray, CT, or
MRI),
[0236] OR [0237] .gtoreq.10 mm with spiral CT scan.
[0238] Non-measurable lesion: All other lesions including lesions
too small to be considered measurable (longest diameter <20 mm
with conventional techniques or <10 mm with spiral CT scan)
including bone lesions, leptomeningeal disease, ascites, pleural or
pericardial effusions, lymphangitis cutis/pulmonis, abdominal
masses not confirmed and followed by imaging techniques, cystic
lesions, or disease documented by indirect evidence only (e.g., by
lab values).
[0239] Methods of Measurement
[0240] Conventional CT and MRI: Minimum sized lesion should be
twice the reconstruction interval. The minimum size of a baseline
lesion may be 20 mm, provided the images are reconstructed
contiguously at a minimum of 10 mm. MRI is preferred, and when
used, lesions must be measured in the same anatomic plane by use of
the same imaging sequences on subsequent examinations. Whenever
possible, the same scanner should be used.
[0241] Spiral CT: Minimum size of a baseline lesion may be 10 mm,
provided the images are reconstructed contiguously at 5 mm
intervals. This specification applies to the tumors of the chest,
abdomen, and pelvis.
[0242] Chest X-ray: Lesions on chest X-ray are acceptable as
measurable lesions when they are clearly defined and surrounded by
aerated lung. However, MRI is preferable.
[0243] Clinical Examination: Clinically detected lesions will only
be considered measurable by RECIST criteria when they are
superficial (e.g., skin nodules and palpable lymph nodes). In the
case of skin lesions, documentation by color photography--including
a ruler and patient study number in the field of view to estimate
the size of the lesion--is required.
[0244] Baseline Documentation of Target and Non-Target Lesions
[0245] All measurable lesions up to a maximum of five lesions per
organ and ten lesions in total, representative of all involved
organs, should be identified as target lesions and recorded and
measured at baseline.
[0246] Target lesions should be selected on the basis of their size
(lesions with the LD) and their suitability for accurate repeated
measurements (either clinically or by imaging techniques).
[0247] A sum of the LD for all target lesions will be calculated
and reported as the baseline sum LD. The baseline sum LD will be
used as a reference by which to characterize the objective tumor
response.
[0248] All other lesions (or sites of disease) should be identified
as non-target lesions and should also be recorded at baseline.
Measurements of these lesions are not required, but the presence or
absence of each should be noted throughout follow-up.
[0249] Documentation of indicator lesion(s) should include date of
assessment, description of lesion site, dimensions, and type of
diagnostic study used to follow lesion(s).
[0250] All measurements should be taken and recorded in metric
notation, using a ruler or calipers.
[0251] Response Criteria
[0252] Disease assessments are to be performed every 6 weeks after
initiating treatment. However, subjects experiencing a partial or
complete response must have a confirmatory disease assessment at
least 28 days later. Assessment should be performed as close to 28
days later (as scheduling allows), but no earlier than 28 days.
[0253] Definitions for assessment of response for target lesion(s)
are as follows:
[0254] Evaluation of Target Lesions
[0255] Complete Response (CR)--disappearance of all target
lesions.
[0256] Partial Response (PR)--at least a 30% decrease in the sum of
the LD of target lesions, taking as a reference, the baseline sum
LD.
[0257] Stable Disease (SD)--neither sufficient shrinkage to qualify
for PR nor sufficient increase to qualify for progressive disease
(PD), taking as a reference, the smallest sum LD since the
treatment started. Lesions, taking as a reference, the smallest sum
LD recorded since the treatment started or the appearance of one or
more new lesions.
[0258] Evaluation of Non-Target Lesions
[0259] Definitions of the criteria used to determine the objective
tumor response for non-target lesions are as follows:
[0260] Complete Response--the disappearance of all non-target
lesions.
[0261] Incomplete Response/Stable Disease--the persistence of one
or more non-target lesion(s).
[0262] Progressive Disease--the appearance of one or more new
lesions and/or unequivocal progression of existing non-target
lesions.
[0263] Evaluation of Overall Response for RECIST-Based Response
[0264] The overall response is the best response recorded from the
start of the treatment until disease progression/recurrence is
documented. In general, the subject's best response assignment will
depend on the achievement of both measurement and confirmation
criteria.
[0265] The following table presents the evaluation of best overall
response for all possible combinations of tumor responses in target
and non-target lesions with or without the appearance of new
lesions.
TABLE-US-00001 Target Overall Lesion Non-Target Lesion New Lesion
response CR CR No CR CR Incomplete response/(SD) No PR PR Non-PD No
PR SD Non-PD No SD PD Any Yes or No PD Any PD Yes of No PD Any Any
Yes PD
[0266] Note: Subjects with a global deterioration of health status
requiring discontinuation of treatment without objective evidence
of disease progression at that time should be classified as having
"symptomatic deterioration". Every effort should be made to
document the objective progression even after discontinuation of
treatment.
[0267] In some circumstances, it may be difficult to distinguish
residual disease from normal tissue. When the evaluation of
complete response depends on this determination, it is recommended
that the residual lesion be investigated (fine needle
aspirate/biopsy) to confirm the complete response status.
[0268] Confirmation Criteria
[0269] To be assigned a status of PR or CR, a confirmatory disease
assessment should be performed no less than 28 days after the
criteria for response are first met.
[0270] To be assigned a status of SD, follow-up measurements must
have met the SD criteria at least once after study entry at a
minimum interval of 12 weeks.
[0271] E. Immunotherapy and Anti-Cancer Agents
[0272] In certain embodiments, the invention may include the
administration of an immunotherapeutic agent (such as an antibody
or cytokine) and/or the administration of a small molecule
chemotherapeutic agent.
[0273] In some embodiments, the subject of the disclosed methods is
further treated with an immunotherapy to enhance the abscopal
effect. For example, dendritic cells (DCs) represent unique
antigen-presenting cells capable of activating T cells to both new
and recall antigens. In fact, these cells are the most potent
antigen-presenting cells. The goal of DC based cancer immunotherapy
is to use the cells to prime specific antitumor immunity through
the generation of effector cells that attack and lyse tumors.
[0274] Therefore, in some embodiments, the disclosed methods
further involve administering DCs to the subject. In some
embodiments, the DCs are administered directly to the tumor lesion
site(s) being irradiated. In some embodiments, the DCs are
administered systemically or to tumor site(s) in addition to or
distinct from the sites being irradiated.
[0275] Additional immunotherapeutic approaches include 1) use of
exogenous cytokines to non-specifically stimulate the immune
system's effector cells to mount an anti-tumor response, 2)
introduction of immuno-stimulatory antigens to precipitate a
targeted immune response (i.e. active immunization or tumor
vaccination), 3) exogenous expansion and reinfusion of
tumor-specific immune cells (adoptive immunotherapy), 4) immune
system checkpoint modulation, and 5) use of cancer-killing and
immune system-stimulating modified viruses (oncolytic
immunotherapy). Vaccination with telomerase vaccine (GV1001) can be
combined with an immune adjuvant, e.g., granulocyte macrophage
colony-stimulating factor (GM-CSF), and a cycle of gemcitabine
chemotherapy.
[0276] Immunostimulatory cytokines include interferon alpha
(IFN-.alpha.) and interleukin-2 (IL-2).
[0277] Anticancer vaccines can facilitate tumor antigen recognition
and a subsequent anti-tumor immune response by artificially
introducing tumor-associated antigens to the body, or cellular
equipment that can help expose those already present. Artificially
introduced antigens can take the form of peptide fragments, whole
proteins, cell lysates or whole cells. For example, telomerase is
highly expressed in essentially all cancer forms, while the
expression in normal tissues is restricted. Moreover, telomerase
activity is considered indispensable for tumor immortalization and
growth. Human telomerase reverse transcriptase (hTERT), the
rate-limiting subunit of the telomerase complex, is therefore an
attractive target for cancer vaccination.
[0278] GV1001, a peptide vaccine representing a 16-aa hTERT
sequence, binds multiple HLA class II molecules and harbors
putative HLA class I epitopes. The peptide may therefore elicit
combined CD4/CD8 T-cell responses, considered important to initiate
tumor eradication and long-term memory.
[0279] Adoptive cell therapy (ACT) involves harvesting autologous
lymphocytes from a patient's tumor or peripheral blood, expanding
them and possibly modifying them in-vitro to express
tumor-associated antigen receptors or secrete specific cytokines,
and reintroducing them back into the host. The adoptive transfer of
autologous tumor infiltrating lymphocytes (TIL) or in vitro
re-directed peripheral blood mononuclear cells has been used to
successfully treat patients with advanced solid tumors, including
melanoma and colorectal carcinoma, as well as patients with
CD19-expressing hematologic malignancies.
[0280] Immunomodulatory monoclonal antibody (mAb) therapies include
cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) inhibition (e.g.,
ipilimumab), Programmed Death-1 (PD-1) inhibition (e.g., nivolumab
and pembrolizumab), CD40 agonism, OX40 agonism, Lymphocyte
Activation Gene-3 (LAG-3) and T cell Immunoglobulin Mucin-3 (TIM-3)
inhibition, and Tolllike receptor agonists. CTLA-4 is a T cell
receptor that naturally interacts with B7-1 (CD-80) and B7-2
(CD-86) on the surface of antigen presenting cells, thereby
down-regulating the T cell response and avoiding potential
autoimmune damage. A costimulatory T cell surface protein, CD-28,
on the other hand, competes with CTLA-4, albeit with less affinity,
for interaction with B7-1 and B7-2, activating the T cell. Blocking
CTLA-4 thereby allows CD-28 to interact with B7-1 and B7-2,
enhancing the body's cellular immune response and ability to
eradicate tumor cells. For poorly immunogenic tumors, CTLA-4
blockade may be effective if used in combination with vaccination
with irradiated tumor cells modified to produce GM-CSF.
[0281] PD-1 receptor is expressed on B, T, and NK cells, and
interacts with Programmed Death Ligands-1 and -2 (PDL-1 and -2),
often subversively expressed on melanoma cells, to induce T cell
exhaustion and down-regulate the immune response. By blocking PD-1,
these medications facilitate a more vigorous anti-tumor cellular
immune response. CD40 is a costimulatory receptor of the tumor
necrosis factor (TNF) family normally expressed on a variety of
cells including dendritic cells and macrophages. Interaction with
its ligand plays a key role in priming and proliferation of
antigen-specific CD4 T cells. When expressed on tumor cells, its
stimulation results in apoptosis. Thus, CD40-stimulating mAbs
(e.g., CD-870873) have direct anti-tumor activity and induce tumor
antigen-specific T cell responses. LAG-3 is a transmembrane protein
expressed on T regulatory (T reg) cells that binds MHC II, often
expressed on melanoma cells, thereby enhancing T reg activity,
negatively regulating the cellular immune response, and protecting
melanoma cells from apoptosis. Blocking LAG-3 could thus help the
body fight tumor cells on two fronts. Another class of
immunomodulators act upon TLRs, a group of cell-surface receptors
found on sentinel immune cells like dendritic cells and macrophages
that naturally activate an innate immune response upon contact with
characteristic pathogen-related antigens. Topical treatment of
melanoma with Imiquimod (IMQ), a TLR-7 agonist, has been shown to
facilitate 1) tumor infiltration with immune effector cells such as
activated, cytotoxic plasmacytoid DCs, 2) a type I IFN response, 3)
anti-angiogenic defenses, and in some cases result in complete
tumor regression.
[0282] The blockade of TGF-.beta. by anti-TGF-.beta. antibody can
synergistically enhance tumor vaccine efficacy, which is mediated
by CD8+ T cells. For example, fresolimumab is an antibody capable
of neutralizing all human isoforms of transforming growth factor
beta (TGF) and has demonstrated anticancer activity.
[0283] Generating optimal "killer" CD8 T cell responses also
requires T cell receptor activation plus co-stimulation, which can
be provided through ligation of tumor necrosis factor receptor
family members, including OX40 (CD134) and 4-IBB (CD137). OX40 is
of particular interest as treatment with an activating (agonist)
anti-OX40 mAb augments T cell differentiation and cytolytic
function leading to enhanced anti-tumor immunity against a variety
of tumors.
[0284] Numerous anti-cancer drugs are available for combination
with the present method and compositions. The following is a
non-exhaustive list of anti-cancer (anti-neoplastic) drugs that can
be used in conjunction with irradiation: Acivicin; Aclarubicin;
Acodazole Hydrochloride; AcrQnine; Adozelesin; Aldesleukin;
Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide;
Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin;
Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa;
Bicalutamide; BisantreneHydrochloride; Bisnafide Dimesylate;
Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine;
Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer;
Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin;
Cedefingol; Chlorambucil; Cirolemycin; Cisplatin; Cladribine;
Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine;
Dactinomycin; Daunorubicin Hydrochloride; Decitabine;
Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone;
Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene;
Droloxifene Citrate; Dromostanolone Propionate; Duazomycin;
Edatrexate; Eflomithine Hydrochloride; Elsamitrucin; Enloplatin;
Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole;
Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate
Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Etoposide
Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine;
Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil;
Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine;
GemcitabineHydrochloride; Gold Au 198; Hydroxyurea; Idarubicin
Hydrochloride; Ifosfamide; Ilmofosine; Iproplatin; Irinotecan
Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate;
Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone
Hydrochloride; Masoprocol; Maytansine; Mechlorethamine
Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan;
Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium;
Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin;
Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone
Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin;
Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin;
Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman;
Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane;
Porfimer Sodium; Porfiromycin; Prednimustine;
ProcarbazineHydrochloride; Puromycin; Puromycin Hydrochloride;
Pyrazofurin; Riboprine; Rogletimide; Safmgol; Safingol
Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium;
Sparsomycin; Spirogermanium Hydrochloride; Spiromustine;
Spiroplatin; Streptonigrin; Streptozocin; Strontium Chloride Sr 89;
Sulofenur; Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur;
Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone;
Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin;
Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate;
Trestolone Acetate; Triciribine Phosphate; Trimetrexate;
Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride;
Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine
Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate;
Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate;
Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate;
Vorozole; Zeniplatin; Zinostatin; Zorubicin Hydrochloride.
[0285] In one embodiment of the invention, the individual receives
carboplatin and idronoxil.
[0286] In one embodiment of the invention, the individual receives
granulocyte macrophage colony stimulating factor (GMCSF) and
idronoxil.
[0287] In one embodiment of the invention, the individual receives
granulocyte macrophage colony stimulating factor (GMCSF), idronoxil
and carboplatin.
[0288] It will be understood that the invention disclosed and
defined in this specification extends to all alternative
combinations of two or more of the individual features mentioned.
All of these different combinations constitute various alternative
aspects of the invention.
EXAMPLES
Example 1
[0289] Individuals selected for treatment have late-stage,
metastatic, solid (non-haematologic) cancer with no standard
therapeutic alternatives other than palliative radiotherapy for
pain or symptom relief. The individuals have a minimum of 3
measurable lesions that are amenable to radiotherapy (RT) and a
projected minimum life expectancy of 12 weeks.
[0290] Idronoxil is self-administered at home as a rectal
suppository. Individuals are instructed in the procedure of
suppository administration.
[0291] Dosage is 400 mg daily (1.times. idronoxil containing
suppository daily) for 7 consecutive days followed by 800 mg daily
(1 idronoxil containing suppository twice daily) for 7 consecutive
days.
[0292] One of 3 measurable lesions, or a maximum 2 of 4 or more
measurable lesions will receive 25 Gy by external beam RT in 5
fractionated doses over 5 consecutive days. Multiple lesions are
irradiated concurrently.
[0293] After a 14-day treatment cycle follow-up CT scans and
clinical assessments are made 6- and 12-weeks post the completion
of the treatment cycle.
[0294] Efficacy is assessed based on tumour response utilising CT
scans and standard RECIST criteria and ECOG status. Tumour response
is assessed by standard RECIST criteria; specifically, target
lesions are the largest lesions (up to a maximum of 7 lesions) and
are measured. Non-target lesions are all other lesions and are
noted but not measured.
* * * * *