2.3.
Novartis AG heeft op 18 februari 2002 een internationale PCT-aanvraag ingediend onder nummer WO 02/066019 (hierna: WO 019 of de aanvraag) voor “Cancer treatment”. De aanvraag is gepubliceerd op 29 augustus 2002 en doet een beroep op het prioriteitsdocumenten GB 0104072.4, gedateerd 19 februari 2001, en GB 0124957.2 (hierna: GB 572), gedateerd 17 oktober 2001. De aanvraag bevat onder meer de volgende passages:
Cancer Treatment
The present invention relates to a new use, in particular a new use for a compound group comprising rapamycin and derivatives thereof.
Rapamycin is a known macrolide antibiotic produced by Streptomyces hygroscopicus. Suitable derivatives of rapamycin include e.g. compounds of formula I
wherein
R, is CH3 or C3-6alkynyl,
R2 is H or -CH2-CH2-OH, and
X is =O, (H.H) or (H,OH)
provided that R2 is other than H when X is =O and R1 is CH3.
Compounds of formula I are disclosed e.g. in WO 94/09010, WO 95/16691 or WO 96/41807, which are incorporated herein by reference. They may be prepared as diclosed or by analogy to the procedures described in these references
Preferred compounds are 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S)-dihydro-rapamycin, 16-pent-2-ynyloxy-32(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin and, more preferably, 40-0-(2-hydroxyethyl)-rapamycin (referred thereafter as Compound A), disclosed as Example 8 in WO 94/09010.
Compounds of formula I have, on the basis of observed activity, e.g. binding to
macrophilin-12 (also known as FK-506 binding protein or FKBP-12), e.g. as described in WO 94/09010, WO 95/16691 or WO 96/41807, been found to be useful e.g. as
immunosuppressant, e.g. in the treatment of acute allograft rejection. It has now been found that Compounds of formula I have potent antiproliferative properties which make them useful for cancer chemotherapy, particularly of solid tumors, especially of advanced solid tumors. There is still the need to expand the armamentarium of cancer treatment of solid tumors, especially in cases where treatment with anticancer compounds is not associated with disease regression or stabilization.
In accordance with the particular findings of the present invention, there is provided:
1.1 A method for treating solid tumors in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I.
1.2 A method for inhibiting growth of solid tumors in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I.
1.3 A method for inducing tumor regression, e.g. tumor mass reduction, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I.
1.4 A method for treating solid tumor invasiveness or symptoms associated with such tumor growth in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I.
1.5 A method for preventing metastatic spread of tumours or for preventing or inhibiting growth of micrometastasis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I.
By "solid tumors" are meant tumors and/or metastasis (whereever
1
located) other than lymphatic cancer, e.g. brain and other central nervous system tumors (eg. tumors of the meninges, brain, spinal cord, cranial nerves and other parts of central nervous system, e.g. glioblastomas or medulla blastomas); head and/or neck cancer;
breast tumors
2
; circulatory system tumors (e.g. heart, mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue); excretory system tumors (e.g. kidney, renal pelvis, ureter, bladder, other and unspecified urinary organs); gastrointestinal tract tumors (e.g. oesophagus, stomach, small intestine, colon, colorectal, rectosigmoid junction, rectum, anus and anal canal), tumors involving the liver and intrahepatic bile ducts, gall bladder, other and unspecified parts of biliary tract, pancreas, other and digestive organs); head and neck; oral cavity (lip, tongue, gum, floor of mouth, palate, and other parts of mouth, parotid gland, and other parts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriform sinus, hypopharynx, and other sites in the lip, oral cavity and pharynx); reproductive system tumors (e.g. vulva, vagina, Cervix uteri, Corpus uteri, uterus, ovary, and other sites associated with female genital organs, placenta, penis, prostate, testis, and other sites associated with male genital organs); respiratory tract tumors (e.g. nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung, e.g. small cell lung cancer or non-small cell lung cancer); skeletal system tumors (e.g. bone and articular cartilage of limbs, bone articular cartilage and other sites); skin tumors (e.g. malignant melanoma of the skin, non-melanoma skin cancer, basal cell carcinoma of skin, squamous cell carcinoma of skin, mesothelioma, Kaposi's sarcoma); and tumors involving other tissues incluing
3
peripheral nerves and autonomic nervous system, connective and soft tissue, retroperitoneum and peritoneum, eye and adnexa, thyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and secondary malignant neoplasm of other sites.
Where hereinbefore and subsequently a tumor, a tumor disease, a carcinoma or a cancer is mentioned, also metastasis in the original organ or tissue and/or in any other location are implied alternatively or in addition, whatever the location of the tumor and/or metastasis is.
In a series of further specific or alternative embodiments, the present invention also provides
1.6
A method for the treatment of a disease associated with deregulated angiogenesis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of rapamycin or a derivative thereof, e.g. CCI779
4
, ABT578
5
or a compound of formula I.
1.7 A method for inhibiting or controlling deregulated angiogenesis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a compound of formula I.
1.8 A method for enhancing the activity of a chemotherapeutic agent or for overcoming resistance to a chemotherapeutic agent in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a compound of formula I, either
concomitantly or sequentially with said chemotherapeutic agent.
1.9 A method according to 1.8 wherein the chemotherapeutic agent is an inhibitor of signal transduction pathways directed either against host cells or processes involved in tumor formation and/or metastases formation or utilised by tumour cells for proliferation, survival, differentiation or development of drug resistance.
1.10 A method as indicated above, wherein rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a compound of formula I is administered intermittently.
CCI779 is a rapamycin derivative, i.e.40- [3-hydroxy-2-(hydroxymethyl)-2-methylpropa-noatej-rapamycin or a pharmaceutically acceptable salt thereof, and is disclosed e.g. in USP 5,362,718. ABT578 is a 40-substituted rapamycin derivative further comprising a diene reduction.
Examples of diseases associated with deregulated angiogenesis include without limitation e.g. neoplastic diseases, e.g. solid tumors. Angiogenesis is regarded as a prerequisite for those tumors which grow beyond a certain diameter, e.g. about 1-2 mm.
In a series of further specific or alternative embodiments, the present invention also provides:
2.1 A compound of formula I for use in any method as defined under 1.1 to 1.5 above.
2.2 Rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a compound of formula I for use in any method as defined under 1.6 to 1.10 above or 7 below.
3.1 A compound of formula I for use in the preparation of a pharmaceutical composition for use in any method as defined under 1.1 to 1.5 above.
3.2 Rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a compound of formula I for use in the preparation of a pharmaceutical composition for use in any method as defined under 1.6 to 1.10 above or 7 below.
4.1 A pharmaceutical composition for use in any method as defined under 1.1 to 1.5 above comprising a compound of formula I together with one or more pharmaceutically acceptable diluents or carriers therefor.
4.2 A pharmaceutical composition for use in any method as defined under 1.6 to 1.10 above or 7 below comprising rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a compound of formula I, e.g. Compound A, together with one or more
pharmaceutically acceptable diluents or carriers therefor.
5.1 A pharmaceutical combination comprising a) a first agent which is rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a compound of formula I, e.g. Compound A, and b) a co-agent which is a chemotherapeutic agent, e.g. as defined hereinafter.
6
5.2 A pharmaceutical combination comprising an amount of a) a first agent which is rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a compound of formula I, e.g. Compound A, and b) a co-agent which is a chemotherapeutic agent selected from the compounds defined under paragraph (iv) or (v) below, to produce a synergistic therapeutic effect.
6. A method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a compound of formula I, e.g. Compound A, and a second drug substance, said second drug substance being a chemotherapeutic agent, e.g. as indicated hereinafter.
7. A method for treating post-transplant lymphoproliferative disorders or a lymphatic cancer, e.g. for treating tumor invasiveness or symptoms associated with such tumor growth in a subject in need thereof, comprising co-administering to said subject, e.g. concomitantly or in sequence, of rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a compound of formula I, e.g. Compound A, and a second drug substance, said second drug substance being a chemotherapeutic agent, e.g. as indicated hereinafter.
By "lymphatic cancer" are meant e.g. tumors of blood and lymphatic system (e.g. Hodgkin's disease, Non-Hodgkin's lymphoma, Burkitt's lymphoma, AIDS-related lymphomas, malignant immunoproliferative diseases, multiple myeloma and malignant plasma cell neoplasms, lymphoid leukemia, myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specified cell type, leukemia of unspecified cell type, other and unspecified malignant neoplasms of lymphoid, haematopoietic and related tissues, for example diffuse large cell lymphoma, T-cell lymphoma or cutaneous T-cell lymphoma).
By the term "chemotherapeutic agent" is meant especially any chemotherapeutic agent other than rapamycin or a derivative thereof. It includes but is not limited to,
i. an aromatase inhibitor,
7
ii. an antiestrogen, an anti-androgen (especially in the case of prostate cancer) or a gonadorelin agonist,
iii. a topoisomerase I inhibitor or a topoisomerase II inhibitor,
iv. a microtubule active agent, an alkylating agent, an antineoplastic antimetabolite or a platin compound,
v. a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid phosphatase activity, a further anti-angiogenic compound or a compound which induces cell differentiation processes,
vi. a bradykinin 1 receptor or an angiotensin II antagonist, vii. a cyclooxygenase inhibitor, a bisphosphonate, a histone deacetylase inhibitor, a heparanase inhibitor (prevents heparan sulphate degradation), e.g. PI-88, a biological response modifier, preferably a lymphokine or interferons, e.g. interferon γ, an ubiquitination inhibitor, or an inhibitor which blocks anti-apoptotic pathways, viii. an inhibitor of Ras oncogenic isoforms, e.g. H-Ras, K-Ras or N-Ras, or a farnesyl transferase inhibitor, e.g. L-744,832 or DK8G557,
ix. a telomerase inhibitor, e.g. telomestatin,
x. a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase inhibitor, e.g. bengamide or a derivative thereof, or a proteosome inhibitor, e.g.
PS-341.
The term "aromatase inhibitor" as used herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane can be administered
, e.g., in the form as it is marketed, e.g. under the trademark AROMASIN™. Formestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark LENTARON™. Fadrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark AFEMA™. Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARI IDEX™. Letrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark FEMARA™ or FEMAR™ Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g. under the trademark ORI ETEN™.
A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g. breast tumors.
8
The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be
administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX™. Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTA™. Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g. under the trademark FASLODEX™. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g. breast tumors.
(…)
A. In Vitro
A.1 Antiproliferative activity in combination with other agents
A cell line, e.g. the Compound A resistant A549 line (IC50 in low nM range) versus the comparative Compound A resistant KB-31 and HCT116 lines (IC50 in the µM range), is added to 96-well plates (1,500 cells/well in 100 µI medium) and incubated for 24 hr. Subsequently, a two-fold dilution series of each compound (Compound of formula I or a known chemotherapeutic agent) is made in separate tubes (starting at 8 x the IC50 of each compound) either alone or in paired combinations, and the dilutions are added to the wells. The cells are then re-incubated for 3 days. Methylene blue staining is performed on day 4 and the amount of bound dye (proportional to the number of surviving cells that bind the dye) determined. IC50s are subsequently determined using the Calcusyn program, which provides a measure of the interaction, namely the so-called non-exclusive combination index (CI), where: CI ∼ 1 = the interaction is nearly additive; 0.85 - 0.9 = slight synergism; < 0.85 = synergy. In this assay, the Compound A shows interesting antiproliferative activity in combination with another chemotherapeutic agent. For example the following CI values are obtained with a combination of Compound A and cisplatinum, paclitaxel, gemcitabine and doxorubicin, showing synergistic effects.
(…)
B.4 Combination with doxorubicin
Mice transplanted with human KB-31 epidermoid tumors are treated for 21 days with doxorubicin at a dose of 5 mg/kg i.v. once per week, a compound of formula I, e.g.
Compound A, at a dose of 2.5 mg/kg p.o once per day, or a combination of both. Thereafter compound of formula I treatment alone is continued in the combination group in order to determine if the compound of formula I can suppress the outgrowth of tumors that respond to conventional agents. Antitumor activity is expressed as T/C% or % regressions as indicated above. For example, the combination of Compound A and doxorubicin produces greater antitumor effect (74 % regressions) as compared to either agent alone (Compound A, T/C 32 %; doxorubicin 44 % regressions). No exacerbation of the body weight losses caused by doxorubicin occurrs
9
when Compound A treatment is added. Continuing
Compound A treatment in the combination group, after ceasing doxorubicin, inhibits tumor outgrowth such that the tumor volumes of the doxorubicin monotherapy group are
significantly larger than those of the combination group. Morever
10
the combination appears to produce a greater cure rate (8/8 tumors) at 14 days post end of treatment than doxorubicin alone (3/8 tumors).
(…)
B.7 Combination with an antiangiogenic agent
B16/BL6 cells (5 X104) are injected intradermally into the ear of C57BIJ6 mice. Seven days later treatment with rapamycin or a derivative thereof, e.g. Compound A, a VEGF receptor tyrosine kinase inhibitor, e.g. 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a salt thereof, e.g. the succinate, or a combination of both is initiated and effects on the growth and weight of the primary tumor and cervical lymph node metastases are monitored, respectively. Daily administration of the antiangiogenic agent (100 mg/kg p.o.) or of rapamycin or a derivative thereof, e.g. Compound A, (1 mg/kg p.o.) alone, reduces the size of the primary tumor (final T/C: 65 % and 74 %, respectively), whereas the combination of these two agents is synergistic (T/C 12 %). Rapamycin or a derivative thereof, e.g.
Compound A and the antiangiogenic agent treatment alone reduces cervical lymph node weights (related to regional metastases) (T/C: 75 % and 34 %, respectively), and the combination further reduces lymph node weights (T/C 13 %). The treatments significantly promote body weight gains as compared to controls. For the primary tumors, analysis of possible interaction shows synergy with Compound A and antiangiogenic agent as antiangiogenic agent /controls = 0.66; Compound A/controls = 0.77; Compound A and antiangiogenic agent /controls = 0.135. As Compound A and antiangiogenic agent /controls < Compound A/controls x antiangiogenic agent /controls (0.51), this is defined as synergy. For the metastases, analysis also shows synergy with Compound A and the antiangiogenic agent as antiangiogenic agent /controls = 0.337; Compound A/controls = 0.75; Compound A and antiangiogenic agent /controls = 0.122. As Compound A and antiangiogenic agent /controls < Compound A controls x antiangiogenic agent /controls (0.252), this is also defined as synergy (Clark, Breast Cancer Research Treatment 1997;46:255).
C. Clinical Trial
(…)
C.2 Combined Treatment
Suitable clinical studies are, for example, open label non-randomized, dose escalation studies in patients with advanced solid tumors. Such studies prove in particular the synergism of the active ingredients of the combination of the invention. The beneficial effects on proliferative diseases can be determined directly through the results of these studies or by changes in the study design which are known as such to a person skilled in the art. Such studies are, in particular, suitable to compare the effects of a monotherapy using the active ingredients and a combination of the invention. Preferably, the dose of agent (a) is escalated until the Maximum Tolerated Dosage is reached, and the co-agent (b) is administered with a fixed dose. Alternatively, the agent (a) is administered in a fixed dose and the dose of co-agent (b) is escalated. Each patient receives doses of the agent (a) either daily or intermittent. The efficacy of the treatment can be determined in such studies, e.g., after 12, 18 or 24 weeks by radiologic evaluation of the tumors every 6 weeks.
Alternatively, a placebo-controlled, double blind study can be used in order to prove the benefits of the combination of the invention mentioned herein.
Daily dosages required in practicing the method of the present invention when a compound of formula I alone is used will vary depending upon, for example, the compound used, the host, the mode of administration and the severity of the condition to be treated. A preferred daily dosage range is about from 0.1 to 25 mg as a single dose or in divided doses. Suitable daily dosages for patients are on the order of from e.g. 0.1 to 25 mg p.o. Compound A may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions. Suitable unit dosage forms for oral administration comprise from ca. 0.05 to 12.5 mg, usually 0.25 to 10 mg Compound A, together with one or more pharmaceutically acceptable diluents or carriers therefor.
The combination of the invention can also be applied in combination with surgical intervention, mild prolonged whole body hyperthermia and/or irradiation therapy.
The administration of a pharmaceutical combination of the invention results not only in a beneficial effect, e.g. a synergistic therapeutic effect, e.g. with regard to slowing down, arresting or reversing the neoplasm formation or a longer duration of tumor response, but also in further surprising beneficial effects, e.g. less side-effects, an improved quality of life or a decreased mortality and morbidity, compared to a monotherapy applying only one of the pharmaceutically active ingredients used in the combination of the invention, in particular in the treatment of a tumor that is refractory to other chemotherapeutics known as anti-cancer agents. In particular, an increased up-take of the co-agent (b) in tumor tissue and tumor cells is observed, when applied in combination with the first agent (a).
A further benefit is that lower doses of the active ingredients of the combination of the invention can be used, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side-effects, while controlling the growth of neoplasm formation. This is in accordance with the desires and requirements of the patients to be treated.
According to one embodiment of the invention, a preferred pharmaceutical combination comprises
a) a compound of formula I, e.g. Compound A, and
b) as co-agent, one or more compounds as indicated in paragraphs (ii), (iii) or (iv) above, e.g. carboplatin, cisplatinum, paclitaxel, docetaxel, gemcitabine or doxorubicin.
A synergistic combination of a compound of formula I, e.g. Compound A, with carboplatin, cisplatinum, paclitaxel, docetaxel, gemcitabine or doxorubicin is particularly preferred.
A further preferred pharmaceutical combination is e.g. a combination comprising
a) rapamycin or a derivative thereof, e.g. CCI-779, ABT578 or Compound A, and
b) as co-agent, one or more compounds as indicated under paragraphs (i)
11
and (v) to (x) above, preferably one or more compounds as specified in paragraph (v) above.
Preferred is e.g. a synergistic combination of rapamycin or a derivative thereof, e.g. CCI-779, ABT578 or Compound A, with a compound which target, decrease or inhibit the activity of VEGFR, EGFR family, PDGFR, c-ABI family members or protein kinase C, e.g. as disclosed above.
One specific embodiment of the invention relates to the use of a combination of the invention for the prevention, delay of progression or treatment of or for the preparation of a
medicament for the prevention, delay of progression or treatment of breast cancer.
Preferably, in such embodiment the combination comprises as co-agent b) an aromatase inhibitor, e.g. the aromatase inhibitor letrozole, an anti-estrogen, e.g. tamoxifen, a topoisomerase II inhibitor, e.g. doxorubicin, or a microtubule active agent, e.g. paclitaxel.
12
Another embodiment of the invention relates to the use of a combination of the invention for the prevention, delay of progression or treatment of or for the preparation of a medicament for the prevention, delay of progression or treatment of lung cancer. Preferably, in such embodiment the combination of the invention comprises as co-agent b) a platin compound, e.g. carboplatin, or a microtubule active agent, e.g. paclitaxel.
Another embodiment of the invention relates to the use of a combination of the invention for the prevention, delay of progression or treatment of or for the preparation of a medicament for the prevention, delay of progression or treatment of pancreatic cancer. Preferably, in such embodiment the combination of the invention comprises as co-agent b) an
antineoplastic antimetabolite, e.g. gemcitabine.
Another embodiment of the invention relates to the use of a combination of the invention for the prevention, delay of progression or treatment of or for the preparation of a medicament for the prevention, delay of progression or treatment of glioblastomas. Preferably, in such embodiment the combination of the invention comprises as co-agent b) an alkylating agent, e.g. BCNU.
A further embodiment of the invention relates to the use of rapamycin or a derivative thereof in combination with a chemotherapeutic agent in the treatment of a lymphatic cancer (…)
2.9.
In de authentieke Engelse versie van de beschrijving van EP 603 is voorts - voor zover hier van belang - het volgende opgenomen:
“[0001]
The present invention relates to a new use, in particular a new use for a 40-O-(2-hydroxyethyl)-rapamycin.
[0002]
Rapamycin is a known macrolide antibiotic produced by Streptomyces hygroscopicus. Derivatives of rapamycin include e.g. compounds of formula I
R1 is CH3 or C3-6alkynyl,
R2 is H or -CH2-CH2-OH, and
X is =O, (H,H) or (H,OH)
provided that R2 is other than H when X is =O and R1 is CH3.
[0003]
Compounds of formula I are disclosed e.g. in WO 94/09010, WO 95/16691 or WO 96/41807. They may be prepared as disclosed or by analogy to the procedures described in these references.
[0004]
WO 97/47317 disclosed a pharmaceutical combination comprising a compound of the somatostatin class and a rapamycin macrolide for use in the prevention or treatment of cell hyperproliferation.
[0005]
Naoko Tsuchiya et. al. (Int J Clin Oncol, 2000, 5: 183-187) disclosed the effects of the aromatase inhibitor fadrozole and the gonadotropin-releasing hormone (GnRH) agonist leuprorelin acetate on aromatase activity and cell proliferation in a human breast cancer cell line (SK-BR-3).
[0006]
WO 97/06793 disclosed non-steroidal compounds useful as steroid sulfatase inhibitors in estrogen dependent illnesses.
[0007]
40-O-(2-hydroxyethyl)-rapamycin (referred thereafter as Compound A), was disclosed as Example 8 in WO 94/09010.
[0008]
Compounds of formula I have, on the basis of observed activity, e.g. binding to macrophilin-12 (also known as 40 FK-506 binding protein or FKBP-12), e.g. as described in WO 94/09010, WO 95/16691 or WO 96/41807, been found to be useful e.g. as immunosuppressant, e.g. in the treatment of acute allograft rejection. It has now been found that Compounds of formula I have potent antiproliferative properties which make them useful for cancer chemotherapy, particularly of solid tumors, especially of advanced solid tumors. There is still the need to expand the armamentarium of cancer treatment of solid tumors, especially in cases where treatment with anticancer compounds is not associated with disease regression or stabilization.
[0009]
In accordance with the particular findings of the present invention, there is provided: 40-O-(2-hydroxyethyl)-rapamycin in combination with exemestane for use in the treatment of hormone receptor positive tumor, wherein the hormone receptor positive tumor is a breast tumor.
(…)
[0011]
Also disclosed are: 1.1 A method for treating solid tumors in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I.
1.2
A method for inhibiting growth of solid tumors in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I.
1.3 A method for inducing tumor regression, e.g. tumor mass reduction, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I.
1.4 A method for treating solid tumor invasiveness or symptoms associated with such tumor growth in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I.
1.5 A method for preventing metastatic spread of tumours or for preventing or inhibiting growth of micrometastasis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I.
[0012]
By "solid tumors" are meant tumors and/or metastasis (whereever located) other than lymphatic cancer, e.g. brain and other central nervous system tumors (eg. tumors of the meninges, brain, spinal cord, cranial nerves and other parts of central nervous system, e.g. glioblastomas or medulla blastomas); head and/or neck cancer; breast tumors; circulatory system tumors (e.g. heart, mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue); excretory system tumors (e.g. kidney, renal pelvis, ureter, bladder, other and unspecified urinary organs); gastrointestinal tract tumors (e.g. oesophagus, stomach, small intestine, colon, colorectal, rectosigmoid junction, rectum, anus and anal canal), tumors involving the liver and intrahepatic bile ducts, gall bladder, other and unspecified parts of biliary tract, pancreas, other and digestive organs); head and neck; oral cavity (lip, tongue, gum, floor of mouth, palate, and other parts of mouth, parotid gland, and other parts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriform sinus, hypopharynx, and other sites in the lip, oral cavity and pharynx); reproductive system tumors (e.g. vulva, vagina, Cervix uteri, Corpus uteri, uterus, ovary, and other sites associated with female genital organs, placenta, penis, prostate, testis, and other sites associated with male genital organs); respiratory tract tumors (e.g. nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung, e.g. small cell lung cancer or non-small cell lung cancer); skeletal system tumors (e.g. bone and articular cartilage of limbs, bone articular cartilage and other sites); skin tumors (e.g. malignant melanoma of the skin, non-melanoma skin cancer, basal cell carcinoma of skin, squamous cell carcinoma of skin, mesothelioma, Kaposi's sarcoma); and tumors involving other tissues including peripheral nerves and autonomic nervous system, connective and soft tissue, retroperitoneum and peritoneum, eye and adnexa, thyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and secondary malignant neoplasm of other sites.
(…)
[0016]
By the term "chemotherapeutic agent" is meant an aromatase inhibitor.
[0017]
The term "aromatase inhibitor" as disclosed herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. (…)
(…)
[0019]
Utility of the compound of Compound A in treating solid tumors as hereinabove specified, may be demonstrated in animal test methods as well as in clinic, for example in accordance with the methods hereinafter described.
A.1 Antiproliferative activity in combination with other agents
[0020]
A cell line, e.g. the Compound A resistant A549 line (IC50 in low nM range) versus the comparative Compound A resistant KB-31 and HCT116 lines (IC50 in the µM range), is added to 96-well plates (1,500 cells/well in 100 µI medium) and incubated for 24 hr. Subsequently, a two-fold dilution series of each compound (Compound of formula I or a known chemotherapeutic agent) is made in separate tubes (starting at 8 x the IC50 of each compound) either alone or in paired combinations, and the dilutions are added to the wells. The cells are then re-incubated for 3 days. Methylene blue staining is performed on day 4 and the amount of bound dye (proportional to the number of surviving cells that bind the dye) determined. IC50s are subsequently determined using the Calcusyn program, which provides a measure of the interaction, namely the so-called non-exclusive combination index (CI), where: CI ∼ 1 = the interaction is nearly additive; 0.85 - 0.9 = slight synergism; < 0.85 = synergy. In this assay, the Compound A shows interesting antiproliferative activity in combination with another chemotherapeutic agent. For example the following CI values are obtained with a combination of Compound A and cisplatinum, paclitaxel, gemcitabine and doxorubicin, showing synergistic effects.
(…)
A.2 Antiangiogenic activity
[0021]
In vitro assay of the antiproliferative activity of Compound A against human umbilical vein endothelial cells (HUVECs) demonstrates IC50 values of 120 ± 22 pM and 841 ± 396, and > 10 000 pM for VEGF- and bFGF- and FBS-stimulated proliferation, respectively. Additionally, no significant effects of Compound A on bFGF-stimulated normal human dermal fibroblast (NHDF) proliferation are observed over the same concentration range. These results indicate that Compound A inhibits the proliferation of HUVECs, being particularly potent against the VEGF-induced proliferation, VEGF being a key pro-angiogenic factor.
[0022]
In the following assays, antitumor activity is expressed as T/C% (mean increase in tumor volumes of treated animals divided by the mean increase of tumor volumes of control animals multiplied by 100) and % regressions (tumor volume minus initial tumor volume divided by the initial tumor volume and multiplied by 100).
(…)
B.4 Combination with doxorubicin
[0027]
Mice transplanted with human KB-31 epidermoid tumors are treated for 21 days with doxorubicin at a dose of 5 mg/kg i.v. once per week, Compound A at a dose of 2.5 mg/kg p.o once per day, or a combination of both. Thereafter Compound A treatment alone is continued in the combination group in order to determine if the Compound A can suppress the outgrowth of tumors that respond to conventional agents. Antitumor activity is expressed as T/C% or % regressions as indicated above. For example, the combination of Compound A and doxorubicin produces greater antitumor effect (74 % regressions) as compared to either agent alone (Compound A, T/C 32 %; doxorubicin 44 % regressions). No exacerbation of the body weight losses caused by doxorubicin occurs when Compound A treatment is added. Continuing Compound A treatment in the combination group, after ceasing doxorubicin, inhibits tumor outgrowth such that the tumor volumes of the doxorubicin monotherapy group are significantly larger than those of the combination group. Moreover, the combination appears to produce a greater cure rate (8/8 tumors) at 14 days post end of treatment than doxorubicin alone (3/8 tumors).
(…)
B.7 Combination with an antiangiogenic agent
[0030]
B16/BL6 cells (5 X 104) are injected intradermally into the ear of C57BL/6 mice. Seven days later treatment with Compound A, a VEGF receptor tyrosine kinase inhibitor, e.g. 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a salt thereof, e.g. the succinate, or a combination of both is initiated and effects on the growth and weight of the primary tumor and cervical lymph node metastases are monitored, respectively. Daily administration of the antiangiogenic agent (100 mg/kg p.o.) or of Compound A, (1 mg/kg p.o.) alone, reduces the size of the primary tumor (final T/C: 65 % and 74 %, respectively), whereas the combination of these two agents is synergistic (T/C 12 %). Compound A and the antiangiogenic agent treatment alone reduces cervical lymph node weights (related to regional metastases) (T/C: 75 % and 34 %, respectively), and the combination further reduces lymph node weights (T/C 13 %). The treatments significantly promote body weight gains as compared to controls. For the primary tumors, analysis of possible interaction shows synergy with Compound A and antiangiogenic agent as antiangiogenic agent /controls = 0.66; Compound A/controls = 0.77; Compound A and antiangiogenic agent /controls = 0.135. As Compound A and antiangiogenic agent /controls < Compound A/controls x antiangiogenic agent /controls (0.51), this is defined as synergy. For the metastases, analysis also shows synergy with Compound A and the antiangiogenic agent as antiangiogenic agent /controls = 0.337; Compound A/controls = 0.75; Compound A and antiangiogenic agent /controls = 0.122. As Compound A and antiangiogenic agent /controls < Compound A/controls x antiangiogenic agent /controls (0.252), this is also defined as synergy (Clark, Breast Cancer Research Treatment 1997;46:255 ).
(…)
C.2 Combined Treatment
[0033]
Suitable clinical studies are, for example, open label non-randomized, dose escalation studies in patients with advanced solid tumors. Such studies prove in particular the synergism of the active ingredients of the combination of the invention. The beneficial effects on proliferative diseases can be determined directly through the results of these studies or by changes in the study design which are known as such to a person skilled in the art. Such studies are, in particular, suitable to compare the effects of a monotherapy using the active ingredients and a combination of the invention. Preferably, the dose of agent (a) is escalated until the Maximum Tolerated Dosage is reached, and the co-agent (b) is administered with a fixed dose. Alternatively, the agent (a) is administered in a fixed dose and the dose of co-agent (b) is escalated. Each patient receives doses of the agent (a) either daily or intermittent. The efficacy of the treatment can be determined in such studies, e.g., after 12, 18 or 24 weeks by radiologic evaluation of the tumors every 6 weeks.
[0034]
Alternatively, a placebo-controlled, double blind study can be used in order to prove the benefits of the combination of the invention mentioned herein.
(…)
[0036]
The administration of a pharmaceutical combination of the invention results not only in a beneficial effect, e.g. a synergistic therapeutic effect, e.g. with regard to slowing down, arresting or reversing the neoplasm formation or a longer duration of tumor response, but also in further surprising beneficial effects, e.g. less side-effects, an improved quality of life or a decreased mortality and morbidity, compared to a monotherapy applying only one of the pharmaceutically active ingredients used in the combination of the invention, in particular in the treatment of a tumor that is refractory to other chemotherapeutics known as anti-cancer agents. In particular, an increased up-take of the co-agent (b) in tumor tissue and tumor cells is observed, when applied in combination with the first agent (a).
(…)
[0038]
One specific embodiment of the invention discloses the use of a combination of the invention for the prevention, delay of progression or treatment of or for the preparation of a medicament for the prevention, delay of progression or treatment of breast cancer. In such embodiment the combination comprises as co-agent b) an aromatase inhibitor.
(…)”
.jpg?width=50&height=55)
.jpg?width=50&height=55)
