US20180353510A1 - Treatment of Biliary Duct Cancer - Google Patents

Treatment of Biliary Duct Cancer Download PDF

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US20180353510A1
US20180353510A1 US15/757,166 US201615757166A US2018353510A1 US 20180353510 A1 US20180353510 A1 US 20180353510A1 US 201615757166 A US201615757166 A US 201615757166A US 2018353510 A1 US2018353510 A1 US 2018353510A1
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compound
formula
cancer
treatment
cholangiocarcinoma
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Bertil Lindmark
Mark Thomas McHale
Lisa Ooi
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Aslan Pharmaceuticals Pte Ltd
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Aslan Pharmaceuticals Pte Ltd
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Priority claimed from GBGB1515718.3A external-priority patent/GB201515718D0/en
Priority claimed from GBGB1515714.2A external-priority patent/GB201515714D0/en
Priority claimed from GBGB1515716.7A external-priority patent/GB201515716D0/en
Priority claimed from GBGB1515712.6A external-priority patent/GB201515712D0/en
Priority claimed from GBGB1608660.5A external-priority patent/GB201608660D0/en
Application filed by Aslan Pharmaceuticals Pte Ltd filed Critical Aslan Pharmaceuticals Pte Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine

Definitions

  • the present disclosure relates to a therapy, for example a monotherapy or combination therapy comprising a type I tyrosine kinase inhibitor for the treatment of biliary cancer, such as cholangiocarcinoma.
  • a therapy for example a monotherapy or combination therapy comprising a type I tyrosine kinase inhibitor for the treatment of biliary cancer, such as cholangiocarcinoma.
  • Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some of the features enabling them to emerge under selective drug pressure. This is a problem that many patients with cancer encounter, and it obviously limits the therapeutic alternatives that are effective and worsens the prognosis.
  • Cancer therapy guidelines describe the sequence of therapies, which are recommended and in which sequence, so that if a patients show disease progression on the first therapy (“first line”), then a next therapy (“second line”) is recommended, and so on. These therapy recommendations are based on available scientific data and experience, and illustrate that resistance to one therapy does not exclude that another therapy may be effective and prolong life or shrink tumor. At a late stage cancers do not respond and no more avenues of therapy exist, and are thus judged as completely therapy refractory, unless new therapies can be found which are effective.
  • Cholangiocarcinoma is a prime example of both primary and secondary resistance and is considered to be an incurable and a rapidly lethal malignancy unless both the primary tumor and any metastases can be fully resected (removed surgically).
  • most patients have advanced stage disease which is inoperable at the time of diagnosis.
  • Patients with cholangiocarcinoma are generally managed—though never cured—with chemotherapy, radiation therapy, and other palliative care measures. These are also used as adjuvant therapies (i.e. post-surgery) in cases where resection has apparently been successful (or nearly so).
  • cholangiocarcinoma In the western hemisphere cholangiocarcinoma is a relatively rare neoplasm that is classified as an adenocarcinoma (a cancer that forms glands or secretes significant amounts of mucins). It has an annual incidence rate of 1-2 cases per 100,000 in the Western world. However, rates of cholangiocarcinoma have been rising worldwide over the past several decades. Furthermore the incidence is higher in Asian countries where it is recognized as a significant problem.
  • Varlitinib monotherapy/combination therapy showed a surprising level of efficacy in these patients.
  • Varlitinib appears to be efficacious and able to overcome both primary and secondary resistance in biliary duct cancer.
  • the biliary duct cancer is selected from the group consisting of cholangiocarcinoma, gall bladder cancer and a combination thereof.
  • a method of treating a cholangiocarcinoma patient by administering a therapeutically effective amount of a compound of formula (I) an enantiomer thereof or a pharmaceutically acceptable salt of any one of the same.
  • the cholangiocarcinoma is intrahepatic.
  • the cholangiocarcinoma is extrahepatic.
  • the biliary duct cancer is in a location selected from intrahepatic bile ducts, left hepatic duct, right hepatic duct, common hepatic duct, cystic duct, common bile duct, Ampulla of Vater and combinations thereof.
  • the biliary duct cancer is in an intrahepatic bile duct.
  • the biliary duct cancer is in a left hepatic duct.
  • the biliary duct cancer is in a right hepatic duct.
  • the biliary duct cancer is in a common hepatic duct.
  • the biliary duct cancer is in a cystic duct.
  • the biliary duct cancer is in a common bile duct.
  • the biliary duct cancer is in an Ampulla of Vater.
  • the biliary duct cancer is a cancer of the Papilla of Vater.
  • the cancer is a metastatic form of a cancer disclosed herein.
  • the cancer according the present disclosure has not metastasized.
  • the compound of formula (I) is (R)—N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4, 5,-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine:
  • Varlitinib at an appropriate dose is capable of inhibiting HER1, HER2 and HER4 directly and thought to be capable of inhibiting HER3 indirectly.
  • the compound of formula (I), such as Varlitinib at least inhibits the activity of HER1 and HER2, HER1 and HER4 or HER2 and HER4.
  • the compound of formula (I) at least inhibits the activity of HER1, HER2 and HER4, for example directly inhibits the activity of HER1, HER2 and HER4.
  • the compound of formula (I) inhibits the activity of HER1, HER2, HER3 and HER4, for example directly inhibits the activity of HER1, HER2, and HER4, and indirectly inhibits the activity of HER3.
  • the compound of formula (I) an enantiomer thereof or a pharmaceutically acceptable salt thereof is employed as a monotherapy, for example first line therapy or second line therapy, such as a first line monotherapy.
  • the compound of formula (I) an enantiomer thereof or a pharmaceutically acceptable salt thereof is employed in a combination therapy, for example in combination with a chemotherapy and/or a biological therapeutic, in particular as a first line therapy or a second line therapy.
  • the compound of formula (I), such as Varlitinib is employed in combination with at least one further HER inhibitor, for example a combination of Varlitinib and Herceptin (trastuzumab) and/or pertuzumab.
  • at least one further HER inhibitor for example a combination of Varlitinib and Herceptin (trastuzumab) and/or pertuzumab.
  • a combination of Varlitinib and Herceptin showed more therapeutic activity than either entity alone.
  • the compound of formula (I) such as Varlitinib is employed in combination with ado-trastuzuma-emtansine.
  • the compound of formula (I) an enantiomer thereof or a pharmaceutically acceptable salt thereof is employed as a second line monotherapy.
  • CA19-9 is a marker employed in the management of cholangiocarcinoma. In a one patient a 90% reduction was seen in CA19-9 within one month of initiating treatment with Varlitinib.
  • a patient has a 10, 20, 30, 40, 50, 60, 70, 80 or 90% decrease in CA19-9 level whilst on the therapy according to the present disclosure, wherein the level is decreased relative to the level of CA19-9 before initiation of said therapy.
  • the compound of formula (I), such as Varlitinib is employed in a second line therapy together with a chemotherapy agent or chemotherapy regimen, for example gemcitabine, capecitabine, 5-FU, FOLFOX, a platin, such as cisplatin or oxaliplatin, and a combination thereof.
  • a chemotherapy agent or chemotherapy regimen for example gemcitabine, capecitabine, 5-FU, FOLFOX, a platin, such as cisplatin or oxaliplatin, and a combination thereof.
  • the compound of formula (I), such as Varlitinib is administered orally.
  • the compound of formula (I), such as Varlitinib is administered at a dose in the range 100 mg to 900 mg on each occasion, in particular 200 mg, 300 mg, 400 mg or 500 mg each dose, such as 400 mg, for example administered once or twice daily, such as twice daily.
  • the compound of formula (I), such as Varlitinib is administered for a 28 days, referred to herein as a 28 day treatment cycle.
  • the compound of formula (I) is administered as pharmaceutical formulation comprising one or more pharmaceutically acceptable excipients.
  • the compound of formula (I) or a formulation comprising the same is administered orally, for example as tablet or capsule.
  • the target patient population is at least HER1 (EGFR) positive.
  • the target patient population is EGFR and HER2 positive.
  • the target patient population is at least HER1 (EGFR) positive.
  • the target patient population are HER2 amplified.
  • the patient has over-expression of 2 or more of the HER 1, 2, 3, 4 receptors, for example over expression of HER 1 & 2; 1 & 3; 1 & 4; 2 & 3 2 & 4; 1, 2 & 3; 1, 2 & 4; 2, 3 & 4; or 1, 2, 3 & 4.
  • the treatment is adjuvant therapy, for example after surgery or after chemotherapy.
  • the treatment is neoadjuvant therapy, for example before surgery, in particular to shrink the tumour or tumours.
  • the cancer is a tumour, in particular a solid tumour.
  • the treatment according to the present disclosure is suitable for the treatment of secondary tumours.
  • the cancer is metastatic cancer.
  • the treatment according to the present disclosure is suitable for the treatment of primary cancer and metastases.
  • the treatment according to the present disclosure is suitable for the treatment of secondary cancer and metastases.
  • the treatment according to the present disclosure is suitable for the treatment of primary cancer, secondary cancer and metastases.
  • the treatment according to the present disclosure is suitable for the treatment of cancerous cells in a lymph node, for a cancer of the present disclosure.
  • the patient is a human.
  • Biliary duct cancer also referred to as biliary cancer as employed herein refers to cancer which starts in the bile ducts and includes cholangiocarcinoma and gallbladder cancer.
  • Cholangiocarcinoma as referred to herein is a form of cancer that is composed of mutated epithelial cells (or cells showing characteristics of epithelial differentiation) that originate in the bile ducts which drain bile from the liver into the small intestine, but not including gallbladder cancer.
  • Gallbladder cancer as employed herein cancer which starts in the gallbladder. The following stages are used for gallbladder cancer:
  • the treatment of the present disclosure is neo-adjuvant therapy, for example to shrink the tumour/carcinoma before surgery to remove the cancerous tissue or before chemotherapy to improve the chances of success of the latter or to reduce the severity of the treatment required.
  • the treatment of the present disclosure is adjuvant therapy, for example following surgery to remove the cancerous tissue.
  • the treatment of the present disclosure is adjuvant therapy, for example following chemotherapy.
  • combination adjuvant therapy comprising a compound of formula (I) and chemotherapy or radiotherapy.
  • First line therapy as employed herein is the first therapy employed for the treatment of the cancer and in some instances the first line therapy may be neo-adjuvant therapy, in this context surgery will generally be considered a treatment.
  • Second line therapy as employed herein is treatment following first line therapy and may be adjuvant therapy.
  • second line therapy is simply therapy other than first line therapy and includes, third line therapy, fourth line therapy etc.
  • Monotherapy as employed herein is wherein the compound of formula (I) an enantiomer thereof and/or a pharmaceutically acceptable salt thereof, is the only active agent being administered to the patient for the treatment of cancer.
  • Combination therapy refers to wherein the compound of formula (I) an enantiomer thereof or a pharmaceutically acceptable salt thereof is employed for the treatment of the cancer in conjunction with one or more further anticancer treatments, for example where the treatment regimens for the two or more active anticancer agents overlap or where the two or more anticancer agents are administered concomitantly.
  • the combination therapy according to the present disclosure comprises a RON inhibitor, for example as disclosed WO2008/058229, incorporated herein by reference.
  • the combination therapy comprises a checkpoint inhibitor, such as a CTLA4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor, in particular an antibody or binding fragment thereof.
  • a checkpoint inhibitor such as a CTLA4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor, in particular an antibody or binding fragment thereof.
  • Examples of pharmaceutically acceptable salts include but are not limited to acid addition salts of strong mineral acids such as HCl and HBr salts and addition salts of strong organic acids, such as a methansulfonic acid salt, tosylates, furoates and the like, including di, tri salts thereof, such as ditosylates.
  • Chemotherapeutic agent and chemotherapy or cytotoxic agent are employed interchangeably herein unless the context indicates otherwise.
  • Chemotherapy as employed herein is intended to refer to specific antineoplastic chemical agents or drugs that are “selectively” destructive to malignant cells and tissues, for example alkylating agents, antimetabolites including thymidylate synthase inhibitors, anthracyclines, anti-microtubule agents including plant alkaloids, taxanes, topoisomerase inhibitors, parp inhibitors and other antitumour agents. Selectively in this context is used loosely because of course many of these agents have serious side effects.
  • the preferred dose may be chosen by the practitioner, based on the nature of the cancer being treated.
  • alkylating agents which may be employed in the method of the present disclosure include an alkylating agent, nitrogen mustards, nitrosoureas, tetrazines, aziridines, platins and derivatives, and non-classical alkylating agents.
  • platinum containing chemotherapeutic agents include cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin and lipoplatin (a liposomal version of cisplatin), in particular cisplatin, carboplatin and oxaliplatin.
  • the dose for cisplatin ranges from about 20 to about 270 mg/m 2 depending on the exact cancer. Often the dose is in the range about 70 to about 100 mg/m 2 .
  • Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan.
  • Nitrosoureas include N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin.
  • Tetrazines include dacarbazine, mitozolomide and temozolomide.
  • Aziridines include thiotepa, mytomycin and diaziquone (AZQ).
  • antimetabolites examples include anti-folates (for example methotrexate and pemetrexed), purine analogues (for example thiopurines, such as azathiopurine, mercaptopurine, thiopurine, fludarabine (including the phosphate form), pentostatin and cladribine), pyrimidine analogues (for example fluoropyrimidines, such as 5-fluorouracil (5-FU) and prodrugs thereof such as capecitabine [Xeloda®]), floxuridine, gemcitabine, cytarabine, decitabine, raltitrexed (tomudex) hydrochloride, cladribine and 6-azauracil.
  • anti-folates for example methotrexate and pemetrexed
  • purine analogues for example thiopurines, such as azathiopurine, mercaptopurine, thiopurine, fludarabine (including the
  • anthracyclines examples include daunorubicin (Daunomycin), daunorubicin (liposomal), doxorubicin (Adriamycin), doxorubicin (liposomal), epirubicin, idarubicin, valrubicin currently are used only to treat bladder cancer and mitoxantrone an anthracycline analog, in particular doxorubicin.
  • anti-microtubule agents examples include vinca alkaloids and taxanes.
  • Vinca alkaloids include completely natural chemicals for example vincristine and vinblastine and also semi-synthetic vinca alkaloids, for example vinorelbine, vindesine, and vinflunine
  • Taxanes include paclitaxel, docetaxel, abraxane, carbazitaxel and derivatives of thereof.
  • Derivatives of taxanes as employed herein includes reformulations of taxanes like taxol, for example in a micelluar formulations, derivatives also include chemical derivatives wherein synthetic chemistry is employed to modify a starting material which is a taxane.
  • Topoisomerase inhibitors which may be employed in a method of the present disclosure include type I topoisomerase inhibitors, type II topoisomerase inhibitors and type II topoisomerase poisons.
  • Type I inhibitors include topotecan, irinotecan, indotecan and indimitecan.
  • Type II inhibitors include genistein and ICRF 193 which has the following structure:
  • Type II poisons include amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin and fluoroquinolones.
  • the chemotherapeutic is a PARP inhibitor.
  • chemotherapeutic agents employed is, for example a platin and 5-FU or a prodrug thereof, for example cisplatin or oxaplatin and capecitabine or gemcitabine, such as FOLFOX.
  • the chemotherapy comprises a combination of chemotherapy agents, in particular cytotoxic chemotherapeutic agents.
  • the chemotherapy combination comprises a platin, such as cisplatin and fluorouracil or capecitabine.
  • the chemotherapy combination is capecitabine and oxaliplatin (XELOX).
  • the chemotherapy is a combination of folinic acid and 5-FU, optionally in combination with oxaliplatin (FOLFOX).
  • the chemotherapy is a combination of folinic acid, 5-FU and irinotecan (FOLFIRI), optionally in combination with oxaliplatin (FOLFIRINOX).
  • the regimen for example includes: irinotecan (180 mg/m 2 IV over 90 minutes) concurrently with folinic acid (400 mg/m 2 [or 2 ⁇ 250 mg/m 2 ] IV over 120 minutes); followed by fluorouracil (400-500 mg/m 2 IV bolus) then fluorouracil (2400-3000 mg/m 2 intravenous infusion over 46 hours). This cycle is typically repeated every two weeks.
  • the dosages shown above may vary from cycle to cycle.
  • the chemotherapy combination employs a microtubule inhibitor, for example vincristine sulphate, epothilone A, N-[2-[(4-Hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide (ABT-751), a taxol derived chemotherapeutic agent, for example paclitaxel, abraxane, or docetaxel or a combination thereof.
  • a microtubule inhibitor for example vincristine sulphate, epothilone A, N-[2-[(4-Hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide (ABT-751), a taxol derived chemotherapeutic agent, for example paclitaxel, abraxane, or docetaxel or a combination thereof.
  • the chemotherapy combination employs an mTor inhibitor.
  • mTor inhibitors include: everolimus (RAD001), WYE-354, KU-0063794, papamycin (Sirolimus), Temsirolimus, Deforolimus (MK-8669), AZD8055 and BEZ235 (NVP-BEZ235).
  • the chemotherapy combination employs a MEK inhibitor.
  • MEK inhibitors include: AS703026, CI-1040 (PD184352), AZD6244 (Selumetinib), PD318088, PD0325901, AZD8330, PD98059, U0126-EtOH, BIX 02189 or BIX 02188.
  • the chemotherapy combination employs an AKT inhibitor.
  • AKT inhibitors include: MK-2206 and AT7867.
  • the combination employs an aurora kinase inhibitor.
  • aurora kinase inhibitors include: Aurora A Inhibitor I, VX-680, AZD1152-HQPA (Barasertib), SNS-314 Mesylate, PHA-680632, ZM-447439, CCT129202 and Hesperadin.
  • the chemotherapy combination employs a p38 inhibitor, for example as disclosed in WO2010/038086, such as N-[4-( ⁇ 4-[3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido]naphthalen-1-yloxy ⁇ methyl)pyridin-2-yl]-2-methoxyacetamide.
  • a p38 inhibitor for example as disclosed in WO2010/038086, such as N-[4-( ⁇ 4-[3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido]naphthalen-1-yloxy ⁇ methyl)pyridin-2-yl]-2-methoxyacetamide.
  • the combination employs a Bcl-2 inhibitor.
  • Bcl-2 inhibitors include: obatoclax mesylate, ABT-737, ABT-263 (navitoclax) and TW-37.
  • the chemotherapy combination comprises an antimetabolite such as capecitabine (xeloda), fludarabine phosphate, fludarabine (fludara), decitabine, raltitrexed (tomudex), gemcitabine hydrochloride and/or cladribine.
  • an antimetabolite such as capecitabine (xeloda), fludarabine phosphate, fludarabine (fludara), decitabine, raltitrexed (tomudex), gemcitabine hydrochloride and/or cladribine.
  • the chemotherapy combination comprises ganciclovir, which may assist in controlling immune responses and/or tumour vasculation.
  • a monotherapy comprising a compound of formula (I), such as Varlitinib (as defined herein including doses described above) is employed, for example a maintenance therapy.
  • a monotherapy comprising a compound of formula (I), such as Varlitinib (as defined herein including doses described above) is employed, for example a maintenance therapy.
  • Embodiments are described herein as comprising certain features/elements. The disclosure also extends to separate embodiments consisting or consisting essentially of said features/elements.
  • FIG. 1 Shows the position of bile ducts in the body
  • FIG. 2 Shows data for a cholangiocarcinoma patient receiving 400 mg of Varlitinib monotherapy bi-daily
  • FIG. 3 Shows data for a cholangiocarcinoma patient receiving 400 mg Varlitinib bi-daily in combination with chemotherapy.
  • FIG. 4 Shows data for a 56 year old male cholangiocarcinoma patient treated with Varlitinib 400 mg bi-daily and cisplatin/capecitabine chemotherapy
  • FIG. 5 Shows data for a 60 year old male cholangiocarcinoma patient treated with Varlitinib 500 mg bi-daily and cisplatin/capecitabine chemotherapy
  • FIG. 6 a Shows change in a lesion of over time for individual cholangiocarcinoma patients receiving between 300 and 500 mg of Varlitinib bi-daily and chemotherapy in a Taiwanese clinical trial
  • FIG. 6 b Shows change in a lesion of over time for individual cholangiocarcinoma patients receiving between 300 and 500 mg of Varlitinib bi-daily and chemotherapy in a Singapore clinical trial
  • FIG. 7 a Shows the maximal % change in tumour size from baseline in individual cholangiocarcinoma patients receiving between 300-500 mg of Varlitinib bi-daily and chemotherapy in Taiwan clinical trial
  • FIG. 7 b Shows the maximal % change in tumour size from baseline in individual cholangiocarcinoma patients receiving between 300-500 mg of Varlitinib bi-daily and chemotherapy in Taiwan clinical trial
  • the patient received Varlitinib 400 mg BID continuously with cisplatin (80 mg/m 2 every 3 weeks) and capecitabine (1000 mg/m2 BID, 2 weeks on, 1 week off).
  • Image scan at the end of cycle 6 showed 85.77% reduction in tumour size.
  • the patient received varlitinib monotherapy and tumor scan at the end of cycle 8 showed 87% reduction.
  • cisplatin and capecitabine After treatment cycle 2 with Varlitinib orally 500 mg bi-daily, cisplatin and capecitabine the patient showed a 4% response, see FIG. 5 .
  • the cisplatin and capecitabine regime was cisplatin 80 mg/m 2 IV infusion and capecitabine 1000 mg/m 2 orally twice daily for 14 days every 3 weeks.
  • Example 9 Treatment of Stage IV Intrahepatic Cholangiocarcinoma and Multiple Lymphadenopathies with Varlitinib 300 mg Bi-Daily Orally and Cisplatin/5FU Combination Chemotherapy 28 Day Cycle
  • the patient was given 300 mg BID Varlitinib combined with Cis/5-FU, 28-day cycle.
  • the current status is the clinical trial is on-going.

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