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WO2018136010A1 - Polythérapie - Google Patents

Polythérapie Download PDF

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Publication number
WO2018136010A1
WO2018136010A1 PCT/SG2018/050035 SG2018050035W WO2018136010A1 WO 2018136010 A1 WO2018136010 A1 WO 2018136010A1 SG 2018050035 W SG2018050035 W SG 2018050035W WO 2018136010 A1 WO2018136010 A1 WO 2018136010A1
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Prior art keywords
cancer
inhibitor
checkpoint
dhodh
treatment
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PCT/SG2018/050035
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English (en)
Inventor
Ann Gee Lisa OOI
Qihui SEET
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Aslan Pharmaceuticals Pte Ltd
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Publication of WO2018136010A1 publication Critical patent/WO2018136010A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to a method of treating cancer with a combination therapy, and a combination therapy for use in the treatment of cancer, in particular a cancer disclosed herein.
  • the pathway and chemotherapy damage of DNA is shown schematically in Figure 1.
  • the DHODH inhibitor may be provided in a pharmaceutical formulation comprising one or more diluents, carriers and/or excipients.
  • the checkpoint inhibitor may also be provided in a pharmaceutical formulation comprising one or more diluents, carriers and/or excipients.
  • the present inventors have demonstrated that the results of the combined therapies are at least additive and may be synergistic, for example, by increasing the therapeutic effect of one or both components (in particular the checkpoint inhibitor] by 2, 3, 4, 5, 6, 7, 8, 9, 10-fold or more.
  • the data generated demonstrates that the combination of a DHODH inhibitor, in particular is 2- (3,5- difluoro-3'-methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof, and a check point inhibition, in particular CHK1 (CHEK1] inhibition, synergistically kills tumours cells and synergistically induces DNA synthesis catastrophe and mitotic catastrophe in tumour cells.
  • a method of treating a cancer patient comprising administering a therapeutically effect amount of a DHODH inhibitor, wherein the DHODH inhibitor is 2-(3,5-difluoro-3'-methoxybiphenyl- 4-ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a checkpoint inhibitor, for example selected from: checkpoint kinase inhibitor 1, checkpoint kinase inhibitor 2 (CHEK2/ CHK2], Ataxia telangiectasia and Rad3 related (ATR] inhibitor, ataxia-telangiectasia mutated (ATM] inhibitor, Weel dual specificity protein kinase (Weel] inhibitor and Poly ADP Ribose polymerase (PARP] inhibitor, such as a checkpoint kinase inhibitor, in particular a CHK1 inhibitor.
  • a checkpoint inhibitor for example selected from: checkpoint kinase inhibitor 1, checkpoint kinase inhibitor 2 (CHEK2/ CH
  • a combination therapy comprising a checkpoint inhibitor (for example selected from: checkpoint kinase 1 inhibitor, checkpoint kinase 2 inhibitor (CHEK2/ CHK2], Ataxia telangiectasia and Rad3 related (ATR] inhibitor, ataxia-telangiectasia mutated (ATM] inhibitor, Weel dual specificity protein kinase (Weel] inhibitor and Poly ADP Ribose polymerase (PARP] inhibitor, such as checkpoint kinase inhibitor, in particular as disclosed herein] and a DHODH inhibitor for use in treatment, in particular for use in the treatment of cancer, such as a cancer disclosed herein.
  • a checkpoint inhibitor for example selected from: checkpoint kinase 1 inhibitor, checkpoint kinase 2 inhibitor (CHEK2/ CHK2], Ataxia telangiectasia and Rad3 related (ATR] inhibitor, ataxia-telangiectasia mutated (ATM] inhibitor, Weel dual specificity protein kin
  • checkpoint inhibitor for example selected from: checkpoint kinase 1 inhibitor, checkpoint kinase 2 inhibitor (CHEK2/ CHK2], Ataxia telangiectasia and Rad3 related (ATR] inhibitor, ataxia-telangiectasia mutated (ATM] inhibitor, Weel dual specificity protein kinase (Weel] inhibitor and Poly ADP Ribose polymerase (PARP] inhibitor, such as checkpoint kinase inhibitor, in particular as disclosed herein] and a DHODH inhibitor in the manufacture of a combination therapy for the treatment of cancer, in particular a cancer disclosed herein.
  • a checkpoint inhibitor for example selected from: checkpoint kinase 1 inhibitor, checkpoint kinase 2 inhibitor (CHEK2/ CHK2], Ataxia telangiectasia and Rad3 related (ATR] inhibitor, ataxia-telangiectasia mutated (ATM] inhibitor, Weel dual specificity protein kinase (Weel] inhibitor
  • a DHODH inhibitor wherein the DHODH inhibitor is 2-(3,5-difluoro-3'- methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof for use in a combination therapy further comprising a checkpoint inhibitor (for example selected from: checkpoint kinase 1 inhibitor, checkpoint kinase 2 inhibitor (CHEK2/ CHK2], Ataxia telangiectasia and Rad3 related (ATR] inhibitor, ataxia-telangiectasia mutated (ATM] inhibitor, Weel dual specificity protein kinase (Weel] inhibitor and Poly ADP Ribose polymerase (PARP] inhibitor, such as a checkpoint kinase 1 inhibitor (CHK1 /CHEK1], in particular as disclosed herein] for the treatment of cancer, such as a cancer disclosed herein.
  • a checkpoint inhibitor for example selected from: checkpoint kinase 1 inhibitor, checkpoint kinase 2
  • checkpoint inhibitor for example selected from: checkpoint kinase 1 inhibitor, checkpoint kinase 2 inhibitor (CHEK2/ CHK2], Ataxia telangiectasia and Rad3 related (ATR] inhibitor, ataxia-telangiectasia mutated (ATM] inhibitor, Weel dual specificity protein kinase (Weel] inhibitor and Poly ADP Ribose polymerase (PARP] inhibitor, such as a checkpoint kinase 1 inhibitor (CHK1/CHEK1]] for use in a combination therapy further comprising a DHODH inhibitor (in particular a DHODH inhibitor disclosed herein], in particular for use in the treatment of cancer, such as a cancer disclosed herein.
  • a checkpoint inhibitor for example selected from: checkpoint kinase 1 inhibitor, checkpoint kinase 2 inhibitor (CHEK2/ CHK2], Ataxia telangiectasia and Rad3 related (ATR] inhibitor, ataxia-telangiectasia mutated (A
  • a co-formulated combination therapy of a DHODH inhibitor wherein the DHODH inhibitor is 2-(3,5-difluoro-3'-methoxybiphenyl-4-ylamino]nicotinic acid or a pharmaceutically acceptable salt thereof and checkpoint inhibitor, (for example selected from: checkpoint kinase 1 inhibitor, checkpoint kinase 2 inhibitor (CHEK2/ CHK2], Ataxia telangiectasia and Rad3 related (ATR] inhibitor, ataxia-telangiectasia mutated (ATM] inhibitor, Weel dual specificity protein kinase (Weel] inhibitor and Poly ADP Ribose polymerase (PARP] inhibitor, such as a checkpoint kinase inhibitor, in particular CHK1/CHEK1].
  • checkpoint inhibitor for example selected from: checkpoint kinase 1 inhibitor, checkpoint kinase 2 inhibitor (CHEK2/ CHK2], Ataxia telangiectasia and Rad3 related (ATR]
  • the cancer has a mutation or mutations that result in modulate of p53 signalling or p53 function or p53 regulation, for example where p53 is deleted or has reduced function.
  • the cancer is a liquid tumour.
  • the cancer is metastatic.
  • the cancer is selected from liver cancer (such as hepatocellular carcinoma], biliary tract cancer, breast cancer (such as non-ER+ breast cancer, in particular double negative breast cancer or triple negative breast cancer], prostate cancer, colorectal cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, gastric cancer, pancreatic cancer, bone cancer, bladder cancer, head and neck cancer, thyroid cancer, skin cancer, renal cancer, oesophageal cancer, nasopharangeal cancer, leukaemia, acute myeloid leukaemia (AML], T-cell lymphoma, B-cell lymphoma, Hodgkins lymphoma, Non-Hodgkins lymphoma, acute lymphocytic leukaemia (ALL], chronic myelogenous leukemia(CML], acute monocytic leukaemia (AMoL], chronic lymphocytic leukaemia (C
  • the cancer is an epithelial cancer for example selected from liver cancer (such as hepatocellular carcinoma], biliary tract cancer, breast cancer (such as non-ER+ breast cancer, in particular double negative or triple negative breast cancer and/or BRACl positive breast cancer], prostate cancer, colorectal cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer (for example non-small cell lung cancer], gastric cancer, pancreatic cancer, bladder cancer, head and neck cancer, thyroid cancer, skin cancer, renal cancer, oesophageal cancer, nasopharangeal cancer or bone cancer, and combinations of two or more of the same.
  • liver cancer such as hepatocellular carcinoma]
  • breast cancer such as non-ER+ breast cancer, in particular double negative or triple negative breast cancer and/or BRACl positive breast cancer
  • prostate cancer colorectal cancer
  • ovarian cancer endometrial cancer
  • cervical cancer for example non-small cell lung cancer
  • lung cancer for example non-small cell lung cancer
  • gastric cancer pancreatic cancer
  • the cancer is selected from the group comprising liver cancer (such as hepatocellular carcinoma], biliary duct cancer, breast cancer (such as non-ER+ breast cancer, in particular double negative or triple negative breast cancer and/or BRAC1 positive breast cancer], prostate cancer, colorectal cancer, bladder cancer, ovarian cancer, endometrial cancer, lung cancer (for example non-small cell lung cancer], gastric cancer, oesophageal cancer, kidney cancer, head and neck cancers, and a combination of two or more of the same.
  • liver cancer such as hepatocellular carcinoma
  • breast cancer such as non-ER+ breast cancer, in particular double negative or triple negative breast cancer and/or BRAC1 positive breast cancer
  • prostate cancer colorectal cancer
  • bladder cancer ovarian cancer
  • endometrial cancer for example non-small cell lung cancer
  • gastric cancer for example non-small cell lung cancer
  • oesophageal cancer kidney cancer
  • head and neck cancers and a combination of two or more of the same.
  • the cancer is selected from hepatocellular carcinoma, biliary duct cancer (for example cholangiocarcinoma], breast cancer (such as non-ER+ breast cancer, in particular double negative or triple negative breast cancer and/or BRAC1 positive breast cancer], lung cancer (for example non-small cell lung cancer], ovarian cancer, pancreatic cancer, gastric cancer and combinations of two or more of the same.
  • biliary duct cancer for example cholangiocarcinoma
  • breast cancer such as non-ER+ breast cancer, in particular double negative or triple negative breast cancer and/or BRAC1 positive breast cancer
  • lung cancer for example non-small cell lung cancer
  • ovarian cancer pancreatic cancer
  • gastric cancer gastric cancer
  • the checkpoint inhibitor is a checkpoint kinase inhibitor, for example the checkpoint kinase inhibitor, is an inhibitor of at a least checkpoint kinase 1 (CHK1/ CHEK1].
  • the checkpoint inhibitor is independently selected from:
  • the checkpoint inhibitor is an antibody or binding fragment specific to a checkpoint protein, in particular one disclosed herein.
  • check point inhibitor employed is prexasertib (LY2606368] or a pharamaceutically acceptable salt thereof.
  • checkpoint inhibitor is administered orally, for example once or twice daily, such as twice daily.
  • the combination therapy continues for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 months or more.
  • DHODH is a key enzyme in the de novo synthesis of pyrimidine nucleotides in human cells, which are central building blocks in the manufacture of DNA and RNA in a human cell.
  • DHODH is the only enzyme in the synthetic pathway for the de novo biosynthesis of pyrimidines whose cellular location is in the inner mitochondrial membrane.
  • the other members of this pyrimidine biosynthetic synthetic pathway are all in the cellular cytoplasm.
  • Recently data has been published demonstrating that DHODH is a key stress sensor in the cell. This is partly by virtue of its position in the inner mitochondrial membrane where DHODH couples the de novo biosynthesis of pyrimindines with the mitochondrial respiratory chain and the manufacture of adenosine triphosphate (ATP].
  • DHODH inhibitor in human cells with a functional p53 pathway it may be that the DHODH inhibitor is able to upregulate p53 mediated cellular apoptosis. Inhibition of DHODH in human cells may lead to cell cycle arrest and at higher levels of prolonged inhibition may lead to p53 mediated apoptosis.
  • the activated checkpoint kinases e.g. CHK1 stall, the cells progress in S phase so that DNA damage can be repaired ensuring that chromosomes are replicated and the mitochondrial spindle is correctly formed before progression into mitosis. Failure to control progression into and out of DNA synthesis and progression into mitosis results in improperly replicated DNA and improperly replicated human chromosomes. Cellular death induced by this mechanism is called synthetic catastrophe and mitotic and results in cellular apoptosis.
  • the human protein E4F1 is a transcription factor and an atypical ubiquitin ligase. Conditional knockout of this gene in human cells results in; depressed levels of cellular pyrimidines, increased reactive oxygen species (ROS] and reduced protein and mRNA levels of CHK1 kinase.
  • ROS reactive oxygen species
  • E4F1 knock-out leads to cell cycle arrest mediated by p53 in order to allow the tumour cells sufficient time to repair DNA that has been damaged by reactive oxygen species before they progress into mitosis.
  • tumour cells that have inactivated the p53 gene via mutation of the gene sequence p53, or in tumour cells that have blocked p53 signalling via mutations that effect other members of the p53 pathway the result is to knock out of the E4F1 gene. This results in cellular death via apoptosis as tumour cells are forced into mitosis before they can repair ROS damaged DNA.
  • E4F1 knockout in tumour cells with p53 mutation results in synthetic and mitotic catastrophe and is a lethal phenotype.
  • the present application contains new and surprising data showing that the E4F1 knockout lethal phenotype in p53 mutated tumours can be recapitulated synthetically by combining an inhibitor of dihydroorotate dehydrogenase (DHODH] and checkpoint kinase 1 (CHK1/ CHEK1] in a p53 mutated tumour.
  • DHODH dihydroorotate dehydrogenase
  • CHK1/ CHEK1 checkpoint kinase 1
  • the combination of DHODH/ CHK1 inhibitor efficiently kill tumour cells that mutate p53. It is estimated that at least 50% of all solid and liquid tumours mutate p53.
  • the synthetic lethality from the combination of DHODH/ CHK1 inhibitor is specific to tumour cells that mutate p53.
  • a target patient population for the therapy according to the present disclosure is cancer patients with a mutated p53 gene.
  • a mutated p53 gene as employed herein refers and non-native/non-natural/non-wild-type p53 gene.
  • inactivation of the p53 tumor suppressor is a frequent event in tumorigenesis.
  • the p53 gene is mutated, giving rise to a stable mutant protein whose accumulation is regarded as a hallmark of cancer cells. Mutant p53 proteins may not only lose their tumor suppressive activities but may gain additional oncogenic functions that endow cells with growth and survival advantages.
  • Checkpoint kinase inhibitor refers to an inhibitor that reduces or eliminates the biological activity of a cell regulatory checkpoint kinase 1 and/or 2.
  • Cells that suffer DNA damage activate the checkpoint kinases CHKl and CHK2, which signal to initiate the DNA repair processes, limit cell-cycle progression and prevent cell replication, until the damaged DNA is repaired.
  • a combination therapy of a DHODH and a checkpoint inhibitor provides effective treatment, in particular an effective cancer treatment.
  • the data generated by the inventors suggests the combination therapy is highly effective in treating cancer.
  • a therapeutically effective amount of the DHODH inhibitor is administered. In one embodiment a therapeutically effective amount which is administered is approximately the same dose as employed in monotherapy of said DHODH inhibitor. In one embodiment a therapeutically effective amount is a dose which is less than a monotherapy of said DHODH inhibitor, for example 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50% less than the dose for monotherapy. In one embodiment a therapeutically effective amount is a dose which is more than the dose employed for monotherapy, for example a dose which is 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50% more than the dose for monotherapy. In one embodiment at least the dose of monotherapy is employed.
  • a DHODH inhibitor as employed herein refers to a compound which inhibits the activity of dihydroorotate dehydrogenase, in particular in vivo.
  • the DHODH inhibitor is administered daily, for example once or twice daily, such as twice daily.
  • the DHODH inhibitor is administered orally.
  • the checkpoint inhibitor (such as a checkpoint kinase inhibitor] is administered orally. In one embodiment the checkpoint inhibitor (such as a checkpoint kinase inhibitor] is administered intravenously.
  • the checkpoint inhibitor is administered once or twice daily, for example twice daily.
  • the checkpoint inhibitor (such as a checkpoint kinase inhibitor] is administered orally and the DHODH inhibitor is administered orally, for example co-formulated or provided as separate formulations.
  • checkpoint kinase inhibitor is administered intravenously and the DHODH inhibitor is administered orally.
  • the DHODH inhibitor and the checkpoint kinase inhibitors are administered simultaneously, at approximately the same time.
  • the cancer is selected from and epithelial cancer, for example selected from the group comprising hepatocellular carcinoma, cholangiocarcinoma, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, lung cancer, stomach cancer, pancreatic and oesophagus cancer.
  • the cancer is selected from other than cancer forms where HER inhibition is effective.
  • therapeutic agent or agents such as an anti-cancer therapy are employed in combination with the therapy of the present disclosure.
  • the combination therapy according to the present disclosure further comprises a RON inhibitor, for example as disclosed WO2008/058229, incorporated herein by reference.
  • the combination therapy of the present disclosure 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.
  • Molecules such as PD-1 and PD-L1 are expressed on cell surfaces and are involve in signalling that downregulates immune responses to the cancer cell.
  • Direct inhibition is where the inhibitor binds directly to or physically blocks a binding interaction to inhibit a biological activity (including where the binding causes a conformational change in the polypeptide structure and reduces and eliminates binding of a ligand] or when the inhibitor inhibits the activation through phosphorylation of the target molecule, or the like.
  • a checkpoint inhibitor as employed herein refers to an inhibitor of biological molecule or pathway in place to reduce the likelihood of a damaged cells (in particular a cell with damaged DNA] replicating.
  • An inhibitor of at least checkpoint kinase 1 as employed herein refers to therapeutic agent, for example biological therapy or a "drug", which inhibits checkpoint kinase 1 but may also inhibit other entities, such as checkpoint kinase 2.
  • a biological therapeutic is one based on a protein, for example an antibody or binding fragment thereof, including fusion proteins and biological molecules conjugated to a polymer, toxin or similar payload.
  • a "drug” as employed herein refers to a chemical entity, organic chemistry molecule with pharmacological activity.
  • the epithelial cancer is a carcinoma.
  • the combination treatment according to the disclosure is adjuvant therapy, for example after surgery.
  • the treatment according to the present disclosure is suitable for the treatment of cancerous cells in a lymph node, for example a cancer of the present disclosure.
  • the gastric cancer is selected from the group comprising adenocarcinoma of the stomach, squamous cell carcinomas, lymphoma of the stomach, gastric stromal tumor, and neuroendocrine tumors.
  • Prostate cancer refers to cancer of the prostate, for example ductal adenocarcinoma, transitional cell (urothelial cancer], squamous cell cancer, carcinoid of the prostate, small cell cancer or sarcoma and sarcomatoid cancer.
  • Pancreatic cancer as employed herein includes exocrine cancers (including rare forms thereof such as cystitic tumours, and cancer of the acinar cells], endocrine pancreatic tumours (including gastrinomas, insulinomas, somatostatinomas, VIPomas, glucagonomas], pancreatoblastoma, sarcomas of the pancreas and lymphoma.
  • exocrine cancers including rare forms thereof such as cystitic tumours, and cancer of the acinar cells
  • endocrine pancreatic tumours including gastrinomas, insulinomas, somatostatinomas, VIPomas, glucagonomas
  • pancreatoblastoma pancreatoblastoma
  • sarcomas of the pancreas and lymphoma include exocrine cancers (including rare forms thereof such as cystitic tumours, and cancer of the acinar cells], endocrine pancreatic tumours (including
  • Colorectal cancer refers to cancer or the colon and/or rectum and includes squamous cell cancers, carcinoid tumours, sarcomas and lymphomas.
  • the epithelial cancer is lung cancer, for example small-cell lung cancer (SCLC] and non-small-cell lung cancer (NSCLC].
  • SCLC small-cell lung cancer
  • NSCLC non-small-cell lung cancer
  • Non-small-cell lung carcinoma The three main subtypes of NSCLC are adenocarcinoma, squamous-cell carcinoma and large-cell carcinoma.
  • the cancer is bladder cancer, for example is any of several types of malignancy arising from the epithelial lining (i.e., the urothelium] of the urinary bladder.
  • the epithelial lining i.e., the urothelium
  • about 90% of bladder cancers are transitional cell carcinoma.
  • the other 10% are squamous cell carcinoma, adenocarcinoma, sarcoma, small cell carcinoma, and secondary deposits from cancers elsewhere in the body.
  • the staging of is given below.
  • N (Lymph nodes) NX Regional lymph nodes cannot be assessed; NO No regional lymph node metastasis; Nl Metastasis in a single lymph node 2 cm or less in greatest dimension; N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension; N3 Metastasis in a lymph node more than 5 cm in greatest dimension.
  • the current disclosure extends to any stage of bladder cancer.
  • ovarian cancer There are more than 30 different types of ovarian cancer which are classified according to the type of cell from which they start Cancerous ovarian tumors can start from three common cell types: Surface Epithelium - cells covering the lining of the ovaries; Germ Cells - cells that are destined to form eggs; and Stromal Cells - Cells that release hormones and connect the different structures of the ovaries
  • the present disclosure relates to treatment of ovarian cancer from any source, for example as described herein, in particular epithelium cells.
  • Epithelial ovarian carcinomas account for 85 to 90 percent of all cancers of the ovaries.
  • LMP tumors There are some ovarian epithelial tumors whose appearance under the microscope does not clearly identify them as cancerous. These are called borderline tumors or tumors of low malignant potential (LMP tumors].
  • the method of the present disclosure includes treatment of the latter.
  • Germ Cell Tumors Ovarian germ cell tumors develop from the cells that produce the ova or eggs. Most germ cell tumors are benign (non-cancerous], although some are cancerous and may be life threatening. The most common germ cell malignancies are maturing teratomas, dysgerminomas, and endodermal sinus tumors. Germ cell malignancies occur most often in teenagers and women in their twenties. Today, 90 percent of patients with ovarian germ cell malignancies can be cured and their fertility preserved.
  • Stromal Tumors - Ovarian stromal tumors are a rare class of tumors that develop from connective tissue cells that hold the ovary together and those that produce the female hormones, estrogen and progesterone. The most common types are granulosa-theca tumors and Sertoli- Leydig cell tumors. These tumors are quite rare and are usually considered low-grade cancers, with approximately 70 percent presenting as Stage I disease (cancer is limited to one or both ovaries].
  • Primary Peritoneal Carcinoma The removal of one's ovaries eliminates the risk for ovarian cancer, but not the risk for a less common cancer called Primary Peritoneal Carcinoma.
  • Primary Peritoneal Carcinoma is closely rated to epithelial ovarian cancer (most common type]. It develops in cells from the peritoneum (abdominal lining] and looks the same under a microscope. It is similar in symptoms, spread and treatment.
  • stage of a tumor can be determined during surgery, when the doctor can tell if the cancer has spread outside the ovaries.
  • the treatment plan and prognosis (the probable course and outcome of your disease] will be determined by the stage of cancer you have.
  • Stage IA - Growth is limited to one ovary and the tumor is confined to the inside of the ovary.
  • Stage IB - Growth is limited to both ovaries without any tumor on their outer surfaces. There are no ascites present containing malignant cells. The capsule is intact.
  • Stage IV This is the most advanced stage of ovarian cancer. Growth of the cancer involves one or both ovaries and distant metastases (spread of the cancer to organs located outside of the peritoneal cavity] have occurred. Finding ovarian cancer cells in pleural fluid (from the cavity which surrounds the lungs] is also evidence of stage IV disease.
  • the ovarian cancer is: type I, for example IA, IB or IC; type II, for example
  • Thyroid cancer refers to cancer of the thyroid originating from follicular or parafollicular thyroid cells and includes papillary thyroid cancer (75% to 85% of cases]; follicular thyroid cancer (10% to 20% of cases]; medullary thyroid cancer (5% to 8% of cases]- cancer of the parafollicular cells, often part of multiple endocrine neoplasia type 2; poorly differentiated thyroid cancer; anaplastic thyroid cancer (less than 5% of cases] is not responsive to treatment and can cause pressure symptoms, thyroid lymphoma, squamous cell thyroid carcinoma, sarcoma of thyroid.
  • Bladder cancer as employed herein refers to cancer of the bladder including transitional cell bladder cancer, carcinoma in situ, papillary cancer and rarer types of bladder cancer such as squamous cell cancer, adenocarcinoma and a combination of two or more of the same.
  • Example a platinum containing chemotherapeutic agent also referred to as platins
  • chemotherapeutic agent such as cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin and lipoplatin (a liposomal version of cisplatin], in particular cisplatin, carboplatin and oxaliplatin.
  • Aziridines include thiotepa, mytomycin and diaziquone (AZQ].
  • antimetabolites which may be employed in the method of the present disclosure, 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 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
  • 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 formulaitons, derivatives also include chemical derivatives wherein synthetic chemistry is employed to modify a starting material which is a taxane.
  • Type II poisons include amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin and fluoroquinolones.
  • 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]
  • ABT-751 N-[2-[(4-Hydroxyphenyl]amino]-3-pyridinyl]-4- methoxybenzenesulfonamide
  • a therapeutically effective dose (such as a daily dose] of a DHODH inhibitor is in the range lOmg to lOOOmg, for example 50 to 500mg, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500mg, in particular administered once or twice a day, such as twice daily.
  • Figures 5A to I show tumor volumes (mm 3 ) of tumors excised from treated mice.

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Abstract

L'invention concerne un procédé de traitement du cancer au moyen d'une polythérapie consistant à administrer un inhibiteur de la DHODH et un inhibiteur de point de contrôle, l'inhibiteur de la DHODH étant l'acide 2-(3,5-difluoro-3'-méthoxybiphényl-4-ylamino)nicotinique ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également une polythérapie destinée à être utilisée dans le traitement du cancer.
PCT/SG2018/050035 2017-01-20 2018-01-19 Polythérapie WO2018136010A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018222134A1 (fr) * 2017-06-02 2018-12-06 Aslan Pharmaceuticals Pte Ltd Cancérothérapie
WO2018222135A1 (fr) * 2017-06-02 2018-12-06 Aslan Pharmaceuticals Pte Ltd Cancérothérapie
CN111205227A (zh) * 2018-11-22 2020-05-29 四川大学 3-乙烯基吲唑类衍生物及其制备方法和用途
WO2021232367A1 (fr) * 2020-05-21 2021-11-25 四川大学 Dérivé de 3-vinyle indazole, son procédé de préparation et son utilisation
US11311548B2 (en) 2017-03-02 2022-04-26 Aslan Pharmaceuticals Pte. Ltd. Cancer therapy
US11382903B2 (en) 2017-03-02 2022-07-12 Aslan Pharmaceuticals Pte. Ltd. Cancer therapy

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US11311548B2 (en) 2017-03-02 2022-04-26 Aslan Pharmaceuticals Pte. Ltd. Cancer therapy
US11382903B2 (en) 2017-03-02 2022-07-12 Aslan Pharmaceuticals Pte. Ltd. Cancer therapy
WO2018222134A1 (fr) * 2017-06-02 2018-12-06 Aslan Pharmaceuticals Pte Ltd Cancérothérapie
WO2018222135A1 (fr) * 2017-06-02 2018-12-06 Aslan Pharmaceuticals Pte Ltd Cancérothérapie
CN111205227A (zh) * 2018-11-22 2020-05-29 四川大学 3-乙烯基吲唑类衍生物及其制备方法和用途
WO2021232367A1 (fr) * 2020-05-21 2021-11-25 四川大学 Dérivé de 3-vinyle indazole, son procédé de préparation et son utilisation

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