US20180296547A1 - Dosage regimen of mdm2 inhibitor for treating cancers - Google Patents

Dosage regimen of mdm2 inhibitor for treating cancers Download PDF

Info

Publication number
US20180296547A1
US20180296547A1 US15/769,054 US201615769054A US2018296547A1 US 20180296547 A1 US20180296547 A1 US 20180296547A1 US 201615769054 A US201615769054 A US 201615769054A US 2018296547 A1 US2018296547 A1 US 2018296547A1
Authority
US
United States
Prior art keywords
days
compound
salt
administered
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/769,054
Other languages
English (en)
Inventor
Ngai-chiu Archie TSE
Shengli CAI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daiichi Sankyo Co Ltd
Original Assignee
Daiichi Sankyo Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Sankyo Co Ltd filed Critical Daiichi Sankyo Co Ltd
Priority to US15/769,054 priority Critical patent/US20180296547A1/en
Publication of US20180296547A1 publication Critical patent/US20180296547A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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

Definitions

  • the present invention relates to a method for treating a cancer in a subject in need thereof, comprising administering a specific MDM2 inhibitor to the subject according to a specific dosage regimen and a pharmaceutical composition for use in treating a cancer according to the dosage regimen.
  • the present invention also relates to a method for treating liposarcoma in a subject in need thereof, comprising administering a specific MDM2 inhibitor to the subject and a pharmaceutical composition for use in treating liposarcoma, comprising the MDM2 inhibitor.
  • MDM2 located on Chromosome 12 q13-15, is a negative regulator of the p53 tumor suppressor protein.
  • the 90 kDa MDM2 protein contains a p53 binding domain at its N-terminus and a RING (really interesting new gene) domain at its C-terminus, which functions as an E3 ligase that ubiquitinates p53.
  • the activation of wild-type p53 by cell stimuli and stresses results in the binding of MDM2 to p53 at the N-terminus to inhibit the transcriptional activation of p53 and promote the degradation of p53 via the ubiquitin-proteasome pathway.
  • MDM2 can interfere with p53-mediated apoptosis and arrest of cancer cell proliferation, attributing a significant oncogenic activity to MDM2 in cancer cells.
  • MDM2 can cause carcinogenesis independent of the p53 pathway, for example, in cells which possess an alternative splice form of MDM2 (H. A. Steinman et al., 2004, J. Biol. Chem., 279(6):4877-4886).
  • MDM2 inhibitors have been developed to treat cancers, including (3′R,4′S,5′R)—N-[(3R,6 S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6′′-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2′′-oxo-1′′,2′′-dihydrodispiro[cyclohexane-1,2′-pyrro lidine-3′,3′′-indole]-5′-carboxamide (WO2012/121361 and US Patent Application Publication No. 2012/0264738A).
  • Liposarcoma is one of the most common soft tissue sarcoma (STS) subtype, comprising about 18 to 26% of STS cases in humans.
  • LPS can be categorized into four subtypes: well-differentiated type (WD, 46 to 54%), de-differentiated type (DD, 18 to 26%), myxoid/round-cell type (13 to 28%) and pleomorphic type (7 to 8%).
  • Chromosome 12 q13-15 amplification is frequently found in WD/DD LPS (i.e. up to ⁇ 90% of patients) (Cowear et al., 2010, Virchows.
  • the present invention provides a method for treating a cancer in a subject in need thereof, comprising administering a specific MDM2 inhibitor to the subject according to a specific dosage regimen and a pharmaceutical composition for use in treating a cancer according to the dosage regimen.
  • the present invention also provides a method for treating liposarcoma in a subject in need thereof, comprising administering a specific MDM2 inhibitor to the subject and a pharmaceutical composition for use in treating liposarcoma, comprising the MDM2 inhibitor.
  • Solid cancers and lymphoma can be treated by orally administering to the subjects (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6′′-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2′′-oxo-1′′,2′′-dihydrodispiro[cyclohexane-1,2′-pyrro lidine-3′,3′′-indole]-5′-carboxamide (hereinafter also referred to as “Compound 1”) or pharmaceutically acceptable salt thereof according to a dosage schedule, wherein the dosage schedule comprises administering a daily dose of 80 to 250 mg of the compound or salt thereof to the subject in a cyclical dosing (QD21/28 or QD28/28).
  • the inventors have also discovered that liposarcoma can be treated with Compound 1.
  • the Present Invention Provides:
  • a pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered according to a dosage schedule comprising administering a daily dose of about 80 mg to about 250 mg of the compound or salt thereof to the subject.
  • a pharmaceutical composition according to above (1), wherein the dosage schedule comprises administering a daily dose of about 80 mg to about 100 mg of the compound or salt thereof to the subject.
  • a pharmaceutical composition according to above (1), wherein the dosage schedule comprises administering a daily dose of about 90 mg of the compound or salt thereof to the subject.
  • a pharmaceutical composition according to above (1), wherein the dosage schedule comprises administering a daily dose of about 100 mg to about 140 mg of the compound or salt thereof to the subject.
  • a pharmaceutical composition according to above (1), wherein the dosage schedule comprises administering a daily dose of about 120 mg of the compound or salt thereof to the subject.
  • a pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of at least 10 days, in which the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 250 mg.
  • a pharmaceutical composition for use in treating a cancer in a subject in need thereof according to any one of above (1) to (37), wherein the compound or salt thereof is in a form of p-toluenesulfonic acid salt monohydrate (hereinafter also referred to as “Compound 2”) as shown in formula (II).
  • a pharmaceutical composition for use in treating liposarcoma comprising (3′R,4′S,5′R)—N-[(3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl]-6′′-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2′′-oxo-1′′,2′′-dihydrodispiro[cyclohexane-1,2′-pyrrol idine-3′,3′′-indole]-5′-carboxamide or pharmaceutically acceptable salt thereof.
  • PD Progressive Disease and Stable Disease, respectively, as are defined in RECIST guidelines v1.1.
  • the term “PD” and “SD” mean Progressive Disease and Stable Disease, respectively, as are defined in RECIST guidelines v1.1.
  • subject refers to a mammal, especially a human, suffering or suspected of suffering from a cancer.
  • the subject can be a subject which has been or was previously treated by other therapy.
  • the subject can be an adult human.
  • treat refers to reducing the severity of the disease or slowing progression of the disease, which can be determined by physicians according to Response Evaluation in Solid Tumors guidelines (RECIST) version 1.1.
  • MDM2 refers to an E3 ubiquitin ligase which can interact with p53 and cause p53 degradation.
  • MDM2 as used herein includes, but not limited to, mouse MDM2 and the human ortholog of MDM2 (also called “Human Double Minute 2” or “HDM2”).
  • MDM2 inhibitor refers to an inhibitor inhibiting MDM2 functions or activities on p53 degradation.
  • binding refers generally to an interaction or association between two substances or molecules, such as the hybridization of one nucleic acid molecule to another (or to itself); the association of an antibody with a polypeptide, protein, or peptide; or the association of a protein with another protein or nucleic acid molecule.
  • An oligonucleotide molecule binds or stably binds to a target nucleic acid molecule if a sufficient amount of the oligonucleotide molecule forms base pairs or is hybridized to its target nucleic acid molecule, to permit detection of that binding.
  • binding refers to an association in which one molecule binds to another with high affinity, and binds to heterologous molecules at a low affinity.
  • Binding can be detected by any procedure known to one skilled in the art, such as by physical or functional properties of the target/oligonucleotide complex. For example, binding can be detected functionally by determining whether there is an observable effect upon a biosynthetic process, e.g., expression of a gene, DNA replication, transcription, translation, etc.
  • gene refers to a DNA sequence which is expressed in a subject as an RNA transcript; a gene can be a full-length gene (protein encoding or non-encoding).
  • RNA expression means the process of converting genetic information encoded in a gene into RNA (e.g., mRNA, rRNA, tRNA, or snRNA) through transcription of the gene (e.g., as mediated by the enzymatic action of an RNA polymerase), and for protein-encoding genes, into protein through “translation” of mRNA.
  • RNA e.g., mRNA, rRNA, tRNA, or snRNA
  • Neoplasms and tumors refer to abnormal growths or abnormally growing cells that can invade surrounding tissues and spread to other organs, i.e., become malignant, if left untreated.
  • Neoplasms are abnormal growths (or masses) of tissues comprised of cells that form as a result of neoplasia, which is the abnormal growth and proliferation of cells, either malignant or benign.
  • Neoplasms and tumors can include the abnormal growths of precancerous and cancerous cells and tissues, which grow more rapidly than normal cells and that will continue to grow and compete with normal cells for nutrients if not treated.
  • Neoplasms may include, without limitation, solid and non-solid tumors, such as hollow or liquid-filled tumors, and also hematological cell neoplasias or neoplasms, e.g., lymphomas, leukemias and myelomas.
  • cancer is also intended to embrace neoplasms and tumors of various origins within and on the body, various types and subtypes, as well as organ, tissue and cell samples and specimens, e.g., biological samples or specimens, thereof.
  • appropriate cancer samples or specimens include any conventional biological samples or specimens, including clinical samples obtained from a human, e.g., a patient undergoing treatment for cancer, or a veterinary subject.
  • a sample may refer to a part of a tissue that is a diseased or healthy portion of the tissue, or to the entire tissue.
  • Tissue samples can be obtained from a subject by employing any method or procedure as known and practiced in the art.
  • liposarcoma is one of the most commons soft tissue sarcomas in adults that resemble fat cells in a histological section under a microscope. Liposarcoma represents about 18 to 26% of soft tissue sarcomas. According to its pathological study, liposarcomas can be classified into four subtypes: well-differentiated (WD, 46 to 54%), de-differentiated (DD, 18 to 26%), myxoid/round-cell (13 to 28%), and pleomorphic (7 to 8%) liposarcomas. Chromosome 12 q13-15 amplification is frequently found in a subject suffering from liposarcoma, such as WD or DD liposarcomas. It is known that MDM2 gene is located on Chromosome 12 q13-15 and therefore it is presumed that MDM2 genes are frequently amplified in a subject suffering from liposarcoma.
  • pharmaceutically acceptable salt refers to salts of the active compounds which are relatively nontoxic acid or base addition salts.
  • acid addition salts include hydrochloric, hydrobromic, nitric, carbonic, phosphoric, acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, fumaric, lactic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, oxalic, and methanesulfonic acids.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable solvate or salt thereof.
  • the solvate is a stoichiometric complex of a molecule and one or more solvent molecules.
  • Non-limited examples of pharmaceutically acceptable solvates include water, methanol, ethanol, dimethylsulfoxide, and acetate as solvent.
  • a solvate which contains water as solvent is hydrate.
  • the pharmaceutically acceptable salt of the compound can be hydrate and more preferably monohydrate.
  • the term “about” used herein refers to the specific value subsequent to the term and a range of values ⁇ 10% of the specific value.
  • the phrase “about 100” refers to 100, which is the specific value in this case, and a range of 90 to 110.
  • the compound of formula (I) means the compound and pharmaceutically acceptable salt and pharmaceutically acceptable solvate, and prodrug thereof.
  • this compound can be the compound of formula (II):
  • the compound of formula (I) can be administered once daily to a subject suffering from a cancer according to a dosage schedule of the present invention in order to treat the cancer in the subject.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 80 mg to about 250 mg of the compound.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 80 mg to about 140 mg, more preferably about 80 mg to about 100 mg, still more preferably about 90 mg of the compound for at least one week, two weeks, three weeks, four weeks or more.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 100 mg to about 140 mg, more preferably about 120 mg of the compound for at least one week, two weeks, three weeks, four weeks or more.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 140 mg to about 180 mg, more preferably about 160 mg of the compound for at least one week, two weeks, three weeks, four weeks or more.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 180 mg to about 250 mg, more preferably about 210 mg of the compound for at least one week, two weeks, three weeks, four weeks or more.
  • the compound of formula (I) or pharmaceutically acceptable salt thereof is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of at least 10 days, in which the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 250 mg is provided.
  • the dosing period is preferably at least 15 days, more preferably between about 15 days to about 25 days, still more preferably about 21 days, and the daily dosage is preferably about 80 mg to about 100 mg or about 100 mg to 140 mg, more preferably about 90 mg or about 120 mg.
  • the dosing period is preferably at least 15 days, more preferably between about 15 days to about 25 days, still more preferably about 21 days, and the daily dosage is preferably about 140 mg to about 180 mg or about 180 mg to 250 mg, more preferably about 160 mg or about 210 mg.
  • the dosing period is at least 15 days and the daily dosage is about 80 mg to about 100 mg, more preferably about 90 mg.
  • the dosing period is at least 15 days and the daily dosage is about 100 mg to about 140 mg, more preferably about 120 mg.
  • the dosing period is at least 15 days and the daily dosage is about 140 mg to about 180 mg, more preferably about 160 mg.
  • the dosing period is at least 15 days and the daily dosage is about 180 mg to about 250 mg, more preferably about 210 mg.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 100 mg to about 140 mg, more preferably about 120 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 5 days to about 10 days in which any of the compounds is not administered.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 120 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, more preferably about 21 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 5 days to about 10 days, more preferably about 7 days in which any of the compounds is not administered.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 120 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 21 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 7 days in which any of the compounds is not administered.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 80 mg to about 100 mg, more preferably about 90 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 5 days to about 10 days in which any of the compounds is not administered.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 90 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, more preferably about 21 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 5 days to about 10 days, more preferably about 7 days in which any of the compounds is not administered.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 90 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 21 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 7 days in which any of the compounds is not administered.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 140 mg to about 180 mg, more preferably about 160 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 5 days to about 10 days in which any of the compounds is not administered.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 160 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, more preferably about 21 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 5 days to about 10 days, more preferably about 7 days in which any of the compounds is not administered.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 160 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 21 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 7 days in which any of the compounds is not administered.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 180 mg to about 250 mg, more preferably about 210 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 5 days to about 10 days in which any of the compounds is not administered.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 210 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, more preferably about 21 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 5 days to about 10 days, more preferably about 7 days in which any of the compounds is not administered.
  • the compound of formula (I) can be orally administered to the subject at a daily dose of about 210 mg of the compound for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 21 days, in which the compound is administered daily at the above-mentioned dose, followed by a rest period of about 7 days in which any of the compounds is not administered.
  • cancers to be treated includes, but not limited to, solid cancers and hematological cancers.
  • Solid cancers to be treated in the invention include, but not limited to, soft tissue sarcoma, such as liposarcoma, melanoma, neuroendocrine cancer, adenoid cystic cancer, leiomyosarcoma, colorectal cancer, renal cancer, lung cancer, chordoma, salivary adenocarcinoma, adrenocortical carcinoma, and maxillary sinus adenocarcinoma.
  • Hematological cancers to be treated in the invention include, but not limited to, lymphoma.
  • solid cancers to be treated can be liposarcoma such as DD or WD liposarcoma.
  • the compound of formula (I) can act as an MDM2 inhibitor.
  • MDM2 is a negative regulator of the p53 tumor suppressor protein.
  • the 90 kDa MDM2 protein contains a p53 binding domain at its N-terminus and a RING (really interesting new gene) domain at its C-terminus, which functions as an E3 ligase that ubiquinates p53.
  • the activation of wild-type p53 by cell stimuli and stresses results in the binding of MDM2 to p53 at the N-terminus to inhibit the transcriptional activation of p53 and promote the degradation of p53 via the ubiquitin-proteosome pathway.
  • MDM2 can interfere with p53-mediated apoptosis and arrest of cancer cell proliferation, attributing a significant oncogenic activity to MDM2 in cancer cells.
  • MDM2 can cause carcinogenesis independent of the p53 pathway, for example, in cells which possess an alternative splice form of MDM2. (H. A. Steinman et al., 2004, J. Biol. Chem., 279(6):4877-4886).
  • about 50% of human cancers are observed to have a mutation in or deletion of the TP53 gene.
  • MDM2 is overexpressed in a number of human cancers, including, for example, melanoma, non-small cell lung cancer (NSCLC), breast cancer, esophageal cancer, leukemia, non-Hodgkin's lymphoma and sarcoma.
  • NSCLC non-small cell lung cancer
  • esophageal cancer leukemia
  • NHL acute lymphoblastic leukemia
  • cancers to be treated in the invention have amplified MDM2 genes or have MDM2 overexpressed in the cancer.
  • cancers to be treated in the invention can be liposarcoma which have amplified MDM2 genes on the genome of the cancer.
  • cancers to be treated in the invention have wild-type TP53 gene on the genome of the cancer.
  • cancers to be treated in the invention can be liposarcoma (for example, DD or WD liposarcoma) which has wild-type TP53 gene on the genome of the cancer.
  • cancers to be treated in the invention can be liposarcoma which has wild-type TP53 gene and amplified MDM2 genes on the genome of the cancer.
  • the cancers which have wild-type TP53 gene and/or amplified MDM2 genes on the genome of the cancer can effectively be treated by the administration of the compound of formula (I), which can act as a MDM2 inhibitor.
  • the pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered to the subject according to a dosage schedule comprising administering to the subject a daily dose of about 80 mg to about 250 mg, more preferably about 100 mg to about 140 mg, about 140 mg to about 180 mg, or about 180 mg to about 250 mg of the compound or salt thereof is provided.
  • the pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising the compound of formula (II), wherein the pharmaceutical composition is orally administered to the subject according to a dosage schedule comprising administering to the subject a daily dose of about 80 mg to about 250 mg, more preferably about 100 mg to about 140 mg, about 140 mg to about 180 mg, or about 180 mg to about 250 mg of the compound is provided.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising the compound of formula (II), wherein the pharmaceutical composition is orally administered to the subject according to a dosage schedule comprising administering to the subject a daily dose of about 80 mg to about 250 mg, more preferably about 100 mg to about 140 mg, about 140 mg to about 180 mg, or about 180 mg to about 250 mg of the compound, wherein the cancer is liposarcoma such as DD or WD liposarcoma.
  • the daily dose is between about 100 mg to about 140 mg
  • the cancer is liposarcoma such as DD or WD liposarcoma.
  • the pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days or at least 15 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 80 mg to about 140 mg. In a specific embodiment, the daily dosage is between about 100 mg to about 140 mg.
  • the dosing period is between about 15 days to about 25 days, more preferably about 21 days. In a specific embodiment of the invention, the dosing period is between about 15 days to about 25 days and the daily dosage is about 100 mg to about 140 mg. In a specific embodiment of the invention, the dosing period is about 21 days and the daily dosage is about 100 mg to about 140 mg, the dosing period is between about 15 days to about 25 days and the daily dosage is about 120 mg, or the dosing period is about 21 days and the daily dosage is about 120 mg.
  • the pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days or at least 15 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 140 mg to about 180 mg.
  • the dosing period is between about 15 days to about 25 days, more preferably about 21 days.
  • the dosing period is between about 15 days to about 25 days and the daily dosage is about 140 mg to about 180 mg. In a specific embodiment of the invention, the dosing period is about 21 days and the daily dosage is about 140 mg to about 180 mg, the dosing period is between about 15 days to about 25 days and the daily dosage is about 160 mg, or the dosing period is about 21 days and the daily dosage is about 160 mg.
  • the pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days or at least 15 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 180 mg to about 250 mg.
  • the dosing period is between about 15 days to about 25 days, more preferably about 21 days.
  • the dosing period is between about 15 days to about 25 days and the daily dosage is about 180 mg to about 250 mg. In a specific embodiment of the invention, the dosing period is about 21 days and the daily dosage is about 180 mg to about 250 mg, the dosing period is between about 15 days to about 25 days and the daily dosage is about 210 mg, or the dosing period is about 21 days and the daily dosage is about 210 mg.
  • the pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days or at least 15 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 80 mg to about 100 mg.
  • the dosing period is between about 15 days to about 25 days, more preferably about 21 days.
  • the dosing period is about 21 days and the daily dosage is about 80 mg to about 100 mg.
  • the pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 100 mg to about 140 mg, more preferably about 120 mg, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which any of the compound and salt thereof is not administered, is provided.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 100 mg to about 140 mg, more preferably about 120 mg, followed by a rest period of about 7 days in which any of the compound and salt thereof is not administered, is provided.
  • the pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 140 mg to about 180 mg, more preferably about 160 mg, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which any of the compound and salt thereof is not administered, is provided.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 140 mg to about 180 mg, more preferably about 160 mg, followed by a rest period of about 7 days in which any of the compound and salt thereof is not administered, is provided.
  • the pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 180 mg to about 250 mg, more preferably about 210 mg, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which any of the compound and salt thereof is not administered, is provided.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 180 mg to about 250 mg, more preferably about 210 mg, followed by a rest period of about 7 days in which any of the compound and salt thereof is not administered, is provided.
  • the pharmaceutical composition for use in treating a cancer in a subject in need thereof comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 80 mg to about 100 mg, more preferably about 90 mg, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which any of the compound and salt thereof is not administered, is provided.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 21 days, in which the compound or salt thereof is administered to the subject daily at a daily dosage of about 80 mg to about 100 mg, more preferably about 90 mg, followed by a rest period of about 7 days in which any of the compound and salt thereof is not administered, is provided.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (II), wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound is administered daily at a daily dosage of about 80 mg to about 140 mg, preferably about 100 mg to about 140 mg, more preferably about 120 mg, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which the compound is not administered, is provided.
  • the daily dosage is between about 100 mg to about 140 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is about 120 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is between about 100 mg to about 140 mg, the dosing period is about 21 days, and the rest period is about 7 days. In another specific embodiment of the invention, the daily dosage is about 120 mg, the dosing period is about 21 days, and the rest period is about 7 days.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (II), wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound is administered daily at a daily dosage of about 140 mg to about 180 mg, more preferably about 160 mg, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which the compound is not administered, is provided.
  • the daily dosage is between about 140 mg to about 180 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is about 160 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is between about 140 mg to about 180 mg, the dosing period is about 21 days, and the rest period is about 7 days. In another specific embodiment of the invention, the daily dosage is about 160 mg, the dosing period is about 21 days, and the rest period is about 7 days.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (II), wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound is administered daily at a daily dosage of about 180 mg to about 250 mg, more preferably about 210 mg, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which the compound is not administered, is provided.
  • the daily dosage is between about 180 mg to about 250 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is about 210 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is between about 180 mg to about 250 mg, the dosing period is about 21 days, and the rest period is about 7 days. In another specific embodiment of the invention, the daily dosage is about 180 mg, the dosing period is about 21 days, and the rest period is about 7 days.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (II), wherein the pharmaceutical composition is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 140 mg, preferably about 100 mg to about 140 mg, more preferably about 120 mg, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which the compound is not administered, wherein the cancer is liposarcoma such as DD or WD liposarcoma is provided.
  • DD DD
  • WD liposarcoma liposarcoma
  • the daily dosage is between about 100 mg to about 140 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is about 120 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is between about 100 mg to about 140 mg, the dosing period is about 21 days, and the rest period is about 7 days. In another specific embodiment of the invention, the daily dosage is about 120 mg, the dosing period is about 21 days, and the rest period is about 7 days.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (II), wherein the pharmaceutical composition is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 140 mg to about 180 mg, more preferably about 160 mg, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which the compound is not administered, wherein the cancer is liposarcoma, for example, DD or WD liposarcoma is provided.
  • the daily dosage is between about 140 mg to about 180 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is about 160 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is between about 140 mg to about 180 mg, the dosing period is about 21 days, and the rest period is about 7 days. In another specific embodiment of the invention, the daily dosage is about 160 mg, the dosing period is about 21 days, and the rest period is about 7 days.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (II), wherein the pharmaceutical composition is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 180 mg to about 250 mg, more preferably about 210 mg, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which the compound is not administered, wherein the cancer is liposarcoma such as DD or WD liposarcoma is provided.
  • DD DD
  • WD liposarcoma liposarcoma
  • the daily dosage is between about 180 mg to about 250 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is about 210 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is between about 180 mg to about 250 mg, the dosing period is about 21 days, and the rest period is about 7 days. In another specific embodiment of the invention, the daily dosage is about 210 mg, the dosing period is about 21 days, and the rest period is about 7 days.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (II), wherein the pharmaceutical composition is orally administered to the subject for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 100 mg, more preferably 90 mg, of the compound, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which the compound is not administered, is provided.
  • the daily dosage is about 90 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is between about 80 mg to about 100 mg, the dosing period is about 21 days, and the rest period is about 7 days. In another specific embodiment of the invention, the daily dosage is about 90 mg, the dosing period is about 21 days, and the rest period is about 7 days.
  • the present pharmaceutical composition for use in treating a cancer in a subject in need thereof, comprising a therapeutically effective amount of the compound of formula (II), wherein the pharmaceutical composition is orally administered for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of about 15 days to about 25 days, preferably about 21 days, in which the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 100 mg of the compound, followed by a rest period of about 5 days to about 10 days, preferably about 7 days, in which the compound is not administered, wherein the cancer is liposarcoma such as DD or WD liposarcoma is provided.
  • DD DD
  • WD liposarcoma liposarcoma
  • the daily dosage is about 90 mg, the dosing period is between about 15 days to about 25 days, and the rest period is between about 5 days to about 10 days. In another specific embodiment of the invention, the daily dosage is between about 80 mg to about 100 mg, the dosing period is about 21 days, and the rest period is about 7 days. In another specific embodiment of the invention, the daily dosage is about 90 mg, the dosing period is about 21 days, and the rest period is about 7 days.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable excipient (for example, vehicles, adjuvants and additives such as bulking agent, viscosity-increasing agent, adhesive, plasticizer, binder, disintegrant, tablet lubricant, glidant, coating agent, antioxidant, preservative, humectant, opacifying agent, polishing agent, sweetening agent, aroma, flavors, and colorant) and can be prepared as a pharmaceutical composition for oral administration.
  • a pharmaceutically acceptable excipient for example, vehicles, adjuvants and additives such as bulking agent, viscosity-increasing agent, adhesive, plasticizer, binder, disintegrant, tablet lubricant, glidant, coating agent, antioxidant, preservative, humectant, opacifying agent, polishing agent, sweetening agent, aroma, flavors, and colorant
  • a pharmaceutically acceptable excipient for example, vehicles, adjuvants and additives such as bulking agent, viscosity-increa
  • the pharmaceutical composition of the invention can be formulated by the ordinary skill in the art.
  • the pharmaceutical composition for oral administration can be tablets, powders, granules, capsules, pills, troches, solutions, syrups, elixirs, emulsions, and oily or aqueous suspension.
  • Pharmaceutical solutions can be made by forming acid addition salt using a pharmaceutically acceptable acid such as p-toluenesulfonate.
  • the compound of formula (I) or (II) can be easily prepared by those skilled in the art according, to Example 70 of WO2012/121361 and Example 7 of WO2014/038606, which patent documents are incorporated by reference herein in its entirety.
  • the compound of formula (II) may be prepared in a form of crystal.
  • a method for treating a cancer in a subject in need thereof comprising orally and daily administering to the subject a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof according to a dosage schedule, wherein the dosage schedule comprises administering a daily dose of about 80 mg to about 250 mg of the compound or salt thereof to the subject.
  • a daily dose of the compound or salt thereof is preferably between about 100 mg to about 140 mg, and more preferably about 120 mg.
  • a daily dose of the compound or salt thereof is preferably between about 140 mg to about 180 mg, and more preferably about 160 mg.
  • a daily dose of the compound or salt thereof is preferably between about 180 mg to about 250 mg, and more preferably about 210 mg. In a preferable embodiment of the dosage schedule, a daily dose of the compound or salt thereof is preferably between about 80 mg to about 100 mg, and more preferably about 90 mg.
  • a cancer to be treated can be liposarcoma, especially a liposarcoma having amplified MDM2 genes in the genome of the liposarcoma.
  • a pharmaceutically acceptable salt of the compound of formula (I) can be the compound of formula (II).
  • a method for treating a cancer in a subject in need thereof comprising orally and daily administering a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof for at least one cycle of a cyclical dosing schedule, wherein each cycle has a dosing period of 15 to 25 days, in which the compound or salt thereof is administered daily at a daily dosage of about 80 mg to about 250 mg of the compound or salt thereof, followed by a rest period of 5 to 10 days in which any of the compound and salt thereof is not administered.
  • a daily dose of the compound or salt thereof is preferably between about 100 mg to about 140 mg, and more preferably about 120 mg.
  • a daily dose of the compound or salt thereof is preferably between about 140 mg to about 180 mg, and more preferably about 160 mg. In a preferable embodiment of the dosage schedule, a daily dose of the compound or salt thereof is preferably between about 180 mg to about 250 mg, and more preferably about 210 mg.
  • a cancer to be treated can be liposarcoma, especially a liposarcoma having amplified MDM2 genes in the genome of the liposarcoma.
  • a pharmaceutically acceptable salt of the compound of formula (I) can be the compound of formula (II).
  • the compound of formula (I) or (II) may be used in combination with additional anti-tumor agent(s).
  • the compound of formula (I) or (II) may be used in combination with additional anti-tumor agent(s).
  • additional anti-tumor agent(s) examples thereof include anti-tumor antibiotics, anti-tumor plant constituents, BRMs (biological response modifiers), hormones, vitamins, anti-tumor antibodies, molecular target drugs, and other anti-tumor agents.
  • anti-tumor agents to be used in combination with the compound of formula (I) or (II) may be or may not be an MDM2 inhibitor.
  • alkylating agents include the following: alkylating agents such as nitrogen mustard, nitrogen mustard N-oxide, bendamustine and chlorambucil; amidine alkylating agents such as carboquone and thiotepa; epoxide alkylating agents such as dibromomannitol and dibromodulcitol; nitrosourea alkylating agents such as carmustine, lomustine, semustine, nimustine hydrochloride, streptozocin, chlorozotocin, and ranimustine; and busulfan, improsulfan tosylate, and dacarbazine.
  • alkylating agents such as nitrogen mustard, nitrogen mustard N-oxide, bendamustine and chlorambucil
  • amidine alkylating agents such as carboquone and thiotepa
  • epoxide alkylating agents such as dibromomannitol and dibromodulcitol
  • Examples of various metabolic antagonists include the following: purine metabolic antagonists such as 6-mercaptopurine, 6-thioguanine, and thioinosine; pyrimidine metabolic antagonists such as fluorouracil, tegafur, tegafur-uracil, carmofur, doxifluridine, broxuridine, cytarabine, and enocitabine; and folic acid metabolic antagonists such as methotrexate and trimetrexate.
  • purine metabolic antagonists such as 6-mercaptopurine, 6-thioguanine, and thioinosine
  • pyrimidine metabolic antagonists such as fluorouracil, tegafur, tegafur-uracil, carmofur, doxifluridine, broxuridine, cytarabine, and enocitabine
  • folic acid metabolic antagonists such as methotrexate and trimetrexate.
  • anti-tumor antibiotics examples include mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, idarubicin, pirarubicin, THP-adriamycin, 4′-epidoxorubicin, and epirubicin; and chromomycin A3 and actinomycin D.
  • anti-tumor plant constituents and their derivatives include the following: vinca alkaloids such as vindesine, vincristine, and vinblastine; taxanes such as paclitaxel, docetaxel, and cabazitaxel; and epipodophyllotoxins such as etoposide and teniposide.
  • BRMs include tumor necrosis factors and indomethacin.
  • hormones include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, prasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, metenolone, fosfestrol, ethinylestradiol, chlormadinone, medroxyprogesterone, and mepitiostane.
  • vitamins examples include vitamin C and vitamin A.
  • anti-tumor antibodies and molecular target drugs examples include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, ipilimumab, nivolumab, pembrolizumab, avelumab, pidilizumab, atezolizumab, ramucirumab imatinib mesilate, dasatinib, gefitinib, erlotinib, sunitinib, lapatinib, vemurafenib, dabrafenib, trametinib, pazopanib, palbociclib, panobinostat, sorafenib, ibrutinib, bortezomib, carfilzomib, ixazomib, and quizartinib.
  • anti-tumor agents examples include cisplatin, carboplatin, oxaliplatin, tamoxifen, letrozole, anastrozole, exemestane, toremifene citrate, fulvestrant, bicalutamide, flutamide, mitotane, leuprorelin, goserelin acetate, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, aceglatone, sizofuran, picibanil, procarbazine, pipobroman, neocarzinostatin, hydroxyurea, ubenimex, azacytidine, decitabine, thalidomide, lenalidomide, pomalidomide, eribulin, tretinoin, and krestin.
  • Compound 2 was administered as an oral capsule comprising a pharmaceutically acceptable carrier (diluting agent, plasticizer, disintegrator and lubricant). Compound 2 was administered to the subjects once daily on Days 1 to 21 of a 28-day cycle (QD21/28). An alternative drug administration schedule was considered after establishing the maximum tolerated dose (MTD) of Compound 2 in solid tumor and/or lymphoma subjects using the above schedule, and upon review of the human safety. Subjects were administered Compound 2 in fasting conditions by avoiding food for 2 hours before and 1 hour after drug administration.
  • a pharmaceutically acceptable carrier drug, plasticizer, disintegrator and lubricant
  • Dose-escalation of Compound 2 to determine the MTD was guided by the modified continuous reassessment method (mCRM) using a Bayesian logistic regression model (BLRM) following escalation with overdose control (EWOC) principle.
  • mCRM modified continuous reassessment method
  • BLRM Bayesian logistic regression model
  • EWOC escalation with overdose control
  • a DLT was defined as any treatment-emergent adverse event (TEAE) not attributable to disease or disease-related processes that occurred during the observation period (Cycle 1) in each dose-level cohort and was grade 3 or higher according to NCI CTCAE, version 4. Subjects who were unable to complete at least 75% of the prescribed doses (i.e., 16 days) of Compound 2 in the first 21 days as a result of nondisease-related ⁇ grade 2 adverse event (AE) were considered to have a DLT.
  • TEAE treatment-emergent adverse event
  • Tumor assessment was performed at baseline, within every 2 cycles while the subject remained on study for the first 9 cycles and then every 3 cycles thereafter (start of Cycles 3, 5, 7, and 9, then Cycles 12, 15, etc.).
  • an optional tumor rebiopsy was performed within 30 days following the last dose of Compound 2 treatment for subjects who had achieved an initial complete response/partial response by standard response criteria but later developed progressive disease while on therapy, preferably prior to initiating new therapy.
  • Tumor TP53 genotyping was performed using archived formalin-fixed paraffin-embedded (FFPE) or frozen samples in all enrolled subjects. Confirmation of TP53 wildtype status was not required prior to Compound 2 dosing. During the study, in the event when a subject was found to contain a nonsynonymous mutation, insertion or deletion in the TP53 gene after Compound 2 had begun, the investigator and subject was informed about the genotyping result and given the option to discontinue study drug early.
  • FFPE formalin-fixed paraffin-embedded
  • each subject received Compound 2 orally once daily on Days 1 to 21 of a 28-day cycle.
  • the safety profile was based on AEs, physical examination findings, vital sign measurements, clinical laboratory measurements, and ECG recordings. All subjects receiving at least 1 dose of Compound 2 were included in the safety analyses.
  • Radiographic assessment was performed according to the Schedule of Events or if disease progression was suspected. Radiographic assessment included computerized tomography (CT) of all affected sites.
  • CT computerized tomography
  • subjects with lymphoma underwent a ( 18 F) fluorodeoxyglucose-positron emission tomography FDG-PET scan.
  • Tumor responses were assessed by the physicians according to RECIST 1.1 criteria for subjects with solid tumors and revised IWG criteria for subjects with lymphoma.
  • Descriptive statistics for the greatest percent change in the sum of longest dimensions (SLD) of measurable tumors were provided.
  • a waterfall plot of the greatest percent change from screening in the SLD for each subject was presented for subjects with advanced solid malignancies and lymphomas.
  • descriptive statistics for FDG-PET scans were provided for lymphoma subjects according to revised IWG criteria.
  • the maximum tolerated dose was determined to be 120 mg with 2 DLTs out of 13 subjects in the QD 21/28 schedule.
  • the 90 mg in QD 28/28 schedule was also determined to be an MTD in this dosing schedule with one out of 9 subjects experiencing a DLT.
  • Treatment emergent adverse events (TEAE) of any grade at any treatment cycle irrespective of causality were observed in 97.1% of the subjects, 55.9% of which were grade 3 or higher in severity.
  • the most common TEAEs irrespective of causality were neutropenia (17.6%), thrombocytopenia (32.4%), anemia (38.2%), nausea (64.7%), vomiting (35.3%), diarrhea (35.3%), constipation (23.5), decreased appetite (50.0%), dysgeusia (20.6%), fatigue (52.9%), dyspnoea (26.5%), hypoalbuminemia (32.4%), peripheral edema (17.6%) and hyperglycemia (29.4%).
  • TEAEs The most common drug-related TEAEs were hematological (thrombocytopenia, anemia, neutropenia), gastrointestinal (nausea, vomiting and diarrhea), and fatigue, consistent with on-target toxic effects of MDM2 inhibitors [Lillian L. Siu, et al, J Clin Oncol 32:5s, 2014 (suppl; abstr 2535) and Isabelle Ray-Coquard, et al, The Lancet Oncology, 13(11):1133-1140 (November 2012)].

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US15/769,054 2015-10-23 2016-10-21 Dosage regimen of mdm2 inhibitor for treating cancers Abandoned US20180296547A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/769,054 US20180296547A1 (en) 2015-10-23 2016-10-21 Dosage regimen of mdm2 inhibitor for treating cancers

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562245632P 2015-10-23 2015-10-23
PCT/JP2016/081975 WO2017069289A1 (en) 2015-10-23 2016-10-21 Dosage regimen of mdm2 inhibitor for treating cancers
US15/769,054 US20180296547A1 (en) 2015-10-23 2016-10-21 Dosage regimen of mdm2 inhibitor for treating cancers

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2016/081975 A-371-Of-International WO2017069289A1 (en) 2015-10-23 2016-10-21 Dosage regimen of mdm2 inhibitor for treating cancers

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/293,926 Continuation US11058673B2 (en) 2015-10-23 2019-03-06 Dosage regimen of MDM2 inhibitor for treating cancers

Publications (1)

Publication Number Publication Date
US20180296547A1 true US20180296547A1 (en) 2018-10-18

Family

ID=57349101

Family Applications (3)

Application Number Title Priority Date Filing Date
US15/769,054 Abandoned US20180296547A1 (en) 2015-10-23 2016-10-21 Dosage regimen of mdm2 inhibitor for treating cancers
US16/293,926 Active US11058673B2 (en) 2015-10-23 2019-03-06 Dosage regimen of MDM2 inhibitor for treating cancers
US17/323,636 Pending US20220071975A1 (en) 2015-10-23 2021-05-18 Dosage regimen of mdm2 inhibitor for treating cancers

Family Applications After (2)

Application Number Title Priority Date Filing Date
US16/293,926 Active US11058673B2 (en) 2015-10-23 2019-03-06 Dosage regimen of MDM2 inhibitor for treating cancers
US17/323,636 Pending US20220071975A1 (en) 2015-10-23 2021-05-18 Dosage regimen of mdm2 inhibitor for treating cancers

Country Status (8)

Country Link
US (3) US20180296547A1 (enrdf_load_stackoverflow)
EP (1) EP3364972A1 (enrdf_load_stackoverflow)
JP (4) JP6855472B2 (enrdf_load_stackoverflow)
KR (1) KR20180064540A (enrdf_load_stackoverflow)
CN (2) CN108135892A (enrdf_load_stackoverflow)
HK (1) HK1253098A1 (enrdf_load_stackoverflow)
TW (3) TW202332444A (enrdf_load_stackoverflow)
WO (1) WO2017069289A1 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023016977A1 (en) * 2021-08-09 2023-02-16 Boehringer Ingelheim International Gmbh Oral composition comprising a mdm2-antagonist for cancer therapy

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2982435C (en) * 2015-04-13 2020-05-26 Daiichi Sankyo Company, Limited Treatment method by combined use of mdm2 inhibitor and btk inhibitor
US20180296547A1 (en) * 2015-10-23 2018-10-18 Daiichi Sankyo Company, Limited Dosage regimen of mdm2 inhibitor for treating cancers
US10409015B1 (en) 2015-12-15 2019-09-10 Optomind Inc. Optical receiving device including focusing lens and reflector mounted to housing body and collimating lens mounted to housing cover
TWI808055B (zh) 2016-05-11 2023-07-11 美商滬亞生物國際有限公司 Hdac 抑制劑與 pd-1 抑制劑之組合治療
TWI794171B (zh) 2016-05-11 2023-03-01 美商滬亞生物國際有限公司 Ｈｄａｃ抑制劑與ｐｄ-ｌ１抑制劑之組合治療

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2007228784B2 (en) * 2006-03-22 2012-03-08 Janssen Pharmaceutica N.V. Cyclic-alkylaminederivatives as inhibitors of the interaction between MDM2 and p53
WO2008024299A2 (en) * 2006-08-21 2008-02-28 Synta Pharmaceuticals Corp. Combination with bis(thiohydrazide amides) for treating cancer
EP2203447B1 (en) * 2007-09-21 2012-02-29 Janssen Pharmaceutica, N.V. Inhibitors of the interaction between mdm2 and p53
ES2666870T3 (es) * 2011-03-10 2018-05-08 Daiichi Sankyo Company, Limited Derivado de dispiropirrolidina
US9937178B2 (en) * 2011-12-07 2018-04-10 Duke University Methods of identifying and using MDM2 inhibitors
TWI586668B (zh) * 2012-09-06 2017-06-11 第一三共股份有限公司 二螺吡咯啶衍生物之結晶
JP5958208B2 (ja) * 2012-09-10 2016-07-27 凸版印刷株式会社 包装袋
KR102272536B1 (ko) * 2013-09-04 2021-07-02 다이이찌 산쿄 가부시키가이샤 스피로옥시인돌 유도체의 제조 방법
WO2015108175A1 (en) * 2014-01-14 2015-07-23 Daiichi Sankyo Company, Limited Gene signatures associated with sensitivity to mdm2 inhibitors
CN107427501B (zh) 2015-02-20 2023-12-01 第一三共株式会社 通过联合使用治疗癌症的方法
CA2982435C (en) * 2015-04-13 2020-05-26 Daiichi Sankyo Company, Limited Treatment method by combined use of mdm2 inhibitor and btk inhibitor
US20180296547A1 (en) * 2015-10-23 2018-10-18 Daiichi Sankyo Company, Limited Dosage regimen of mdm2 inhibitor for treating cancers

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023016977A1 (en) * 2021-08-09 2023-02-16 Boehringer Ingelheim International Gmbh Oral composition comprising a mdm2-antagonist for cancer therapy

Also Published As

Publication number Publication date
JP2021098750A (ja) 2021-07-01
TW202332444A (zh) 2023-08-16
TW202515561A (zh) 2025-04-16
US20190201386A1 (en) 2019-07-04
JP2018531273A (ja) 2018-10-25
JP6855472B2 (ja) 2021-04-07
TWI806822B (zh) 2023-07-01
US20220071975A1 (en) 2022-03-10
US11058673B2 (en) 2021-07-13
JP7192011B2 (ja) 2022-12-19
JP2023025214A (ja) 2023-02-21
KR20180064540A (ko) 2018-06-14
CN108135892A (zh) 2018-06-08
CN113521069A (zh) 2021-10-22
JP2024164122A (ja) 2024-11-26
EP3364972A1 (en) 2018-08-29
TW201722427A (zh) 2017-07-01
WO2017069289A1 (en) 2017-04-27
HK1253098A1 (zh) 2019-06-06

Similar Documents

Publication Publication Date Title
US20220071975A1 (en) Dosage regimen of mdm2 inhibitor for treating cancers
US20200253979A1 (en) Therapeutic methods relating to hsp90 inhibitors
US20230272083A1 (en) Combination of an anti-pd-l1 antibody and a dna-pk inhibitor for the treatment of cancer
JP2018531273A6 (ja) がんを治療するためのｍｄｍ２阻害剤の投与計画
CN110325212B (zh) 用于治疗癌症的方法的法尼基转移酶抑制剂
JP2017521396A (ja) 癌のための併用療法
KR20230015888A (ko) 사시투주맙 고비테칸 요법에 대한 바이오마커
CN115867669A (zh) 监测kras突变的方法
US20230145764A1 (en) Blood-based tumor mutation burden predicts overall survival in nsclc
BR112021011493A2 (pt) Terapia de combinação para tratamento de câncer
US20240165112A1 (en) Therapy for the treatment of cancer
WO2025049904A1 (en) Egfr inhibitor for use in the treatment of lung cancer positive for an egfr exon 20 mutation
JP2025508399A (ja) 脳がんの処置のためのニラパリブの使用
EP4504202A1 (en) Combination therapies comprising gdc-6036 and gdc-0077 for the treatment of cancer
CN111989107A (zh) 治疗儿科患者的癌症的方法

Legal Events

Date Code Title Description
STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION