WO2018060833A1 - Schéma posologique pour l'alpelisib, un inhibiteur de la phosphatidylinositol 3-kinase spécifique de l'isoforme alpha - Google Patents

Schéma posologique pour l'alpelisib, un inhibiteur de la phosphatidylinositol 3-kinase spécifique de l'isoforme alpha Download PDF

Info

Publication number
WO2018060833A1
WO2018060833A1 PCT/IB2017/055814 IB2017055814W WO2018060833A1 WO 2018060833 A1 WO2018060833 A1 WO 2018060833A1 IB 2017055814 W IB2017055814 W IB 2017055814W WO 2018060833 A1 WO2018060833 A1 WO 2018060833A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
dose
acceptable salt
Prior art date
Application number
PCT/IB2017/055814
Other languages
English (en)
Inventor
Marie-Caroline GERMA
Cristina Karen RODRIGUEZ LORENC
Original Assignee
Novartis Ag
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 Novartis Ag filed Critical Novartis Ag
Publication of WO2018060833A1 publication Critical patent/WO2018060833A1/fr

Links

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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a method of treating or preventing a proliferative disease in a human in need thereof by orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound to said human for one week immediately thereafter and then repeating this cycle for one to several cycles; use of said compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease administered in accordance with said dosage regimen; a therapeutic regimen comprising administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof in accordance with said dosage regimen; and related pharmaceutical compositions and packages thereof.
  • Phosphatidylinositol 3-kinases comprise a family of lipid kinases that catalyze the transfer of phosphate to the D-3' position of inositol lipids to produce phosphoinositol-3- phosphate ("PIP"), phosphoinositol-3,4-diphosphate (“PIP2”) and phosphoinositol-3,4,5- triphosphate (“PIP3”) that, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling complexes often at the plasma membrane (Vanhaesebroeck et al., Annu.
  • Human cells contain three genes (PIK3CA, PIK3CB and PIK3CD) encoding the catalytic p1 10 subunits ( ⁇ , ⁇ , ⁇ isoforms) of class IA PI3K enzymes.
  • PIK3CA, PIK3CB and PIK3CD encoding the catalytic p1 10 subunits ( ⁇ , ⁇ , ⁇ isoforms) of class IA PI3K enzymes.
  • These catalytic p1 10a, p1 10 ⁇ , and p1 105 subunits are constitutively associated with a regulatory subunit that can be p85a, p55a, p50a, ⁇ 85 ⁇ or ⁇ 55 ⁇ .
  • p1 10a and p1 10 ⁇ are expressed in most tissues.
  • Class 1 B PI3K has one family member, a heterodimer composed of a catalytic p1 10 ⁇ subunit associated with one of two regulatory subunits, either the p101 or the p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005)).
  • the modular domains of the p85/55/50 subunits include Src Homology (SH2) domains that bind phosphotyrosine residues in a specific sequence context on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and localization of Class 1A PI3Ks.
  • SH2 Src Homology
  • Class 1 B is activated directly by G protein-coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 89: 105 (1997)); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001)).
  • PI3K Aberrant regulation of PI3K, which often increases survival through Akt activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels.
  • the tumor suppressor gene PTEN which dephosphorylates phosphoinositides at the 3' position of the inositol ring and in so doing antagonizes PI3K activity, is functionally deleted in a variety of tumors.
  • the genes for the p1 10a isoform, PIK3CA, and for Akt are amplified and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocation of p85a that serve to up-regulate the p85-p1 10 complex have been described in human cancers.
  • Deregulation of PI3K is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey at el., Nature Rev. Drug Disc. 4:988-1004 (2005)).
  • SJ-Pyrrolidine-1 ,2-dicarboxylic acid 2-amide 1 -( ⁇ 4-methyl-5-[2-(2,2,2-trifluoro-1 , 1- dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl ⁇ -amideJ is a specific 2-carboxamide cycloamino urea derivative compound that potently and selectively targets the alpha (a)-isoform of class IA PI3K. (See, e.g., Examples A and C of PCT Application No. WO2010/029082).
  • This compound has the following chemical structure:
  • this alpha-isoform selective PI3K inhibitor compound Alpelisib demonstrated clinical efficacy in the single-agent treatment of human patients having advanced solid malignancies carrying an alteration in the PIK3CA gene.
  • patients were orally administered this compound either (a) at a dosage ranging from 30 mg to 450 mg once per day (q.d.) on a continuous daily schedule for 28-days, or (b) at a dosage ranging from 120 mg to 200 mg twice per day (b.i.d.) on a continuous daily schedule for 28- days, as guided by Bayesian logistic regression model with overdose control.
  • the dose expansion phase was conducted to additionally treat patients having head and neck cancer with a PIK3CA alteration, patients having solid tumors with PIK3CA alteration, and patients having PIK3CA wildtype ER+/ HER2- breast cancer.
  • Clinical efficacy of this compound has been demonstrated preliminarily. As of February 15, 2013, confirmed partial responses have been observed in several patients treated at > 270 mg/day, including patients suffering from breast cancer (1 patient, confirmed), colorectal cancer (1 patient confirmed), endometrial cancer (1 patient, confirmed) and cervical cancer (1 patient confirmed).
  • AST Transaminase/ GOT
  • a potent alpha (a)-isoform selective PI3K inhibitor which can be administered to human patients in a dosage or dosage regimen that is therapeutically effective for treatment of a proliferative disease, particularly a cancer, but also that relieves, reduces, or alleviates side effects (e.g, by severity, occurrence rate, or frequency) of the drug. It is believed that this has not been achieved for any alpha-isoform selective PI3K inhibitor prior to the present invention.
  • the dosage regimen of the present invention could improve safety and tolerability of the alpha-isoform selective PI3K inhibitor compound Alpelisib and may relieve, reduce or alleviate the severity, occurrence or frequency of side effects, particularly hepatobiliary toxicity, in patients administered said drug.
  • the present invention relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I)
  • the present invention further relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for from one to several cycles.
  • the present invention further relates to the compound of formula (I) or a
  • pharmaceutically acceptable salt thereof is for use in the treatment or prevention of a proliferative disease, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for one to several cycles.
  • the present invention further relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one cycle to several cycles until the proliferative disease is treated, or until the disease progresses, or until at least one side effect is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.
  • the present invention further relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one to several cycles, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.
  • the present invention further relates to a therapeutic regimen comprising orally administering to a human suffering from a proliferative disease a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically acceptable salt thereof to said human for one week immediately thereafter, and then repeating this cycle for one to several cycles.
  • the present invention further relates to a package comprising a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients together with instructions to orally administer said pharmaceutical composition at a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then to not administer said pharmaceutical composition to said human for one week immediately thereafter, and then to repeat this cycle for one to several cycles.
  • a package comprising a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients together with instructions to orally administer said pharmaceutical composition at a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then to not administer said pharmaceutical composition to said human for one week immediately thereafter, and then to repeat this cycle for one to several cycles.
  • the present invention relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I)
  • the period of three weeks that the compound of formula (I) is administered to the human in need thereof may be referred to as the "treatment period".
  • the period of one week that the compound of formula (I) is not administered to the human in need thereof may be referred to as the "interruption period”.
  • Each "cycle" of the dosage regimen of the present invention comprises one treatment period and one interruption period.
  • the first day that the first dose of the compound of formula (I) or any pharmaceutically acceptable salt thereof is administered to the patient is considered to be the first day of the treatment period.
  • the first day that the first dose of the compound of formula (I) is not administered to the patient after such treatment period is considered to be the first day of the interruption period.
  • a phosphatidylinositol 3-kinase inhibitor or "PI3K inhibitor” is defined herein to refer to a compound which targets, decreases or inhibits activity of the phosphatidylinositol 3- kinase.
  • pharmaceutically acceptable is defined herein to refer to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of a patient without excessive toxicity, irritation allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.
  • treat comprises a treatment or therapeutic regimen relieving, reducing or alleviating at least one symptom in a patient or effecting a delay of progression of a proliferative disorder.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a proliferative disease, such as cancer.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disorder) and/or reduce the risk of developing or worsening a proliferative disease.
  • prevent means the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.
  • daily dose refers to the total dosage amount of the therapeutic agent administered to a specific patient in any single day.
  • terapéuticaally effective is an observable improvement over the baseline clinically observable signs and symptoms of the state, disease or disorder treated with the therapeutic agent.
  • terapéuticaally effective amount is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the state, disease or disorder treated with the therapeutic agent.
  • composition refers to a mixture or solution containing at least one therapeutic agent to be administered to a patient, in order to prevent or treat a particular disease or condition affecting the patient.
  • day refers to either one calendar day or one 24-hour period.
  • week refers to either seven consecutive calendar days or seven consecutive 24-hour periods.
  • three weeks refers to either twenty-one consecutive calendar days or twenty-one consecutive 24-hour periods starting on any day of the calendar week.
  • the term “combination” refers to either a fixed combination in one dosage unit form, a non-fixed combination or a kit of parts for the combined administration where the compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent may be administered simultaneously, independently at the same time or separately within time intervals that allow that the combination partners show a cooperative, e.g., synergistic, effect.
  • the term "fixed combination” means that the therapeutic agents, e.g. the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent, are both administered to a patient simultaneously in the form of a single entity or dosage unit.
  • non-fixed combination or “kit of parts” means that the therapeutic agents, e.g.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent are both administered to a patient as separate entities or dosage units either simultaneously, concurrently or sequentially within time intervals, especially where these time intervals allow that the therapeutic agents show cooperative, e.g., synergistic, effect.
  • cocktail therapy e.g. the administration of three or more therapeutic agents.
  • combined administration is defined to encompass the administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the therapeutic agents are not necessarily administered by the same route of administration or at the same time.
  • patient or “subject” is intended to include warm-blooded-animals.
  • subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the patient is human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a cancer.
  • WO2010/029082 describes specific 2-carboxamide cycloamino urea derivatives, which have been found to have highly selective inhibitory activity for the alpha-isoform of
  • PI3K phosphatidylinositol 3-kinase
  • compound of formula (I) or “Compound A” or “Alpelisib” or pharmaceutically acceptable salts thereof.
  • the compound of formula (I) is also known as the chemical compound (S)-Pyrrolidine-I , 2-dicarboxylic acid 2-amide 1 -( ⁇ 4-methyl-5-[2-(2,2,2-trifluoro-1 ,1 - dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl ⁇ -amide), and it is also known as Alpelisib.
  • the compound of formula (I), its pharmaceutically acceptable salts and suitable formulations are described in PCT Application No. WO2010/029082, which is hereby incorporated by reference in its entirety, and methods of its preparation have been described, for example, in Example 15 therein.
  • salts can be present alone or in mixture with free base form of the compound of formula (I) and are preferably pharmaceutically acceptable salts.
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from the compound of formula (I) with a basic nitrogen atom.
  • Suitable in-organic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, e.g., carboxylic acids or sulfonic acids, such as fumaric acid or methansulfonic acid.
  • carboxylic acids or sulfonic acids such as fumaric acid or methansulfonic acid.
  • any reference to the free base form of the compound hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate.
  • the salts of compound of the formula (I) are preferably pharmaceutically acceptable salts; suitable counter-ions forming pharmaceutically acceptable salts are known in the field.
  • the compound of formula (I) is used in the free base form.
  • the compound of formula (I) or its pharmaceutically acceptable salts may be orally administered at a daily dose of about 100 mg to about 450 mg per day to a human in need thereof, preferably an adult human in need thereof.
  • the compound of formula (I) may be administered to a human at a daily dose of about 200 mg to about 400 mg per day, or about 240 mg to about 400 mg per day, or about 300 mg to about 400 mg per day, or about 350 mg to about 400 mg per day.
  • the compound of formula (I) is administered to a human at a daily dose of about 350 mg to about 400 mg per day.
  • the effective dosage of the compound of formula (I) or pharmaceutically acceptable salt thereof may vary depending on the pharmaceutical composition employed, the mode of administration, the condition being treated, and the severity of the condition being treated.
  • the specific dosage selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; and the renal and hepatic function of the patient.
  • a physician or clinician of ordinary skill can readily determine and prescribe the effective daily dosage amount of the therapeutic agent required to alleviate, counter or arrest the proliferative disease when using the dosage regimen of the present invention.
  • the optimum dosage of the compound of formula (I) or pharmaceutically acceptable salt thereof that yield efficacy without toxicity are based on the kinetics of the compound.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to the human in a single dose (once per day, q.d.) or divided doses (more than once per day, e.g., twice per day, b.i.d.). In one embodiment of the present invention, the daily dose is administered in a once per day (q.d.). In a further embodiment of the present invention, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice per day (b.i.d.)
  • the daily dose may be administered to the human in a single dosage unit or amounts of multiple dosage units to make up the daily dose.
  • the present invention relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I)
  • the present invention further relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for from one to several cycles.
  • the present invention further relates to the compound of formula (I) or a
  • pharmaceutically acceptable salt thereof is for use in the treatment or prevention of a proliferative disease, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for one to several cycles.
  • the present invention further relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg, or about 200 mg to about 400 mg, of the compound of formula (I) or a pharmaceutically acceptable salt thereof once per day (q.d.) each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one cycle to several cycles.
  • the present invention relates to the above method of treatment except the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice per day (b.i.d.).
  • the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof thereof once per day (q.d.) each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for from one to several cycles.
  • the present invention relates to the above use except the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice per day (b.i.d.).
  • the dosage regimen of the present invention comprises a cycle comprising (a) a treatment period wherein said compound of formula (I) or a pharmaceutically salt thereof is administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day for a period of three weeks, and (b) an interruption period wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is not administered to said human for one week immediately thereafter (together one treatment period and one interruption period are "a cycle"), wherein this cycle is repeated for one to several cycles.
  • a cycle comprising (a) a treatment period wherein said compound of formula (I) or a pharmaceutically salt thereof is administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day for a period of three weeks, and (b) an interruption period wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is not administered to said human for one week immediately thereafter (together one treatment period and one interruption period are "a cycle"), wherein this cycle is repeated for one to several
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a human in need thereof for a period of three consecutive weeks in each cycle.
  • the defined cycle of the dosage regimen of the present invention is repeated for 1 cycle to several cycles, for example, for an additional 1 cycle to 10 or more cycles.
  • the cycle is repeated for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more cycles.
  • the cycle is repeated for 1 to 10 cycles.
  • the cycles may be repeated for one cycle to several cycles until the proliferative disease is treated, or until the disease progresses, or until at least one side effect is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human patient.
  • the cycle is repeated for one cycle or several cycles until at least one side effect, particularly hepatic dysfunction or hepatobiliary toxicity, is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human patient.
  • the present invention relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a
  • the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof thereof each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for 1 cycle to 10 cycles.
  • the dosage regimen of the present invention is particularly suitable for the treatment of a human suffering from a proliferative disease, especially a cancer.
  • Proliferative diseases that may be treated or prevented by the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof in accordance with the dosage regimen of the present invention are particularly those mediated by the alpha-isoform of the PI3K. It is understood that one embodiment of the present invention includes the treatment of the proliferative disease, and that a further embodiment of the present invention includes the prevention of the proliferative disease.
  • the proliferative disease is a cancer.
  • cancer refers to tumors and/or cancerous cell growth preferably mediated by the alpha-isoform of the
  • the compounds are useful in the treatment of cancers including, for example, sarcoma, lung cancer, bronchial cancer, prostate cancer, breast cancer (including hormone-receptor-positive, HER2-negative breast cancer, sporadic breast cancers and sufferers of Cowden disease), a mammary carcinoma, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, adrenal gland cancer, gastric cancer, esophageal cancer, glioma, glioblastoma, melanoma, kidney cancer, renal pelvic cancer, urinary bladder cancer, cancer of the uterine corpus, cancer of the uterine cervix, vaginal cancer, ovarian cancer, multiple myeloma, a leukemia (including acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leuk
  • a leukemia including acute myelogenous leukemia, chronic
  • the proliferative disease is a solid tumor.
  • the proliferative disease is a cancer selected from lung cancer, breast cancer (including hormone-receptor-positive, HER2-negative breast cancer, sporadic breast cancers and sufferers of Cowden disease), head and neck cancer, prostate cancer, colon cancer, rectal cancer, and squamous cell carcinoma.
  • the proliferative disease is a breast cancer, particularly hormone- receptor-positive, HER2-negative breast cancer.
  • Proliferative diseases may include those proliferative diseases (particularly cancers) mediated by the alpha-subunit of PI3K, e.g., characterized by or dependent on overexpression or amplification of PI3K alpha, somatic mutation of PIK3CA or germline mutations or somatic mutation of PTEN or mutations and translocation of p85a that serve to up-regulate the p85-p1 10 complex.
  • the cancer is a tumor and/or cancerous growth mediated by the alpha isoform of PI3K.
  • the present invention relates to the treatment of a cancer by the administration of the compound of formula (I) or a pharmaceutically acceptable in accordance with the dosage regimen of the present invention.
  • Examples of such side effects which may relieved, reduced, or alleviated by the dosage regimen of the present invention include, but are not limited to, neutropenia, elevated bilirubin, cardiac toxicity, unstable angina, myocardial infarction, persistent hypertension, peripheral sensory or motor neuropathy/ pain, hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), reduced red and/or white blood cell count, hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, pancreatitis, dysgeusia, and dyspepsia.
  • neutropenia e.g., elevated bilirubin
  • cardiac toxicity
  • the side effect relieved, reduced, or alleviated by the dosage regimen of the present invention is a condition selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia.
  • hepatic dysfunction or hepatobiliary toxicity e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.
  • hyperglycemia e.g., nausea, decreased appetite, diarrhea, rash (e.g, maculo
  • the side effect relieved, reduced, or alleviated by the dosage regimen of the present invention is hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.).
  • hepatic dysfunction or hepatobiliary toxicity e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.
  • the present invention relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a
  • the cycles are repeated for one to several cycles until the side effect of hepatic dysfunction or hepatobiliary toxicity is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.
  • the present invention relates to a method of treating or preventing a proliferative disease in accordance with the dosage regimen herein, wherein the cycle is repeated for one to several cycles until at least one side effect is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.
  • the side effect relieved, reduced, or alleviated in severity, occurrence rate, or frequency is hepatic dysfunction or hepatobiliary toxicity.
  • the present invention relates to a method of treating or preventing a proliferative disease in accordance with the dosage regimen herein, wherein the cycle is repeated for one to several cycles until the proliferative disease is treated. In a further embodiment, the present invention relates to a method of treating or preventing a proliferative disease in accordance with the dosage regimen herein, wherein the cycle is repeated for one to several cycles until the disease progresses.
  • the present invention relates to a method of treating or preventing a proliferative disease comprising: first, orally administering to a human in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof in a daily dose of about 100 mg to about 450 mg each day on a continuous schedule; second, determining said human has a side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia after administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof to said
  • the present invention relates to a method of reducing at least one side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia from prior treatment with the compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising orally administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a daily dose of about 100 mg to about 450 mg each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week
  • the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered in accordance with the dosage regimen herein and the cycle is repeated for one cycle to several cycles until the proliferative disease is treated, or until the disease progresses, or until at least one side effect is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.
  • the cycles are repeated until the side effect of hepatic dysfunction or hepatobiliary toxicity is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.
  • the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered in accordance with the dosage regimen herein and the cycle is repeated for one cycle to several cycles until the proliferative disease is treated.
  • the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered in accordance with the dosage regimen herein and the cycle is repeated for one cycle to several cycles until the disease progresses.
  • the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein: first, the medicament comprising compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day on a continuous schedule; second, said human is determined to have a side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and
  • the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing at least one side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine
  • the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention of a proliferative disease, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for one to several cycles until the proliferative disease is treated, or until the disease progresses, or until at least one side effect is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.
  • the cycles are repeated until the side effect of hepatic dysfunction or hepatobiliary toxicity is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.
  • the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a proliferative disease, wherein said medicament is orally administered in accordance with the dosage regimen herein and the cycle is repeated for one cycle to several cycles until the proliferative disease is treated.
  • the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a proliferative disease, wherein said medicament is orally administered in accordance with the dosage regimen herein and the cycle is repeated for one cycle to several cycles until the disease progresses.
  • the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a proliferative disease, wherein: first, said compound is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day on a continuous schedule; second, said human is determined to have a side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia after administration of said medicament to said human; and third, said compound is orally
  • the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the reduction of at least one side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia from prior treatment with the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the medicament comprising compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or
  • pharmacological activity of the compound of formula (I) or its pharmaceutically acceptable salt may, for example, be demonstrated in a clinical study, an animal study or in a test procedure as essentially described herein.
  • Suitable clinical studies are in particular, for example, open-label, dose escalation and/or dose expansion studies in patients with a proliferative disease, including for example a cancer, e.g., breast cancer, wherein said patients are orally administered the compound of formula (I) in accordance with the dosage regimen of the present invention.
  • patients are assigned to different groups wherein at least one group is administered the compound of formula (I) on a continuous daily schedule and at least one group is administered the compound of formula (I) in accordance with the dosage regimen of the present invention.
  • Such studies prove in particular the efficacy of the therapeutic agent and its impact on existing or potential side effects.
  • the beneficial effects on a proliferative disease may be determined directly through the results of these studies which are known as such to a person skilled in the art. Such studies may be, in particular, suitable to compare the efficacy or side effects of a continuous daily schedule using the therapeutic agents and the dosing regimen of the present invention.
  • Each patient may receive doses of the compound of formula (I) or its pharmaceutically acceptable salt either once per day or more than once (e.g., twice) per day.
  • the efficacy of the treatment may be determined in such studies, e.g., after 8, 16, 24, 32, 40 and/or 48 weeks by evaluation of symptom scores and/or tumor size measurements every 6 or 12 weeks.
  • compositions or medicament that contain a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients suitable for oral administration.
  • the pharmaceutical composition may comprise an amount of about 100 mg to about 450 mg of a compound of formula (I) or pharmaceutically acceptable salt thereof to be administered in single dosage unit or a single dosage unit subdivided into multiple dosage units.
  • compositions or medicaments used according to the dosage regimen of present invention can be prepared in a manner known per se to be suitable for oral administration to humans.
  • Pharmaceutical compositions or medicaments for oral administration may include, for example, those in dosage unit forms, such as sugar-coated tablets, tablets, capsules, sachets and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilizing processes. It will be appreciated that the amount of the active ingredient contained in an individual dose or dosage unit need not in itself constitute a therapeutically effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.
  • the pharmaceutical composition or medicament may contain, for example, from about 10 % to about 100 %, preferably from about 20 % to about 60 %, of the active ingredient.
  • any of the usual pharmaceutically acceptable excipients may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents; or excipients such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical excipients are obviously employed.
  • disintegrants examples include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL from International Specialty Products (Wayne, NJ); cross-linked sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC- DI-SOL from FMC; and cross-linked calcium carboxymethylcellulose; soy polysaccharides; and guar gum.
  • the disintegrant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the disintegrant is present in an amount from about 0.1 % to about 5% by weight of composition.
  • binders examples include, but are not limited to, starches; celluloses and derivatives thereof, for example, microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia, PA), hydroxypropyl cellulose hydroxylethyl cellulose and hydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp. (Midland, Ml); sucrose; dextrose; corn syrup; polysaccharides; and gelatin.
  • the binder may be present in an amount from about 0% to about 50%, e.g., 2-20% by weight of the composition.
  • Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
  • the lubricant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the lubricant may be present in an amount from about 0.1 % to about 1 .5% by weight of composition.
  • the glidant may be present in an amount from about 0.1 % to about 10% by weight.
  • Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.
  • the filler and/or diluent e.g., may be present in an amount from about 0% to about 80% by weight of the composition.
  • the present invention relates to a pharmaceutical composition or medicament comprising an amount of about 100 mg to about 450 mg of a compound of formula (I) or pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients for use in the treatment or prevention of a proliferative disease in a human in need thereof, wherein the pharmaceutical composition is orally administered to a human each day for a period of three weeks and then not administered to said human for one week immediately thereafter and then this cycle is repeated for one to several cycles.
  • the present invention includes a method of treating or preventing a proliferative disorder in accordance with any other embodiment disclosed above for the present invention.
  • the present invention includes any use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease in accordance with the methods of treatment or any other embodiment disclosed above for the present invention.
  • the present invention includes the compound of formula (I) or a
  • the present invention further relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one to several cycles, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.
  • Suitable additional therapeutic agents for use in accordance with the present invention include, but are not limited to, kinase inhibitors, anti-estrogens, anti androgens, other inhibitors, cancer chemotherapeutic drugs, alkylating agents, chelating agents , biological response modifiers, cancer vaccines, agents for antisense therapy. Examples are set forth below: A. Kinase Inhibitors including inhibitors of Epidermal Growth Factor Receptor (EGFR) kinases such as gefitinib (US 5457105, US 5616582, and US 5770599), ZD-6474 (WO
  • EGFR Epidermal Growth Factor Receptor
  • VEGFR Vascular Endothelial Growth Factor Receptor
  • SU-1 1248 WO 01/60814
  • SU 5416 US 5,883, 1 13 and WO 99/61422
  • SU 6668 US 5,883,1 13 and WO 99/61422
  • CHIR-258 US 6,605,617 and US 6,774,237
  • vatalanib or PTK-787 US 6,258,812
  • VEGF-Trap WO 02/57423
  • B43-Genistein WO-096061 16
  • fenretinide retinoic acid p- hydroxyphenylamine
  • IM-862 WO 02/62826
  • bevacizumab or Avastin® WO 94/10202
  • KRN-951 3-[5-(methylsulfonyl)
  • Estrogen-targeting agents include Selective Estrogen Receptor Modulators (SERMs) including tamoxifen, toremifene, raloxifene; aromatase inhibitors including Arimidex® or anastrozole; Estrogen Receptor Downregulators (ERDs) including Faslodex® or fulvestrant.
  • SERMs Selective Estrogen Receptor Modulators
  • ESDs Estrogen Receptor Downregulators
  • Anti-Androgens include flutamide, bicalutamide, finasteride, aminoglutethamide, ketoconazole, and corticosteroids.
  • Inhibitors including protein farnesyl transferase inhibitors including tipifarnib or R-1 15777 (US 2003134846 and WO 97/21701 ), BMS-214662, AZD-3409, and FTI-277;
  • topoisomerase inhibitors including merbarone and diflomotecan (BN-80915); mitotic kinesin spindle protein (KSP) inhibitors including SB-743921 and MKI-833; proteasome modulators such as bortezomib or Velcade® (US 5,780,454), XL-784; cyclooxygenase 2 (COX-2) inhibitors including non-steroidal antiinflammatory drugs I (NSAIDs); letrozole; exemestane; and eribulin.
  • KSP mitotic kinesin spindle protein
  • proteasome modulators such as bortezomib or Velcade® (US 5,780,454), XL-784
  • COX-2 cyclooxygenase 2
  • NSAIDs non-steroidal antiinflammatory drugs I
  • letrozole exemestane
  • eribulin eribulin.
  • E. Cancer Chemotherapeutic Drugs including anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection
  • Alkylating Agents including VNP-40101 M or cloretizine, oxaliplatin (US 4,169,846, WO 03/24978 and WO 03/04505), glufosfamide, mafosfamide, etopophos (US 5,041 ,424), prednimustine; treosulfan; busulfan; irofluven (acylfulvene); penclomedine; pyrazoloacridine (PD-1 15934); 06-benzylguanine; decitabine (5-aza-2-deoxycytidine); brostallicin; mitomycin C (MitoExtra); TLK-286 (Telcyta®); temozolomide; trabectedin (US 5,478,932); AP-5280 (Platinate formulation of Cisplatin); porfiromycin; and clearazide (meclorethamine).
  • oxaliplatin US 4,169,846, WO 03/24978 and WO
  • Chelating Agents including tetrathiomolybdate (WO 01/60814); RP-697; Chimeric T84.66 (cT84.66); gadofosveset (Vasovist®); deferoxamine; and bleomycin optionally in combination with electorporation (EPT).
  • H. Biological Response Modifiers such as immune modulators, including staurosprine and macrocyclic analogs thereof, including UCN-01 , CEP-701 and midostaurin (see WO 02/30941 , WO 97/07081 , WO 89/07105, US 5,621 , 100, WO 93/07153, WO 01/04125, WO 02/30941 , WO 93/08809, WO 94/06799, WO 00/27422, WO 96/13506 and WO 88/07045); squalamine (WO 01/79255); DA-9601 (WO 98/04541 and US 6,025,387); alemtuzumab;
  • interferons e.g. IFN-a, IFN-b etc.
  • interleukins specifically IL-2 or aldesleukin as well as IL-1 , IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-1 1 , IL-12, and active biological variants thereof having amino acid sequences greater than 70% of the native human sequence
  • altretamine Hexalen®
  • SU 101 or leflunomide WO 04/06834 and US 6,331 ,555
  • imidazoquinolines such as resiquimod and imiquimod (US 4,689,338, 5,389,640, 5,268,376, 4,929,624, 5,266,575, 5,352,784, 5,494,916, 5,482,936, 5,346,905, 5,395,937, 5,238,944, and 5,525,612)
  • SMIPs including benzazoles, anthraquinones, thiosemicarbazone
  • Anticancer vaccines including Avicine® (Tetrahedron Lett. 26:2269- 70 (1974)); oregovomab (OvaRex®); Theratope® (STn-KLH); Melanoma Vaccines; GI-4000 series (GI-4014, GI-4015, and GI-4016), which are directed to five mutations in the Ras protein; GlioVax-1 ; MelaVax; Advexin® or INGN-201 (WO 95/12660); Sig/E7/LAMP-1 , encoding HPV-16 E7; MAGE-3 Vaccine or M3TK (WO 94/05304); HER-2VAX; ACTIVE, which stimulates T-cells specific for tumors; GM-CSF cancer vaccine; and Listeria monocytogenes-based vaccines.
  • Avicine® Tetrahedron Lett. 26:2269- 70 (1974)
  • oregovomab Theratope®
  • Theratope® STn-
  • Anticancer agents including antisense compositions, such as AEG-35156 (GEM-640); AP-12009 and AP-1 1014 (TGF-beta2-specific antisense
  • oligonucleotides oligonucleotides
  • AVI-4126 AVI-4557
  • AVI-4472 oblimersen (Genasense®)
  • JFS2 oligonucleotides
  • aprinocarsen (WO 97/29780); GTI-2040 (R2 ribonucleotide reductase mRNA antisense oligo) (WO 98/05769); GTI-2501 (WO 98/05769); liposome-encapsulated c-Raf antisense
  • oligodeoxynucleotides (LErafAON) (WO 98/43095); and Sirna-027 (RNAi-based therapeutic targeting VEGFR-1 mRNA).
  • the additional therapeutic agent is the CDK 4/6 inhibitor 7- Cyclopentyl-2-(5-piperazin-1 -yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and referred to herein as the compound having the structure of formula (II):
  • Compound of formula (II) in general, is administered in a dose in the range from 10 mg to 2000 mg per day in human.
  • Compound of formula (II) is administered 600mg once daily on a continuous or intermittent schedule (e.g., three week treatment followed by one week interruption on a repeated 28 day cycle).
  • Compound of formula (II) is administered 300mg once daily on a continuous or intermittent schedule (e.g., three week treatment followed by one week interruption on a repeated 28 day cycle).
  • Compound of formula (II) is administered in 900mg once daily on a continuous or intermittent schedule (e.g., three week treatment followed by one week interruption on a repeated 28 day cycle). .
  • the additional therapeutic agent is selected from gefinitib, erlotinib, T-DM1 , pertuzumab, trastuzumab, tamoxifen, fulvestrant, capecitabine, cisplatin, carboplatin, cetuximab, paclitaxel, temozolamide, letrozole, exemestane, eribulin, and Compound of formula (II) and any pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent is selected from T-DM1 , fulvestrant, cetuximab, letrozole, and Compound of formula (II) and any pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent is fulvestrant. In one embodiment, the additional therapeutic agent is T-DM1 . In one embodiment, the additional therapeutic agent is letrozole. In one embodiment, the additional therapeutic agent is the Compound of formula (II) or any pharmaceutically acceptable salt thereof. In one embodiment, the additional therapeutic agent is letrozole and Compound of formula (II) or any pharmaceutically acceptable salt thereof.
  • the compound of formula (I) and the additional therapeutic agent may be administered together in a single pharmaceutical composition, separately in two or more separate unit dosage forms, or sequentially.
  • the pharmaceutical composition or dosage unit form comprising the additional therapeutic agent may be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, topical, and parenteral administration to humans.
  • a therapeutically effective amount of each of the therapeutic agents may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination, preferably in synergistically effective amounts.
  • the individual therapeutic agents of the combination may be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • “Synergy” or “synergistic” refers to the action of two therapeutic agents such as, for example, (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (b) an additional therapeutic agent, producing an effect, for example, slowing the symptomatic progression of a proliferative disease or disorder, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each therapeutic agent administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin.
  • proliferative diseases that may be treated with a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent include, but not limited to, those set forth above.
  • a combination of the present invention results in the beneficial effects described herein before.
  • the person skilled in the art is fully enabled to select a relevant test model to prove such beneficial effects.
  • the pharmacological activity of a combination of the present invention may, for example, be demonstrated in a clinical study or in a test procedure as essentially described herein.
  • the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease in accordance with the dosage regimen of the present invention, wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.
  • the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a proliferative disease in accordance with the dosage regimen of the present invention, wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.
  • the present invention further relates to a therapeutic regimen comprising orally administering to a human suffering from a proliferative disease a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically acceptable salt thereof to said human for one week immediately thereafter, and then repeating this cycle for one to several cycles.
  • the present invention further relates to a package comprising a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients together with instructions to orally administer said pharmaceutical composition at a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then to not administer said pharmaceutical composition to said human for one week immediately thereafter, and then to repeat this cycle for one to several cycles.
  • Utility of the dosage regimen of the compounds of formula (I) of the present invention may be demonstrated in vitro, in animal test methods as well as in clinic studies. For example in the utility of the compounds of formula (I) in accordance with the present invention may be demonstrated in accordance with the methods hereinafter described:
  • a phase Ib/ll , multi-center, open-label, five-arm, dose finding clinical study is conducted to assess the MTD and/or RP2D and the safety and tolerability of the following combination treatments in adult patients with advanced hormone-receptor-positive (HR+), HER2-negative breast cancer: 1. Ribociclib and standard dose letrozole (ARM 1 ),
  • the study is conducted in adult post-menopausal women with locally advanced or metastatic Hormone Receptor-positive /HER2-negative breast cancer.
  • patients may have any number of prior lines of endocrine therapy with up to one prior cytotoxic regimen in the metastatic or locally advanced setting.
  • ARMS 1 , 2 and 3 patients must not have received prior systemic treatment with the exception of more than one month of systemic therapy with letrozole in the advanced
  • PR+ progesterone receptor positive breast cancer by local laboratory. Postmenopausal women. Postmenopausal status is defined either by:
  • follicle- stimulating hormone FSH
  • estradiol levels are in postmenopausal range (according to the local laboratory)
  • estradiol are needed to ensure postmenopausal status (NCCN Guidelines Version 2.2014).
  • Ovarian radiation or treatment with a luteinizing hormone- releasing hormone (LH-RHa) (goserelin acetate or leuprolide acetate) is not permitted for induction for ovarian suppression in this trial.
  • LH-RHa luteinizing hormone- releasing hormone
  • WWO World Health Organization
  • Dose escalation Any number of prior lines of endocrine therapy is allowed with the exception of cytotoxic therapy which is limited to one prior line administered in the advanced (metastatic or locally advanced) setting.
  • ARMS 1 , 2 and 3 At least one measurable lesion (as per RECIST 1 .1 criteria) Isolated bone lesions (lytic or mixed lesions) are acceptable in the absence of other measurable or non-measurable disease.
  • ARMS 4 and 5 At least one measurable (as per RECIST 1.1 criteria) visceral (lung or liver) lesion.
  • a representative tumor specimen (archival or newly obtained) is requested for molecular testing, for all patients.
  • patient For dose expansion ARMS 2 to 5 and dose escalation ARMS 4 and 5, patient must have adequate formalin-fixed paraffin embedded (FFPE) tumor tissue for the analysis of PIK3CA mutation status by PCR conducted at a Novartis-designated central laboratory.
  • FFPE formalin-fixed paraffin embedded
  • One tumor block (preferred) or a minimum of 5 slides need to be shipped to the central laboratory for the determination of PIK3CA status. Time since the last prior therapy to treat underlying malignancy:
  • Cytotoxic chemotherapy greater than the duration of the most recent cycle of the previous regimen (with a minimum of two weeks for all, except six weeks for nitrosoureas and mitomycin-C)
  • HER2-overexpression in the patient's tumor tissue by local laboratory testing IHC 3+ or in situ hybridization positive.
  • AST/SGOT or ALT/SGPT > 2.5 x Upper Limit of Normal (ULN) or > 5.0 x ULN if liver metastases are present
  • Dose escalation Prior treatment with CDK4/6, AKT, mTOR or PI3K inhibitor and failure to benefit. Enrollment of patients previously treated with such agents requires approval by Novartis. Enrollment of patients with prior treatment with Ribociclib (Dose escalation ARM 1 and ARM 3) and Alpelisib (Dose escalation ARM 2 and ARM 3) is not allowed. Dose expansion only: Any prior treatment with CDK4/6, AKT, mTOR or PI3K inhibitor. Patients currently receiving hormone replacement therapy, unless discontinued 5 half- lives prior to starting study treatment Severe and /or uncontrolled medical conditions such as:
  • Impairment of gastrointestinal function or who have gastrointestinal disease that may significantly alter the absorption of study drugs e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
  • LVEF Left ventricular ejection fraction
  • MUGA multiple gated acquisition scan
  • ECHO echocardiogram
  • TdP Torsades de Pointe
  • Sinus tachycardia (heart rate >90 bpm) Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to the start of the treatment:
  • the Dose Expansion phase in ARMS 1 and 2 commence enrollment once the RP2D for the corresponding double combination is identified in the dose escalation cohorts.
  • Dose expansion in ARMS 3 to 5 commence once the RP2D for the triple combinations is identified.
  • Patients in all Arms are screened to assess mutational status of PIK3CA.
  • Patients whose disease has progressed while enrolled in either of the doublet combinations (ARM 1 or 2) may be eligible to receive treatment with the triplet combination if and when the RP2D has been identified, in the optional crossover group.
  • Ribociclib capsule for oral use 50 mg, 200 mg Daily (21 days or
  • Alpelisib tablet for oral use 50 mg, 200 mg Daily (21 days or
  • Letrozole is administered orally at a dose of 2.5 mg oral QD.
  • Ribociclib is administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle) in all applicable Arms, except for ARM 4 in which Ribociclib is administered once daily on a continuous dosing schedule (28 day-cycle).
  • Alpelisib is administered orally, once daily on a continuous dosing schedule (28-day cycle) in all applicable arms with the exception of ARM 5 in which Alpelisib is administered once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle). All drugs are administered in the morning with the exception of ARM 2, Cohort 2 in which Alpelisib is administered in the evening and letrozole isadministered in the morning.
  • Ribociclib and letrozole together with a large glass of water (about 250 mL) daily in the morning preferably within 1 hour of meal.
  • the preferred time of dosing of ribocicilib and Alpelisib is in the morning one hour after breakfast. Ribociclib and letrozole can be taken without regard to meals. Alpelisib must be taken within 1 hour of a meal.
  • Fasting glucose testing will be assessed in all patients for safety purposes (Cycle 1 Days 1 , 8, 15 and 22, Cycle 2 Days 1 and 15 and Day 1 on Cycle 3 and subsequent cycles, and EOT visit). Patients should be instructed to fast overnight at least 8 hours before the collection of the blood sample for fasting glucose testing. Note: If a non-fasting glucose sample is abnormally elevated, then the patient should also have a fasting glucose test within 24 hours for confirmation. o Patients may then have a light breakfast, followed 1 hour later by the study treatment administration. o Patient should continue to fast for 1 hour after the study treatment
  • pre-dose PK sample should be collected just prior to study treatment administration.
  • Alpelisib should be taken within 1 hour after a meal (e.g. dinner or late snack).
  • PK sampling will be performed in on all patients treated. On Day 1 and 21 of Cycle 1 , pre-dose PK sample will be collected in the evening before
  • Fasting glucose testing will also be assessed in all patients for safety purposes (Cycle 1 Days 1 , 2, 8, 15 and 22, Cycle 2 Days 1 and 15 and Day 1 on Cycle 3 and subsequent cycles, and EOT visit). Patients should be instructed to fast overnight at least 8 hours before the collection of the blood sample for fasting glucose testing. Note: If a non-fasting glucose sample is abnormally elevated, then the patient should also have a fasting glucose test within 24 hours for confirmation.
  • patients may continue study treatment until disease progression, unacceptable toxicity occurs that precludes any further treatment and/or treatment is discontinued at the discretion of the investigator or the patient, as well as in the event of patient's death.
  • the dose escalation process is implemented stepwise. Initially, cohorts of patients are enrolled and treated with the dual combinations. ARM 1 (Ribociclib and letrozole) is completing enrollment of the first dose cohort before enrollment into a cohort in ARM 2 (Alpelisib and letrozole). After the MTD/RP2D of both the dual combinations has been determined, cohorts of patients are enrolled into ARM 3 to 5 (Ribociclib, Alpelisib and letrozole).
  • each cohort consists of 3 to 6 newly enrolled patients who are treated at the specified combination dose levels.
  • the first cohort is treated with the starting combination doses of Ribociclib 600 mg QD and letrozole 2.5 mg QD.
  • the second cohort is treated with the starting combination doses of Alpelisib 300 mg QD and letrozole 2.5 mg QD.
  • the starting dose for the study drug combination is 600 mg QD for Ribociclib and 2.5 mg daily for letrozole.
  • Table 1 -2 sets forth the starting dose and the dose levels that may be evaluated:
  • the starting dose for the study drug combination is 300 mg QD for Alpelisib and 2.5 mg daily for letrozole.
  • Table 1 -3 sets forth the starting dose and the dose levels that may be evaluated:
  • Dose level -1 is the dose level for patients requiring dose reduction. A dose lower than the dose indicated may be explored. Dose escalation is continued until MTD/RP2D is reached. In the case that any Alpelisib dose in combination with letrozole 2.5 mg QD is considered to be too toxic by the BLRM after any cohort, no MTD/RP2D can be defined for this treatment. Alpelisib and letrozole will be administered as a flat-fixed dose, and not by body weight or body surface area.
  • the starting doses of Ribociclib, Alpelisib, and letrozole of the triple combination are 400 mg QD for Ribociclib, 100 mg QD for Alpelisib, and 2.5 mg QD for letrozole.
  • Table 1-4 sets forth the starting dose and the dose levels that may be evaluated:
  • Table 1 -6 sets forth the starting dose and the dose levels that may be evaluated:
  • *lt is possible for additional and/or intermediate dose levels to be added during the course of the study. Cohorts may be added at any dose level below the MTD/RP2D in order to better understand safety, PK or PD.
  • the MTD is defined as the highest combination drug dosage not causing medically unacceptable, dose-limiting toxicity (DLT) in 35% or more of the treated patients in the first cycle of treatment.
  • AEs and laboratory abnormalities considered to be DLTs are defined in the following Table 1 -7:
  • Metabolism Grade 2 hyperglycemia (Fasting glucose 200 - 249 mg/dL)
  • CTCAE grade 3 amylase and/or lipase not reversible to ⁇ CTCAE grade 2 for > 7 consecutive days
  • ECG QT Interval QTcF interval ⁇ 501 ms on at least two separate ECGs
  • the MTD is a tested dose with maximum probability of targeted toxicity (DLT rate in the interval [16%-35%)).
  • Dose escalation decisions for a given combination occur when the cohort of patients in the corresponding arm has met these criteria.
  • the recommended doses for the next cohort of subjects are guided by the Bayesian logistic regression model (BLRM) with EWOC principle. If the first two patients in a previously untested dose level experience a DLT, enrollment to that cohort stops, and the next cohort is opened at the next lower dose level or an intermediate dose that satisfies the EWOC criteria. However, if the first two patients in a new cohort at a previously tested dose level experience a DLT (e.g., a total of eight patients are treated on this dose level with two DLTs observed), further enrollment to that cohort stops. By incorporating information gained at the preceding dose cohorts, additional patients may be enrolled into the current dose cohort only if the combination still meets the EWOC criteria and as agreed by Investigators and Study Sponsor.
  • BLRM Bayesian logistic regression model
  • a new cohort of patients may be recruited to a lower dose combination as agreed by Investigators and Study Sponsor and if the BLRM predicts that the risk for this lower dose combination to exceed the MTD remains below 25% (EWOC). Re-escalation may then occur if data in subsequent cohorts supports this (EWOC criteria are satisfied) and Investigators and Study Sponsor agree.
  • Dose escalation for each arm is continued until identification of the MTD or a suitable lower dose for dose expansion and/or Phase II (RP2D) for each treatment, respectively. This will occur when the following conditions are met:
  • This dose satisfies one of the following conditions:
  • the posterior probability of targeted toxicity (in the interval [16%, 35%) ) at this dose exceeds 50% and is highest among potential doses, or
  • the RP2D for each Arm is selected based on available safety, tolerability, PK, PD and efficacy data, as well as the recommendations from the BLRM using EWOC and the
  • additional patients may be enrolled in a dose expansion at the RP2D for each double combination with approximately 30 patients for the Ribociclib + letrozole combination and approximately 45 patients in Cohort 1 and approximately 20 patients in Cohort 2 for the Alpelisib + letrozole combination each.
  • enrollment commences in ARM 3 to 5 beginning with the dose escalation of the triple combination at the specified starting doses.
  • enrollment of approximately 45 patients commences for ARM 3 dose expansion.
  • either ARM 4 or ARM 5 enrolls approximately 25 patients in the dose expansion.
  • Intra-patient dose escalation prior to declaration of MTD/RP2D is not permitted at any time during this study. However once the MTD/RP2D is declared, for a given combination regimen (i.e. either doublet or the triplet regimen), individual patients may be considered for escalation to treatment at the RP2D of the combination.
  • DLTs Dose Limiting Toxicities
  • DLT DLT-related tyrosine kinase
  • a DLT is defined as an adverse event or abnormal laboratory value assessed as having a reasonable possibility related to the study medication, unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment (cycle 1 ) with Ribociclib, Alpelisib and letrozole and meets any of the criteria included in Table 1-7.
  • National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 are used for all grading.
  • Treatment may be resumed at a lower dose level.
  • the dose during Cycle 1 should not be reduced unless the patient has experienced a DLT.
  • All patients in all arms are routinely asked about and observed for the occurrence of adverse events including new or changed pulmonary symptoms (consistent with lung abnormalities).
  • Patients receiving Alpelisib who are suspected to have developed pneumonitis should stop Alpelisib and Ribociclib immediately and undergo appropriate imaging (high resolution CT scan requiring slice thickness of 5mm or less) and bronchoalveolar lavage for biopsy should be considered. Treatment with letrozole may continue.
  • Investigators should follow institutional practice for management of pneumonitis
  • ARMS 4 and 5 upon the determination of the recommended dose for dose expansion, up to 2 dose reductions are permitted per patient per study drug (Ribociclib or Alpelisib). If a patient requires more than 2 dose reductions for a given study drug (Ribociclib or Alpelisib), then this study drug must be discontinued.
  • ARMS 4 and 5 upon the determination of the recommended dose for dose expansion, up to two dose reductions are permitted per patient per study drug. If a patient requires more than two dose reductions for a given study drug (Ribociclib or Alpelisib), then this study drug must be discontinued.
  • Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. However, for events requiring a
  • Hyperglycemia Grade 4 (> 500 mg/dL) [ ⁇ Omit Alpelisib, confirm fasting status of
  • the patient should be monitored weekly (including LFTs), or more frequently if clinically indicated, until total bilirubin have resolved to baseline or stabilization over 4 weeks
  • Grade 4 (> 10.0 x ULN) Discontinue Ribociclib and Alpelisib treatment.
  • the patient should be monitored weekly (including LFTs), or more frequently if clinically indicated, until total bilirubin have resolved to baseline or stabilization over 4 weeks
  • grade 0 or 1 to grade 2 (> If resolved to ⁇ baseline grade in ⁇ 21 3.0 - 5.0 x ULN) days, then maintain dose level
  • Grade 4 (> 20.0 x ULN) Discontinue Ribociclib treatment. Hold Alpelisib until resolved to ⁇ grade 1 , then reduce dose of Alpelisib by 1 dose level.
  • Serum creatinine Grade ⁇ 3 (>3 xULN) Discontinue Alpelisib.
  • pancreatitis resolves to Grade 0 within 21 days, then treatment may be restarted.
  • pancreatitis is not resolved to Grade 0 within 21 days, then Alpelisib treatment should be discontinued.
  • Alpelisib should be permanently discontinued in all patients with confirmed pneumonitis related to study drugs.
  • Grade 3 Determine attribution of toxicity. Hold assigned therapy until resolved to ⁇ Grade 1 or baseline. If toxicity cannot be attributed to one study drug, hold both Ribociclib and Alpelisib. Initiate appropriate medical therapy and monitor. Re-initiate Ribociclib and/or Alpelisib at the next lower dose level.
  • Patients are assessed for efficacy, safety and tolerability, physical signs and symptoms (including laboratory evaluations (e.g., hematology, clinical chemistry, urinalysis, glucose safety monitoring, hepatic safety markers, and electrocardiogram), and pharmacokinetics during the study.
  • laboratory evaluations e.g., hematology, clinical chemistry, urinalysis, glucose safety monitoring, hepatic safety markers, and electrocardiogram
  • pharmacokinetics during the study.
  • Tumor response are evaluated locally by the investigator according to the Sponsor's guideline (Version 3.1) based on RECIST version 1.1 1. The following assessments are required at screening/baseline (within 28 days prior to the start of treatment):
  • tumor evaluations are performed every 8 weeks through cycle 6. After cycle 6 tumor evaluations will be performed every 12 weeks (C2D28+/- 7, C4D28+/- 7, C6D28+/- 7, C9D28+/- 7, C12D28+/- 7, etc.), or sooner if there is clinical evidence of disease progression. Tumor evaluations will also be performed at End of Treatment. All efficacy evaluations have a +/- 7 day window. If the last prior tumor evaluation was within 28 days of End of Treatment or objective evidence of progressive disease has already been documented, then tumor evaluations do not need to be repeated at End of Treatment. Tumor evaluations after the screening assessment include evaluation of all sites of disease identified at baseline. Chest, abdomen, pelvis scans need to be repeated at each tumor assessment visit (including if negative at baseline).
  • Any potentially measurable lesion that has been previously treated with radiotherapy should be considered as a non-measurable lesion. However, if a lesion previously treated with radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable lesion.
  • ORR Overall response rate
  • DCR Disease control rate
  • Clinical Benefit is defined as CR or PR or SD for 24 weeks or longer.
  • CR, PR and SD are defined according to RECIST 1 .1 .
  • An adverse event is defined as the appearance of (o worsening of any pre-existing) undesirable sign(s), symptom(s), or medical conditions that occur after patient's signed informed consent is obtained.
  • Adverse events are assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. All adverse events should be treated appropriately. All safety assessments are performed pre-dose unless otherwise specified.
  • Serious adverse event is defined as one of the following:
  • Is medically significant i.e., defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes listed above
  • the first end of treatment study visit will occur when the patient reaches progressive disease while on the doublet in dose escalation or dose expansion. Tumor imaging does not need to be repeated prior to the crossover. Blood tests are only repeated if outside the screening (14 day) window from first triplet dose. The second end of treatment study visit will occur when the patient reaches progressive disease while on the crossover triplet.
  • the End of Treatment visit occurs within 14 days after the last administration of study treatment, or within 14 days of the decision to discontinue treatment due to an AE, in the case that treatment was already on hold due to an AE.
  • Safety follow-up assessments should be completed 30 days after the last dose of the study treatment.
  • End of Study is achieved when the treatment period, safety follow-up and disease follow- up have ended for all patients, or when the study is terminated early.

Abstract

L'invention concerne des méthodes qui permettent de traiter ou de prévenir une maladie proliférative chez l'être humain, qui en a besoin, en administrant par voie orale audit humain une dose quotidienne, comprise entre environ 100 mg et environ 450 mg, du composé de la formule (I), ou d'un sel de qualité pharmaceutique de celui-ci, tous les jours pendant trois semaines, ensuite en s'abstenant d'administrer ledit composé audit humain pendant la semaine immédiatement ultérieure, puis en répétant ce cycle, une à plusieurs fois. L'invention concerne également l'utilisation dudit composé de la formule (I) ou d'un sel de qualité pharmaceutique de celui-ci pour la fabrication d'un médicament destiné au traitement ou à la prévention de maladies prolifératives et administré conformément audit régime posologique, un schéma thérapeutique comprenant l'administration dudit composé de la formule (I) ou d'un sel de qualité pharmaceutique de celui-ci conformément audit schéma posologique, ainsi que des compositions pharmaceutiques et conditionnements de celles-ci.
PCT/IB2017/055814 2016-09-27 2017-09-26 Schéma posologique pour l'alpelisib, un inhibiteur de la phosphatidylinositol 3-kinase spécifique de l'isoforme alpha WO2018060833A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662400106P 2016-09-27 2016-09-27
US62/400,106 2016-09-27

Publications (1)

Publication Number Publication Date
WO2018060833A1 true WO2018060833A1 (fr) 2018-04-05

Family

ID=60153377

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/055814 WO2018060833A1 (fr) 2016-09-27 2017-09-26 Schéma posologique pour l'alpelisib, un inhibiteur de la phosphatidylinositol 3-kinase spécifique de l'isoforme alpha

Country Status (1)

Country Link
WO (1) WO2018060833A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020036999A1 (fr) * 2018-08-14 2020-02-20 Mei Pharma, Inc. Traitement des malignités des lymphocytes b
US11304953B2 (en) 2017-05-23 2022-04-19 Mei Pharma, Inc. Combination therapy
WO2022093770A1 (fr) * 2020-10-27 2022-05-05 Memorial Sloan Kettering Cancer Center Polythérapie à l'aide d'inhibiteurs de pi3k-akt-mtor et d'agents induisant la ferroptose pour traiter un cancer
US11351176B2 (en) 2017-08-14 2022-06-07 Mei Pharma, Inc. Combination therapy
US11400097B2 (en) 2011-03-28 2022-08-02 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases

Citations (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4169846A (en) 1976-09-06 1979-10-02 Kenji Inagaki Cis-platinum (ii) complex of trans-l-1,2-diaminocyclohexane
US4323581A (en) 1978-07-31 1982-04-06 Johnson & Johnson Method of treating carcinogenesis
US4689338A (en) 1983-11-18 1987-08-25 Riker Laboratories, Inc. 1H-Imidazo[4,5-c]quinolin-4-amines and antiviral use
WO1988007045A1 (fr) 1987-03-09 1988-09-22 Kyowa Hakko Kogyo Co., Ltd. Derives de la substance physiologiquement active k-252
WO1989007105A1 (fr) 1988-02-04 1989-08-10 Kyowa Hakko Kogyo Co., Ltd. Derives de staurosporine
US4929624A (en) 1989-03-23 1990-05-29 Minnesota Mining And Manufacturing Company Olefinic 1H-imidazo(4,5-c)quinolin-4-amines
US5041424A (en) 1987-08-04 1991-08-20 Bristol-Myers Company Epipodophyllotoxin glucoside 4'-phosphate derivatives
WO1993007153A1 (fr) 1991-10-10 1993-04-15 Schering Corporation Derives de staurosporine 4'-(n-substituee-n-oxydee)
WO1993008809A1 (fr) 1991-11-08 1993-05-13 The University Of Southern California Compositions contenant des composes k-252 et destinees a potentialiser l'activite de la neurotrophine
US5238944A (en) 1988-12-15 1993-08-24 Riker Laboratories, Inc. Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine
US5266575A (en) 1991-11-06 1993-11-30 Minnesota Mining And Manufacturing Company 2-ethyl 1H-imidazo[4,5-ciquinolin-4-amines
US5268376A (en) 1991-09-04 1993-12-07 Minnesota Mining And Manufacturing Company 1-substituted 1H-imidazo[4,5-c]quinolin-4-amines
WO1994005304A1 (fr) 1992-08-31 1994-03-17 Ludwig Institute For Cancer Research Nonapeptide isole derive du gene mage-3 et presente par hla-a1, et ses utilisations
WO1994006799A1 (fr) 1992-09-21 1994-03-31 Kyowa Hakko Kogyo Co., Ltd. Remede contre la thrombopenie
WO1994010202A1 (fr) 1992-10-28 1994-05-11 Genentech, Inc. Antagonistes du facteur de croissance des cellules endotheliales vasculaires
US5352784A (en) 1993-07-15 1994-10-04 Minnesota Mining And Manufacturing Company Fused cycloalkylimidazopyridines
US5389640A (en) 1991-03-01 1995-02-14 Minnesota Mining And Manufacturing Company 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines
US5395937A (en) 1993-01-29 1995-03-07 Minnesota Mining And Manufacturing Company Process for preparing quinoline amines
WO1995012660A2 (fr) 1993-10-29 1995-05-11 Board Of Regents, The University Of Texas System Procedes et compositions relatifs a l'adenovirus p53 recombine
WO1995017182A1 (fr) 1993-12-23 1995-06-29 Eli Lilly And Company Inhibiteurs de la proteine-kinase c
US5457105A (en) 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
US5478932A (en) 1993-12-02 1995-12-26 The Board Of Trustees Of The University Of Illinois Ecteinascidins
US5482936A (en) 1995-01-12 1996-01-09 Minnesota Mining And Manufacturing Company Imidazo[4,5-C]quinoline amines
US5494916A (en) 1993-07-15 1996-02-27 Minnesota Mining And Manufacturing Company Imidazo[4,5-C]pyridin-4-amines
WO1996006116A1 (fr) 1994-08-19 1996-02-29 Regents Of The University Of Minnesota Immunoconjugues a base d'inhibiteurs de la tyrosine kinase
WO1996013506A1 (fr) 1994-10-26 1996-05-09 Cephalon, Inc. Inhibiteurs de la proteine-kinase pour le traitement de troubles neurologiques
WO1996030347A1 (fr) 1995-03-30 1996-10-03 Pfizer Inc. Derives de quinazoline
WO1997007081A2 (fr) 1995-08-11 1997-02-27 Yale University Synthese d'indolocarbazols glycosyles
US5621100A (en) 1992-07-24 1997-04-15 Cephalon, Inc. K-252a derivatives for treatment of neurological disorders
WO1997020842A1 (fr) 1995-12-01 1997-06-12 Centre National De La Recherche Scientifique (C.N.R.S.) Nouveaux derives de purine possedant notamment des proprietes anti-proliferatives et leurs applications biologiques
WO1997021701A1 (fr) 1995-12-08 1997-06-19 Janssen Pharmaceutica N.V. Derives de la (imidazol-5-yl)methyl-2-quinoleinone comme inhibiteur de la proteine farnesyle-transferase
WO1997029780A1 (fr) 1996-02-14 1997-08-21 Isis Pharmaceuticals, Inc. Oligonucleotides methoxyethoxy modulant l'expression de la proteine kinase c
WO1998004541A1 (fr) 1996-07-25 1998-02-05 Dong A Pharmaceutical Co., Ltd. Composes de flavone/flavonone de protection contre la gastrite et leur effet therapeutique sur l'affection intestinale inflammatoire
WO1998005769A2 (fr) 1996-08-02 1998-02-12 Genesense Technologies, Inc. Sequences antisens et antitumorales dirigees conte les constituants r1 et r2 de la ribonucleotide reductase
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US5770599A (en) 1995-04-27 1998-06-23 Zeneca Limited Quinazoline derivatives
US5780454A (en) 1994-10-28 1998-07-14 Proscript, Inc. Boronic ester and acid compounds
WO1998043095A1 (fr) 1997-03-21 1998-10-01 Georgetown University Liposomes renfermant des oligonucleotides
WO1999002162A1 (fr) 1997-07-12 1999-01-21 Cancer Research Campaign Technology Limited Derives de purine inhibant la kinase dependant de la cycline
US5883113A (en) 1995-06-07 1999-03-16 Sugen, Inc. 3-(4'-Bromobenzylindenyl)-2-indolinone and analogues thereof for the treatment of disease
WO1999061422A1 (fr) 1998-05-29 1999-12-02 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2000027422A2 (fr) 1998-11-06 2000-05-18 Biogen, Inc. Methodes et compositions permettant de traiter ou de prevenir des neuropathies peripheriques
WO2001000245A2 (fr) 1999-06-25 2001-01-04 Genentech, Inc. Anticorps anti-erbb2 humanises et traitement a l'aide de ces anticorps
WO2001000244A2 (fr) 1999-06-25 2001-01-04 Genentech, Inc. Techniques de traitement utilisant des conjugues maytansinoides-anticorps anti-erbb
WO2001004125A1 (fr) 1999-07-13 2001-01-18 Kyowa Hakko Kogyo Co., Ltd. Derives de staurosporine
WO2001032651A1 (fr) 1999-11-05 2001-05-10 Astrazeneca Ab Derives de quinazoline utilises en tant qu'inhibiteurs du facteur de croissance endotheliale vasculaire (vegf)
US6258812B1 (en) 1997-02-13 2001-07-10 Novartis Ag Phthalazines with angiogenesis inhibiting activity
WO2001060814A2 (fr) 2000-02-15 2001-08-23 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2001079255A1 (fr) 2000-04-12 2001-10-25 Genaera Corporation Procede de preparation de 7.alpha.-hydroxy 3-aminosubstitues sterols au moyen de produits intermediaires dotes d'un groupe 7.alpha.-hydroxy non protege
US6331555B1 (en) 1995-06-01 2001-12-18 University Of California Treatment of platelet derived growth factor related disorders such as cancers
WO2002002552A1 (fr) 2000-06-30 2002-01-10 Glaxo Group Limited Composes ditosylates de quinazoline
WO2002030941A2 (fr) 2000-10-06 2002-04-18 Bristol-Myers Squibb Company Inhibiteurs des topo-isomerases
WO2002057423A2 (fr) 2001-01-16 2002-07-25 Regeneron Pharmaceuticals, Inc. Isolement de cellules exprimant des protéines sécrétées
WO2002062826A1 (fr) 2001-02-07 2002-08-15 Vadim Viktorovich Novikov Procede de fabrication des peptides
WO2003004505A1 (fr) 2001-07-02 2003-01-16 Debiopharm S.A. Substance active a base d'oxaliplatine presentant une faible teneur en acide oxalique
WO2003024978A1 (fr) 2001-09-18 2003-03-27 Postech Foundation Compose d'inclusion contenant des derives de cucurbituril en tant que molecule receptrice et composition pharmaceutique les contenant
US20030134846A1 (en) 2001-10-09 2003-07-17 Schering Corporation Treatment of trypanosoma brucei with farnesyl protein transferase inhibitors
US6605617B2 (en) 2000-09-11 2003-08-12 Chiron Corporation Quinolinone derivatives
US20030171303A1 (en) 2002-02-19 2003-09-11 Gallop Mark A. Methods for synthesis of prodrugs from 1-acyl-alkyl derivatives and compositions thereof
WO2003082272A1 (fr) 2002-03-29 2003-10-09 Chiron Corporation Benzazoles substitues et leur utilisation en tant qu'inhibiteurs de la kinase raf
WO2004006834A2 (fr) 2002-07-15 2004-01-22 Unitech Pharmaceuticals, Inc. Analogues de leflunomide pour traiter l'arthrite rhumatoide
WO2004009769A2 (fr) 2002-07-24 2004-01-29 The Trustees Of The University Of Pennsylvania Compositions et procede d'inhibition de l'angiogenese par arn-si
US6727256B1 (en) 1998-01-12 2004-04-27 Smithkline Beecham Corporation Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
WO2004060308A2 (fr) 2002-12-27 2004-07-22 Chiron Corporation Thiosemicarbazones antiviraux et immunostimulants
WO2004064759A2 (fr) 2003-01-21 2004-08-05 Chiron Corporation Utilisation de composes de tryptanthrine dans la potentialisation immunologique
WO2004087153A2 (fr) 2003-03-28 2004-10-14 Chiron Corporation Utilisation de petites molecules de composes pour une immunopotentialisation
WO2010020675A1 (fr) 2008-08-22 2010-02-25 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
WO2010029082A1 (fr) 2008-09-10 2010-03-18 Novartis Ag Composés organiques
WO2014199294A1 (fr) * 2013-06-11 2014-12-18 Novartis Ag Combinaisons pharmaceutiques d'un inhibiteur de pi3k et d'un déstabilisateur de microtubule
WO2015083101A1 (fr) * 2013-12-06 2015-06-11 Novartis Ag Schéma posologique d'un inhibiteur de la phosphatidylinositol 3-kinase sélectif de l'isoforme alpha
WO2017077445A1 (fr) * 2015-11-02 2017-05-11 Novartis Ag Schéma posologique pour un inhibiteur de la phosphatidylinositol 3-kinase

Patent Citations (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4169846A (en) 1976-09-06 1979-10-02 Kenji Inagaki Cis-platinum (ii) complex of trans-l-1,2-diaminocyclohexane
US4323581A (en) 1978-07-31 1982-04-06 Johnson & Johnson Method of treating carcinogenesis
US4689338A (en) 1983-11-18 1987-08-25 Riker Laboratories, Inc. 1H-Imidazo[4,5-c]quinolin-4-amines and antiviral use
WO1988007045A1 (fr) 1987-03-09 1988-09-22 Kyowa Hakko Kogyo Co., Ltd. Derives de la substance physiologiquement active k-252
US5041424A (en) 1987-08-04 1991-08-20 Bristol-Myers Company Epipodophyllotoxin glucoside 4'-phosphate derivatives
WO1989007105A1 (fr) 1988-02-04 1989-08-10 Kyowa Hakko Kogyo Co., Ltd. Derives de staurosporine
US5238944A (en) 1988-12-15 1993-08-24 Riker Laboratories, Inc. Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine
US4929624A (en) 1989-03-23 1990-05-29 Minnesota Mining And Manufacturing Company Olefinic 1H-imidazo(4,5-c)quinolin-4-amines
US5389640A (en) 1991-03-01 1995-02-14 Minnesota Mining And Manufacturing Company 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines
US5346905A (en) 1991-09-04 1994-09-13 Minnesota Mining And Manufacturing Company 1-substituted 1H-imidazo-[4,5-C]quinolin-4-amines
US5268376A (en) 1991-09-04 1993-12-07 Minnesota Mining And Manufacturing Company 1-substituted 1H-imidazo[4,5-c]quinolin-4-amines
US5525612A (en) 1991-09-04 1996-06-11 Minnesota Mining And Manufacturing Company 1-substituted 1H-imidazo-[4,5-c]quinolin-4-amines
WO1993007153A1 (fr) 1991-10-10 1993-04-15 Schering Corporation Derives de staurosporine 4'-(n-substituee-n-oxydee)
US5266575A (en) 1991-11-06 1993-11-30 Minnesota Mining And Manufacturing Company 2-ethyl 1H-imidazo[4,5-ciquinolin-4-amines
WO1993008809A1 (fr) 1991-11-08 1993-05-13 The University Of Southern California Compositions contenant des composes k-252 et destinees a potentialiser l'activite de la neurotrophine
US5616582A (en) 1992-01-20 1997-04-01 Zeneca Limited Quinazoline derivatives as anti-proliferative agents
US5457105A (en) 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
US5621100A (en) 1992-07-24 1997-04-15 Cephalon, Inc. K-252a derivatives for treatment of neurological disorders
WO1994005304A1 (fr) 1992-08-31 1994-03-17 Ludwig Institute For Cancer Research Nonapeptide isole derive du gene mage-3 et presente par hla-a1, et ses utilisations
WO1994006799A1 (fr) 1992-09-21 1994-03-31 Kyowa Hakko Kogyo Co., Ltd. Remede contre la thrombopenie
WO1994010202A1 (fr) 1992-10-28 1994-05-11 Genentech, Inc. Antagonistes du facteur de croissance des cellules endotheliales vasculaires
US5395937A (en) 1993-01-29 1995-03-07 Minnesota Mining And Manufacturing Company Process for preparing quinoline amines
US5352784A (en) 1993-07-15 1994-10-04 Minnesota Mining And Manufacturing Company Fused cycloalkylimidazopyridines
US5494916A (en) 1993-07-15 1996-02-27 Minnesota Mining And Manufacturing Company Imidazo[4,5-C]pyridin-4-amines
WO1995012660A2 (fr) 1993-10-29 1995-05-11 Board Of Regents, The University Of Texas System Procedes et compositions relatifs a l'adenovirus p53 recombine
US5478932A (en) 1993-12-02 1995-12-26 The Board Of Trustees Of The University Of Illinois Ecteinascidins
WO1995017182A1 (fr) 1993-12-23 1995-06-29 Eli Lilly And Company Inhibiteurs de la proteine-kinase c
WO1996006116A1 (fr) 1994-08-19 1996-02-29 Regents Of The University Of Minnesota Immunoconjugues a base d'inhibiteurs de la tyrosine kinase
WO1996013506A1 (fr) 1994-10-26 1996-05-09 Cephalon, Inc. Inhibiteurs de la proteine-kinase pour le traitement de troubles neurologiques
US5780454A (en) 1994-10-28 1998-07-14 Proscript, Inc. Boronic ester and acid compounds
US5482936A (en) 1995-01-12 1996-01-09 Minnesota Mining And Manufacturing Company Imidazo[4,5-C]quinoline amines
WO1996030347A1 (fr) 1995-03-30 1996-10-03 Pfizer Inc. Derives de quinazoline
US5770599A (en) 1995-04-27 1998-06-23 Zeneca Limited Quinazoline derivatives
US6331555B1 (en) 1995-06-01 2001-12-18 University Of California Treatment of platelet derived growth factor related disorders such as cancers
US5883113A (en) 1995-06-07 1999-03-16 Sugen, Inc. 3-(4'-Bromobenzylindenyl)-2-indolinone and analogues thereof for the treatment of disease
WO1997007081A2 (fr) 1995-08-11 1997-02-27 Yale University Synthese d'indolocarbazols glycosyles
WO1997020842A1 (fr) 1995-12-01 1997-06-12 Centre National De La Recherche Scientifique (C.N.R.S.) Nouveaux derives de purine possedant notamment des proprietes anti-proliferatives et leurs applications biologiques
WO1997021701A1 (fr) 1995-12-08 1997-06-19 Janssen Pharmaceutica N.V. Derives de la (imidazol-5-yl)methyl-2-quinoleinone comme inhibiteur de la proteine farnesyle-transferase
WO1997029780A1 (fr) 1996-02-14 1997-08-21 Isis Pharmaceuticals, Inc. Oligonucleotides methoxyethoxy modulant l'expression de la proteine kinase c
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
WO1998004541A1 (fr) 1996-07-25 1998-02-05 Dong A Pharmaceutical Co., Ltd. Composes de flavone/flavonone de protection contre la gastrite et leur effet therapeutique sur l'affection intestinale inflammatoire
US6025387A (en) 1996-07-25 2000-02-15 Dong A Pharmaceutical Co., Ltd. Gastroprotective flavone/flavanone compounds with therapeutic effect on inflammatory bowel disease
WO1998005769A2 (fr) 1996-08-02 1998-02-12 Genesense Technologies, Inc. Sequences antisens et antitumorales dirigees conte les constituants r1 et r2 de la ribonucleotide reductase
US6258812B1 (en) 1997-02-13 2001-07-10 Novartis Ag Phthalazines with angiogenesis inhibiting activity
WO1998043095A1 (fr) 1997-03-21 1998-10-01 Georgetown University Liposomes renfermant des oligonucleotides
WO1999002162A1 (fr) 1997-07-12 1999-01-21 Cancer Research Campaign Technology Limited Derives de purine inhibant la kinase dependant de la cycline
US6727256B1 (en) 1998-01-12 2004-04-27 Smithkline Beecham Corporation Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
WO1999061422A1 (fr) 1998-05-29 1999-12-02 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2000027422A2 (fr) 1998-11-06 2000-05-18 Biogen, Inc. Methodes et compositions permettant de traiter ou de prevenir des neuropathies peripheriques
WO2001000244A2 (fr) 1999-06-25 2001-01-04 Genentech, Inc. Techniques de traitement utilisant des conjugues maytansinoides-anticorps anti-erbb
WO2001000245A2 (fr) 1999-06-25 2001-01-04 Genentech, Inc. Anticorps anti-erbb2 humanises et traitement a l'aide de ces anticorps
WO2001004125A1 (fr) 1999-07-13 2001-01-18 Kyowa Hakko Kogyo Co., Ltd. Derives de staurosporine
WO2001032651A1 (fr) 1999-11-05 2001-05-10 Astrazeneca Ab Derives de quinazoline utilises en tant qu'inhibiteurs du facteur de croissance endotheliale vasculaire (vegf)
WO2001060814A2 (fr) 2000-02-15 2001-08-23 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2001079255A1 (fr) 2000-04-12 2001-10-25 Genaera Corporation Procede de preparation de 7.alpha.-hydroxy 3-aminosubstitues sterols au moyen de produits intermediaires dotes d'un groupe 7.alpha.-hydroxy non protege
WO2002002552A1 (fr) 2000-06-30 2002-01-10 Glaxo Group Limited Composes ditosylates de quinazoline
US6605617B2 (en) 2000-09-11 2003-08-12 Chiron Corporation Quinolinone derivatives
US6774237B2 (en) 2000-09-11 2004-08-10 Chiron Corporation Quinolinone derivatives
WO2002030941A2 (fr) 2000-10-06 2002-04-18 Bristol-Myers Squibb Company Inhibiteurs des topo-isomerases
WO2002057423A2 (fr) 2001-01-16 2002-07-25 Regeneron Pharmaceuticals, Inc. Isolement de cellules exprimant des protéines sécrétées
WO2002062826A1 (fr) 2001-02-07 2002-08-15 Vadim Viktorovich Novikov Procede de fabrication des peptides
WO2003004505A1 (fr) 2001-07-02 2003-01-16 Debiopharm S.A. Substance active a base d'oxaliplatine presentant une faible teneur en acide oxalique
WO2003024978A1 (fr) 2001-09-18 2003-03-27 Postech Foundation Compose d'inclusion contenant des derives de cucurbituril en tant que molecule receptrice et composition pharmaceutique les contenant
US20030134846A1 (en) 2001-10-09 2003-07-17 Schering Corporation Treatment of trypanosoma brucei with farnesyl protein transferase inhibitors
US20030171303A1 (en) 2002-02-19 2003-09-11 Gallop Mark A. Methods for synthesis of prodrugs from 1-acyl-alkyl derivatives and compositions thereof
WO2003082272A1 (fr) 2002-03-29 2003-10-09 Chiron Corporation Benzazoles substitues et leur utilisation en tant qu'inhibiteurs de la kinase raf
WO2004006834A2 (fr) 2002-07-15 2004-01-22 Unitech Pharmaceuticals, Inc. Analogues de leflunomide pour traiter l'arthrite rhumatoide
WO2004009769A2 (fr) 2002-07-24 2004-01-29 The Trustees Of The University Of Pennsylvania Compositions et procede d'inhibition de l'angiogenese par arn-si
WO2004060308A2 (fr) 2002-12-27 2004-07-22 Chiron Corporation Thiosemicarbazones antiviraux et immunostimulants
WO2004064759A2 (fr) 2003-01-21 2004-08-05 Chiron Corporation Utilisation de composes de tryptanthrine dans la potentialisation immunologique
WO2004087153A2 (fr) 2003-03-28 2004-10-14 Chiron Corporation Utilisation de petites molecules de composes pour une immunopotentialisation
WO2010020675A1 (fr) 2008-08-22 2010-02-25 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
WO2010029082A1 (fr) 2008-09-10 2010-03-18 Novartis Ag Composés organiques
WO2014199294A1 (fr) * 2013-06-11 2014-12-18 Novartis Ag Combinaisons pharmaceutiques d'un inhibiteur de pi3k et d'un déstabilisateur de microtubule
WO2015083101A1 (fr) * 2013-12-06 2015-06-11 Novartis Ag Schéma posologique d'un inhibiteur de la phosphatidylinositol 3-kinase sélectif de l'isoforme alpha
WO2017077445A1 (fr) * 2015-11-02 2017-05-11 Novartis Ag Schéma posologique pour un inhibiteur de la phosphatidylinositol 3-kinase

Non-Patent Citations (31)

* Cited by examiner, † Cited by third party
Title
BACKMAN ET AL., CANCER BIOL. THER., vol. 3, no. 8, 2004, pages 772 - 775
CAMPBELL ET AL., CANCER RESEARCH, vol. 64, no. 21, 2004, pages 7678 - 7681
CANTLEY ET AL., CELL, vol. 64, 1991, pages 281
CHOU, T. C.; TALALAY, P., ADV. ENZYME REGUL., vol. 22, 1984, pages 27 - 55
ESCOBEDO; WILLIAMS, NATURE, vol. 335, 1988, pages 85
FANTL ET AL., CELL, vol. 69, 1992, pages 413
FRUMAN ET AL., ANNU REV. BIOCHEM., vol. 67, 1998, pages 481
GENNARO: "Remington: the Science and Practice of Pharmacy, 20th ed.", 2003, LIPPINCOTT WILLIAMS & WILKINS
GONZALEZ-ANGULO ET AL., PRESENTATION AT THE 2013 ASCO ANNUAL MEETING, 31 May 2013 (2013-05-31)
GONZALEZ-ANGULO ET AL.: "Safety, pharmacokinetics, and preliminary activity of the a-specific PI3K inhibitor BYL719: results from the first-in-human study", PRESENTATION AT THE 2013 ASCO ANNUAL MEETING, 31 May 2013 (2013-05-31)
GRITSMAN KIRA ET AL: "Examination of Phosphoprotein Targets in Timed Samples from Patients with RAS-Mutated AML during Concurrent Treatment with Alpelisib and Binimetinib on the Phase Ib Clinical Trial CMEK162X2109", BLOOD, vol. 128, no. 22, 2 December 2016 (2016-12-02), & 58TH ANNUAL MEETING AND EXPOSITION OF THE AMERICAN-SOCIETY-OF-HEMATOLOGY; SAN DIEGO, CA, USA; DECEMBER 03 -06, 2016, pages 2749, XP009502140 *
HARTMANN ET AL., ACTA NEUROPATHOL., vol. 109, no. 6, June 2005 (2005-06-01), pages 639
HENNESSEY, NATURE REV. DRUG DISC., vol. 4, 2005, pages 988 - 1004
HOLFORD, N. H. G.; SCHEINER, L. B., CLIN. PHARMACOKINET., vol. 6, 1981, pages 429 - 453
JURIC D ET AL: "A Phase Ib/II study of alpelisib (BYL719) and ganitumab (AMG 479) in adult patients with selected advanced solid tumors", EUROPEAN JOURNAL OF CANCER, vol. 51, no. Suppl. 3, September 2015 (2015-09-01), & EUROPEAN CANCER CONGRESS 2015 / 18TH MEETING OF THE EUROPEAN-CANCER-ORGANIZATION (ECCO) / 40TH MEETI; VIENNA, AUSTRIA; SEPTEMBER 25 -29, 2015, pages S68, XP009502139 *
KATSO ET AL., ANNU. REV. CELL DEV. BIOL., vol. 17, 2001, pages 615
KATSO ET AL., ANNU. REV. CELL DEV. BIOL., vol. 17, 2001, pages 615 - 675
LEE ET AL., ONCOGENE, vol. 24, no. 8, 2005, pages 1477
LEVINE ET AL., CLIN. CANCER RES., vol. 11, no. 8, 2005, pages 2875 - 2878
LI ET AL., BMC CANCER, vol. 5, no. 29, March 2005 (2005-03-01)
LOEWE, S.; MUISCHNEK, H., ARCH. EXP. PATHOL PHARMACOL., vol. 114, 1926, pages 313 - 326
MAYER INGRID A ET AL: "A Phase Ib Study of Alpelisib (BYL719), a PI3K alpha-Specific Inhibitor, with Letrozole in ER+/HER2(-) Metastatic Breast Cancer", CLINICAL CANCER RESEARCH, vol. 23, no. 1, 28 April 2016 (2016-04-28), pages 26 - 34, XP009502141 *
PARSONS ET AL., NATURE, vol. 436, 2005, pages 792
PAYAL D. SHAH ET AL: "Abstract PD5-3: Phase I trial: PI3K[alpha] inhibitor BYL719 plus aromatase inhibitor (AI) for patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC)", CANCER RESEARCH, 1 May 2015 (2015-05-01), pages 1 - 4, XP055338223, Retrieved from the Internet <URL:http://cancerres.aacrjournals.org/content/75/9_Supplement/PD5-3> [retrieved on 20170124], DOI: 10.1158/1538-7445.SABCS14-PD5-3 *
ROWE ET AL.: "The Handbook of Pharmaceutical Excipients, 4th ed.", 2003, AMERICAN PHARMACEUTICALS ASSOCIATION
SAMUELS ET AL., CELL CYCLE, vol. 3, no. 10, 2004, pages 1221
STEPHENS ET AL., CELL, vol. 89, 1997, pages 105
SUIRE ET AL., CURR. BIOL., vol. 15, 2005, pages 566
TETRAHEDRON LETT., vol. 26, 1974, pages 2269 - 70
VANHAESEBROECK ET AL., ANNU. REV. BIOCHEM, vol. 70, 2001, pages 535
WU ET AL., BREAST CANCER RES., vol. 7, no. 5, 2005, pages R609 - R616

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11400097B2 (en) 2011-03-28 2022-08-02 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US11304953B2 (en) 2017-05-23 2022-04-19 Mei Pharma, Inc. Combination therapy
US11351176B2 (en) 2017-08-14 2022-06-07 Mei Pharma, Inc. Combination therapy
WO2020036999A1 (fr) * 2018-08-14 2020-02-20 Mei Pharma, Inc. Traitement des malignités des lymphocytes b
WO2022093770A1 (fr) * 2020-10-27 2022-05-05 Memorial Sloan Kettering Cancer Center Polythérapie à l'aide d'inhibiteurs de pi3k-akt-mtor et d'agents induisant la ferroptose pour traiter un cancer

Similar Documents

Publication Publication Date Title
WO2018060833A1 (fr) Schéma posologique pour l&#39;alpelisib, un inhibiteur de la phosphatidylinositol 3-kinase spécifique de l&#39;isoforme alpha
TWI607754B (zh) 醫藥組合
RU2630975C2 (ru) Режим дозирования pi-3 киназы
CA2872541A1 (fr) Combinaison d&#39;un inhibiteur de 17-alpha-hydroxylase (c17,20-lyase) et d&#39;un inhibiteur specifique de pi-3k pour le traitement d&#39;une maladie tumorale
US20210196696A1 (en) Dosage regimen for an alpha-isoform selective phosphatidylinositol 3-kinase inhibitor
AU2017245302B2 (en) Pharmaceutical combinations
US20180280370A1 (en) Dosage regimen for a phosphatidylinositol 3-kinase inhibitor
US9913846B2 (en) Combination of a PI3 kinase inhibitor with pacitaxel for use in the treatment or prevention of a cancer of the head and neck
WO2023070023A1 (fr) Polythérapie pour maladies ou troubles associés à pik3ca

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17787630

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17787630

Country of ref document: EP

Kind code of ref document: A1