[go: up one dir, main page]

US20160184311A1 - Combination Therapy for the Treatment of Cancer - Google Patents

Combination Therapy for the Treatment of Cancer Download PDF

Info

Publication number
US20160184311A1
US20160184311A1 US14/911,160 US201414911160A US2016184311A1 US 20160184311 A1 US20160184311 A1 US 20160184311A1 US 201414911160 A US201414911160 A US 201414911160A US 2016184311 A1 US2016184311 A1 US 2016184311A1
Authority
US
United States
Prior art keywords
compound
agent
combination
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/911,160
Other languages
English (en)
Inventor
Yan Chen
Xizhong Huang
Sunkyu Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=51355593&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20160184311(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Novartis AG filed Critical Novartis AG
Priority to US14/911,160 priority Critical patent/US20160184311A1/en
Assigned to NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH reassignment NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, YAN, HUANG, XIZHONG, KIM, SUNKYU
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
Assigned to NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC. reassignment NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, YAN, HUANG, XIZHONG, KIM, SUNKYU
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
Publication of US20160184311A1 publication Critical patent/US20160184311A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present disclosure relates to a pharmaceutical combination comprising a CDK inhibitor and an anti-hormonal agent for the treatment of cancer; the uses of such combinations in the treatment of cancer; and to a method of treating warm-blooded animals including humans suffering cancer comprising administering to said animal in need of such treatment an effective dose of a CDK inhibitor and an anti-hormonal agent.
  • the combination can optionally include an agent that regulates the PI3K/Akt/mTOR pathway.
  • CDKs The function of CDKs is to phosphorylate and thus activate or deactivate certain proteins, including e.g. retinoblastoma proteins, lamins, histone H1, and components of the mitotic spindle.
  • the catalytic step mediated by CDKs involves a phospho-transfer reaction from ATP to the macromolecular enzyme substrate.
  • Several groups of compounds (reviewed in e.g. Fischer, P. M. Curr. Opin. Drug Discovery Dev. 2001, 4, 623-634) have been found to possess anti-proliferative properties by virtue of CDK-specific ATP antagonism.
  • CDK phosphorylation is performed by a group of CDK activating kinases (CAKs) and/or kinases such as wee1, Myt1 and Mik1.
  • Dephosphorylation is performed by phosphatases such as cdc25(a & c), pp2a, or KAP.
  • CDK/cyclin complex activity may be further regulated by two families of endogenous cellular proteinaceous inhibitors: the Kip/Cip family, or the INK family.
  • the INK proteins specifically bind CDK4 and CDK6.
  • p16ink4 also known as MTS1
  • MTS1 is a potential tumour suppressor gene that is mutated, or deleted, in a large number of primary cancers.
  • the Kip/Cip family contains proteins such as p21Cip1, Waf1, p27Kip1 and p57kip2, where p21 is induced by p53 and is able to inactivate the CDK2/cyclin(E/A) complex.
  • Atypically low levels of p27 expression have been observed in breast, colon and prostate cancers.
  • Conversely over expression of cyclin E in solid tumours has been shown to correlate with poor patient prognosis.
  • Over expression of cyclin D1 has been associated with oesophageal, breast, squam
  • CDKs The pivotal roles of CDKs, and their associated proteins, in co-ordinating and driving the cell cycle in proliferating cells have been outlined above. Some of the biochemical pathways in which CDKs play a key role have also been described. The development of monotherapies for the treatment of proliferative disorders, such as cancers, using therapeutics targeted generically at CDKs, or at specific CDKs, is therefore potentially highly desirable. Thus, there is a continued need to find new therapeutic agents to treat human diseases.
  • Anti-hormonal agent works in two ways: (1) by lowering the amount of the hormone in the body or (2) by blocking the action of hormone on cells.
  • Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue.
  • the main source of estrogen is the ovaries in premenopausal women, while in post-menopausal women most of the body's estrogen is produced in peripheral tissues (outside the CNS), and also a few CNS sites in various regions within the brain.
  • Estrogen is produced and acts locally in these tissues, but any circulating estrogen, which exerts systemic estrogenic effects in men and women, is the result of estrogen escaping local metabolism and spreading to the circulatory system.
  • aromatase inhibitors There are two types: (1) steroidal inhibitors, such as exemestane (Aromasin) which forms a permanent and deactivating bond with the aromatase enzyme; and (2) non-steroidal inhibitors, such as anastrozole (Arimidex) or Letrozole (Femara) which inhibit the synthesis of estrogen via reversible competition for the aromatase enzyme.
  • estrogen receptor antagonist Another type of anti-hormonal agent is estrogen receptor antagonist.
  • An example of an estrogen receptor antagonist is fulvestrant (Faslodex).
  • Estrogen receptors are found in and on breast cells. Estrogen binds to estrogen receptors, like a key fitting into a lock. This can activate the receptor and cause hormone receptor-positive tumors to grow. Fulvestrant binds to and blocks estrogen receptors and reduces the number of estrogen receptors in breast cells.
  • SERMs selective estrogen receptor modulators
  • tamoxifen is an estrogen receptor agonist at bone and uterus, but an antagonist at breast.
  • Phosphatidylinositol 3-kinases are widely expressed 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 (PIP 2 ) and phosphoinositol-3,4,5-triphosphate (PIP 3 ).
  • PIP phosphoinositol-3-phosphate
  • PIP 2 phosphoinositol-3,4-diphosphate
  • PIP 3 phosphoinositol-3,4,5-triphosphate
  • Class 1A PI3Ks are heterodimers composed of a catalytic p110 subunit ( ⁇ , ⁇ , ⁇ isoforms) constitutively associated with a regulatory subunit that can be p85 ⁇ , p55 ⁇ , p50 ⁇ , p85 ⁇ or p55 ⁇ .
  • the Class 1B sub-class has one family member, a heterodimer composed of a catalytic p110 ⁇ subunit associated with one of two regulatory subunits, p101 or p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005)).
  • PIP2 and PIP3 recruit AKT to the plasma membrane where it acts as a nodal point for many intracellular signaling pathways important for growth and survival (Fant) et al., Cell 69:413-423(1992); Bader et al., Nature Rev. Cancer 5:921 (2005); Vivanco and Sawyer, Nature Rev. Cancer 2:489 (2002)).
  • 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 p110 ⁇ isoform, PIK3CA, and for AKT are amplified and increased protein expression of their gene products has been demonstrated in several human cancers.
  • somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers (Kang at el., Proc. Natl. Acad. Sci.
  • inhibitors of PI3K alpha are known to be of particular value in the treatment of cancer and other disorders.
  • mTOR is a kinase protein predominantly found in the cytoplasm of the cell. It acts as a central regulator of many biological processes related to cell proliferation, angiogenesis, and cell metabolism. mTOR exerts its effects primarily by turning on and off the cell's translational machinery, which includes the ribosomes, and is responsible for protein synthesis. mTOR is a key intracellular point of convergence for a number of cellular signaling pathways. mTOR performs its regulatory function in response to activating or inhibitory signals transmitted through these pathways, which are located upstream from mTOR in the cell.
  • VEGFs vascular endothelial growth factors
  • PDGF platelet-derived growth factor
  • EGF epidermal growth factor
  • IGF-1 insulin-like growth factor 1
  • hormones estrogen, progesterone
  • glucose glucose
  • one or more of these signaling pathways may be abnormally activated in patients with many different types of cancer, resulting in deregulated cell proliferation, tumor angiogenesis, and abnormal cell metabolism.
  • the present disclosure relates to a pharmaceutical combination
  • a pharmaceutical combination comprising (1) a first agent which is a CDK inhibitor or a pharmaceutically acceptable salt thereof and (2) a second agent which is an anti-hormonal agent or a pharmaceutically acceptable salt thereof.
  • the present disclosure also relates to a pharmaceutical combination
  • a pharmaceutical combination comprising (1) a first agent which is a CDK inhibitor or a pharmaceutically acceptable salt thereof, (2) a second agent which is an anti-hormonal agent or a pharmaceutically acceptable salt thereof, and (3) a third agent which is an agent that regulates the PI3K/Akt/mTOR pathway or a pharmaceutically acceptable salt thereof.
  • Such combination may be for simultaneous, separate or sequential use for the treatment of a cancer.
  • the CDK inhibitor is CDK4/6 inhibitor.
  • the CDK4/6 inhibitor can be, for example,
  • Compound A3 also known as PD-0332991.
  • Compound A1 is also described by the chemical name 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide.
  • Compound A2 is also described by the chemical name 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.
  • Compound A3 is also described by the chemical name 6-Acetyl-8-cyclopentyl-5-methyl-2- ⁇ [5-(1-piperazinyl)-2-pyridinyl]amino ⁇ pyrido[2,3-d]pyrimidin-7(8H)-one.
  • the anti-hormonal agent is an aromatase inhibitor.
  • aromatase inhibitor can be either a non-steroidal aromatase inhibitor or a steroidal aromatase inhibitor.
  • Letrozole (hereinafter referred as Compound B1) is an example of a non-steroidal aromatase inhibitor.
  • Exemestane (hereinafter referred as Compound B2) is an example of a steroidal aromatase inhibitor.
  • the anti-hormonal agent is an estrogen receptor antagonist.
  • Fulvestrant (hereinafter referred as Compound B3) is an example of an estrogen receptor antagonist.
  • the anti-hormonal agent is a selective estrogen receptor modulator.
  • Tamoxifen (hereinafter referred as Compound B4) is an example of a selective estrogen receptor modulator.
  • the agent that regulates the PI3K/Akt/mTOR pathway is a PI3K inhibitor.
  • the PI3K inhibitor can be, for example,
  • Compound C1 is also described by the chemical name (S)-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 ⁇ -amide).
  • Compound C2 is also described by the chemical name 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-(trifluoromethyl)-2-pyrimidinamine.
  • the agent that regulates the PI3K/Akt/mTOR pathway is a mTOR inhibitor.
  • Everolimus (hereinafter referred as Compound C3) is an example of a mTOR inhibitor.
  • the present disclosure further relates to the above pharmaceutical combination(s) for use in the treatment of a cancer.
  • the present disclosure further relates to a method for the treatment of a cancer comprising administering the above pharmaceutical combination(s) in jointly therapeutically effective amount, to a warm-blooded animal, preferably a human, in need thereof.
  • the compounds in the pharmaceutical combination(s) may be administered either as a single pharmaceutical composition, as separate compositions, or sequentially.
  • the disclosure relates to a pharmaceutical combination
  • a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a pharmaceutical combination
  • a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a pharmaceutical combination
  • a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a pharmaceutical combination
  • a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a pharmaceutical combination
  • a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a pharmaceutical combination
  • a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a pharmaceutical combination
  • a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a method of treating HR+, HER2 ⁇ breast cancer comprising administering to a subject a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a method of treating ER+, HER2 ⁇ advanced breast cancer comprising administering to a subject a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a method of treating ER+ advanced breast cancer comprising administering to a subject a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a method of treating ER+ advanced breast cancer comprising administering to a subject a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a method of treating postmenopausal woman with ER+, HER2 ⁇ breast cancer comprising administering to a subject a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a method of treating postmenopausal woman with ER+, HER2 ⁇ breast cancer comprising administering to a subject a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a method of treating postmenopausal woman with ER+, HER2 ⁇ breast cancer comprising administering to a subject a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the disclosure relates to a method of treating ER+ breast cancer comprising administering to a subject a pharmaceutical combination comprising (1) a first agent which is Compound A1 described by Formula A1 below or a pharmaceutically acceptable salt thereof:
  • the present disclosure further relates to a kit comprising the pharmaceutical combination.
  • FIG. 1 shows an extended dose matrix and isobologram demonstrating the effects of combining Compound A1 and Compound B1 doses on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 2 shows an extended dose matrix and isobologram demonstrating the effects of combining Compound A1 and Compound B2 doses on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 3 shows an extended dose matrix and isobologram demonstrating the effects of combining Compound A1 and Compound B3 doses on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 4 shows an extended dose matrix demonstrating the effects of combining Compound A1 and Compound B1 with or without the presence of Compound C1, Compound C2 or Compound C3 on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 5 shows an extended dose matrix demonstrating the effects of combining Compound A1 and Compound B2 with or without the presence of Compound C1, Compound C2 or Compound C3 on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 6 shows an extended dose matrix demonstrating the effects of combining Compound A1 and Compound B3 with or without the presence of Compound C1, Compound C2 or Compound C3 on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 7 shows the MCF7/Aro Cell Growth for 6 Days w ⁇ 4A with the CTG Assay.
  • FIG. 8 shows an extended dose matrix and isobologram demonstrating the effects of combining Compound A3 and Compound B1 doses on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 9 shows an extended dose matrix and isobologram demonstrating the effects of combining Compound A2 and Compound B1 doses on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 10 shows an extended dose matrix demonstrating the effects of combining Compound A3 and Compound B1 with or without the presence of Compound C1 or Compound C3 on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 11 shows an extended dose matrix demonstrating the effects of combining Compound A2 and Compound B1 with or without the presence of Compound C1 or Compound C3 on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 12 shows an extended dose matrix and isobologram demonstrating the effects of combining Compound A3 and Compound B2 doses on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 13 shows an extended dose matrix and isobologram demonstrating the effects of combining Compound A2 and Compound B2 doses on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 14 shows an extended dose matrix demonstrating the effects of combining Compound A3 and Compound B2 with or without the presence of Compound C1 or Compound C3 on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 15 shows an extended dose matrix demonstrating the effects of combining Compound A2 and Compound B2 with or without the presence of Compound C1 or Compound C3 on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 16 shows an extended dose matrix and isobologram demonstrating the effects of combining Compound A3 and Compound B3 doses on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 17 shows an extended dose matrix and isobologram demonstrating the effects of combining Compound A2 and Compound B3 doses on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 18 shows an extended dose matrix demonstrating the effects of combining Compound A3 and Compound B3 with or without the presence of Compound C1 or Compound C3 on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIG. 19 shows an extended dose matrix demonstrating the effects of combining Compound A2 and Compound B3 with or without the presence of Compound C1 or Compound C3 on proliferation of MCF7/ARO human breast carcinoma cells with ⁇ 4A.
  • FIGS. 20-22 show antitumor efficacy of various compounds used as single agent, in double or in triple combination in the HBCx-34 human breast patient-derived xenograft model.
  • FIG. 23 illustrates the study design of clinical trial described in Example 3.
  • FIGS. 24 and 25 show the duration of exposure to treatment in ARM1 and ARM2 of the clinical trial described in Example 3 (interim results).
  • FIG. 26 shows the partial response observed for patient with metastatic breast carcinoma treated with Compound A1 and Letrozole.
  • FIG. 27 illustrates the study design of clinical trial described in Example 5.
  • FIGS. 28 and 29 show the Mean plasma concentration-time profiles for Compound A1 and EVE in patients treated with Compound A1+EVE+EXE on C1 D15.
  • FIG. 30 shows the duration of exposure to treatment of the clinical trial described in Example 5 (interim results).
  • FIG. 31 shows improvement in soft tissue metastases in a patient with lymph node, plura, lung, and soft tissue metastases who had received 1 prior line of anastrozole and 1 prior line of fulvestrant in the advanced/metastatic setting.
  • “Aromatase inhibitor” used herein relates to compounds which inhibit the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. Such compounds will be referred to as “aromatase inhibitors”.
  • SERM selective estrogen receptor modulator
  • PI3K inhibitor is defined herein to refer to a compound which targets, decreases or inhibits phosphatidylinositol 3-kinase. Phosphatidylinositol 3-kinase activity has been shown to increase in response to a number of hormonal and growth factor stimuli, including insulin, platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, colony-stimulating factor, and hepatocyte growth factor, and has been implicated in processes related to cellular growth and transformation.
  • Combination refers to either a fixed combination in one dosage unit form, or a non-fixed combination (or kit of parts) for the combined administration where a compound and a combination partner (e.g. another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • a combination partner e.g. another drug as explained below, also referred to as “therapeutic agent” or “co-agent”
  • therapeutic agent e.g. another drug as explained below, also referred to as “therapeutic agent” or “co-agent”
  • combined administration or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • fixed combination means that the active ingredients, e.g. a compound of formula A1 and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination or “kit of parts” mean that the active ingredients, e.g. a compound of formula A1 and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • Treatment includes prophylactic and therapeutic treatment (including but not limited to palliative, curing, symptom-alleviating, symptom-reducing) as well as the delay of progression of a cancer disease or disorder.
  • prophylactic means the prevention of the onset or recurrence of a cancer.
  • delay of progression means administration of the combination to patients being in a pre-stage or in an early phase of the cancer to be treated, a pre-form of the corresponding cancer is diagnosed and/or in a patient diagnosed with a condition under which it is likely that a corresponding cancer will develop.
  • “Pharmaceutical preparation” or “pharmaceutical composition” refers to a mixture or solution containing at least one therapeutic agent to be administered to a warm-bloodeded, e.g., a human.
  • Co-administer “co-administration” or “combined administration” or the like are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • “Pharmaceutically acceptable” refers 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 mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • “Therapeutically effective” preferably relates to an amount of a therapeutic agent that is therapeutically or in a broader sense also prophylactically effective against the progression of a cancer.
  • “Jointly therapeutically effective” means that the therapeutic agents may be given separately (in a chronologically staggered manner, especially a sequence-specific manner) in such time intervals that they prefer, in the warm-blooded animal, especially human, to be treated, still show a (preferably synergistic) interaction. Whether this is the case can, inter alia, be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.
  • Single pharmaceutical composition refers to a single carrier or vehicle formulated to deliver effective amounts of both therapeutic agents to a patient.
  • the single vehicle is designed to deliver an effective amount of each of the agents, along with any pharmaceutically acceptable carriers or excipients.
  • the vehicle is a tablet, capsule, pill, or a patch. In other embodiments, the vehicle is a solution or a suspension.
  • Dose range refers to an upper and a lower limit of an acceptable variation of the amount of therapeutic agent specified. Typically, a dose of the agent in any amount within the specified range can be administered to patients undergoing treatment.
  • Subject is intended to include animals. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a brain tumor disease.
  • the subject or warm-blooded animal is human.
  • the terms “about” or “approximately” usually means within 20%, more preferably within 10%, and most preferably still within 5% of a given value or range. Alternatively, especially in biological systems, the term “about” means within about a log (i.e., an order of magnitude) preferably within a factor of two of a given value.
  • the present disclosure relates to a pharmaceutical combination comprising (1) a CDK inhibitor or a pharmaceutically acceptable salt thereof and (2) an anti-hormonal agent or a pharmaceutically acceptable salt thereof.
  • the present disclosure also relates to a pharmaceutical combination
  • a pharmaceutical combination comprising (1) a CDK inhibitor or a pharmaceutically acceptable salt thereof, (2) an anti-hormonal agent or a pharmaceutically acceptable salt thereof, and (3) an agent that regulates the PI3K/Akt/mTOR pathway or a pharmaceutically acceptable salt thereof.
  • Such combination may be for simultaneous, separate or sequential use for the treatment of a cancer.
  • the CDK inhibitor is CDK4/6 inhibitor.
  • the CDK4/6 inhibitor can be, for example,
  • Compound A3 also known as PD-0332991.
  • Compound A1 is also described by the chemical name 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide.
  • Compound A2 is also described by the chemical name 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yOpyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.
  • Compound A3 is also described by the chemical name 6-Acetyl-8-cyclopentyl-5-methyl-2- ⁇ [5-(1-piperazinyl)-2-pyridinyl]amino ⁇ pyrido[2,3-d]pyrimidin-7(8H)-one.
  • the anti-hormonal agent is an aromatase inhibitor.
  • aromatase inhibitor can be either a non-steroidal aromatase inhibitor or a steroidal aromatase inhibitor.
  • Letrozole (hereinafter referred as Compound B1) is an example of a non-steroidal aromatase inhibitor.
  • Exemestane (hereinafter referred as Compound B2) is an example of a steroidal aromatase inhibitor.
  • the anti-hormonal agent is an estrogen receptor antagonist.
  • Fulvestrant (hereinafter referred as Compound B3) is an example of an estrogen receptor antagonist.
  • the anti-hormonal agent is a selective estrogen receptor modulator.
  • Tamoxifen (hereinafter referred as Compound B4) is an example of a selective estrogen receptor modulator.
  • the agent that regulates the PI3K/Akt/mTOR pathway is a PI3K inhibitor.
  • the PI3K inhibitor can be, for example,
  • Compound C1 is also described by the chemical name (S)-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 ⁇ -amide).
  • Compound C2 is also described by the chemical name 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-(trifluoromethyl)-2-pyrimidinamine.
  • the agent that regulates the PI3K/Akt/mTOR pathway is a mTOR inhibitor.
  • Everolimus (hereinafter referred as Compound C3) is an example of a mTOR inhibitor.
  • the present disclosure further relates to the above pharmaceutical combination(s) for use in the treatment of a cancer.
  • the present disclosure further relates to a method for the treatment of a cancer comprising administering the above pharmaceutical combination(s) in jointly therapeutically effective amount, to a warm-blooded animal, preferably a human, in need thereof.
  • the compounds in the pharmaceutical combination(s) may be administered either as a single pharmaceutical composition, as separate compositions, or sequentially.
  • the present disclosure further relates to a kit comprising the pharmaceutical combination.
  • the Compounds A1-A3, B1-B4, C1-C3 may be incorporated in the combination of the present disclosure in either the form of its free base or any salt thereof.
  • Salts can be present alone or in mixture with free compound, e.g. the compound of the formula A1, and are preferably pharmaceutically acceptable salts.
  • Such salts of the compounds of formula A1 are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula A1 with a basic nitrogen atom.
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, e.g., succinic acid, carboxylic acids or sulfonic acids, such as fumaric acid or methansulfonic acid.
  • succinic acid carboxylic acids or sulfonic acids, such as fumaric acid or methansulfonic acid.
  • carboxylic acids or sulfonic acids such as fumaric acid or methansulfonic acid.
  • pharmaceutically unacceptable salts for example picrates or perchlorates.
  • only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
  • Compounds A1-A3, B1-B4, C1-C3 can be synthesized by one skilled in the art. Specifically, Compound A1 is disclosed as Example 74 of WO2010/020675; Compound A2 is disclosed in WO2011/101409; Compound C1 is disclosed as Example 15 of WO2010/029082; and Compound C2 is disclosed as Example 10 of WO2007/084786.
  • Suitable aromatase inhibitors include, but are not limited to,
  • Comprised are likewise the pharmaceutically acceptable salts thereof, the corresponding racemates, diastereoisomers, enantiomers, tautomers, as well as the corresponding crystal modifications of above disclosed compounds where present, e.g. solvates, hydrates and polymorphs, which are disclosed therein.
  • the compounds used as active ingredients in the combinations of the present disclosure can be prepared and administered as described in the cited documents, respectively. Also within the scope of this disclosure is the combination of more than two separate active ingredients as set forth above, i.e., a pharmaceutical combination within the scope of this disclosure could include three active ingredients or more.
  • the combination(s) of the present disclosure possesses beneficial therapeutic properties, e.g. synergistic interaction, strong in vitro or in vivo anti-proliferative activity and/or strong in vitro or in vivo antitumor response, which render it particularly useful for the treatment of cancer.
  • Suitable cancers that can be treated with the combination of the present disclosure include, but are not limited to, sarcoma, lymphomas, cancer of the lung, bronchus, prostate, breast (including sporadic breast cancers and sufferers of Cowden disease), pancreas, gastrointestine, colon, rectum, colon, colorectal adenoma, thyroid, liver, intrahepatic bile duct, hepatocellular, adrenal gland, stomach, gastric, glioma, glioblastoma, endometrial, melanoma, kidney, renal pelvis, urinary bladder, uterine corpus, cervix, vagina, ovary, multiple myeloma, esophagus, a leukaemia, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, brain, a carcinoma of the brain, oral cavity and pharynx, larynx, small
  • metastasis in the original organ or tissue and/or in any other location are implied alternatively or in addition, whatever the location of the tumor and/or metastasis.
  • the combination of the present disclosure is particularly useful for the treatment of a cancer mediated by phosphatidylinositol 3-kinase (PI3K), particularly the alpha-subunit of PI3K.
  • Proliferative diseases may include those showing overexpression or amplification of PI3K alpha, somatic mutation of PIK3CA or germline mutations or somatic mutation of PTEN or mutations and translocation of p85 ⁇ that serve to up-regulate the p85-p110 complex.
  • the cancer is a tumor and/or cancerous growth mediated by the alpha isoform of PI3K.
  • Disease may include those showing overexpression or amplification of the alpha-isoform of PI3K and/or somatic mutation of PIK3CA.
  • Hormone sensitive cancers may include, but are not limited to, breast cancer, endometrial cancer, ovarian cancer, and/or cervical cancer.
  • Hormone-receptor positive cancers may include estrogen receptor positive cancers (i.e., cancer that grows in response to the hormone estrogen) or progesterone receptor positive cancers (ie., cancer that grows in response to the hormone progesterone.
  • the hormone receptor positive cancer is estrogen receptor positive breast cancer.
  • the cancer is a solid tumor.
  • the cancer is selected from the group consisting of cancer of the breast, endometrial, ovary and cervix.
  • the cancer is a cancer showing both (a) overexpression or amplification of the alpha-isoform of PI3K and/or somatic mutation of PIK3CA, and (b) hormone receptor positive status.
  • the cancer is breast cancer.
  • the cancer is a breast cancer having either hormone receptor positive, a mutation in the PIK3CA, or a combination thereof. More preferably, the cancer is estrogen receptor positive (+) breast cancer.
  • the cancer is a hormone receptor positive (+) breast cancer resistant to treatment with hormone therapy (e.g., estrogen or progesterone).
  • hormone therapy e.g., estrogen or progesterone
  • a cancer “resistant to treatment with hormone therapy” refers to a cancer or tumor that either fails to respond favorably to treatment with prior hormone therapy, or alternatively, recurs or relapses after responding favorably to hormone therapy. Said hormone therapy is understood to be in the absence of a PI3K inhibitor.
  • the cancer or tumor may be resistant or refractory at the beginning of treatment or it may become resistant or refractory during treatment.
  • It is one objective of this disclosure to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective at targeting or preventing a cancer, of each therapeutic agent of the disclosure.
  • agents in the composition of the present disclosure may be administered together in a single pharmaceutical composition, separately in two or more separate unit dosage forms, or sequentially.
  • the unit dosage form may also be a fixed combination.
  • compositions for separate administration of agents or for the administration in a fixed combination 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 subjects, including mammals (warm-blooded animals) such as humans, comprising a therapeutically effective amount of at least one pharmacologically active combination partner alone, e.g., as indicated above, or in combination with one or more pharmaceutically acceptable carriers or diluents, especially suitable for enteral or parenteral application.
  • Suitable pharmaceutical compositions contain, e.g., from about 0.1% to about 99.9%, preferably from about 1% to about 60%, of the active ingredient(s).
  • compositions for the combination therapy for enteral or parenteral administration are, e.g., those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, ampoules, injectable solutions or injectable suspensions.
  • Topical administration is e.g. to the skin or the eye, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form. If not indicated otherwise, these are prepared in a manner known per se, e.g., by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of each agent contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.
  • compositions may comprise one or more pharmaceutical acceptable carriers or diluents and may be manufactured in conventional manner by mixing one or both combination partners with a pharmaceutically acceptable carrier or diluent.
  • pharmaceutically acceptable diluents include, but are not limited to, lactose, dextrose, mannitol, and/or glycerol, and/or lubricants and/or polyethylene glycol.
  • Examples of pharmaceutically acceptable acceptable binders include, but are not limited to, magnesium aluminum silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, pharmaceutically acceptable disintegrators include, but are not limited to, starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. It is also possible to use the compounds of the present disclosure in the form of parenterally administrable compositions or in the form of infusion solutions.
  • compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting compounds and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
  • excipients for example preservatives, stabilizers, wetting compounds and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
  • a therapeutically effective amount of each of the combination partner of the combination of the disclosure may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
  • the method of preventing or treating a cancer according to the disclosure may comprise: (i) administration of the first agent in free or pharmaceutically acceptable salt form; and (ii) administration of a second agent in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g., in daily or intermittently dosages corresponding to the amounts described herein.
  • the individual combination partners of the combination of the disclosure may be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • administering also encompasses the use of a pro-drug of a combination partner that convert in vivo to the combination partner as such.
  • the instant disclosure is therefore to be understood as embracing all such regimens of simultaneous or alternating treatment and the term “administering” is to be interpreted accordingly.
  • each of combination partner agents employed in the combination of the disclosure may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition being treated.
  • the dosage regimen of the combination of the disclosure is 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; the route of administration; the renal and hepatic function of the patient; and the particular compound employed.
  • a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • a further benefit is that lower doses of the active ingredients of the combination of the disclosure can be used, e.g., that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
  • the combination of the agents can be combined in the same pharmaceutical preparation or in the form of combined preparations “kit of parts” in the sense that the combination partners can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners, i.e., simultaneously or at different time points.
  • the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the present disclosure further relates to a kit comprising a first compound selected from the group consisting of Compounds A1-A3 or pharmaceutically acceptable salts thereof, a second compound selected from the group consisting of Compounds B1-B4 or pharmaceutically acceptable salts thereof, and a package insert or other labeling including directions for treating a cancer.
  • the present disclosure further relates to a kit comprising a first compound selected from the group consisting of Compounds A1-A3 or pharmaceutically acceptable salts thereof, a second compound selected from the group consisting of Compounds B1-B4 or pharmaceutically acceptable salts thereof, a third compound selected from the group consisting of Compounds C1-C3 or pharmaceutically acceptable salts thereof, and a package insert or other labeling including directions for treating a cancer.
  • Compound A1 (a CDK4/6 inhibitor, 10 mM), Compound B1 (Letrozole, Sigma, 10 mM), Compound B3 (Fulvestrant, Sigma, 10 mM), Compound B2 (Exemestane, Sigma, 10 mM), Compound C1 (a PI3K inhibitor, 10 mM), Compound C3 (an mTor inhibitor, 10 mM) and Compound C2 (a PI3K inhibitor, 10 mM) were dissolved in DMSO.
  • ⁇ 4A the precursor androstenedione 10 mM
  • All these reagents were stored in aliquots at ⁇ 20° C.
  • MCF7 human breast carcinoma cells were provided by Dr. Chen Shivan (City of Hope National Medical Center, CA, USA), which were stably transfected with the aromatase expression vector bearing the neomycin (G418) resistance gene (also named MCF7/Aro).
  • Aromatase converts the precursor androstenedione ( ⁇ 4A) into 17 ⁇ -estradiol (E2), which is required for the proliferation of the host cell line. Unless otherwise mentioned, all cell culture reagents were obtained from Invitrogen.
  • Cells were maintained in MEM (#11095-080) supplemented with 10% v/v fetal bovine serum (FBS, #10099-141), 1 mM sodium pyruvate (#11360-070), 1% v/v non-essential amino acids (#11140-050) and G418 (geneticin, #10131) in a humidified incubator at 37° C. in 5% CO2. The cells were passaged twice a week and the medium was changed every 2 to 3 days. To assess estrogen driven cell proliferation, it was necessary to deplete the medium of steroids.
  • SD steroid-depleted
  • MEM steroid-depleted medium
  • charcoal stripped FBS #12676-029
  • Glutamax #35050-061
  • MCF7/Aro cells were steroid deprived for 3 days before trypsinized using TryPLE Express (#12604-013, without phenol red) and 1500 cells/well were plated on clear-bottom 384-well black plates (Greiner, #781091) in triplicates with 30 ⁇ l/well growth media, cells were allowed to attach overnight and were followed by 6 days of incubation with 10 nM of ⁇ 4A and various concentrations of drugs or drug combinations (10 ⁇ l/well). Cell viability was determined by measuring cellular ATP content using the CellTiter-Glo® (CTG) luminescent cell viability assay (Promega). Each single agent and combination treatment of cells was compared to controls (cells treated with an equivalent volume of medium).
  • CTG CellTiter-Glo®
  • Compound A1 Compound B1 (Letrozole), Compound B2 (Exemestane) and Compound B3 (Fulvestant) were in multiple doses, and Compound C1, Compound C2 and Compound C3 were in a single dose as a background compounds (doses as labeled above) in all the triple combinations.
  • the “dose matrix, Compound A1/Compound B1, Compound A1/Compound B3 and Compound A1/Compound B2” were consisted of the followings:
  • Example 1 The results from Example 1 are shown in FIGS. 1-7 .
  • Compound A2 (a CDK4/6 inhibitotor, 10 mM), Compound A3 (a CDK4/6 inhibitor, 10 mM), Compound B1 (Letrozole, Sigma, 10 mM), Compound B3 (Fulvestrant, Sigma, 10 mM), Compound B2 (Exemestane, Sigma, 10 mM), Compound C1 (a PI3K inhibitor, 10 mM), and Compound C3 (an mTor inhibitor, 10 mM) were dissolved in DMSO.
  • ⁇ 4A the precursor androstenedione, 10 mM
  • All these reagents were stored in aliquots at ⁇ 20° C.
  • MCF7 human breast carcinoma cells were provided by Dr. Chen Shivan (City of Hope National Medical Center, CA, USA), which were stably transfected with the aromatase expression vector bearing the neomycin (G418) resistance gene (also named MCF7/Aro).
  • Aromatase converts the precursor androstenedione ( ⁇ 4A) into 17 ⁇ -estradiol (E2), which is required for the proliferation of the host cell line. Unless otherwise mentioned, all cell culture reagents were obtained from Invitrogen.
  • Cells were maintained in MEM (#11095-080) supplemented with 10% v/v fetal bovine serum (FBS, #10099-141), 1 mM sodium pyruvate (#11360-070), 1% v/v non-essential amino acids (#11140-050) and G418 (geneticin, #10131) in a humidified incubator at 37° C. in 5% CO2. The cells were passaged twice a week and the medium was changed every 2 to 3 days. To assess estrogen driven cell proliferation, it was necessary to deplete the medium of steroids.
  • SD steroid-depleted
  • MEM steroid-depleted medium
  • charcoal stripped FBS #12676-029
  • Glutamax #35050-061
  • MCF7/Aro cells were steroid deprived for 3 days before trypsinized using TryPLE Express (#12604-013, without phenol red) and 1500 cells/well were plated on clear-bottom 384-well black plates (Greiner, #781091) in triplicates with 30 ⁇ l/well growth media, cells were allowed to attach overnight and were followed by 6 days of incubation with 10 nM of A4A and various concentrations of drugs or drug combinations (10 ⁇ l/well).
  • Cell viability was determined by measuring cellular ATP content using the CellTiter-Glo® (CTG) luminescent cell viability assay (Promega). Each single agent and combination treatment of cells was compared to controls (cells treated with an equivalent volume of medium).
  • Compound A2 Compound A3, Letrozole (Compound B1), Exemestane (Compound B2) and Fulvestant (Compound B3) were in multiple doses, and Compound C1 (1 uM) and Compound C2 (20 nM) were in a single dose as a background in all the triple combinations.
  • the “dose matrix, Compound A2/Compound B1, Compound A2/Compound B3, Compound A2/Compound B2, Compound A3/Compound B1, Compound A3/Compound B3 and Compound A3/Compound B2” were consisted of the followings:
  • Example 2 The results from Example 2 are shown in FIGS. 8-19 .
  • Phase Ib part is a three-part dose escalation study to estimate the MTD and/or RP2D for two double combinations: Compound A1 with letrozole and Compound C1 with letrozole followed by estimation of the MTD and/or RP2D of the triple combination of Compound A1+Compound C1 with letrozole.
  • the three-part Phase Ib will be followed by a randomized Phase II study to assess the preliminary anti-tumor activity of the two double combination regimens (Compound A1+letrozole and Compound C1+letrozole) versus the triple combination (Compound A1+Compound C1 with letrozole) and to further evaluate their safety in patients with ER+/HER2 ⁇ locally advanced or metastatic breast cancer.
  • MTD maximum tolerated dose
  • R2D recommended Phase II dose
  • PK pharmacokinetic
  • BLRM Bayesian Logistic Regression Model
  • PK assessments were conducted prior to dose-escalation decisions during the study to monitor exposure and evaluate possibility of cytochrome P450-mediated drug-drug interactions.
  • the BLRM Upon determination of the MTD/RP2D in Arms 1 and 2, the BLRM will be updated with the most recent data from the dose-escalation in Arms 1 and 2, and this will be used to determine the starting dose for Arm 3.
  • Representative tumor specimen (archival or new) available for molecular testing (unless otherwise agreed).
  • Tumor response evaluated locally by the investigator, using computerized tomography and magnetic resonance imaging, based on Response Evaluation Criteria In Solid Tumors v1.1. Evaluations conducted at baseline, every 8 weeks through to Cycle 6, every 12 weeks thereafter (or sooner if there is clinical evidence of disease progression), and at end of treatment.
  • DLTs dose-limiting toxicities
  • Duration of exposure to treatment is shown in FIGS. 24 and 25 .
  • Neutropenia is an anticipated side effect of Compound A1, potentially due to inhibition of proliferation via CDK4/6 inhibition.
  • Hyperglycemia observed in Arm 2 may be an on-target effect of PI3K inhibition.
  • a multi-center, pre-surgical, randomized, phase II study is planned, to assess the biological activity of Compound A1, 400 mg or 600 mg daily, in combination with letrozole 2.5 mg daily, as compared to single agent letrozole daily in postmenopausal patients with newly diagnosed HR+, HER2-negative, early breast cancer.
  • a total of approximately 120 patients will be randomized. Patients will receive trial therapy for 14 days ( ⁇ 3 days) and then undergo surgery. Patients will be randomly assigned to treatment with:
  • the primary objective of the study is to assess the cell cycle response rate defined as the percentage of patients who achieve a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 (Baselga 2009). Although the trial is designed as open label, all pharmacodynamics and clinical pharmacology endpoints will be assessed by experts who are blinded to randomized treatment.
  • a Phase Ib/II Trial of Compound A1 with everolimus and exemestane in the treatment of ER+Her2 ⁇ Advanced Breast Cancer is on-going.
  • the purpose of the trial is to estimate the MTD(s) and/or RP2D of Compound A1 in combination with everolimus+exemestane, and Compound A1 in combination with exemestane, and to characterize the safety and tolerability of the combinations of everolimus+exemestane ⁇ Compound A1 and Compound A1+exemestane in patients with ER+HER2 ⁇ advanced breast cancer.
  • the study consists of 3 arms:
  • Compound A1 + everolimus + Compound A1 is taken orally once per exemestane triple combination day for 21 days of each 28 day cycle. Exemestane is taken orally once per day. Everolimus is taken orally once per day. Compound A1 + exemestane Compound A1 is taken orally once per double combination day for 21 days of each 28 day cycle Exemestane is taken orally once per day. everolimus + exemestane Exemestane is taken orally once per day. double combination Everolimus is taken orally once per day. Compound A1 comes in 50 mg and 200 mg capsules. Exemestane comes in 25 mg tablets. Everolimus comes in 2.5 mg, 5 mg, and 7.5 mg tablets. The objectives of the Phase Ib portion of this study are:
  • PK pharmacokinetics
  • Phase Ib portion of this Phase Ib/II multicenter, open-label study postmenopausal women with ER+/HER2 ⁇ advanced BC, resistant to letrozole or anastrozole, are being treated with escalating doses of Compound A1+EVE+EXE (25 mg/day) or a safety run-in of Compound A1 (600 mg/day)+EXE (25 mg/day; FIG. 27 ).
  • Dose escalation is being guided by the adaptive Bayesian Logistic Regression Model along with the Escalation with Overdose Control principle and PK was assessed prior to dose-escalation decisions.
  • Representative tumor specimen (archival or new) available for molecular testing.
  • Tumor response assessed locally by the investigator using computerized tomography or magnetic resonance imaging according to Response Evaluation Criteria In Solid Tumors v1.1 at baseline and on Day (D) 1 of Cycles (C) 3, 5, and 7, on D1 of every 4th subsequent cycle (or sooner if clinically indicated), and at the end of treatment.
  • PK evaluations for Compound A1 and EVE performed in patients treated with Compound A1+EVE+EXE during C1 on D1, 2, 8, 15, 16, and 21, and D1 of each subsequent cycle up to and including C6.
  • Tumor samples analyzed by next-generation sequencing to determine any alterations in genes of interest.
  • N 16
  • DLTs dose-limiting toxicities
  • FIGS. 28 and 29 Mean plasma concentration-time profiles for Compound A1 and EVE in patients treated with Compound A1+EVE+EXE on C1 D15 are shown in FIGS. 28 and 29 .
  • a Phase Ib/II trial is planned.
  • the trial will have 3 arms as described below:
  • Compound A1 Compound A1 600 mg each day, 21 days on, and 7 days off; Fulvestrant Fulvestrant: 500 mg IM Day 1 and 15, followed by Q month Compound A1 Compound A1: 400 mg each day, and 21 days on, 7 days off; Compound C2 Compound C2: 20 mg each day continuous; and Fulvestrant Fulvestrant: 500 mg IM Day 1 and 15, followed by Q month Compound A1 Compound A1: 400 mg each day, 21 days on, and 7 days off; Compound C1 Compound C1: 100 mg each day continuous; and Fulvestrant Fulvestrant: 500 mg IM Day 1 and 15, followed by Q month
  • This on-going study aims at determining antitumor efficacy of various compounds used as single agent, in double or in triple combination in the HBCx-34 human breast patient-derived xenograft model.
  • HBCx-34 The xenograft model proposed in this study is HBCx-34.
  • HBCx-34 is a ductal carcinoma with wild type P53, no HER2 overexpression and PR and ER ⁇ overexpression.
  • the tumor is highly responsive to adriamycine/cyclophosphamide and responsive to docetaxel and capecitabine.
  • HBCx-34 has got no cachexia properties, but no body weight gain is observed for HBCx-34 bearing mice.
  • HBCx-34 breast tumor-bearing mice will receive estrogen diluted in drinking water (R-oestradiol, 8.5 mg/I), from the date of tumor implant to the date of inclusion. No estrogen will be added during the rest of the study.
  • mice Female athymic nude mice (Hsd:Athymic Nude-Fox1nu), 6- to 9-week-old at the beginning of the experimental phase, will be obtained from Harlan Laboratories (Gannat, France). Animals will be maintained in specific pathogen-free animal housing at the Center for Exploration and Experimental Functional Research (CERFE, Evry, France) animal facility. Animals will be delivered to the laboratory at least 7 days before the experiments during which time they are acclimatized to laboratory conditions. Mice will be housed in groups of a maximum of 7 animals during acclimation period and 5 animals during experimental phase.
  • CERFE Exploration and Experimental Functional Research
  • mice will be housed inside individually ventilated cages (IVC) of Polysulfone (PSU) plastic (mm 213 W ⁇ 362 D ⁇ 185 H, Allentown, USA) with sterilized and dust-free bedding cobs. Food and water will be sterilized. Animals will be housed under a light-dark cycle (14-hour circadian cycle of artificial light) and controlled room temperature and humidity.
  • IVC individually ventilated cages
  • PSU Polysulfone
  • Compound A1 75 mg/kg free base, p.o. Volume of administration: 5 ml/kg (i.e. 125 ⁇ l for a 25 g mouse) Route of administration: p.o. Form: solution Vehicle: 0.5% Methylcellulose in water Concentration: 15 mg/ml free base Compound C2: 30 and 20 mg/kg free base, p.o.
  • Letrozole (Compound B1) 2.5 mg/kg (Femara®, Novartis) Volume of administration: 5 ml/kg (i.e. 125 ⁇ l for a 25 g mouse) Route of administration: p.o.
  • Tumors of the same passage will be transplanted subcutaneously onto 5-10 mice (donor mice, passage (n ⁇ 1)). When these tumors reach 1000 to 2000 mm 3 , donor mice will be sacrificed by cervical dislocation, tumors will be aseptically excised and dissected. After removing necrotic areas, tumors will be cut into fragments measuring approximately 20 mm 3 and transferred in culture medium before grafting.
  • Mice will be anaesthetized with ketamine/xylazine, and then skin will be aseptized with a chlorhexidine solution, incised at the level of the interscapular region, and a 20 mm 3 tumor fragment will be placed in the subcutaneous tissue. Skin will be closed with clips.
  • mice from the same experiment will be implanted on the same day.
  • mice Healthy mice aged 6 to 9 weeks and weighing at least 20 g will be included in the study. Mice will be allocated to different groups according to their tumor volume to give homogenous mean and median tumor volume in each treatment arms. Treatments will be randomly attributed to cages housing up to 5 mice.
  • mice with established tumors and average tumor volume ranging 108 (6 ⁇ 6) to 288 (9 ⁇ 8) mm 3 will be included in the study.
  • group size may be reduced (up to 8 mice/group) and/or inclusion may be staggered.
  • Tumor volume will be evaluated by measuring tumor diameters, with a calliper, biweekly during the treatment period and once a week during the follow-up period.
  • the formula TV (mm 3 ) [length (mm) ⁇ width (mm) 2 ]/2 will be used, where the length and the width are the longest and the shortest diameters of the tumor, respectively.
  • Tumors will not be weighed at the end of experimental phase.
  • All animals will be weighted biweekly during the treatment period and once a week during the follow-up period.
  • Day 0 will be always considered the first day of treatment.
  • the days of the experiment will be subsequently numbered according to this definition. Recordings will be expressed as mean+/ ⁇ standard error of the mean (mean+/ ⁇ sem) and median+/ ⁇ interquartile (median+/ ⁇ IQR).
  • FIGS. 20-22 illustrates some results of this study.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Plant Substances (AREA)
US14/911,160 2013-08-14 2014-08-07 Combination Therapy for the Treatment of Cancer Abandoned US20160184311A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/911,160 US20160184311A1 (en) 2013-08-14 2014-08-07 Combination Therapy for the Treatment of Cancer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201361865804P 2013-08-14 2013-08-14
US201361894029P 2013-10-22 2013-10-22
PCT/IB2014/063782 WO2015022609A1 (en) 2013-08-14 2014-08-07 Combination therapy for the treatment of cancer
US14/911,160 US20160184311A1 (en) 2013-08-14 2014-08-07 Combination Therapy for the Treatment of Cancer

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2014/063782 A-371-Of-International WO2015022609A1 (en) 2013-08-14 2014-08-07 Combination therapy for the treatment of cancer

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/998,710 Continuation US20190046533A1 (en) 2013-08-14 2018-08-16 Combination therapy for the treatment of cancer

Publications (1)

Publication Number Publication Date
US20160184311A1 true US20160184311A1 (en) 2016-06-30

Family

ID=51355593

Family Applications (7)

Application Number Title Priority Date Filing Date
US14/911,160 Abandoned US20160184311A1 (en) 2013-08-14 2014-08-07 Combination Therapy for the Treatment of Cancer
US15/998,710 Abandoned US20190046533A1 (en) 2013-08-14 2018-08-16 Combination therapy for the treatment of cancer
US17/504,177 Abandoned US20220193079A1 (en) 2013-08-14 2021-10-18 Combination therapy for the treatment of cancer
US18/450,594 Pending US20230398121A1 (en) 2013-08-14 2023-08-16 Combination therapy for the treatment of cancer
US18/450,559 Pending US20230405011A1 (en) 2013-08-14 2023-08-16 Combination therapy for the treatment of cancer
US18/469,975 Pending US20240016808A1 (en) 2013-08-14 2023-09-19 Combination therapy for the treatment of cancer
US18/479,410 Pending US20240066034A1 (en) 2013-08-14 2023-10-02 Combination therapy for the treatment of cancer

Family Applications After (6)

Application Number Title Priority Date Filing Date
US15/998,710 Abandoned US20190046533A1 (en) 2013-08-14 2018-08-16 Combination therapy for the treatment of cancer
US17/504,177 Abandoned US20220193079A1 (en) 2013-08-14 2021-10-18 Combination therapy for the treatment of cancer
US18/450,594 Pending US20230398121A1 (en) 2013-08-14 2023-08-16 Combination therapy for the treatment of cancer
US18/450,559 Pending US20230405011A1 (en) 2013-08-14 2023-08-16 Combination therapy for the treatment of cancer
US18/469,975 Pending US20240016808A1 (en) 2013-08-14 2023-09-19 Combination therapy for the treatment of cancer
US18/479,410 Pending US20240066034A1 (en) 2013-08-14 2023-10-02 Combination therapy for the treatment of cancer

Country Status (20)

Country Link
US (7) US20160184311A1 (pt)
EP (2) EP3033086B1 (pt)
JP (2) JP2016528246A (pt)
KR (4) KR102529049B1 (pt)
CN (2) CN110368497B (pt)
AU (3) AU2014307633A1 (pt)
BR (1) BR112016002465B1 (pt)
CA (1) CA2918190C (pt)
CY (1) CY1124810T1 (pt)
DK (1) DK3033086T3 (pt)
ES (1) ES2900829T3 (pt)
HR (1) HRP20211879T1 (pt)
HU (1) HUE057061T2 (pt)
LT (1) LT3033086T (pt)
MX (2) MX378263B (pt)
PL (1) PL3033086T3 (pt)
PT (1) PT3033086T (pt)
RU (1) RU2680714C2 (pt)
SI (1) SI3033086T1 (pt)
WO (1) WO2015022609A1 (pt)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110996962A (zh) * 2017-08-03 2020-04-10 诺华股份有限公司 第三代egfr酪氨酸激酶抑制剂和周期素d激酶抑制剂的治疗组合
WO2022184146A1 (zh) * 2021-03-03 2022-09-09 正大天晴药业集团股份有限公司 Cdk4/6抑制剂的联用药物组合物及其用途
WO2022218956A1 (en) * 2021-04-12 2022-10-20 Sanofi Combination comprising ribociclib and amcenestrant
WO2022218958A1 (en) * 2021-04-12 2022-10-20 Sanofi Combination comprising everolimus and amcenestrant
WO2023046200A1 (zh) * 2021-09-27 2023-03-30 正大天晴药业集团股份有限公司 Cdk4/6抑制剂和芳香酶抑制剂的联用药物组合物
US11713296B2 (en) 2018-09-07 2023-08-01 Sanofi Salts of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-l-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate and preparation process thereof

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX376083B (es) 2015-06-04 2025-03-07 Pfizer Formas de dosificacion solidas de palbociclib.
CN105130992B (zh) * 2015-07-16 2018-02-09 苏州大学 具有激酶抑制活性的含氮杂环化合物、制备方法和用途
WO2017021177A1 (en) * 2015-08-04 2017-02-09 Universitat De Barcelona Pharmaceutical combinations for use in the treatment of cancer
CN108348514A (zh) * 2015-08-28 2018-07-31 诺华股份有限公司 含pi3k抑制剂alpelisib和cdk4/6抑制剂ribociclib的药物组合以及其在治疗/预防癌症中的应用
JP2018525402A (ja) * 2015-08-28 2018-09-06 ノバルティス アーゲー Ｐｉ３ｋ阻害剤のアルペリシブおよびｂ−ｒａｆ阻害剤のダブラフェニブを含む組合せ医薬、がんの治療または予防におけるそのような組合せの使用
EP3402529A1 (en) 2016-01-11 2018-11-21 Syndevrx, Inc. Treatment for tumors driven by metabolic dysfunction
CN107137409A (zh) * 2016-03-01 2017-09-08 江苏恒瑞医药股份有限公司 一种cdk4/6抑制剂与雌激素受体拮抗剂联合在制备治疗乳腺癌的药物中的用途
CN107137408A (zh) * 2016-03-01 2017-09-08 江苏恒瑞医药股份有限公司 一种cdk4/6抑制剂与芳香化酶抑制剂联合在制备治疗乳腺癌的药物中的用途
US20190091227A1 (en) * 2016-03-15 2019-03-28 Merrimack Pharmaceuticals, Inc. Methods for treating er+, her2-, hrg+ breast cancer using combination therapies comprising an anti-erbb3 antibody
US10449195B2 (en) 2016-03-29 2019-10-22 Shenzhen Pharmacin Co., Ltd. Pharmaceutical formulation of palbociclib and a preparation method thereof
WO2018001270A1 (en) * 2016-06-30 2018-01-04 Noratech Pharmaceuticals, Inc. Palbociclib prodrugs and composition thereof
WO2018017410A1 (en) 2016-07-22 2018-01-25 Eli Lilly And Company Combination therapy of abemaciclib and a pi3 kinase/mtor dual inhibitor for use in the treatment of breast cancer
AU2017315357B2 (en) * 2016-08-23 2022-12-01 Eisai R&D Management Co., Ltd. Combination therapies for the treatment of hepatocellular carcinoma
MA47776A (fr) * 2017-03-16 2020-01-22 Eisai R&D Man Co Ltd Polythérapies pour le traitement du cancer du sein
EP3434272A1 (en) * 2017-07-25 2019-01-30 Sanofi Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid
WO2019097426A1 (en) 2017-11-16 2019-05-23 Novartis Ag Pharmaceutical combination comprising lsz102 and ribociclib
WO2019106604A1 (en) 2017-12-01 2019-06-06 Novartis Ag Pharmaceutical combination comprising lsz102 and alpelisib
WO2021110122A1 (zh) * 2019-12-05 2021-06-10 基石药业（苏州）有限公司 Cdk4/6抑制剂的组合疗法
EP4149476A1 (en) * 2020-05-12 2023-03-22 Genentech, Inc. Treatment of breast cancer using combination therapies comprising gdc-9545 and a cdk4/6 inhibitor
CN114306245A (zh) 2020-09-29 2022-04-12 深圳市药欣生物科技有限公司 无定形固体分散体的药物组合物及其制备方法
WO2022199656A1 (zh) * 2021-03-24 2022-09-29 贝达药业股份有限公司 药物组合、包含其的试剂盒及其用途
KR102658209B1 (ko) * 2021-10-05 2024-04-18 재단법인 아산사회복지재단 Cdk 억제제 및 id2 활성화제를 포함하는 방광암의 예방 또는 치료용 약학 조성물
JP2024540529A (ja) * 2021-11-18 2024-10-31 オンコノヴァ セラピューティクス， インコーポレイテッド がんを処置するための方法および組成物
MX2024006678A (es) * 2021-12-02 2024-06-19 Pfizer Inhibidor de cdk4 para el tratamiento del cancer.
WO2024107955A1 (en) * 2022-11-17 2024-05-23 Onconova Therapeutics, Inc. Methods and compositions for treating cancer
WO2024115680A1 (en) 2022-12-01 2024-06-06 Krka, D.D., Novo Mesto Ribociclib salts and formulations thereof
WO2024201299A1 (en) 2023-03-27 2024-10-03 Novartis Ag Method of treating early breast cancer with ribociclib in combination with an aromatase inhibitor

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4978672A (en) 1986-03-07 1990-12-18 Ciba-Geigy Corporation Alpha-heterocyclc substituted tolunitriles
US4749713A (en) 1986-03-07 1988-06-07 Ciba-Geigy Corporation Alpha-heterocycle substituted tolunitriles
JP2710053B2 (ja) 1988-07-05 1998-02-10 スズキ株式会社 自動車の車体構造
US7196092B2 (en) * 2002-09-04 2007-03-27 Schering Corporation N-heteroaryl pyrazolopyrimidines as cyclin dependent kinase inhibitors
US7605155B2 (en) * 2002-09-04 2009-10-20 Schering Corporation Substituted pyrazolo[1,5-a]pyrimidines as protein kinase inhibitors
US20070104721A1 (en) * 2005-11-04 2007-05-10 Wyeth Antineoplastic combinations with mTOR inhibitor,herceptin, and/or hki-272
BRPI0618473A2 (pt) * 2005-11-11 2011-08-30 Pfizer combinações e métodos de uso de um oligodeoxinucleotìdeo imunomodulador
JO2660B1 (en) 2006-01-20 2012-06-17 نوفارتيس ايه جي Pi-3 inhibitors and methods of use
PT2331547E (pt) 2008-08-22 2014-10-29 Novartis Ag Compostos de pirrolopirimidina como inibidores de cdk
UA104147C2 (uk) 2008-09-10 2014-01-10 Новартис Аг Похідна піролідиндикарбонової кислоти та її застосування у лікуванні проліферативних захворювань
US20120114636A1 (en) * 2009-03-11 2012-05-10 The Board Of Regents Of The University Of Texas System Low molecular weight cyclin e (lmw-e) as a biomarker for personalization of cancer therapies
WO2011010349A1 (ja) 2009-07-23 2011-01-27 株式会社アドバンテスト 試験装置
UY33227A (es) 2010-02-19 2011-09-30 Novartis Ag Compuestos de pirrolopirimidina como inhibidores de la cdk4/6
UY33226A (es) 2010-02-19 2011-09-30 Novartis Ag Compuestos de pirrolopirimidina deuterada como inhibidores de la cdk4/6
RU2589696C2 (ru) * 2010-04-13 2016-07-10 Новартис Аг КОМБИНАЦИЯ, ВКЛЮЧАЮЩАЯ ИНГИБИТОР ЦИКЛИНЗАВИСИМОЙ КИНАЗЫ 4 ИЛИ ЦИКЛИНЗАВИСИМОЙ КИНАЗЫ 6 (CDK4/6) И ИНГИБИТОР mTOR, ДЛЯ ЛЕЧЕНИЯ РАКА
UY34072A (es) * 2011-05-17 2013-01-03 Novartis Ag Derivados sustituidos de indol
US9271988B2 (en) * 2011-07-01 2016-03-01 Novartis Ag Combination therapy comprising a CDK4/6 inhibitor and a P13K inhibitor for use in the treatment of cancer
WO2019097426A1 (en) * 2017-11-16 2019-05-23 Novartis Ag Pharmaceutical combination comprising lsz102 and ribociclib

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Sanchez et al., "Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer." Breast Cancer Research, 13:R21, 2011, pages 1-17 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110996962A (zh) * 2017-08-03 2020-04-10 诺华股份有限公司 第三代egfr酪氨酸激酶抑制剂和周期素d激酶抑制剂的治疗组合
US11713296B2 (en) 2018-09-07 2023-08-01 Sanofi Salts of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-l-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate and preparation process thereof
US12157721B2 (en) 2018-09-07 2024-12-03 Sanofi Process for the preparation of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate
WO2022184146A1 (zh) * 2021-03-03 2022-09-09 正大天晴药业集团股份有限公司 Cdk4/6抑制剂的联用药物组合物及其用途
WO2022218956A1 (en) * 2021-04-12 2022-10-20 Sanofi Combination comprising ribociclib and amcenestrant
WO2022218958A1 (en) * 2021-04-12 2022-10-20 Sanofi Combination comprising everolimus and amcenestrant
WO2023046200A1 (zh) * 2021-09-27 2023-03-30 正大天晴药业集团股份有限公司 Cdk4/6抑制剂和芳香酶抑制剂的联用药物组合物

Also Published As

Publication number Publication date
PL3033086T3 (pl) 2022-01-31
MX384403B (es) 2025-03-14
KR20240160682A (ko) 2024-11-11
MX2016001793A (es) 2016-05-18
AU2017213541A1 (en) 2017-08-31
US20240016808A1 (en) 2024-01-18
BR112016002465B1 (pt) 2022-09-20
CY1124810T1 (el) 2022-11-25
DK3033086T3 (da) 2022-01-03
SI3033086T1 (sl) 2022-01-31
KR102529049B1 (ko) 2023-05-08
RU2016108667A3 (pt) 2018-07-10
US20230405011A1 (en) 2023-12-21
HRP20211879T1 (hr) 2022-03-04
CA2918190A1 (en) 2015-02-19
EP3033086B1 (en) 2021-09-22
HUE057061T2 (hu) 2022-04-28
RU2680714C2 (ru) 2019-02-26
CN110368497A (zh) 2019-10-25
RU2016108667A (ru) 2017-09-14
RU2019104078A (ru) 2019-04-08
AU2019202674B2 (en) 2020-07-23
KR20210132219A (ko) 2021-11-03
KR102736746B1 (ko) 2024-12-03
CN105828822A (zh) 2016-08-03
BR112016002465A2 (pt) 2017-08-01
CN105828822B (zh) 2019-10-18
EP4005573A1 (en) 2022-06-01
US20190046533A1 (en) 2019-02-14
MX378263B (es) 2025-03-10
WO2015022609A1 (en) 2015-02-19
US20230398121A1 (en) 2023-12-14
AU2019202674A1 (en) 2019-05-16
AU2014307633A1 (en) 2016-02-11
US20220193079A1 (en) 2022-06-23
ES2900829T3 (es) 2022-03-18
PT3033086T (pt) 2021-12-15
JP2016528246A (ja) 2016-09-15
KR20230067702A (ko) 2023-05-16
AU2017213541B2 (en) 2019-01-24
US20240066034A1 (en) 2024-02-29
CA2918190C (en) 2023-01-17
EP3033086A1 (en) 2016-06-22
KR102318306B1 (ko) 2021-10-28
KR20160041920A (ko) 2016-04-18
LT3033086T (lt) 2021-12-27
CN110368497B (zh) 2022-05-13
JP2019131570A (ja) 2019-08-08
MX2020002150A (es) 2021-07-07

Similar Documents

Publication Publication Date Title
US20240066034A1 (en) Combination therapy for the treatment of cancer
AU2019200881A1 (en) Combination therapy
TWI607754B (zh) 醫藥組合
US20230330106A1 (en) Treatment of breast cancer using combination therapies comprising an atp competitive akt inhibitor, a cdk4/6 inhibitor, and fulvestrant
DK2897644T3 (en) Pharmaceutical combination comprising a phosphatidylinositol 3-kinase inhibitor and an aromatase inhibitor
RU2805145C2 (ru) Комбинированная терапия для лечения рака
TW202110447A (zh) 降低阿帕替尼臨床毒性的方法

Legal Events

Date Code Title Description
AS Assignment

Owner name: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, MASSA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CHEN, YAN;HUANG, XIZHONG;KIM, SUNKYU;REEL/FRAME:037702/0523

Effective date: 20131003

Owner name: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.,

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CHEN, YAN;HUANG, XIZHONG;KIM, SUNKYU;SIGNING DATES FROM 20140310 TO 20140321;REEL/FRAME:037704/0003

Owner name: NOVARTIS AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.;REEL/FRAME:037704/0197

Effective date: 20140523

Owner name: NOVARTIS AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.;REEL/FRAME:037702/0648

Effective date: 20131017

STCB Information on status: application discontinuation

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