US20100298338A1 - Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor kit - Google Patents

Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor kit Download PDF

Info

Publication number
US20100298338A1
US20100298338A1 US12/863,627 US86362709A US2010298338A1 US 20100298338 A1 US20100298338 A1 US 20100298338A1 US 86362709 A US86362709 A US 86362709A US 2010298338 A1 US2010298338 A1 US 2010298338A1
Authority
US
United States
Prior art keywords
imatinib
patient
cmin
kit
pharmaceutically acceptable
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
US12/863,627
Other languages
English (en)
Inventor
Yanfeng Wang
Elisabeth Wehrle
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
Individual
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=40435094&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20100298338(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Priority to US12/863,627 priority Critical patent/US20100298338A1/en
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WANG, YANFENG, WEHRLE, ELISABETH
Publication of US20100298338A1 publication Critical patent/US20100298338A1/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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57446—Specifically defined cancers of stomach or intestine

Definitions

  • the present invention relates to a method of treating proliferative diseases mediated by the tyrosine kinase receptor KIT, in particular gastro-intestinal stromal tumors (GIST), in a human patient population.
  • GIST gastro-intestinal stromal tumors
  • GIST are uncommon visceral sarcoma that arise predominantly in the gastrointestinal tract. GIST are the most common subtype of GI sarcomas, which also include leiomyosarcomas, liposarcomas and other more rare histologic subtypes. GIST have been reported to represent about 3% of all malignant tumours. GIST are most common in the stomach (60 to 70%), followed by small intestine (20-30%).
  • GIST cells are positive for CD117, a cell surface antigen localised on the extracellular domain of the trans-membrane tyrosine kinase receptor KIT, the protein of the proto-oncogene c-KIT and receptor for stem cell factor.
  • KIT Upon binding its ligand, stem cell factor, KIT forms a dimer that is autophosphorylated and activates signaling cascades that lead to cell growth.
  • Mutations that lead to an activated form of KIT are known and are believed to play a role in certain proliferative diseases, such as mast cell diseases, like mastocytosis, particularly systemic mastocytosis, acute myelogenous leukemia, GIST, sinonasal NK/T-cell lymphoma, seminomas and dysgerminomas. It is hypothesized that virtually all malignant GIST harbour mutations of c-KIT as the driving factor of this disease, resulting in constitutive activation of KIT associated with the signal transduction pathway for cell division and tumour growth. KIT overexpression is determined by immunohistochemistry, which is performed in standard practice.
  • the present invention relates to a method for minimizing or avoiding the issues of tolerability, lack of efficacy and the risk of relapse in human patients suffering from a proliferative disease mediated by the tyrosine kinase receptor KIT.
  • the invention is based on the finding that the treatment of a proliferative disease, which is mediated by the tyrosine kinase receptor KIT, comprising the administration of a KIT inhibitor or a pharmaceutically acceptable salt thereof to a patient suffering from such proliferative disease can be optimized by adjusting the dose of the KIT inhibitor or a pharmaceutically acceptable salt thereof applied to an individual vidual patient in a manner that a specific minimum plasma trough level (Cmin) of the KIT inhibitor is achieved in each single patient. It was found that an individual adjustment for each patient is often required in view of high patient intervariability of the Cmin values after administration of KIT inhibitor to each patient.
  • Cmin plasma trough level
  • proliferative disease mediated by the tyrosine kinase receptor KIT should include mast cell diseases, such as mast cell leukemia and systemic mastocytosis, acute myelogenous leukemia (AML), GIST, seminomas, dysgerminomas and metastatic melanoma.
  • mast cell diseases such as mast cell leukemia and systemic mastocytosis, acute myelogenous leukemia (AML), GIST, seminomas, dysgerminomas and metastatic melanoma.
  • proliferative disease mediated by the tyrosine kinase receptor KIT means especially the proliferative disease systemic mastocytosis, particularly aggressive systemic mastocytosis and GIST, more specifically GIST.
  • KIT inhibitor means a therapeutically active compound such as a small organic molecule or an antibody, which inhibits the activity of the tyrosine kinase receptor KIT, more specifically wild type KIT and certain KIT mutations as defined below.
  • the KIT inhibitor inhibits preferably KIT harboring activating mutations.
  • the KIT inhibitor employed in the present invention is Imatinib, which has the structure of formula (I),
  • Compound (I) is a tyrosine kinase inhibitor that selectively inhibits wild type KIT and certain KIT mutations.
  • the mesylate salt of N- ⁇ 5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl ⁇ -4-(3-pyridyl)-2-pyrimidine-amine (Imatinib mesylate, STI571, Glivec®) was approved by the FDA for the treatment of adult patients with CD117 positive unresectable and/or metastatic malignant GIST.
  • the KIT inhibitor employed in the present invention is Nilotinib or a pharmaceutically acceptable salt thereof.
  • Nilotinib is a tyrosine kinase inhibitor that selectively inhibits KIT.
  • the monohydrochloride monohydrate salt of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-phenyl]benzamide (Nilotinib monohydrochloride monohydrate, Tasigna®), which has the structure (II), hereinafter “Compound (II)”,
  • Mutations that lead to an activated form of KIT as referred to herein include, but are not limited to D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del VV559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C and T670I.
  • the present invention provides for the first time an individualized treatment schedule for single patients suffering from a proliferative disease mediated by the tyrosine kinase receptor KIT based on a Cmin lower threshold which was shown to be correlated with an increased overall response (OR) rate and an increased time to progression (TTP).
  • disease mediated by the tyrosine kinase receptor KIT means a disease, wherein KIT is activated by mutations or other molecular mechanisms or overexpressed, in particular to GIST and systemic mastocytosis, more preferably GIST.
  • GIST belongs to the group of disease mediated by the tyrosine kinase receptor KIT.
  • the results obtained with the GIST patient population described herein can be transferred directly to the whole group of disease mediated by the tyrosine kinase receptor KIT.
  • method of treatment as used herein relates also to a method of prevention of the diseases mentioned herein, i.e. the prophylactic administration of a pharmaceutical composition comprising a KIT inhibitor to healthy patients to prevent the development of the diseases mentioned herein.
  • adjusting the dose and “the dose of . . . is adjusted” as used herein preferably denote that the dose referred to is increased or decreased.
  • the terms “adjusting the dose” and the “dose of . . . is adjusted” encompass a situation wherein the dose remains unchanged.
  • the present invention provides a method of treating a proliferative disease mediated by the tyrosine kinase receptor KIT in a human patient wherein the dose of Imatinib or a pharmaceutically acceptable salt thereof is adjusted in a manner that a Cmin of at least 1100 ng/mL, especially between about 1100 and about 2500 ng/mL, preferably a Cmin between 2050 and about 2500 ng/mL, of Imatinib is maintained in said patient.
  • the present invention relates to a method of treating GIST in a human patient comprising the steps of
  • the predetermined fixed amount referred to herein under step (a) represents a therapeutically effective amount.
  • the monomesylate salt of Imatinib is used in step (a), e.g. in an oral daily dose of between about 200 and about 800 mg, preferably in a daily dose of about 400 or 600 mg.
  • Imatinib or a pharmaceutically acceptable salt thereof, especially Imatinib mesylate for the manufacture of a medicament for the treatment of GIST, wherein the dose of the pharmaceutically acceptable salt is adjusted in a manner that a Cmin of at least 1100 ng/mL, especially between about 1100 and about 2500 ng/mL, preferably a Cmin between 2050 and about 2500 ng/mL, of Imatinib is maintained in said patient.
  • the present invention is in particular of benefit for patients with GIST harboring the exon 11 KIT mutation.
  • the OOR was 67% for patients with a Cmin below 1100 ng/mL compared to 100% for patients with a Cmin above 1100 ng/mL.
  • Imatinib is preferably applied in the form of its mono-mesylate salt.
  • Imatinib mono-mesylate can also be prepared in accordance with the processes disclosed in U.S. Pat. No. 6,894,051 the subject-matter of which is hereby incorporated into the present application by reference. Comprised are likewise the corresponding polymorphs, e.g. crystal modifications, which are disclosed therein.
  • a daily dose of between about 200 and about 800 mg, e.g. 400 mg, of the mono-mesylate salt of Imatinib is administered orally.
  • Imatinib mono-mesylate can be administered in dosage forms as described in U.S. Pat. No. 5,521,184, U.S. Pat. No. 6,894,051, US 2005-0267125 or WO2006/121941.
  • the collecting of a blood sample from patients required under the methods described herein can be accomplished by standard procedures being state of the art.
  • a suitable procedure for the determination of the plasma trough level Cmin of Imatinib and N- ⁇ 5-[4-(piperazino-methyl)-benzoylamido]-2-methylphenyl ⁇ -4-(3-pyridyl)-2-pyrimidine-amine was described by R. Bakhtiar R et al. in J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Mar. 5; 768(2):325-40.
  • FIG. 1 depicts the Imatinib trough distribution of the study described in Example 1 (400 mg and 600 mg data combined).
  • PK Pharmacokinetics
  • GIST Unresectable/Metastatic Gastrointestinal Stromal Tumor
  • PURPOSE In the randomized Phase II study (B2222), 147 pts with unresectable/metastatic GIST were randomized 1:1 to receive imatinib (IM) at 400 vs 600 mg daily. Fifty-two (52%) percent of patients are alive for >5 years, regardless of initial dose level. We report the pharmacokinetics (PK) of imatinib (IM) and the relationship between IM levels and clinical response.
  • PK pharmacokinetics
  • the effect of patients demographics and blood chemistry parameters on IM PK was evaluated using a population PK approach.
  • a relationship between IM plasma exposure and clinical outcome was explored by grouping patients into quartiles according to IM trough levels (Cmin).
  • the clinical outcome parameters evaluated include overall objective responses (OOR ⁇ CR+PR+SD), time to progression (TTP), and KIT mutations.
  • Exon 9 KIT mutation was found in only 12 patients with Cmin data, limiting the power of any correlative analyses in this subset.
  • the IM plasma AUC, peak concentration, and Cmin were highly correlated, with IM Cmin having the best correlation with response.
  • IM demonstrated good oral absorption, but large inter-patient variability in IM exposure. Patients with the lowest IM trough levels ( ⁇ 1100 ng/mL) show lowest OOR rate and shortest TTP.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Food Science & Technology (AREA)
  • Hospice & Palliative Care (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US12/863,627 2008-01-23 2009-01-21 Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor kit Abandoned US20100298338A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/863,627 US20100298338A1 (en) 2008-01-23 2009-01-21 Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor kit

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US2294508P 2008-01-23 2008-01-23
US12/863,627 US20100298338A1 (en) 2008-01-23 2009-01-21 Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor kit
PCT/US2009/031510 WO2009094360A1 (en) 2008-01-23 2009-01-21 Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor kit with imatinib

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/031510 A-371-Of-International WO2009094360A1 (en) 2008-01-23 2009-01-21 Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor kit with imatinib

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14/924,207 Continuation US20160045501A1 (en) 2008-01-23 2015-10-27 Method of Optimizing the treatment of Proliferative Diseases Mediated by the Tyrosine Kinase Receptor KIT with Imatinib

Publications (1)

Publication Number Publication Date
US20100298338A1 true US20100298338A1 (en) 2010-11-25

Family

ID=40435094

Family Applications (3)

Application Number Title Priority Date Filing Date
US12/863,627 Abandoned US20100298338A1 (en) 2008-01-23 2009-01-21 Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor kit
US14/924,207 Abandoned US20160045501A1 (en) 2008-01-23 2015-10-27 Method of Optimizing the treatment of Proliferative Diseases Mediated by the Tyrosine Kinase Receptor KIT with Imatinib
US15/297,372 Expired - Fee Related US9763944B2 (en) 2008-01-23 2016-10-19 Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor KIT with imatinib

Family Applications After (2)

Application Number Title Priority Date Filing Date
US14/924,207 Abandoned US20160045501A1 (en) 2008-01-23 2015-10-27 Method of Optimizing the treatment of Proliferative Diseases Mediated by the Tyrosine Kinase Receptor KIT with Imatinib
US15/297,372 Expired - Fee Related US9763944B2 (en) 2008-01-23 2016-10-19 Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor KIT with imatinib

Country Status (14)

Country Link
US (3) US20100298338A1 (enExample)
EP (1) EP2237783B1 (enExample)
JP (2) JP5936821B2 (enExample)
KR (1) KR101579993B1 (enExample)
CN (1) CN101951910B (enExample)
AU (1) AU2009206566A1 (enExample)
BR (1) BRPI0906504A2 (enExample)
CA (1) CA2712087A1 (enExample)
ES (1) ES2526537T3 (enExample)
MX (1) MX2010008103A (enExample)
PL (1) PL2237783T3 (enExample)
PT (1) PT2237783E (enExample)
RU (1) RU2537223C2 (enExample)
WO (1) WO2009094360A1 (enExample)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2753391C1 (ru) * 2020-09-29 2021-08-13 Государственное бюджетное учреждение здравоохранения Московской области "Московский областной научно-исследовательский клинический институт им. М.Ф. Владимирского" (ГБУЗ МО МОНИКИ им. М.Ф. Владимирского) Способ оптимизации лечения стромальных опухолей желудочно-кишечного тракта

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040054186A1 (en) * 1999-04-15 2004-03-18 Jagabandhu Das Cyclic protein tyrosine kinase inhibitors
US20050049268A1 (en) * 2001-11-21 2005-03-03 Francois-Xavier Mahon Use of at least one abl, kit and/or platelet-derived growth factor receptor tyrosine kinases inhibitor for treating hair depigmentation
US20060019280A1 (en) * 2004-06-09 2006-01-26 Board Of Regents, The University Of Texas System Mutations in KIT confer imatinib resistance in gastrointestinal stromal tumors
US20070213317A1 (en) * 2003-11-18 2007-09-13 Elisabeth Buchdunger Inhibitors of the Mutant Form of Kit

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY148074A (en) * 2005-05-10 2013-02-28 Novartis Ag Pharmaceutical compositions comprising imatinib and a release retardant
EP2068938B1 (en) * 2006-09-22 2011-01-19 Novartis AG Optimization of the treatment of philadelphia-positive leukemia with abl tyrosine kinase inhibitor imatinib
CN101594857B (zh) 2006-11-07 2012-10-31 诺瓦提斯公司 阿利吉仑半富马酸盐的晶形

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040054186A1 (en) * 1999-04-15 2004-03-18 Jagabandhu Das Cyclic protein tyrosine kinase inhibitors
US20050049268A1 (en) * 2001-11-21 2005-03-03 Francois-Xavier Mahon Use of at least one abl, kit and/or platelet-derived growth factor receptor tyrosine kinases inhibitor for treating hair depigmentation
US20070213317A1 (en) * 2003-11-18 2007-09-13 Elisabeth Buchdunger Inhibitors of the Mutant Form of Kit
US20060019280A1 (en) * 2004-06-09 2006-01-26 Board Of Regents, The University Of Texas System Mutations in KIT confer imatinib resistance in gastrointestinal stromal tumors

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Manley et al. Imatinib: a selective tyrosinase kinase inhibitor. European Journal of Cancer, Vol. 38, Suppl. 5, 2002, S19-S27 *
Manley et al., "Imatinib: A Selective Tyrosine Kinase Inhibitor," European Journal of Cancer, Vol. 38, Suppl. 5 (2002) S19-S27 *
Perik et al., "Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinib-induced cardiotoxicity," Ann Oncol (2007) (first published online October 24, 2007). *
Picard et al., Trough Imatinib Plasma Levels are Associated with Both Cytogenetic and Molecular Responses to Standard-Dose Imatinib in Chronic Myeloid Lukemia," Blood, April 15, 2007, Vol. 109, No. 8 *
Verweij et al., "Progression-Free Survival in Gastrointestinal Stromal Tumours with High-Dose Imatinib: Randomised Trial," Lancet, September 25, 2004, Vol. 364: 1127-1134 *
White et al., (Blood) (2007); 110;4064-4072. *

Also Published As

Publication number Publication date
BRPI0906504A2 (pt) 2015-07-14
US20160045501A1 (en) 2016-02-18
CN101951910B (zh) 2013-07-17
PT2237783E (pt) 2014-12-23
JP5881671B2 (ja) 2016-03-09
JP2014094946A (ja) 2014-05-22
US9763944B2 (en) 2017-09-19
RU2537223C2 (ru) 2014-12-27
ES2526537T3 (es) 2015-01-13
KR20100105778A (ko) 2010-09-29
CN101951910A (zh) 2011-01-19
RU2010134916A (ru) 2012-02-27
PL2237783T3 (pl) 2015-04-30
MX2010008103A (es) 2010-08-23
CA2712087A1 (en) 2009-07-30
EP2237783B1 (en) 2014-11-19
WO2009094360A1 (en) 2009-07-30
EP2237783A1 (en) 2010-10-13
KR101579993B1 (ko) 2015-12-23
US20170035757A1 (en) 2017-02-09
AU2009206566A1 (en) 2009-07-30
JP5936821B2 (ja) 2016-06-22
JP2011510086A (ja) 2011-03-31

Similar Documents

Publication Publication Date Title
US20220152026A1 (en) Pharmaceutical combination comprising tno155 and a krasg12c inhibitor
US9486445B2 (en) Combination therapy for proliferative disorders
US20120202836A1 (en) Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity
JP2020517696A (ja) Ｈｅｒ２陽性がんの処置
CN118416236A (zh) 治疗胃肠道间质瘤的组合疗法
KR20250069693A (ko) 암 치료
US8673930B2 (en) Pyrimidylaminobenzamide derivatives for systemic mastocytosis
JP2021522246A (ja) 癌治療のための併用
US9763944B2 (en) Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor KIT with imatinib
CN1889952A (zh) (a)N－{5－[4－(4－甲基－(哌嗪－1－基)－甲基)－苯甲酰胺基]－2－甲基苯基}－4－(3－吡啶基)－2－嘧啶－胺和( b )至少一种羟丁赖氨酸形成抑制剂的组合产品及其用途
AU2013201993B2 (en) Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor KIT with imatinib
WO2021025148A1 (ja) 抗ｃｃｒ４抗体抵抗性のがんの治療剤
WO2023244639A1 (en) Methods of predicting cns cancer response to treatment with egfr inhibitors
RU2695362C2 (ru) Новое сочетание з-[(3-{ [4-(4-морфолинилметил)-1н-пиррол-2-ил]метилен} -2-оксо-2,3-дигидро-1н-индол-5-ил)метил]-1,3-тиазолидин-2,4-диона и ингибитора тирозинкиназы egfr
US20230330112A1 (en) Composition and treatment for cancer with mutations
US20240269136A1 (en) Egfr inhibitor and perk activator in combination therapy and their use for treating cancer
JP5751568B2 (ja) 悪性末梢神経鞘腫瘍の処置
JP2012510470A (ja) メシル酸イマチニブを用いたフィラデルフィア陽性白血病の処置を最適化する方法

Legal Events

Date Code Title Description
AS Assignment

Owner name: NOVARTIS AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WANG, YANFENG;WEHRLE, ELISABETH;SIGNING DATES FROM 20090817 TO 20100311;REEL/FRAME:024758/0015

STCB Information on status: application discontinuation

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