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

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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
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imatinib
patient
cmin
kit
pharmaceutically acceptable
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Yanfeng Wang
Elisabeth Wehrle
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/5753—Immunoassay; Biospecific binding assay; Materials therefor for cancer of the stomach or small 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.

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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)

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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

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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
WO2008036792A2 (en) * 2006-09-22 2008-03-27 Novartis Ag Method of optimizing the treatment of philadelphia-positive leukemia with abl tyrosine kinase inhibitors
NZ577320A (en) 2006-11-07 2012-01-12 Novartis Ag CRYSTALLINE FORMS OF ALISKIREN HEMIFUMARATE N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)-4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide

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. *

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

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