WO2011146458A1 - Méthode d'administration et de traitement - Google Patents

Méthode d'administration et de traitement Download PDF

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Publication number
WO2011146458A1
WO2011146458A1 PCT/US2011/036778 US2011036778W WO2011146458A1 WO 2011146458 A1 WO2011146458 A1 WO 2011146458A1 US 2011036778 W US2011036778 W US 2011036778W WO 2011146458 A1 WO2011146458 A1 WO 2011146458A1
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patient
polymorphism
cancer
genotype
compound
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PCT/US2011/036778
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English (en)
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Elaine Marie Paul
Albert B. Suttle
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Glaxo Wellcome Manufacturing Pte Ltd
Ottesen, Lone Harild
Xu, Chun-Fang
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Publication of WO2011146458A1 publication Critical patent/WO2011146458A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/142—Toxicological screening, e.g. expression profiles which identify toxicity
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to the administration of drug and its effects on patients with particular genetic variants.
  • Pazopanib (VotrientTM, GlaxoSmithKline, Philadelphia, PA) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, platelet- derived growth factor receptors(PDGFR) -a and - ⁇ , and the stem cell factor receptor c-Kit (Sonpavde G, Hutson TE., Pazopanib: a novel multitargeted tyrosine kinase inhibitor, Curr. Oncol. Rep. 2007;9:115-119).
  • Pazopanib is approved for the treatment of patients with advanced renal cell carcinoma (RCC) in the USA and Chile.
  • ALT alanine aminotransferase
  • total bilirubin alanine aminotransferase
  • Transaminase elevations were generally asymptomatic and reversible.
  • Statins are a class of drug that inhibit the 3-hydroxy-3-methylglutaryl coenzyme A reductase, which are widely used for the treatment of hypercholesterolaemia and prevention of coronary artery disease. Although each statin (atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin and rosuvastatin) has a unique pharmacology and drug interaction profile, when used as monotherapy for hyperlipidemia, there is an overall very low incidence of severe toxicity.
  • statins in combination with other drugs that alter their metabolism can lead to increasing blood levels with consequent risk of liver or muscle toxicity. This has been demonstrated for most of the statins, but most commonly for those metabolised by CYP3A4 enzymes (Rossi and McLeod 2009, The pharmacogenetics of statin therapy: when the body aches, the mind will follow, J. Am. Coll. Cardiol, (2009) 54(17): 1617-8). Pharmacogenetic analysis showed that the SLCOIBI 521 T>C (*5) polymorphism was associated with simvastatin-induced myopathy and higher simvastatin plasma levels in 521 C allele carriers (Link et al. 2008, SLCOIBI variants and statin-induced myopathy - A genomewide study,
  • aminotransferases is unknown and, to the best of the inventors' knowledge, no pharmacogenetic studies have been published where genetic markers were investigated in relation to elevated aminotransferases or liver toxicity.
  • patients who have at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism can experience an increased risk of (ALT) > 3x ULN when a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof was coadministered with simvastatin compared to the incidence of ALT > 3xULN experienced by patients who are do not have at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism and are co-administered a compound of formula (I) or a pharmaceutically acceptable salt thereof with simvastatin.
  • patients who have at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism can experience an increased risk of (ALT) > 3x ULN when a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof was co-administered with simvastatin compared to the incidence of ALT > 3xULN experienced by patients who are not co-administered a compound of formula (I) or a
  • a method of administering a compound of formula (I) to a patient in need thereof includes determining whether the patient has the GG (or *3*3) genotype of the CYP2C8*3 1196A>G (K399R) (rsl0509681) polymorphism, determining whether the patient is being administered simvastatin, and, if the patient is being administered simvastatin and does not have the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681) polymorphism, administering to the patient a compound of formula
  • a method of prescribing a compound of formula (I) to a patient in need thereof includes determining whether the patient has the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681)
  • polymorphism determining whether the patient is being administered simvastatin, and, if the patient is being administered simvastatin and does not have the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681) polymorphism, prescribing to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a patient in need thereof includes determining whether the patient has the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681) polymorphism, determining whether the patient is being administered simvastatin, and, if the patient is being administered simvastatin and does not have the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681) polymorphism, administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a patient in need thereof includes determining whether the patient has the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681) polymorphism and determining whether the patient is being administered simvastatin. If the patient is being administered simvastatin and has the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681)
  • a method of administering a compound of formula (I) to a patient in need thereof includes determining whether the patient has at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, determining whether the patient is being administered simvastatin, and, if the patient is being administered simvastatin and does not have at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, administering to the patient a compound of formula (I):
  • a method of prescribing a compound of formula (I) to a patient in need thereof includes determining whether the patient has at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, determining whether the patient is being administered simvastatin, and, if the patient is being administered simvastatin and does not have at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, prescribing to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a patient in need thereof includes determining whether the patient has at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, determining whether the patient is being administered simvastatin, and, if the patient is being administered simvastatin and does not have at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a patient in need thereof includes determining whether the patient has at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism and determining whether the patient is being administered simvastatin.
  • the patient is being administered simvastatin and has at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, and if administration of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is being considered for treating the cancer in the patient, considering alternative treatment or treatment strategies, and (i) halting the administration of simvastatin or reducing the amount of simvastatin administered in order to reduce the plasma level of simvastatin or its metabolites in the patient, and
  • a method of administering a compound of formula (I) to a patient in need thereof includes determining whether the patient has at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, such as the AG or GG genotype of the CYP3A4* IB -392 A>G (rs2740574) polymorphism, determining whether the patient is being administered simvastatin, and if the patient is being administered simvastatin and does not have at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, administering to the patient a compound of formula (I):
  • a method of prescribing a compound of formula (I) to a patient in need thereof includes determining whether the patient has at least one G allele of the CYP3A4* IB -392 A>G (rs2740574) polymorphism, such as the AG or GG genotype of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, determining whether the patient is being administered simvastatin, and if the patient is being administered simvastatin and does not have at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, prescribing to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a patient in need thereof includes determining whether the patient has at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, such as the AG or GG genotype of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, determining whether the patient is being administered simvastatin, and if the patient is being administered simvastatin and does not have at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • rs2740574 polymorphism such as the AG or GG genotype of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism
  • a method of treating cancer in a patient in need thereof includes determining whether the patient has at least one G allele of the CYP3A4* IB -392 A>G (rs2740574) polymorphism, such as the AG or GG genotype of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, and determining whether the patient is being administered simvastatin.
  • the patient is being administered simvastatin and has at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, and if administration of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is being considered for treating the cancer in the patient, considering alternative treatment or treatment strategies, and (i) halting the administration of simvastatin or reducing the amount of simvastatin administered in order to reduce the plasma level of simvastatin or its metabolites in the patient, and administering to said patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or (ii) halting the administration of simvastatin, administering a statin that is different from simvastatin, and administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or (iii) administering to the patient a compound known to treat the cancer from which the patient is suffering instead of administer
  • Figure 1 illustrates the number of patients evaluated who received pazopanib as a monotherapy for cancer and also received particular statins versus the number of patients who received pazopanib as a monotherapy for cancer and did not receive statins;
  • Figure 2 illustrates the incidence of ALT > 3xULN in patients who received statins, and particularly simvastatin, compared with the incidence of ALT > 3xULN in non-statin users;
  • Figure 3 illustrates a comparison between ALT elevation for the CC genotype of the ABCG2 polymorphism versus the AC genotype of the ABCG2 polymorphism
  • Figure 4 illustrates a comparison between ALT elevation for the AA genotype of the CYP3A4* IB polymorphism versus the AG genotype of the CYP3A4* IB polymorphism.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, compounds of formula (I), (II), (III), or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • the solvent used is water.
  • One of ordinary skill in the art will readily appreciate how to determine if a solvate of compounds I, ⁇ , and/or I" will form and how to determine the composition of the solvate using standard solvate screening technology understood by those skilled in the art, for example.
  • CYP2C8*3 1196 A>G (K399R) single nucleotide polymorphism, rs10509681 is understood to have the sequence:
  • the ABCG2 single nucleotide polymorphism, rs2231142, is understood to have the sequence:
  • CYP3A4* 1B single nucleotide polymorphism rs2740574, is understood to have the sequence:
  • wild type refers to a polypeptide or polynucleotide sequence that occurs in a native population without genetic modification.
  • a “variant” includes a polypeptide or polynucleotide sequence having at least one modification to an amino acid or nucleic acid compared to the corresponding amino acid or nucleic acid found in a wild type polypeptide or polynucleotide, respectively. Included in the term variant is Single Nucleotide Polymorphism (SNP) where a single base pair distinction exists in the sequence of a nucleic acid strand compared to the most prevalently found (wild type, WT) nucleic acid strand.
  • SNP Single Nucleotide Polymorphism
  • genetic modification or “genetically modified” refers to, but is not limited to, any suppression, substitution, deletion and/or insertion of one or more bases into DNA sequence(s). Also, as used herein “genetically modified” can refer to a gene encoding a polypeptide or a polypeptide having at least one deletion, substitution or suppression of a nucleic acid or amino acid, respectively.
  • SNPs can be identified by known methods. For example, wild type or SNPs can be identified by DNA amplification and sequencing techniques, DNA and RNA detection techniques, including, but not limited to Northern and Southern blot,
  • WT and mutant polypeptides can be detected by a variety of techniques including, but not limited to immunodiagnostic techniques such as ELISA and western Blot.
  • the process of detecting an allele or polymorphism includes but is not limited to serologic and genetic methods.
  • the allele or polymorphism detected may be functionally involved in affecting an individual's phenotype, or it may be an allele or polymorphism that is in linkage disequilibrium with a functional polymorphism/allele.
  • Polymorphisms/alleles are evidenced in the genomic DNA of a subject, but may also be detectable from RNA, cDNA or protein sequences transcribed or translated from this region, as will be apparent to one skilled in the art.
  • nucleotide and related amino acid sequences obtained from different sources for the same gene may vary both in the numbering scheme and in the precise sequence. Such differences may be due to numbering schemes, inherent sequence variability within the gene, and/or to sequencing errors. Accordingly, reference herein to a particular polymorphic site by number will be understood by those of skill in the art to include those polymorphic sites that correspond in sequence and location within the gene, even where different numbering/nomenclature schemes are used to describe them.
  • genotyping means detecting which allelic or polymorphic form(s) of the gene(s) or gene expression products (e.g. , hnRNA, mRNA or protein) are present or absent in a subject (or a sample).
  • Related RNA or protein expressed from such gene may also be used to detect polymorphic variation.
  • an individual may be heterozygous or homozygous for a particular allele. More than two allelic forms may exist, thus, there may be more than three possible genotypes.
  • genotyping includes the determination of HLA alleles using suitable serologic techniques, as are known in the art.
  • an allele may be 'detected' when other possible allelic variants have been ruled out; e.g., where a specified nucleic acid position is found to be neither adenine (A), thymine (T) or cytosine (C), it can be concluded that guanine (G) is present at that position (i.e., G is 'detected' or 'diagnosed' in a subject).
  • a "genetic subset" of a population consists of those members of the population having a particular genotype.
  • a population can potentially be divided into three subsets: homozygous for allele 1 (1,1), heterozygous (1,2), and homozygous for allele 2 (2,2).
  • a 'population' of subjects may be defined using various criteria, e.g. , individuals being treated with pazopanib or individuals with cancer.
  • a subject that is "predisposed to” or "at increased risk of a particular phenotypic response based on genotyping will be more likely to display that phenotype than an individual with a different genotype at the target polymorphic locus (or loci).
  • the phenotypic response is based on a multi-allelic polymorphism, or on the genotyping of more than one gene, the relative risk may differ among the multiple possible genotypes.
  • An allele refers to one specific form of a genetic sequence (such as a gene) within a cell, a sample, an individual or within a population, the specific form differing from other forms of the same gene in the sequence of at least one, and frequently more than one, variant sites within the sequence of the gene.
  • the sequences at these variant sites that differ between different alleles are termed "variants", “polymorphisms", or “mutations.”
  • polymorphism is used to refer to variants that have a frequency of at least 1% in a population, while the term mutation is generally used for variants that occur at a frequency of less than 1% in a population.
  • a polymorphism may comprise one or more base changes, an insertion, a repeat, or a deletion.
  • a polymorphic locus may be as small as one base pair.
  • Polymorphic markers include restriction fragment length polymorphisms, variable number of tandem repeats (VNTR's), hypervariable regions, minisatellites, dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats, simple sequence repeats, and insertion elements such as Alu.
  • VNTR's variable number of tandem repeats
  • minisatellites dinucleotide repeats
  • trinucleotide repeats trinucleotide repeats
  • tetranucleotide repeats simple sequence repeats
  • insertion elements such as Alu.
  • Diploid organisms may be homozygous or heterozygous for allelic forms.
  • a diallelic polymorphism has two forms.
  • a triallelic polymorphism has three forms.
  • a polymorphism between two nucleic acids can occur naturally, or be caused by exposure to or contact with chemicals, enzymes, or other agents, or exposure to agents that cause damage to nucleic acids, for example, ultraviolet radiation, mutagens or carcinogens.
  • SNPs Single nucleotide polymorphisms
  • SNPs Single nucleotide polymorphisms
  • SNPs are positions at which two alternative bases occur at appreciable frequency (>1%) in the human population, and are the most common type of human genetic variation. Approximately 90% of all polymorphisms in the human genome are SNPs. SNPs are single base positions in DNA at which different alleles, or alternative nucleotides, exist in a population. An individual may be homozygous or heterozygous for an allele at each SNP position.
  • a SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP is an amino acid coding sequence.
  • references to SNPs and SNP genotypes include individual SNPs and/or haplotypes, which are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with diseases or other phenotypic effects compared with individual SNPs, and therefore may provide increased diagnostic accuracy in some cases (Stephens et al. Science 293, 489-493, 20 Jul. 2001).
  • the DNA region spanning the nucleotide of interest is amplified by PCR, or any other suitable amplification technique.
  • a primer is hybridized to a target nucleic acid sequence, wherein the last nucleotide of the 3' end of the primer anneals immediately 5' to the nucleotide position on the target sequence that is to be analyzed.
  • the annealed primer is extended by a single, labelled nucleotide triphosphate. The incorporated nucleotide is then detected.
  • sequence of any nucleic acid including a gene or PCR product or a fragment or portion thereof may be sequenced by any method known in the art (e.g., chemical sequencing or enzymatic sequencing).
  • “Chemical sequencing” of DNA may denote methods such as that of Maxam and Gilbert (1977) (Proc. Natl. Acad. Sci. USA 74:560), in which DNA is randomly cleaved using individual base-specific reactions.
  • “Enzymatic sequencing” of DNA may denote methods such as that of Sanger (Sanger, et al, (1977) Proc. Natl. Acad. Sci. USA 74:5463).
  • PNA affinity assay is a derivative of traditional hybridization assays (Nielsen et al, Science 254: 1497-1500 (1991); Egholm et al, J. Am. Chem. Soc.
  • PNAs are structural DNA mimics that follow Watson-Crick base pairing rules, and are used in standard DNA hybridization assays. PNAs display greater specificity in hybridization assays because a
  • PNA/DNA mismatch is more destabilizing than a DNA/DNA mismatch and complementary PNA/DNA strands form stronger bonds than complementary DNA/DNA strands.
  • the Protein Truncation Test (PTT) is also commonly used to detect genetic defects
  • the gene of interest is PCR amplified, subjected to in vitro transcription/translation, purified, and analyzed by polyacrylamide gel electrophoresis.
  • Genetic testing also called genetic screening as used herein refers to the testing of a biological sample from a subject to determine the subject's genotype; and may be utilized to determine if the subject's genotype comprises alleles that either cause, or increase susceptibility to, a particular phenotype (or that are in linkage disequilibrium with allele(s) causing or increasing susceptibility to that phenotype).
  • Linkage disequilibrium refers to the tendency of specific alleles at different genomic locations to occur together more frequently than would be expected by chance. Alleles at given loci are in complete equilibrium if the frequency of any particular set of alleles (or haplotype) is the product of their individual population frequencies A commonly used measure of linkage disequilibrium is r:
  • nr 2 has an approximate chi square distribution with 1 degree freedom for biallelic markers. Loci exhibiting an r such that nr 2 is greater than 3.84, corresponding to a significant chi-squared statistic at the 0.05 level, are considered to be in linkage disequilibrium (BS Weir 1996 Genetic Data Analysis II Sinauer Associates, Sunderland, MD).
  • a normalized measure of linkage disequilibrium can be defined as:
  • the value of the D " has a range of -1.0 to 1.0.
  • statistically significant absolute D " value for two markers is not less than 0.3 they are considered to be in linkage disequilibrium.
  • the process of detecting or determining the presence of an allele or polymorphism includes but is not limited to serologic and genetic methods.
  • the allele or polymorphism detected may be functionally involved in affecting an individual's phenotype, or it may be an allele or polymorphism that is in linkage disequilibrium with a functional polymorphism/allele.
  • Polymorphisms/alleles are evidenced in the genomic DNA of a subject, but may also be detectable from RNA, cDNA or protein sequences transcribed or translated from this region, as will be apparent to one skilled in the art.
  • Polymorphic alleles may be detected by determining the DNA polynucleotide sequence, or by detecting the corresponding sequence in RNA transcripts from the polymorphic gene, or where the nucleic acid polymorphism results in a change in an encoded protein by detecting such amino acid sequence changes in encoded proteins; using any suitable technique as is known in the art.
  • Polynucleotides utilized for typing are typically genomic DNA, or a polynucleotide fragment derived from a genomic polynucleotide sequence, such as in a library made using genomic material from the individual (e.g. a cDNA library).
  • the polymorphism may be detected in a method that comprises contacting a polynucleotide or protein sample from an individual with a specific binding agent for the polymorphism and determining whether the agent binds to the polynucleotide or protein, where the binding indicates that the polymorphism is present.
  • the binding agent may also bind to flanking nucleotides and amino acids on one or both sides of the polymorphism, for example at least 2, 5, 10, 15 or more flanking nucleotide or amino acids in total or on each side.
  • flanking nucleotides and amino acids on one or both sides of the polymorphism, for example at least 2, 5, 10, 15 or more flanking nucleotide or amino acids in total or on each side.
  • the binding agent may be a polynucleotide (single or double stranded) typically with a length of at least 10 nucleotides, for example at least 15, 20, 30, or more nucleotides.
  • a polynucleotide agent which is used in the method will generally bind to the polymorphism of interest, and the flanking sequence, in a sequence specific manner (e.g. hybridize in accordance with Watson-Crick base pairing) and thus typically has a sequence which is fully or partially complementary to the sequence of the polymorphism and flanking region.
  • a binding agent is used as a probe.
  • the probe may be labelled or may be capable of being labelled indirectly.
  • the detection of the label may be used to detect the presence of the probe on (bound to) the polynucleotide or protein of the individual.
  • the binding of the probe to the polynucleotide or protein may be used to immobilize either the probe or the polynucleotide or protein (and, thus, to separate it from one composition or solution).
  • the polynucleotide or protein of the individual is immobilized on a solid support and then contacted with the probe.
  • the presence of the probe immobilized to the solid support (via its binding to the polymorphism) is then detected, either directly by detecting a label on the probe or indirectly by contacting the probe with a moiety that binds the probe.
  • the solid support is generally made of nitrocellulose or nylon.
  • the method may be based on an ELISA system.
  • the probe is used in a heteroduplex analysis based system to detect polymorphisms.
  • a heteroduplex analysis based system when the probe is bound to a polynucleotide sequence containing the polymorphism, it forms a heteroduplex at the site where the polymorphism occurs (i.e. it does not form a double strand structure).
  • Such a heteroduplex structure can be detected by the use of an enzyme that is single or double strand specific.
  • the probe is an R A probe and the enzyme used is RNAse H that cleaves the heteroduplex region, thus, allowing the polymorphism to be detected by means of the detection of the cleavage products.
  • the method may be based on fluorescent chemical cleavage mismatch analysis which is described for example in PCR Methods and Applications 3:268-71 (1994) and Proc. Natl. Acad. Sci. 85:4397-4401 (1998).
  • the polynucleotide agent is able to act as a primer for a PCR reaction only if it binds a polynucleotide containing the polymorphism (i.e. a sequence- or allele-specific PCR system).
  • a polynucleotide containing the polymorphism i.e. a sequence- or allele-specific PCR system.
  • a PCR product will only be produced if the polymorphism is present in the polynucleotide of the individual, and the presence of the polymorphism is determined by the detection of the PCR product.
  • the region of the primer which is complementary to the polymorphism is at or near the 3 ' end the primer.
  • the polynucleotide the agent will bind to the wild-type sequence but will not act as a primer for a PCR reaction.
  • the method may be a Restriction Fragment Length Polymorphism (RFLP) based system.
  • RFLP Restriction Fragment Length Polymorphism
  • This can be used if the presence of the polymorphism in the polynucleotide creates or destroys a restriction site that is recognized by a restriction enzyme.
  • treatment of a polynucleotide that has such a polymorphism will lead to different products being produced compared to the corresponding wild-type sequence.
  • the detection of the presence of particular restriction digest products can be used to determine the presence of the polymorphism.
  • the presence of the polymorphism may be determined based on the change that the presence of the polymorphism makes to the mobility of the polynucleotide or protein during gel electrophoresis.
  • SSCP polynucleotide single-stranded conformation polymorphism
  • the presence of the polymorphism may be determined using a fluorescent dye and quenching agent-based PCR assay such as the TAQMANTM PCR detection system.
  • a polynucleotide comprising the polymorphic region is sequenced across the region which contains the polymorphism to determine the presence of the polymorphism.
  • detection techniques suitable for use in the present methods will be apparent to those conversant with methods of detecting, identifying, and/or distinguishing polymorphisms.
  • detection techniques include but are not limited to direct sequencing, use of "molecular beacons” (oligonucleotide probes that fluoresce upon hybridization, useful in real- time fluorescence PCR; see e.g., Marras et al., Genet Anal 14: 151 (1999)); electrochemical detection (reduction or oxidation of DNA bases or sugars; see US Patent No.
  • any suitable detection technique as is known in the art may be utilized in the present methods.
  • treatment means any manner in which one or more symptoms associated with the disorder are beneficially altered. Accordingly, the term includes healing or amelioration of a symptom or side effect of the disorder or a decrease in the rate of advancement of the disorder.
  • a method of administering a compound of formula (I) to a patient in need thereof includes determining whether the patient has the GG (or *3*3) genotype of the CYP2C8*3 1196A>G (K399R) (rsl0509681) polymorphism, determining whether the patient is being administered simvastatin, and, if the patient is being administered simvastatin and does not have the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681) polymorphism, administering to the patient a compound of formula
  • polymorphism determining whether the patient is being administered simvastatin, and, if the patient is being administered simvastatin and does not have the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681) polymorphism, prescribing to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a patient in need thereof includes determining whether the patient has the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681) polymorphism and determining whether the patient is being administered simvastatin. If the patient is being administered simvastatin and has the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681)
  • a method of prescribing a compound of formula (I) to a patient in need thereof includes determining whether the patient has at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, such as the AA or AC genotype of the ABCG2 421 C>A (rs2231142) polymorphism, determining whether the patient is being administered simvastatin, and, if the patient is being administered simvastatin and does not have at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, prescribing to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a patient in need thereof includes determining whether the patient has at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, such as the AA or AC genotype of the ABCG2 421 C>A (rs2231142) polymorphism, determining whether the patient is being administered simvastatin, and, if the patient is being administered simvastatin and does not have at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a patient in need thereof includes determining whether the patient has at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, such as the AA or AC genotype of the ABCG2 421 C>A (rs2231142) polymorphism, and determining whether the patient is being administered simvastatin.
  • the patient is being administered simvastatin and has at least one A allele of the ABCG2 421 C>A (rs2231142) polymorphism, and if administration of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is being considered for treating the cancer in the patient, considering alternative treatment or treatment strategies, and (i) halting the administration of simvastatin or reducing the amount of simvastatin administered in order to reduce the plasma level of simvastatin or its metabolites in the patient, and administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or (ii) halting the administration of simvastatin, administering a statin that is different from simvastatin, and administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or (iii) administering to the patient a compound known to treat the cancer from which the patient is suffering instead of administering a compound of formula (
  • a method of administering a compound of formula (I) to a patient in need thereof includes determining whether the patient has at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, such as the AG or GG genotype of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, determining whether the patient is being administered simvastatin, and if the patient is being administered simvastatin and does not have at least one G allele of the CYP3A4* IB -392 A>G (rs2740574)
  • a method of prescribing a compound of formula (I) to a patient in need thereof includes determining whether the patient has at least one G allele of the CYP3A4* IB -392 A>G (rs2740574) polymorphism, such as the AG or GG genotype of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, determining whether the patient is being administered simvastatin, and if the patient is being administered simvastatin and does not have at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, prescribing to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a patient in need thereof includes determining whether the patient has at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, such as the AG or GG genotype of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, determining whether the patient is being administered simvastatin, and if the patient is being administered simvastatin and does not have at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • rs2740574 polymorphism such as the AG or GG genotype of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism
  • a method of treating cancer in a patient in need thereof includes determining whether the patient has at least one G allele of the CYP3A4* IB -392 A>G (rs2740574) polymorphism, such as the AG or GG genotype of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, and determining whether the patient is being administered simvastatin.
  • the patient is being administered simvastatin and has at least one G allele of the CYP3A4* 1B -392 A>G (rs2740574) polymorphism, and if administration of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is being considered for treating the cancer in the patient, considering alternative treatment or treatment strategies, and (i) halting the administration of simvastatin or reducing the amount of simvastatin administered in order to reduce the plasma level of simvastatin or a its metabolites in the patient, and administering to said patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or (ii) halting the administration of simvastatin, administering a statin that is different from simvastatin, and administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or (iii) administering to the patient a compound known to treat the cancer from which the patient is suffering instead
  • Embodiments of the various aspects of the invention described herein can include discontinuing treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the salt of the compound of formula (I) is a hydrochloride salt.
  • the salt of the compound of formula (I) is a monohydro chloride salt as illustrated by formula ( ⁇ ).
  • the monohydrochloride salt of the compound of formula (I) has the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide monohydrochloride.
  • the salt of the compound of formula (I) is a monohydrochloride monohydrate solvate of the compound of formula (I).
  • the monohydrochloride monohydrate solvate of the compound of formula (I) has the chemical name 5-( ⁇ 4-[(2,3-dimethyl-2H-indazol- 6-yl)methylamino]-2-pyrimidinyl ⁇ amino)-2-methylbenzenesulfonamide monohydrochloride monohydrate, as illustrated in formula (I").
  • the free base, salts and solvates of the compound of formula (I) may be prepared, for example, according to the procedures of International Patent Application No. PCT/USO 1/49367 filed December 19, 2001, and published as WO 02/059110 on August 1, 2002, and International Patent Application No. PCT/US03/19211 filed June 17, 2003, and published as WO 03/106416 on December 24, 2003, the entire disclosures of each of which are incorporate herein by reference, or according to the methods provided herein.
  • salts may comprise acid addition salts derived from a nitrogen on a substituent in the compound of formula (I).
  • Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
  • the determination of whether a patient has a particular genotype at a given reference single nucleotide polymorphism includes performing genetic testing of the patient for the particular genotype at the given reference single nucleotide polymorphism.
  • the genetic testing of a patient to determine whether the patient has a particular genotype at a given reference single nucleotide polymorphism can be done by various methods as will be understood by those skilled in the art, for example as described herein and in the Examples section below.
  • a first reference single nucleotide polymorphism is correlated to a second single nucleotide polymorphism if detection of the first reference single nucleotide
  • the determination of whether a patient has a particular genotype at a given reference single nucleotide polymorphism includes: a. performing a genotyping technique on a biological sample from the subject to determine whether the subject has a genotype of at least one single nucleotide polymorphism that is correlated with the GG (or *3*3) genotype of the CYP2C8*3 1196 A>G (K399R) (rsl0509681) polymorphism;
  • the biological sample is selected from the group consisting of cells, blood, blood components, urine and saliva.
  • the determination of whether a patient has a particular genotype at a given reference single nucleotide polymorphism includes: d. performing a genotyping technique on a biological sample from the subject to determine whether the subject has a genotype of at least one single nucleotide polymorphism that is correlated with a genotype of the ABCG2 421 C>A (rs2231142) polymorphism that includes at least one A allele, such as the AC or AA genotype;
  • the biological sample is selected from the group consisting of cells, blood, blood components, urine and saliva.
  • the biological sample is selected from the group consisting of cells, blood, blood components, urine and saliva.
  • embodiments of the invention further provide pharmaceutical compositions, which include therapeutically effective amounts of the compound of formula (I) or pharmaceutically acceptable salts and solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing the compound of formula (I) or pharmaceutically acceptable salts and solvates thereof with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 0.5mg to lg, preferably lmg to 800mg, of a compound of the formula (I) depending on the condition being treated, the route of administration and the age, weight and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • Dosage unit forms can also be in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines .
  • the compound of formula (I) or pharmaceutically acceptable salts and solvates thereof can also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof will depend upon a number of factors including, for example, the age and weight of the patient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician.
  • an effective amount of a compound of formula (I) or a salt or solvate thereof for the treatment of a cancerous condition such as those described herein will generally be in the range of 1 to 12 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 840 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt or solvate thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • the compound of formula (I) or a salt or solvate thereof may be employed alone or in combination with other therapeutic agents for the treatment of the above-mentioned conditions.
  • combination therapies according to the present invention thus comprise the administration of a compound of formula (I) or a salt or solvate thereof, and the use of at least one other cancer treatment method, including one or more additional vascular endothelial growth factor (VEGF) or vascular endothelial growth factor (VEGFR) inhibitors.
  • VEGF vascular endothelial growth factor
  • VAGFR vascular endothelial growth factor
  • combination therapies according to the present invention comprise the administration of the compound of formula (I) or a salt or solvate thereof, and at least one other pharmaceutically active agent, preferably an anti-neoplastic agent.
  • the compound of formula (I) or a salt or solvate thereof and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound of formula (I) or a salt or solvate thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the compound of formula (I) or a salt or solvate thereof and at least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies.
  • the other anti-cancer therapy is at least one additional chemotherapeutic therapy including administration of at least one anti-neoplastic agent.
  • the administration in combination of a compound of formula (I) or pharmaceutically acceptable salts or solvates thereof with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one anti-neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms.
  • Anti-neoplastic agents useful in combination with the compound of the compound of formula (I) or a salt or solvate thereof can include the following:
  • diterpenoids such as paclitaxel and its analog docetaxel
  • vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine
  • epipodophyllotoxins such as etoposide and teniposide
  • fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine
  • antimetabolites such as allopurinol, fludurabine, methotrexate, cladrabine, cytarabine, mercaptopurine, pemetrexed and thioguanine
  • camptothecins such as 9-amino camptothecin, irinotecan, CPT-11 and the various optical forms of 7-(4-methylpiperazino-methylene)-10,l l-ethylenedioxy-20- camptothecin;
  • cytotoxic chemotherapeutic agents including, but not limited to, alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine; anti-tumour antibiotics such as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dacttinomycin and mithramycin; and platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; and
  • chemotherapeutic agents including, but not limited to, mTOR inhibitors such as temsirolimus and everolimus; anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene; progestrogens such as megestrol acetate; aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane; antiandrogens such as flutamide, nilutamide, bicalutamide, and cyproterone acetate; LHRH agonists and antagagonists such as goserelin acetate and luprolide, testosterone 5a-dihydroreductase inhibitors such as finasteride or dutasteride; metalloproteinase inhibitors such as marimastat; antiprogestogens; urokinase plasminogen activator receptor function
  • the compound of formula (I) or a salt or solvate thereof can be used to provide additive or synergistic effects with certain existing cancer chemotherapies and radiation, and/or be used to restore effectiveness of certain existing cancer chemotherapies and radiation.
  • the level of VEGF or VEGFR activity does not have to be abnormal to be considered inappropriate, rather the activity derives from an abnormal source.
  • the inappropriate angiogenesis referred to herein is any angiogenic activity that deviates from the normal angiogenic activity expected in a particular mammalian subject.
  • Inappropriate angiogenesis may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of angiogenic activity.
  • Such inappropriate activity may result then, for example, from overexpression or mutation of a protein kinase or ligand leading to inappropriate or uncontrolled activation of angiogenesis.
  • unwanted angiogenic activity may reside in an abnormal source, such as a malignancy. That is, the level of angiogenic activity does not have to be abnormal to be considered inappropriate, rather the activity derives from an abnormal source.
  • the condition to be treated is a disease characterized by cellular proliferation in the area of disorders associated with neo-vascularization and/or vascular permeability including blood vessel proliferative disorders including arthritis and restenosis; fibrotic disorders including hepatic cirrhosis and atherosclerosis; mesangial cell proliferative disorders include glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, proliferative retinopathies, organ transplant rejection and glomerulopathies; and metabolic disorders include psoriasis, diabetes mellitus, chronic wound healing, inflammation and neurodegenerative diseases.
  • the disorder is cancer.
  • the cancer is selected from the group consisting of breast cancer, renal cell carcinoma, melanoma, lung cancer including non-small cell lung cancer, gastric cancer, colorectal cancer, neuroendocrine cancer, thyroid cancer, head and neck cancer, brain cancer, cervical cancer, bladder cancer, esophageal cancer, pancreatic cancer, prostate cancer, mesothelioma, liver and hepatobiliary cancer, multiple myeloma, leukemia, thyroid cancer including Hurthle cell, soft tissue sarcoma, and bone sarcoma (chondrosarcoma and osteocarcoma).
  • a further aspect of the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment of a disorder characterized by inappropriate VEGFR2 activity.
  • ALT 787 international units/ liter IU/L
  • AST aspartate transaminase
  • total bilirubin 3.4 mg/dL (direct 0.5mg/dL).
  • Clinical symptoms included fatigue; no jaundice, fever, hypersensitivity, or hepatomegaly was observed.
  • treatment with both paclitaxel and pazopanib was discontinued and blood samples were drawn for evaluation of pharmacokinetics (PK) and viral serology.
  • PGx pharmacogenetic
  • ALT remained high (day 25: 838 IU/L); therefore simvastatin was discontinued (on day 26) due to previous association with ALT elevation; additional PK samples were drawn. After simvastatin was discontinued ALT decreased (day 27 709 IU/L; day 35 489 IU/L; day 56 117 IU/L). Liver Chemistry Measurements
  • ALT, AST, and bilirubin measurements were performed by local institutional laboratories.
  • the elevated liver enzymes in this patient appear to have resulted from the increased exposure of simvastatin and simvastatin acid when simvastatin was co-administered with pazopanib.
  • This drug-drug interaction may be the result of inhibition of one or more pathways in the presence of a homozygous defective CYP2C8*3 allele.
  • Clinical data were pooled from patients in eleven trials evaluating the pharmacokinetics, efficacy, and safety of pazopanib in various cancer types. A total of 977 patients received pazopanib as a monotherapy for the treatment of cancer and 959 patients had at least one on- treatment ALT measurement and genotyping data for the CYP2C8*3 polymorphism were available for 546 patients.
  • Germline DNA was extracted from peripheral blood by Quest Diagnostics (Van Huys, USA; Heston, UK) and MDS Pharma Services (Beijing, China).
  • the CYP2C8 1196 A>G (K399R) (*3) polymorphism was genotyped using the GoldenGate platform (Illumina, San Diego, CA).
  • ALT measurements were performed by local institutional laboratories. These values were converted to the unit of 'upper limit of normal' (ULN) by dividing the laboratory values with the institutional lab-specific upper limit of normal values.
  • Germline DNA was extracted from peripheral blood by Quest Diagnostics (Van Huys, USA; Heston, UK) and MDS Pharma Services (Beijing, China).
  • G>T/A (A893S/T) polymorphism was genotyped by sequencing (GSK, Research Triangle Park, NC).
  • the UGT1 Al TA6TA7 (*28) polymorphism was genotyped using an Invader® Assay
  • ANCOVA covariance model
  • ALT>3xULN is 20%> (5/25), which is slightly higher, however not significant different from the incidence of 17% (57/338) seen in those with the wild type AA genotype.
  • ALT > 3xULN was increased when simvastatin was co-administered in patients having the ABCG2 (421 C>A) polymorphism.
  • the incidence of ALT > 3xULN was increased when simvastatin was co-administered in patients having the CYP3A4* 1B (-392A>G) polymorphism.

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Abstract

L'invention concerne des méthodes d'administration de pazopanib ou de sels pharmaceutiquement acceptables ou de solvates de ceux-ci ainsi que des méthodes de traitement du cancer chez des patients qui en ont besoin lorsqu'on leur administre en plus de la simvastatine et lorsqu'ils ont un ou plusieurs génotypes particuliers du gène CYP2C8*3, ABCG2 ou CYP3A4*1B.
PCT/US2011/036778 2010-05-18 2011-05-17 Méthode d'administration et de traitement WO2011146458A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US34587410P 2010-05-18 2010-05-18
US34587910P 2010-05-18 2010-05-18
US34587010P 2010-05-18 2010-05-18
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