WO2014093750A1 - Method of administration and treatment - Google Patents

Method of administration and treatment Download PDF

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Publication number
WO2014093750A1
WO2014093750A1 PCT/US2013/074889 US2013074889W WO2014093750A1 WO 2014093750 A1 WO2014093750 A1 WO 2014093750A1 US 2013074889 W US2013074889 W US 2013074889W WO 2014093750 A1 WO2014093750 A1 WO 2014093750A1
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cancer
compound
pharmaceutically acceptable
ros1
human
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PCT/US2013/074889
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French (fr)
Inventor
Tona M. Gilmer
Li Liu
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Glaxosmithkline Llc
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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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to the administration of drug and its effects on patients with particular genetic variant cancers.
  • the rosl gene is a proto-oncogene tyrosine-protein kinase that encodes ROS enzyme.
  • Human rosl oncogene is located in a region of chromosome 6 associated with tumor-specific rearrangements. Rabin, M. et al. Oncogene Res. 1987 Jul; 1 (2): 169-78.
  • a human rosl gene cloned from a glioblastoma cell line, then sequenced has been described. Birchmeier C, O'Neill K, Riggs M, Wigler M (1990). Characterization of ROS1 cDNA from a human glioblastoma cell line has been reported. Proc. Natl. Acad. Sci. U.S.A. 87 (12): 4799-803.
  • NSCLC non-small-cell lung cancer
  • astrocyomas cholangiocarcinomas
  • glioblastoma multiforme glioblastoma multiforme
  • lung adenocarcinomas Birchmeier, et al. Proc Natl Acad Sci U S A. 1987 Dec; 84(24):9270-4. Wu, JK and Chikaraishi, DM. Cancer Res. 1990 May 15; 50(10):3032- 5.
  • Chin, LP et al. J. Thoracic Oncology 2012 Nov; 7(1 1 ):1625-30; Suehara, et al. Clin Cancer Res. 2012.
  • rosl mutations that have been noted in cancers and cancer cell lines include various chromosomal rearrangements, rosl fusion variants, and mutations of the rosl 3' region.
  • Chin, LP et al. J. Thoracic Oncology 2012 Nov; 7(1 1 ):1625-30; Kurtis,
  • ROS1 rearrangements described in NSCLC include, for example, SLC34A2-ROS1 ,
  • CD74-ROS1 CD74-ROS1 , EZR-ROS1 , TPM3-ROS1 , GOPC-ROS1 (FIG-ROS1 ), and SDC4-ROS1.
  • ROS1 protein using certain kinase inhibitors has been described as a potential therapy for a subset of non-small-cell lung cancer. Chin, LP, et al. J. Thoracic Oncology 2012 Nov; 7(1 1 ):1625-30. Further, the kinase inhibitor crizotinib is used to treat
  • ALK-rearranged non-small cell lung cancer Crizotinib has also been shown to inhibit
  • ROS1 enzyme in ROS 1 -rearranged NSCLC Ou, SH, et al. Oncologist. 2012; 17(1 1 ):1351-
  • Foretinib (also referred to as Formula I herein) is an oral multikinase inhibitor targeting c-Met, Tie-2, RON, Axl, and VEGFR.
  • HGF/Met signaling plays a pivotal role in tumor cell proliferation, migration and invasion, and circulating levels of HGF correlate with poor prognosis in certain cancers.
  • Compounds that simultaneously inhibit VEGF and c- MET RTKs may be more effective anticancer agents than agents targeting each of these receptors individually (Pennacchietti, et al.
  • foretinib has activity against other RTKs that have been implicated in tumor pathobiology, including the transmembrane tyrosine kinase KIT, platelet-derived growth factor receptors, FMS-like tyrosine kinase 3, and the receptor for angiopoietin-2, Tie-2.
  • the 4-anilino quinazolines derivatives gefitinib and erlotinib are EGFR inhibitors that have been approved to treat certain human cancers. Cohen, M. H., et al. Oncologist 2003,
  • AXL belongs to the subfamily of receptor tyrosine kinases (RTKs) and has been reported as a potential therapeutic target in cancer. Li, Y. et al. Oncogene (2009) 28, 3442-3455.
  • An embodiment of the invention is a method of administering a compound of formula I):
  • Another embodiment of the invention is a marker for use as a diagnostic marker therapy or treatment using a compound of formula (I):
  • (I) or a pharmaceutically acceptable salt, ester, or solvate thereof to a patient such as in a patient with rosl variant cancer or a kinase variant cancer, wherein the marker is a ROS1 protein, a rosl gene, a kinase protein selected from Table 1 or 2, or a gene encoding a kinase protein selected from Table 1 or 2.
  • a further embodiment of the invention is a method of treating cancer in a human having a rosl variant cancer or a kinase variant cancer comprising administration of a therapeuticall effective amount of a compound of formula (I):
  • a still further embodiment of the invention is a method of treating cancer in a human comprising identifying, selecting, or determining a human having rosl variant cancer or kinase variant cancer and administering a therapeutically effective amount of a compound of formula (I):
  • An embodiment of the invention is a method of treating cancer in a human comprising the steps of: obtaining a sample from a human; testing the sample for a rosl variant cancer or optionally for a kinase variant cancer; and administering to the patient having a rosl variant cancer or a kinase variant cancer a therapeutically effective amount of a com ound of formula (I):
  • a method of treating cancer in a human comprising the steps of:
  • a human has a rosl variant cancer or a kinase variant cancer; and isterin a therapeutically effective amount of amount of a compound of formula (I):
  • Another embodiment of the invention is a method of treating cancer in a human classified as a foretinib responder, wherein a responder is characterized by the presence of rosl variant cancer or a kinase variant cancer, comprising administration of a therapeuticall effective amount of a compound of formula (I):
  • a further embodiment of the invention is a method of treating cancer in a human comprising the steps of: optionally obtaining a sample from said human; testing for a rosl gene expression or ROS1 protein; optionally comparing or determining levels of rosl gene expression or ROS1 protein; optionally correlating the level with outcome; and if conditions are met, then administering a therapeutically effective amount of amount of a compound of formula I):
  • a still further embodiment of the invention is a method of treating cancer in a human comprising the steps of: optionally obtaining a sample from said human; testing for a kinase protein selected from Table 1 or Table 2 or testing for expression of a gene encoding a kinase protein selected from Table 1 or Table 2; optionally comparing or determining a level of expression of the gene or of the kinase protein; optionally correlating the level with a level that indicates treatment foretinib; and if conditions are met, then administerin a therapeutically effective amount of amount of a compound of formula (I):
  • An embodiment of the invention is a method of treating cancer in a human comprising the steps of: determining that a sample contains a rosl variant cancer or determining that a human has a rosl variant cancer; and if conditions are met, then administerin a therapeutically effective amount of amount of a compound of formula (I):
  • the determining and administering steps can be combined.
  • Another embodiment of the invention is a compound of formula (I):
  • Yet another embodiment of the invention is a com ound of formula (I):
  • a foretinib responder is characterized by the presence of a rosl variant cancer or a kinase variant cancer, or is characterized using the method for identifying a foretinib responder.
  • methods for treating a human with a ROS1 variant cancer comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to said human, wherein said human has previously receive crizotinib.
  • the compound of Formula I or pharmaceutically acceptable salt thereof is administered at a dose of 60 mg/day.
  • the human is resistant to crizotinib.
  • the ROS1 variant cancer is non-small cell lung cancer.
  • foretinib is administered as monotherapy.
  • the dose of foretinib is reduced from 60 mg/day to 45 mg/day or 30 mg/day or 15 mg/day as is necessary for effective treatment.
  • Another embodiment of the invention is a use of an amount of a compound of formula I):
  • (I) or a pharmaceutically acceptable salt, ester, or solvate thereof characterized in that it is for the manufacture of a medicament for use in the treatment of cancer in a human classified as a foretinib responder, wherein a foretinib responder is characterized by presenting with a rosl variant cancer or a kinase variant cancer.
  • a further embodiment of the invention is a method of treating cancer in a human comprising the steps of: obtaining a sample from a human; testing the sample for a the level or state of phosphorylation of a ROS1 protein or a kinase in Table 1 or Table 2, and administering to the patient having a rosl variant cancer or a kinase variant cancer a therapeutically effective amount of a compound of formula (I):
  • Yet another embodiment of the invention is a method of treating cancer in a human having a rosl variant cancer and an an axl variant cancer, such as for example, an AXL expressing cancer comprising administration of a therapeutically effective amount of a compound of formula I):
  • An embodiment of the invention is a ROS1 protein or rosl gene and an AXL protein or axl gene for use as a diagnostic marker in therapy or treatment using a compound of formula I):
  • a further embodiment of the invention is a method of treating cancer in a human comprising identifying a human having rosl variant cancer and AXL expressing cancer and administerin a therapeutically effective amount of a compound of formula (I):
  • a still further embodiment of the invention is a method of treating cancer in a human comprising the steps of: obtaining a sample from a human; testing the sample for a rosl variant cancer; testing the sample for AXL expression in said cancer; and
  • An embodiment of the invention is a method of treating cancer in a human comprising identifying a human having rosl variant cancer and an AXL expressing cancer and administering a therapeutically effective amount of at least one erbB-1 inhibitor and a composition comprising Formula I or a pharmaceutically acceptable salt thereof to said human.
  • an erbB-1 inhibitor comprises eriotinib or gefetinib, or for example, comprises a compound of formula (III):
  • Another embodiment of the invention is a method of treating cancer in a human comprising the steps of: administering at least one erbB-1 inhibitor to said human wherein said human has a rosl variant cancer; and a therapeutically effective amount of amount of a compound of formula (I):
  • Methods of the invention also comprise an embodiment further comprising a step or steps of determining if a tumor cell from said cancer expresses AXL.
  • Methods of the invention also comprise an embodiment wherein a cancer shows resistance to an erbB-1 inhibitor, or wherein the compound comprising Formula I is coadministered with said erbB-1 inhibitor, or wherein the administration of compound of Formula I or a pharmaceutically acceptable salt thereof is administered after said erbB-1 inhibitor.
  • Methods of the invention also comprise a step or steps wherien said erbB-1 inhibitor comprises erlotinib or a pharmaceutically acceptable salt thereof, or wherein administration of said erbB-1 inhibitor is discontinued prior to or following administration of the com ound of formula (I):
  • Still further embodiments of the invention comprise methods wherein treating lung cancer in a human comprises: determining if said lung cancer is a rosl variant cancer: determining if a tumor cell from said lung cancer expresses or over expresses AXL;
  • said cancer is a rosl variant cancer and is an axl variant cancer, such as, for example, said cancer comprises a tumor cell expressing or overexpressing AXL.
  • embodiments of the invention comprise a method of treating a human with lung cancer that is resistant to erlotinib comprising determining if said cancer expresses AXL and if said cancer is a rosl variant cancer and administering erlotinib or a pharmaceutically acceptable salt thereof and foretinib or a pharmaceutically acceptable salt thereof to said human if said cancer is a rosl variant cancer and is an axl variant cancer, such as, for example, said cancer comprises a tumor cell expressing AXL.
  • the invention further provides a method with an optional step or steps of comparing and/or determining the level or state of phosphorylation and/or other enzyme activity of a ROS1 protein, AXL protein, or a kinase in Table 1 and/or Table 2.
  • methods for treating ROS1 variant cancer comprising treating a human in need thereof with about 60 mg/day or foretinib.
  • foretinib is administered as monotherapy.
  • the foretinib is co-administered with another anti-neoplastic agent.
  • the foretinib is in the free-base form.
  • foretinib is administered to said human and then it is determined if said cancer is ROS1 variant cancer.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, compounds of formula (I), 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
  • 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.
  • rosl variant cancer means a cancer (as cancer is disclosed herein and as otherwise understood by the skilled artisan) that comprises a cell(s) that (i) expresses a rosl gene in a way that differs from a "wild type” rosl gene or ⁇ e.g., a higher or lower level or change in temporal expression) (ii) comprises a rosl gene having a sequence
  • Ros 1 variant cancer also refers to any ROS1 rearrangement.
  • ROS1 rearrangement are described in Davies, K. D. et al.,. Clin Cancer Res 2012; 18:4570-9. and Bergethon, et al. J Clin Oncol. 2012 March 10; 30(8): 863-870.
  • axl variant cancer means a cancer (as cancer is disclosed herein and as otherwise understood by the skilled artisan) that (i) expresses an axl gene in a way that differs from an "wild type” axl gene or (e.g., a higher or lower level or change in temporal expression) (ii) comprises an axl gene having a sequence (including, e.g. coding sequence and/or non-coding 3' and 5' control sequences) that differs from such "wild type" axl gene sequence by at least one nucleotide (including, e.g.
  • a sequence point mutation, an insertion, or a deletion) and/or post-transcriptionally added or removed moiety e.g., a methyl moiety
  • expresses an AXL protein in a way that differs from a "wild type" AXL protein e.g. a higher or lower level or change in temporal expression
  • a sequence point substitution, an insertion, or a deletion), and/or post-translationally added or removed moiety e.g., an acetyl moiety
  • (v) comprises a polymorphic variant of axl gene
  • kinase variant cancer means a cancer (as cancer is disclosed herein and as otherwise understood by the skilled artisan) that comprises a cell(s) that (i) expresses a kinase gene that encodes a kinase in Table 1 or Table 2 in a way that differs from the "wild type” version of such kinase gene or ⁇ e.g., a higher or lower level or change in temporal expression) (ii) comprises a gene that encodes a kinase in Table 1 or Table 2 such gene having a sequence (including, e.g.
  • coding sequence and/or non-coding 3' and 5' control sequences that differs from the "wild type" version of such gene sequence by at least one nucleotide (including, e.g. a sequence point mutation, an insertion, or a deletion) and/or post-transcriptionally added or removed moiety (e.g., a methyl moiety), or (iii) expresses a kinase protein in Table 1 or 2 in a way that differs from the "wild type” version of such kinase protein (e.g.
  • kinase protein in Table 1 or 2 having a sequence that differs from the "wild type” version of such kinase protein by at least one amino acid (including, e.g.
  • a sequence point substitution, an insertion, or a deletion), and/or post-translationally added or removed moiety e.g., an acetyl moiety
  • (v) comprises a polymorphic variant of a gene that encodes a kinase protein in Table 1 or Table 2, or (vi) or expresses a kinase protein in Table 1 or Table 2 that as compared to a "wild type" version of such protein has a higher degree of phosphorylation (e.g. per ROS1 protein or relative stoichiometric level compared to "wild type”), a higher level of phosphorylation activity or other enzyme activity, or a change or difference
  • variant cancer protein also refers to polypeptide that include, but are not limited to, allelic variants, splice variants, derivative variants, substitution variants, deletion variants, and/or insertion variants, fusion polypeptides, orthologs, and interspecies homologs, polypeptides comprising additional residues at the C- or N-terminus, such as, but not limited to, leader sequence residues, targeting residues, amino terminal methionine residues, lysine residues, tag residues and/or fusion protein residues.
  • the present invention relates to kinase variant cancers with an enzyme activity value (from "value” column) in Table 1 or Table 2, of 30 or less, of 25 or less, of 20 or less, 10 or less, 7 or less, 5 or less, or 1 or less, or 0 or less.
  • 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
  • SNP Polymorphism
  • a “gene” is a sequence of DNA present in a cell that directs the expression of a “gene product,” most commonly by transcription to produce RNA and translation to produce protein.
  • An “allele” is a particular form of a gene. The term allele is relevant when there are two or more forms of a particular gene. Genes and alleles are not limited to the open reading frame of the genomic sequence or the cDNA sequence corresponding to processed RNA. A gene and allele can also include sequences upstream and downstream of the genomic sequence such as promoters and enhancers.
  • the term "gene product” or “polymorphic variant allele product” refer to a product resulting from transcription of a gene.
  • Gene and polymorphic variant allele products include partial, precursor, mature transcription products such as pre-mRNA and mRNA, and translation products with or without further processing including, without limitation, lipidation, phosphorylation, glycosylation, other modifications known in the art, and combinations of such processing.
  • RNA may be modified without limitation by complexing with proteins, polyadenylation, splicing, capping or export from the nucleus.
  • a "polymorphism” is a site in the genome that varies between two or more individuals or within an individual in the case of a heterozygote.
  • the frequency of the variation can be defined above a specific value for inclusion of variations generally observed in a population as opposed to random mutations.
  • Polymorphisms that can be screened according to the invention include variation both inside and outside the open reading frame. When outside the reading frame the polymorphism can occur within 200, 500, 1000, 2000, 3000, 5000, or more of either the 5' or 3' end of the open reading frame. When inside the reading frame, the polymorphism may occur within an exon or intron, or overlapping an exon/intron boundary. A polymorphism could also overlap the open reading frame and a sequence outside of that frame. Many polymorphisms have been given a "rs" designation in the SNP database of NCBI's Entrez, some of these designations have been provided herein.
  • a “polymorphic variant” is a particular form or embodiment of a polymorphism.
  • a particular variant could potentially be an "A" (adenosine), "G” (guanine), “T” (thymine), and “C” (cytosine).
  • A adenosine
  • G guanine
  • T thymine
  • C cytosine
  • U uracil
  • PositionNUC1 >NUC2 is used to indicate a polymorphism contrasting one variant from another.
  • 242A>C would refer to a cytosine instead of an adenosine occurring at position 242 of a particular nucleic acid sequence.
  • the variation can be to two or more different bases, e.g., 242A>C/T.
  • 242A>C when used in respect to a mRNA/cDNA, it can also be used to represent the polymorphism as it occurs in the genomic DNA with the understanding that the position number will likely be different in the genome. Sequence and polymorphic location information for both coding domain sequence and genomic sequence is described herein for the genes relevant to the invention.
  • Polymorphic variant allele refers to an allele comprising a particular polymeric variant or a particular set of polymorphic variants corresponding to a particular set of polymorphisms. Two alleles can both be considered the same polymorphic variant allele if they share the same variant or set of variants defined by the polymorphic variant allele even though they may differ in respect to other polymorphisms or variation outside the definition. For a mutation at the amino acid level, the convention "AA1 PositionAA2" is used.
  • M726L in the context of amino acid sequence, M726L, would indicate that the underlying, nucleotide level polymorphism(s) has resulted in a change from a methionine to a leucine at position 726 in the amino acid sequence.
  • a “genotype” can refer to a characterization of an individual's genome in respect to one or both alleles and/or one or more polymorphic variants within that allele.
  • a subject can be characterized at the level that the subject contains a particular allele, or at the level of identifying both members of an allelic pair, the corresponding alleles on the set of two chromosomes.
  • One can also be characterized at the level of having one or more polymorphic variants.
  • haplotype refers to a cis arrangement of two or more polymorphic variants, on a particular chromosome such as in a particular gene.
  • the haplotype preserves the information of the phase of the polymorphic nucleotides-that is, which set of polymorphic variants were inherited from one parent, and which from the other. Wherein methods, materials, and experiments are described for the invention in respect to polymorphic variants, one will understand that can also be adapted for use with an analogous haplotype.
  • a "diplotype” is a haplotype that includes two polymorphisms.
  • a single nucleotide polymorphism refers to a variation at a single nucleotide location.
  • the variations at the position could be any one of the four nucleotide bases, in others the variation is some subset of the four bases.
  • the variation could be between either purine base or either pyrimidine base.
  • Simple- sequence length polymophisms SSLPs
  • short tandem repeat polymorphisms STRPs
  • RFLP restriction fragment length polymorphism
  • 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, respectively, and/or various biochip and array technologies. 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.
  • amplification and grammatical variations thereof refers to the presence of one or more extra gene copies in a chromosome complement.
  • a gene encoding a Ras protein may be amplified in a cell.
  • Amplification of the HER2 gene has been correlated with certain types of cancer. Amplification of the HER2 gene has been found in human salivary gland and gastric tumor-derived cell lines, gastric and colon
  • 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. 1 14:1895-1897 (1992); James et al., Protein Science 3:1347-1350 (1994)).
  • 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 microarrays have been developed to detect genetic variations and
  • DNA microarrays are fabricated by high-speed robotics, on glass or nylon substrates, and contain DNA fragments with known identities ("the probe”). The microarrays are used for matching known and unknown DNA fragments ("the target”) based on traditional base-pairing rules.
  • At least one mutation in a polypeptide or a gene encoding a polypeptide and grammatical variations thereof means a polypeptide or gene encoding a polypeptide having one or more allelic variants, splice variants, derivative variants, substitution variants, deletion variants, truncation variants, and/or insertion variants, fusion
  • At least one mutation of a protein of the invention would include a protein in which part of all of the sequence of a polypeptide or gene encoding the protein is absent or not expressed in the cell for at least one protein produced in the cell.
  • a protein may be produced by a cell in a truncated form and the sequence of the truncated form may be wild type over the sequence of the truncate.
  • a deletion may mean the absence of all or part of a gene or protein encoded by a gene.
  • some of a protein expressed in or encoded by a cell may be mutated while other copies of the same protein produced in the same cell may be wild type.
  • a mutation in a protein would include a protein having one or more amino acid differences in its amino acid sequence compared with wild type of the same type of protein.
  • polypeptide As used herein "genetic abnormality” is meant a deletion, substitution, addition, translocation, amplification and the like relative to the normal native nucleic acid content of a cell of a subject.
  • polypeptide and “protein” are used interchangeably and are used herein as a generic term to refer to native protein, fragments, peptides, or analogs of a polypeptide sequence. Hence, native protein, fragments, and analogs are species of the polypeptide genus.
  • 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.
  • gene encoding a kinase variant cancer protein means any part of a gene or polynucleotide encoding any kinase variant cancer protein
  • gene encoding a rosl variant cancer protein means any part of a gene or polynucleotide encoding any rosl variant cancer protein. Included within the meaning of this term are exons encoding a rosl variant cancer protein.
  • Genes encoding rosl variant cancer proteins include but are not limited to genes encoding part or all rosl gene sequence in rearranged chromosome, rosl rearranged genes, and rosl fusion genes.
  • genotyping a subject (or DNA or other biological sample) for a polymorphic allele of a gene(s) 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.
  • 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).
  • diagnostic marker means a marker, such as a polynucleotide or polypeptide, or combination, for use as a tool for the diagnosis of a particular disease or in a particular patient, or for predicting disease outcome/progression, or for predicting the response to, or monitoring treatment subsequent to treatment with, for example, a particular drug.
  • diagnostic polynucleotide variations may be detected directly (by, e.g., sequencing) or indirectly (e.g., by restriction fragment length polymorphism analysis, or detection of the hybridization of a probe of known sequence, or reference strand conformation polymorphism), or by using other known methods.
  • Diagnosis includes, for example, discerning the identity, sequence, or structure of a diagnostic marker.
  • 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 foretinib 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.
  • 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:
  • a normalized measure of linkage disequilibrium can be defined as:
  • the value of the D " has a range of -1.0 to 1 .0. When statistically significant absolute D " value for two markers is not less than 0.3 they are considered to be in linkage
  • treating means: (1 ) to ameliorate or prevent the condition of one or more of the biological manifestations of the condition, such as signs or symptoms, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects, signs, or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • Prophylactic therapy is also contemplated thereby.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
  • Foretinib (also referred to herein as / ⁇ / 1 - ⁇ 3-fluoro-4-[(6-(methyloxy)-7- ⁇ [3-(4- morpholinyl)propyl]oxy ⁇ -4-quinolinyl)oxy]phenyl ⁇ -/ ⁇ / 1 -(4-fluorophenyl)-1 , 1- cyclopropanedicarboxamide), is disclosed and claimed, along with pharmaceutically acceptable salts and solvates thereof, methods of preparation, and as being useful as an inhibitor of cMET, particularly in treatment of cancer, in International Application No.
  • Examples 25 (p. 193), 36 (pp. 202-203), 42 (p. 209), 43 (p. 209), and 44 (pp. 209-210) describe how Formula I can be prepared.
  • Formula I can be prepared as described in International Application No. PCT/US2009/064341 having an International filing date of November 13, 2008; International Publication Number WO2010/056960 and an
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention.
  • examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers.
  • a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti- folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; receptor tyrosine kinase inhibitors; serine-threonine kinase inhibitors; non-receptor tyrosine kinase inhibitors;
  • angiogenesis inhibitors immunotherapeutic agents; proapoptotic agents; and cell cycle signalling inhibitors.
  • the present invention also provides methods for treating cancer comprising administering Formula I or pharmaceutically acceptable salt thereof with or without another anti-neoplastic agent.
  • foretinib is the compound of Formula (I) or a
  • foretinib which has the chemical / ⁇ / 1 - ⁇ 3-fluoro-4-[(6-(methyloxy)-7- ⁇ [3-(4-morpholinyl)propyl]oxy ⁇ -4- quinolinyl)oxy]phenyl ⁇ -/V 1 -(4-fluorophenyl)-1 , 1 -cyclopropanedicarboxamide) and is known by the generic name foretinib.
  • foretinib is administered as monotherapy. In some embodiments, foretinib is administered at a dose of 60 mg/day.
  • a compound comprising Formula I is administered as a free base.
  • Formula I can be administered at a dose of at least 7.5 mg daily.
  • Formula I can be administered, for instance, at a dose of about 7.5 mg, 15.0 mg, 30.0 mg, 45.0 mg and/or 60 mg/daily.
  • Formula I may be provided in tablet form.
  • tablets comprise hypromellose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
  • Some tablets may comprise hypromellose, titanium dioxide, polyethylene glycol. Tablets may comprise polysorbate 80 and iron oxide yellow.
  • 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, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnit
  • phosphate/diphosphate polygalacturonate
  • potassium salicylate
  • sodium stearate
  • subacetate succinate
  • tannate tartrate
  • teoclate tosylate
  • triethiodide trimethylammonium and valerate.
  • the determination of whether a patient has a particular genotype at a given reference single nucleotide polymorphism includes testing the patient for the particular genotype at the given reference single nucleotide polymorphism.
  • the 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 in the Examples section below.
  • the determination of whether a patient has a particular genotype at a given reference single nucleotide polymorphism includes testing the patient for at least one single nucleotide polymorphism that is correlated with the given reference single nucleotide polymorphism.
  • a first reference single nucleotide polymorphism is correlated to a second single nucleotide polymorphism if detection of the first reference single nucleotide polymorphism, or a particular genotype of the first single nucleotide polymorphism, indicates that the individual would have the second reference single nucleotide
  • polymorphism if the individual were to be tested for the second reference single nucleotide polymorphism or particular genotype thereof.
  • the determination of whether a patient has a particular genotype at a given reference single nucleotide polymorphism is performed.
  • the biological sample is selected from the group consisting of cells, blood, blood components, urine and saliva.
  • treating means: (1 ) to ameliorate or prevent the condition of one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • Prophylactic therapy is also contemplated thereby.
  • prevention is not an absolute term.
  • prevention is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • terapéuticaally effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • ком ⁇ онент and grammatical variations thereof, as used herein is meant either simultaneous administration or any manner of separate sequential administration of a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B or a pharmaceutically acceptable salt thereof.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and the other compound may be administered orally.
  • both compounds are administered orally.
  • combination kit as used herein is meant the pharmaceutical composition or compositions that are used to administer Compound A, or a
  • the combination kit can contain Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions.
  • the combination kit will contain Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B, or a
  • the combination kit can comprise Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions in a single package or in separate pharmaceutical compositions in separate packages.
  • a combination kit comprising the components: Compound A, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier; and
  • Compound B or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  • first container comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier
  • second container comprising Compound B, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, and a container means for containing said first and second containers.
  • the "combination kit” can also be provided by instruction, such as dosage and administration instructions.
  • dosage and administration instructions can be of the kind that is provided to a doctor, for example by a drug product label, or they can be of the kind that is provided by a doctor, such as instructions to a patient.
  • Compound A 2 means— Compound A, or a
  • Compound B 2 means— Compound B, or a
  • the combinations of this invention are administered within a "specified period”.
  • specified period and grammatical variations thereof, as used herein is meant the interval of time between the administration of one of Compound A 2 and
  • the specified period can include simultaneous administration. Unless otherwise defined the specified period refers to administration of Compound A 2 and Compound B 2 during a single day.
  • the specified period will be about 24 hours; suitably they will both be administered within about 12 hours of each other - in this case, the specified period will be about 12 hours; suitably they will both be administered within about 1 1 hours of each other - in this case, the specified period will be about 1 1 hours; suitably they will both be administered within about 10 hours of each other - in this case, the specified period will be about 10 hours; suitably they will both be administered within about 9 hours of each other - in this case, the specified period will be about 9 hours; suitably they will both be administered within about 8 hours of each other - in this case, the specified period will be about 8 hours; suitably they will both be administered within about 7 hours of each other - in this case, the specified period will be about 7 hours; suitably they will both be
  • the specified period will be about 6 hours; suitably they will both be administered within about 5 hours of each other - in this case, the specified period will be about 5 hours; suitably they will both be
  • the specified period will be about 4 hours; suitably they will both be administered within about 3 hours of each other - in this case, the specified period will be about 3 hours; suitably they will be administered within about 2 hours of each other - in this case, the specified period will be about 2 hours; suitably they will both be administered within about 1 hour of each other - in this case, the specified period will be about 1 hour.
  • the administration of Compound A 2 and Compound B 2 in less than about 45 minutes apart is considered simultaneous administration.
  • the compounds when the combination of the invention is administered for a "specified period", the compounds will be co-administered for a "duration of time".
  • duration of time and grammatical variations thereof, as used herein is meant that both compounds of the invention are administered for an indicated number of consecutive days. Unless otherwise defined, the number of consecutive days does not have to commence with the start of treatment or terminate with the end of treatment, it is only required that the number of consecutive days occur at some point during the course of treatment.
  • both compounds will be administered within a specified period for at least one day - in this case, the duration of time will be at least one day; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 3 consecutive days - in this case, the duration of time will be at least 3 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 5 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 7 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 14 consecutive days - in this case, the duration of time will be at least 14 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 30 consecutive days - in this case, the duration of time will be at least 30 days.
  • the compounds are not administered during a "specified period", they are administered sequentially.
  • sequential administration and derivates thereof, as used herein is meant that one of Compound A 2 and Compound B 2 is administered once a day for two or more consecutive days and the other of Compound A 2 and Compound B 2 is subsequently administered once a day for two or more consecutive days.
  • a drug holiday utilized between the sequential administration of one of Compound A 2 and Compound B 2 and the other of Compound A 2 and Compound B 2 .
  • a drug holiday is a period of days after the sequential administration of one of Compound A 2 and Compound B 2 and before the administration of the other of Compound A 2 and Compound B 2 where neither Compound A 2 nor Compound B 2 is administered.
  • the drug holiday will be a period of days selected from: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days,
  • one of Compound A 2 and Compound B 2 is administered for from 2 to 30 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A 2 and Compound B 2 for from 2 to 30 consecutive days.
  • one of Compound A 2 and Compound B 2 is administered for from 2 to 21 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A 2 and Compound B 2 for from 2 to 21 consecutive days.
  • one of Compound A 2 and Compound B 2 is administered for from 2 to 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of the other of Compound A 2 and Compound B 2 for from 2 to 14 consecutive days.
  • one of Compound A 2 and Compound B 2 is administered for from 3 to 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of the other of Compound A 2 and
  • Compound B 2 for from 3 to 7 consecutive days.
  • Compound B 2 will be administered first in the sequence, followed by an optional drug holiday, followed by administration of Compound A 2 .
  • Compound B 2 is administered for from 3 to 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound A 2 for from 3 to 21 consecutive days.
  • Compound B 2 is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of Compound A 2 for from 3 to 21 consecutive days.
  • Compound B 2 is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of Compound A 2 for from 3 to 21 consecutive days.
  • Compound B 2 is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound A 2 for 14 consecutive days.
  • Compound B 2 is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by
  • Compound A 2 for 14 consecutive days is administered.
  • Compound B 2 is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of Compound A 2 for 7 consecutive days.
  • Compound B 2 is administered for 3 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of Compound A 2 for 7 consecutive days.
  • Compound B 2 is administered for 3 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of Compound A 2 for 3 consecutive days. It is understood that a "specified period" administration and a "sequential" administration can be followed by repeat dosing or can be followed by an alternate dosing protocol, and a drug holiday may precede the repeat dosing or alternate dosing protocol.
  • the amount of Compound A 2 administered as part of the combination according to the present invention will be an amount selected from about 0.125mg to about 10mg; suitably, the amount will be selected from about 0.25mg to about 9mg;
  • the amount will be selected from about 0.25mg to about 8mg; suitably, the amount will be selected from about 0.5mg to about 8mg; suitably, the amount will be selected from about 0.5mg to about 7mg; suitably, the amount will be selected from about 1 mg to about 7mg; suitably, the amount will be about 5mg. Accordingly, the amount of Compound A administered as part of the combination according to the present invention will be an amount selected from about 0.125mg to about 10 mg.
  • the amount of Compound A 2 administered as part of the combination according to the present invention can be 0.125mg, 0.25mg, 0.5mg, 0.75mg, 1 mg, 1 .5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg.
  • the amount of Compound B 2 administered as part of the combination according to the present invention will be an amount selected from about 75mg to about 1 ,000mg; suitably, the amount will be selected from about 100mg to about 900mg;
  • the amount will be selected from about 150mg to about 850mg; suitably, the amount will be selected from about 200mg to about 800mg; suitably, the amount will be selected from about 250mg to about 750mg; suitably, the amount will be selected from about 300mg to about 6000mg; suitably, the amount will be about 450mg. Accordingly, the amount of Compound B 2 administered as part of the combination according to the present invention will be an amount selected from about 75mg to about 1 ,000mg.
  • the amount of Compound B 2 administered as part of the combination according to the present invention can be 75mg, 100 mg, 125mg, 150 mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg or 1 ,000mg.
  • the method of the present invention may also be employed with other therapeutic methods of cancer treatment. While it is possible that, for use in therapy, therapeutically effective amounts of the combinations of the present invention may be administered as the raw chemical, it is preferable to present the combinations as a pharmaceutical composition or compositions. Accordingly, the invention further provides pharmaceutical compositions, which include Compound A 2 and/or Compound B 2 , and one or more pharmaceutically acceptable carriers.
  • the combinations of the present invention are as described above.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing Compound A 2 and/or Compound B 2 with one or more pharmaceutically acceptable carriers.
  • Such elements of the pharmaceutical combination utilized may be presented in separate pharmaceutical compositions or formulated together in one pharmaceutical formulation.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • amount of active ingredient per dose will depend 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, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • Compound A 2 and Compound B 2 may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that Compound A 2 and Compound B 2 may be compounded together in a pharmaceutical composition/formulation.
  • routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and
  • compositions which include therapeutically effective amounts of foretinib, 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 foretinib with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • 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
  • 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,
  • 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.
  • 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.
  • 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 sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • 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,
  • flavor additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • 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,
  • Foretinib 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.
  • 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.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Eye-drop formulations are described further herein below.
  • Suitable routes for ocular administration include extraocular and intraocular (including, for example, intravitreal, subretinal, subscleral, intrachoroidal, and
  • the pharmaceutical formulations may also be applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water- in-oil base.
  • the pharmaceutical formulations are adapted for intraocular administration by means of intraocular injection or other device for ocular delivery.
  • ocular devices that may be used in the methods of the invention include periocular or intravitreal devices, contact lenses and liposomes. See, for example, U.S. Pat. Nos. 3,416,530; 3,828,777; 4,014,335; 4,300,557; 4,327,725;
  • Formulations for drug delivery using ocular devices may combine one or more active agents and adjuvants appropriate for the indicated route of administration.
  • the active agents may be admixed with any pharmaceutically acceptable excipient, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, tableted or encapsulated for conventional administration.
  • the compounds may be dissolved in polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.
  • the compounds may also be mixed with compositions of both biodegradable and non-biodegradable polymers, and a carrier or diluent that has a time delay property.
  • biodegradable compositions can include albumin, gelatin, starch, cellulose, dextrans, polysaccharides, poly (D,L-lactide), poly (D,L-lactide-co-glycolide), poly (glycolide), poly (hydroxybutyrate), poly (alkylcarbonate) and poly (orthoesters) and mixtures thereof.
  • non-biodegradable polymers can include EVA copolymers, silicone rubber and poly (methylacrylate), and mixtures thereof.
  • compositions for ocular delivery also include in situ gellable aqueous composition.
  • a composition comprises a gelling agent in a concentration effective to promote gelling upon contact with the eye or with lacrimal fluid.
  • Suitable gelling agents include but are not limited to thermosetting polymers.
  • the term "in situ gellable” as used herein is includes not only liquids of low viscosity that form gels upon contact with the eye or with lacrimal fluid, but also includes more viscous liquids such as semi-fluid and thixotropic gels that exhibit substantially increased viscosity or gel stiffness upon administration to the eye. See, for example, Ludwig (2005) Adv. Drug Deliv. Rev. 3; 57:1595-639, herein incorporated by reference for purposes of its teachings of examples of polymers for use in ocular drug delivery.
  • Pharmaceutical formulations 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 vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • 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.
  • 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 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 12 mg/kg body weight per day.
  • an effective amount of a salt or solvate thereof can typically be from a lower limit of 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg to an upper limit of about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245,
  • This amount may be given in a single dose per day or 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.
  • Foretinib 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 foretinib, and the use of at least one other cancer treatment method, including one or more additional compounds.
  • combination therapies according to the present invention comprise the administration of foretinib, and at least one other pharmaceutically active agent, preferably an anti-neoplastic agent.
  • Foretinib 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 foretinib 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.
  • Foretinib 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 antineoplastic 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 foretinib can include the following:
  • cell cycle specific anti-neoplastic agents including, but not limited to,
  • 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 and thioguanine; and camptothecins such as 9-amino camptothecin, irinotecan, CPT-1 1 and the various optical forms of 7-(4-methylpiperazino-methylene)- 10, 1 1 -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
  • 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
  • metalloproteinase inhibitors such as marimastat
  • antiprogestogens urokinase plasminogen activator receptor function inhibitors
  • cyclooxygenase type 2 (COX-2) inhibitors such as celecoxi
  • Foretinib 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.
  • foretinib is administered or prescribed in the treatment of disorders mediated by inappropriate c-MET activity.
  • the inappropriate c-METactivity referred to herein is any c-MET activity that deviates from the normal c-MET activity expected in a particular mammalian subject.
  • Inappropriate C-MET activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of c-MET activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase or ligand leading to inappropriate or uncontrolled activation of the receptor. Furthermore, it is also understood that unwanted c-MET activity may reside in an abnormal source, such as a malignancy.
  • overexpressed and “overexpression” of a protein or polypeptide and grammatical variations thereof means that a given cell produces an increased number of a certain protein relative to a normal cell.
  • a ras protein may be overexpressed by a tumor cell relative to a non-tumor cell.
  • a mutant ras protein may be overexpressed compared to wild type ras protein in a cell.
  • expression levels of a polypeptide in a cell can be normalized to a housekeeping gene such as actin.
  • a certain polypeptide may be underexpressed in a tumor cell compared with a non-tumor cell.
  • cancer As used herein, the terms "cancer,” “neoplasm,” and “tumor,” are used
  • a cancer cell refers to cells that have undergone a malignant transformation that makes them pathological to the host organism.
  • Primary cancer cells that is, cells obtained from near the site of malignant transformation
  • the definition of a cancer cell includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells.
  • a "clinically detectable" tumor is one that is detectable on the basis of tumor mass; e.g., by procedures such as CAT scan, MR imaging, X-ray, ultrasound or palpation, and/or which is detectable because of the expression of one or more cancer-specific antigens in a sample obtainable from a patient.
  • Tumors may be hematopoietic tumor, for example, tumors of blood cells or the like, meaning liquid tumors.
  • Specific examples of clinical conditions based on such a tumor include leukemia such as chronic myelocytic leukemia or acute myelocytic leukemia; myeloma such as multiple myeloma; lymphoma and the like.
  • the disorder is cancer.
  • the cancer is a lung cancer, such as non-small cell lung cancer (NSCLC), or a ROS1 -rearranged NSCLC, such as for example NSCLC comprising rosl rearrangements SLC34A2-ROS1 , CD74-ROS1 , EZR-ROS1 , TPM3-ROS1 , and/or SDC4- ROS1 .
  • NSCLC non-small cell lung cancer
  • ROS1 -rearranged NSCLC such as for example NSCLC comprising rosl rearrangements SLC34A2-ROS1 , CD74-ROS1 , EZR-ROS1 , TPM3-ROS1 , and/or SDC4- ROS1 .
  • Another embodiments includes, for example, an oncogene addicted ROS1- rearranged cancer.
  • Still another embodiment provides a lung cancer, such as a NSCLC that recurs after or is refractory to treatment with crizotinib
  • the cancer is selected from the group of colon cancer, breast cancer, renal cell carcinoma, melanoma, lung cancer including non-small cell lung cancer and adenocarcinoma, 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-hepatobiliary cancer, multiple myeloma, leukemia, thyroid cancer including Hurthle cell, muscle sarcoma (leiomyosarcoma) and bone sarcoma
  • the present invention relates to a method for treating or lessening the severity of cancers selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia,
  • cell lymphoma Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.
  • GIST gastrointestinal stromal tumor
  • the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), and colon polyps.
  • the precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Car
  • a further aspect of the present invention provides the use of foretinib of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment of cancer and malignant tumours.
  • the present invention relates to the treatment of treatment of a cancer selected from the group of a subset of the cancers disclosed herein.
  • aspects of the present invention include similar aspects directed to methods of treating diseases where a kinase is disregulated, such as a kinase in Table 1 or Table 1 , for example Ros1 kinase.
  • the therapeutic agents may be administered together or separately.
  • the same means for administration may be used for more than one therapeutic agent of the combination therapy; alternatively, different therapeutic agents of the combination therapy may be administered by different means.
  • the therapeutic agents When the therapeutic agents are administered separately, they may be administered simultaneously or sequentially in any order, both close and remote in time.
  • the amounts of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and/or the other pharmaceutically active agent or agents and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • compositions for administration to the eye may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Such a unit may contain, for example, 1 g to 1 g, such as 5 ⁇ g to 500 ⁇ g, 10 g-250 ⁇ g, 0.5 mg to 700 mg, 2 mg to 350 mg, or 5 mg to100 mg of a compound of formula (I) or
  • pharmaceutically acceptable salts or solvates thereof depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a
  • the 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.
  • the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered or prescribed to be administered one, two, three, four, or more times per day.
  • the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered or prescribed to be administered by administering one, two, three, four or more drops of a suitable pharmaceutical formulation one, two, three, four, or more times per day.
  • the suitable pharmaceutical formulation comprises between a lower limit of 1 , 2, 3, 4, 5, 6, 7, 8, or 9 and an upper limit of 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof per ml.
  • foretinib is co-administered with at least one additional antineoplastic agent, such as an anti-cancer agent.
  • additional antineoplastic agent such as an anti-cancer agent.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention.
  • examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers.
  • a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti- folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; receptor tyrosine kinase inhibitors; serine-threonine kinase inhibitors; non-receptor tyrosine kinase inhibitors;
  • angiogenesis inhibitors immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • Diterpenoids which are derived from natural sources, are phase specific anticancer agents that operate at the G 2 /M phases of the cell cycle. It is believed that the diterpenoids stabilize the ⁇ -tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • Paclitaxel 5p,20-epoxy-1 ,2 ⁇ ,4,7 ⁇ , 10 ⁇ , 13a-hexa-hydroxytax-1 1 -en-9-one 4, 10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325. 1971 ), who characterized its structure by chemical and X-ray crystallographic methods.
  • Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 1 1 1 :273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990).
  • the Formula llso shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature,
  • Docetaxel (2R,3S)- N-carboxy-3-phenylisoserine,N-ferf-butyl ester, 13-ester with 5p-20-epoxy-1 ,2a,4,7p, 10p, 13a-hexahydroxytax-1 1-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®.
  • Docetaxel is indicated for the treatment of breast cancer.
  • Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is
  • Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
  • Vinblastine vincaleukoblastine sulfate
  • VELBAN® an injectable solution.
  • Myelosuppression is the dose limiting side effect of vinblastine.
  • Vincristine vincaleukoblastine, 22-oxo-, sulfate
  • ONCOVIN® an injectable solution.
  • Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.
  • Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
  • Vinorelbine 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R * ,R * )-2,3- dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.
  • Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
  • Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA.
  • the platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor.
  • Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
  • Cisplatin cis-diamminedichloroplatinum
  • PLATINOL® an injectable solution.
  • Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
  • the primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
  • Carboplatin platinum, diammine [1 , 1-cyclobutane-dicarboxylate(2-)-0,0'], is commercially available as PARAPLATIN® as an injectable solution.
  • Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
  • Alkylating agents are non-phase anti-cancer specific agents and strong
  • alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death.
  • alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
  • Cyclophosphamide 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
  • Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
  • Chlorambucil 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.
  • Busulfan 1 ,4-butanediol dimethanesulfonate, is commercially available as
  • Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
  • Carmustine 1 ,3-[bis(2-chloroethyl)-1 -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®.
  • Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
  • dacarbazine 5-(3,3-dimethyl-1 -triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®.
  • dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
  • Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death.
  • antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthracyclins such as daunorubicin and doxorubicin; and bleomycins.
  • Dactinomycin also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
  • Daunorubicin (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo- hexopyranosyl)oxy]-7,8,9, 10-tetrahydro-6,8, 1 1 -trihydroxy-1 -methoxy-5, 12
  • naphthacenedione hydrochloride is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.
  • Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.
  • Doxorubicin (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-8- glycoloyl, 7, 8, 9, 10-tetrahydro-6, 8, 1 1 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®.
  • Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
  • Bleomycin a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of
  • Streptomyces verticillus is commercially available as BLENOXANE®.
  • Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
  • Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
  • Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Etoposide 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene-p-D- glucopyranoside]
  • VePESID® an injectable solution or capsules
  • VP-16 an injectable solution or capsules
  • Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
  • Teniposide 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene-p-D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children.
  • Teniposide can induce both leucopenia and thrombocytopenia.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows.
  • Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine,
  • mecaptopurine mecaptopurine, thioguanine, and gemcitabine.
  • 5-fluorouracil 5-fluoro-2,4- (1 H,3H) pyrimidinedione
  • fluorouracil is commercially available as fluorouracil.
  • Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
  • 5- fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil.
  • Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5- fluorodeoxyuridine monophosphate.
  • Cytarabine 4-amino-1-p-D-arabinofuranosyl-2 (I H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2', 2'- difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
  • Mercaptopurine 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®.
  • Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses.
  • a useful mercaptopurine analog is azathioprine.
  • Thioguanine 2-amino-1 ,7-dihydro-6H-purine-6-thione
  • TABLOID® Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration.
  • Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
  • Gemcitabine 2'-deoxy-2', 2'-difluorocytidine monohydrochloride ( ⁇ -isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
  • Methotrexate N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of
  • choriocarcinoma meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.
  • Myelosuppression leucopenia, thrombocytopenia, and anemia
  • mucositis are expected side effect of methotrexate administration.
  • Camptothecins including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of
  • camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10, 1 1 -ethylenedioxy-20-camptothecin described below.
  • hydrochloride is commercially available as the injectable solution CAMPTOSAR®.
  • Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.
  • Topotecan HCI (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3, 14-(4H, 12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®.
  • Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer.
  • Pazopanib which commercially available as VOTRIENT® is a tyrosine kinase inhibitor (TKI).
  • TKI tyrosine kinase inhibitor
  • Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide monohydrochloride.
  • Pazoponib is approved for treatment of patients with advanced renal cell carcinoma.
  • Rituximab is a chimeric monoclonal antibody which is sold as RITUXAN® and MABTHERA®.
  • Rituximab binds to CD20 on B cells and causes cell apoptosis.
  • Rituximab is administered intravenously and is approved for treatment of rheumatoid arthritis and B- cell non-Hodgkin's lymphoma.
  • Ofatumumab is a fully human monoclonal antibody which is sold as ARZERRA®.
  • Ofatumumab binds to CD20 on B cells and is used to treat chronic lymphocytic leukemia (CLL; a type of cancer of the white blood cells) in adults who are refractory to treatment with fludarabine (Fludara) and alemtuzumab (Campath).
  • CLL chronic lymphocytic leukemia
  • mTOR inhibitors include but are not limited to rapamycin (FK506) and rapalogs, RAD001 or everolimus (Afinitor), CCI-779 or temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687 and Pp121 .
  • Bexarotene is sold as Targretin® and is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs).
  • RXRs retinoid X receptors
  • RARs retinoic acid receptors
  • the chemical name is 4-[1 - (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid.
  • Bexarotene is used to treat cutaneous T-cell lymphoma (CTCL, a type of skin cancer) in people whose disease could not be treated successfully with at least one other medication.
  • CTCL cutaneous T-cell lymphoma
  • Sorafenib marketed as Nexavar® is in a class of medications called multikinase inhibitors. Its chemical name is 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-/V-methyl-pyridine-2-carboxamide. Sorafenib is used to treat advanced renal cell carcinoma (a type of cancer that begins in the kidneys). Sorafenib is also used to treat unresectable hepatocellular carcinoma (a type of liver cancer that cannot be treated with surgery).
  • erbB inhibitors examples include lapatinib, erlotinib, and gefitinib.
  • the free base, HCI salts, and ditosylate salts of the compound of formula (II) may be prepared according to the procedures disclosed in WO 99/35146, published July 15, 1999; and WO 02/02552 published January 10, 2002.
  • the free base and HCI salt of eriotinib may be prepared, for example, according to
  • TARCEVA® tablets contain eriotinib hydrochloride (27.3 mg, 109.3 mg, and 163.9 mg) equivalent to 25 mg, 100 mg and 150 mg eriotinib and the following inactive ingredients: lactose monohydrate, hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulphate, and titanium dioxide.
  • Gefitinib which is commercially available under the trade name IRESSA® (Astra- Zenenca) is an erbB-1 inhibitor that is indicated as monotherapy for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of both platinum-based and docetaxel chemotherapies.
  • the free base, HCI salts, and diHCI salts of gefitinib may be prepared according to the procedures of International Patent
  • the present invention relates to the treatment of treatment of a cancer using an antineoplastic agent or antineoplastic agents selected from the group of a subset of the such agents disclosed herein.
  • Example I Foretinib (GSK1363089G) is a potent human ROS1 kinase inhibitor.
  • a working stock of foretinib is prepared at 50x the final assay concentration in 100% DMSO and spotted into a 96-well assay plate.
  • Human ROS protein (ROS h) is then added in a buffer containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, 10 mM MnCI2 and 250 ⁇ KKKSPGEYVNIEFG kinase substrate.
  • the kinase reaction is initiated by the addition of the MgATP mix (MgAcetate and [ ⁇ -33 ⁇ - ⁇ ] (specific activity approx. 500 cpm/pmol) to give a final assay concentration of 200 uM ATP.
  • reaction After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 3% phosphoric acid solution. Ten microliters of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and counted in a scintillation counter.
  • Tables 1 and 2 show the remaining enzyme activity (in “value” column) following incubation with foretinib. Assay protocols used can be found in Protocol Guide,
  • Table 3 ROS1 IC50 for foretinib Kinase activity using a concentration range of 0.001 micromolar to 10 micromolar.
  • Stage 1 will be used to determine the response to treatment, explore the relationship between a set of biomarkers and efficacy endpoints, and based on emerging data, identify a subpopulation of subjects with a specific biomarker of interest who may be more likely to respond.
  • Stage 2 will evaluate the response rate to treatment in the selected subpopulations.
  • Cohort 3 Subjects with non-small cell lung cancer (NSCLC) that are predicted to be sensitive to foretinib based on biomarkers identified with preclinical or clinical data will receive 60 mg foretinib once daily until disease progression.
  • the first subset to be evaluated will be subjects with NSCLC exhibiting ROS1 rearrangements that are naive to or have progressed on crizotinib/ROS1 inhibitor.
  • Cohort 3 may enroll simultaneously with Cohort 1. A maximum of 20 subjects will be enrolled in each subset in Stage 1 .
  • the subset may be: (1 ) terminated for futility if there are no responses; (2) progress to Stage 2 if a selected subpopulation can be identified, or (3) continue enrollment to a total of 20 subjects to confirm the unselected ORR. After 20 subjects, proceed to Stage 2 if selection criteria are identified based on the cumulative number of subjects in Stage 1.
  • the null hypothesis tested in unselected subjects (Stage 1 ) is that the response rate is no more than 10%.
  • Cohort 3 the objective of the translational research is to determine which if any of the potential predictive biomarkers is associated with response to monotherapy with foretinib. For example, if a specific ROS1 gene fusion is associated with response, this association could be used to select subjects for Stage 2 of this study and could form the basis of a diagnostic test.
  • Cohort 3 predictive Biomarkers: Biomarkers of drug sensitivity optimize the risk/benefit profile for subjects and the intent of this protocol is to utilize emerging preclinical and clinical data to identify cohorts of subjects by specific selection criteria.
  • the first subset of such subjects to be enrolled in Cohort 3 is based on preclinical data showing that foretinib is active against the ROS1 kinase at fifty percent inhibitory concentration (IC50) of 25 nM. ROS1 rearrangements occur in 1 -2% of all NSCLC clinically (Bergethon, et al. J Clin Oncol. 2012;
  • an assessment of the ROS1 fusion partners and the identification of any specific crizotinib/ROS1 inhibitor resistant mutations in baseline biopsy samples in association with tumor response data may define which subjects are most likely to respond and can be used as a selection criterion for Stage 2 of the study.
  • Additional cohorts of NSCLC subjects predicted to be sensitive to the drug based on biomarkers identified with preclinical or clinical data e.g., NRTK, RET, etc.
  • the 15 mg foretinib tablet core contains hypromellose, sodium lauryl sulphate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
  • the tablet coating which is yellow, contains polysorbate 80, iron oxide yellow, hypromellose, titanium dioxide, and polyethylene glycol.
  • Dosage form Tablet; Round yellow tablet
  • De-escalation dose may be reduced in dose 2 times, by 15 mg each time.

Abstract

The present invention relates to the administration of a multikinase inhibitor and its effect on patients with particular genetic variant cancers. More specifically, this present invention is directed to methods of administering foretinib or pharmaceutically acceptable salts or solvates thereof to patients with a ros1 variant cancer including non-small cell lung cancer.

Description

METHOD OF ADMINISTRATION AND TREATMENT
FIELD OF THE INVENTION
The present invention relates to the administration of drug and its effects on patients with particular genetic variant cancers. BACKGROUND OF THE INVENTION
The rosl gene is a proto-oncogene tyrosine-protein kinase that encodes ROS enzyme. Human rosl oncogene is located in a region of chromosome 6 associated with tumor-specific rearrangements. Rabin, M. et al. Oncogene Res. 1987 Jul; 1 (2): 169-78. A human rosl gene cloned from a glioblastoma cell line, then sequenced has been described. Birchmeier C, O'Neill K, Riggs M, Wigler M (1990). Characterization of ROS1 cDNA from a human glioblastoma cell line has been reported. Proc. Natl. Acad. Sci. U.S.A. 87 (12): 4799-803.
Mutations involving rosl gene have been noted in a variety of cancers including non-small-cell lung cancer ("NSCLC"), astrocyomas, cholangiocarcinomas, glioblastoma multiforme, and lung adenocarcinomas. Birchmeier, et al. Proc Natl Acad Sci U S A. 1987 Dec; 84(24):9270-4. Wu, JK and Chikaraishi, DM. Cancer Res. 1990 May 15; 50(10):3032- 5. Chin, LP, et al. J. Thoracic Oncology 2012 Nov; 7(1 1 ):1625-30; Suehara, et al. Clin Cancer Res. 2012.
A number of the rosl mutations that have been noted in cancers and cancer cell lines include various chromosomal rearrangements, rosl fusion variants, and mutations of the rosl 3' region. Chin, LP, et al. J. Thoracic Oncology 2012 Nov; 7(1 1 ):1625-30; Kurtis,
D. et al. Clin Cancer Res 2012; 18:4570-4579.
ROS1 rearrangements described in NSCLC include, for example, SLC34A2-ROS1 ,
CD74-ROS1 , EZR-ROS1 , TPM3-ROS1 , GOPC-ROS1 (FIG-ROS1 ), and SDC4-ROS1.
Davies, et al. Clin Cancer Res. 2012 Sep 1 ; 18(17):4570-9.; Rikova et al. Cell. 2007 Dec
14; 131 (6): 1 190-203; Takeuchi et al. Nat Med. 2012 Feb 12; 18(3):378-81. Suehara, et al.,
Clin Cancer Res. 2012, Nov. 14.
Targeting ROS1 protein using certain kinase inhibitors has been described as a potential therapy for a subset of non-small-cell lung cancer. Chin, LP, et al. J. Thoracic Oncology 2012 Nov; 7(1 1 ):1625-30. Further, the kinase inhibitor crizotinib is used to treat
ALK-rearranged non-small cell lung cancer. Crizotinib has also been shown to inhibit
ROS1 enzyme in ROS 1 -rearranged NSCLC. Ou, SH, et al. Oncologist. 2012; 17(1 1 ):1351-
75. Patients with Rosl rearrangement in NSCLC have been shown to benefit from treatment with crizotinib. Bergethon, et al. J Clin Oncol. 2012 March 10; 30(8): 863-870. Foretinib (also referred to as Formula I herein) is an oral multikinase inhibitor targeting c-Met, Tie-2, RON, Axl, and VEGFR. HGF/Met signaling plays a pivotal role in tumor cell proliferation, migration and invasion, and circulating levels of HGF correlate with poor prognosis in certain cancers. Compounds that simultaneously inhibit VEGF and c- MET RTKs may be more effective anticancer agents than agents targeting each of these receptors individually (Pennacchietti, et al. Cancer Cell. 2003; 3:347-61 . 2003). In addition, foretinib has activity against other RTKs that have been implicated in tumor pathobiology, including the transmembrane tyrosine kinase KIT, platelet-derived growth factor receptors, FMS-like tyrosine kinase 3, and the receptor for angiopoietin-2, Tie-2.
The 4-anilino quinazolines derivatives gefitinib and erlotinib are EGFR inhibitors that have been approved to treat certain human cancers. Cohen, M. H., et al. Oncologist 2003,
8, 303; Cohen, M. H., et al. Oncologist 2005; 10:461.
AXL belongs to the subfamily of receptor tyrosine kinases (RTKs) and has been reported as a potential therapeutic target in cancer. Li, Y. et al. Oncogene (2009) 28, 3442-3455.
U.S. Patent Publication No. US20090274693 discloses methods of treating cancer using AXL inhibitors, and is incorporated by reference herein in its entirety.
It would be useful to provide novel methods of treatment for an individual suffering from ros1 variant cancer or other kinase variant cancer, as well as to provide new uses for foretinib.
SUMMARY OF THE INVENTION
An embodiment of the invention is a method of administering a compound of formula I):
Figure imgf000003_0001
or a pharmaceutically acceptable salt, ester, or solvate thereof to a patient with a ros1 variant cancer or a kinase variant cancer.
Another embodiment of the invention is a marker for use as a diagnostic marker therapy or treatment using a compound of formula (I):
Figure imgf000004_0001
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof to a patient, such as in a patient with rosl variant cancer or a kinase variant cancer, wherein the marker is a ROS1 protein, a rosl gene, a kinase protein selected from Table 1 or 2, or a gene encoding a kinase protein selected from Table 1 or 2.
A further embodiment of the invention is a method of treating cancer in a human having a rosl variant cancer or a kinase variant cancer comprising administration of a therapeuticall effective amount of a compound of formula (I):
Figure imgf000004_0002
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof.
A still further embodiment of the invention is a method of treating cancer in a human comprising identifying, selecting, or determining a human having rosl variant cancer or kinase variant cancer and administering a therapeutically effective amount of a compound of formula (I):
Figure imgf000005_0001
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof.
An embodiment of the invention is a method of treating cancer in a human comprising the steps of: obtaining a sample from a human; testing the sample for a rosl variant cancer or optionally for a kinase variant cancer; and administering to the patient having a rosl variant cancer or a kinase variant cancer a therapeutically effective amount of a com ound of formula (I):
Figure imgf000005_0002
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof
A method of treating cancer in a human comprising the steps of:
determining that a human has a rosl variant cancer or a kinase variant cancer; and isterin a therapeutically effective amount of amount of a compound of formula (I):
Figure imgf000005_0003
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof.
Another embodiment of the invention is a method of treating cancer in a human classified as a foretinib responder, wherein a responder is characterized by the presence of rosl variant cancer or a kinase variant cancer, comprising administration of a therapeuticall effective amount of a compound of formula (I):
Figure imgf000006_0001
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof.
A further embodiment of the invention is a method of treating cancer in a human comprising the steps of: optionally obtaining a sample from said human; testing for a rosl gene expression or ROS1 protein; optionally comparing or determining levels of rosl gene expression or ROS1 protein; optionally correlating the level with outcome; and if conditions are met, then administering a therapeutically effective amount of amount of a compound of formula I):
Figure imgf000006_0002
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof.
A still further embodiment of the invention is a method of treating cancer in a human comprising the steps of: optionally obtaining a sample from said human; testing for a kinase protein selected from Table 1 or Table 2 or testing for expression of a gene encoding a kinase protein selected from Table 1 or Table 2; optionally comparing or determining a level of expression of the gene or of the kinase protein; optionally correlating the level with a level that indicates treatment foretinib; and if conditions are met, then administerin a therapeutically effective amount of amount of a compound of formula (I):
Figure imgf000007_0001
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof.
An embodiment of the invention is a method of treating cancer in a human comprising the steps of: determining that a sample contains a rosl variant cancer or determining that a human has a rosl variant cancer; and if conditions are met, then administerin a therapeutically effective amount of amount of a compound of formula (I):
Figure imgf000007_0002
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof, and optionally wherein
the determining and administering steps can be combined.
Another embodiment of the invention is a compound of formula (I):
Figure imgf000008_0001
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof for use in the treatment of cancer in a human classified as a foretinib responder, wherein a responder is characterized by the presence of a rosl variant cancer.
Yet another embodiment of the invention is a com ound of formula (I):
Figure imgf000008_0002
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof for use in the treatment of cancer in a human classified as a foretinib responder using a method of identifying a foretinib responder.
A further embodiment of the invention is a use of amount of a compound of formula
(I):
Figure imgf000008_0003
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof in the manufacture of a medicament for the treatment of cancer in a human classified as a foretinib responder, wherein a foretinib responder is characterized by the presence of a rosl variant cancer or a kinase variant cancer, or is characterized using the method for identifying a foretinib responder.
In another embodiment, methods are provided for treating a human with a ROS1 variant cancer comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to said human, wherein said human has previously receive crizotinib. In some aspects the compound of Formula I or pharmaceutically acceptable salt thereof is administered at a dose of 60 mg/day. In some aspects, the human is resistant to crizotinib. In some aspects, the ROS1 variant cancer is non-small cell lung cancer. In some aspects, foretinib is administered as monotherapy. In some aspects, the dose of foretinib is reduced from 60 mg/day to 45 mg/day or 30 mg/day or 15 mg/day as is necessary for effective treatment.
Another embodiment of the invention is a use of an amount of a compound of formula I):
Figure imgf000009_0001
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof characterized in that it is for the manufacture of a medicament for use in the treatment of cancer in a human classified as a foretinib responder, wherein a foretinib responder is characterized by presenting with a rosl variant cancer or a kinase variant cancer.
A further embodiment of the invention is a method of treating cancer in a human comprising the steps of: obtaining a sample from a human; testing the sample for a the level or state of phosphorylation of a ROS1 protein or a kinase in Table 1 or Table 2, and administering to the patient having a rosl variant cancer or a kinase variant cancer a therapeutically effective amount of a compound of formula (I):
Figure imgf000010_0001
(I) or a pharmaceutically acceptable salt, ester, or solvate thereof.
Yet another embodiment of the invention is a method of treating cancer in a human having a rosl variant cancer and an an axl variant cancer, such as for example, an AXL expressing cancer comprising administration of a therapeutically effective amount of a compound of formula I):
Figure imgf000010_0002
(I) or a pharmaceutically acceptable salt thereof if said human has a rosl variant cancer and an AXL expressing cancer.
An embodiment of the invention is a ROS1 protein or rosl gene and an AXL protein or axl gene for use as a diagnostic marker in therapy or treatment using a compound of formula I):
Figure imgf000010_0003
(I) or a pharmaceutically acceptable salt thereof to a patient.
A further embodiment of the invention is a method of treating cancer in a human comprising identifying a human having rosl variant cancer and AXL expressing cancer and administerin a therapeutically effective amount of a compound of formula (I):
Figure imgf000011_0001
(I) or a pharmaceutically acceptable salt thereof if said cancer is a rosl variant cancer and expresses AXL.
A still further embodiment of the invention is a method of treating cancer in a human comprising the steps of: obtaining a sample from a human; testing the sample for a rosl variant cancer; testing the sample for AXL expression in said cancer; and
administering to said human a therapeutically effective amount of a compound of formula (I):
Figure imgf000011_0002
(I) or a pharmaceutically acceptable salt thereof if said cancer is a rosl variant cancer and expresses AXL.
An embodiment of the invention is a method of treating cancer in a human comprising identifying a human having rosl variant cancer and an AXL expressing cancer and administering a therapeutically effective amount of at least one erbB-1 inhibitor and a composition comprising Formula I or a pharmaceutically acceptable salt thereof to said human.
Further embodiments comprise methods of the invention wherein an erbB-1 inhibitor comprises eriotinib or gefetinib, or for example, comprises a compound of formula (III):
Figure imgf000012_0001
(HI), or a compound of formula (IV):
Figure imgf000012_0002
(iv), or a combination thereof, or alternatively a pharmaceutically acceptable salt of either or both a compound of formula (III) or a compound of formula (IV).
Another embodiment of the invention is a method of treating cancer in a human comprising the steps of: administering at least one erbB-1 inhibitor to said human wherein said human has a rosl variant cancer; and a therapeutically effective amount of amount of a compound of formula (I):
Figure imgf000013_0001
(I) or a pharmaceutically acceptable salt thereof.
Methods of the invention also comprise an embodiment further comprising a step or steps of determining if a tumor cell from said cancer expresses AXL.
Methods of the invention also comprise an embodiment wherein a cancer shows resistance to an erbB-1 inhibitor, or wherein the compound comprising Formula I is coadministered with said erbB-1 inhibitor, or wherein the administration of compound of Formula I or a pharmaceutically acceptable salt thereof is administered after said erbB-1 inhibitor.
Methods of the invention also comprise a step or steps wherien said erbB-1 inhibitor comprises erlotinib or a pharmaceutically acceptable salt thereof, or wherein administration of said erbB-1 inhibitor is discontinued prior to or following administration of the com ound of formula (I):
Figure imgf000013_0002
(I) or a pharmaceutically acceptable salt thereof.
Further embodiments of the invention comprise methods wherein a cancer is lung cancer.
Still further embodiments of the invention comprise methods wherein treating lung cancer in a human comprises: determining if said lung cancer is a rosl variant cancer: determining if a tumor cell from said lung cancer expresses or over expresses AXL;
administering to said human a therapeutically effective amount of erlotinib or a pharmaceutically acceptable salt thereof and foretinib or a pharmaceutically acceptable salt thereof if said cancer is a rosl variant cancer and is an axl variant cancer, such as, for example, said cancer comprises a tumor cell expressing or overexpressing AXL.
Additionally, embodiments of the invention comprise a method of treating a human with lung cancer that is resistant to erlotinib comprising determining if said cancer expresses AXL and if said cancer is a rosl variant cancer and administering erlotinib or a pharmaceutically acceptable salt thereof and foretinib or a pharmaceutically acceptable salt thereof to said human if said cancer is a rosl variant cancer and is an axl variant cancer, such as, for example, said cancer comprises a tumor cell expressing AXL.
In the methods of treating cancer of the invention the invention further provides a method with an optional step or steps of comparing and/or determining the level or state of phosphorylation and/or other enzyme activity of a ROS1 protein, AXL protein, or a kinase in Table 1 and/or Table 2.
In another embodiment of the present invention methods are provided for treating ROS1 variant cancer comprising treating a human in need thereof with about 60 mg/day or foretinib. In one aspect, foretinib is administered as monotherapy. In another aspect the foretinib is co-administered with another anti-neoplastic agent. In another embodiment, the foretinib is in the free-base form. In one aspect, foretinib is administered to said human and then it is determined if said cancer is ROS1 variant cancer. In some aspects the cancer is lung cancer. In some aspect the cancer is non-small cell lung cancer.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, compounds of formula (I), or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a
pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. In particular embodiments, the solvent used is water. One of ordinary skill in the art will readily appreciate how to determine if a solvate of compounds I, Γ, 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.
The term "rosl variant cancer" means a cancer (as cancer is disclosed herein and as otherwise understood by the skilled artisan) that comprises a cell(s) that (i) expresses a rosl gene in a way that differs from a "wild type" rosl gene or {e.g., a higher or lower level or change in temporal expression) (ii) comprises a rosl gene having a sequence
(including, e.g. coding sequence and/or non-coding 3' and 5' control sequences) that differs from such "wild type" rosl gene sequence by at least one nucleotide (including, e.g. a sequence point mutation, an insertion, or a deletion) and/or post-transcriptionally added or removed moiety (e.g., a methyl moiety), or (iii) expresses a ROS1 protein in a way that differs from a "wild type" ROS1 protein (e.g. a higher or lower level or change in temporal expression), or (iv) comprises a ROS1 protein having a sequence that differs from such "wild type" ROS1 protein by at least one amino acid (including, e.g. a sequence point substitution, an insertion, or a deletion), and/or post-translationally added or removed moiety (e.g., an acetyl moiety), or (v) comprises a polymorphic variant of rosl gene, or (vi) or expresses a ROS1 protein that as compared to "wild type" ROS1 protein has a higher degree of phosphorylation (e.g. per ROS1 protein or relative stoichiometric level compared to "wild type"), a higher level of phosphorylation activity or other enzyme activity, or a change or difference phosphorylation. Ros 1 variant cancer also refers to any ROS1 rearrangement. ROS1 rearrangement are described in Davies, K. D. et al.,. Clin Cancer Res 2012; 18:4570-9. and Bergethon, et al. J Clin Oncol. 2012 March 10; 30(8): 863-870.
The term "axl variant cancer" means a cancer (as cancer is disclosed herein and as otherwise understood by the skilled artisan) that (i) expresses an axl gene in a way that differs from an "wild type" axl gene or (e.g., a higher or lower level or change in temporal expression) (ii) comprises an axl gene having a sequence (including, e.g. coding sequence and/or non-coding 3' and 5' control sequences) that differs from such "wild type" axl gene sequence by at least one nucleotide (including, e.g. a sequence point mutation, an insertion, or a deletion) and/or post-transcriptionally added or removed moiety (e.g., a methyl moiety), or (iii) expresses an AXL protein in a way that differs from a "wild type" AXL protein (e.g. a higher or lower level or change in temporal expression), or (iv) comprises an AXL protein having a sequence that differs from such "wild type" AXL protein by at least one amino acid (including, e.g. a sequence point substitution, an insertion, or a deletion), and/or post-translationally added or removed moiety (e.g., an acetyl moiety), or (v) comprises a polymorphic variant of axl gene, or (vi) or expresses an AXL protein that as compared to "wild type" AXL protein has a higher degree of phosphorylation (e.g. per AXL protein or relative stoichiometric level compared to "wild type"), a higher level of phosphorylation activity or other enzyme activity, or a change or difference
phosphorylation, or that is disclosed in U.S. Serial No. 12/435, 473. The term "kinase variant cancer" means a cancer (as cancer is disclosed herein and as otherwise understood by the skilled artisan) that comprises a cell(s) that (i) expresses a kinase gene that encodes a kinase in Table 1 or Table 2 in a way that differs from the "wild type" version of such kinase gene or {e.g., a higher or lower level or change in temporal expression) (ii) comprises a gene that encodes a kinase in Table 1 or Table 2 such gene having a sequence (including, e.g. coding sequence and/or non-coding 3' and 5' control sequences) that differs from the "wild type" version of such gene sequence by at least one nucleotide (including, e.g. a sequence point mutation, an insertion, or a deletion) and/or post-transcriptionally added or removed moiety (e.g., a methyl moiety), or (iii) expresses a kinase protein in Table 1 or 2 in a way that differs from the "wild type" version of such kinase protein (e.g. a higher or lower level or change in temporal expression), or (iv) comprises a kinase protein in Table 1 or 2 having a sequence that differs from the "wild type" version of such kinase protein by at least one amino acid (including, e.g. a sequence point substitution, an insertion, or a deletion), and/or post-translationally added or removed moiety (e.g., an acetyl moiety), or (v) comprises a polymorphic variant of a gene that encodes a kinase protein in Table 1 or Table 2, or (vi) or expresses a kinase protein in Table 1 or Table 2 that as compared to a "wild type" version of such protein has a higher degree of phosphorylation (e.g. per ROS1 protein or relative stoichiometric level compared to "wild type"), a higher level of phosphorylation activity or other enzyme activity, or a change or difference
phosphorylation.
The term "variant cancer protein" also refers to polypeptide that include, but are not limited to, allelic variants, splice variants, derivative variants, substitution variants, deletion variants, and/or insertion variants, fusion polypeptides, orthologs, and interspecies homologs, polypeptides comprising additional residues at the C- or N-terminus, such as, but not limited to, leader sequence residues, targeting residues, amino terminal methionine residues, lysine residues, tag residues and/or fusion protein residues.
Suitably, the present invention relates to kinase variant cancers with an enzyme activity value (from "value" column) in Table 1 or Table 2, of 30 or less, of 25 or less, of 20 or less, 10 or less, 7 or less, 5 or less, or 1 or less, or 0 or less.
The term "wild type" as is understood in the art refers to a polypeptide or polynucleotide sequence that occurs in a native population without genetic modification. As is also understood in the art, 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) nucleic acid strand. As used herein "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.
As used herein, a "gene" is a sequence of DNA present in a cell that directs the expression of a "gene product," most commonly by transcription to produce RNA and translation to produce protein. An "allele" is a particular form of a gene. The term allele is relevant when there are two or more forms of a particular gene. Genes and alleles are not limited to the open reading frame of the genomic sequence or the cDNA sequence corresponding to processed RNA. A gene and allele can also include sequences upstream and downstream of the genomic sequence such as promoters and enhancers. The term "gene product" or "polymorphic variant allele product" refer to a product resulting from transcription of a gene. Gene and polymorphic variant allele products include partial, precursor, mature transcription products such as pre-mRNA and mRNA, and translation products with or without further processing including, without limitation, lipidation, phosphorylation, glycosylation, other modifications known in the art, and combinations of such processing. RNA may be modified without limitation by complexing with proteins, polyadenylation, splicing, capping or export from the nucleus.
A "polymorphism" is a site in the genome that varies between two or more individuals or within an individual in the case of a heterozygote. The frequency of the variation can be defined above a specific value for inclusion of variations generally observed in a population as opposed to random mutations. Polymorphisms that can be screened according to the invention include variation both inside and outside the open reading frame. When outside the reading frame the polymorphism can occur within 200, 500, 1000, 2000, 3000, 5000, or more of either the 5' or 3' end of the open reading frame. When inside the reading frame, the polymorphism may occur within an exon or intron, or overlapping an exon/intron boundary. A polymorphism could also overlap the open reading frame and a sequence outside of that frame. Many polymorphisms have been given a "rs" designation in the SNP database of NCBI's Entrez, some of these designations have been provided herein.
A "polymorphic variant" is a particular form or embodiment of a polymorphism. For example, if the polymorphism is a single nucleotide polymorphism, a particular variant could potentially be an "A" (adenosine), "G" (guanine), "T" (thymine), and "C" (cytosine). When the variant is a "T", it is understood that a "U" (uracil) can occur in those instances wherein the relevant nucleic acid molecule is RNA, and "C" (cytosine) in respect to DNA. The convention "PositionNUC1 >NUC2" is used to indicate a polymorphism contrasting one variant from another. For example, 242A>C would refer to a cytosine instead of an adenosine occurring at position 242 of a particular nucleic acid sequence. In some cases, the variation can be to two or more different bases, e.g., 242A>C/T. When 242A>C is used in respect to a mRNA/cDNA, it can also be used to represent the polymorphism as it occurs in the genomic DNA with the understanding that the position number will likely be different in the genome. Sequence and polymorphic location information for both coding domain sequence and genomic sequence is described herein for the genes relevant to the invention. "Polymorphic variant allele" refers to an allele comprising a particular polymeric variant or a particular set of polymorphic variants corresponding to a particular set of polymorphisms. Two alleles can both be considered the same polymorphic variant allele if they share the same variant or set of variants defined by the polymorphic variant allele even though they may differ in respect to other polymorphisms or variation outside the definition. For a mutation at the amino acid level, the convention "AA1 PositionAA2" is used. For example, in the context of amino acid sequence, M726L, would indicate that the underlying, nucleotide level polymorphism(s) has resulted in a change from a methionine to a leucine at position 726 in the amino acid sequence.
A "genotype" can refer to a characterization of an individual's genome in respect to one or both alleles and/or one or more polymorphic variants within that allele. A subject can be characterized at the level that the subject contains a particular allele, or at the level of identifying both members of an allelic pair, the corresponding alleles on the set of two chromosomes. One can also be characterized at the level of having one or more polymorphic variants. The term "haplotype" refers to a cis arrangement of two or more polymorphic variants, on a particular chromosome such as in a particular gene. The haplotype preserves the information of the phase of the polymorphic nucleotides-that is, which set of polymorphic variants were inherited from one parent, and which from the other. Wherein methods, materials, and experiments are described for the invention in respect to polymorphic variants, one will understand that can also be adapted for use with an analogous haplotype. A "diplotype" is a haplotype that includes two polymorphisms.
A single nucleotide polymorphism (SNPs) refers to a variation at a single nucleotide location. In some cases the variations at the position could be any one of the four nucleotide bases, in others the variation is some subset of the four bases. For example, the variation could be between either purine base or either pyrimidine base. Simple- sequence length polymophisms (SSLPs) or short tandem repeat polymorphisms (STRPs) involve the repeat of a particular sequence of one or more nucleotides. A restriction fragment length polymorphism (RFLP) is a variation in the genetic sequence that results in the appearance or disappearance of an enzymatic cleavage site depending on which base(s) are present in a particular allele.
Genetic variants and/or 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, respectively, and/or various biochip and array technologies. 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.
As used herein the term "amplification" and grammatical variations thereof refers to the presence of one or more extra gene copies in a chromosome complement. In certain embodiments a gene encoding a Ras protein may be amplified in a cell. Amplification of the HER2 gene has been correlated with certain types of cancer. Amplification of the HER2 gene has been found in human salivary gland and gastric tumor-derived cell lines, gastric and colon
adenocarcinomas, and mammary gland adenocarcinomas. Semba et al., Proc. Natl. Acad. Sci. USA, 82:6497-6501 (1985); Yokota et al., Oncogene, 2:283-287 (1988); Zhou et al., Cancer Res., 47:6123-6125 (1987); King et al., Science, 229:974-976 (1985); Kraus et al., EMBO J., 6:605-610 (1987); van de Vijver et al., Mol. Cell. Biol., 7:2019-2023 (1987); Yamamoto et al., Nature, 319:230-234 (1986).
The 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).
Conventional molecular biology, microbiology, and recombinant DNA techniques including sequencing techniques are well known among those skilled in the art. Such techniques are explained fully in the literature. See, e.g., Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (herein "Sambrook, et al., 1989"); DNA Cloning: A Practical Approach, Volumes I and II (D. N. Glover ed. 1985); Oligonucleotide Synthesis (M. J. Gait ed. 1984); Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins eds. (1985)); Transcription And Translation (B. D. Hames & S. J. Higgins, eds. (1984)); Animal Cell Culture (R. I. Freshney, ed. (1986)); Immobilized Cells And Enzymes (IRL Press, (1986)); B. Perbal, A Practical Guide To Molecular Cloning (1984); F. M. Ausubel, et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994
The Peptide Nucleic Acid (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. 1 14:1895-1897 (1992); James et al., Protein Science 3:1347-1350 (1994)). 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.
DNA microarrays have been developed to detect genetic variations and
polymorphisms (Taton et al., Science 289:1757-60, 2000; Lockhart et al., Nature 405:827- 836 (2000); Gerhold et al., Trends in Biochemical Sciences 24:168-73 (1999); Wallace, R. W., Molecular Medicine Today 3:384-89 (1997); Blanchard and Hood, Nature
Biotechnology 149:1649 (1996)). DNA microarrays are fabricated by high-speed robotics, on glass or nylon substrates, and contain DNA fragments with known identities ("the probe"). The microarrays are used for matching known and unknown DNA fragments ("the target") based on traditional base-pairing rules.
The term "at least one mutation" in a polypeptide or a gene encoding a polypeptide and grammatical variations thereof means a polypeptide or gene encoding a polypeptide having one or more allelic variants, splice variants, derivative variants, substitution variants, deletion variants, truncation variants, and/or insertion variants, fusion
polypeptides, orthologs, and/or interspecies homologs. By way of example, at least one mutation of a protein of the invention would include a protein in which part of all of the sequence of a polypeptide or gene encoding the protein is absent or not expressed in the cell for at least one protein produced in the cell. For example, a protein may be produced by a cell in a truncated form and the sequence of the truncated form may be wild type over the sequence of the truncate. A deletion may mean the absence of all or part of a gene or protein encoded by a gene. Additionally, some of a protein expressed in or encoded by a cell may be mutated while other copies of the same protein produced in the same cell may be wild type. By way of another example a mutation in a protein would include a protein having one or more amino acid differences in its amino acid sequence compared with wild type of the same type of protein.
As used herein "genetic abnormality" is meant a deletion, substitution, addition, translocation, amplification and the like relative to the normal native nucleic acid content of a cell of a subject. The terms "polypeptide" and "protein" are used interchangeably and are used herein as a generic term to refer to native protein, fragments, peptides, or analogs of a polypeptide sequence. Hence, native protein, fragments, and analogs are species of the polypeptide genus.
As used herein, 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.
As is well known genetics, 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.
As used herein "gene encoding a kinase variant cancer protein" means any part of a gene or polynucleotide encoding any kinase variant cancer protein, and "gene encoding a rosl variant cancer protein" means any part of a gene or polynucleotide encoding any rosl variant cancer protein. Included within the meaning of this term are exons encoding a rosl variant cancer protein. Genes encoding rosl variant cancer proteins include but are not limited to genes encoding part or all rosl gene sequence in rearranged chromosome, rosl rearranged genes, and rosl fusion genes.
As used herein, "genotyping" a subject (or DNA or other biological sample) for a polymorphic allele of a gene(s) 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. As is well known in the art, 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. As used herein, 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). Herein "diagnostic marker" means a marker, such as a polynucleotide or polypeptide, or combination, for use as a tool for the diagnosis of a particular disease or in a particular patient, or for predicting disease outcome/progression, or for predicting the response to, or monitoring treatment subsequent to treatment with, for example, a particular drug. To diagnose, diagnostic polynucleotide variations may be detected directly (by, e.g., sequencing) or indirectly (e.g., by restriction fragment length polymorphism analysis, or detection of the hybridization of a probe of known sequence, or reference strand conformation polymorphism), or by using other known methods.
Diagnosis (or diagnosing) includes, for example, discerning the identity, sequence, or structure of a diagnostic marker.
As used herein, a "genetic subset" of a population consists of those members of the population having a particular genotype. In the case of a biallelic polymorphism, 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 foretinib or individuals with cancer.
As used herein, 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). Where 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.
"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:
Figure imgf000023_0001
where
¾ = PA(1'PA)> r B = pB(l-pB), DA = PM - fAi DB = PBB ~pB 2 n nr2 has an approximate chi square distribution with 1 degree freedom for biallelic markers. Loci exhibiting an r such that nr2 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).
Alternatively, a normalized measure of linkage disequilibrium can be defined as:
Figure imgf000023_0002
The value of the D" has a range of -1.0 to 1 .0. When statistically significant absolute D" value for two markers is not less than 0.3 they are considered to be in linkage
disequilibrium.
By the term "treating," treatment, and grammatical variations thereof as used herein, is meant therapeutic therapy or healing. In reference to a particular condition, treating means: (1 ) to ameliorate or prevent the condition of one or more of the biological manifestations of the condition, such as signs or symptoms, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects, signs, or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition. Prophylactic therapy is also contemplated thereby. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
Foretinib (also referred to herein as /\/1-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4- morpholinyl)propyl]oxy}-4-quinolinyl)oxy]phenyl}-/\/1-(4-fluorophenyl)-1 , 1- cyclopropanedicarboxamide), is disclosed and claimed, along with pharmaceutically acceptable salts and solvates thereof, methods of preparation, and as being useful as an inhibitor of cMET, particularly in treatment of cancer, in International Application No.
PCT/US2004/031523, having an International filing date of September 24, 2004;
International Publication Number WO2005/030140 and an International Publication date of April 7, 2005, the entire disclosure of which is hereby incorporated by reference.
Examples 25 (p. 193), 36 (pp. 202-203), 42 (p. 209), 43 (p. 209), and 44 (pp. 209-210) describe how Formula I can be prepared. Formula I can be prepared as described in International Application No. PCT/US2009/064341 having an International filing date of November 13, 2008; International Publication Number WO2010/056960 and an
International Publication date of May 20, 2010, the entire disclosure of which is hereby incorporated by reference and in International Application No. PCT/US2009/058276 having an International filing date of September 25, 2009; International Publication
Number WO2010/036831 and an International Publication date of April 1 , 2010 the entire disclosure of which is hereby incorporated by reference.
The general preparation for Formula I is outlined in Scheme 1 :
Scheme 1
Figure imgf000025_0001
Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti- folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; receptor tyrosine kinase inhibitors; serine-threonine kinase inhibitors; non-receptor tyrosine kinase inhibitors;
angiogenesis inhibitors, immunotherapeutic agents; proapoptotic agents; and cell cycle signalling inhibitors.
The present invention also provides methods for treating cancer comprising administering Formula I or pharmaceutically acceptable salt thereof with or without another anti-neoplastic agent.
In some embodiments, foretinib is the compound of Formula (I) or a
harmaceutically acceptable salt or solvate thereof:
Figure imgf000026_0001
which has the chemical /\/1-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4- quinolinyl)oxy]phenyl}-/V1-(4-fluorophenyl)-1 , 1 -cyclopropanedicarboxamide) and is known by the generic name foretinib. In some embodiments, foretinib is administered as monotherapy. In some embodiments, foretinib is administered at a dose of 60 mg/day.
In one aspect, a compound comprising Formula I is administered as a free base. Formula I can be administered at a dose of at least 7.5 mg daily. Formula I can be administered, for instance, at a dose of about 7.5 mg, 15.0 mg, 30.0 mg, 45.0 mg and/or 60 mg/daily. Formula I may be provided in tablet form. In some instances, tablets comprise hypromellose, sodium lauryl sulfate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. Some tablets may comprise hypromellose, titanium dioxide, polyethylene glycol. Tablets may comprise polysorbate 80 and iron oxide yellow. As used herein, the term "pharmaceutically acceptable 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, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N- methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate,
phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium and valerate.
In embodiments according to the various aspects of the present invention described herein, the determination of whether a patient has a particular genotype at a given reference single nucleotide polymorphism includes testing the patient for the particular genotype at the given reference single nucleotide polymorphism. The 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 in the Examples section below.
In embodiments according to the various aspects of the present invention described herein, the determination of whether a patient has a particular genotype at a given reference single nucleotide polymorphism includes testing the patient for at least one single nucleotide polymorphism that is correlated with the given reference single nucleotide polymorphism.
As used herein, a first reference single nucleotide polymorphism is correlated to a second single nucleotide polymorphism if detection of the first reference single nucleotide polymorphism, or a particular genotype of the first single nucleotide polymorphism, indicates that the individual would have the second reference single nucleotide
polymorphism, or a particular genotype of the second reference single nuclear
polymorphism, if the individual were to be tested for the second reference single nucleotide polymorphism or particular genotype thereof.
In some embodiments according to the present invention, the determination of whether a patient has a particular genotype at a given reference single nucleotide polymorphism is performed. In other embodiments, the biological sample is selected from the group consisting of cells, blood, blood components, urine and saliva.
By the term "treating" and grammatical variations thereof as used herein, is meant therapeutic therapy. In reference to a particular condition, treating means: (1 ) to ameliorate or prevent the condition of one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition. Prophylactic therapy is also contemplated thereby. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
By the term "combination" and grammatical variations thereof, as used herein is meant either simultaneous administration or any manner of separate sequential administration of a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B or a pharmaceutically acceptable salt thereof. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and the other compound may be administered orally. Suitably, both compounds are administered orally. By the term "combination kit" as used herein is meant the pharmaceutical composition or compositions that are used to administer Compound A, or a
pharmaceutically acceptable salt or solvate thereof, and Compound B, or a
pharmaceutically acceptable salt thereof, according to the invention. When both compounds are administered simultaneously, the combination kit can contain Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. When the compounds are not administered simultaneously, the combination kit will contain Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B, or a
pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions. The combination kit can comprise Compound A, or a pharmaceutically acceptable salt or solvate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions in a single package or in separate pharmaceutical compositions in separate packages.
In one aspect there is provided a combination kit comprising the components: Compound A, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier; and
Compound B, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
In one embodiment of the invention the combination kit comprises the following components:
Compound A, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier; and
Compound B, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier,
wherein the components are provided in a form which is suitable for sequential, separate and/or simultaneous administration.
In one embodiment the combination kit comprises:
a first container comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier; and a second container comprising Compound B, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, and a container means for containing said first and second containers.
The "combination kit" can also be provided by instruction, such as dosage and administration instructions. Such dosage and administration instructions can be of the kind that is provided to a doctor, for example by a drug product label, or they can be of the kind that is provided by a doctor, such as instructions to a patient.
As used herein the term "Compound A2" means— Compound A, or a
pharmaceutically acceptable salt or solvate thereof— .
As used herein the term "Compound B2" means— Compound B, or a
pharmaceutically acceptable salt thereof— .
Suitably the combinations of this invention are administered within a "specified period".
By the term "specified period" and grammatical variations thereof, as used herein is meant the interval of time between the administration of one of Compound A2 and
Compound B2 and the other of Compound A2 and Compound B2. Unless otherwise defined, the specified period can include simultaneous administration. Unless otherwise defined the specified period refers to administration of Compound A2 and Compound B2 during a single day.
Suitably, if the compounds are administered within a "specified period" and not administered simultaneously, they are both administered within about 24 hours of each other - in this case, the specified period will be about 24 hours; suitably they will both be administered within about 12 hours of each other - in this case, the specified period will be about 12 hours; suitably they will both be administered within about 1 1 hours of each other - in this case, the specified period will be about 1 1 hours; suitably they will both be administered within about 10 hours of each other - in this case, the specified period will be about 10 hours; suitably they will both be administered within about 9 hours of each other - in this case, the specified period will be about 9 hours; suitably they will both be administered within about 8 hours of each other - in this case, the specified period will be about 8 hours; suitably they will both be administered within about 7 hours of each other - in this case, the specified period will be about 7 hours; suitably they will both be
administered within about 6 hours of each other - in this case, the specified period will be about 6 hours; suitably they will both be administered within about 5 hours of each other - in this case, the specified period will be about 5 hours; suitably they will both be
administered within about 4 hours of each other - in this case, the specified period will be about 4 hours; suitably they will both be administered within about 3 hours of each other - in this case, the specified period will be about 3 hours; suitably they will be administered within about 2 hours of each other - in this case, the specified period will be about 2 hours; suitably they will both be administered within about 1 hour of each other - in this case, the specified period will be about 1 hour. As used herein, the administration of Compound A2 and Compound B2 in less than about 45 minutes apart is considered simultaneous administration.
Suitably, when the combination of the invention is administered for a "specified period", the compounds will be co-administered for a "duration of time".
By the term "duration of time" and grammatical variations thereof, as used herein is meant that both compounds of the invention are administered for an indicated number of consecutive days. Unless otherwise defined, the number of consecutive days does not have to commence with the start of treatment or terminate with the end of treatment, it is only required that the number of consecutive days occur at some point during the course of treatment.
Regarding "specified period" administration:
Suitably, both compounds will be administered within a specified period for at least one day - in this case, the duration of time will be at least one day; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 3 consecutive days - in this case, the duration of time will be at least 3 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 5 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 7 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 14 consecutive days - in this case, the duration of time will be at least 14 days; suitably, during the course to treatment, both compounds will be administered within a specified period for at least 30 consecutive days - in this case, the duration of time will be at least 30 days.
Suitably, if the compounds are not administered during a "specified period", they are administered sequentially. By the term "sequential administration", and derivates thereof, as used herein is meant that one of Compound A2 and Compound B2 is administered once a day for two or more consecutive days and the other of Compound A2 and Compound B2 is subsequently administered once a day for two or more consecutive days. Also, contemplated herein is a drug holiday utilized between the sequential administration of one of Compound A2 and Compound B2 and the other of Compound A2 and Compound B2. As used herein, a drug holiday is a period of days after the sequential administration of one of Compound A2 and Compound B2 and before the administration of the other of Compound A2 and Compound B2 where neither Compound A2 nor Compound B2 is administered. Suitably the drug holiday will be a period of days selected from: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days,
13 days and 14 days.
Regarding sequential administration:
Suitably, one of Compound A2 and Compound B2 is administered for from 2 to 30 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A2 and Compound B2 for from 2 to 30 consecutive days. Suitably, one of Compound A2 and Compound B2 is administered for from 2 to 21 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A2 and Compound B2 for from 2 to 21 consecutive days. Suitably, one of Compound A2 and Compound B2 is administered for from 2 to 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of the other of Compound A2 and Compound B2 for from 2 to 14 consecutive days. Suitably, one of Compound A2 and Compound B2 is administered for from 3 to 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of the other of Compound A2 and
Compound B2 for from 3 to 7 consecutive days.
Suitably, Compound B2 will be administered first in the sequence, followed by an optional drug holiday, followed by administration of Compound A2. Suitably, Compound B2 is administered for from 3 to 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound A2 for from 3 to 21 consecutive days. Suitably, Compound B2 is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of Compound A2 for from 3 to 21 consecutive days. Suitably, Compound B2 is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of Compound A2 for from 3 to 21 consecutive days. Suitably, Compound B2 is administered for 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound A2 for 14 consecutive days. Suitably, Compound B2 is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by
administration of Compound A2 for 14 consecutive days. Suitably, Compound B2 is administered for 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of Compound A2 for 7 consecutive days. Suitably, Compound B2 is administered for 3 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of Compound A2 for 7 consecutive days. Suitably, Compound B2 is administered for 3 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of Compound A2 for 3 consecutive days. It is understood that a "specified period" administration and a "sequential" administration can be followed by repeat dosing or can be followed by an alternate dosing protocol, and a drug holiday may precede the repeat dosing or alternate dosing protocol.
Suitably, the amount of Compound A2 administered as part of the combination according to the present invention will be an amount selected from about 0.125mg to about 10mg; suitably, the amount will be selected from about 0.25mg to about 9mg;
suitably, the amount will be selected from about 0.25mg to about 8mg; suitably, the amount will be selected from about 0.5mg to about 8mg; suitably, the amount will be selected from about 0.5mg to about 7mg; suitably, the amount will be selected from about 1 mg to about 7mg; suitably, the amount will be about 5mg. Accordingly, the amount of Compound A administered as part of the combination according to the present invention will be an amount selected from about 0.125mg to about 10 mg. For example, the amount of Compound A2 administered as part of the combination according to the present invention can be 0.125mg, 0.25mg, 0.5mg, 0.75mg, 1 mg, 1 .5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg.
Suitably, the amount of Compound B2 administered as part of the combination according to the present invention will be an amount selected from about 75mg to about 1 ,000mg; suitably, the amount will be selected from about 100mg to about 900mg;
suitably, the amount will be selected from about 150mg to about 850mg; suitably, the amount will be selected from about 200mg to about 800mg; suitably, the amount will be selected from about 250mg to about 750mg; suitably, the amount will be selected from about 300mg to about 6000mg; suitably, the amount will be about 450mg. Accordingly, the amount of Compound B2 administered as part of the combination according to the present invention will be an amount selected from about 75mg to about 1 ,000mg. For example, the amount of Compound B2 administered as part of the combination according to the present invention can be 75mg, 100 mg, 125mg, 150 mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg or 1 ,000mg.
As used herein, all amounts specified for Compound A2 and Compound B2 are indicated as the administered amount of free or unsalted and unsolvated compound per dose.
The method of the present invention may also be employed with other therapeutic methods of cancer treatment. While it is possible that, for use in therapy, therapeutically effective amounts of the combinations of the present invention may be administered as the raw chemical, it is preferable to present the combinations as a pharmaceutical composition or compositions. Accordingly, the invention further provides pharmaceutical compositions, which include Compound A2 and/or Compound B2, and one or more pharmaceutically acceptable carriers. The combinations of the present invention are as described above. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing Compound A2 and/or Compound B2 with one or more pharmaceutically acceptable carriers. As indicated above, such elements of the pharmaceutical combination utilized may be presented in separate pharmaceutical compositions or formulated together in one pharmaceutical formulation.
Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. As is known to those skilled in the art, the amount of active ingredient per dose will depend 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, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
Compound A2 and Compound B2 may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that Compound A2 and Compound B2 may be compounded together in a pharmaceutical composition/formulation.
While it is possible that, the compound of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, as well as the various other compositions comprising foretinib described herein, may be administered as the raw chemical, it is also possible to present the active ingredient as a pharmaceutical composition. Accordingly, embodiments of the invention further provide pharmaceutical compositions, which include therapeutically effective amounts of foretinib, 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. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing foretinib with one or more pharmaceutically acceptable carriers, diluents or excipients.
Pharmaceutical formulations 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).
Pharmaceutical formulations 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.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with 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.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. 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. 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. As an alternative to granulating, 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 sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
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.
Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
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.
Foretinib 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. Furthermore, 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.
Pharmaceutical formulations 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. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For treatments of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Eye-drop formulations are described further herein below.
Suitable routes for ocular administration include extraocular and intraocular (including, for example, intravitreal, subretinal, subscleral, intrachoroidal, and
subconjuctival). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient.
For treatments of the eye, the pharmaceutical formulations may also be applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water- in-oil base.
In some embodiments of the present invention, the pharmaceutical formulations are adapted for intraocular administration by means of intraocular injection or other device for ocular delivery. Examples of ocular devices that may be used in the methods of the invention include periocular or intravitreal devices, contact lenses and liposomes. See, for example, U.S. Pat. Nos. 3,416,530; 3,828,777; 4,014,335; 4,300,557; 4,327,725;
4,853,224; 4,946,450; 4,997,652; 5, 147,647; 5, 164, 188; 5, 178,635; 5,300,1 14; 5,322,691 ; 5,403,901 ; 5,443,505; 5,466,466; 5,476,51 1 ; 5,516,522; 5,632,984; 5,679,666; 5,710, 165; 5,725,493; 5,743,274; 5,766,242; 5,766,619; 5,770,592; 5,773,019; 5,824,072; 5,824,073; 5,830,173; 5,836,935; 5,869,079, 5,902,598; 5,904, 144; 5,916,584; 6,001 ,386; 6,074,661 ; 6, 1 10,485; 6,126,687; 6, 146,366; 6,251 ,090; 6,299,895; 6,331 ,313; 6,416,777; 6,649, 184; 6,719,750; 6,660,960; and U.S. Patent Publication Nos. 2003/0064088, 2004/0247645, and, 2005/01 13806; each of which is herein incorporated by reference for purposes of their teachings of optical devices.
Formulations for drug delivery using ocular devices may combine one or more active agents and adjuvants appropriate for the indicated route of administration. For example, the active agents may be admixed with any pharmaceutically acceptable excipient, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, tableted or encapsulated for conventional administration. Alternatively, the compounds may be dissolved in polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. The compounds may also be mixed with compositions of both biodegradable and non-biodegradable polymers, and a carrier or diluent that has a time delay property. Representative examples of biodegradable compositions can include albumin, gelatin, starch, cellulose, dextrans, polysaccharides, poly (D,L-lactide), poly (D,L-lactide-co-glycolide), poly (glycolide), poly (hydroxybutyrate), poly (alkylcarbonate) and poly (orthoesters) and mixtures thereof. Representative examples of non-biodegradable polymers can include EVA copolymers, silicone rubber and poly (methylacrylate), and mixtures thereof.
Pharmaceutical compositions for ocular delivery also include in situ gellable aqueous composition. Such a composition comprises a gelling agent in a concentration effective to promote gelling upon contact with the eye or with lacrimal fluid. Suitable gelling agents include but are not limited to thermosetting polymers. The term "in situ gellable" as used herein is includes not only liquids of low viscosity that form gels upon contact with the eye or with lacrimal fluid, but also includes more viscous liquids such as semi-fluid and thixotropic gels that exhibit substantially increased viscosity or gel stiffness upon administration to the eye. See, for example, Ludwig (2005) Adv. Drug Deliv. Rev. 3; 57:1595-639, herein incorporated by reference for purposes of its teachings of examples of polymers for use in ocular drug delivery. Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
Pharmaceutical formulations 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.
Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.
Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations 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.
It should be understood that in addition to the ingredients particularly mentioned above, the 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 animal, 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 or veterinarian. However, 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 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 12 mg/kg body weight per day. Thus, an effective amount of a salt or solvate thereof can typically be from a lower limit of 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg to an upper limit of about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895 or 900 mg 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. This amount may be given in a single dose per day or 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.
Foretinib may be employed alone or in combination with other therapeutic agents for the treatment of the above-mentioned conditions. In particular, in anti-cancer therapy, combination with other chemotherapeutic, hormonal or antibody agents is envisaged as well as combination with surgical therapy and radiotherapy. Combination therapies according to the present invention thus comprise the administration of foretinib, and the use of at least one other cancer treatment method, including one or more additional compounds. Preferably, combination therapies according to the present invention comprise the administration of foretinib, and at least one other pharmaceutically active agent, preferably an anti-neoplastic agent. Foretinib 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 foretinib 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.
Foretinib 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. In one embodiment, 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. Alternatively, the combination may be administered separately in a sequential manner wherein one antineoplastic 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 foretinib can include the following:
(1 ) cell cycle specific anti-neoplastic agents including, but not limited to,
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 and thioguanine; and camptothecins such as 9-amino camptothecin, irinotecan, CPT-1 1 and the various optical forms of 7-(4-methylpiperazino-methylene)- 10, 1 1 -ethylenedioxy-20-camptothecin;
(2) 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
(3) other chemotherapeutic agents including, but not limited to, 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; metalloproteinase inhibitors such as marimastat; antiprogestogens; urokinase plasminogen activator receptor function inhibitors; cyclooxygenase type 2 (COX-2) inhibitors such as celecoxib; other angiogenic inhibiting agents such as VEGFR inhibitors and TIE-2 inhibitors; growth factor function inhibitors such as inhibitors of the functions of hepatocyte growth factor; erb-B2, erb-B4, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), vascular endothelial growth factor receptor (VEGFR) other than those described in the present invention, and TIE-2; and other tyrosine kinase inhibitors such as cyclin dependent inhibitors such as CDK2 and CDK4 inhibitors.
Foretinib 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.
In some embodiments according to the various aspects of the present invention, foretinib is administered or prescribed in the treatment of disorders mediated by inappropriate c-MET activity.
The inappropriate c-METactivity referred to herein is any c-MET activity that deviates from the normal c-MET activity expected in a particular mammalian subject.
Inappropriate C-MET activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of c-MET activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase or ligand leading to inappropriate or uncontrolled activation of the receptor. Furthermore, it is also understood that unwanted c-MET activity may reside in an abnormal source, such as a malignancy.
As used herein "overexpressed" and "overexpression" of a protein or polypeptide and grammatical variations thereof means that a given cell produces an increased number of a certain protein relative to a normal cell. By way of example, a ras protein may be overexpressed by a tumor cell relative to a non-tumor cell. Additionally, a mutant ras protein may be overexpressed compared to wild type ras protein in a cell. As is understood in the art, expression levels of a polypeptide in a cell can be normalized to a housekeeping gene such as actin. In some instances, a certain polypeptide may be underexpressed in a tumor cell compared with a non-tumor cell.
As used herein, the terms "cancer," "neoplasm," and "tumor," are used
interchangeably and in either the singular or plural form, refer to cells that have undergone a malignant transformation that makes them pathological to the host organism. Primary cancer cells (that is, cells obtained from near the site of malignant transformation) can be readily distinguished from non-cancerous cells by well-established techniques, particularly histological examination. The definition of a cancer cell, as used herein, includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells. When referring to a type of cancer that normally manifests as a solid tumor, a "clinically detectable" tumor is one that is detectable on the basis of tumor mass; e.g., by procedures such as CAT scan, MR imaging, X-ray, ultrasound or palpation, and/or which is detectable because of the expression of one or more cancer-specific antigens in a sample obtainable from a patient. Tumors may be hematopoietic tumor, for example, tumors of blood cells or the like, meaning liquid tumors. Specific examples of clinical conditions based on such a tumor include leukemia such as chronic myelocytic leukemia or acute myelocytic leukemia; myeloma such as multiple myeloma; lymphoma and the like.
In embodiments according to aspects of the present invention, the disorder is cancer. In some instances, the cancer is a lung cancer, such as non-small cell lung cancer (NSCLC), or a ROS1 -rearranged NSCLC, such as for example NSCLC comprising rosl rearrangements SLC34A2-ROS1 , CD74-ROS1 , EZR-ROS1 , TPM3-ROS1 , and/or SDC4- ROS1 . Another embodiments includes, for example, an oncogene addicted ROS1- rearranged cancer. Still another embodiment provides a lung cancer, such as a NSCLC that recurs after or is refractory to treatment with crizotinib. In some embodiments according to the various aspects of the present invention, the cancer is selected from the group of colon cancer, breast cancer, renal cell carcinoma, melanoma, lung cancer including non-small cell lung cancer and adenocarcinoma, 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-hepatobiliary cancer, multiple myeloma, leukemia, thyroid cancer including Hurthle cell, muscle sarcoma (leiomyosarcoma) and bone sarcoma
(chonrosarcoma).
Suitably the present invention relates to a method for treating or lessening the severity of cancers selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non- hodgkins lymphoma, lymphoblastic ! cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.
Suitably the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), and colon polyps.
A further aspect of the present invention provides the use of foretinib of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment of cancer and malignant tumours.
Suitably the present invention relates to the treatment of treatment of a cancer selected from the group of a subset of the cancers disclosed herein.
While the foregoing aspects according to the present invention have been described with respect to methods of treating cancer, it is also to be understood that aspects of the present invention include similar aspects directed to methods of treating diseases where a kinase is disregulated, such as a kinase in Table 1 or Table 1 , for example Ros1 kinase.
Where a combination therapy is employed, the therapeutic agents may be administered together or separately. The same means for administration may be used for more than one therapeutic agent of the combination therapy; alternatively, different therapeutic agents of the combination therapy may be administered by different means. When the therapeutic agents are administered separately, they may be administered simultaneously or sequentially in any order, both close and remote in time. The amounts of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and/or the other pharmaceutically active agent or agents and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
The amount of administered or prescribed Formula lccording to these aspects of the present invention will depend upon a number of factors including, for example, the age and weight of the patient, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the amount will be at the discretion of the attendant physician. Pharmaceutical formulations for administration to the eye may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 1 g to 1 g, such as 5 μg to 500 μg, 10 g-250 μg, 0.5 mg to 700 mg, 2 mg to 350 mg, or 5 mg to100 mg of a compound of formula (I) or
pharmaceutically acceptable salts or solvates thereof depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a
predetermined amount of active ingredient per unit dose. In some embodiments, the 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. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered or prescribed to be administered one, two, three, four, or more times per day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered or prescribed to be administered by administering one, two, three, four or more drops of a suitable pharmaceutical formulation one, two, three, four, or more times per day. In some embodiments of pharmaceutical formulations suitable for topical administration to the eye, the suitable pharmaceutical formulation comprises between a lower limit of 1 , 2, 3, 4, 5, 6, 7, 8, or 9 and an upper limit of 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof per ml.
In another embodiment foretinib is co-administered with at least one additional antineoplastic agent, such as an anti-cancer agent. Non-limiting examples of other anti- neoplastic agents are described herein.
Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti- folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; receptor tyrosine kinase inhibitors; serine-threonine kinase inhibitors; non-receptor tyrosine kinase inhibitors;
angiogenesis inhibitors, immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
Diterpenoids, which are derived from natural sources, are phase specific anticancer agents that operate at the G2/M phases of the cell cycle. It is believed that the diterpenoids stabilize the β-tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
Paclitaxel, 5p,20-epoxy-1 ,2α,4,7β, 10β, 13a-hexa-hydroxytax-1 1 -en-9-one 4, 10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93:2325. 1971 ), who characterized its structure by chemical and X-ray crystallographic methods. One mechanism for its activity relates to paclitaxel's capacity to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561-1565 (1980); Schiff et ai, Nature, 277:665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981 ). For a review of synthesis and anticancer activity of some paclitaxel derivatives see: D. G. I. Kingston et al., Studies in Organic Chemistry vol. 26, entitled "New trends in Natural Products Chemistry 1986", Attaur-Rahman, P.W. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.
Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 1 1 1 :273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990). The Formula llso shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature,
368:750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guide, 1998) related to the duration of dosing above a threshold concentration (50nM) (Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16-23, 1995).
Docetaxel, (2R,3S)- N-carboxy-3-phenylisoserine,N-ferf-butyl ester, 13-ester with 5p-20-epoxy-1 ,2a,4,7p, 10p, 13a-hexahydroxytax-1 1-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is
neutropenia.
Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is the dose limiting side effect of vinblastine.
Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN® as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas. Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
Vinorelbine, 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine. Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
Cisplatin, cis-diamminedichloroplatinum, is commercially available as PLATINOL® as an injectable solution. Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
Carboplatin, platinum, diammine [1 , 1-cyclobutane-dicarboxylate(2-)-0,0'], is commercially available as PARAPLATIN® as an injectable solution. Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
Alkylating agents are non-phase anti-cancer specific agents and strong
electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.
Busulfan, 1 ,4-butanediol dimethanesulfonate, is commercially available as
MYLERAN® TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
Carmustine, 1 ,3-[bis(2-chloroethyl)-1 -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®. Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
Dacarbazine, 5-(3,3-dimethyl-1 -triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthracyclins such as daunorubicin and doxorubicin; and bleomycins.
Dactinomycin, also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo- hexopyranosyl)oxy]-7,8,9, 10-tetrahydro-6,8, 1 1 -trihydroxy-1 -methoxy-5, 12
naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.
Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-8- glycoloyl, 7, 8, 9, 10-tetrahydro-6, 8, 1 1 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of
Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene-p-D- glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene-p-D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children.
Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.
Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine,
mecaptopurine, thioguanine, and gemcitabine.
5-fluorouracil, 5-fluoro-2,4- (1 H,3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 5- fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5- fluorodeoxyuridine monophosphate.
Cytarabine, 4-amino-1-p-D-arabinofuranosyl-2 (I H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2', 2'- difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
Mercaptopurine, 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses. A useful mercaptopurine analog is azathioprine.
Thioguanine, 2-amino-1 ,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
Gemcitabine, 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of
choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder. Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.
Camptothecins, including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of
camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10, 1 1 -ethylenedioxy-20-camptothecin described below.
Irinotecan HCI, (4S)-4, 1 1-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)
carbonyloxy]-1 H-pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3,14(4H, 12H)-dione
hydrochloride, is commercially available as the injectable solution CAMPTOSAR®.
Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.
Topotecan HCI, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3, 14-(4H, 12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer. The dose limiting side effect of topotecan HCI is myelosuppression, primarily neutropenia. Pazopanib which commercially available as VOTRIENT® is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide monohydrochloride. Pazoponib is approved for treatment of patients with advanced renal cell carcinoma.
Rituximab is a chimeric monoclonal antibody which is sold as RITUXAN® and MABTHERA®. Rituximab binds to CD20 on B cells and causes cell apoptosis. Rituximab is administered intravenously and is approved for treatment of rheumatoid arthritis and B- cell non-Hodgkin's lymphoma.
Ofatumumab is a fully human monoclonal antibody which is sold as ARZERRA®.
Ofatumumab binds to CD20 on B cells and is used to treat chronic lymphocytic leukemia (CLL; a type of cancer of the white blood cells) in adults who are refractory to treatment with fludarabine (Fludara) and alemtuzumab (Campath).
mTOR inhibitors include but are not limited to rapamycin (FK506) and rapalogs, RAD001 or everolimus (Afinitor), CCI-779 or temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687 and Pp121 .
Bexarotene is sold as Targretin® and is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). The chemical name is 4-[1 - (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid.
Bexarotene is used to treat cutaneous T-cell lymphoma (CTCL, a type of skin cancer) in people whose disease could not be treated successfully with at least one other medication.
Sorafenib marketed as Nexavar® is in a class of medications called multikinase inhibitors. Its chemical name is 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-/V-methyl-pyridine-2-carboxamide. Sorafenib is used to treat advanced renal cell carcinoma (a type of cancer that begins in the kidneys). Sorafenib is also used to treat unresectable hepatocellular carcinoma (a type of liver cancer that cannot be treated with surgery).
Examples of erbB inhibitors include lapatinib, erlotinib, and gefitinib. Lapatinib, N- (3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-
(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine (represented by formula II, as illustrated), is a potent, oral, small-molecule, dual inhibitor of erbB-1 and erbB-2 (EGFR and HER2) tyrosine kinases that is approved in combination with capecitabine for the treatment of HER2-positive metastatic breast cancer.
Figure imgf000054_0001
(II)
The free base, HCI salts, and ditosylate salts of the compound of formula (II) may be prepared according to the procedures disclosed in WO 99/35146, published July 15, 1999; and WO 02/02552 published January 10, 2002.
Eriotinib, A/-(3-ethynylphenyl)-6,7-bis{[2-(methyloxy)ethyl]oxy}-4-quinazolinamine (commercially available under the tradename Tarceva) is represented by formula III, as illustrated:
Figure imgf000054_0002
(H i)
The free base and HCI salt of eriotinib may be prepared, for example, according to
U.S. 5,747,498, Example 20. TARCEVA® tablets contain eriotinib hydrochloride (27.3 mg, 109.3 mg, and 163.9 mg) equivalent to 25 mg, 100 mg and 150 mg eriotinib and the following inactive ingredients: lactose monohydrate, hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulphate, and titanium dioxide.
Gefitinib, 4-quinazolinamine,N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4- morpholin)propoxy] is represented by formula IV, as illustrated:
Figure imgf000055_0001
(IV)
Gefitinib, which is commercially available under the trade name IRESSA® (Astra- Zenenca) is an erbB-1 inhibitor that is indicated as monotherapy for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. The free base, HCI salts, and diHCI salts of gefitinib may be prepared according to the procedures of International Patent
Application No. PCT/GB96/00961 , filed April 23, 1996, and published as WO 96/33980 on October 31 , 1996. Suitably the present invention relates to the treatment of treatment of a cancer using an antineoplastic agent or antineoplastic agents selected from the group of a subset of the such agents disclosed herein.
The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way.
EXAMPLES
Example I Foretinib (GSK1363089G) is a potent human ROS1 kinase inhibitor.
A working stock of foretinib is prepared at 50x the final assay concentration in 100% DMSO and spotted into a 96-well assay plate. Human ROS protein (ROS h) is then added in a buffer containing 8 mM MOPS pH 7.0, 0.2 mM EDTA, 10 mM MnCI2 and 250 μΜ KKKSPGEYVNIEFG kinase substrate. The kinase reaction is initiated by the addition of the MgATP mix (MgAcetate and [γ-33Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol) to give a final assay concentration of 200 uM ATP. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 3% phosphoric acid solution. Ten microliters of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and counted in a scintillation counter.
Using the above method in single concentration screening, the resulting assays showed 86% ROS1 kinase inhibition at 10 micromolar (14% activity remaining) and 100% ROS1 kinase inhibition at 1 micromolar (no measurable activity remaining). Foretinib was also tested in a full dose curve against kinases that showed >50% inhibition at 1 micromolar (see Table 3). Foretinib showed an IC50 of 20 nanomolar for ROS1 and an IC50 of 17 nanomolar for c-MET kinase in a similar assay. A dose response of ROS1 for foretinib was IC50 = 20nM as determined using standard methods. These results indicated that foretinib is a potent human ROS1 kinase inhibitor.
Tables 1 and 2 show the remaining enzyme activity (in "value" column) following incubation with foretinib. Assay protocols used can be found in Protocol Guide,
KinaseProfiler™ Service Assay Protocols v.54, EMD Millipore Corporation, Lit. No.
PF3036EN00 04/1 1 Job No. DD-SBU-1 1 -04383, 201 1 .
Figure imgf000057_0001
Figure imgf000058_0001
Table 2: Kinase activity using 1 μΜ foretinib
Figure imgf000059_0001
Table 3: ROS1 IC50 for foretinib Kinase activity using a concentration range of 0.001 micromolar to 10 micromolar.
ATP Concentration: 200 μΜ
Figure imgf000060_0001
* NB. Where n = 2, the value reported here is actually range / V 2
Example 2
This is a phase II, open label, uncontrolled, parallel, multi-cohort, multicenter 2-stage study. Subjects will be sequentially assigned to treatment. In Cohort 1 , subjects with EGFRm NSCLC who have responded for at least 4 months and then progressed on an EGFR-TKI within the last 30 days will receive 150 mg eriotinib once daily and 45 mg foretinib once daily. In Cohort 2, subjects with EGFR/WT NSCLC who have responded for at least 2 months and then progressed on an EGFR-TKI within the last 30 days will receive 150 mg eriotinib once daily and 45 mg foretinib once daily. In Cohort 3, subjects with NSCLC that are predicted to be sensitive to foretinib based on biomarkers identified with preclinical or clinical data will receive 60 mg foretinib monotherapy once daily. The first subset to be evaluated will be subjects with NSCLC exhibiting ROS1 rearrangements. For each cohort, Stage 1 will be used to determine the response to treatment, explore the relationship between a set of biomarkers and efficacy endpoints, and based on emerging data, identify a subpopulation of subjects with a specific biomarker of interest who may be more likely to respond. Stage 2 will evaluate the response rate to treatment in the selected subpopulations.
Cohort 3: Subjects with non-small cell lung cancer (NSCLC) that are predicted to be sensitive to foretinib based on biomarkers identified with preclinical or clinical data will receive 60 mg foretinib once daily until disease progression. The first subset to be evaluated will be subjects with NSCLC exhibiting ROS1 rearrangements that are naive to or have progressed on crizotinib/ROS1 inhibitor. Cohort 3 may enroll simultaneously with Cohort 1. A maximum of 20 subjects will be enrolled in each subset in Stage 1 . After the first 10 subjects, the subset may be: (1 ) terminated for futility if there are no responses; (2) progress to Stage 2 if a selected subpopulation can be identified, or (3) continue enrollment to a total of 20 subjects to confirm the unselected ORR. After 20 subjects, proceed to Stage 2 if selection criteria are identified based on the cumulative number of subjects in Stage 1. The null hypothesis tested in unselected subjects (Stage 1 ) is that the response rate is no more than 10%.
In Cohort 3, the objective of the translational research is to determine which if any of the potential predictive biomarkers is associated with response to monotherapy with foretinib. For example, if a specific ROS1 gene fusion is associated with response, this association could be used to select subjects for Stage 2 of this study and could form the basis of a diagnostic test. Cohort 3 (Predictive Biomarkers): Biomarkers of drug sensitivity optimize the risk/benefit profile for subjects and the intent of this protocol is to utilize emerging preclinical and clinical data to identify cohorts of subjects by specific selection criteria. The first subset of such subjects to be enrolled in Cohort 3 is based on preclinical data showing that foretinib is active against the ROS1 kinase at fifty percent inhibitory concentration (IC50) of 25 nM. ROS1 rearrangements occur in 1 -2% of all NSCLC clinically (Bergethon, et al. J Clin Oncol. 2012;
30(8): 863-70; Rimkunas, et al. Clin Cane Res. 2012; 18(16): 4449-57). Moreover, foretinib has shown potent low nanomolar activity in ROS1 -fusion (FIG-ROS1 and SCL-ROS1 ) transformed BaF3 cell lines compared to crizotinib. Taken together, these data suggest that foretinib monotherapy may be efficacious in subjects selected for ROS1 rearrangements. Since these preliminary data are currently just emerging, this current study will assess foretinib in subjects with ROS1 rearrangements who have progressed on or are intolerant to crizotinib/ROS1 inhibitor therapy or crizotinib/ROS1 inhibitor naive subjects for whom crizotinib/ROS1 inhibitor is not available and participation in this trial is their only option for targeted ROS1 treatment, regardless of the presence or absence of crizotinib/ROS1 inhibitor-specific mutations.
However, an assessment of the ROS1 fusion partners and the identification of any specific crizotinib/ROS1 inhibitor resistant mutations in baseline biopsy samples in association with tumor response data may define which subjects are most likely to respond and can be used as a selection criterion for Stage 2 of the study. Additional cohorts of NSCLC subjects predicted to be sensitive to the drug based on biomarkers identified with preclinical or clinical data (e.g., NRTK, RET, etc.) may be added as subsets to Cohort 3 without protocol amendment based on emerging data.
Description of Investigational Products
Foretinib The 15 mg foretinib tablet core contains hypromellose, sodium lauryl sulphate, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The tablet coating, which is yellow, contains polysorbate 80, iron oxide yellow, hypromellose, titanium dioxide, and polyethylene glycol.
Dosage form: Tablet; Round yellow tablet
Route/Administration/Duration: Oral/once daily
Tablet strength: 15 mg
Dose Level: 60 mg (4 x 15 mg);
De-escalation dose: may be reduced in dose 2 times, by 15 mg each time.
Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

Claims

CLAIMS What is claimed is:
1. A method of treating cancer in a human having a rosl variant cancer comprising administration of a thera eutically effective amount of a compound of Formula (I):
Figure imgf000063_0001
(I) or a pharmaceutically acceptable salt thereof.
2. A method of treating cancer in a human comprising identifying a human having rosl variant cancer and administering a therapeutically effective amount of a compound of Formula (I :
Figure imgf000063_0002
(I) or a pharmaceutically acceptable salt thereof to said human, if said human has Rosl variant cancer.
3. The method of claim 1 or 2 wherein the cancer is selected from the group of: ROS1 - rearranged NSCLC, NSCLC SLC34A2-ROS1 , NSCLC CD74-ROS1 , NSCLC EZR-ROS1 , NSCLC TPM3-ROS1 , NSCLC FIG-ROS1 and NSCLC SDC4-ROS1 , and an oncogene addicted ROS1 -rearranged cancer.
4. The method of claim 1 or 2 wherein the cancer is selected from the group of:
adenocarcinoma, glioblastoma, cholangiocarcinoma, glioblastoma multiforme, and melanoma.
5. The method of any one of claims 1 to 4 wherein the cancer is a lung cancer.
6. The method of claim 5 wherein the lung cancer is a non-small cell lung cancer.
7. The method of any one of claims 1 to 6 further comprising treating the human with at least one additional anti-neoplastic agent.
8. The method of any one of claims 1 to 6 wherein said compound of Formula I or pharmaceutically acceptable salt thereof is administered as monotherapy.
9. The method of any one of claims 1 to 8 wherein said compound of Formula I pharmaceutically acceptable salt thereof is administered at a dose of 60 mg/day.
10. The method of any one of claims 1 to 9 wherein said Ros1 variant cancer is resistant to crizotinib.
1 1 . A method of treating cancer in a human comprising identifying a human having rosl variant cancer and AXL expressing cancer and administering a therapeutically effective amount of a com ound of Formula (I):
Figure imgf000064_0001
(I) or a pharmaceutically acceptable salt thereof if said cancer is a Ros1 variant cancer and expresses AXL.
12. The method of claim 1 1 wherein said cancer is lung cancer.
13. The method of claim 1 1 or 12 wherein said cancer is non-small cell lung cancer.
14. The method of any one of claims 1 1 to 13 wherein said compound of Formula I pharmaceutically acceptable salt thereof is administered at a dose of 60 mg/day.
15. A method of treating a human with lung cancer that is resistant to erlotinib comprising determining if said cancer expresses AXL and if said cancer is a rosl variant cancer and administering erlotinib or a pharmaceutically acceptable salt thereof and foretinib or a pharmaceutically acceptable salt thereof to said human if said cancer is a rosl variant cancer and expresses AXL.
16. A method of treating cancer in a human comprising identifying a human having rosl variant cancer and an AXL expressing cancer and administering a therapeutically effective amount of at least one erbB-1 inhibitor and a composition comprising Formula I or a
pharmaceutically acceptable salt thereof to said human.
17. The method of claim 16 wherein said erbB-1 inhibitor comprises erlotinib or a pharmaceutically acceptable salt thereof.
18. The method of claim 16 or 17 wherein the cancer shows resistance to an erbB-1 inhibitor.
19. The method of any one of claims 16 to 18 wherein administration of said erbB-1 inhibitor is discontinued rior to or following administration of the compound of formula (I):
Figure imgf000065_0001
(I) or a pharmaceutically acceptable salt thereof.
20. The method of any one of claims 16 to 19 wherein said cancer is non-small cell lung cancer.
INTERNATIONAL SEARCH REPORT PCT/US2Q13/Ο74889 21.04.201 A
International application No.
WO 2014/093750 PlPCT/US2013/074889
Box No. IV Text of the abstract (Continuation of item 5 of the first sheet)
The present invention relates to the administration of a multikinase inhibitor and its effect on patients with particular genetic variant cancers. More specifically, this present invention is directed to methods of administering foretinib or pharmaceutically acceptable salts or solvates thereof to patients with a ros1 variant cancer including non-small cell lung cancer.
Form PCT/ISA/210 (continuation of first sheet (3)) (July 2009)
PCT/US2013/074889 2012-12-14 2013-12-13 Method of administration and treatment WO2014093750A1 (en)

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US10085979B2 (en) 2014-12-02 2018-10-02 Ignyta, Inc. Combinations for the treatment of neuroblastoma
US10357490B2 (en) 2014-12-02 2019-07-23 Ignyta, Inc. Combinations for the treatment of neuroblastoma
US10869864B2 (en) 2015-12-18 2020-12-22 Ignyta, Inc. Combinations for the treatment of cancer
US10398693B2 (en) 2017-07-19 2019-09-03 Ignyta, Inc. Pharmaceutical compositions and dosage forms
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