WO2006042313A2 - Methode de traitement destinee a combattre l'accumulation de liquide sereux dans des cavites sereuses du corps - Google Patents

Methode de traitement destinee a combattre l'accumulation de liquide sereux dans des cavites sereuses du corps Download PDF

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WO2006042313A2
WO2006042313A2 PCT/US2005/036885 US2005036885W WO2006042313A2 WO 2006042313 A2 WO2006042313 A2 WO 2006042313A2 US 2005036885 W US2005036885 W US 2005036885W WO 2006042313 A2 WO2006042313 A2 WO 2006042313A2
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egfr
patient
egfr antagonist
cavity
serous
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PCT/US2005/036885
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WO2006042313A3 (fr
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Harlan W. Waksal
Martin Birkhofer
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Imclone Systems Incorporated
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention is directed to methods of treating the accumulation of serous fluid in a serous body cavity, such as the peritoneal, pleural, or pericardial cavity, of a patient in need thereof by administering an EGFR antagonist to the patient.
  • a serous body cavity such as the peritoneal, pleural, or pericardial cavity
  • Serous fluids are the fluids contained within the closed cavities of the body. These closed cavities, known as serous cavities, are lined by a contiguous membrane which forms a double layer of mesothelial cells, referred to as the serous membrane.
  • the serous cavities are the pleural (around the lungs), the pericardial (around the heart), and the peritoneal (around the abdominal and pelvic organs) cavities. Serous fluid fills the space between the serous membrane and serves to lubricate the surfaces of these membranes as the surfaces move against each other.
  • the serous fluids are ultrafiltrates of plasma, which are continuously formed and reabsorbed, leaving only a very small volume within the cavities. Under pathological conditions, however, an increased volume of any of the serous fluids can accumulate in their respective cavities.
  • An accumulation of serous fluid in the peritoneal cavity is referred to as ascites
  • an accumulation of serous fluid in the pleural cavity is referred to as pleural effusion
  • an accumulation of serous fluid in the pericardial cavity is referred to as pericardial effusion.
  • Ascites typically occurs because there is disease in the peritoneal cavity, such as cancer or infection, that is producing excessive serous fluid, or there is fluid back-up from the liver or large blood vessels into the peritoneal cavity (portal hypertension), or the body is in a low protein state.
  • Current treatment options for ascites include therapeutic paracentesis, a peritonovenous shunt, liver transplantation, extracorporeal ultrafiltration of ascitic fluid with reinfusion, and transjugular intrahepatic portosystemic stent shunt.
  • Pleural effusion typically occurs because of heart failure, cancer, or pulmonary embolism.
  • Current treatment options for pleural effusion include administering diuretics or antibiotics, or by draining the serous fluid using a chest tube in the pleural space (in one side of the chest cavity around the lung).
  • Pericardial effusion typically occurs because of pericarditis, which is inflammation of the pericardial tissue, although there are many etiologies including pericardial tumors, postpericardiotomy syndrome, radiation, collagen vascular diseases, uraemia, heart failure, chylopericardium and myxoedema. Kidney dialysis and administration of non-steroidal anti ⁇ inflammatory medications are example of current treatment options for pericardial effusion. Drainage of the serous fluid from the chest is another treatment option.
  • the present invention provides a method of treating the accumulation of serous fluid in a serous cavity of a patient in need thereof by administering a therapeutically effective amount of an EGFR antagonist to the patient.
  • the accumulation of serous fluid may be ascites, pleural effusion, or pericardial effusion.
  • the EGFR antagonist is an antibody, such as cetuximab.
  • the patient has a tumor, such as a refractory tumor.
  • the present invention provides a method of treating the accumulation of serous fluid in a serous cavity of a patient in need thereof by administering an initial dose of 400 mg/m 2 of an EGFR antibody and preferably, administering subsequent weekly doses of 150, 200, or 250 mg/m 2 of the EGFR antibody.
  • the present invention provides a method of treating the accumulation of serous fluid in a serous cavity of a patient in need thereof comprising administering a therapeutically effective amount of an EGFR antagonist to the patient and further administering an anti-neoplastic to the patient such as chemotherapy or radiation.
  • the present invention provides methods of treating the accumulation of serous fluid in a serous body cavity of a patient in need thereof by administering an antagonist of the epidermal growth factor receptor (EGFR) family (referred to herein as an EGFR antagonist) to the patient.
  • an antagonist of the epidermal growth factor receptor (EGFR) family referred to herein as an EGFR antagonist
  • the methods of the present invention can be used to treat ascites in the peritoneal cavity, pleural effusion in the pleural cavity, and pericardial effusion in the pericardial cavity.
  • the EGFR antagonists used in the present inventive methods are antagonists of any member of the EGFR family of receptor tyrosine kinases (RTKs), which have been implicated in the control and regulation of cell proliferation and differentiation.
  • RTKs receptor tyrosine kinases
  • EGFR has an extracellular region, a transmembrane hydrophobic domain, and an intracellular region bearing a kinase domain.
  • a ligand binds to the extracellular binding region on the cell surface of EGFR, a conformational change in the receptor is generated, which exposes the phosphorylation sites of the intracellular tyrosine kinase domains. Phosphorylation of these domains stimulates tyrosine kinase activity, initiating a signal transduction pathway, which is turn results in gene activation and cell cycle progression and ultimately cellular proliferation and differentiation. Aberrations in the signaling pathways associated with EGFR are thought to contribute to a number of pathological outcomes.
  • an EGFR antagonist is administered to a patient in need thereof.
  • Such patients have an effusion or accumulation of serous fluid in any of the serous cavities of the body. This excess serous fluid can be in the peritoneal cavity, the pleural cavity, and/or the pericardial cavity. Any suitable method can be used to determine those patients in need thereof, which methods are known to those skilled in the art.
  • a patient in need thereof has detrimental ascites, which can be detected by various methods known to one of skill in the art.
  • a detection can be accomplished by identifying the presence of clinical manifestations of ascites, conducting ultrasonography or computed tomography (CT) of the abdomen, or performing abdominal paracentesis.
  • Clinical manifestation of ascites can be identified by a physical examination and include manifestations such as abdominal distension, shifting dullness, liver enlargement, and bulging flanks.
  • Ultrasonography or CT scans of the abdomen can be performed to detect the presence of ascitic fluid and are preferable modes of identifying ascites when physical examination is not definitive.
  • Abdominal paracentesis can be performed to analyze the ascitic fluid to determine the type of ascites and/or the amount of ascites.
  • the amount of ascites can be determined by methods known to one of skill in the art, such as measuring the patient's serum-ascites albumin gradient (SAAG).
  • SAAG serum-ascites albumin gradient
  • the SAAG is generally calculated by subtracting the albumin concentration of the ascitic fluid from the albumin concentration of a serum specimen obtained from the patient.
  • Ascites in the patient may be related to any pathological condition characterized by such formation such as, for example, diseases in the peritoneal cavity, portal hypertension, or low protein (albumin) conditions.
  • diseases in the peritoneal cavity include cancers such as peritoneal carcinomatosis, hepatocellular carcinoma, cancers metastasized to the liver, and psuedomyxoma; infections such as bacterial peritonitis, fungal peritonitis, tuberculosis peritonitis, HIV-associated peritonitis; and other conditions such as vasculitis, granulomatous, familial Mediterranean fever, and eosinophilic peritonitis.
  • Non-limiting examples of portal hypertension or pathologies associated with portal hypertension include liver disease such as massive hepatic metastases, fulminant hepatic failure, fatty liver of pregnancy and hepatic fibrosis; hepatic congestion such as congestive heart failure, tricuspid insufficiency, constrictive pericarditis, and veno-occlusive disease; and portal vein occlusion.
  • Non-limiting examples of low protein conditions include severe malnutrition with anasarca, protein losing enteropathy, and nephrotic syndrome.
  • liver diseases such as cirrhosis, chronic hepatitis, and hepatic vein obstruction (Budd-Chiari syndrome).
  • Non-hepatic causes of ascites include generalized fluid retention associated with systemic disease ⁇ e.g. heart failure, nephrotic syndrome, severe hypoalbuminemia, constrictive pericarditis) and intra ⁇ abdominal disorders ⁇ e.g. carcinomatosis, tuberculosis, peritonitis).
  • Hypothyroidism may also cause ascites and patients with renal failure, especially those on hemodialysis, occasionally develop unexplained ascites.
  • the present invention contemplates administration of an EGFR antagonist to any patient in need thereof, in a preferred embodiment of the method of treating ascites according to the present invention, the patient has a tumor.
  • the serous cavity is the pleural cavity and a patient in need of treatment has detrimental pleural effusion, which can be detected by various methods known to one of skill in the art. For example, such a detection can be accomplished by identifying the presence of clinical manifestations of pleural effusion, performing a chest x-ray or ultrasonography of the chest, performing a CT scan of the lungs, and performing thoracentesis to analyze the pleural fluid to determine, for example, the amount of fluid in the pleural cavity.
  • pleural effusion can be identified by a physical examination and include manifestations such as pleuritic pain, dyspnea, percussion dullness, decreased motion of the hemithorax, absent tactile fremitus, and absent breath sounds. Because many pleural effusions are asymptomatic, however, preferably identifying whether the patient has pleural effusion involves confirming physical findings by performing a chest x-ray or other imaging techniques to detect the presence of pleural fluid. [0020] Pleural effusion in the patient may be related to any pathological condition characterized by excess formation of serous fluid.
  • Such pathological conditions include, for example, cardiac failure, liver disease, kidney disease, cancer, pneumonia, tuberculosis, and other lung infections or conditions such as pulmonary embolism, rheumatoid disease, hypoalbuminemia, mycotic pluerisy, acute pancreatitis, metastatic neoplasms, drug reactions, collagen- vascular diseases, asbestosis, and sarcoidosis.
  • lung infections or conditions such as pulmonary embolism, rheumatoid disease, hypoalbuminemia, mycotic pluerisy, acute pancreatitis, metastatic neoplasms, drug reactions, collagen- vascular diseases, asbestosis, and sarcoidosis.
  • the serous body cavity is the pericardium and a patient in need thereof has detrimental pericardial effusion, which can be detected by various methods known to one of skill in the art. For example, such a detection can be accomplished by identifying the presence of clinical manifestations of pericardial effusion; checking the central venous pressure; conducting laboratory tests including determining the sedimentation rate and detecting the present of antinuclear antibodies and rheumatoid factor; performing a chest X-ray to determine if the patient has an enlarged cardiac silhouette; performing an electrocardiogram or an echocardiogram; and performing pericardiocentesis to analyze the pericardial fluid to determine, for example, the amount of fluid in the pericardial cavity.
  • Clinical manifestations of pericardial effusion include manifestations such as tachycardia, pericardial rub, tachypnea, pulsus paradoxus, and ascites.
  • identifying whether the patient has pericardial effusion involves conducting an echocardiogram to confirm a diagnosis.
  • Pericardial effusion in the patient may be related to any pathological condition characterized by such formation such as, for example, Dressler's syndrome, renal failure, uremia, trauma, cancer, rheumatic fever, tuberculosis, radiation induced pericarditis, systemic lupus, hypothyroidism, and rheumatoid arthritis.
  • a pathological condition characterized by such formation
  • uremia trauma, cancer
  • rheumatic fever tuberculosis
  • radiation induced pericarditis systemic lupus
  • hypothyroidism and rheumatoid arthritis.
  • inflammation of the pericardium which may be acute or chronic, causes pericardial effusion.
  • the present invention contemplates administration of an EGFR antagonist to any patient in need thereof, in a preferred embodiment of the method of treating pleural effusion according to the present invention, the patient has a tumor.
  • the method of the present invention provides administering to the patient a therapeutically effective amount of an EGFR antagonist.
  • the therapeutically effective amount can be determined by a physician or other qualified medical professional and depends on factors such as the nature of the accumulation of serous fluid, the route of administration of the EGFR antagonist, the duration of treatment, and the condition of the patient.
  • determining a therapeutically effective amount may further require, for example, evaluating the severity of the patient's ascites such as the amount of the ascitic fluid. For example, a high SAAG (i.e. greater than or equal to 1.1 g/dl) may require a higher therapeutically effective amount than a low SAAG (i.e. lower than 1.1 g/dl).
  • determining a therapeutically effective amount may further require, for example, evaluating the severity of the patient's pleural effusion such as the amount of pleural fluid in the pleural cavity or by determining if the patient has other pathological conditions associated with the pleural effusion.
  • ascites may be associated with pleural effusion because fluid can move from the periteneal space into the pleural space through diaphragmatic defects or lymphatic channels, hi such a case, the therapeutically effective amount of the EGFR antagonist may be greater than if ascites were not associated with the pleural effusion.
  • determining a therapeutically effective amount may further require, for example, evaluating the severity of the patient's pericardial effusion such as the amount of pericardial fluid in the pericardial cavity or the severity of the clinical manifestations.
  • the EGFR antagonist that is administered to the patient to treat the accumulation of fluid in the serous body cavities is any antagonist that inhibits activation of any member of the EGFR family, including EGFR (also known as erbB- 1/HERl), HER2 (also known as c-neu/erB-2), erbB-3/HER3, and erbB-4/HER4.
  • the EGFR antagonist can be any intracellular or extracellular EGFR antagonist. Extracellular EGFR antagonists interact with the extracellular binding region of EGFR through sufficient physical or chemical interaction between the EGFR antagonist and the extracellular binding region of the receptor such that tyrosine kinase activity is inhibited.
  • Intracellular antagonists inhibit the tyrosine kinase activity of the EGFR by preventing receptor phosphorylation and/or the phosphorylation of other proteins involved in the various EGFR signaling pathways.
  • the intracellular EGFR antagonist may inhibit tyrosine kinase activity of the EGFR by binding to or inhibiting activation of the intracellular region bearing a kinase domain or by binding to or inhibiting activation of any intracellular protein involved in the signaling pathway of the EGFR.
  • the extracellular and intracellular EGFR antagonist in the context of the present invention, can be biological molecules, small molecules, or any other substances that inhibit activation of the EGFR by interaction with the extracellular binding region of the receptor (i.e. extracellular antagonist) or inhibits phosphorylation by interaction with the intracellular tyrosine kinase domain or any other intracellular protein involved in the pathway (i.e., intracellular antagonist), thereby ultimately inhibiting gene activation or cellular proliferation.
  • Biological molecules in the context of the present invention, include all amino acids, nucleotides, lipids and polymers of monosaccharides that generally have a molecular weight greater than 650 D.
  • biological molecules include, for example, oligopeptides, polypeptides, peptides, and proteins, oligonucleotides and polynucleotides such as, for example, DNA and RNA, and oligosaccharides and polysaccharides.
  • biological molecules include modifications of any of the molecules described above, such as lipids and glycosylation derivatives or oligopeptides, polypeptides, peptides, and proteins.
  • biological molecules include lipid derivatives of oligosaccharides and polysaccharides, e.g. lipopolysaccharides. Most typically, biological molecules are antibodies and antibody fragments.
  • the EGFR antagonists decrease the activation of EGFR, without necessarily completely preventing or stopping activation of EGFR.
  • Such antibodies according to the present invention may be, for example, naturally- occurring antibodies, bivalent fragments such as (Fab') 2 , monovalent fragments such as Fab, single chain antibodies such as single chain Fvs (scFv), single domain antibodies, multivalent single chain antibodies, diabodies, triabodies, and the like, which may be mono or bi-specific, that bind specifically with antigens.
  • the antibodies according to the present invention may also be single domain antibodies, which bind efficiently and include a single antibody variable domain that provides efficient binding. Antibodies that are homodimers of heavy chains and are devoid of light chains and the first constant domain may also be used.
  • the antibodies of the present invention comprise human V H and V L framework regions (FWs) as well as human complementary determining regions (CDRs).
  • the entire V H and V L variable domains are human or derived from human sequences.
  • the variable domains of the antibodies of the present invention may be a complete antibody heavy or light chain variable domain, or it may be a functional equivalent or a mutant or derivative of a naturally occurring domain, or a synthetic domain constructed using techniques known to those skilled in the art. For instance, it is possible to join together domains corresponding to antibody variable domains that are missing at least one amino acid.
  • the important characterizing feature is the ability of each domain to associate with a complementary domain to form an antigen-binding site.
  • V L and V H domains from a selected source may be incorporated into chimeric antibodies with functional human constant domains.
  • Antibodies of the invention can also be humanized, and comprise one or more complementarity determining regions (CDRs) of non- human origin grafted to human framework regions (FRs) or can be fully humanized antibodies.
  • CDRs complementarity determining regions
  • FRs human framework regions
  • Such antibodies can be obtained from methods known to one of skill in the art such as by phage display or from transgenic animals.
  • human binding domains or antibodies can be obtained from transgenic animals into which unrearranged human Ig gene segments have been introduced and in which the endogenous mouse Ig genes have been inactivated (reviewed in Bruggemann and Taussig (1997) Curr. Opin. Biotechnol. 8, 455-458).
  • Monoclonal antibodies produced from such mice are human.
  • antibodies include functional equivalents of antibodies such as polypeptides with amino acid sequences substantially the same as the amino acid sequence of the variable or hypervariable regions of the full length antibodies. Substantially the same amino acid sequence is defined herein as a sequence with at least 70%, preferably at least about 80%, and more preferably at least about 90% homology to another amino acid sequence, as determined by the FASTA search method in accordance with Pearson and Lipman, Proc. Natl. Acad. ScL USA 85, 2444-8 (1988). Antibodies of the present invention also include those for which binding characteristics (e.g., affinity and specificity) have been improved by direct mutation, methods of affinity maturation, phage display, or chain shuffling.
  • binding characteristics e.g., affinity and specificity
  • the antibody binds to the extracellular domain of EGFR and more preferably neutralizes EGFR activation, for example by blocking receptor dimerization and/or ligand binding.
  • EGFR antibody is cetuximab (IMC-C225) (GenBank Accession No. INQLA), which is a chimeric (human/mouse) IgG monoclonal antibody. See e.g., U.S. Patent No. 4,943,533 (Mendelsohn et al.), which is incorporated by reference; U.S. Patent No. 6,217,866 (Schlessinger et al.), which is incorporated by reference; U.S. Application Nos.
  • Cetuximab specifically binds to EGFR and blocks binding of a ligand, such as EGF.
  • Cetuximab Fab contains the Fab fragment of Cetuximab, i.e., the heavy and light chain variable region sequences of murine antibody M225 (U.S. App. Ser. No. 2004/0006212, incorporated herein by reference) with human IgGl C H I heavy and kappa light chain constant domains.
  • Cetuximab includes all three IgGl heavy chain constant domains.
  • the CDR regions of the heavy chain of Cetuximab have the following sequences: a CDRl region with a sequence of N Y G V H, a CDR2 region with a sequence ofV I W S G G N T D Y N T P F T S, and a CDR3 region with a sequence of A L T Y Y D Y E F A Y.
  • the CDR regions of the light chain ol Cetuximab have the following sequences: a CDRl region with a sequence ofR A S Q S I G T N I H, a CDR2 region with a sequence of Y A S E S I S, and a CDR3 region with a sequence of Q Q
  • ABX-EGF is a fully human IgG 2 monoclonal antibody specific for EGFR.
  • ABX-EGF binds EGFR with high specificity, blocking binding of EGFR to both of its ligands, EGF and TGF- ⁇ .
  • EGF EGF
  • TGF- ⁇ TGF- ⁇
  • Herceptin® is a recombinant DNA-derived humanized monoclonal antibody that selectively binds with high affinity in a cell-based assay (Kd of 5 nM) to the extracellular domain of the human EGFR2 protein, HER2.
  • the antibody is an IgG 1 kappa that contains human framework regions with the complementarity-determining regions of a murine antibody (4D5) that binds to HER2. See, e.g., International Patent Publication No. WO 01/89566 : which is incorporated by reference herein.
  • EMD 72000 Merck KGaA
  • EMD 55900 h-R3 (TheraCIM)
  • YlO which is a murine monoclonal antibody and was raised against a murine homologue of the human EGFRvIII mutation
  • MDX-447 Medarex
  • the EGFR antagonist of the present invention may also be a small molecule.
  • small molecules include organic compounds, organometallic compounds, salts of organic compounds and organometallic compounds, and inorganic compounds.
  • Atoms in a small molecule are linked together via covalent and ionic bonds; the former is typical for small organic compounds such as small molecule tyrosine kinase inhibitors and the latter is typical of small inorganic compounds.
  • the arrangement of atoms in a small organic molecule may represent a chain, e.g. a carbon-carbon chain or carbon-heteroatom chain or may represent a ring containing carbon atoms, e.g.
  • small molecules can have any molecular weight they generally include molecules that would otherwise be considered biological molecules, except their molecular weight is not greater than 650 D. Small molecules include both compounds found in nature, such as hormones, neurotransmitters, nucleotides, amino acids, sugars, lipids, and their derivatives as well as compounds made synthetically, either by traditional organic synthesis, bio-mediated synthesis, or a combination thereof. See e.g. Ganesan, Drug Discov. Today 7(1): 47-55 (Jan. 2002); Lou, Drug Discov. Today 6(24): 1288-1294 (Dec. 2001), which are incorporated by reference herein.
  • the small molecule competes with ATP for binding to EGFR's intracellular binding region having a kinase domain.
  • a small molecule EGFR antagonist is IRESSATM (ZD1939), which is a quinozaline derivative that functions as an ATP-mimetic to inhibit EGFR. See U.S. Patent No. 5,616,582 (Zeneca Limited); WO 96/33980 (Zeneca Limited) at p.
  • TARCEV ATM (OSI-774), which is a 4-(substitutedphenylamino)quinozaline derivative [6,7-Bis(2-methoxy-ethoxy) ⁇ quinazolin-4-yl]- (3-ethynyl-phenyl)amine hydrochloride] EGFR inhibitor.
  • OSI-774 4-(substitutedphenylamino)quinozaline derivative [6,7-Bis(2-methoxy-ethoxy) ⁇ quinazolin-4-yl]- (3-ethynyl-phenyl)amine hydrochloride] EGFR inhibitor.
  • OSI-774 4-(substitutedphenylamino)quinozaline derivative [6,7-Bis(2-methoxy-ethoxy) ⁇ quinazolin-4-yl]- (3-ethynyl-phenyl)amine hydrochloride] EGFR inhibitor.
  • TARCEV ATM may function by inhibiting phosphorylation of EGFR and its downstream PI3/Akt and MAP (mitogen activated protein) kinase signal transduction pathways resulting in p27-mediated cell-cycle arrest. See Hidalgo et al., Abstract 281 presented at the 37th Annual Meeting of ASCO, San Francisco, CA, 12-15 May 2001, which is incorporated by reference herein.
  • Naturally derived EGFR tyrosine kinase inhibitors include genistein, herbimycin A, quercetin, and erbstatin
  • Examples of specific small molecule EGFR antagonists include Cl-1033 (Pfizer), which is a quinozaline (N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-mo ⁇ holin-4-yl-propoxy)- quinazolin-6-yl]-acrylamide) inhibitor of tyrosine kinases, particularly EGFR and is described in WO 00/31048 at page 8, lines 22-6, which is incorporated by reference herein; PKIl 66 (Novartis) which is a pyrrolopyrimidine inhibitor of EGFR and is described in WO 97/27199 at pages 10-12 which is incorporated by reference herein; GW2016 (GlaxoSmithKline), which is an inhibitor of EGFR and HER2, which is incorporated by reference herein; EKB569 (Wyeth), which is reported to inhibit the growth of tumor cells that overexpress EGFR or HER2 in vitro and in vivo
  • EGFR antagonists which are not necessarily small molecules and/or antagonists specific for only EGFR are styrl-substituted heteroaryl compounds such as the compounds described in U.S. Patent No. 5,656,655, which is incorporated by reference herein; bis mono- and bicyclic aryl and heteroaryl compounds such as the compounds described in U.S. Patent No. 5,646,153, which is incorporated by reference herein; PD 153035 described in Fry et al. (265 Science 1093-1095 (March 1994)), which is incorporated by reference herein; tyrphostins such as those described in Osherov et al. (J. Biol. Chem., Vol. 268, No.
  • Administering the EGFR antagonist to a patient according to the present invention includes delivering the EGFR antagonist to a patient by any method that may achieve EGFR inhibition.
  • the EGFR antagonists may be delivered to a patient orally, parenterally (intramuscularly or intravenously), topically, transdermally, or by inhalation.
  • patient as used herein means a mammal and the term mammal is intended to include, but is not limited to, humans, laboratory animals, domestic pets and farm animals.
  • the EGFR antagonist according to the present invention can also be administered to the patient as part of a pharmaceutical composition that contains the EGFR antagonist as the active agent or a pharmaceutically acceptable salt, hydrate, or pro-drug thereof, in combination with a pharmaceutically acceptable carrier.
  • the compositions can also include solubilizing agents, buffering agents, preservatives, and the like. Such compositions may be delivered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.
  • the EGFR antagonist may be administered, for example, in liquid form with an inert diluent or assimilable carrier, or incorporated into a solid dosage form.
  • oral liquid and solid dosage forms include, for example, solutions, suspensions, syrups, emulsions, tablets, lozenges, capsules (including soft gelatin capsules) and the like.
  • Oral dosage forms may be formulated as sustained release products using, for example, a coating to delay disintegration or to control diffusion of the EGFR antagonist.
  • the EGFR antagonist may be administered in an injectable dosage such as sterile liquids or solids.
  • Sterile liquids include solutions, emulsions and suspension and sterile solids include sterile powders that are reconstituted, dissolved or suspended in a liquid prior to injection.
  • Carriers of such injectable dosages include sterile water, saline, injectable organic esters, peanut oil, vegetable oil, and the like.
  • Such sterile formulations can be prepared by heating, irradiation, microfiltration, and/or by addition of various antibacterial and antifungal agents such as, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • EGFR antagonists of the present invention can be administered, for example, in the form of gels, creams, or ointments, or paints. Typical carriers for such application include hydrophobic or hydrophilic bases, oleaginous or alcoholic liquids, and dry powders.
  • the EGFR antagonist may also be incorporated in a gel or matrix base for application in a patch, optionally providing controlled release of the pharmaceutical composition containing the EGFR antagonist through a transdermal barrier.
  • EGFR antagonists can also be formulated by known methods for rectal administration.
  • the EGFR antagonist may be administered as frequently as necessary in order to obtain the desired therapeutic effect of reduction of serous fluid accumulation. Frequency of administration will depend, for example, on the nature of the dosage form used and the stage of the serous fluid accumulation being treated.
  • Suitable dosages of the EGFR antagonist can be determined by a physician or qualified medical professional and depend on factors such as the nature of the fluid accumulation, the route of administration, the duration of treatment, and the condition of the patient, hi embodiments where the EGFR antagonist is an antibody, an exemplary dosage schedule for a human patient is intravenously administering an initial dose of 400 mg/m 2 of the EGFR antagonist for a time period of preferably two hours and then subsequently intravenously administering weekly doses of 250 mg/m 2 of the EGFR antagonist for a time period of preferably one hour. If necessary, the subsequent weekly doses may be lowered to 200 mg/m 2 or 150 mg/m 2 .
  • an exemplary dosage schedule is orally administering daily doses of 250 mg (IRESSATM); orally administering daily doses of 150 mg (TARCEV ATM); or orally administering weekly doses of 560 mg (CI-1033).
  • the EGFR antagonist may be administered alone or in combination with other therapeutic techniques.
  • any conventional therapy known in the art can be used in combination with the present inventive methods.
  • the EGFR antagonist can be used in combination with other RTK antagonists such as a vascular endothelial growth factor receptor (VEGFR) or VEGF antagonists, including VEGFR antibodies, VEGF antibodies, and small molecules.
  • VEGFR vascular endothelial growth factor receptor
  • VEGFR antibodies VEGF antibodies
  • small molecules small molecules.
  • CEP-5214 CEP-5214.
  • ZD-6474 ZD-6474.
  • the EGFR antagonist can also be administered in combination with one or more antineoplastic agents.
  • any suitable antineoplastic agent can be used, such as a chemotherapeutic agent or radiation.
  • chemotherapeutic agents include, but are not limited to, cisplatin doxorubicin, paclitaxel, irinotecan (CPT-11), topotecan, and oxaliplatin, or a combination thereof
  • the source of the radiation can be either external (external beam radiation therapy - EBRT) or internal (brachytherapy - BT) to the patient being treated.
  • the dose of the antineoplastic agent administered depends on numerous factors, including, for example, the type of agent, the type and severity of the accumulation of serous fluid being treated and the route of administration of the agent.
  • the EGFR antagonist can be administered in combination with one or more suitable adjuvants, such as, for example, cytokines (IL-10 and IL-13, for example) or other immune stimulators as well as with cytotoxic agents.
  • suitable adjuvants such as, for example, cytokines (IL-10 and IL-13, for example) or other immune stimulators as well as with cytotoxic agents.

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Abstract

L'invention porte sur une méthode de traitement destinée à combattre l'accumulation de liquide dans une cavité séreuse d'un patient ayant besoin de ce liquide par administration au patient d'une quantité efficace sur le plan thérapeutique d'un antagoniste R-EGF. L'accumulation de liquide peut provenir d'ascites, d'un épanchement pleural, ou d'un épanchement péricardique.
PCT/US2005/036885 2004-10-12 2005-10-12 Methode de traitement destinee a combattre l'accumulation de liquide sereux dans des cavites sereuses du corps WO2006042313A2 (fr)

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US61709004P 2004-10-12 2004-10-12
US60/617,090 2004-10-12

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WO2006042313A2 true WO2006042313A2 (fr) 2006-04-20
WO2006042313A3 WO2006042313A3 (fr) 2007-01-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130230581A1 (en) * 2010-11-30 2013-09-05 Qingping Feng Egfr antagonist for the treatment of heart disease

Citations (2)

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US6217866B1 (en) * 1988-09-15 2001-04-17 Rhone-Poulenc Rorer International (Holdings), Inc. Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same
US20040191328A1 (en) * 2002-12-31 2004-09-30 Warrell Raymond P. Combination of gallium compounds with nonchemotherapeutic anticancer agents in the treatment of neoplasia

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6217866B1 (en) * 1988-09-15 2001-04-17 Rhone-Poulenc Rorer International (Holdings), Inc. Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same
US20040191328A1 (en) * 2002-12-31 2004-09-30 Warrell Raymond P. Combination of gallium compounds with nonchemotherapeutic anticancer agents in the treatment of neoplasia

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130230581A1 (en) * 2010-11-30 2013-09-05 Qingping Feng Egfr antagonist for the treatment of heart disease
US9861694B2 (en) * 2010-11-30 2018-01-09 Qingping Feng EGFR antagonist for the treatment of heart disease

Also Published As

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