US20070224203A1 - Tumor therapy with an antibody for vascular endothelial growth factor and an antibody for human epithelial growth factor receptor type 2 - Google Patents

Tumor therapy with an antibody for vascular endothelial growth factor and an antibody for human epithelial growth factor receptor type 2 Download PDF

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US20070224203A1
US20070224203A1 US11/725,777 US72577707A US2007224203A1 US 20070224203 A1 US20070224203 A1 US 20070224203A1 US 72577707 A US72577707 A US 72577707A US 2007224203 A1 US2007224203 A1 US 2007224203A1
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antibody
vegf antibody
patient
her2
cancer
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Thomas Friess
Max Hasmann
Werner Scheuer
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Hoffmann La Roche Inc
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Priority to US12/947,264 priority Critical patent/US9090700B2/en
Priority to US14/745,026 priority patent/US20150283238A1/en
Priority to US15/591,922 priority patent/US20170239353A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3015Breast
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507Comprising a combination of two or more separate antibodies
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the present invention is directed to combined therapy with anti-HER2 and anti-VEGF antibodies.
  • the invention concerns the use of such antibodies to treat breast cancer disease in a patient who has failed prior breast cancer treatment with an anti-VEGF antibody.
  • Angiogenesis is implicated in the pathogenesis of a variety of disorders which include solid tumors, intraocular neovascular syndromes such as proliferative retinopathies or age-related macular degeneration (AMD), rheumatoid arthritis, and psoriasis (Folkman, J., et al., J. Biol. Chem. 267 (1992) 10931-10934; Klagsbrun, M., et al., Annu. Rev. Physiol.
  • VEGF Vascular endothelial growth factor
  • Anti-VEGF neutralizing antibodies suppress the growth of a variety of human tumor cell lines in mice (Kim, K. J., et al., Nature 362 (1993) 841-844; Warren, R. S., et al., J. Clin. Invest. 95 (1995) 1789-1797; Borgstrom, P., et al., Cancer Res. 56 (1996) 4032-4039; and Melnyk, O., et al., Cancer Res. 56 (1996) 921-924).
  • WO 94/10202, WO 98/45332, WO 2005/00900 and WO00/35956 refer to antibodies against VEGF.
  • Humanized monoclonal antibody bevacizumab (sold under the tradename Avastin®) is an anti-VEGF antibody used in tumor therapy and is the only anti-angiogenic agent approved for treatment of cancer (WO 98/45331).
  • HER2 is a member of the human epidermal growth factor receptor family and possesses protein kinase activity in its cytoplasmic domain. HER2 is over-expressed in tumor cells and is correlated with poor prognosis and survival. HER2 is therefore a valuable target of breast cancer therapy.
  • Antibodies against HER2 are known from Takai, N., et al., Cancer 104 (2005) 2701-2708; Yeon, C. H., et al., Invest. New Drugs 23 (2005) 391-409; Wong, W. M., et al., Cancer Pract. 7 (1999) 48-50; Albanell, J., et al., Drugs Today (Barc). 35 (1999) 931-46.
  • trastuzumab (sold under the tradename Herceptin®) is a recombinant humanized anti-HER2 monoclonal antibody used for the treatment of HER2 over-expressed/HER2 gene amplified metastatic breast cancer. Preclinical studies demonstrated that the antibody has anti-tumor activity in vivo and in vitro. Moreover, additive or synergistic enhancement of anti-tumor activity of trastuzumab was observed in combination with various anti-tumor agents in mouse models. In clinical studies, extension of survival was observed in HER2 overexpressing metastatic breast cancer patients.
  • WO 98/45331 the effectiveness of an anti-VEGF antibody in preventing or treating disease may be improved by administering the antibody serially or in combination with another agent that is effective for those purposes, such as an antibody capable of binding to HER2 receptor.
  • WO 2005/012531 describes antibodies that may be combined with an anti-VEGF antibody (e.g. Avastin®) and/or anti-ErbB antibodies (e.g. Herceptin®) in the treatment of colorectal cancer, metastatic breast cancer and kidney cancer.
  • anti-VEGF antibodies may be combined with anti-ErbB antibodies in a treatment of metastatic breast cancer.
  • WO 2005/00090 and WO 2003/077841 also disclose the combination of anti-VEGF antibodies with anti-ErbB2 antibodies for tumor therapy.
  • the invention comprises the use of an anti-HER2 antibody and an anti-VEGF antibody for the manufacture of a medicament for treating a breast cancer disease in a patient who has failed prior cancer therapy with an anti-VEGF antibody, comprising administering to the patient a therapeutically effective amount of an anti-HER2 antibody and an anti-VEGF antibody.
  • the invention comprises the use of trastuzumab and bevacizumab for the manufacture of a medicament for treating a breast cancer disease characterized by an overexpression of the HER2 receptor protein in a patient who has failed prior therapy with an anti-VEGF antibody such as bevacizumab, comprising administering to the patient a therapeutically effective amount of trastuzumab and bevacizumab.
  • the invention further comprises a method of treating a breast cancer disease in a patient who has failed prior therapy with an anti-VEGF antibody, comprising administering to the patient a therapeutically effective amount of an anti-HER2 antibody while continuing said anti-VEGF antibody therapy.
  • the invention further comprises a method of treating a breast cancer disease, in a patient who has failed prior therapy with an anti-VEGF antibody, comprising administering to the patient a therapeutically effective amount of trastuzumab while continuing bevacizumab therapy, wherein the breast cancer disease is characterized by an overexpression of the HER2 receptor protein.
  • the invention further comprises a method for increasing the duration of survival of a patient having breast cancer disease who has failed prior therapy with an anti-VEGF antibody, comprising administering to the patient effective amounts of an anti-VEGF antibody and an anti-HER2 antibody, whereby the co-administration of the anti-VEGF antibody and the anti-HER2 antibody effectively increases the duration of survival.
  • the invention further comprises a method for increasing the progression free survival of a patient having breast cancer disease who has failed prior therapy with an anti-VEGF antibody, comprising administering to the patient effective amounts of an anti-VEGF antibody and an anti-HER2 antibody, whereby the co-administration of the anti-VEGF antibody and the anti-HER2 antibody effectively increases the duration of progression free survival.
  • the invention further comprises a method for treating a group of patients, having breast cancer disease and having failed prior therapy with an anti-VEGF antibody, comprising administering to the patient effective amounts of an anti-VEGF antibody and an anti-HER2 antibody, whereby the co-administration of the anti-VEGF antibody and the anti-HER2 antibody effectively increases the response rate in the group of patients.
  • the invention further comprises a method for increasing the duration of response of a patient having breast cancer disease who has failed prior therapy with an anti-VEGF antibody, comprising administering to the patient effective amounts of an anti-VEGF antibody and an anti-HER2 antibody, whereby the co-administration of the anti-VEGF antibody and the anti-HER2 antibody effectively increases the duration of response.
  • the invention further comprises a method of treating a patient having breast cancer disease who has failed prior therapy with an anti-VEGF antibody, comprising administering to the patient effective amounts of an anti-VEGF antibody and an anti-HER2 antibody, whereby the co-administration of the anti-VEGF antibody and the anti-HER2 antibody results in statistically significant and clinically meaningful improvement of the treated patient as measured by the duration of survival, progression free survival, response rate or duration of response.
  • This invention further comprises a method for reducing metastasis in a patient having breast cancer disease who has failed prior therapy with an anti-VEGF antibody, comprising administering to the patient effective amounts of an anti-VEGF antibody and an anti-HER2 antibody, whereby the co-administration of the anti-VEGF antibody and the anti-HER2 antibody effectively reduces metastasis.
  • the invention further comprises a method for treating a group of patients, having breast cancer disease and having failed prior therapy, with an anti-VEGF antibody, comprising administering to the patient effective amounts of an anti-VEGF antibody and an anti-HER2 antibody, whereby the co-administration of the anti-VEGF antibody and the anti-HER2 antibody effectively reduces metastasis in the group of patients.
  • the invention provides an article of manufacture (e.g., pharmaceutical kit) comprising one or more containers, and preferably at least two containers, a pharmaceutical composition within a first container comprising an anti-VEGF antibody, a pharmaceutical composition within a second container comprising an anti-HER2 antibody and a package insert instructing the user of the composition to administer to a patient, having breast cancer disease who has failed prior therapy with an anti-VEGF antibody, the anti-VEGF antibody within said first container and an anti-HER2 antibody within said second container.
  • an article of manufacture e.g., pharmaceutical kit
  • a pharmaceutical composition within a first container comprising an anti-VEGF antibody
  • a pharmaceutical composition within a second container comprising an anti-HER2 antibody
  • a package insert instructing the user of the composition to administer to a patient, having breast cancer disease who has failed prior therapy with an anti-VEGF antibody, the anti-VEGF antibody within said first container and an anti-HER2 antibody within said second container.
  • the invention further provides for a pharmaceutical composition comprising an anti-HER2 antibody and an anti-VEGF antibody useful in the treatment of breast cancer disease in a patient which has failed prior therapy with an anti-VEGF antibody.
  • an anti-HER2 antibody is trastuzumab.
  • the anti-VEGF antibody is bevacizumab.
  • FIG. 1 Antitumor activity of combined trastuzumab and bevacizumab treatment on tumor growth after bevacizumab treatment failure. Mean values of tumor volume (mm 3 ) plotted on the y-axis; number of days after injection of tumor cells plotted on the x-axis. Vehicle (circles), trastuzumab at loading dose of 30 mg/kg and maintenance dose of 15 mg/kg (squares), bevacizumab at 5 mg/kg until day 55 when treatment, also includes trastuzumab at 15 mg/kg (triangles).
  • FIG. 2 Effect of combined trastuzumab and bevacizumab treatment on lung metastasis. Mean value of human Alu DNA sequence (ng/ml) quantitated from lung tissue using real-time PCR and plotted on the y-axis.
  • VEGF refers to the vascular endothelial cell growth factor (Swiss-Prot No. P 15692), alternative splicing forms (see e.g. Leung, D. W., et al., Science, 246 (1989) 1306-1309; and Houck, K. A., et al., Mol. Endocrin. 5 (1991) 1806-1814) and active fragments, preferably N-terminal fragments thereof.
  • anti-VEGF antibody is an antibody that binds specifically to VEGF.
  • the preferred humanized anti-VEGF antibody or variant anti-VEGF antibody herein binds human VEGF with a Kd value of no more than about 1 ⁇ 10 ⁇ 8 M and preferably no more than about 5 ⁇ 10 ⁇ 9 M.
  • the anti-VEGF antibody is a monoclonal antibody that binds to the same epitope as recombinant humanized anti-VEGF monoclonal antibody generated according to Presta, L. G., et al., Cancer Res. 57 (1997) 4593-4599.
  • a preferred antibody is bevacizumab.
  • Anti-VEGF antibodies and methods for their manufacture are e.g. described in U.S. Pat. No. 6,054,297, US 2003/0190317, U.S. Pat. No. 6,632,926, U.S. Pat. No. 6,884,879, and US 2005/0112126.
  • Bevacizumab comprises mutated human IgG1 framework regions and antigen-binding complementarity-determining regions from a murine anti-hVEGF monoclonal antibody that blocks binding of human VEGF to its receptors. Approximately 93% of the amino acid sequence of bevacizumab, including most of the framework regions, is derived from human IgG1, and about 7% of the sequence is derived from the murine antibody A4.6.1. Bevacizumab has a molecular mass of about 149,000 Daltons and is glycosylated. Bevacizumab and its method of preparation are described in EP 1 325 932.
  • HER2 is a 185-kDa growth factor receptor also referred to as neu and c-erbB-2 (Slamon, D. J., et al., Science 235 (1987) 177-182; Swiss-Prot P04626) whose function is related to neoplastic transformation in human breast cancer cells. Overexpression of this protein has been identified in 20-30% of breast cancer patients where it correlates with regionally advanced disease, increased probability of tumor recurrence, and reduced patient survival. As many as 30-40% of patients having gastric, endometrial, salivary gland, non-small cell lung, pancreatic, ovarian, peritoneal, prostate, or colorectal cancers may also exhibit overexpression of this protein.
  • Anti-HER2 antibodies and methods for their manufacture are e.g. described in U.S. Pat. No. 6,054,297, WO 89/06692, U.S. Pat. No. 6,953,842, U.S. Pat. No. 6,949,245, U.S. Pat. No. 6,399,063, U.S. Pat. No. 6,165,464, U.S. Pat. No. 6,054,297, U.S. Pat. No. 5,772,997, WO 2003/087131, WO 01/00245, WO 01/00238, WO 00/69460, WO 00/52054, WO 99/31140 and WO 98/17797.
  • the anti-HER2 antibody is trastuzumab. Trastuzumab and its method of preparation are described in EP 0 590 058.
  • overexpression of the HER2 receptor protein is intended to indicate an abnormal level of expression of the HER2 receptor protein in a cell from a tumor within a specific tissue or organ of the patient relative to the level of expression in a normal cell from that tissue or organ.
  • Patients having a cancer characterized by overexpression of the HER2 receptor can be determined by standard assays known in the art. Preferably overexpression is measured in fixed cells of frozen or paraffin-embedded tissue sections using immunohistochemical (IHC) detection. When coupled with histological staining, localization of the targeted protein can be determined and extent of its expression within a tumor can be measured both qualitatively and semi-quantitatively.
  • IHC immunohistochemical
  • IHC detection assays are known in the art and include the Clinical Trial Assay (CTA), the commercially available LabCorp 4D5 test, and the commercially available DAKO HercepTest® (DAKO, Carpinteria, Calif.).
  • CTA Clinical Trial Assay
  • DAKO DAKO HercepTest®
  • the latter assay uses a specific range of 0 to 3+ cell staining (0 being normal expression, 3+ indicating the strongest positive expression) to identify cancers having overexpression of the HER2 protein (see the Herceptin® (trastuzumab) full prescribing information, September 1998, Genentech Inc., San Francisco, Calif.).
  • Herceptin® trasuzumab
  • patients having a cancer characterized by overexpression of the HER2 protein in the range of 1+, 2+, or 3+, preferably 2+ or 3+, more preferably 3+ would benefit from the methods of therapy of the present invention.
  • breast cancer disease refers to the uncontrolled growth of abnormal breast cells. It includes ductal carcinoma in situ, invasive ductal carcinoma, lobular carcinoma in situ, invasive lobular carcinoma, medullary carcinoma, Paget's disease of the nipple and metastatic breast cancer, as well as other cancer diseases of the breast as known to one of ordinary skill in the art.
  • failed prior therapy with an anti-VEGF antibody refers to tumor patients who failed to respond to previous therapy with an anti-VEGF antibody (“non-responders”) or who initially responded to previous therapy, but in whom the therapeutic response was not maintained (referred to as “relapsers”).
  • relapsers tumor patients who failed to respond to previous therapy with an anti-VEGF antibody (“non-responders”) or who initially responded to previous therapy, but in whom the therapeutic response was not maintained (referred to as “relapsers”).
  • relapsers referred to as “relapsers”.
  • Treatment failure is established based on the medical judgment of a practitioner ascertained by the results from clinical and laboratory data that are generally known in the art to assess patient treatment.
  • treatment failure is defined as the absence of clinical improvement.
  • RECIST criteria may be used to determine tumor response (Therasse, P., et al., J. Nat. Cancer Institute 92 (2000) 205-216)
  • treatment failure is defined as either “incomplete response/stable disease” or “progressive disease”.
  • tumor response for solid tumors is categorized in dependency of the volume progression or regression of the tumors (e.g. measured via CT) into four levels: complete response (CR) or partial response (PR), stable disease (SD) and progressive disease (PD) (see Table 1).
  • CR complete response
  • PR partial response
  • SD stable disease
  • PD progressive disease
  • EORTC European Organization for Research and Treatment of Cancer
  • FDG-PET 2-[ 18 F]-Fluoro-2-deoxyglucose positron emission tomography
  • CMR complete metabolic response
  • PMR partial metabolic response
  • SMD stable metabolic disease
  • PMD progressive metabolic disease
  • CT-Criteria (acc. to RECIST) CT-measurement: Change in sums longest diameters RECIST Disappearance; CR confirmed at 4 weeks (after treatment start) 30% decrease; PR confirmed at 4 weeks Neither PR nor PD SD criteria met 20% increase, no CR, PD PR, SD documented before increased disease
  • “Response (RE)” and “Non-Response (NR)” are established based on data acquired by the combination of computer tomography (CT) and 2-[ 18 F]-Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) (Kellof, G. J., et al., Clin. Cancer Res. 11 (2005) 2785-2808, and Young H., et al., Eur. J. Canc. 35 (1999) 1773-1782) using both the RECIST and FDG-PET criteria described above. Accordingly Response (RE) and Non-Response (NR) according to this invention are determined preferably as follows:
  • CR or PR is established via CT-RECIST criteria (Table 1) and at the same time CMR or PMR is established via FDG-PET (Table 2).
  • Response (RE) means one of the following four cases for combined CT and PET measurement: CR and CMR, PR and PMR, CR and PMR, and PR and CMR.
  • Non-Response SD or PD is established via CT-RECIST criteria (Table 1) and at the same time SMD or PMD is established via FDG-PET (Table 2).
  • CT-RECIST criteria Table 1
  • SMD or PMD is established via FDG-PET (Table 2).
  • FDG-PET FDG-PET
  • the response is determined at around 3 to 8 weeks, preferably at around 6 weeks, after treatment start. This response determination is usually repeated at intervals of 4 to 8 weeks, preferably of 6 to 8 weeks.
  • a relapse that means a Non-Response (RE) after the first determination
  • the term “patient who has failed prior therapy with an anti-VEGF antibody” refers to a patient, in whom either at the first response determination Non-Response (NR) is established (“Non-Responder”) or at the first response determination Response (RE) is established, and in the second or a subsequent response determination Non-Response (NR) is established (“Relapser”).
  • NR first response determination Non-Response
  • RE first response determination Response
  • Relapser a subsequent response determination Non-Response
  • metastatic tumor refers to the transmission of cancerous cells from the primary tumor to one or more sites elsewhere in a patient causing secondary tumors.
  • a tumor formed by cells that have spread is called a “metastatic tumor” or a “metastasis”.
  • the metastatic tumor contains cells that are like those in the original (primary) tumor.
  • Means to determine if a cancer has metastasized are known in the art and include tumor marker tests, bone scan, chest X-ray, computed tomography (CT), computerized axial tomography (CAT), molecular resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), fluorescence imaging (FI), and bioluminescent imaging (BLI) and tumor marker tests (see e.g. Helms, M. W., et al., Contributions to microbiology 13 (2006) 209-231, and Pantel, K., et al., J. Nat. Cancer Inst. 91 (1999) 1113-1124).
  • CT computed tomography
  • CAT computerized axial tomography
  • MRI molecular resonance imaging
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • FI fluorescence imaging
  • BBI bioluminescent imaging
  • the term “patient” preferably refers to a human in need of treatment to treat cancer, or a precancerous condition or lesion.
  • the term “patient” can also refer to non-human animals, preferably mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others, that are in need of treatment.
  • group refers to a group of patients as well as a sub-group of patients.
  • package insert refers to instructions customarily included in commercial packages of therapeutic products, which may include information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
  • the cancer may be, for example, lung cancer, non small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or urethra, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma
  • the precancerous condition or lesion includes, for example, the group consisting of oral leukoplakia, actinic keratosis (solar keratosis), precancerous polyps of the colon or rectum, gastric epithelial dysplasia, adenomatous dysplasia, hereditary nonpolyposis colon cancer syndrome (HNPCC), Barrett's esophagus, bladder dysplasia, and precancerous cervical conditions.
  • the cancer to be treated is a breast cancer disease.
  • the cancer is characterized by an overexpression of the HER2 receptor protein.
  • the invention provides a combined therapy method of treating a breast cancer disease, comprising administering to the patient a therapeutically effective amount of an anti-HER2 antibody and an anti-VEGF antibody wherein the breast cancer disease is characterized by an overexpression of the HER2 receptor protein. More specifically, the invention provides a method of treating a breast cancer disease in a patient who has failed prior therapy with an anti-VEGF antibody, comprising administering to the patient a therapeutically effective amount of an anti-HER2 antibody and an anti-VEGF antibody wherein preferably the anti-VEGF antibody is bevacizumab, the patient is human; the anti-HER2 antibody is trastuzumab, and wherein preferably the breast cancer disease is characterized by an overexpression of the HER2 receptor protein.
  • the invention further comprises a method of treating a breast cancer disease in a patient who has failed prior therapy with an anti-VEGF antibody, comprising administering to the patient a therapeutically effective amount of an anti-HER2 antibody while continuing said anti-VEGF antibody therapy.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing, either partially or completely, the growth of tumors, tumor metastases, or other cancer-causing or neoplastic cells in a patient.
  • treatment refers to the act of treating.
  • a method of treating when applied to, for example, cancer refers to a procedure or course of action that is designed to reduce or eliminate the number of cancer cells in a patient, or to alleviate the symptoms of a cancer.
  • a method of treating does not necessarily mean that the cancer cells or other disorder will, in fact, be eliminated, that the number of cells or disorder will, in fact, be reduced, or that the symptoms of a cancer or other disorder will, in fact, be alleviated.
  • a method of treating cancer will be performed even with a low likelihood of success, but which, given the medical history and estimated survival expectancy of a patient, is nevertheless deemed an overall beneficial course of action.
  • patient as used herein means a mammal, preferably a human.
  • terapéuticaally effective amount or “effective amount” means the amount of the subject compound or combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the invention further comprises the use of an anti-HER2 antibody and an anti-VEGF antibody for the manufacture of a medicament for treating a breast cancer disease in a patient who has failed prior therapy with an anti-VEGF antibody, comprising administering to the patient a therapeutically effective amount of an anti-HER2 antibody while continuing said anti-VEGF antibody therapy.
  • the antibodies may be administered separately or simultaneously.
  • method for manufacturing a medicament relates to the manufacturing of a medicament for use in the indication as specified herein and in particular for use in the treatment of tumors, tumor metastases, or cancer in general.
  • the term relates to the so-called “Swiss-type” claim format in the indication specified.
  • cytotoxic, chemotherapeutic or anti-cancer agents or compounds that enhance the effects of such agents may be used in the anti-VEGF antibody plus anti-HER2 antibody combination.
  • agents include, for example: alkylating agents or agents with an alkylating action, such as cyclophosphamide (CTX; e.g. cytoxan®), chlorambucil (CHL; e.g. leukeran®), cisplatin (CisP; e.g. platinol®) busulfan (e.g.
  • myleran® myleran®
  • melphalan carmustine (BCNU)
  • streptozotocin triethylenemelamine (TEM)
  • mitomycin C and the like
  • anti-metabolites such as methotrexate (MTX), etoposide (VP16; e.g. vepesid®), 6-mercaptopurine (6MP), 6-thiocguanine (6TG), cytarabine (Ara-C), 5-fluorouracil (5-FU), capecitabine (e.g. Xeloda®), dacarbazine (DTIC), and the like
  • antibiotics such as actinomycin D, doxorubicin (DXR; e.g.
  • adriamycin® daunorubicin (daunomycin), bleomycin, mithramycin and the like
  • alkaloids such as vinca alkaloids such as vincristine (VCR), vinblastine, and the like
  • antitumor agents such as paclitaxel (e.g. taxol®) and pactitaxel derivatives, the cytostatic agents, glucocorticoids such as dexamethasone (DEX; e.g.
  • decadron® and corticosteroids such as prednisone, nucleoside enzyme inhibitors such as hydroxyurea, amino acid depleting enzymes such as asparaginase, leucovorin and other folic acid derivatives, and similar, diverse antitumor agents.
  • the following agents may also be used as additional agents: arnifostine (e.g. ethyol®), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, lomustine (CCNU), doxorubicin lipo (e.g. doxil®), gemcitabine (e.g. gemzar®), daunorubicin lipo (e.g.
  • daunoxome® procarbazine, mitomycin, docetaxel (e.g. taxotere®), aldesleukin, carboplatin, oxaliplatin, cladribine, camptothecin, CPT 11 (irinotecan), 10-hydroxy 7-ethyl-camptothecin (SN38), floxuridine, fludarabine, ifosfamide, idarubicin, mesna, interferon beta, interferon alpha, mitoxantrone, topotecan, leuprolide, megestrol, melphalan, mercaptopurine, plicamycin, mitotane, pegaspargase, pentostatin, pipobroman, plicamycin, tamoxifen, teniposide, testolactone, thioguanine, thiotepa, uracil mustard, vinorelbine, chlorambucil.
  • taxotere® aldes
  • an anti-hormonal agent may be used in the anti-VEGF antibody plus anti-HER2 antibody combination.
  • anti-hormonal agent includes natural or synthetic organic or peptidic compounds that act to regulate or inhibit hormone action on tumors.
  • Antihormonal agents include, for example: steroid receptor antagonists, anti-estrogens such as tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, other aromatase inhibitors, 42-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (e.g.
  • anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above; agonists and/or antagonists of glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH) and LHRH (leuteinizing hormone-releasing hormone); the LHRH agonist goserelin acetate, commercially available as Zoladex® (AstraZeneca); the LHRH antagonist D-alaninamide N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-N6-(3-pyridinylcarbonyl)-L-lysyl-N6-(3-pyridinylcarbonyl)-L
  • cytotoxic and other anticancer agents described above in chemotherapeutic regimens is generally well characterized in the cancer therapy arts, and their use herein falls under the same considerations for monitoring tolerance and effectiveness and for controlling administration routes and dosages, with some adjustments.
  • the actual dosages of the cytotoxic agents may vary depending upon the patient's cultured cell response determined by using histoculture methods. Generally, the dosage will be reduced compared to the amount used in the absence of additional other agents.
  • Typical dosages of an effective cytotoxic agent can be in the ranges recommended by the manufacturer, and where indicated by in vitro responses or responses in animal models, can be reduced by up to about one order of magnitude concentration or amount.
  • the actual dosage will depend upon the judgment of the physician, the condition of the patient, and the effectiveness of the therapeutic method based on the in vitro responsiveness of the primary cultured malignant cells or histocultured tissue sample, or the responses observed in the appropriate animal models.
  • additional antiproliferative agents may be used in the anti-VEGF antibody plus anti-HER2 antibody combination, including, for example: Inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFR, including the compounds disclosed and claimed in U.S. Pat. Nos. 6,080,769; 6,194,438; 6,258,824; 6,586,447; 6,071,935; 6,495,564; 6,150,377; 6,596,735 and 6,479,513, and International Publication WO 01/40217.
  • an effective amount of ionizing radiation may be carried out and/or a radiopharmaceutical may be used in addition to the anti-VEGF antibody plus anti-HER2 antibody combination.
  • the source of radiation can be either external or internal to the patient being treated. When the source is external to the patient, the therapy is known as external beam radiation therapy (EBRT). When the source of radiation is internal to the patient, the treatment is called brachytherapy (BT).
  • EBRT external beam radiation therapy
  • BT brachytherapy
  • Radioactive atoms for use in the context of this invention can be selected from the group including, but not limited to, radium, cesium-137, iridium-192, americium-241, gold-198, cobalt-57, copper-67, technetium-99, iodine-123, iodine-131, and indium-111.
  • the EGFR kinase inhibitor according to this invention is an antibody, it is also possible to label the antibody with such radioactive isotopes.
  • Radiation therapy is a standard treatment for controlling unresectable or inoperable tumors and/or tumor metastases. Improved results have been seen when radiation therapy has been combined with chemotherapy. Radiation therapy is based on the principle that high-dose radiation delivered to a target area will result in the death of reproductive cells in both tumor and normal tissues.
  • the radiation dosage regimen is generally defined in terms of radiation absorbed dose (Gy), time and fractionation, and must be carefully defined by the oncologist.
  • the amount of radiation a patient receives will depend on various considerations, but the two most important are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread.
  • a typical course of treatment for a patient undergoing radiation therapy will be a treatment schedule over a 1 to 6 week period, with a total dose of between 10 and 80 Gy administered to the patient in a single daily fraction of about 1.8 to 2.0 Gy, 5 days a week.
  • the inhibition of tumor growth by means of the agents comprising the combination of the invention is enhanced when combined with radiation, optionally with additional chemotherapeutic or anticancer agents.
  • Parameters of adjuvant radiation therapies are, for example, contained in International Publication WO 99/60023.
  • the antibodies are administered to a patient according to known methods, by intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, or intrathecal routes. Intravenous or subcutaneous administration of the antibodies is preferred.
  • the amount of anti-VEGF and anti-HER2 antibody administration and the timing of administration will depend on the type (species, gender, age, weight, etc.) and condition of the patient being treated and the severity of the disease or condition being treated.
  • Dosages for administration of the antibodies according to the invention are about 1 ⁇ g/kg to 50 mg/kg (e.g. 0.1-20 mg/kg) of antibody by one or more separate administrations, or by continuous infusion.
  • a typical daily dosage might range from about 1 ⁇ g/kg to about 100 mg/kg.
  • the antibodies are administered every two to three weeks, at a dose ranged from about 1 mg/kg to about 15 mg/kg.
  • a preferred dose for bevacizumab is 5 mg/kg once every 14 days as an IV infusion until disease progression is detected.
  • a preferred dose for trastuzumab is a loading dose of 4 mg/kg administered over a 90-minute period and subsequent weekly infusions of 2 mg/kg administered over a 30-minute period.
  • the present invention further provides a kit (pharmaceutical kit) comprising an anti-VEGF antibody (preferably a pharmaceutical composition thereof), an anti-HE2 antibody (preferably a pharmaceutical composition thereof) and a package insert instructing the user of said compositions to administer to a patient, having breast cancer disease who has failed prior therapy with an anti-VEGF antibody, the anti-VEGF antibody, preferably within pharmaceutical composition and the anti-HER2 antibody, preferably within a pharmaceutical composition.
  • the kit containers may further include a pharmaceutically acceptable carrier.
  • the kit may further include a sterile diluent, which is preferably stored in a separate additional container.
  • the kit may further include a package insert comprising printed instructions directing the use of the combined treatment as a method for a breast cancer disease.
  • the pharmaceutical kit will include a first container storing a pharmaceutical composition comprising an anti-VEGF antibody and a second container storing a pharmaceutical composition comprising an anti-HER2 antibody.
  • the present invention also provides a pharmaceutical kit comprising a pharmaceutical composition comprising an anti-VEGF antibody, a pharmaceutical composition comprising an anti-HE2 antibody, and a package insert instructing the user of said compositions to administer to a patient having breast cancer disease, who has failed prior therapy with an anti-VEGF antibody, said anti-VEGF antibody pharmaceutical composition and an anti-HER2 antibody pharmaceutical composition, wherein the anti-VEGF antibody pharmaceutical composition and the anti-HER2 antibody pharmaceutical composition are packaged either in a single container or in two separate containers.
  • the present invention further provides a pharmaceutical composition, in particular for use in treating a breast cancer disease that has failed prior therapy with anti-VEGF antibody, comprising an anti-HER2 antibody and an anti-VEGF antibody.
  • a pharmaceutical composition optionally comprises pharmaceutically acceptable carriers and/or excipients, such as those commonly known to one of ordinary skill in the art.
  • the anti-VEGF antibody is bevacizumab and the anti-HER2 antibody is trastuzumab.
  • the present invention also provides a pharmaceutical kit comprising said pharmaceutical composition comprising said anti-HER2 antibody and said anti-VEGF antibody.
  • the current study examined the antitumor activity of the combination of bevacizumab and trastuzumab after the failure of bevacizumab treatment alone in human breast xenograft model. Further aims of the study were to examine the effects of treatment on metastasis.
  • Trastuzumab was provided as a 25 mg/ml stock solution in Histidine-HCl, alpha-alpha Trehalose (60 mM), 0.01% Polysorb, pH 6.0 (Herceptin®). Bevacizumab was provided as a 25 mg/ml stock solution in Na-phosphate, alpha-alpha Trehalose (60 mM), 0.01% Polysorb, pH 6.0 (Avastin®). Both solutions were diluted appropriately in PBS for injections.
  • the human breast cancer cell line KPL-4 has been established from the malignant pleural effusion of a breast cancer patient with an inflammatory skin metastasis and overexpresses ErbB family receptors.
  • Tumor cells are routinely cultured in DMEM medium (PAA Laboratories, Austria) supplemented with 10% fetal bovine serum (PAA) and 2 mM L-glutamine (Gibco) at 37° C. in a water-saturated atmosphere at 5% CO2. Culture passage is performed with trypsin/EDTA 1 ⁇ (PAA) splitting twice/week. Cell passage P6 was used for in vivo study.
  • SCID beige mice C.B.-17 mice; age 10-12 weeks; body weight 18-20 g (Charles River, Sulzfeld, Germany) are maintained under specific-pathogen-free condition with daily cycles of 12 h light/12 h darkness according to international guidelines (GV-Solas; Felasa; TierschG).
  • GV-Solas Felasa
  • TierschG international guidelines
  • animals are housed in the quarantine part of the animal facility for one week to get accustomed to new environment and for observation. Continuous health monitoring is carried out on regular basis. Diet food (Alltromin) and water (acidified pH 2.5-3) are provided ad libitum.
  • Tumor cells were harvested (trypsin-EDTA) from culture flasks (Greiner TriFlask) and transferred into 50 ml culture medium, washed once and resuspended in PBS. After an additional washing step with PBS and filtration (cell strainer; Falcon 100 ⁇ m) the final cell titer was adjusted to 0.75 ⁇ 10 8 /ml. Tumor cell suspension was carefully mixed with transfer pipette to avoid cell aggregation. Anesthesia was performed using a Stephens inhalation unit for small animals with preincubation chamber (plexiglas), individual mouse nose-mask (silicon) and Isoflurane (Pharmacia-Upjohn, Germany) in a closed circulation system.
  • Vehicle group (group 1) received 10 ml/kg PBS buffer intraperitoneally (i.p.) once weekly.
  • Trastuzumab (group 2) was administered i.p. at a loading dose of 30 mg/kg, followed by once weekly doses of 15 mg/kg (maintenance dose).
  • the anti-VEGF antibody bevacizumab was given i.p. at a dosage of 5 mg/kg twice weekly (group 3).
  • treatment for group 3 was switched to a combination treatment of bevacizumab (5 mg/kg twice weekly i.p.) with trastuzumab (15 mg/kg once weekly i.p.).
  • Metastasis was measured according to Schneider, T., et al., Clin. Exp. Metastasis 19 (2002) 571-582. Briefly, lung tissue was harvested and human Alu sequences were quantified by real-time PCR. Higher human DNA levels, quantified by real-time PCR, correspond to higher levels of metastasis.
  • FIG. 1 and Table 3 The effect of treatment on primary tumor growth is shown in FIG. 1 and Table 3.
  • Tumors in the vehicle group (group 1) grew rapidly and mice were sacrificed 38 days after injection of tumor cells because of ulceration of tumors and the development of clinical symptoms.
  • Monotherapy with trastuzumab (group 2) exerted no significant effect on tumor volume and mice were therefore sacrificed at day 44.
  • Treatment with bevacizumab suppressed tumor growth significantly; however, tumors started to regrow around day 44.
  • Combination treatment of bevacizumab and trastuzumab beginning at day 55 resulted in complete inhibition of tumor growth during the duration of the experiment (day 99) and treatment was well tolerated.

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