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WO2015153866A1 - Thérapie anticancéreuse basée sur le ganetespib et un inhibiteur de l'egfr - Google Patents

Thérapie anticancéreuse basée sur le ganetespib et un inhibiteur de l'egfr Download PDF

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Publication number
WO2015153866A1
WO2015153866A1 PCT/US2015/024051 US2015024051W WO2015153866A1 WO 2015153866 A1 WO2015153866 A1 WO 2015153866A1 US 2015024051 W US2015024051 W US 2015024051W WO 2015153866 A1 WO2015153866 A1 WO 2015153866A1
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cancer
egfr
ganetespib
subject
small cell
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PCT/US2015/024051
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English (en)
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David Proia
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Synta Pharmaceuticals Corp.
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • HSPs Heat shock proteins
  • HSPs are a class of chaperone proteins that are up-regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins), facilitate their proper folding and repair and aid in the refolding of misfolded client proteins.
  • client proteins There are several known families of HSPs, each having its own set of client proteins.
  • the Hsp90 family is one of the most abundant HSP families accounting for about 1-2% of proteins in a cell that is not under stress and increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in the degradation of its client proteins via the ubiquitin proteasome pathway.
  • the client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer.
  • Ganetespib and EGFR inhibitor combinations are found to be effective at treating subjects with certain type of cancer without further increasing the side effect profile of the single agents.
  • the particular combination therapies disclosed herein demonstrate surprising biological activity by demonstrating significant anticancer effects.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab, wherein the cancer has wild-type EGFR.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of erlotinib wherein the cancer has wild-type EGFR.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of afatinib wherein the cancer has wild-type EGFR.
  • methods of treating cancer with an EGFR mutation in a subject wherein the cancer was previously treated with a therapeutic agent includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of erlotinib wherein the cancer has an EGFR mutation.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of afatinib wherein the cancer has an EGFR mutation.
  • the method of treating cancer with wild-type EGFR in a subject wherein the cancer was previously treated with a therapeutic agent includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of erlotinib wherein the cancer has an EGFR mutation.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of afatinib wherein the cancer has an EGFR mutation.
  • the method of treating cancer with an EGFR mutation in a subject wherein the cancer was previously treated with a therapeutic agent and becomes refractory/resistant to further treatment includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of erlotinib wherein the cancer has an EGFR mutation
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of afatinib wherein the cancer has an EGFR mutation.
  • the method includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of erlotinib wherein the cancer has an EGFR mutation.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of afatinib wherein the cancer has an EGFR mutation.
  • the method of treating cancer with an EGFR mutation in a subject wherein the cancer has proven refractory/resistant to the treatment of an EGFR inhibitor includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of erlotinib wherein the cancer has an EGFR mutation.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of afatinib wherein the cancer has an EGFR mutation.
  • the method of treating cancer with wild-type EGFR in a subject wherein the cancer has proven refractory/resistant to the treatment of an EGFR inhibitor includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of erlotinib wherein the cancer has an EGFR mutation.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of afatinib wherein the cancer has an EGFR mutation.
  • the administration of ganetespib and the EGFR inhibitor are done concurrently. In another aspect, the administration of ganetespib and the EGFR inhibitor are done sequentially. In another aspect, the administration of ganetespib and the EGFR inhibitor are dosed independently. In any one of these embodiments, the EGFR inhibitor may be erlotinib, afatinib, gefitinib or cetuximab.
  • the method includes use of ganetespib for the manufacture of a medicament for treating cancer in combination with an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the method includes use of ganetespib for the manufacture of a medicament for treating cancer in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab, wherein the cancer has an EGFR mutation.
  • the method includes use of ganetespib for the manufacture of a medicament for treating cancer in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab, wherein the cancer has wild-type EGFR.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab, wherein the cancer has wild-type EGFR.
  • the treatment utilizes ganetespib with an EGFR inhibitor to help arrest, partially or fully, or reduce the development of multidrug resistant cancerous cells in a subject.
  • the combinations described herein may allow a reduced efficacious amount of the EGFR inhibitor given to a subject, because ganetespib should inhibit the development of multidrug-resistant cancerous cells.
  • the EGFR inhibitor may be erlotinib, afatinib, gefitinib or cetuximab.
  • the EGFR inhibitor may be erlotinib.
  • the EGFR inhibitor may be afatinib.
  • Figure 1 is a graph showing average tumor volume change over time following NCI-HCC827 tumor implantation in mice. Mice bearing NCI-HCC827 tumors, were i.v. administered ganetespib or p.o. dosed with erlotinib each at 50 mg/kg on a weekly dosing regimen, either alone or in combination. Data are expressed as mean and SEM for each time point. Numerical T/C values are indicated to the right of each growth curve.
  • Figure 2 is a graph showing average body weight change over time after tumor implantation as described in Figure 1. The body weights were measured 5 times per week for the first 2 weeks of dosing, and twice per week thereafter. Mean values are plotted against vehicle controls.
  • Figure 3 shows the western blotting of cell lysates from NCTH1975 cells incubated with the indicated concentrations of ganetespib for 24 h.
  • Figure 4 is a graph showing average tumor volume change over time following NCTH1975 NSCLC tumor implantation in mice. Mice bearing NCTH1975 tumors were i.v. administered ganetespib at 50 mg/kg or p.o. dosed with erlotinib at 200 mg/kg on a weekly dosing regimen, either alone or in combination. Data are expressed as mean and SEM for each time point. Numerical T/C values are indicated to the right of each growth curve.
  • Figure 5 is a graph showing average tumor volume change over time following NCTH1975 NSCLC tumor implantation in mice. Mice bearing NCTH1975 tumors were i.v. dosed with ganetespib at 50 mg/kg once weekly and afatinib administered p.o. five times/week at 5 mg/kg, either alone or in combination.
  • Figure 6 is a graph showing average tumor volume change over time following NCTH1975 NSCLC tumor implantation in mice. Mice bearing NCI-H1975 tumors were i.v. dosed with ganetespib at 50 mg/kg once weekly and afatinib administered p.o. five times/week at 20 mg/kg, either alone or in combination.
  • Figure 7 shows the western blotting of cell lysates from NCI-H1666 cells incubated with the indicated concentrations of ganetespib for 24 h.
  • Figure 8 shows the western blotting of cell lysates from NCI-H1666 cells treated with 100 nM ganetespib for the indicated time periods.
  • Figure 9 is a graph showing the average tumor volume change over time following NCI-H1666 tumor implantation in mice.
  • the mice bearing NCI-H1666 tumors were i.v. administered ganetespib at 150 mg/kg on a weekly dosing regimen for 3 weeks. Data are expressed as mean and SEM for each time point. Numerical T/C values are indicated to the right of each growth curve.
  • Figure 10 shows the western blotting of cell lysates from NCI-H322 cells incubated with the graded concentrations of erlotinib for 24 h, with or without 500 nM ganetespib.
  • Figure 11 is a graph showing the average tumor volume change over time following NCI-H322 tumor implantation in mice. The mice bearing NCI-H322 tumors were i.v. dosed with ganetespib at 50 mg/kg once weekly and erlotinib administered p.o. five times/week at 25 mg/kg, either alone or in combination. Numerical T/C values are indicated to the right of each growth curve and the errors bars are the SEM.
  • Figure 12 is a graph showing average body weight change over time following NCTH1975 tumor implantation in mice. Body weights were measured 5 times per week. Mean values are plotted against vehicle controls.
  • Figure 13 shows the western blotting of cell lysates from WT-EGFR H292 cells following erlotinib and ganetespib treatment. NCTH292 cells were incubated with graded concentrations of erlotinib for 24 h, with or without 200 nM ganetespib.
  • composition that "substantially" comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about 90% by weight, even more preferably more than about 95% by weight, and most preferably more than about 97% by weight of the compound.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a disease or disorder, delay of the onset of a disease or disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a disease or disorder, resulting from the administration of one or more therapies (e.g. , one or more therapeutic agents such as a compound of the invention).
  • the terms “treat”, “treatment” and “treating” also encompass the reduction of the risk of developing a disease or disorder, and the delay or inhibition of the recurrence of a disease or disorder.
  • the disease or disorder being treated is a
  • the terms “treat”, “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a disease or disorder, such as growth of a tumor, not necessarily discernible by the patient.
  • the terms “treat”, “treatment” and “treating” refer to the inhibition of the progression of a disease or disorder, e.g., a proliferative disorder, either physically by the stabilization of a discernible symptom, physiologically by the stabilization of a physical parameter, or both.
  • the terms “treat”, “treatment” and “treating” of a proliferative disease or disorder refers to the reduction or stabilization of tumor size or cancerous cell count, and/or delay of tumor formation.
  • the terms “treat”, “treating” and “treatment” also encompass the administration of a compound described herein as a prophylactic measure to patients with a predisposition (genetic or environmental) to any disease or disorder described herein.
  • cancer or "tumor” are well known in the art and refer to the presence, e.g., in a subject, of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, decreased cell death/apoptosis, and certain characteristic morphological features.
  • subject e.g., a bird such as a chicken, quail or turkey, or a mammal
  • non-primate e.g.
  • the subject is a non-human animal such as a farm animal (e.g. , a horse, cow, pig or sheep), or a pet (e.g. , a dog, cat, guinea pig or rabbit).
  • the subject is a human.
  • Hsp90 includes each member of the family of heat shock proteins having a mass of about 90-kiloDaltons.
  • the highly conserved Hsp90 family includes the cytosolic Hsp90a and Hsp90P isoforms, as well as GRP94, which is found in the endoplasmic reticulum, and HSP75/TRAP1, which is found in the mitochondrial matrix.
  • Hsp90 plays an essential role in regulating the functional stability and maturation of numerous key signal transduction proteins, termed 'client' proteins.
  • a number of sensitive Hsp90 clients have been implicated in the pathogenesis of NSCLC, including EGFR, anaplastic lymphoma kinase (ALK), and intermediates of oncogenic signaling cascades such as RAF and AKT.
  • the chaperone activity of Hsp90 is commonly exploited by cancer cells to facilitate multiple aspects of the tumorigenic process, including aberrant survival, oncogene addiction, and metastatic potential. Because inhibition of Hsp90 activity targets its clients for proteasomal destruction, pharmacological blockade of the chaperone provides a mechanism to
  • this unique characteristic also serves as a means to overcome signaling redundancies and drug resistance mechanisms observed in many cancers.
  • Ganetespib is a potent, resorcinol-based small molecule inhibitor of Hsp90 that exhibits robust preclinical activity against a range of cancer models, including NSCLC.
  • ganetespib can potentiate the effects of other molecularly targeted and chemotherapeutic agents while simultaneously counteracting both intrinsic and acquired drug resistance in a variety of tumor models.
  • a maturing clinical profile has revealed evidence of therapeutic efficacy in NSCLC, most notably as a single agent in ALK-driven disease and as part of combination therapy with docetaxel in advanced adenocarcinoma patients.
  • Epidermal growth factor receptor or "EGFR”, as used herein, means any epidermal growth factor receptor (EGFR) protein, peptide, or polypeptide having EGFR or EGFR family activity (e.g., Herl, Her2, Her3 and/or Her4), such as encoded by EGFR Genbank Accession Nos. shown in Table I of U.S. Patent Application No. 10/923,354, filed on August 20, 2004, or any other EGFR transcript derived from a EGFR gene and/or generated by EGFR translocation.
  • EGFR epidermal growth factor receptor
  • EGFR is also meant to include other EGFR protein, peptide, or polypeptide derived from EGFR isoforms (e.g., Herl, Her2, Her3 and/or Her4), mutant EGFR genes, splice variants of EGFR genes, and EGFR gene polymorphisms.
  • EGFR is a member of the type 1 subgroup of receptor tyrosine kinase family of growth factor receptors which play critical roles in cellular growth, differentiation and survival. Activation of these receptors typically occurs via specific ligand binding which results in hetero- or homodimerization between receptor family members, with subsequent autophosphorylation of the tyrosine kinase domain.
  • Specific ligands which bind to EGFR include epidermal growth factor (EGF), transforming growth factor a (TGFa), amphiregulin and some viral growth factors.
  • EGFR activation stimulates a variety of intracellular signaling cascades, including the JAK/STAT, RAS/RAF/ERK, and PI3K/AKT pathways.
  • EGFR activity may become dysregulated through a number of mechanisms, including activating mutations, amplification of gene copy number, and/or receptor overexpression.
  • EGFR overexpression is a feature of NSCLC tumors, particularly in patients with metastatic disease, and is correlated with poor prognosis.
  • Gefitinib and erlotinib, both small-molecule EGFR tyrosine kinase inhibitors (TKIs) were the first molecularly targeted agents used in the treatment of advanced NSCLC.
  • EGFR Aberrant or overexpression of EGFR has been associated with an adverse prognosis in a number of human cancers, including cancers of the head and neck, breast, colon, prostate, lung (e.g., NSCLC, adenocarcinoma and squamous lung cancer), ovaries, gastrointestinal tract (gastric, colon, pancreatic), kidneys, bladder, central nervous system (e.g., glioma), prostate, and gynecological carcinomas.
  • overexpression of tumor EGFR has been correlated with both chemoresistance and a poor prognosis (Lei, et al., Anticancer Res. (1999), 19:221-8; Veale, et al., Br. J. Cancer (1993); 68: 162-5.
  • EGFR is a validated therapeutic target in NSCLC, with three small molecule TKIs (erlotinib, gefitinib, and afatinib) currently approved for the treatment of advanced disease. All of these agents show preferential clinical efficacy in NSCLC patients whose tumors harbor activating EGFR mutations. Mutant EGFR oncoproteins are particularly reliant on the chaperone activity of Hsp90 for their conformational stability and function. Thus, pharmacological blockade of Hsp90, leading to the degradation and loss of mutant EGFR protein, is considered a rational and alternative strategy to TKI inhibition for treating tumors driven by such genetic modifications.
  • EGFR associated cancer refers to a cancer which has aberrant expression and/or activation of EGFR.
  • EGFR associated cancers include head and neck, breast, colon, prostate, lung (e.g., NSCLC, adenocarcinoma and squamous lung cancer), ovaries, gastrointestinal cancers (gastric, colon, pancreatic), renal cell cancer, bladder cancer, glioma, gynecological carcinomas, and prostate cancer.
  • Gliomas are another type of cancer characterized by the amplification and/or mutation of the EGFR gene.
  • EGFRvIII is a deletion of exons 2-7 which results in a truncated form of EGFR in which amino acids 6-273 of the extracellular domain are replaced with a single glycine residue. This mutation is called EGFRvIII, and is expressed in about half of all glioblastomas. EGFRvIII is unable to bind EGF and TGFa and has constitutive, ligand-independent tyrosine kinase activity. Hsp90 co- purifies with EGFRvIII, indicating that Hsp90 complexes with EGFRvIII.
  • Hsp90 inhibitor geldanamycin a benzoquinone ansamycin antibiotic
  • geldanamycin a benzoquinone ansamycin antibiotic
  • Hsp90 is able to decrease the expression of EGFRvIII, indicating that interaction with Hsp90 is essential to maintain high expression levels of EGFRvIII.
  • a "subject with a mutation" in EGFR or a “subject with a cancer with a mutation” in EGFR, and the like, are understood as a subject having cancer, wherein the tumor has at least one alteration (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, or more) in the indicated gene from the wild-type sequence in the gene and/or transcriptional, translational, and/or splicing control regions of the gene that result in the cell becoming cancerous, e.g., developing characteristics such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, decreased cell death/apoptosis, and certain characteristic morphological features.
  • alteration e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, or more
  • Mutations include, for example, insertions, deletions, truncations, point mutations, and translocations. Mutations within a gene product can result in constituent activation of the gene product. Mutations that include alterations in transcriptional, translational, or splicing control regions can result in aberrant expression, typically over-expression, of a wild-type gene product. It is understood that not all gene mutations, even in oncogenes, result in a cell becoming cancerous. Mutations that result in oncogenesis are well known in the art. Methods to test mutations for oncogenic activity are well known in the art.
  • a subject with a "wild-type” EGFR, or a “subject with a cancer with a wild-type” EGFR, and the like are understood as a subject suffering from cancer, wherein the tumor does not have any significant alterations (i.e., alterations that result in a change of function) in the indicated gene from the native sequence in the gene and/or transcriptional, translational, and/or splicing control regions of the native gene that result in the cell becoming cancerous, e.g., developing characteristics such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, decreased cell death/apoptosis, and certain characteristic morphological features.
  • a wild-type" gene is expressed at a level that does not result in the cell becoming cancerous.
  • a mutation can be detected using any of a number of known methods in the art.
  • the specific method to detect the mutation will depend, for example, on the type of mutation to be detected. For example, alterations in nucleic acid sequences can be easily detected using polymerase chain reaction and fluorescence in situ hybridization methods (FISH). Protein expression levels can be detected, for example, using immunohistochemistry. An aberrant expression level of a wild-type protein can be used as a surrogate for detection of a mutation in a transcriptional, translational, and/or splicing control regions of the gene without direct detection of the specific genetic change in the nucleic acid in the subject sample.
  • the specific method of detection of the mutation is not a limitation of the invention. Methods to compare protein expression levels to appropriate controls are well known in the art.
  • Mutations or protein expression levels are preferably detected in a subject sample from the cancer tissue or tumor tissue, e.g., cells, extracellular matrix, and other naturally occurring components associated with the tumor.
  • the mutation or expression level can be detected in a biopsy sample or in a surgical sample after resection of the tumor.
  • sample refers to a collection of similar fluids, cells, or tissues isolated from a subject.
  • sample includes any body fluid (e.g., urine, serum, blood fluids, lymph, gynecological fluids, cystic fluid, ascetic fluid, ocular fluids, and fluids collected by bronchial lavage and/or peritoneal rinsing), ascites, tissue samples (e.g., tumor samples) or a cell from a subject.
  • Other subject samples include tear drops, serum, cerebrospinal fluid, feces, sputum, and cell extracts.
  • the sample is removed from the subject.
  • the sample is urine or serum.
  • the sample comprises cells.
  • the sample does not comprise cells.
  • the sample can be the portion of the subject that is imaged. Samples are typically removed from the subject prior to analysis; however, tumor samples can be analyzed in the subject, for example, using imaging or other detection methods.
  • identify or “select” refer to a choice in preference to another.
  • identify a subject or select a subject is to perform the active step of picking out that particular subject from a group and confirming the identity of the subject by name or other distinguishing feature.
  • identifying a subject or selecting a subject as having one or more mutations in one or more genes of interest, having a wild-type gene, or having a change in the expression level of a protein can include any of a number of acts including, but not limited to, performing a test and observing a result that is indicative of a subject having a specific mutation; reviewing a test result of a subject and identifying the subject as having a specific mutation; reviewing documentation on a subject stating that the subject has a specific mutation and identifying the subject as the one discussed in the documentation by confirming the identity of the subject e.g., by an identification card, hospital bracelet, asking the subject for his/her name and/ or other personal information to confirm the subjects identity.
  • refractory cancer or tumor is understood as a malignancy which is either initially unresponsive to chemo- or radiation therapy, or which becomes unresponsive over time.
  • a cancer refractory to one intervention may not be refractory to all interventions.
  • a refractory cancer is typically not amenable to treatment with surgical interventions.
  • relapse is understood as the return of a cancer or the signs and symptoms of a cancer after a period of improvement.
  • An "EGFR inhibitor”, as used herein, includes any compound that disrupts EGFR production within a cell. Activation of EGFR leads to the Ras signaling cascade that results in uncontrolled cell proliferation.
  • EGFR inhibitors include monoclonal antibodies that bind EGFR to inactivate it, and compounds that bind to the tyrosine kinase domain of EGFR to inhibit it.
  • EGFR inhibitors include drugs such as erlotinib, afatinib, gefitinib, and cetuximab. Particularly, erlotinib is described in US Patent Nos. 5,747,498, 6,900,221, 7,087,613, and RE41065.
  • EGFR inhibitors employed herein may also be called other names such as Tarceva ® , Iressa ® , and Erbitux ® , which are all well-known anti-cancer drugs. A more detailed description of some of these drugs is presented below.
  • Gefitinib (CAS No. 184475-35-2), a chemotherapeutic agent that inhibits the activity of EGFR, has been found to be highly efficacious in a subset of lung cancer patients that have mutations in the tyrosine kinase domain of EGFR. In the presence of EGF, these mutants displayed two to three times higher activity than wild-type EGFR. In addition, wild- type EGFR was internalized by the cells and down-regulated after 15 minutes, whereas mutant EGFR was internalized more slowly and continued to be activated for up to three hours. Lynch, et al., New Eng. J. Med. (2006), 550:2129-2139.
  • erlotinib Another chemotherapeutic agent that inhibits EGFR is erlotinib (Tarceva , CAS No. 183321-74-6). Erlotinib is approved for advanced unresectable or metastatic pancreatic cancer and metastatic non-small cell lung cancer. In addition to being a potent EGFR inhibitor, erlotinib also potently inhibits the JAK2 mutant JAK2V617F, which is found in many myeloproliferative disorders, such as polycythemia vera.
  • afatinib (CAS No. 439081-18-2, also called Gilotrif ® or Giotrif®) that inhibits EGFR.
  • Afatinib is approved in much of the world (including the United States, Canada, the United Kingdom and Australia) for the treatment of metastatic non-small cell lung carcinoma (NSCLC), although there is emerging evidence to support its use in other cancers such as breast cancer.
  • Suitable bases include hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2- hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N, N,
  • a pharmaceutically acceptable salt can also be formed by reacting the amine functional groups and a pharmaceutically acceptable inorganic or organic acid.
  • Suitable acids include hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HC1), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, isonicotinic acid, oleic acid, tannic acid, pantothenic acid, saccharic acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, palmoic acid and p- toluenesulfonic acid.
  • a pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compound(s).
  • the pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic and devoid of other undesired reactions upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed, such as those described in
  • Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate, and the like.
  • Methods for encapsulating compositions, such as in a coating of hard gelatin or cyclodextran, are known in the art. See BAKER, ETAL., CONTROLLED RELEASE OF BIOLOGICAL ACTIVE AGENTS, (John Wiley and Sons, 1986).
  • the term "effective amount” refers to an amount of a compound described herein which is sufficient to reduce or ameliorate the severity, duration, progression, or onset of a disease or disorder, delay onset of a disease or disorder, retard or halt the advancement of a disease or disorder, cause the regression of a disease or disorder, prevent or delay the recurrence, development, onset or progression of a symptom associated with a disease or disorder, or enhance or improve the therapeutic effect(s) of another therapy.
  • the disease or disorder is a proliferative disorder.
  • the precise amount of compound administered to a subject will depend on the mode of administration, the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. For example, for a proliferative disease or disorder, determination of an effective amount will also depend on the degree, severity and type of cell proliferation. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • an "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used.
  • Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the invention being used. In cases where no amount is expressly noted, an effective amount should be assumed. Non-limiting examples of an effective amount of a compound described herein are provided herein below.
  • the invention provides a method of treating, managing, or ameliorating a disease or disorder, e.g. a proliferative disorder, or one or more symptoms thereof, said method comprising
  • a dose of the Hsp90 inhibitor at least 150 ⁇ g/kg, at least 250 ⁇ g/kg, at least 500 ⁇ g/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds described herein once every day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
  • the dosage of an individual EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab, used in combination therapy may be equal to or lower than the dose of an individual therapeutic agent when given independently to treat, manage, or ameliorate a disease or disorder, or one or more symptoms thereof.
  • the disease or disorder being treated with a combination therapy is a proliferative disorder.
  • the proliferative disorder is cancer.
  • the recommended dosages of therapeutic agents currently used for the treatment, management, or amelioration of a disease or disorder, or one or more symptoms thereof, can obtained from any reference in the art. See, e.g.,
  • the terms "therapeutic agent” and “therapeutic agents” refer to any agent(s) that can be used in the treatment of a disease or disorder, e.g. a proliferative disorder, or one or more symptoms thereof.
  • the term “therapeutic agent” refers to a compound described herein.
  • a therapeutic agent does not refer to a compound described herein.
  • a therapeutic agent is an agent that is known to be useful for, or has been or is currently being used for the treatment of a disease or disorder, e.g., a proliferative disorder, or one or more symptoms thereof.
  • the term "synergistic” refers to a combination of a compound described herein and another therapeutic agent, which, when taken together, is more effective than the additive effects of the individual therapies.
  • a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapeutic agent(s) and/or less frequent administration of said agent(s) to a subject with a disease or disorder, e.g., a proliferative disorder.
  • a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a disease or disorder, e.g. a proliferative disorder.
  • a synergistic effect of a combination of therapies may avoid or reduce adverse or unwanted side effects associated with the use of either therapeutic agent alone.
  • side effects encompasses unwanted and adverse effects of a therapeutic agent. Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapeutic agent might be harmful or uncomfortable or risky to a subject. Side effects include fever, chills, lethargy,
  • gastrointestinal toxicities including gastric and intestinal ulcerations and erosions
  • the term "in combination” refers to the use of more than one therapeutic agent.
  • a first therapeutic agent such as a compound described herein, can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g.
  • the Hsp90 inhibitor and the EGFR inhibitor are dosed on independent schedules. In another embodiment, the Hsp90 inhibitor and the EGFR inhibitor are dosed on approximately the same schedule. In another embodiment, the Hsp90 inhibitor and the EGFR inhibitor are dosed concurrently or sequentially on the same day.
  • therapies can refer to any protocol(s), method(s), and/or agent(s) that can be used in the prevention, treatment, management, or amelioration of a disease or disorder, e.g., a proliferative disorder, or one or more symptoms thereof.
  • a disease or disorder e.g., a proliferative disorder, or one or more symptoms thereof.
  • a used herein, a "protocol” includes dosing schedules and dosing regimens.
  • the protocols herein are methods of use and include therapeutic protocols.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • the present method utilizes ganetespib, in combination with an EGFR inhibitor, for treating certain types of cancer.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of an EGFR inhibitor.
  • the method includes the step of administering to a subject with cancer an effective amount of ganetespib and an effective amount of an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab, wherein the cancer has an EGFR mutation.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the present method includes treating, managing, or
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the present method includes treating, managing, or ameliorating cancer, or one or more symptoms thereof, comprising administering to a subject in need thereof an effective amount of ganetespib, in combination with afatinib, wherein the cancer has an EGFR mutation.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the present method includes treating, managing, or ameliorating cancer, or one or more symptoms thereof, comprising administering to a subject in need thereof an effective amount of ganetespib, in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab, wherein the cancer has wild-type EGFR.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab, wherein the cancer has wild-type EGFR.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non-small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non-small cell lung cancer.
  • the present method includes treating, managing, or ameliorating cancer, or one or more symptoms thereof, comprising administering to a subject in need thereof an effective amount of ganetespib, in combination with erlotinib, wherein the cancer has wild-type EGFR.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the present method includes treating, managing, or ameliorating cancer, or one or more symptoms thereof, comprising administering to a subject in need thereof an effective amount of ganetespib, in combination with afatinib, wherein the cancer has wild-type EGFR.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject wherein the subject is being or has been treated with a chemotherapeutic agent includes administering to the subject an effective amount of ganetespib, in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • pancreatic cancer ovarian cancer
  • gastrointestinal cancer gastrointestinal cancer
  • prostate cancer small cell lung carcinoma
  • stomach cancer cervical cancer
  • gastric cancer rectal cancer
  • kidney cancer liver cancer
  • gallbladder cancer gallbladder cancer
  • transitional cell carcinoma squamous cell carcinoma
  • melanoma glioblasto
  • the cancer is preferably non-small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non- small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject, wherein the subject is being or has been treated with a chemotherapeutic agent includes administering to the subject an effective amount of ganetespib, in combination with erlotinib.
  • the cancer may be non- small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject wherein the subject is being or has been treated with a chemotherapeutic agent includes administering to the subject an effective amount of ganetespib, in combination with afatinib.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject wherein the subject is being or has been treated with a chemotherapeutic agent includes administering to the subject an effective amount of ganetespib, in combination with an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • pancreatic cancer ovarian cancer
  • gastrointestinal cancer gastrointestinal cancer
  • prostate cancer small cell lung carcinoma
  • stomach cancer cervical cancer
  • gastric cancer rectal cancer
  • kidney cancer liver cancer
  • gallbladder cancer gallbladder cancer
  • transitional cell carcinoma squamous cell carcinoma
  • melanoma glioblasto
  • the cancer is preferably non-small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non- small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject with cancer, wherein the subject is being or has been treated with a chemotherapeutic agent includes administering to the subject an effective amount of ganetespib, in combination with erlotinib.
  • the cancer may be non- small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject wherein the subject is being or has been treated with a chemotherapeutic agent includes administering to the subject an effective amount of ganetespib, in combination with afatinib.
  • the cancer may be non- small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non-small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject wherein the subject has proven refractory to other therapies but is no longer on these therapies includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the cancer may be non- small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non-small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject wherein the subject has proven refractory to other therapies but is no longer on these therapies includes administering to the subject an effective amount of ganetespib in combination with erlotinib.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject wherein the subject has proven refractory to other therapies but is no longer on these therapies includes administering to the subject an effective amount of ganetespib in combination with afatinib.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject wherein the subject has proven refractory to other therapies but is no longer on these therapies includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the cancer may be non- small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non-small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject wherein the subject has proven refractory to other therapies but is no longer on these therapies includes administering to the subject an effective amount of ganetespib in combination with erlotinib.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject wherein the subject has proven refractory to other therapies but is no longer on these therapies includes administering to the subject an effective amount of ganetespib in combination with afatinib.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject wherein the subject has proven refractory/resistant to the treatment of an EGFR inhibitor includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the cancer may be non- small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non-small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject wherein the subject has proven refractory/resistant to the treatment of an EGFR inhibitor includes administering to the subject an effective amount of ganetespib in combination with erlotinib.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject wherein the subject has proven refractory/resistant to the treatment of an EGFR inhibitor includes administering to the subject an effective amount of ganetespib in combination with afatinib.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject wherein the subject has proven refractory/resistant to the treatment of an EGFR inhibitor includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • pancreatic cancer ovarian cancer
  • gastrointestinal cancer gastrointestinal cancer
  • prostate cancer small cell lung carcinoma
  • stomach cancer cervical cancer
  • gastric cancer rectal cancer
  • kidney cancer liver cancer
  • gallbladder cancer gallbladder cancer
  • transitional cell carcinoma squamous cell carcinoma
  • melanoma glioblasto
  • the cancer is preferably non-small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non- small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject wherein the subject has proven refractory/resistant to the treatment of an EGFR inhibitor includes administering to the subject an effective amount of ganetespib in combination with erlotinib.
  • the cancer may be non- small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject wherein the subject has proven refractory/resistant to the treatment of an EGFR inhibitor includes administering to the subject an effective amount of ganetespib in combination with afatinib.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject wherein the subject has proven refractory/resistant to the treatment of erlotinib includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • pancreatic cancer ovarian cancer
  • gastrointestinal cancer gastrointestinal cancer
  • prostate cancer small cell lung carcinoma
  • stomach cancer cervical cancer
  • gastric cancer rectal cancer
  • kidney cancer liver cancer
  • gallbladder cancer gallbladder cancer
  • transitional cell carcinoma squamous cell carcinoma
  • melanoma glioblasto
  • the cancer is preferably non-small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non- small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject wherein the subject has proven refractory/resistant to the treatment of erlotinib includes administering to the subject an effective amount of ganetespib in combination with erlotinib.
  • the cancer may be non- small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer.
  • the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with an EGFR mutation in a subject wherein the subject has proven refractory/resistant to the treatment of erlotinib includes administering to the subject an effective amount of ganetespib in combination with afatinib.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject wherein the subject has proven refractory/resistant to the treatment of erlotinib includes administering to the subject an effective amount of ganetespib in combination with an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the cancer may be non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • pancreatic cancer ovarian cancer
  • gastrointestinal cancer gastrointestinal cancer
  • prostate cancer small cell lung carcinoma
  • stomach cancer cervical cancer
  • gastric cancer rectal cancer
  • kidney cancer liver cancer
  • gallbladder cancer gallbladder cancer
  • transitional cell carcinoma squamous cell carcinoma
  • melanoma glioblasto
  • the cancer is preferably non-small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non- small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non- small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject wherein the subject has proven refractory/resistant to the treatment of erlotinib includes administering to the subject an effective amount of ganetespib in combination with erlotinib.
  • the cancer may be non- small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non-small cell lung cancer.
  • the method of treating cancer with wild-type EGFR in a subject wherein the subject has proven refractory/resistant to the treatment of erlotinib includes administering to the subject an effective amount of ganetespib in combination with afatinib.
  • the cancer may be non- small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, prostate cancer, small cell lung carcinoma, stomach cancer, cervical cancer, gastric cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, gliosarcoma, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine tumors, colon carcinoma, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  • the cancer is preferably non- small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer. In an embodiment, the cancer is more preferably non-small cell lung cancer, or breast cancer. In an embodiment, the cancer is even more preferably non-small cell lung cancer.
  • the administration of ganetespib, the Hsp90 inhibitor, and the EGFR inhibitor are done concurrently. In another aspect, the administration of ganetespib and the EGFR inhibitor are done sequentially. In another aspect, the administration of ganetespib and the EGFR inhibitor are dosed independently. In any one of these embodiments, the EGFR inhibitor may be erlotinib, afatinib, gefitinib or cetuximab.
  • anti-proliferative or anti-cancer therapies may be combined with the compounds described herein to treat proliferative diseases such as cancer.
  • Other therapies or anti-cancer agents that may be used in combination with the anti-cancer agents described herein include surgery, radiotherapy (including gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, biologic response modifiers (including interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs.
  • radiotherapy including gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes
  • endocrine therapy including interferons, interleukins, and tumor necrosis factor (TNF)
  • TNF tumor necros
  • the recommended daily dose range of ganetespib for the conditions described herein lie within the range of from about 0.01 mg to about 1000 mg per day, given as a single once-a-day dose preferably as divided doses throughout a day.
  • the daily dose is administered twice daily in equally divided doses.
  • a daily dose range should be from about 5 mg to about 500 mg per day, more specifically, between about 10 mg and about 200 mg per day.
  • the therapy should be initiated at a lower dose, perhaps about 1 mg to about 25 mg, and increased if necessary up to about 200 mg to about 1000 mg per day as either a single dose or divided doses, depending on the patient's global response. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art.
  • the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
  • the dosage of the composition comprising ganetespib administered to prevent, treat, manage, or ameliorate cancer, or one or more symptoms thereof in a patient is 150 ⁇ g/kg, preferably 250 ⁇ g/kg, 500 ⁇ g/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's body weight.
  • the dosage of the composition comprising a compound described herein administered to prevent, treat, manage, or ameliorate cancer, or one or more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7m g, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
  • the unit dose can be administered 1, 2, 3, 4 or more times daily, or once every 2, 3, 4, 5, 6 or 7 days, or once weekly, once every two weeks, once every three weeks or once monthly.
  • the therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part.
  • two or more therapies are administered within the same patient visit.
  • one or more compounds described herein and one or more other the therapies are cyclically administered. Cycling therapy involves the administration of a first therapy (e.g. , a first prophylactic or therapeutic agents) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agents) for a period of time, followed by the administration of a third therapy (e.g.
  • a third prophylactic or therapeutic agents for a period of time and so forth, and repeating this sequential administration, i.e., the cycle in order to reduce the development of resistance to one of the agents, to avoid or reduce the side effects of one of the agents, and/or to improve the efficacy of the treatment.
  • administration of the same compound described herein may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • a method of preventing, treating, managing, or ameliorating cancer, or one or more symptoms thereof comprising administering to a subject in need thereof a dose of at least 150 ⁇ g/kg, preferably at least 250 ⁇ g/kg, at least 500 ⁇ g/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds described herein once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
  • the dose can be divided into portions (typically equal portions) administered two, three, four or more times a day.
  • the method provides a kit for administration of the combination therapy, which includes separate pharmaceutical compositions containing ganetespib and the EGFR inhibitor.
  • the kit includes one
  • each pharmaceutical composition may include one or more
  • the EGFR inhibitor may be erlotinib, afatinib, gefitinib or cetuximab.
  • the present invention also provides pharmaceutical combinations for the treatment, prophylaxis, and amelioration of cancer.
  • the combination comprises ganetespib and an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab, for treating cancer wherein the cancer has an EGFR mutation.
  • the combination comprises ganetespib and an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab, for treating cancer wherein the cancer has wild-type EGFR .
  • the combination comprises ganetespib and erlotinib for treating cancer wherein the cancer has an EGFR mutation.
  • the combination comprises ganetespib and erlotinib for treating cancer wherein the cancer has wild-type EGFR .
  • the combination comprises ganetespib and afatinib for treating cancer wherein the cancer has an EGFR mutation.
  • the combination comprises ganetespib and afatinib or treating cancer wherein the cancer has wild-type EGFR .
  • the present invention also provides pharmaceutical combinations for the treatment, prophylaxis, and amelioration of non-small cell lung cancer.
  • the combination comprises ganetespib and an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab, for treating non-small cell lung cancer with an EGFR mutation.
  • the combination comprises ganetespib and an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab, for treating non-small cell lung cancer with wild-type EGFR.
  • the combination comprises ganetespib and erlotinib for treating non-small cell lung cancer with an EGFR mutation. In an embodiment, the combination comprises ganetespib and erlotinib for treating non- small cell lung cancer with wild-type EGFR. In an embodiment, the combination comprises ganetespib and afatinib for treating non-small cell lung cancer with an EGFR mutation. In an embodiment, the combination comprises ganetespib and afatinib or treating non- small cell lung cancer with wild-type EGFR.
  • the combination includes a pharmaceutical composition or a single unit dosage form containing both an Hsp90 inhibitor and an EGFR inhibitor, such as erlotinib, afatinib, gefitinib or cetuximab.
  • Pharmaceutical combinations and dosage forms described herein comprise the two active ingredients in relative amounts and formulated in such a way that a given pharmaceutical combination or dosage form can be used to treat cancer.
  • the and the EGFR inhibitor may be in individual or separate pharmaceutical compositions, depending on the dosing schedules, preferred routes of administration, and available formulations of the two inhibitors.
  • these embodiments can also contain one or more additional therapeutic agents.
  • the pharmaceutical combinations described herein are formulated to be compatible with its intended route of administration.
  • routes of administration include, parenteral, e.g. , intravenous, intradermal, subcutaneous, oral (e.g. , inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration.
  • the combination is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings.
  • the combination is formulated in accordance with routine procedures for subcutaneous administration to human beings.
  • the method includes inhibiting the growth of a cancer or tumor cell wherein the cancer or tumor cell has an EGFR mutation, comprising the steps of: (a) contacting said cell with an effective amount of ganetespib or a pharmaceutically acceptable salt thereof; and (b) exposing said cell to an effective amount of an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the method includes inhibiting the growth of a cancer or tumor cell, wherein the cancer or tumor cell has an EGFR mutation, comprising the steps of: (a) contacting said cell with an effective amount of ganetespib or a pharmaceutically acceptable salt thereof; and (b) exposing said cell to an effective amount of erlotinib.
  • the method includes inhibiting the growth of a cancer or tumor cell, wherein the cancer or tumor cell has an EGFR mutation, comprising the steps of: (a) contacting said cell with an effective amount of ganetespib or a pharmaceutically acceptable salt thereof; and (b) exposing said cell to an effective amount of afatinib.
  • the method includes inhibiting the growth of a cancer or tumor cell wherein the cancer or tumor cell is with a wild-type EGFR, comprising the steps of: (a) contacting said cell with an effective amount of ganetespib or a pharmaceutically acceptable salt thereof; and (b) exposing said cell to an effective amount of an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • an EGFR inhibitor such as erlotinib, afatinib, gefitinib or cetuximab.
  • the method includes inhibiting the growth of a cancer or tumor cell, wherein the cancer or tumor cell with a wild-type EGFR, comprising the steps of: (a) contacting said cell with an effective amount of ganetespib or a pharmaceutically acceptable salt thereof; and (b) exposing said cell to an effective amount of erlotinib.
  • the method includes inhibiting the growth of a cancer or tumor cell, wherein the cancer or tumor cell with a wild-type EGFR, comprising the steps of: (a) contacting said cell with an effective amount of ganetespib or a pharmaceutically acceptable salt thereof; and (b) exposing said cell to an effective amount of afatinib.
  • NCI-HCC827, NCI-H1975, NCI-H1395, NCI-H1666, and NCI-H292 cell lines were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA).
  • NCI-H322 cells were purchased from Sigma-Aldrich (St. Louis, MO, USA). All were maintained at 37 °C in 5% (v/v) C0 2 using culture medium recommended by the supplier.
  • the remaining NSCLC lines listed in Table 1 were part of a collection assembled by The Center for Molecular Therapeutics (Massachusetts General Hospital Cancer Center) who performed the drug sensitivity analysis. All primary antibodies were purchased from Cell Signaling Technology (CST, Beverly, MA, USA) with the exception of p-EGFR
  • Ganetespib [3-(2,4- dihydroxy-5-isopropylphenyl)-4-(l-methyl-lH-l,2,4-triazol-5(4H)-one] was synthesized by Synta Pharmaceuticals Corp. Erlotinib and afatinib were purchased from LC Laboratories (Woburn, MA, USA).
  • Cellular viability was assessed using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, Madison, WI, USA) according to the manufacturer's protocol. Lung cancer cell lines were seeded into 96-well plates based on optimal growth rates determined empirically for each line. Twenty-four hours after plating, cells were dosed with graded concentrations of drug for 72 h. CellTiter-Glo was added (50% v/v) to the cells, and the plates incubated for 10 min prior to luminescent detection in a Victor 2 microplate reader (Perkin Elmer, Waltham, MA, USA). Data were normalized to percent of control and IC 50 values were determined using XLFit software.
  • mice Female CB-17/SCID mice (Charles River Laboratories, Wilmington, MA) at 7-12 weeks of age were maintained in a pathogen-free environment and all in vivo procedures were performed in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals and approved by the Synta Pharmaceuticals Corp. Institutional Animal Care and Use Committee. NCI-HCC827, NCI-H1975, NCI-H1666, or NCI-H322 cells (5 x 106) were subcutaneously implanted into SCID mice.
  • Tumor growth inhibition was determined from the change in average tumor volumes of each treated group relative to the vehicle-treated, or itself in the case of tumor regression. Statistical significance was determined using two-way ANOVA followed by Bonferroni post tests.
  • Example 1 Ganetespib confers superior antitumor efficacy in combination with erlotinib in NCI-HCC827 NSCLC xenografts.
  • Ganetespib exhibits robust cytotoxic activity against NSCLC lines harboring a spectrum of activating EGFR mutations and, moreover, ganetespib retains potent activity against erlotinib-resistant NSCLC tumor phenotypes in vitro.
  • experiments were designed to determine whether concurrent ganetespib exposure could potentiate EGFR TKI activity in vivo.
  • SCID mice bearing NCI-HCC827 xenografts were dosed with ganetespib and erlotinib, either alone or in combination, on a weekly dosing schedule (Figure 1).
  • NCI-HCC827 cells express a mutationally activated EGFRDel E746_A750 receptor, and are sensitive to erlotinib treatment.
  • ganetespib displayed only modest antitumor activity at this dose level.
  • ganetespib greatly improved the therapeutic response, significantly enhancing the overall degree of regression in this model.
  • the molecular basis underlying the superior efficacy remains to be fully elucidated.
  • coordinate impacts on both the signaling activity and functional stability of EGFRDel E746_A750 (afforded by selective kinase and Hsp90 inhibition, respectively) promoted a more robust and durable loss of EGFR oncogenic driver activity that resulted in greater tumor shrinkage.
  • Example 2 Ganetespib confers superior antitumor efficacy in combination with erlotinib in NCI-HCC1975 NSCLC xenografts.
  • Ganetespib (50 mg/kg) monotherapy was moderately efficacious, inhibiting tumor growth by 39% (T/C value, 61 ).
  • T/C value 39%
  • p ⁇ 0.0001 a significant improvement in efficacy was seen ( Figure 4, T/C, 28%; p ⁇ 0.0001).
  • This combinatorial benefit suggested that ganetespib co-treatment was sufficient to overcome erlotinib resistance in these tumors.
  • ganetespib potentiates the activity of tyrosine kinase inhibitors and overcomes erlotinib resistance in NSCLC tumors driven by activating EGFR mutations.
  • Example 3 Ganetespib confers superior antitumor efficacy in combination with afatinib in NCI-H1975 xenografts.
  • afatinib covalently binds to EGFR to irreversibly block receptor tyrosine kinase activity. Accordingly, afatinib has shown robust activity in preclinical models against tumor lines harboring the T790M mutation, including NCI-H1975.
  • Afatinib dosed at 20 mg/kg resulted in effective stabilization of NCI-H1975 xenograft tumor growth (T/C, 6%), with dual therapy causing 78% tumor regression (p ⁇ 0.0001). All treatments were well tolerated, with no significant toxicity or loss of body weights observed over the course of the dosing regimen (Figure 12; average body weight changes following combination ganetespib + afatinib treatment in NCTH1975 xenografts. Body weights were measured 5 times per week. Mean values are plotted against vehicle controls). Taken together, these data indicated that ganetespib possesses potent sensitizing properties when combined with standard of care TKI drugs in EGFR mutant-driven NSCLC.
  • Example 4 Ganetespib suppresses tumor growth in wild-type EGFR NSCLC models.
  • NCI-H1838 cells exhibit genomic amplification of wild-type EGFR
  • NCI-H1666 cells harbor a mutant BRAFG466V kinase.
  • Mutant BRAF proteins are particularly reliant on Hsp90 activity for stability and, accordingly, destabilization of BRAFG466V protein levels also occurred following ganetespib treatment.
  • BRAFV600E BRAFV600E
  • BRAFG466V is kinase impaired, and thus not likely to be a primary driver of oncogenesis in this cell line.
  • the coordinate impacts on these upstream signaling mediators arising from ganetespib treatment produced convergent effects on MAPK and survival pathway signaling (Figure 7).
  • Example 5 Ganetespib combination with erlotinib induces tumor regressions in WT- EGFR NSCLC.
  • ganetespib 500 nM was sufficient to effectively degrade EGFR protein levels (inducing a concomitant loss of p-EGFR activity), abrogate AKT signaling and reduce, although not completely inhibit, p-ERK expression in NCI-H322 cells.
  • ganetespib concurrent treatment with increasing concentrations of erlotinib partially stabilized EGFR protein levels in a dose-dependent manner.
  • no reactivation of EGFR kinase activity as evidenced by p-EGFR expression, occurred with concomitant ganetespib exposure.
  • erlotinib In contrast to its established role as first- line therapy for NSCLC patients with EGFR-mutated tumors, the use of erlotinib as a second- or third-line salvage treatment for WT-EGFR patients that have progressed on prior chemotherapy remains contentious. For example, the recent TAILOR Phase III trial comparing erlotinib with docetaxel in advanced NSCLC patients with wild-type EGFR tumors for whom first-line platinum therapy had failed demonstrated a clear superiority for the standard chemotherapy arm.

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Abstract

L'invention concerne des méthodes de traitement anticancéreux avec du ganetespib en association avec un inhibiteur de l'EGFR. L'invention concerne également des méthodes de traitement des cancers présentant une mutation de l'EGFR avec du ganetespib en association avec un inhibiteur de l'EGFR tel que l'erlotinib, l'afatinib, le gefitinib ou le cétuximab. L'invention concerne également des méthodes de traitement des cancers où l'EGFR est de type sauvage avec du ganetespib en association avec un inhibiteur de l'EGFR tel que l'erlotinib, l'afatinib, le gefitinib ou le cétuximab. L'invention concerne également des méthodes de traitement des cancers présentant une mutation de l'EGFR avec du ganetespib en association avec un inhibiteur de l'EGFR tel que l'erlotinib, l'afatinib, le gefitinib ou le cétuximab, dans le cas où le cancer est réfractaire ou résistant au traitement, ou a été préalablement traité. L'invention concerne également des méthodes de traitement des cancers où l'EGFR est de type sauvage avec du ganetespib en association avec un inhibiteur de l'EGFR tel que l'erlotinib, l'afatinib, le gefitinib ou le cétuximab, dans le cas où le cancer est réfractaire ou résistant au traitement, ou a été préalablement traité.
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CN110191721A (zh) * 2016-09-26 2019-08-30 集合集团控股公司 有淋巴系统失调的受试者中癌症的评估与治疗方法
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FRIEDLAND ET AL: "Targeted inhibition of Hsp90 by ganetespib is effective across a broad spectrum of breast cancer subtypes.", INVEST.NEW DRUGS, vol. 32, 18 May 2013 (2013-05-18) - 18 May 2013 (2013-05-18), pages 14 - 24, XP002739543 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110191721A (zh) * 2016-09-26 2019-08-30 集合集团控股公司 有淋巴系统失调的受试者中癌症的评估与治疗方法
US11395821B2 (en) 2017-01-30 2022-07-26 G1 Therapeutics, Inc. Treatment of EGFR-driven cancer with fewer side effects

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