WO2012058462A2 - Polythérapie destinée au traitement du cancer - Google Patents

Polythérapie destinée au traitement du cancer Download PDF

Info

Publication number
WO2012058462A2
WO2012058462A2 PCT/US2011/058140 US2011058140W WO2012058462A2 WO 2012058462 A2 WO2012058462 A2 WO 2012058462A2 US 2011058140 W US2011058140 W US 2011058140W WO 2012058462 A2 WO2012058462 A2 WO 2012058462A2
Authority
WO
WIPO (PCT)
Prior art keywords
days
docetaxel
eif
aso
prostate cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2011/058140
Other languages
English (en)
Other versions
WO2012058462A3 (fr
Inventor
T. Jesse Kwoh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ionis Pharmaceuticals Inc
Original Assignee
Isis Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Isis Pharmaceuticals Inc filed Critical Isis Pharmaceuticals Inc
Publication of WO2012058462A2 publication Critical patent/WO2012058462A2/fr
Publication of WO2012058462A3 publication Critical patent/WO2012058462A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
    • C12N2310/334—Modified C
    • C12N2310/3341—5-Methylcytosine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/341—Gapmers, i.e. of the type ===---===
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/346—Spatial arrangement of the modifications having a combination of backbone and sugar modifications
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/31—Combination therapy

Definitions

  • Sequence Listing is provided as a file entitled BIOL0136USLSEQ.txt created 10/25/2010, which is 4 Kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirely.
  • the present invention relates to the use of an antisense oligonucleotide (ASO) therapeutic targeted to eukaryotic translation initiation factor 4E (eIF-4E) in combination with docetaxel in order to achieve an enhanced therapeutic effect in treating cancers.
  • ASO antisense oligonucleotide
  • eIF-4E is elevated in multiple human cancers and is directly related to disease progression. Elevated eIF-4E function triggers enhanced assembly of the eIF-4F translation initiation complex, which includes elF- 4E as a component, driving the expression of a pool of mRNAs that are exceptionally dependent on elevated eIF-4E activity for translation and which promotes tumor cell growth, proliferation, development, survival, and angiogenesis. In view of the involvement of eIF-4E in tumor growth and development, this protein is an attractive therapeutic target.
  • PCT International Publication WO 2005/028628 discloses antisense oligonucleotides targeted to eIF-4E, including the ASO disclosed herein, and methods of using these ASOs for modulating the expression or overexpression of eIF-4E in vitro and in vivo.
  • Docetaxel ((2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 53-20-epoxy- l,2a,4 ⁇ ,103,13a-hexahydroxytax-l l-en-9-one 4-acetate 2-benzoate, trihydrate) is an anti-mitotic agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. It is used to treat breast, ovarian, and castrate-resistant prostate cancers (S.J. Clarke and L.P. Rivory (1999) Clin. Pharmacokinet. 36: 99-114).
  • Methods are provided herein for the combined use of the chemically modified eIF-4E ASOs disclosed herein with docetaxel to achieve an additive, or greater-than-additive, effect in reducing tumor volume compared to the reduction in tumor volume achieved with ASO or docetaxel alone.
  • Methods are provided herein for the combined use of the chemically modified eIF-4E ASO disclosed herein with docetaxel to achieve an additive, or greater-than- additive, effect in increasing survival compared to increase in survival achieved with ASO or docetaxel alone.
  • Methods are provided herein for the combined use of the chemically modified eLF-4E ASO disclosed herein with docetaxel to achieve an additive, or greater-than-additive, effect in reducing serum prostate-specific antigen (PSA) compared to the reduction in serum PSA achieved with ASO or docetaxel alone.
  • Methods are provided herein for the combined use of the chemically modified eIF-4E ASO disclosed herein with docetaxel to achieve an additive, or greater-than-additive, effect in reducing pain compared to the reduction of pain achieved with ASO or docetaxel alone.
  • Methods are provided herein for the combined use of the chemically modified eIF-4E ASO disclosed herein with docetaxel to achieve an additive, or greater-than- additive, effect in the reduction of bone metastases compared to the reduction of bone metastases achieved with ASO or docetaxel alone.
  • the additive, or greater-than-additive, effect is achieved with toxicity that is no greater than the additive effect of the toxicities of each drug.
  • the chemical modifications of the ASO enhances resistance to degradation by cellular nucleases and increase nucleic acid duplex stability with the eIF-4E mRNA target.
  • the high target selectivity of the ASO minimizes non-target related undesired and adverse side effects.
  • Docetaxel and ASO can be administered systemically and distribute throughout the body. The combination of the ASO and docetaxel is therefore a potent and effective therapeutic combination of high selectivity in cancer cells.
  • the drug combination disclosed herein possesses other highly desirable pharmacologic properties, such as high bioavailability associated with intravenous administration, good in vivo metabolic stability, and
  • the present invention provides:
  • a method of treating prostate cancer comprising administering to a patient in need thereof a therapeutically effective combination of docetaxel and a modified eD?-4E antisense oligonucleotide.
  • the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt can be a sodium salt.
  • docetaxel is administered after administration of the modified eIF-4E antisense oligonucleotide, within a therapeutically effective interval.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, about 4 days to about 7 days, about 4 days to about 14 days, about 4 days to about 21 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days.
  • a method of treating prostate cancer comprising administering to a patient in need thereof a modified eIF-4E antisense oligonucleotide and docetaxel in amounts that in combination are effective in treating said prostate cancer.
  • the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt can be a sodium salt.
  • docetaxel is administered after administration of the modified eDF-4E antisense oligonucleotide, within a therapeutically effective interval.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, about 4 days to about 7 days, about 4 days to about 14 days, about 4 days to about 21 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days.
  • a method of treating prostate cancer comprising sequentially administering to a patient in need thereof an amount of a modified eIF-4E antisense oligonucleotide, followed by an amount of docetaxel, wherein said amounts of said modified eEF-4E antisense oligonucleotide and said docetaxel in combination are effective in treating said prostate cancer in said patient, and wherein said docetaxel is administered within a therapeutically effective interval after administration of said modified eIF-4E antisense oligonucleotide.
  • the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt can be a sodium salt.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, about 4 days to about 7 days, about 4 days to about 14 days, about 4 days to about 21 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days.
  • a method of treating prostate cancer comprising administering to a patient in need thereof a docetaxel-sensitizing amount of a modified eIF-4E antisense oligonucleotide, followed by administering to said patient an effective amount of docetaxel within a therapeutically effective interval, wherein together said amounts result in an additive or greater-than-additive reduction in the volume of a prostate cancer tumor compared to the sum of the reductions in the volume of said prostate cancer tumor achieved by administering said modified eIF-4E antisense oligonucleotide alone and said docetaxel alone.
  • the prostate cancer is castrate-resistant.
  • the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt can be a sodium salt.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, about 4 days to about 7 days, about 4 days to about 14 days, about 4 days to about 21 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days.
  • a method of sensitizing a prostate cancer cell to docetaxel comprising contacting said castrate- resistant prostate cancer cell and a docetaxel-sensitizing amount of a modified eIF-4E antisense oligonucleotide and subsequently contacting said prostate cancer cell and an effective amount of docetaxel within an effective interval.
  • the prostate cancer is castrate-resistant.
  • the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt can be a sodium salt.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, about 4 days to about 7 days, about 4 days to about 14 days, about 4 days to about 21 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days.
  • a method of inhibiting the growth or proliferation of a prostate cancer cell comprising contacting said prostate cancer cell with an amount of a modified eIF-4E antisense oligonucleotide and an amount of docetaxel, wherein said amounts of said modified eIF-4E antisense oligonucleotide and said docetaxel is effective in combination in inhibiting the growth or proliferation of said prostate cancer cell.
  • the prostate cancer is castrate-resistant.
  • the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt can be a sodium salt.
  • the prostate cancer cell is first contacted with the modified eIF-4E antisense oligonucleotide and, subsequently, with docetaxel, within an effective interval.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, about 4 days to about 7 days, about 4 days to about 14 days, about 4 days to about 21 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days.
  • a method of inhibiting the growth or proliferation of a prostate cancer cell comprising contacting said prostate cancer cell and a docetaxel-sensitizing amount of a modified eIF-4E antisense oligonucleotide, followed by contacting said prostate cancer cell and an effective amount of docetaxel within an effective interval, wherein together said amounts produce an additive or greater-than-additive-effect in inhibiting the growth or proliferation of said prostate cancer cell compared to the sum of the effect achieved with said modified eIF-4E antisense oligonucleotide alone and said docetaxel alone.
  • the prostate cancer is castrate-resistant.
  • the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt can be a sodium salt.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, about 4 days to about 7 days, about 4 days to about 14 days, about 4 days to about 21 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days.
  • a method of inhibiting prostate tumor growth comprising administering to a patient in need thereof a modified eIF-4E antisense oligonucleotide and docetaxel in amounts that in combination are effective in inhibiting growth of said prostate tumor.
  • the amounts produce an additive or greater-than-additive-effect in inhibiting the growth.
  • the prostate cancer is castrate- resistant.
  • the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt can be a sodium salt.
  • docetaxel is administered after administration of the modified eIF-4E antisense oligonculetoide, within a therapeutically effective interval.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, about 4 days to about 7 days, about 4 days to about 14 days, about 4 days to about 21 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days.
  • a method of inhibiting bone metastases in a prostate cancer patient comprising administering to a patient in need thereof a modified eIF-4E antisense oligonucleotide and docetaxel in amounts that in combination are effective in reducing said bone metastases.
  • the amounts produce an additive or greater-than-additive-effect in inhibiting bone metastases.
  • the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt can be a sodium salt.
  • docetaxel is administered after administration of the modified elF- 4E antisense oligonculetoide, within a therapeutically effective interval.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, about 4 days to about 7 days, about 4 days to about 14 days, about 4 days to about 21 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days.
  • a method of enhancing the therapeutic effectiveness of docetaxel in treating prostate cancer comprising administering to a patient in need thereof a therapeutically effective combination of (1) a modified eIF-4E antisense oligonucleotide and (2) docetaxel.
  • the prostate cancer is castrate- resistant.
  • the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt can be a sodium salt.
  • docetaxel is administered after administration of the modified eIF-4E antisense oligonucleotide, within a therapeutically effective interval.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, about 4 days to about 7 days, about 4 days to about 14 days, about 4 days to about 21 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days.
  • the prostate cancer is castrate-resistant prostate cancer.
  • the compound of formula I, or other pharmaceutically acceptable salt thereof, and docetaxel is administered sepaiately, within a therapeutically effective hilerval.
  • the docetaxel is administered after the compound of formula I or other pharmaceutically acceptable salt thereof, within a therapeutically effective interval.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days, about 1 day to about 7 days, about 1 day to about 14 days, about 1 day to about 21 days, about 1 day to about 28 days, about 4 days to about 7 days, about 4 days to about 14 days, about 4 days to about 21 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days.
  • the combination therapy is via the parenteral route, including via intravenous administration, including via slow infusion.
  • each of the compound of formula I, or other pharmaceutically acceptable salt thereof and docetaxel is in the form of a sterile injectable solution.
  • Formula I has the nucleotide sequence 5'- TGTCATATTCCTGGATCCTT- 3' (SEQ ID NO: 1), wherein every intemucleoside linkage is a phosphorothioate linkage, nucleosides 1-5 and 16-20 reading from the 5' end to the 3' end each comprise a 2'-0-(2-methoxyethyl) modified sugar, nucleosides 6-15 are 2'-deoxynucleosides, and every cytosine residue is a 5-methylcytosine.
  • each of the compound of formula I, or other pharmaceutically acceptable salt thereof and docetaxel is in the form of a sterile injectable solution.
  • Example 1 is directed to the effect of combined administration of the eIF-4E ASO (Formula I; SEQ ID NO: 1) and docetaxel on tumor number and mean tumor volume of human castrate-resistant prostate cancer in human patients with castrate-resistant prostate cancer.
  • Mean tumor volume after treatment with eIF-4E ASO and docetaxel can be compared to mean tumor volume after treatment with docetaxel alone.
  • Example 2 is directed to the effect of combined administration of the eIF-4E ASO (Formula I; SEQ ID NO: 1) and docetaxel on survival in human patients with castrate-resistant prostate cancer. Survival after treatment with eIF-4E ASO and docetaxel can be compared to survival after treatment with docetaxel alone.
  • Example 3 is directed to the effect of combined administration of the eIF-4E ASO (Formula I; SEQ ID NO: 1;
  • Example 4 is directed to the effect of combined administration of the eIF-4E ASO (Formula I; SEQ ID NO: 1) and docetaxel on reduction of pain in human patients with castrate-resistant prostate cancer. Reduction in pain can be compared to the reductions achieved via treatment with docetaxel alone.
  • Combination treatment may result in an additive, or greater-than-additive, effect in reducing PSA levels achieved with docetaxel treatment alone.
  • Example 5 is directed to the effect of combined administration of the eIF-4E ASO (Formula I; SEQ ID NO: 1) and docetaxel on reduction of bone metastases in human patients with castrate-resistant prostate cancer. Reduction of bone metastases can be compared to the reductions achieved via treatment with docetaxel alone. Combination treatment may result in an additive, or greater-than-additive, effect in reducing bone metastases achieved with docetaxel treatment alone.
  • Clinical protocols in cancer chemotherapy commonly employ multiple drugs rather than a single therapeutic.
  • the combined effect may be antagonism, additivity, or synergism. If one of the drugs has no effect by itself but increases the effects of other drug(s), the result is called potentiation. Prediction of synergy is difficult.
  • Each drug in combination has its own effects, i.e., its own potency and a specific shape of dose-effect curve. These effects are also related to affinity and efficacy. Factors such as feedback inhibition, spatial, temporal, and microenvironmental factors (such as H, ionic strength, and temperature) add to the biological complexity and intricacy of drug effects.
  • Mizushima et al. discloses that investigators should use caution when using antisense oligonucleotides for chemosensitization of cells. Pretreatment with antisense oligonucleotides can at times have a tendency to reduce rather than enhance drug cytotoxicity. This may be caused by a number of nonspecific oligonucleotide effects, such as the ability of the oligonucleotide to interact directly with the cytotoxic drug (Blagosklonny et al. (1994) Anticancer Drugs 5(4):437-442).
  • docetaxel binds to microtubules and prevents their breakdown.
  • the movement of the replicated chromosomes during mitosis requires both polymerization of tubulin to form microtubules as well as the breakdown of those microtubules.
  • chromosomes are unable to move to opposite sides of the dividing cell because microtubules are not broken down. Thus, cell division is halted, and cell death is induced (C. Baer and B. Williams (1992) Clinical Pharmacology and Nursing, 2nd Edition, Springhouse Corporation).
  • a demonstration that a docetaxel-sensitizing-effect of an eIF-4E ASO in cancer cells can achieve an additive or greater-than-additive effect in inhibiting cancer cell proliferation, tumor growth, tumor number, tumor volume, pain, and bone metastases and/or increase patient survival achieved by the combined use of the eIF-4E ASO and docetaxel would be novel, surprisingly unexpected, and therapeutically useful.
  • the therapeutically effective interval is in the range of about 1 day to about 4 days,” it is implied that the range is within 22 hours to 98 hours.
  • eIF-4E antisense oligonucleotide or "eIF-4E ASO,” also, Formula I, as used herein refers to the eIF-4E antisense oligonucleotide originally described in WO 2005/028628 and known by the chemical name: d(P-thio) ([2'-0-(2-methoxyethyl)] m5rU - ([2'-0-(2-methoxyethyl)] rG -([2'-0-(2-methoxyethyl)] m5rU - ([2'-0-(2-methoxyethyl)] m5rC - ([2'-0-(2-methoxyethyl)] rA-T-A-T-T-m5C-m5C-T-G-G-A- ([2'-0- (-methoxyethyl)] m5rU - ([2'- O -(2-thio
  • the eIF-4e ASO has the linked nucleoside sequence 5 '- TGTCATATTCCTGGATCCTT-3 ' (SEQ ED NO: 1), wherein every internucleoside linkage is a phosphorothioate linkage, nucleosides 1-5 and 16-20 reading from the 5' end to the 3' end each comprise a 2'-0-(2-methoxyethyl) modified sugar, nucleosides 6-15 are 2'-deoxynucleosides, and every cytosine residue is a 5-methylcytosine.
  • the chemical structure of the eIF-4E ASO is:
  • Docetaxel ((2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5 -20-epoxy- l,2 ⁇ ,4,7 ⁇ ,10 ⁇ ,13 ⁇ -hexahydroxytax-l l-en-9-one 4-acetate 2-benzoate, trihydrate) is an anti-mitotic agent.
  • the structure of Docetaxel is:
  • the term "patient” refers to a mammal afflicted with one or more disorders associated with eIF-4E expression or overexpression.
  • the patient is a human.
  • treating refers to curative treatment of disorders associated with eIF-4E activity, including various cancers.
  • Curative treatment refers to processes involving a slowing, interrupting, arresting, controlling, stopping, reducing, or reversing the progression or severity of a symptom, disorder, condition, or disease, but does not necessarily involve a total elimination of all disease-related symptoms, disorders, or conditions, or the disease itself.
  • Inhibiting means restraining, retarding, restricting, reducing, holding back, or preventing.
  • sensitizing to docetaxel in connection with the eIF-4E ASO means making responsive to, susceptible to the action(s) of, or readily or easily affected by docetaxel. In some cases, this can also mean eliciting a greater response to a dose or amount of docetaxel than that which would occur in the absence of the ASO.
  • docetaxel-sensitizing amount refers to an amount or dose of the eIF-4E ASO that is effective in making cancer cells responsive to, susceptible to the action(s) of, or readily or easily affected by docetaxel or eliciting a greater cancer cell response to the action of an amount or dose of docetaxel than that which would occur in response to this amount or dose of docetaxel in the absence of the eDF-4E ASO.
  • Therapeutically effective amounts of the eIF-4E ASO which include docetaxel-sensitizing amounts in the therapeutic context, are in the range of from about 100 mg to about 2000 mg in humans.
  • a preferred dose in terms of efficacy and tolerability is about 300 mg to about 1,200 mg, about 600 mg to about 1000 mg or about 800 to about 1000 mg per single dose or administration, administered parenterally, including intravenously, including via slow intravenous infusion, over 1-3 hours.
  • Effective amount of docetaxel refers to an amount or dose of docetaxel, when used in combination with the eEF-4 E ASO that produces the particular cancer cell growth- or proliferation-inhibiting effect, tumor growth inhibiting effect, tumor volume increase-inhibiting effect, or cancer treatment effect in a cancer cell or tumor.
  • Docetaxel is a clinically well established anti-mitotic chemotherapy medication used mainly for the treatment of prostate, breast, ovarian, and non-small cell lung cancer. Docetaxel has been used for treatment of locally advanced or metastatic breast cancer after failure of prior chemotherapy. The usual dosage of docetaxel is 60-100 mg/m 2 given intravenously for over 3 hours every 3 weeks. Patients who experience severe neutropenia ( ⁇ 500 cells/mm3 for a week or longer) during the course of treatment should have the dose reduced by 20% for subsequent treatment sessions. Docetaxel may also cause patients to develop severe reactions including hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria.
  • patients are usually premedicated for hypersensitivity with a corticosteroid including dexamethasone or prednisone (8 mg orally twice daily at 1, 3, and 12 hours before docetaxel infusion for patients with prostate cancer.
  • a corticosteroid including dexamethasone or prednisone (8 mg orally twice daily at 1, 3, and 12 hours before docetaxel infusion for patients with prostate cancer.
  • the dose should be 8 mg twice daily for 3 days starting 1 day before docetaxel infusion).
  • optimum dosages of each of the present therapeutic agents can vary depending on the relative potency of the active ingredients in individual patients. Medical practitioners can determine dose and repetition rates for dosing based on measured residence times and concentrations of the active ingredients in bodily fluids or tissues and/or monitoring of relevant disease-related biomarkers for particular cancers. In view of the additive and greater-than-additive treatment effects disclosed herein achieved via the combined use of the eIF-4E ASO and docetaxel it is expected that subclinically effective amounts of docetaxel, compared to those when these drugs are used alone, will be therapeutically effective in the methods of combination therapy disclosed herein.
  • therapeutically effective amounts of the eIF-4E ASO and docetaxel when used in combination can be determined by the healthcare provider by monitoring the effect of the combination on a relevant cancer biomarker.
  • relevant biomarkers can be assessed by chest radiography, computed tomography (CT), low-dose spiral CT evaluation, magnetic resonance imaging (MRI), gallium scanning (scintigraphy), or position emission tomographic (PET) scanning. Analysis of the data obtained by these methods permits modification of the treatment regimen during therapy so that optimal amounts of the eIF-4E ASO and docetaxel in combination therapy are administered, and so that the duration of treatment can be determined as well.
  • the dosing/treatment regimen can be modified over the course of therapy so that the lowest amounts of the eIF-4E ASO and docetaxel used in combination that exhibit satisfactory therapeutic effectiveness are administered, and so that administration of these compounds is continued only so long as is necessary to successfully treat the patient.
  • the term "effective interval" is a period of time beginning upon contact of a cancer cell and the elF- 4E ASO and during which the cell is responsive to the cell growth- and proliferation-inhibiting effects of the combination of the ASO and docetaxel. This effect can be manifested by: (a) sensitization of the cancer cell to the effects of docetaxel; (b) inhibition of growth or proliferation of the cancer cell; ( c) inhibition of tumor growth; (d) inhibition of increase in tumor volume; (d) increased survival; or (e) therapeutically enhanced cancer treatment effect, in a cancer cell or tumor.
  • the effective interval is 4-21 days.
  • the therapeutically effective eIF-4E ASO/docetaxel combination therapies disclosed herein can be achieved by separate administration of the eIF-4E ASO and docetaxel.
  • the ASO can be administered first, followed by administration of docetaxel within a therapeutically effective interval.
  • the eIF-4E ASO and docetaxel can be introduced into the patient on different schedules, as long as the time between the two administrations falls within a therapeutically effective interval.
  • therapeutically effective interval is a period of time after administration of the eIF-4E ASO to a patient during which a tumor is responsive to the beneficial anti-neoplastic therapeutic effects of the combination of the ASO and docetaxel.
  • the therapeutically effective interval may optionally include a pre-docetaxel treatment period comprising administration of one or more doses of the eIF-4 E ASO, i.e., a 1-3 hour infusion of 600 mg - 1000 mg of the eEF-4E ASO once per day for one more days during the interval, followed by one or more cycles of combination therapy.
  • the one or more doses is 3 doses delivered on 3 consecutive days during the first week of the interval.
  • the optional pre- docetaxel treatment period only occurs at commencement of patient therapy.
  • the one or more cycles of combination therapy may be 21 days in length, wherein a 1-3 hour infusion of 600 mg - 1000 mg of the eIF-4 ASO is administered on day 1, and optionally on 8, and/or 15. Additionally, on day 1 of each cycle, 1 hour after infusion with the eEF-4E ASO, docetaxel is administered at a dose of 45-75 mg m 2 as a 1 hour intravenous infusion. This regimen sensitizes the tumor cells to the anti-proliferative insult delivered by docetaxel.
  • a therapeutically effective interval for any individual patient undergoing treatment with the eIF-4E ASO and docetaxel can be determined by monitoring of a biomarker appropriate for the cancer.
  • a biomarker appropriate for the cancer.
  • the biomarker is PSA. It should be noted that the 21 day intervals discussed above in connection with both the initial therapeutically effective interval and the subsequent therapeutically effective intervals represent typical starting procedures that are flexible and subject to modification. These intervals can be further optimized, and can be shorter or longer, the effectiveness of which can be monitored via the use of relevant biomarkers as noted above.
  • treatment with the eIF-4E ASO and docetaxel optionally includes a pre- docetaxel treatment period comprising administration of one or more doses, e.g., 3 loading doses, of the elF- ⁇ E ASO, i.e., a 1-3 hour infusion of the eEF-4E ASO once per day for one or more days, e.g., 3 consecutive days, during the first week, followed by administration of the eIF-4E ASO and docetaxel as described above during the second week (or first week with no pre-docetaxel treatment period).
  • the therapeutically effective interval in this case is about 4-7 days.
  • docetaxel can be administered every approximately 14, 21, or 28 days in conjunction with weekly administration of the eIF-4E ASO for as long as treatment continues.
  • the methods also provide for administering docetaxel every approximately 14, 21, or 28 days in conjunction with administration of the eIF-4E ASO every other week or every 14, 21 or 28 days for as long as treatment continues.
  • therapeutically effective intervals include about 4 days to about 21 days, about 4 days to about 7 days, about 4 days to about 28 days, about 7 days to about 14 days, about 7 days to about 21 days, about 7 days to about 28, about 14 days to about 21 days, about 14 days to about 28 days, or about 21 days to about 28 days, about 14 days, about 21, and about 28 days after administration of the eEF-4E ASO alone.
  • the effective interval can also be about 4 days to about 21 days, about 4 days to about 7 days, about 14 days, and about 21 days after administration of the eIF-4E ASO alone.
  • the eIF-4 E ASO is used in the form of a pharmaceutically acceptable salt, preferably an alkali metal salt, more preferably a lithium, sodium, or potassium salt, most preferably a sodium salt.
  • a pharmaceutically acceptable salt preferably an alkali metal salt, more preferably a lithium, sodium, or potassium salt, most preferably a sodium salt.
  • Such salts, and common methodology for preparing them, are well known in the art. See, e.g., P. Stahl et al. (2002) Handbook of Pharmaceutical Salts: Properties, Selection and Use, VCRA/Wiley-VCR; Berge et al. (1977) "Pharmaceutical Salts," Journal of Pharmaceutical Sciences 66(1):1-19.
  • Docetaxel is a chemotherapy drug of the taxane class and is a semi-synthetic analogue of paclitaxel.
  • the compounds of the present invention can be used as medicaments in human or veterinary medicine, administered by a variety of routes. Most preferably, such compositions are for parenteral administration, especially intravenous administration by slow infusion. Administration of solutions of these compounds, especially sterile injectable, non-pyrogenic solutions, by slow intravenous infusion is most preferred.
  • compositions can be prepared by methods well known in the art (See, e.g., Remington: The Science and Practice of Pharmacy, 19th ed. (1995), A. Gennaro et al., Mack Publishing Co.), and comprise compounds of the invention and a pharmaceutically acceptable carrier, diluent, or excipient.
  • Example 1 Reduction of Tumors and Tumor Volume by Combined Use of the eIF-4E ASO and Docetaxel
  • patient therapy is commenced with a pre-docetaxel treatment period comprising administration of 3 loading doses of the eIF-4 E ASO, i.e., a 3 hour infusion of 600 mg, 800 mg, or 1000 mg of the eIF-4E ASO once per day for 3 consecutive days during the first week, followed by 10 cycles of combination therapy.
  • Each cycle of combination therapy is 21 days in length, during which patients are treated with a 3 hour infusion of 600 mg, 800 mg, or 1000 mg of the eIF-4ASO on days 1, 8, and 15.
  • patients are treated with 45, 60, or 75 mg/m 2 of docetaxel, administered as a 1 hour intravenous infusion.
  • Patients in the control group are treated similarly to those in the eIF-4E experimental group, except they do not receive the eIF-4E ASO. Thus, patients receive 10 cycles of chemotherapy. Each cycle is 21 days in length. On day 1 of each of cycles 1 through 10, patients are treated with 45, 60, or 75 mg/m 2 of docetaxel, administered as a 1 hour intravenous infusion.
  • Patients receiving the eIF-4E ASO in combination to docetaxel may have fewer tumors and reduced tumor volume as compared to patients receiving docetaxel without the eIF-4E ASO.
  • the effect on tumor number and tumor volume by treatment with eEF-4E ASO in combination with docetaxel may be additive or greater-than-additive when compared to the reduction in tumor number and tumor volume achieved with elF- 4E ASO alone or docetaxel alone.
  • Tumors are evaluated by chest X-ray, computerized tomography (CT) scan, magnetic resonance imaging (MRI).
  • Tumor lesions were evaluated by whole body CT scan prior to initial dosing (i.e., "pre-dose") and subsequently at the end of each cycle. The sum of the lesion diameters, if any, was calculated, per RECIST guidelines (Eisenhauer, E.A. et al., Eur. J. Cancer 45: 228-247, 2009). RECIST (Response Evaluation
  • Criteria in Solid Tumors is an internationally accepted set of guidelines used in clinical trials of solid tumor disease. According to RECIST guidelines, a complete tumor response is achieved when all target lesions have disappeared. Partial response is achieved when the sum of the diameters of all tumor lesions is reduced at least 30% compared to the sum of the tumor lesion diameters at pre-dose. And, total response rate is the percentage of patients who achieve either a complete or partial response.
  • pre-dose two measurable lesions at the initial CT scan performed prior to initial dosing.
  • the lesions were located in the visceral lymph nodes to the right and the left of the midline.
  • Table 1 in this patient, the sum diameter of all tumor lesions decreased from 34 mm to 19 mm, or 44% by cycle 10.
  • this patient achieved a partial response.
  • eIF-4E ASO (Formula I, SEQ ID NO: 1) complements or enhances the activity of docetaxel
  • the effect of the combined use of the eIF-4E ASO and docetaxel on survival in patients with castrate-resistant prostate cancer is studied as follows.
  • patient therapy is commenced with a pre-docetaxel treatment period comprising administration of 3 loading doses of the eIF-4 E ASO, i.e., a 3 hour infusion of 600 mg, 800 mg, or 1000 mg of the eIF-4E ASO once per day for 3 consecutive days during the first week, followed by 10 cycles of combination therapy.
  • Each cycle of combination therapy is 21 days in length, during which patients are treated with a 3 hour infusion of 600 mg, 800 mg, or 1000 mg of the eIF-4ASO on days 1, 8, and 15.
  • patients are treated with 45, 60, or 75 mg/m 2 of docetaxel, administered as a 1 hour intravenous infusion.
  • Patients in the control group are treated similarly to those in the eIF-4E experimental group, except they do not receive the eIF-4E ASO. Thus, patients receive 10 cycles of chemotherapy. Each cycle is 21 days in length. On day 1 of each of cycles 1 through 10, patients are treated with 45, 60, or 75 mg/m 2 of docetaxel, administered as a 1 hour intravenous infusion.
  • Patients receiving the eIF-4E ASO in combination to docetaxel may have increased survival as compared to patients receiving docetaxel without the eIF-4E ASO.
  • the effect on patient survival when treated with eIF-4E ASO in combination with docetaxel may be additive or greater-than-additive when compared to survival achieved with ASO alone or docetaxel alone.
  • Example 3 Reduction of Prostate-Specific Antigen (PSA) By Combined Use of the eUME ASO and Docetaxel
  • patient therapy is commenced with a pre-docetaxel treatment period comprising administration of 3 loading doses of the eIF-4 E ASO, i.e., a 3 hour infusion of 600 mg, 800 mg, or 1000 mg of the eIF-4E ASO once per day for 3 consecutive days during the first week, followed by 10 cycles of combination therapy.
  • Each cycle of combination therapy is 21 days in length, during which patients are treated with a 3 hour infusion of 600 mg, 800 mg, or 1000 mg of the eIF-4ASO on days 1, 8, and 15.
  • patients are treated with 45, 60, or 75 mg/m 2 of docetaxel, administered as a 1 hour intravenous infusion.
  • Patients in the control group are treated similarly to those in the eIF-4E experimental group, except they do not receive the eEF-4E ASO.
  • patients receive 10 cycles of chemotherapy. Each cycle is 21 days in length.
  • patients are treated with 45, 60, or 75 mg/m 2 of docetaxel, administered as a 1 hour intravenous infusion.
  • Patients receiving the eIF-4E ASO in combination to docetaxel may have reduced levels of PSA as compared to patients receiving docetaxel without the eIF-4E ASO.
  • the effect on serum PSA when treated with eIF-4E ASO in combination with docetaxel may be additive or greater-than-additive when compared to PSA reduction achieved with eIF-4E ASO alone or docetaxel alone.
  • Serum PSA levels are measured in serum obtained from the patient.
  • eIF-4 E ASO Forma I, SEQ ED NO: 1
  • eIF-4 E ASO Forma I, SEQ ED NO: 1
  • a 3 hour infusion of 800 mg of the eEF-4E ASO once per day for 3 consecutive days during the first week, followed by 10 cycles of combination therapy.
  • Each cycle of combination therapy was 21 days in length, during which patients were treated with a 3 hour infusion of 800 mg of the eEF-4ASO on days 1, 8, and 15.
  • days 1 of each of cycles 1 through 10 one hour after infusion with the eIF-4E ASO, patients were treated with 75 mg/m 2 of docetaxel, administered as a 1 hour intravenous infusion.
  • PSA levels were measured for each patient prior to initial dosing (e.g., "pre-dose") and subsequently at the end of each cycle.
  • Patients were evaluated for PSA response, which is a field accepted term denoting patients achieving a 50% reduction in their PSA level as compared to their pre-dose PSA level.
  • PSA response rate is the percentage of patients who achieve a PSA response (i.e., the percentage of patients in a study achieving a 50% reduction in PSA level) (Arai et al., J. Urol. 144: 1415-1419, 1990).
  • PSA response was measured in patients based on the interim data provided in Table 2. As shown in Table 2, 7 of the 8 patients treated with eBF-4e ASO and docetaxel achieved a PSA response. Therefore, the interim PSA response rate for this study is 88%.
  • eIF-4E ASO (Formula I, SEQ ID NO: 1) complements or enhances the activity of docetaxel
  • the effect of the combined use of the eIF-4E ASO and docetaxel on reduction in pain for patients with castrate-resistant prostate cancer is studied as follows.
  • patient therapy is commenced with a pre-docetaxel treatment period comprising administration of 3 loading doses of the eIF-4 E ASO, i.e., a 3 hour infusion of 600 mg, 800 mg, or 1000 mg of the eEF-4E ASO once per day for 3 consecutive days during the first week, followed by 10 cycles of combination therapy.
  • Each cycle of combination therapy is 21 days in length, during which patients are treated with a 3 hour infusion of 600 mg, 800 mg, or 1000 mg of the eIF-4ASO on days 1, 8, and 15.
  • patients are treated with 45, 60, or 75 mg/m 2 of docetaxel, administered as a 1 hour intravenous infusion.
  • Patients in the control group are treated similarly to those in the eIF-4E experimental group, except they do not receive the eIF-4E ASO. Thus, patients receive 10 cycles of chemotherapy. Each cycle is 21 days in length. On day 1 of each of cycles 1 through 10, patients are treated with 45, 60, or 75 mg/m 2 of docetaxel, administered as a 1 hour intravenous infusion.
  • Patients receiving the eIF-4E ASO in combination with docetaxel may have reduced pain as compared to patients receiving docetaxel without the eIF-4E ASO.
  • the effect on patient pain when treated with eIF-4E ASO in combination with docetaxel may be additive or greater-than-additive when compared to pain levels in patients treated with eIF-4E ASO alone or docetaxel alone.
  • eIF-4E ASO (Formula I, SEQ ID NO: 1) complements or enhances the activity of docetaxel
  • the effect of the combined use of the e ⁇ F-4E ASO and docetaxel on reduction of bone metastasis with castrate-resistant prostate cancer is studied as follows.
  • patient therapy is commenced with a pre-docetaxel treatment period comprising administration of 3 loading doses of the eIF-4 E ASO, i.e., a 3 hour infusion of 600 mg, 800 mg, or 1000 mg of the eEF-4E ASO once per day for 3 consecutive days during the first week, followed by 10 cycles of combination therapy.
  • Each cycle of combination therapy is 21 days in length, during which patients are treated with a 3 hour infusion of 600 mg, 800 mg, or 1000 mg of the eIF-4ASO on days 1, 8, and 15.
  • patients are treated with 45, 60, or 75 mg/m 2 of docetaxel, administered as a 1 hour intravenous infusion.
  • Patients in the control group are treated similarly to those in the eEF-4E experimental group, except they do not receive the eIF-4E ASO. Thus, patients receive 10 cycles of chemotherapy. Each cycle is 21 days in length. On day 1 of each of cycles 1 through 10, patients are treated with 45, 60, or 75 mg/m 2 of docetaxel, administered as a 1 hour intravenous infusion.
  • Patients receiving the eIF-4E ASO in combination with docetaxel have reduced bone metastases as compared to patients receiving docetaxel without the eIF-4E ASO.
  • the effect on bone metastases when treated with eIF-4E ASO in combination with docetaxel may be additive or greater-than-additive when compared to rate of metastasis or number of bone metastases in patients treated with eIF-4E ASO alone or docetaxel alone.
  • patient #31011 with bilateral rib, right mid lateral sternum, and left parietal occipital calvarium tumors at pre-dose achieved considerable improvement in the bony metastatic disease at cycle 8, after new tumors were found after cycle 4 in the left 4 th and 8 th rib, left sacrum, and possibly the left occipital calvarium.
  • patient #3101 achieved improvement in bone metastasis during the course of combination therapy with the eIF-4E ASO and docetaxel.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de sensibilisation des cellules du cancer de la prostate au docétaxel, d'inhibition de la croissance des tumeurs du cancer de la prostate en nombre et/ou en volume, d'augmentation de la survie, de diminution de l'APS, de diminution de la douleur, et de réduction de la métastase osseuse chez des patients souffrant du cancer de la prostate. Lesdits procédés utilisent un oligonucléotide antisens eIF-4E modifié en association avec du docétaxel.
PCT/US2011/058140 2010-10-29 2011-10-27 Polythérapie destinée au traitement du cancer Ceased WO2012058462A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US40847510P 2010-10-29 2010-10-29
US61/408,475 2010-10-29

Publications (2)

Publication Number Publication Date
WO2012058462A2 true WO2012058462A2 (fr) 2012-05-03
WO2012058462A3 WO2012058462A3 (fr) 2012-06-21

Family

ID=45994772

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/058140 Ceased WO2012058462A2 (fr) 2010-10-29 2011-10-27 Polythérapie destinée au traitement du cancer

Country Status (1)

Country Link
WO (1) WO2012058462A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140323543A1 (en) * 2013-04-25 2014-10-30 Jeremy Richard Graff Treatment of Prostate Cancer with eIF4E Antisense Compounds
US11299737B1 (en) 2020-02-28 2022-04-12 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating SMN2
US12013403B2 (en) 2014-09-12 2024-06-18 Biogen Ma Inc. Compositions and methods for detection of SMN protein in a subject and treatment of a subject

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2256201A3 (fr) * 2003-09-18 2012-07-04 Isis Pharmaceuticals, Inc. Modulation de l'expression de eIF4E
SI1913947T1 (sl) * 2004-04-22 2012-02-29 Lilly Co Eli Kombinirana terapija za zdravljenje raka
BRPI0617663A2 (pt) * 2005-10-21 2011-08-02 Panacea Biotec Ltd composições aperfeiçoadas para terapia de cáncer
US20110301222A1 (en) * 2008-11-21 2011-12-08 Isis Pharmaceuticals, Inc. Combination therapy for the treatment of cancer

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140323543A1 (en) * 2013-04-25 2014-10-30 Jeremy Richard Graff Treatment of Prostate Cancer with eIF4E Antisense Compounds
US12013403B2 (en) 2014-09-12 2024-06-18 Biogen Ma Inc. Compositions and methods for detection of SMN protein in a subject and treatment of a subject
US11299737B1 (en) 2020-02-28 2022-04-12 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating SMN2

Also Published As

Publication number Publication date
WO2012058462A3 (fr) 2012-06-21

Similar Documents

Publication Publication Date Title
Chamberlain et al. Salvage chemotherapy with paclitaxel for recurrent primary brain tumors.
JP2003528920A (ja) 血管損傷性活性を有する併用療法
WO2013158143A1 (fr) Polythérapies par glufosfamide pour le cancer
JP2009536956A (ja) 抗癌治療法
WO2017138925A1 (fr) Combinaisons antitumorales d'oligonucléotides antisens et d'agents anticancéreux
TW201728334A (zh) 用於治療癌症之組合物及方法
WO2012058462A2 (fr) Polythérapie destinée au traitement du cancer
US9963703B2 (en) Compositions and methods for treating pancreatic cancer
US20140323543A1 (en) Treatment of Prostate Cancer with eIF4E Antisense Compounds
US9539231B2 (en) Method for treating triple-negative breast cancer using AMPI-109
US20110301222A1 (en) Combination therapy for the treatment of cancer
US20160317540A1 (en) Therapeutic Treatment
WO2017138924A1 (fr) Compositions et méthodes de traitement du cancer du pancréas
JP2025535604A (ja) 抗がん剤
US8268797B2 (en) Combination therapy for the treatment of cancer
WO2012061306A1 (fr) Polythérapie pour le traitement du cancer
Menendez et al. Growth and molecular interactions of the anti-EGFR antibody cetuximab and the DNA cross-linking agent cisplatin: new prospects in the treatment of triple-negative/basal-like breast cancer
WO2018221735A1 (fr) Nouveaux oligonucléotides
Schild IIIB. 2 The therapy of locally advanced non-small cell lung cancer (NSCLC) in the elderly
Gridelli IIIB. 3 Targeted therapies and chemotherapy: new challenge for the treatment of advanced NSCLC elderly patients
HK1193771B (en) Therapeutic treatment

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11837114

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11837114

Country of ref document: EP

Kind code of ref document: A2