WO2013085902A1 - Procédés de polythérapie pour le traitement d'un cancer du sein inflammatoire - Google Patents

Procédés de polythérapie pour le traitement d'un cancer du sein inflammatoire Download PDF

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WO2013085902A1
WO2013085902A1 PCT/US2012/067759 US2012067759W WO2013085902A1 WO 2013085902 A1 WO2013085902 A1 WO 2013085902A1 US 2012067759 W US2012067759 W US 2012067759W WO 2013085902 A1 WO2013085902 A1 WO 2013085902A1
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cancer
composition
agent
breast cancer
paclitaxel
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PCT/US2012/067759
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Fredika M. Robertson
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The University Of Texas M.D.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/15Depsipeptides; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

Definitions

  • the present invention relates to methods and compositions for the treatment of cancer comprising an administration of a combination of a taxane and romidepsin.
  • the cancer is an inflammatory breast cancer.
  • Cancer is a leading cause of death world wide. Despite significant advances in the field of chemotherapy, many of the most prevalent forms of cancer still resist chemotherapeutic intervention.
  • Breast cancer is the most prevalent form of cancer in women.
  • 2009 an estimated 192,370 new cases of invasive breast cancer were expected to be diagnosed in women in the U.S., along with 62,280 new cases of non-invasive (in situ) breast cancer.
  • About 40,170 women in the U.S. were expected to die in 2009 from breast cancer.
  • IBC Inflammatory breast cancer
  • IBC is diagnosed at an earlier age than other types of breast cancers ( ⁇ 52 years of age), and because it is often diagnosed during the child-bearing years, IBC is commonly misdiagnosed as an infection such as mastitis, leading to delays in accurate diagnosis and treatment.
  • IBC does not present as a lump but rather is first noticeable as diffuse erythema of the breast often appearing as a rash or mosquito bite, rapidly progressing, often within days or weeks, to involvement of more than two-thirds of the skin overlying the breast, with swelling and enlargement of the breast and dimpled skin defined as "peau d'orange” (Cristofanilli et al, Cancer, 2007 Oct 1;110(7): 1436- 44).
  • Taxanes have been shown to have significant antineoplastic and anticancer effects in a wide variety of cancers.
  • paclitaxel acts by interfering with the normal function of microtubule breakdown.
  • Paclitaxel binds to the beta subunit of tubulin, the building blocks of microtubules, causing hyper-stabilization of the microtubule structures.
  • the resulting paclitaxel/microtubule structure is unable to disassemble, thereby arresting mitosis and inhibiting angiogenesis.
  • the poor aqueous solubility for the taxanes presents significant challenges for developing effective taxane-based cancer therapeutics.
  • the interaction of different taxane formulations with other therapeutic agents in the combination therapy context remains to be studied.
  • Albumin-based nanoparticle compositions have been developed as a drug delivery system for delivering substantially water insoluble drugs such as taxanes. See, for example, U.S. Pat. Nos. 5,916,596; 6,506,405; 6,749,868, 6,537,579, 7,820,788, U.S. Pat. Pub. Nos. 2007/0082838, WO08/057562, WO2009126938A1, WO2009126401A1 , and WO2009126175A1.
  • the albumin-based nanoparticle technology utilizes the natural properties of the protein albumin to transport and deliver substantially water insoluble drugs to the site of disease. These nanoparticles are readily incorporated into the body's own transport processes and are able to exploit the tumors' attraction to albumin, enabling the delivery of higher
  • the albumin-based nanoparticle technology offers the ability to improve a drug's solubility by avoiding the need for toxic chemicals, such as solvents, in the administration process, thus potentially improving safety through the elimination of solvent-related side effects.
  • the invention provides combination therapy methods of treating a proliferative disease (such as cancer), comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel) and b) an effective amount of at least one other agent that modifies the epigenetics in a cell (also referred herein as an "epigenetic modifier" or "the other agent”).
  • a proliferative disease such as cancer
  • the invention provides a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual a) an effective amount of a composition comprising paclitaxel and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the other agent modifies (such as inhibits) DNA methylation.
  • the other agent modifies histone modification, which includes, but is not limited to, histone acetylation, histone methylation, histone sumoylation, and histone
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as decitabine). In some embodiments, the other agent is an inhibitor of a histone deacetylase (such as romidepsin).
  • the proliferative disease is resistant or refractory to the treatment of taxane when administered alone or in conjunction with an agent other than the epigenetic modifier. In some embodiments, the proliferative disease is resistant or refractory to the treatment when the epigenetic modifier is administered alone or in conjunction with another agent (such as a taxane including paclitaxel).
  • the methods of the present application are useful for the treatment of various diseases, including, for example, breast cancer, lung cancer (such as small cell lung cancer and non-small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the proliferative disease is solid tumor. In some embodiments, the proliferative disease is liquid tumor.
  • compositions for use in the methods described herein comprises paclitaxel and a pharmaceutically acceptable carrier.
  • the composition comprising paclitaxel and the composition comprising another agent are administered simultaneously, either in the same composition or in separate compositions.
  • the composition and the other agent are administered sequentially, i.e., the composition is administered either prior to or after the administration of the other agent.
  • the administration of the composition and the other agent is concurrent, i.e., the administration period of the composition and that of the other agent overlap with each other.
  • the composition is administered for at least one cycle (for example, at least any of 2, 3, or 4 cycles) prior to the administration of the other agent.
  • the other agent is administered for at least any of one, two, three, or four weeks after the termination of the nanoparticle composition.
  • the composition and the epigenetic modifier are administered over the same treatment cycles.
  • the administration of the composition and the other agent are non-concurrent.
  • the administration of the composition is terminated before the other agent is administered.
  • the administration of the other agent is terminated before the composition is administered.
  • the other agent is a histone deacetylase inhibitor, including, but not limited to, romidepsin, vorinostat, panobinostat, belinostat, and entinostat.
  • the other agent is an inhibitor of DNA
  • methyltransferase including, but not limited to, 5-azacytidine (azacitidine or Vidaza), 5-aza-2'-deoxycytidine (decitabine or Dacogen), l-P-D-arabinofuranosil-5- azacytosine, dihydro-5-azacytidine, antisense oligonucleotide MG98, and zebularine.
  • 5-azacytidine azacitidine or Vidaza
  • 5-aza-2'-deoxycytidine decitabine or Dacogen
  • l-P-D-arabinofuranosil-5- azacytosine dihydro-5-azacytidine
  • antisense oligonucleotide MG98 antisense oligonucleotide MG98
  • zebularine including, but not limited to, 5-azacytidine (azacitidine or Vidaza), 5-aza-2'-deoxycytidine (decitabine or Dacogen), l-P
  • proliferative disease such as cancer
  • a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel) and b) an effective amount of romidepsin.
  • a method of treating a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel) and b) an effective amount of an azacitidine.
  • a method of treating a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel) and b) an effective amount of a decitabine.
  • a proliferative disease such as cancer
  • a method of treating breast cancer in an individual comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel) and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • a method of treating breast cancer in an individual wherein the individual is negative for ER, PR, and HER2, comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel) and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the method further comprises conducting definitive surgery within about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 following the preoperative therapy.
  • the methods of the invention generally comprise administration of a composition comprising a taxane (such as paclitaxel).
  • a taxane such as paclitaxel
  • the composition comprises paclitaxel.
  • a method of treating breast cancer comprising administering to said individual a) an effective amount of paclitaxel and b) an effective amount of a histone deacetylase inhibitor.
  • a method of treating breast cancer comprising administering to said individual a) an effective amount of paclitaxel and b) an effective amount of a DNA methyltransferase inhibitor.
  • a method of treating breast cancer comprising administering to said individual a) an effective amount of paclitaxel and b) an effective amount ofromidepsin.
  • the method further comprises administering to the individual an effective amount of a platinum-based agent.
  • a method of treating breast cancer comprising: a) intravenously administering an effective amount of paclitaxel to the individual, and b) orally administering an effective amount of romidepsin to the individual.
  • the method further comprises intravenously administering to the individual an effective amount of a platinum-based agent (such as carboplatin).
  • a method of treating breast cancer comprising: a) intravenously administering about 80 to about 200 mg/m 2 (such as about 100 mg/m 2 ) of paclitaxel to the individual, and b) orally administering about 10 mg/m 2 to about 300 mg/m 2 of romidepsin to the individual.
  • the method further comprises intravenously administering to the individual an effective amount of a platinum-based agent (such as carboplatin) at the dose of AUC2.
  • a platinum-based agent such as carboplatin
  • a method of treating breast cancer comprising: a) intravenously administering about 80 to about 200 mg/m 2 (such as about 100 mg/m 2 ) of paclitaxel to the individual weekly, and b) orally administering about 10 to about 300 mg/m 2 of romidepsin to the individual three out of every seven days.
  • the method further comprises
  • the composition (and the carboplatin) is administered on day one of each week, and romidepsin is administered on days 1-3 of each week.
  • the combination treatment is repeated every four weeks for four or more cycles.
  • kits and compositions useful for methods described herein are kits and compositions useful for methods described herein.
  • Figure 1 shows moleclular subtypes of breat cancer cell lines.
  • Figure 2 shows dose dependent inhibition of proliferation, invasion, anchorage and independent growth of soft agar and clonogenic growth in breast cancer cell lines by romidepsin.
  • Figure 3 shows the Mary-X model of IBC that recapitulates formation of tumor emboli with E-cadherin expression, shown as stains that invade into the skin and chest wall as cohesive aggregates of tumor cells.
  • Figures 4 A - 4F show induction of a dose dependent apoptosis in the Mary-X IBC tumor spheroids by romidepsin.
  • Figures 5 A - 5G show induction of a dose dependent apoptosis in the Mary-X IBC tumor spheroids by romidepsin.
  • Figure 6 shows a dose-dependent induction of p21, acetylated histone 3 and acetylated tubulin proteins in breast cancer cell lines by romidepsin.
  • Figure 7 shows an inhibition of growth of Mary-X xenografts by romidepsin.
  • Mary-X tumor spheroids were injected into NOD.Cg-Prkdc scld I I- 2ry tmlWj! /SzJ female mice via the subcutaneous route.
  • Animals were matched for tumor size into treatment groups at day 105 after cell injection and treated with romidepsin in a dose of 2.5 mg/kg iv in a vehicle of N-Methyl-Pyrrolidone at 2.5%, 5% Dextrose dosed Q4D x 3 at days 105, 108, and 1 12.
  • Mice were imaged weekly using bioluminescence live in vivo imaging techniques. Study was terminated at day 154 and tissues isolated for histological and molecular analysis.
  • FIGS 8 A - 8B show inhibition of growth of SUM 149 IBC xenografts (by tumor volume and luminescence) by romidepsin.
  • SUM 149 cells (5 x 105) were injected into mammary fat pads of NOD.Cg-Prkdc scld II-2i-y ti l w ' '/SzJ female mice and treated with 2.5 mg/kg of romidepsin Q4Dx3 at days 3 1 , 35, amd 38 after tumor cell injection; 7.5 mg/kg Paclitaxel Q4D beginning at day 30 in a vehicle of 5% cremaphor, 5% ethanol and 5% dextrose or the combination of these 2 agents.
  • Figures 9A - 9D demonstrate inhibition of growth of SUM 149 IBC xenografts by romidepsin (B), paclitaxel (C), and the combaination of romidepsin Abd paclitaxel.
  • Figure 9A demonstrates vehicle control.
  • the present invention provides methods of combination therapy comprising administration of a taxane (such as paclitaxel) in conjunction with a second agent that modifies the epigenetics in a cell (also referred to as an "epigenetic modifier").
  • a taxane such as paclitaxel
  • a second agent that modifies the epigenetics in a cell also referred to as an "epigenetic modifier”
  • the present application thus provides methods of combination therapy. It is to be understood by a person of ordinary skill in the art that the combination therapy methods described herein requires that one agent or composition be administered in conjunction with another agent.
  • “In conjunction with” refers to administration of one treatment modality in addition to another treatment modality, such as administration of a nanoparticle composition described herein in addition to administration of the other agent to the same individual.
  • “in conjunction with” refers to administration of one treatment modality before, during or after delivery of the other treatment modality to the individual.
  • treatment is an approach for obtaining beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, preventing or delaying spread (e.g., metastasis, for example metastasis to the lung or to the lymph node) of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, and remission (whether partial or total).
  • treatment is a reduction of pathological consequence of a proliferative disease.
  • the methods of the invention contemplate any one or more of these aspects of treatment.
  • An "agent that modifies the epigenetics in a cell” or “epigenetic modifier” refers to an agent that modifies an epigenetic status of a cell, namely, a phenotype or gene expression in the cell that is caused by mechanisms other than changes in the DNA sequence.
  • An epigenetic status of a cell includes, for example, DNA
  • triple negative breast cancer refers to individuals who are clinically negative for expression of estrogen receptor (ER), progesterone receptors (PR) and HER2 protein.
  • ER estrogen receptor
  • PR progesterone receptors
  • HER2 protein HER2 protein.
  • inflammatory breast cancer used herein refers to a special type of non metastatic breast tumor that is characterized by the presence of invasion of tumor cells into the lympatics of the dermis and subdermis.
  • an effective amount refers to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease such as ameliorate, palliate, lessen, and/or delay one or more of its symptoms.
  • an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation.
  • the term "individual" is a mammal, including humans.
  • An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is human.
  • adjuvant setting refers to a clinical setting in which an individual has had a history of a proliferative disease, particularly cancer, and generally (but not necessarily) been responsive to therapy, which includes, but is not limited to, surgery (such as surgical resection), radiotherapy, and chemotherapy. However, because of their history of the
  • proliferative disease such as cancer
  • Treatment or administration in the "adjuvant setting” refers to a subsequent mode of treatment.
  • the degree of risk i.e., when an individual in the adjuvant setting is considered as "high risk” or "low risk" depends upon several factors, most usually the extent of disease when first treated.
  • the methods provided herein may also be practiced in a "neoadjuvant setting," i.e., the method may be carried out before the primary/definitive therapy.
  • the individual has previously been treated.
  • the individual has not previously been treated.
  • the treatment is a first line therapy.
  • Romidepsin is a natural product which was isolated from
  • Chromobacterium violaceum by Fujisawa Pharmaceuticals published Japanese Patent Application No. 64872, U.S. Patent 4,977,138, issued December 11, 1990, Ueda et al., J. Antibiot (Tokyo) 47:301-310, 1994; Nakajima et al, Exp Cell Res 241 : 126-133, 1998; and WO 02/20817; each of which is incorporated herein by reference. It is a bicyclic peptide consisting of four amino acid residues (D-valine, D- cysteine, dehydrobutyrine, and L-valine) and a novel acid (3-hydroxy-7-mercapto-4- heptenoic acid) containing both amide and ester bonds.
  • romidepsin can also be prepared by synthetic or semi-synthetic means.
  • the total synthesis of romidepsin reported by Kahn et al. involves 14 steps and yields romidepsin in 18% overall yield (Kahn et al. J. Am. Chem. Soc. 118:7237-7238, 1996).
  • romidepsin The chemical name of romidepsin is (lS,4S,7Z,10S,16E,21R)-7- ethylidene-4,21 -bis(l -methylethyl)-2-oxa- 12, 13-dithia-5,8,20,23- tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone.
  • the empirical formula is C24H 36 N 4 0 6 S2.
  • the molecular weight is 540.71. At room temperature, romidepsin is a white powder.
  • Romidepsin has been shown to have anti-microbial, immunosuppressive, and anti-tumor activities. It was tested, for example, for use in treating patients with hematological malignancies (e.g, cutaneous T-cell lymphoma (CTCL), peripheral T- cell lymphoma (PTCL), multiple myeloma, etc) and solid tumors ⁇ e.g., prostate cancer, pancreatic cancer, etc.) and is thought to act by selectively inhibiting deacetylases ⁇ e.g., histone deacetylase, tubulin deacetylase), thus promising new targets for the development of a new class of anti-cancer therapies (Nakajima et al., Exp Cell Res 241 : 126-133, 1998).
  • CTCL cutaneous T-cell lymphoma
  • PTCL peripheral T- cell lymphoma
  • multiple myeloma e.g., prostate cancer, pancreatic cancer, etc.
  • solid tumors
  • romidepsin involves the inhibition of one or more classes of histone deacetylases (HDAC). Preparations and purification of romidepsin is described, for example, in U.S. Patent 4,977,138 and International PCT Application Publication WO 02/20817, each of which is incorporated herein by reference.
  • HDAC histone deacetylases
  • romidepsin examples include, but are not limited to, salts, esters, pro-drugs, isomers, stereoisomers ⁇ e.g., enantiomers, diastereomers), tautomers, protected forms, reduced forms, oxidized forms, derivatives, and combinations thereof, with the desired activity ⁇ e.g., deacetylase inhibitory activity, aggressive inhibition, cytotoxicity).
  • romidepsin is a pharmaceutical grade material and meets the standards of the U.S. Pharmacopoeia, Japanese Pharmacopoeia, or European Pharmacopoeia.
  • the romidepsin is at least 95%, at least 98%>, at least 99%, at least 99.9%, or at least 99.95%) pure. In certain embodiments, the romidepsin is at least 95%, at least 98%>, at least 99%, at least 99.9%, or at least 99.95% monomeric. In certain embodiments, no impurities are detectable in the romidepsin materials ⁇ e.g., oxidized material, reduced material, dimerized or oligomerized material, side products, etc.). Romidepsin typically includes less than 1.0%, less than 0.5%, less than 0.2%, or less than 0.1% of total other unknowns.
  • the purity of romidepsin may be assessed by appearance, HPLC, specific rotation, NMR spectroscopy, IR spectroscopy, UV/Visible spectroscopy, powder x-ray diffraction (XRPD) analysis, elemental analysis, LC-mass spectroscopy, or mass spectroscopy.
  • Romidepsin is sold under the tradename Istodax® and is approved for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy, and for the treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.
  • CTCL cutaneous T-cell lymphoma
  • PTCL peripheral T-cell lymphoma
  • Paclitaxel is a natural product with antitumor activity.
  • TAXOL paclitaxel
  • TAXOL paclitaxel
  • the chemical name for paclitaxel is 5P,20-Epoxy-l,2a,4,7P,10p,13a-hexahydroxytax-l l-en-9-one 4,10- diacetate 2-benzoate 13-ester with (2i?,3S)-N-benzoyl-3-phenylisoserine.
  • Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51N014 and a molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216-217° C.
  • the present invention provides methods of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • a proliferative disease such as cancer
  • proliferative disease such as cancer
  • administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of at least one other agent that modifies the epigenetics in a cell, wherein the composition and the other agent are administered concurrently.
  • the administrations of the composition and the other agent are initiated at about the same time (for example, within any one of 1, 2, 3, 4, 5, 6, or 7 days).
  • the administrations of the composition and the other agent are terminated at about the same time (for example, within any one of 1, 2, 3, 4, 5, 6, or 7 days).
  • the administration of the other agent continues (for example for about any one of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) after the termination of the administration of the composition.
  • the administration of the other agent is initiated after (for example after about any one of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) the initiation of the administration of the composition.
  • the administrations of the composition and the other agent are initiated and terminated at about the same time.
  • the administrations of the composition and the other agent are initiated at about the same time and the administration of the other agent continues (for example for about any one of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) after the termination of the administration of the composition.
  • the administration of the composition and the other agent stop at about the same time and the administration of the other agent is initiated after (for example after about any one of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) the initiation of the administration of the composition. In some embodiments, the administration of the composition and the other agent stop at about the same time and the administration of the composition is initiated after (for example after about any one of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) the initiation of the administration of the other agent.
  • the taxane is any of (and in some embodiments consisting essentially of) paclitaxel, docetaxel, and ortataxel. In some embodiments, the taxane is paclitaxel. In some embodiments, the taxane is docetaxel.
  • proliferative disease in an individual, comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel)); and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the composition and the other agent are administered concurrently.
  • the proliferative disease is a cancer selected from the group consisting of breast cancer, lung cancer (such as small cell lung cancer and non-small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the other agent modifies DNA methylation or histone modification. In some embodiments, the other agent modifies (such as inhibits) DNA methylation. In some embodiments, the other agent modifies histone modification, which include, but not limited to, histone acetylation, histone methylation, histone sumoylation, and histone phosphorylation. In some
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine). In some embodiments, the other agent is an inhibitor of DNA
  • the other agent is an inhibitor of a histone deacetylase (such as romidepsin).
  • proliferative disease such as cancer
  • a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that inhibits DNA methylation.
  • a method of treating a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of an inhibitor of DNA methyltransferase.
  • methylation include, but are not limited to, 5-azacytidine (azacitidine or Vidaza), 5-aza-2'-deoxycytidine, l-P-D-arabinofuranosil-5-azacytosine, dihydro-5-azacytidine, antisense oligonucleotide MG98, and zebularine.
  • proliferative disease such as cancer
  • a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies histone modification.
  • a method of treating a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies histone acetylation.
  • a method of treating a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies histone methylation.
  • a method of treating a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies histone sumoylation.
  • a method of treating a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies histone phosphorylation.
  • a proliferative disease such as cancer
  • proliferative disease such as cancer
  • administering comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of an inhibitor of a histone deacetylase ("HDAC").
  • HDACs are classified in four groups based on their homology to yeast histone deacetylases. Class I includes HDAC1, -2, -3 and -8, which are related to yeast RPD3 gene. Class II includes HDAC4, -5, -6, -7, -9 and -10, which are related to yeast Hdal gene.
  • Class III also known as the sirtuins, are related to the Sir2 gene and includes SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7.
  • Class IV which contains only HDAC11, has features of both Class I and II.
  • the histone deacetylase inhibitors described herein in some embodiments are specific to only one specific HDAC. In some embodiments, the histone deacetylase inhibitor is specific to one specific class of HDAC. In some embodiments, the histone deacetylase inhibitor is an inhibitor of two or more HDACs or two or more classes of HDACs. In some embodiments, the histone deacetylase inhibitor inhibits class I and II HDACs. In some embodiments, the histone deacetylase inhibitor inhibits class III HDAC.
  • the other agent is a hydroxamic acid, including, but not limited to, vorinostat (suberoylanilide hydroxamic acid or "SAHA”), trichostatin A (“TSA”), LBH589 (panobinostat), PXD101 (belinostat), oxamflatin, tubacin, seriptaid, NVP-LAQ824, cinnamic acid hydroxamic acid (CBHA), CBHA
  • Vorinostat or suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDAC). It is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after treatment with other medicines.
  • CTCL cutaneous T cell lymphoma
  • Trichostatin A (TSA, 7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6- dimethyl-7-oxohepta-2,4-dienamide) is an organic compound that selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs (i.e., Sirtuins). TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage.
  • HDAC histone deacetylase
  • the other agent is a cyclic peptide, including, but not limited to, trapoxin B, FK228 (romidepsin), trapoxin A, apicidin, depsipeptide, and CHAP.
  • the other agent is a benzamide, including, but not limited to, mocetinostat (MGCD0103), benzamide M344, BML-210, entinostat (SNDX-275 or MS-275), pimelic diphenylamide 4b, pimelic diphenylamide 106, MS- 994, CI-994 (acetyldinaline, PD 123654, and 4-acetylamino-N-(Uaminophenyl)- benzamide.
  • MGCD0103 mocetinostat
  • Mocetinostat N-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2- yl)amino]methyl] benzamide works by inhibiting mainly histone deacetylase 1 (HDAC1). It also inhibits HDAC2, HDAC3, and HDAC1 1.
  • the other agent is an electrophilic ketone, including, but not limited to, trifluoromethyl ketones and ketoamides.
  • the other agent is an aliphatic acid compound, including, but not limited to, butyrate, phenylbutyrate, valproic acid (vpa), and phenylacetate.
  • the other agent is selected from the group consisting of vorinostat (SAHA), belinostat (PXD101), LAQ824, panobinostat (LBH589); entinostat (MS275), CI994, and mocetinostat (MGCD0103).
  • the other agent is selected from the group consisting of vorinostat, romidepsin, panobinostat, valproic acid, and mocetinostat.
  • the other agents described herein can be the agents themselves, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable esters thereof, as well as stereoisomer, enantiomers, racemic mixtures, and the like.
  • the other agent or agents as described can be administered as well as a pharmaceutical composition containing the agent(s), wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier vehicle, or the like.
  • references to an agent herein applies to the other agent or its derivatives and accordingly the invention contemplates and includes either of these embodiments (agent; agent or derivative(s)).
  • “Derivatives” or “analogs” of an agent or other chemical moiety include, but are not limited to, compounds that are structurally similar to the other agent or moiety or are in the same general chemical class as the other agent or moiety.
  • the derivative or analog of the other agent or moiety retains similar chemical and/or physical property (including, for example, functionality) of the other agent or moiety.
  • the other agent is vorinostat.
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of vorinostat.
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; and b) an effective amount of vorinostat.
  • the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer (such as small cell lung cancer and non-small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the cancer is breast cancer, such as triple negative breast cancer.
  • the cancer is inflammatory breast cancer.
  • the other agent is romidepsin.
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of Romidepsin.
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; and b) an effective amount of romidepsin.
  • the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer (such as small cell lung cancer and non-small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the cancer is breast cancer, such as triple negative breast cancer.
  • the cancer is inflammatory breast cancer.
  • proliferative disease such as cancer
  • a proliferative disease in an individual, comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of romidepsin, wherein the composition is administered intravenously, wherein the romidepsin is administered orally.
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; and b) an effective amount of romidepsin wherein the composition is administered intravenously and wherein the romidepsin is administered orally.
  • the composition and the romidepsin are administered concurrently.
  • the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer (such as small cell lung cancer and non-small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the cancer is breast cancer, such as triple negative breast cancer.
  • the cancer is inflammatory breast cancer.
  • proliferative disease such as cancer
  • a composition comprising a taxane (such as paclitaxel), wherein the taxane is in the dosage range of about 60-300 mg/m 2
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 60-300 mg/m 2 (including for example about 80-200 mg/m 2 for example about 100 mg/m 2 ), and b) about 10 mg/m 2 to about 300 mg/m 2 romidepsin.
  • tromidepsin is administered orally.
  • the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer (such as small cell lung cancer and non-small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the cancer is breast cancer, such as triple negative breast cancer.
  • the cancer is inflammatory breast cancer.
  • proliferative disease such as cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of a DNA methyltransferase inhibitor.
  • a method of treating cancer such as breast cancer, including triple negative breast cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of a DNA methyltransferase inhibitor.
  • a method of treating cancer comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; and b) an effective amount of azacitidine.
  • a method of treating cancer comprising: a) intravenously administering an effective amount of a composition comprising paclitaxel; b) intravenously or subcutaneously administering an effective amount of azacitidine.
  • proliferative disease such as cancer
  • a proliferative disease such as cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of azacitidine.
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; and b) an effective amount of azacitidine.
  • the composition and the azacitidine are administered concurrently.
  • the composition is administered intravenously.
  • the azacitidine is administered intravenously or subcutaneously.
  • the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer (such as small cell lung cancer and non- small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the cancer is breast cancer, such as triple negative breast cancer.
  • the cancer is inflammatory breast cancer.
  • proliferative disease such as cancer
  • a proliferative disease in an individual, comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of azacitidine, wherein the composition and the azacitidine are administered intravenously.
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; and b) an effective amount of azacitidine.
  • the composition is administered intravenously.
  • the azacitidine is administered intravenously or subcutaneously. In some
  • the composition and the azacitidine are administered concurrently.
  • the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer (such as small cell lung cancer and non- small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the cancer is breast cancer, such as triple negative breast cancer.
  • the cancer is inflammatory breast cancer.
  • proliferative disease such as cancer
  • a composition comprising a taxane (such as paclitaxel), wherein the taxane is in the dosage range of about 60-300 mg/m 2 (including for example about 80-200 mg/m 2 for example about 100 mg/m 2 ), and b) about 5-500 mg/m 2 (including for example about 10-200 mg/m 2 for example about 50-100 mg/m 2 or for example about 75 mg/m 2 ) azacitidine.
  • a taxane such as paclitaxel
  • a method of treating a proliferative disease comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 60-300 mg/m 2 (including for example about 80-200 mg/m 2 for example about 100 mg/m 2 ), and b) about 5-500 mg/m 2 (including for example about 10-200 mg/m 2 for example about 50-100 mg/m 2 for example about 75 mg/m 2 ) azacitidine.
  • the composition is administered intravenously.
  • the azacitidine is administered intravenously or subcutaneously.
  • the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer (such as small cell lung cancer and non-small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the cancer is breast cancer, such as triple negative breast cancer.
  • the cancer is inflammatory breast cancer.
  • a method of treating cancer comprising: a) intravenously administering a composition comprising paclitaxel at the dose of about 80 to about 200 mg/m 2 (such as aboutlOO mg/m 2 ); b) intravenously or subcutaneously administering about 20 to about 200 mg/m 2 (such as about 50-100 mg/m 2 or for example about 75 mg/m 2 ) azacitidine.
  • a method of treating cancer comprising: a) intravenously administering a composition comprising paclitaxel at the dose of about 80 to about 200 mg/m 2 (such as aboutlOO mg/m 2 ) weekly; b) intravenously or subcutaneously administering about 20 to about 200 mg/m 2 (such as about 50-100 mg/ m 2 , for example about 75 mg/m 2 ) azacitidine daily.
  • the administrations of the composition and the azacitidine are concurrent.
  • the composition is
  • proliferative disease such as cancer
  • a proliferative disease comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel)l; and b) an effective amount of a DNA methyltransferase inhibitor.
  • a method of treating cancer such as breast cancer, including triple negative breast cancer
  • administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of a DNA methyltransferase inhibitor comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of a DNA methyltransferase inhibitor.
  • a method of treating cancer comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; and b) an effective amount of decitabine.
  • a method of treating cancer comprising: a) intravenously administering an effective amount of a composition comprising paclitaxel; b) intravenously or intraperitoneally administering an effective amount of azacitidine.
  • proliferative disease such as cancer
  • a proliferative disease such as cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of decitabine.
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; and b) an effective amount of decitabine.
  • the composition and the decitabine are administered concurrently.
  • the composition is administered intravenously or
  • the decitabine is administered intravenously or intraperitoneally.
  • the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer (such as small cell lung cancer and non-small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the cancer is breast cancer, such as triple negative breast cancer.
  • the cancer is inflammatory breast cancer.
  • proliferative disease such as cancer
  • a proliferative disease such as cancer
  • administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of decitabine, wherein the composition and the decitabine are administered intravenously.
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; and b) an effective amount of decitabine.
  • the composition is administered intravenously.
  • the decitabine is administered intravenously or intraperitoneally. In some
  • the composition and the decitabine are administered concurrently.
  • the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer (such as small cell lung cancer and non- small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the cancer is breast cancer, such as triple negative breast cancer.
  • the cancer is inflammatory breast cancer.
  • proliferative disease such as cancer
  • a composition comprising a taxane (such as paclitaxel), wherein the taxane is in the dosage range of about 60-300 mg/m 2
  • a method of treating a proliferative disease comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 60-300 mg/m 2
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel), wherein the taxane is in the dosage range of about 60-300 mg/m 2 (including for example about 80-200 mg/m 2 for example about 100 mg/m 2 ), and b) about 5-500 mg/ m 2 (including for example about 10-200 mg/m 2 for example about 15-20 mg/m 2 ) decitabine.
  • a taxane such as paclitaxel
  • the composition is administered intravenously.
  • the decitabine is administered intravenously or intraperitoneally.
  • the proliferative disease is cancer selected from the group consisting of breast cancer, lung cancer (such as small cell lung cancer and non-small cell lung cancer), renal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, brain cancer, colorectal cancer, leukemia, lymphoma, and multiple myeloma.
  • the cancer is breast cancer, such as triple negative breast cancer.
  • the cancer is inflammatory breast cancer.
  • a method of treating cancer comprising: a) intravenously administering a composition comprising paclitaxel at the dose of about 80 to about 200 mg/m 2 (such as aboutlOO mg/m 2 ); b) intravenously or intraperitoneally administering about 5 to about 200 mg/m 2 (such as about 15-20 mg/m 2 ) decitabine.
  • a method of treating cancer comprising: a) intravenously administering a composition comprising paclitaxel at the dose of about 80 to about 200 mg/m 2 (such as aboutlOO mg/m 2 ) weekly; b) intravenously or intraperitoneally administering about 5 to about 200 mg/m 2 (such as about 15-20 mg/m 2 ) decitabine daily.
  • a method of treating cancer comprising: a) intravenously administering a composition comprising paclitaxel at the dose of about 80 to about 200 mg/m 2 (such as aboutlOO mg/m 2 ) weekly; b) intravenously or intraperitoneally administering about 5 to about 200 mg/m 2 (such as about 15-20 mg/m 2 ) decitabine every eight hours for three days.
  • the composition is administered three out of four weeks and the decitabine is administered on days 1-3 on a six week cycle.
  • the administrations of the composition and the decitabine are concurrent.
  • a method of treating cancer comprising: a) intravenously administering a composition comprising paclitaxel at the dose of about 80 to about 200 mg/m 2 (such as about 100 mg/m 2 ) weekly; b) intravenously or intraperitoneally administering about 5 to about 200 mg/m 2 (such as about 15-20 mg/m 2 ) decitabine daily for five days.
  • the administrations of the composition and the decitabine are concurrent.
  • the composition is administered three out of four weeks and the decitabine is administered on days 1-5 on a four week cycle.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer in an individual comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of a DNA methyltransferase inhibitor.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer in an individual comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); and b) an effective amount of azacitidine.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; and b) an effective amount of a DNA
  • a method of treating breast cancer comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel, and b) an effective amount of azacitidine.
  • the composition is
  • the azacitidine is administered intravenously or subcutaneously.
  • the breast cancer is an early stage breast cancer, non-metastatic breast cancer, stage IV breast cancer, locally advanced breast cancer, metastatic breast cancer, hormone receptor positive metastatic breast cancer, breast cancer in remission, breast cancer in an adjuvant setting, ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), or breast cancer in a neoadjuvant setting.
  • the breast cancer is hormone receptor positive metastatic breast cancer.
  • the breast cancer (which may be HER2 positive or HER2 negative) is advanced breast cancer.
  • the breast cancer is ductal carcinoma in situ.
  • the individual may be a human who has a gene, genetic mutation, or polymorphism associated with breast cancer (e.g., BRCAl , BRCA2, ATM, CHEK2, RAD51 , AR, DIRAS3, ERBB2, TP53, AKT, PTEN, and/or PI3K) or has one or more extra copies of a gene (e.g., one or more extra copies of the HER2 gene) associated with breast cancer.
  • a gene, genetic mutation, or polymorphism associated with breast cancer e.g., BRCAl , BRCA2, ATM, CHEK2, RAD51 , AR, DIRAS3, ERBB2, TP53, AKT, PTEN, and/or PI3K
  • a gene, genetic mutation, or polymorphism associated with breast cancer e.g., BRCAl , BRCA2, ATM, CHEK2, RAD51 , AR, DIRAS3, ERBB2, TP53, AKT, PTEN, and/or PI3K
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer
  • administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel), wherein the taxane is in the dosage range of about 60-300 mg/m 2 (including for example about 80-200 mg/m 2 or for example about 100 mg/m 2 ), and b) about 5-500 mg/m 2 (including for example about 10-200 mg/m 2 or for example about 50-100 mg/m 2 ) azacitidine.
  • a taxane such as paclitaxel
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer
  • administering to the individual: a) an effective amount of a composition comprising paclitaxel, wherein the paclitaxel is in the dosage range of about 60-300 mg/m 2 (including for example about 80-200 mg/m 2 or for example about 100 mg/m 2 ), and b) about 5-500 mg/m 2 (including for example about 10-200 mg/m 2 or for example about 50-100 mg/m 2 or for example about 75 mg/m 2 ) azacitidine.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer
  • administering to the individual: a) an effective amount of a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 100 mg/m 2 , and b) about 50 mg/m 2 to about 100 mg/m 2 (such as 75 mg/m 2 ) azacitidine.
  • the composition is administered first followed by administration of the azacitidine.
  • the azacitidine is administered first followed by administration of the composition.
  • the administrations of the composition and the azacitidine are concurrent.
  • the composition is administered three out of four weeks and the azacitidine is administered on the first, second, third, fourth, fifth, or sixth day (such as on days 1-5) on a four week cycle.
  • the azacitadine is administered on days 1-5, followed by administration of the
  • nanoparticle composition on days 8, 15, and 22 of a 28-day cycle, for a total of 6 cycles.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 100 mg/m 2 , and b) about 50 mg/m 2 to about 100 mg/m 2 (such as 75 mg/m 2 ) azacitidine, wherein the azacitadine is administered on days 1-5 followed by administration of the composition on days 8, 15, and 22 of a 28-day cycle, for a total of 6 cycles.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 100-150 mg/m 2 (such as 100 mg/m 2 ) and b) subcutaneously administering to the individual about 50-100 mg/m 2 (such as 75 mg/m 2 ) azacitidine, wherein the azacitadine is subcutaneously administered on days 1-5, followed by intravenous administration of the composition on days 8, 15, and 22 of a 28-day cycle, for a total of 6 cycles.
  • the individual suffering from breast cancer has not had prior cytotoxic regimens.
  • the individual suffering from breast cancer has had no more than 2 prior cytotoxic regimens.
  • the individual suffering from breast cancer has had more than 2 prior cytotoxic regimens.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of a DNA methyltransferase inhibitor.
  • a taxane such as paclitaxel
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of decitabine.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • administering to the individual a) an effective amount of a composition comprising paclitaxel, and b) an effective amount of a DNA methyltransferase inhibitor.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel), and b) an effective amount of decitabine.
  • the composition is
  • the decitabine is administered intravenously or intraperitoneally.
  • the breast cancer is an early stage breast cancer, non-metastatic breast cancer, stage IV breast cancer, locally advanced breast cancer, metastatic breast cancer, hormone receptor positive metastatic breast cancer, breast cancer in remission, breast cancer in an adjuvant setting, ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), or breast cancer in a neoadjuvant setting.
  • the breast cancer is hormone receptor positive metastatic breast cancer.
  • the breast cancer (which may be HER2 positive or HER2 negative) is advanced breast cancer.
  • the breast cancer is ductal carcinoma in situ.
  • the individual may be a human who has a gene, genetic mutation, or polymorphism associated with breast cancer (e.g., BRCAl , BRCA2, ATM, CHEK2, RAD51 , AR, DIRAS3, ERBB2, TP53, AKT, PTEN, and/or PI3K) or has one or more extra copies of a gene (e.g., one or more extra copies of the HER2 gene) associated with breast cancer.
  • a gene, genetic mutation, or polymorphism associated with breast cancer e.g., BRCAl , BRCA2, ATM, CHEK2, RAD51 , AR, DIRAS3, ERBB2, TP53, AKT, PTEN, and/or PI3K
  • a gene, genetic mutation, or polymorphism associated with breast cancer e.g., BRCAl , BRCA2, ATM, CHEK2, RAD51 , AR, DIRAS3, ERBB2, TP53, AKT, PTEN, and/or PI3K
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel), wherein the taxane is in the dosage range of about 60-300 mg/m 2 (including for example about 80-200 mg/m 2 or for example about 100 mg/m 2 ), and b) about 5-500 mg/m 2 (including for example about 10-200 mg/m 2 or for example about 15-20 mg/m 2 ) decitabine.
  • a taxane such as paclitaxel
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel, wherein the paclitaxel is in the dosage range of about 60-300 mg/m 2 (including for example about 80-200 mg/m 2 or for example about 100 mg/m 2 ), and b) about 5-500 mg/m 2 (including for example about 10-200 mg/m 2 or for example about 15-20 mg/m 2 ) decitabine.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 100 mg/m 2 , and b) about 5 mg/m 2 to about 100 mg/m 2 (such as 15 mg/m 2 ) decitabine.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • administering to the individual: a) an effective amount of a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 100 mg/m 2 , and b) about 5 mg/m 2 to about 100 mg/m 2 (such as 20 mg/m 2 ) decitabine.
  • the composition is administered first followed by administration of the decitabine.
  • the decitabine is administered first followed by administration of the composition.
  • the administrations of the composition and the decitabine are concurrent.
  • the composition for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • composition is administered three out of four weeks and the decitabine is
  • the composition is administered three times a day on the first, second, third, fourth, fifth, or sixth day (such as on days 1-3) on a four week cycle.
  • the composition is administered three out of four weeks and the decitabine is administered on the first, second, third, fourth, fifth or sixth day (such as on days 1-5) on a four week cycle.
  • the decitabine is administered three times a day on days 1-3, followed by administration of the composition on days 8, 15, and 22 of a 28-day cycle, for a total of 6 cycles.
  • the decitabine is administered on days 1-5, followed by administration of the composition on days 8, 15, and 22 of a 28-day cycle, for a total of 6 cycles.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 100 mg/m 2 , and b) about 5 mg/m 2 to about 100 mg/m 2 (such as 15 mg/m 2 ) decitabine, wherein the decitabine is administered three times a day on days 1-3 followed by administration of the composition on days 8, 15, and 22 of a 28-day cycle, for a total of 6 cycles.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • administering comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 100 mg/m 2 , and b) about 5 mg/m 2 to about 100 mg/m 2 (such as 20 mg/m 2 ) decitabine, wherein the decitabine is administered on days 1-5 followed by administration of the composition on days 8, 15, and 22 of a 28-day cycle, for a total of 6 cycles.
  • a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 100 mg/m 2
  • about 5 mg/m 2 to about 100 mg/m 2 such as 20 mg/m 2
  • decitabine is administered on days 1-5 followed by administration of the composition on days 8, 15, and 22 of a 28-day cycle, for a total of 6 cycles.
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • a method of treating breast cancer comprising: a) intravenously administering to the individual an effective amount of a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 100-150 mg/m 2 (such as 100 mg/m 2 ) and b) intravenously or intraperitoneally administering to the individual about 5 mg/m 2 to about 100 mg/m 2 (such as 15 mg/m 2 ) decitabine, wherein the decitabine is intravenously or
  • a method of treating breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer
  • a method of treating breast cancer comprising: a) intravenously administering to the individual an effective amount of a composition comprising paclitaxel, wherein the taxane is in the dosage range of about 100-150 mg/m 2 (such as 100 mg/m 2 ) and b) intravenously or intraperitoneally administering to the individual about 5-100 mg/m 2 (such as 20 mg/m 2 ) decitabine, wherein the decitabine is intravenously or intraperitoneally administered on days 1-5, followed by intravenous administration of the composition on days 8, 15, and 22 of a 28-day cycle, for a total of 6 cycles.
  • the individual suffering from breast cancer has not had prior cytotoxic regimens.
  • the individual suffering from breast cancer has had no more than 2 prior cytotoxic regimens.
  • the individual suffering from breast cancer has had more than 2 prior cytotoxic regimens.
  • the methods further comprise administration of one or more additional agent.
  • the additional agent is another agent that modifies the epigenetics in a cell, such as the agents described herein.
  • the additional agent is a chemotherapeutic agent, such as
  • the additional agent is any one of dexamethasone, bortezomib, imatinib, sorafenib, gemcitabine, capecitabine, lenalidomide, sunitinib, paclitaxel, and docetaxel.
  • dexamethasone bortezomib, imatinib, sorafenib, gemcitabine, capecitabine, lenalidomide, sunitinib, paclitaxel, and docetaxel.
  • a method of treating a proliferative disease comprising: a) an effective amount of a composition comprising a taxane (such as paclitaxel), b) an effective amount of romidepsin, and c) an effective amount of an additional agent selected from the group consisting of dexamethasone, bortezomib, imatinib, sorafenib, gemcitabine, capecitabine, lenalidomide, sunitinib, paclitaxel, and docetaxel.
  • a taxane such as paclitaxel
  • romidepsin an additional agent selected from the group consisting of dexamethasone, bortezomib, imatinib, sorafenib, gemcitabine, capecitabine, lenalidomide, sunitinib, paclitaxel, and docetaxel.
  • a method of treating a proliferative disease comprising: a) an effective amount of a composition comprising a taxane (such as paclitaxel), b) an effective amount of romidepsin, and c) an effective amount of capecitabine.
  • a method of treating a proliferative disease comprising: a) an effective amount of a composition comprising a taxane (such as paclitaxel), b) an effective amount of romidepsin, and c) an effective amount of azacitidine.
  • the method further comprises the administration of a platinum-based agent, including for example carboplatin and cisplatin.
  • a platinum-based agent including for example carboplatin and cisplatin.
  • a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); b) an effective amount of a histone deacetylase inhibitor, and c) an effective amount of a platinum-based agent.
  • a method of treating cancer comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel); b) an effective amount of a histone deacetylase inhibitor, and c) an effective amount of a platinum-based agent.
  • a taxane such as paclitaxel
  • a histone deacetylase inhibitor such as paclitaxel
  • a method of treating cancer comprising administering to the individual: a) an effective amount of a composition comprising paclitaxel; b) an effective amount of romidepsin, and c) an effective amount of carboplatin.
  • a method of treating cancer comprising: a) intravenously
  • administering an effective amount of a composition comprising paclitaxel; b) orally administering an effective amount of romidepsin, and c) intravenously administering an effective amount of carboplatin.
  • a method of treating cancer comprising: a) intravenously administering a composition comprising paclitaxel at the dose of about 80 to about 200 mg/m 2 (such as about 100 mg/m 2 ); b) orally administering about 10 mg/m 2 to about 300 mg/m 2 of romidepsin, and c) intravenously administering carboplatin at the dose of AUC 2-6 (such as AUC2).
  • a method of treating cancer such as breast cancer, including triple negative breast cancer, or for example, inflammatory breast cancer
  • a method of treating cancer comprising: a) intravenously administering a composition comprising paclitaxel at the dose of about 80 to about 200 mg/m 2 (such as about 100 mg/m 2 ); b) orally administering about 10 mg/m 2 to about 300 mg/m 2 of romidepsin, and c) intravenously administering carboplatin at the dose of AUC 2-6 (such as AUC2).
  • a method of treating cancer such as breast cancer,
  • compositions comprising paclitaxel at the dose of about 80 to about 200 mg/m 2 (such as aboutlOO mg/m 2 ) weekly; b) orally administering about 10 mg/m 2 to about 300 mg/m 2 of romidepsin three out of seven days, and c) intravenously administering carboplatin at the dose of AUC 2-6 (such as AUC2) weekly.
  • the administrations of the composition, the romidepsin, and the carboplatin are concurrent.
  • the composition and the carboplatin are administered on day one of each week, and the romidepsin is administered on days 1-3 of each week.
  • the present invention in some embodiments provides a method of treating a proliferative disease in an individual comprising administering to the individual: a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the other agent can be an inhibitor of histone deacetylase (such as romidepsin) or an inhibitor of DNA methyltransferase (such as azacitidine or decitabine).
  • the method further comprises administering to said individual a platinum-based agent.
  • the proliferative disease is cancer, such as breast cancer.
  • the individual is negative for ER, PR, or HER2. In some embodiments, individual is negative for ER, PR, and HER2.
  • the proliferative disease is ovarian cancer. In some embodiments, the proliferative disease is lung cancer (such as non-small cell lung cancer).
  • the composition comprising taxane and the other agent are administered simultaneously. In some embodiments of any of the methods described above, the composition comprising taxane and the other agent are administered sequentially. In some embodiments of any of the methods described above, the composition comprising taxane and the other agent are administered concurrently.
  • the taxane is paclitaxel. In some embodiments of any of the methods described above, the individual is a human.
  • the present application also provides pharmaceutical compositions comprising a taxane (such as paclitaxel) for use in the treatment of a proliferative disease (such as cancer), wherein said use comprises simultaneous, sequential, and/or concurrent administration of an agent that modifies the epigenetics in a cell.
  • the invention provides a pharmaceutical composition comprising an agent that modifies the epigenetics in a cell for use in the treatment of a proliferative disease (such as cancer), wherein said use comprises simultaneous, sequential, and/or concurrent administration of a composition comprising a taxane (such as paclitaxel).
  • the invention provides taxane-containing compositions and compositions comprising an agent that inhibits prosurvival and/or inflammatory signal for simultaneous, sequential, and/or concurrent use for treatment of a proliferative disease (such as cancer).
  • kits comprising: a) a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the other agent is romidepsin.
  • a medicine comprising: a) a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the other agent is romidepsin.
  • the combination therapy methods described herein are useful for treating proliferative diseases.
  • the methods require administration of the composition and the other agent in effective amounts.
  • an effective amount is an amount sufficient to delay development.
  • an effective amount is an amount sufficient to prevent or delay recurrence.
  • An effective amount can be administered in one or more administrations.
  • the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • a method of inhibiting cell proliferation (such as tumor growth) in an individual comprising administering to the individual: a) an effective amount of a composition comprising taxane, and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the effective amounts of the taxane composition and the other agent synergistically inhibit cell proliferation (such as tumor cell growth).
  • at least about 10% including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%
  • cell proliferation is inhibited.
  • the taxane is paclitaxel.
  • the other agent is an inhibitor of a histone deacetylase (such as romidepsin). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as azacitidine). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as decitabine). In some embodiments, the taxane in the composition is administered by intravenous administration. In some embodiments, the other agent is administered by oral administration. In some embodiments, the other agent is administered intravenously or subcutaneously.
  • a histone deacetylase such as romidepsin
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine).
  • the other agent is an inhibitor of DNA methyltransferase (such as decitabine).
  • the taxane in the composition is administered by intravenous administration. In some embodiments, the other agent is administered by oral administration. In some embodiments, the other agent is administered intravenously or subcutaneously.
  • a method of inhibiting tumor metastasis (such as metastasis of breast cancer, pulmonary metastasis or metastasis to the lymph node) in an individual, comprising administering to the individual: a) an effective amount of a composition comprising taxane, and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the effective amounts of the taxane composition and the other agent synergistically inhibit tumor metastasis.
  • at least about 10% including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%
  • metastasis is inhibited.
  • method of inhibiting metastasis to lymph node is provided.
  • method of inhibiting metastasis to the lung is provided.
  • the taxane is paclitaxel.
  • the taxane is paclitaxel.
  • the other agent is an inhibitor of a histone deacetylase (such as romidepsin).
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine).
  • the other agent is an inhibitor of DNA methyltransferase (such as decitabine).
  • the taxane in the composition is administered by intravenous administration.
  • the other agent is administered by oral administration.
  • the other agent is administered
  • a method of reducing (such as eradiating) pre-existing tumor metastasis (such as pulmonary metastasis or metastasis to the lymph node) in an individual comprising administering to the individual: a) an effective amount of a composition comprising taxane, and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the effective amounts of the taxane composition and the other agent synergistically reduces (such as eradicates) tumor metastasis.
  • at least about 10% including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%), or 100%) metastasis is reduced.
  • method of reducing metastasis to lymph node is provided. In some embodiments, method of reducing metastasis to the lung is provided.
  • the taxane is paclitaxel. In some embodiments, the taxane is paclitaxel. In some embodiments, the other agent is an inhibitor of a histone deacetylase (such as romidepsin). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as azacitidine). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as decitabine). In some embodiments, the taxane in the composition is administered by intravenous administration. In some embodiments, the other agent is administered by oral administration. In some embodiments, the other agent is administered
  • a method of reducing incidence or burden of preexisting tumor metastasis comprising administering to the individual: a) an effective amount of a composition comprising taxane, and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the taxane is paclitaxel.
  • the other agent is an inhibitor of a histone deacetylase (such as romidepsin).
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine).
  • the other agent is an inhibitor of DNA methyltransferase (such as decitabine).
  • the taxane in the composition is administered by intravenous administration.
  • the other agent is administered by oral administration.
  • the other agent is administered intravenously or subcutaneously.
  • a method of reducing tumor size in an individual comprising administering to the individual: a) an effective amount of a composition comprising taxane, and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the effective amounts of the taxane composition and the other agent synergistically reduces tumor size.
  • the tumor size is reduced at least about 10% (including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%).
  • the taxane is paclitaxel.
  • the other agent is an inhibitor of a histone deacetylase (such as romidepsin).
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as decitabine). In some embodiments, the taxane in the composition is administered by intravenous administration. In some embodiments, the other agent is administered by intraperitoneal administration. In some embodiments, the other agent is administered by oral administration. In some embodiments, the other agent is administered intravenously or subcutaneously.
  • DNA methyltransferase such as azacitidine
  • the other agent is an inhibitor of DNA methyltransferase (such as decitabine).
  • the taxane in the composition is administered by intravenous administration. In some embodiments, the other agent is administered by intraperitoneal administration. In some embodiments, the other agent is administered by oral administration. In some embodiments, the other agent is administered intravenously or subcutaneously.
  • a method of prolonging time to disease progression of a proliferative disease comprising administering to the individual: a) an effective amount of a composition comprising taxane, and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the method prolongs the time to disease progression by at least any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.
  • the taxane is paclitaxel.
  • the other agent is an inhibitor of a histone deacetylase (such as romidepsin).
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine).
  • the other agent is an inhibitor of DNA
  • the taxane in the composition is administered by intravenous administration.
  • the other agent is administered by intraperitoneal administration.
  • the other agent is administered by oral administration.
  • the other agent is administered intravenously or subcutaneously.
  • a method of prolonging survival of an individual having a proliferative disease comprising administering to the individual: a) an effective amount of a composition comprising taxane, and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the method prolongs the survival of the individual by at least any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, or 24 month.
  • the taxane is paclitaxel.
  • the other agent is an inhibitor of a histone deacetylase (such as romidepsin).
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as decitabine). In some embodiments, the taxane in the composition is administered by intravenous administration. In some embodiments, the other agent is administered by intraperitoneal administration. In some embodiments, the other agent is administered by oral administration. In some embodiments, the other agent is administered intravenously or subcutaneously.
  • DNA methyltransferase such as azacitidine
  • the other agent is an inhibitor of DNA methyltransferase (such as decitabine).
  • the taxane in the composition is administered by intravenous administration. In some embodiments, the other agent is administered by intraperitoneal administration. In some embodiments, the other agent is administered by oral administration. In some embodiments, the other agent is administered intravenously or subcutaneously.
  • a method of reducing (such as eradiating) pre-existing tumor metastasis (such as pulmonary metastasis or metastasis to the lymph node) in an individual comprising administering to the individual: a) an effective amount of a composition comprising taxane, and b) an effective amount of a vorinostat, wherein the composition and the romdiepsin are administered
  • a method of reducing (such as eradiating) pre-existing tumor metastasis (such as pulmonary metastasis or metastasis to the lymph node) in an individual comprising administering to the individual: a) an effective amount of paclitaxel, and b) an effective amount of th romidepsin, wherein the composition and the romidepsin are administered concurrently.
  • a method of reducing (such as eradiating) pre-existing tumor metastasis (such as pulmonary metastasis or metastasis to the lymph node) in an individual comprising administering to the individual: a) an effective amount of a composition comprising taxane, and b) an effective amount of a histone deacetylase inhibitor, wherein the composition and the histone deacetylase inhibitor are administered concurrently.
  • a method of reducing (such as eradiating) pre-existing tumor metastasis (such as pulmonary metastasis or metastasis to the lymph node) in an individual comprising
  • administering to the individual: a) an effective amount of paclitaxel, and b) an effective amount of a histone deacetylase inhibitor, wherein the composition and the bcl-2 are administered concurrently.
  • the effectiveness of the methods of the present invention can be assessed by one or more criteria, which include, but are not limited to, markers of proliferation and/or apoptosis, gene methylation, gene expression profile, and tissue histone acetylation.
  • the effectiveness of the method can be assessed by functional imaging, such as PET/CT scans and/or fludeoxyglucose F 18-position emission tomography (FDG-PET) (Sun, X. et al. J. Nucl. Med. (2011) 52(1): 140- 146).
  • a method of treating a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel) and b) an effective amount of at least one other agent that modifies the epigenetics in a cell, wherein the standard uptake value (SUV) determined in a FDG- PET scan in the individual is decreased by at least about any of 10%, 20%>, 30%>, 40%>, 50%, 60%, 70%, 80%, 90%, or 95%.
  • the taxane is paclitaxel.
  • the other agent is an inhibitor of a histone deacetylase (such asromidepsin). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as azacitidine). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as decitabine). In some embodiments, the taxane in the composition is administered by intravenous administration. In some embodiments, the other agent is administered by intraperitoneal administration. In some embodiments, the other agent is administered by oral administration. In some embodiments, the method further comprises determining a baseline SUV value in the individual prior to the treatment. In some embodiments, the method further comprises determining the SUV value in the individual after the treatment.
  • a histone deacetylase such asromidepsin
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as decitabine).
  • proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies the epigenetics in a cell, wherein the level of C1D15 is decreased by at least about any of 10%, 20%>, 30%>, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.
  • the taxane is paclitaxel.
  • the other agent is an inhibitor of a histone deacetylase (such as romidepsin).
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine).
  • the other agent is an inhibitor of DNA methyltransferase (such as decitabine).
  • the taxane in the composition is administered by intravenous administration. In some embodiments, the other agent is administered by
  • the method further comprises determining a baseline C1D15 level in the individual prior to the treatment. In some embodiments, the method further comprises determining the C1D15 level in the individual after the treatment.
  • proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies the epigenetics in a cell, wherein the level of DNA methylation in one or more genes in the individual is decreased by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.
  • the taxane is paclitaxel.
  • the other agent is an inhibitor of a histone deacetylase (such as romidepsin).
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine).
  • the other agent is an inhibitor of DNA
  • the taxane in the composition is administered by intravenous administration.
  • the other agent is administered by intraperitoneal administration.
  • the other agent is administered by oral administration.
  • the method further comprises determining a baseline DNA methylation level in the individual prior to the treatment.
  • the method further comprises determining the DNA methylation level in the individual after the treatment.
  • the level of DNA methylation is determined based on the methylation of one or more target genes, such as ER-alpha, APC-1, RAR-beta, cyclin D2, Twist, RASSFIA, and HIN-1.
  • the levels of methylation can be determined, for example, by quantitative multiplex methylation-specific PCR.
  • the responsiveness of the method is determined by gene expression profile.
  • a method of treating a proliferative disease comprising administering to the ⁇ individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies the epigenetics in a cell, wherein the level of expression in one or more genes in the individual is changed by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%), 80%), 90%), or 95%.
  • the taxane is paclitaxel.
  • the other agent is an inhibitor of a histone deacetylase (such as
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as decitabine).
  • the taxane in the composition is administered by intravenous administration. In some embodiments, the other agent is administered by intraperitoneal administration. In some embodiments, the other agent is administered by oral administration.
  • the method further comprises determining a baseline gene expression profile in the individual prior to the treatment. In some embodiments, the method further comprises determining the gene expression profile in the individual after the treatment. Changes of gene expression can be determined, for example, by RT-PCR or immunohistochemistry.
  • the responsiveness of the method is determined by the level of histone deacetylation.
  • a method of treating a proliferative disease comprising administering to the individual a) an effective amount of a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies the epigenetics in a cell, wherein the level of histone deacetylation in the individual is decreased by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%), 80%), 90%), or 95%.
  • the taxane is paclitaxel.
  • the other agent is an inhibitor of a histone deacetylase (such as paclitaxel).
  • the other agent is an inhibitor of DNA methyltransferase (such as azacitidine). In some embodiments, the other agent is an inhibitor of DNA methyltransferase (such as decitabine).
  • the taxane in the composition is administered by intravenous administration. In some embodiments, the other agent is administered by intraperitoneal administration. In some embodiments, the other agent is administered by oral administration.
  • the method further comprises determining a baseline histone acetylation level in the individual prior to the treatment. In some embodiments, the method further comprises determining the histone acetylation level in the individual after the treatment. Level of histone acetylation can be determined, for example, by determination of histone acetylation level in tissue and/or peripheral blood
  • the treatment methods can also be evaluated for safety and toxicity, for example, based on NCI CTCAE analyses.
  • the proliferative disease is a non-cancerous disease, including, but not limited to, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • fibrosis especially pulmonary, but also other types of fibrosis, such as renal fibrosis
  • angiogenesis psoriasis
  • atherosclerosis smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • smooth muscle proliferation such as stenosis or restenosis following angioplasty.
  • the proliferative disease is cancer.
  • the proliferative disease is a benign or malignant tumor. Where hereinbefore and subsequently a tumor, a tumor disease, a carcinoma or a cancer are mentioned, also metastasis in the original organ or tissue and/or in any other location are implied alternatively or in addition, whatever the location of the tumor and/or metastasis is.
  • the method is used to treat a primary tumor.
  • a method of treating metastatic cancer that is, cancer that has metastasized from the primary tumor
  • the method is for the treatment of an advanced disease or a lesser extent of disease, such as low tumor burden.
  • there is provided a method of treating cancer at an advanced stage In some embodiments, the method is for the treatment of an early stage breast cancer.
  • the methods may be practiced in an adjuvant setting.
  • the methods provided herein may also be practiced in a neoadjuvant setting, i.e., the method may be carried out before the primary/definitive therapy.
  • the method further comprises conducting surgery on the individual following the completion of the treatment.
  • breast conserving surgery or mastectomy can be carried out within about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks after completion of the neoadjuvant chemotherapy.
  • the individual has previously been treated. In some embodiments, the individual has not previously been treated. In some embodiments, the treatment is a first line therapy. In some embodiments, the breast cancer has reoccurred after a remission.
  • the cancer is breast cancer.
  • These methods can be used, for example, to treat, stabilize, prevent, and/or delay any type or stage of breast cancer, such as early stage breast cancer, non-metastatic breast cancer, advanced breast cancer, stage IV breast cancer, locally advanced breast cancer, metastatic breast cancer, breast cancer in remission, breast cancer in an adjuvant setting, or breast cancer in a neoadjuvant setting.
  • the method is useful for preoperative systemic therapy (PST).
  • a method of treating breast cancer (which may be HER2 positive or HER2 negative), including, for example, advanced breast cancer, stage IV breast cancer, locally advanced breast cancer, and metastatic breast cancer.
  • the breast cancer is inflammatory breast cancer.
  • the breast cancer is basal cell breast cancer.
  • the individual is diagnosed with T2, T3, or T4 lesion, or a stage N, M0 or Tic, Nl-3 and MO.
  • the individual has an ECOG
  • the individual has skin metastasis to the ipsilateral breast.
  • the individual has undergone prior therapy (such as hormonal therapy).
  • the individual has not undergone prior therapy (such as hormonal therapy).
  • the individual is awaiting definitive surgery.
  • the breast cancer is resected breast cancer.
  • the breast cancer is unresected breast cancer, such as unresected stage II or III breast cancer.
  • the method is for treating an individual having one or more of these risk factors resulting in a higher probability of developing breast cancer than an individual without these risk factor(s).
  • These risk factors include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic (i.e., hereditary) considerations, and environmental exposure.
  • the individual may be a human who is genetically or otherwise predisposed to developing breast cancer who has or has not been diagnosed with breast cancer.
  • Individuals at risk for breast cancer include, e.g., those having relatives who have experienced this disease, and those whose risk is determined by analysis of genetic or biochemical markers.
  • the individual may be a human who has a gene, genetic mutation, or polymorphism associated with breast cancer (e.g., BRCA1, BRCA2, ATM, CHEK2, RAD51, AR, DIRAS3, ERBB2, and/or TP53) or has one or more extra copies of a gene (e.g., one or more extra copies of the HER2 gene) associated with breast cancer.
  • the breast cancer is HER2 negative.
  • the breast cancer is ER negative.
  • the breast cancer is PR negative.
  • the breast cancer is EP negative and HER2 negative.
  • the breast cancer is PR negative and HER2 negative.
  • the breast cancer is ER negative and PR negative.
  • the breast cancer is ER negative and PR negative.
  • the breast cancer is ER negative, PR negative, and HER2 negative.
  • a method of treating lung cancer including, for example, non-small cell lung cancer (NSCLC, such as advanced NSCLC), small cell lung cancer (SCLC, such as advanced SCLC), and advanced solid tumor malignancy in the lung.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • advanced solid tumor malignancy in the lung there is provided a method of treating any of ovarian cancer, head and neck cancer, gastric malignancies, melanoma (including metastatic melanoma and malignant melanoma), ovarian cancer, colorectal cancer, and pancreatic cancer.
  • the method is useful for treating one or more of the following: cutaneous T cell lymphoma (CTCL), leukemia, follicular lymphoma, Hodgkin lymphoma, and acute myeloid leukemia.
  • CCL cutaneous T cell lymphoma
  • the disease is a cancer of any one of the following: basal cell carcinoma, medulloblastoma, glioblastoma, multiple myeloma, chronic myelogenous leukemia (CML), acute myelogenous leukemia, pancreatic cancer, lung cancer (small cell lung cancer and non-small cell lung cancer), esophageal cancer, stomach cancer, biliary cancer, prostate cancer, liver cancer, hepatocellular cancer, gastrointestinal cancer, gastric cancer, and ovarian and bladder cancer.
  • basal cell carcinoma medulloblastoma
  • glioblastoma multiple myeloma
  • multiple myeloma multiple myeloma
  • chronic myelogenous leukemia (CML) chronic myelogenous leukemia
  • pancreatic cancer lung cancer (small cell lung cancer and non-small cell lung cancer), esophageal cancer, stomach cancer, biliary cancer, prostate cancer, liver cancer, hepatocellular cancer,
  • the cancer is selected from the group consisting of pancreas ductal adenocarcinoma, colon adenocarcinoma, and ovary cystadenocarcinoma. In some embodiments, the cancer is pancreas ductal adenocarcinoma. In some embodiments, the cancer is a tumor that is poorly perfused and/or poorly vascularized.
  • the cancer is pancreatic cancer, including for example pancreatic adenocarcinoma, pancreatic adenosquamous carcinoma, pancreatic squamous cell carcinoma, and pancreatic giant cell carcinoma.
  • the pancreatic cancer is exocrine pancreatic cancer.
  • the pancreatic cancer is endocrine pancreatic cancer (such as islet cell carcinoma).
  • the pancreatic cancer is advanced metastatic pancreatic cancer.
  • cancers that may be treated by the methods of the invention include, but are not limited to, adenocortical carcinoma, agnogenic myeloid metaplasia, AIDS-related cancers (e.g., AIDS-related lymphoma), anal cancer, appendix cancer, astrocytoma (e.g., cerebellar and cerebral), basal cell carcinoma, bile duct cancer (e.g., extrahepatic), bladder cancer, bone cancer, (osteosarcoma and malignant fibrous histiocytoma), brain tumor (e.g., glioma, brain stem glioma, cerebellar or cerebral astrocytoma (e.g., pilocytic astrocytoma, diffuse astrocytoma, anaplastic (malignant) astrocytoma), malignant glioma, ependymoma,
  • adenocortical carcinoma e.g., AIDS-related lymphoma
  • oligodenglioma meningioma, craniopharyngioma, haemangioblastomas,
  • medulloblastoma supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, and glioblastoma
  • breast cancer bronchial
  • adenomas/carcinoids carcinoid tumor (e.g., gastrointestinal carcinoid tumor), carcinoma of unknown primary, central nervous system lymphoma, cervical cancer, colon cancer, colorectal cancer, chronic myeloproliferative disorders, endometrial cancer (e.g., uterine cancer), ependymoma, esophageal cancer, Ewing's family of tumors, eye cancer (e.g., intraocular melanoma and retinoblastoma), gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, (e.g., extracranial, extragonadal, ovarian), gestational trophoblastic tumor, head and neck cancer, hepatocellular (liver) cancer (e.g., hepatic carcinoma and heptoma), hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas),
  • mesothelioma metastatic squamous neck cancer, mouth cancer, multiple endocrine neoplasia syndrome, myelodysplasia syndromes, myelodysplastic/myeloproliferative diseases, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer,
  • neuroblastoma neuroendocrine cancer, oropharyngeal cancer
  • ovarian cancer e.g., ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor
  • pancreatic cancer parathyroid cancer
  • penile cancer cancer of the peritoneal, pharyngeal cancer
  • pheochromocytoma pineoblastoma and supratentorial primitive neuroectodermal tumors
  • pituitary tumor pleuropulmonary blastoma
  • lymphoma primary central nervous system lymphoma (microglioma)
  • pulmonary cancer e.g., ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor
  • pancreatic cancer parathyroid cancer
  • penile cancer cancer of the peritoneal, pharyngeal cancer
  • pheochromocytoma pineoblastoma and supratentorial primitive neuroectodermal tumors
  • pituitary tumor pleur
  • lymphangiomyomatosis rectal cancer, renal cancer, renal pelvis and ureter cancer (transitional cell cancer), rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., non-melanoma (e.g., squamous cell carcinoma), melanoma, and Merkel cell carcinoma), small intestine cancer, squamous cell cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, urethral cancer, vaginal cancer, vulvar cancer, Wilms' tumor, and post-transplant
  • skin cancer e.g., non-melanoma (e.g., squamous cell carcinoma), melanoma, and Merkel cell carcinoma
  • small intestine cancer squamous cell cancer
  • testicular cancer throat cancer
  • thymoma and thymic carcinoma thyroid cancer
  • tuberous sclerosis urethral cancer
  • vaginal cancer
  • PTLD lymphoproliferative disorder
  • phakomatoses abnormal vascular proliferation associated with phakomatoses
  • edema abnormal vascular proliferation associated with brain tumors
  • Meigs' syndrome abnormal vascular proliferation associated with brain tumors
  • the cancer is a solid tumor (such as advanced solid tumor).
  • Solid tumor includes, but is not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, Kaposi's sarcoma, soft tissue sarcoma, uterine sacronomasynovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,
  • rhabdomyosarcoma colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma,
  • adenocarcinoma sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma (including for example
  • adenocarcinoma clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct renal cell carcinoma, granular renal cell carcinoma, mixed granular renal cell carcinoma, renal angiomyo lipomas, or spindle renal cell carcinoma.
  • hepatoma bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma.
  • the lymphoid neoplasm is a B-cell neoplasm.
  • B-cell neoplasms include, but are not limited to, precursor B- cell neoplasms (e.g., precursor B-lymphoblastic leukemia/lymphoma) and peripheral B-cell neoplasms (e.g. , B-cell chronic lymphocytic leukemia/pro lymphocytic leukemia/small lymphocytic lymphoma (small lymphocytic (SL) NHL),
  • precursor B- cell neoplasms e.g., precursor B-lymphoblastic leukemia/lymphoma
  • peripheral B-cell neoplasms e.g. , B-cell chronic lymphocytic leukemia/pro lymphocytic leukemia/small lymphocytic lymphoma (small lymphocytic (SL) NHL
  • lymphoplasmacytoid lymphoma/immunocytoma mantel cell lymphoma, follicle center lymphoma, follicular lymphoma (e.g., cytologic grades: I (small cell), II (mixed small and large cell), III (large cell) and/or subtype: diffuse and predominantly small cell type), low grade/follicular non-Hodgkin's lymphoma (NHL), intermediate grade/follicular NHL, marginal zone B-cell lymphoma (e.g., extranodal (e.g., MALT- type +/- monocytoid B cells) and/or Nodal (e.g., +/- monocytoid B cells)), splenic marginal zone lymphoma (e.g., +/- villous lymphocytes), Hairy cell leukemia, plasmacytoma/plasma cell myeloma (e.g., myeloma and multiple myeloma), diffuse large B-
  • the lymphoid neoplasm is a T-cell and/or putative NK-cell neoplasm.
  • T-cell and/or putative NK-cell neoplasms include, but are not limited to, precursor T-cell neoplasm (precursor T- lymphoblastic lymphoma/leukemia) and peripheral T-cell and NK-cell neoplasms (e.g.
  • T-cell chronic lymphocytic leukemia/pro lymphocytic leukemia and large granular lymphocyte leukemia (LGL)
  • LGL large granular lymphocyte leukemia
  • T-cell type and/or NK-cell type T-cell type and/or NK-cell type
  • cutaneous T-cell lymphoma e.g., mycosis fungoides/Sezary syndrome
  • primary T- cell lymphomas unspecified e.g., cyto logical categories (e.g., medium-sized cell, mixed medium and large cell), large cell, lymphoepitheloid cell, subtype
  • hepatosplenic ⁇ T-cell lymphoma hepatosplenic ⁇ T-cell lymphoma, and subcutaneous panniculitic T-cell lymphoma
  • angioimmunoblastic T-cell lymphoma AILD
  • angiocentric lymphoma intestinal T- cell lymphoma (e.g., +/- enteropathy associated), adult T-cell lymphoma/leukemia (ATL), anaplastic large cell lymphoma (ALCL) (e.g., CD30+, T- and null-cell types), anaplastic large-cell lymphoma, and Hodgkin's like).
  • the lymphoid neoplasm e.g., lymphoma
  • the Hodgkin's disease may be lymphocyte predominance, nodular sclerosis, mixed cellularity, lymphocyte depletion, and/or lymphocyte-rich.
  • the cancer is leukemia.
  • the leukemia is chronic leukemia.
  • Examples of chronic leukemia include, but are not limited to, chronic myelocytic I (granulocytic) leukemia, chronic myelogenous, and chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • the leukemia is acute leukemia.
  • acute leukemia examples include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia, acute lymphocytic leukemia, and acute myelocytic leukemia (e.g., myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia).
  • ALL acute lymphoblastic leukemia
  • acute myeloid leukemia e.g., acute myeloid leukemia, acute lymphocytic leukemia
  • acute myelocytic leukemia e.g., myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia.
  • the cancer is liquid tumor or plasmacytoma.
  • Plasmacytoma includes, but is not limited to, myeloma.
  • Myeloma includes, but is not limited to, an extramedullary plasmacytoma, a solitary myeloma, and multiple myeloma.
  • the plasmacytoma is multiple myeloma.
  • the cancer is multiple myeloma.
  • multiple myeloma include, but are not limited to, IgG multiple myeloma, IgA multiple myeloma, IgD multiple myeloma, IgE multiple myeloma, and nonsecretory multiple myeloma.
  • the multiple myeloma is IgG multiple myeloma.
  • the multiple myeloma is IgA multiple myeloma.
  • the multiple myeloma is a smoldering or indolent multiple myeloma.
  • the multiple myeloma is progressive multiple myeloma.
  • multiple myeloma may be resistant to a drug, such as, but not limited to, bortezomib, dexamethasone (Dex-), doxorubicin (Dox-), and melphalan (LR).
  • a drug such as, but not limited to, bortezomib, dexamethasone (Dex-), doxorubicin (Dox-), and melphalan (LR).
  • composition comprising taxane (also referred to as “composition") and the other agent can be administered simultaneously (i.e., simultaneous
  • composition and the other agent are administered simultaneously.
  • compositions and the other agent are administered with a time separation of no more than about 15 minute(s), such as no more than about any of 10, 5, or 1 minutes.
  • the drug and the other agent may be contained in the same composition (e.g., a composition comprising both the drug and the other agent) or in separate compositions (e.g., the drug is contained in one composition and the other agent is contained in another composition).
  • composition and the other agent are
  • sequential administration means that the drug in the composition and the other agent are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60 or more minutes. Either the composition or the other agent may be
  • compositions which may be contained in the same or different packages.
  • the administration of the composition and the other agent are concurrent, i.e., the administration period of the composition and that of the other agent overlap with each other.
  • the composition is administered for at least one cycle (for example, at least any of 2, 3, or 4 cycles) prior to the administration of the other agent.
  • the other agent is administered for at least any of one, two, three, or four weeks.
  • the administrations of the composition and the other agent are initiated at about the same time (for example, within any one of 1, 2, 3, 4, 5, 6, or 7 days).
  • the administrations of the composition and the other agent are terminated at about the same time (for example, within any one of 1, 2, 3, 4, 5, 6, or 7 days).
  • the administration of the other agent continues (for example for about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) after the termination of the administration of the composition.
  • the administration of the other agent is initiated after (for example after about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or we months) the initiation of the administration of the composition.
  • the administrations of the composition and the other agent are initiated and terminated at about the same time.
  • the administrations of the composition and the other agent are initiated at about the same time and the administration of the other agent continues (for example for about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) after the termination of the administration of the composition.
  • the administration of the composition and the other agent stop at about the same time and the administration of the other agent is initiated after (for example after about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or we months) the initiation of the administration of the composition.
  • the administration of the composition and the other agent are non-concurrent.
  • the administration of the composition is terminated before the other agent is administered.
  • the administration of the other agent is terminated before the composition is administered.
  • the time period between these two non-concurrent administrations can range from about two to eight weeks, such as about four weeks.
  • the dosing frequency of the drug-containing composition and the other agent may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • the drug-containing composition and the other agent can be administered at different dosing frequency or intervals.
  • the drug-containing composition can be administered weekly, while another agent can be administered more or less frequently.
  • sustained continuous release formulation of the composition or an agent may be used.
  • Various formulations and devices for achieving sustained release are known in the art.
  • Exemplary dosing frequencies are further provided herein.
  • the composition and the other agent can be administered using the same route of administration or different routes of administration. Exemplary
  • the taxane in the composition and the other agent are administered at a predetermined ratio.
  • the ratio by weight of the taxane in the composition and the other agent is about 1 to 1.
  • the weight ratio may be between about 0.001 to about 1 and about 1000 to about 1, or between about 0.01 to about 1 and 100 to about 1.
  • the ratio by weight of the taxane in the composition and the other agent is less than about any of 100: 1, 50: 1, 30: 1, 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4: 1, 3: 1, 2: 1, and 1 : 1 In some embodiments, the ratio by weight of the taxane in the composition and the other agent is more than about any of 1 : 1, 2: 1, 3: 1, 4:1, 5 :1, 6: 1, 7: 1, 8: 1, 9: 1, 30: 1, 50:1, 100:1. Other ratios are contemplated.
  • the doses required for the taxane and/or the other agent may (but not necessarily) be lower than what is normally required when each agent is administered alone.
  • a subtherapeutic amount of the drug in the composition and/or the other agent are administered.
  • “Subtherapeutic amount” or “subtherapeutic level” refer to an amount that is less than therapeutic amount, that is, less than the amount normally used when the drug in the composition and/or the other agent are administered alone. The reduction may be reflected in terms of the amount administered at a given administration and/or the amount administered over a given period of time (reduced frequency).
  • enough other agent is administered so as to allow reduction of the normal dose of the drug in the composition required to effect the same degree of treatment by at least about any of 5%, 10%, 20%, 30%>, 50%>, 60%>, 70%), 80%o, 90%), or more.
  • enough drug in the composition is administered so as to allow reduction of the normal dose of the other agent required to effect the same degree of treatment by at least about any of 5%>, 10%>, 20%>, 30%>, 50%, 60%, 70%, 80%, 90%, or more.
  • the dose of both the taxane in the composition and the other agent are reduced as compared to the corresponding normal dose of each when administered alone.
  • both the taxane in the composition and the other agent are administered at a subtherapeutic, i.e., reduced, level.
  • the dose of the composition and/or the other agent is substantially less than the established maximum toxic dose (MTD).
  • the dose of the composition and/or the other agent is less than about 50%, 40%>, 30%>, 20%>, or 10%> of the MTD.
  • the dose of taxane and/or the dose of the other agent is higher than what is normally required when each agent is administered alone.
  • the dose of the composition and/or the other agent is substantially higher than the established maximum toxic dose (MTD).
  • the dose of the composition and/or the other agent is more than about 50%, 40%, 30%, 20%, or 10% of the MTD of the agent when administered alone.
  • the amount of a taxane (e.g., paclitaxel) in the composition is included in any of the following ranges: about 0.5 to about 5 mg, about 5 to about 10 mg, about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg, about 75 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg.
  • a taxane e.g., paclitaxel
  • the amount of a taxane (e.g., paclitaxel) or derivative thereof in the effective amount of the composition (e.g., a unit dosage form) is in the range of about 5 mg to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg to about 200 mg.
  • the concentration of the taxane (e.g., paclitaxel) in the composition is dilute (about 0.1 mg/ml) or concentrated (about 100 mg/ml), including for example any of about 0.1 to about 50 mg/ml, about 0.1 to about 20 mg/ml, about 1 to about 10 mg/ml, about 2 mg/ml to about 8 mg/ml, about 4 to about 6 mg/ml, about 5 mg/ml.
  • the concentration of the taxane is at least about any of 0.5 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, or 50 mg/ml.
  • the taxane e.g., paclitaxel
  • Exemplary effective amounts of a taxane (e.g., paclitaxel) in the composition include, but are not limited to, at least about any of 25 mg/m 2 , 30 mg/m 2 ,
  • paclitaxel 50 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 90 mg/m 2 , 100 mg/m 2 , 120 mg/m 2 , 125 mg/m 2 , 150 mg/m 2 , 160 mg/m 2 , 175 mg/m 2 , 180 mg/m 2 , 200 mg/m 2 , 210 mg/m 2 , 220 mg/m 2 , 250 mg/m 2 , 260 mg/m 2 , 300 mg/m 2 , 350 mg/m 2 , 400 mg/m 2 , 500 mg/m 2 , 540 mg/m 2 , 750 mg/m 2 , 1000 mg/m 2 , or 1080 mg/m 2 of a taxane (e.g., paclitaxel).
  • a taxane e.g., paclitaxel
  • the composition includes less than about any of 350 mg/m 2 , 300 mg/m 2 , 250 mg/m 2 , 200 mg/m 2 , 150 mg/m 2 , 120 mg/m 2 , 100 mg/m 2 , 90 mg/m 2 , 50 mg/m 2 , or 30 mg/m 2 of a taxane (e.g., paclitaxel).
  • a taxane e.g., paclitaxel
  • the amount of the taxane (e.g., paclitaxel) per administration is less than about any of 25 mg/m 2 , 22 mg/m2 , 20 mg/m2 , 18 mg/m2 , 15 mg/m2 , 14 mg/m2 , 13 mg/m2 , 12 mg/m2 ,
  • the effective amount of a taxane (e.g., paclitaxel) in the composition is included in any of the following ranges: about 1 to about 5 mg/m 2 , about 5 to about 10 mg/m 2 , about 10 to about 25 mg/m 2 , about 25 to about 50 mg/m 2 , about 50 to about 75 mg/m 2 , about 75 to about 100 mg/m 2 , about 100 to about 125 mg/m 2 , about 125 to about 150 mg/m 2 , about 150 to about 175 mg/m 2 , about 175 to about 200 mg/m 2 , about 200 to about 225 mg/m 2 , about 225 to about 250 mg/m 2 , about 250 to about 300 mg/m 2 , about 300 to about 350 mg/m 2 , or about 350 to about 400 mg/m 2 .
  • a taxane e.g., paclitaxel
  • the effective amount of a taxane (e.g., paclitaxel) in the composition is about 5 to about 300 mg/m 2 , such as about 20 to about 300 mg/m 2 , about 50 to about 250 mg/m 2 , about 100 to about 150 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , or about 140 mg/m 2 , or about 260 mg/m 2 .
  • the effective amount of a taxane (e.g., paclitaxel) in the composition includes at least about any of 1 mg/kg, 2.5 mg/kg, 3.5 mg/kg, 5 mg/kg, 6.5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg.
  • a taxane e.g., paclitaxel
  • the effective amount of a taxane (e.g., paclitaxel) in the composition includes less than about any of 350 mg/kg, 300 mg/kg, 250 mg/kg, 200 mg/kg, 150 mg/kg, 100 mg/kg, 50 mg/kg, 25 mg/kg, 20 mg/kg, 10 mg/kg, 7.5 mg/kg, 6.5 mg/kg, 5 mg/kg, 3.5 mg/kg, 2.5 mg/kg, or 1 mg/kg of a taxane (e.g., paclitaxel).
  • Exemplary dosing frequencies for the composition include, but are not limited to, weekly without break; weekly, three out of four weeks; once every three weeks; once every two weeks; weekly, two out of three weeks.
  • the composition is administered about once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks.
  • the composition is administered at least about any of lx, 2x, 3x, 4x, 5x, 6x, or 7x (i.e., daily) a week, or three times daily, two times daily.
  • the intervals between each administration are less than about any of 6 months, 3 months, 1 month, 20 days, 15 days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, the intervals between each administration are more than about any of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. In some embodiments, there is no break in the dosing schedule. In some embodiments, the interval between each administration is no more than about a week.
  • the taxane in the composition is administered weekly. In some embodiments, the taxane in the composition is administered every two weeks. In some embodiments, the taxane in the composition is administered every three weeks. In some embodiments, the other agent is administered lx, 2x, 3x, 4x, 5x, 6x, or 7 times a week. In some embodiments, the other agent is administered every two weeks or two out of three weeks. In some embodiments, the taxane is paclitaxel. In some embodiment, the other agent is romidepsin. In some embodiments of the above dosages and/or administrations, the taxane is paclitaxel and the other agent is vorinostat.
  • composition (and for the other agent) can be extended over an extended period of time, such as from about a month up to about seven years.
  • the composition is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 48, 60, 72, or 84 months.
  • the taxane e.g., paclitaxel
  • the interval between each administration is no more than about a week
  • the dose of the taxane (e.g., paclitaxel) at each administration is about 0.25 mg/m 2 to about 75 mg/m 2 , such as about 0.25 mg/m 2 to about 25 mg/m 2 or about 25 mg/m 2 to about 50 mg/m 2 .
  • the dosage of a taxane (e.g., paclitaxel) in a composition can be in the range of 5-400 mg/m 2 when given on a 3 week schedule, or 5-250 mg/m 2 when given on a weekly schedule.
  • the amount of a taxane (e.g., paclitaxel) can be about 60 to about 300 mg/m 2 (e.g., about 260 mg/m 2 ) when given on a three week schedule.
  • composition include, but are not limited to, 100 mg/m 2 , weekly, without break; 75 mg/m 2 weekly, 3 out of four weeks; 100 mg/m 2 , weekly, 3 out of 4 weeks; 125 mg/m 2 , weekly, 3 out of 4 weeks; 125 mg/m 2 , weekly, 2 out of 3 weeks; 130 mg/m 2 , weekly, without break; 175 mg/m 2 , once every 2 weeks; 260 mg/m 2 , once every 2 weeks; 260 mg/m 2 , once every 3 weeks; 180-300 mg/m 2 , every three weeks; 60-175 mg/m 2 , weekly, without break; 20-150 mg/m 2 , twice a week; and 150-250 mg/m 2 twice a week.
  • the dosing frequency of the composition may be adjusted over the course of the treatment based on the judgment of the administering physician.
  • the individual is treated for at least about any of one, two, three, four, five, six, seven, eight, nine, or ten treatment cycles.
  • the compositions described herein allow infusion of the composition to an individual over an infusion time that is shorter than about 24 hours. For example, in some
  • the composition is administered over an infusion period of less than about any of 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, or 10 minutes. In some embodiments, the composition is administered over an infusion period of about 30 minutes.
  • exemplary dose of the taxane (in some embodiments paclitaxel) in the nanoparticle composition include, but is not limited to, about any of 50 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 90 mg/m 2 , 100 mg/m 2 , 120 mg/m 2 , 160 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 210 mg/m 2 , 220 mg/m 2 , 260 mg/m 2 , and 300 mg/m 2.
  • the dosage of paclitaxel in a composition can be in the range of about 100- 400 mg/m 2 when given on a 3 week schedule, or about 50-250 mg/m 2 when given on a weekly schedule.
  • the dosing frequency of the other agent can be the same or different from that of the composition. Exemplary frequencies are provided above.
  • the other agent can be administered three times a day, two times a day, daily, 6 times a week, 5 times a week, 4 times a week, 3 times a week, two times a week, weekly. In some embodiments, the other agent is administered twice daily or three times daily.
  • Exemplary amounts of the other agent include, but are not limited to, any of the following ranges: about 0.5 to about 5 mg, about 5 to about 10 mg, about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg, about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about 75 mg, about 50 to about 100 mg, about 75 to about 100 mg, about 100 to about 125 mg, about 125 to about 150 mg, about 150 to about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about 225 to about 250 mg, about 250 to about 300 mg, about 300 to about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or about 450 to about 500 mg, about 500 to about 550 mg, about 550 to about 600 mg, about 600 to about 650 mg, about 650 to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, about 950 mg to about
  • the other agent can be administered at a dose of about 1 mg/kg to about 200 mg/kg (including for example about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 mg/kg, about 140 mg/kg to about 200 mg/kg).
  • romidepsin is administered (for example by oral administration) at about 10-300 mg/m 2 (including for example
  • azacitidine is administered (for example by intraperitoneal administration) at about 20-200 mg/kg/day (including for example 50 mg/kg/day, 80 mg/kg/day, 100 mg/kg/day, 120 mg/kg/day, 140 mg/kg/day, 180 mg/kg/day).
  • decitabine is administered (for example by intraperitoneal administration) at about 0.75-4 mg/kg/day (including for example 1.0 mg/kg/day, 1.5 mg/kg/day, 2.00 mg/kg/day, 2.5 mg/kg/day, 3.0 mg/kg/day, 3.5 mg/kg/day).
  • the effective amount of taxane in the composition is between about 45 mg/m 2 to about 350 mg/m 2 and the effective amount of the other agent is about 1 mg/kg to about 200 mg/kg (including for example about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 mg/kg, about 140 mg/kg to about 200 mg/kg).
  • the effective amount of taxane in the composition is between about 80 mg/m 2 to about 350 mg/m 2 and the effective amount of the other agent is about 1 mg/kg to about 200 mg/kg (including for example about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 mg/kg, about 140 mg/kg to about 200 mg/kg).
  • the effective amount of taxane in the composition is between about 80 mg/m 2 to about 300 mg/m 2 and the effective amount of the other agent is about 1 mg/kg to about 200 mg/kg (including for example about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 mg/kg, about 140 mg/kg to about 200 mg/kg).
  • the effective amount of taxane in the composition is between about 150 mg/m 2 to about 350 mg/m 2 and the effective amount of the other agent is about 1 mg/kg to about 200 mg/kg (including for example about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 mg/kg, about 140 mg/kg to about 200 mg/kg).
  • the effective amount of taxane in the composition is between about 80 mg/m 2 to about 150 mg/m 2 and the effective amount of the other agent is about 1 mg/kg to about 200 mg/kg (including for example about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 mg/kg, about 140 mg/kg to about 200 mg/kg).
  • the effective amount of taxane (e.g., paclitaxel) in the composition is about 100 mg/m 2 .
  • the effective amount of taxane in the composition is between about 170 mg/m 2 to about 200 mg/m 2 and the effective amount of the other agent is about 1 mg/kg to about 200 mg/kg (including for example about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 mg/kg, about 140 mg/kg to about 200 mg/kg).
  • the effective amount of taxane in the composition is between about 200 mg/m 2 to about 350 mg/m 2 and the effective amount of the other agent is about 1 mg/kg to about 200 mg/kg (including for example about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140 mg/kg, about 140 mg/kg to about 200 mg/kg).
  • the effective amount of taxane (e.g., paclitaxel) in the composition is about 260 mg/m 2 .
  • the effective amount of the other agent is about 20-30 mg/kg, about 30-40 mg/kg, about 40-50 mg/kg, about 50-60 mg/kg, about 60-70 mg/kg, about 70-80 mg/kg, about 80-100 mg/kg, or about 100-120 mg/kg.
  • the effective amount of taxane in the composition is between about 45 mg/m 2 to about 350 mg/m 2 and the effective amount of the other agent is about 80 mg to about 1000 mg (including for example about 80 to about 100 mg, about 100 to about 200 mg, about 200 to about 300 mg, about 300 to about 400 mg, about 400 to about 500 mg, about 500 to about 600 mg, about 600 to about 700 mg, about 700 to about 800 mg, about 800 to about 900 mg, about 900 mg to about 1000 mg).
  • the effective amount of taxane in the composition is between about 80 mg/m 2 to about 350 mg/m 2 and the effective amount of the other agent is about 80 mg to about 1000 mg (including for example about 80 to about 100 mg, about 100 to about 200 mg, about 200 to about 300 mg, about 300 to about 400 mg, about 400 to about 500 mg, about 500 to about 600 mg, about 600 to about 700 mg, about 700 to about 800 mg, about 800 to about 900 mg, about 900 mg to about 1000 mg).
  • the effective amount of taxane in the composition is between about 80 mg/m 2 to about 300 mg/m 2 and the effective amount of the other agent is about 80 mg to about 1000 mg (including for example about 80 to about 100 mg, about 100 to about 200 mg, about 200 to about 300 mg, about 300 to about 400 mg, about 400 to about 500 mg, about 500 to about 600 mg, about 600 to about 700 mg, about 700 to about 800 mg, about 800 to about 900 mg, about 900 mg to about 1000 mg).
  • the effective amount of taxane in the composition is between about 1 0 mg/m 2 to about 350 mg/m 2 and the effective amount of the other agent is about 80 mg to about 1000 mg (including for example about 80 to about 100 mg, about 100 to about 200 mg, about 200 to about 300 mg, about 300 to about 400 mg, about 400 to about 500 mg, about 500 to about 600 mg, about 600 to about 700 mg, about 700 to about 800 mg, about 800 to about 900 mg, about 900 mg to about 1000 mg).
  • the effective amount of taxane in the composition is between about 80 mg/m 2 to about 150 mg/m 2 and the effective amount of the other agent is about 80 mg to about 1000 mg (including for example about 80 to about 100 mg, about 100 to about 200 mg, about 200 to about 300 mg, about 300 to about 400 mg, about 400 to about 500 mg, about 500 to about 600 mg, about 600 to about 700 mg, about 700 to about 800 mg, about 800 to about 900 mg, about 900 mg to about 1000 mg).
  • the effective amount of taxane in the composition is between about 170 mg/m 2 to about 200 mg/m 2 and the effective amount of the other agent is about 80 mg to about 1000 mg (including for example about 80 to about 100 mg, about 100 to about 200 mg, about 200 to about 300 mg, about 300 to about 400 mg, about 400 to about 500 mg, about 500 to about 600 mg, about 600 to about 700 mg, about 700 to about 800 mg, about 800 to about 900 mg, about 900 mg to about 1000 mg).
  • the effective amount of taxane in the composition is between about 200 mg/m 2 to about 350 mg/m 2 and the effective amount of the other agent is about 80 mg to about 1000 mg (including for example about 80 to about 100 mg, about 100 to about 200 mg, about 200 to about 300 mg, about 300 to about 400 mg, about 400 to about 500 mg, about 500 to about 600 mg, about 600 to about 700 mg, about 700 to about 800 mg, about 800 to about 900 mg, about 900 mg to about 1000 mg).
  • the effective amount of taxane (e.g., paclitaxel) in the composition is about 100 mg/m 2 .
  • the effective amount of the other agent is about 100-200 mg, about 200-300 mg, about 300-400 mg, about 400-500 mg.
  • the effective amount of paclitaxel in the composition is about 100 mg/m 2 and the effective amount of the other agent (such as romidepsin) is about 10 to 300 mg/m 2 .
  • the effective amount of paclitaxel in the composition is about 50-300 mg/m 2 (including for example about 100 mg/m 2 ) and the effective amount of the other agent (such as azacitidine) is about 10-200 mg/mw (including for example about 50-100 mg/m 2 or for example about 75 mg/m 2 ). In some embodiments, the effective amount of paclitaxel in the composition is about 50- 300 mg/m 2 (including for example about 100 mg/m 2 ) and the effective amount of the other agent (such as decitabine) is about 10-200 mg/m 2 (including for example about 50-100 mg/m 2 or for example about 75 mg/m 2 ).
  • composition (and the other agent) described herein can be any composition (and the other agent) described herein.
  • sustained continuous release formulation of the composition may be used.
  • a combination of the administration configurations described herein can be used.
  • the combination therapy methods described herein may be performed alone or in conjunction with another therapy, such as surgery, radiation, chemotherapy, immunotherapy, gene therapy, and the like. Additionally, a person having a greater risk of developing the proliferative disease may receive treatments to inhibit or and/or delay the development of the disease.
  • the appropriate doses of other agents will be approximately those already employed in clinical therapies wherein the other agent are administered alone or in combination with other agents. Variation in dosage will likely occur depending on the condition being treated. As described above, in some embodiments, the other agents may be administered at a reduced level.
  • Romidepsin and paclitaxel can be used as compositions when combined with an acceptable carrier or excipient. Such compositions are useful in the methods provided herein.
  • compositions comprising romidepsin as an active ingredient, including an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug in combination with a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
  • compositions comprising paclitaxel as an active ingredient or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug in combination with a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
  • Suitable excipients are well known to those skilled in the art, and non- limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition.
  • lactose-free compositions comprise an active ingredient provided herein, a binder/filler, and a lubricant.
  • lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
  • dosage forms provided herein comprise romidepsin or a
  • dosage forms provided herein comprise romidepsin or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in an amount of from about 0.5 mg/m 2 to 28 mg/m 2 .
  • dosage forms provided herein comprise romidepsin or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in an amount of about 8 mg/m 2 , 10 mg/m 2 , 12 mg/m 2 , or 14 mg/m 2 .
  • dosage forms provided herein comprise paclitaxel or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in a dose of from about 60-300 mg/m 2 (including for example about 80-200 mg/m 2 for example about 100 mg/m 2 ),.
  • dosage forms provided herein comprise paclitaxel or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in an dose of about 60, 80, 100, 150, 200, 250 mg/m 2 .
  • a preferred dosage form of paclitaxel is 100 mg/m 2 .
  • compositions provided herein can be used in the preparation of individual, single unit dosage forms.
  • Single unit dosage forms are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal or
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g.
  • aqueous or non-aqueous liquid suspensions oil- in-water emulsions, or a water-in-oil liquid emulsions
  • solutions and elixirs
  • liquid dosage forms suitable for parenteral administration to a patient eye drops or other ophthalmic preparations suitable for topical administration
  • sterile solids e.g., crystalline or amorphous solids that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • compositions provided herein formulated in various dosage forms for oral administration.
  • compositions provided herein formulated in various dosage forms for parenteral administration.
  • compositions are provided in a dosage form for oral administration, which comprise romidepsin or a
  • a dosage form is a capsule or tablet comprising romidepsin in an amount of about
  • capsule or tablet dosage form comprises romidepsin in an amount of about 50 mg/m 2 or 75 mg/m 2 .
  • the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise romidepsin or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and one or more pharmaceutically acceptable excipients or carriers.
  • a dosage form is a syringe or vial comprising romidepsin in an amount of about
  • syringe or vial dosage form comprises romidepsin in an amount of about 8 mg/m 2 , 10 mg/m 2 , 12 mg/m 2 , or 14 mg/m 2 .
  • the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise paclitaxel or a
  • a dosage form is a syringe or vial comprising paclitaxel in a dose of about 60-300 mg/m 2 .
  • the pharmaceutical compositions provided herein can be provided in a unit-dosage form or multiple-dosage form.
  • a unit-dosage form include an ampoule, syringe, and individually packaged tablet and capsule.
  • a 100 mg unit dose contains about 100 mg of an active ingredient in a packaged tablet or capsule.
  • a unit-dosage form may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.
  • compositions provided herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxye
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the amount of a binder or filler in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • the amount of a diluent in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Suitable disintegrants include, but are not limited to, agar; bentonite;
  • celluloses such as methylcellulose and carboxymethylcellulose; wood products;
  • microcrystalline cellulose such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.
  • compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • Suitable lubricants include, but are not limited to, calcium stearate;
  • magnesium stearate mineral oil; light mineral oil; glycerin; sorbitol; mannitol;
  • glycols such as glycerol behenate and polyethylene glycol (PEG); stearic acid;
  • sodium lauryl sulfate talc
  • hydrogenated vegetable oil including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil
  • zinc stearate ethyl oleate
  • ethyl laureate agar
  • starch lycopodium
  • silica or silica gels such as AEROSIL ® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL ® (Cabot Co. of Boston, MA); and mixtures thereof.
  • the pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
  • Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL ® (Cabot Co. of Boston, MA), and asbestos-free talc.
  • Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
  • a color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN ® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN ® 80), and triethanolamine oleate.
  • Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.
  • Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.
  • Suitable organic acids include, but are not limited to, citric and tartaric acid.
  • Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
  • compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar- coated, or film-coated tablets.
  • Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
  • Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled- release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • the soft elastic capsule is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms.
  • Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule.
  • Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in- water or water-in-oil.
  • Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions.
  • a pharmaceutically acceptable acetal such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal
  • a water-miscible solvent having one or more hydroxyl groups such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions.
  • Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550- dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • a dialkylated mono- or poly-alkylene glycol including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550- dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • formulations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • BHT butyl
  • Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
  • compositions provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the above dosage forms.
  • compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous
  • compositions provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to
  • compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles
  • non-aqueous vehicles non-aqueous vehicles
  • antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emuls
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil.
  • Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N- dimethylacetamide, and dimethyl sulfoxide.
  • Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate and citrate.
  • Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including a-cyclodextrin, ⁇ - cyclodextrin, hydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin, and sulfobutylether 7- -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • cyclodextrins including a-cyclodextrin, ⁇ - cyclodextrin, hydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin, and sulfobutylether 7- -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
  • the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions.
  • the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile suspensions.
  • the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions.
  • the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile suspensions.
  • the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions.
  • compositions are provided as ready-to-use sterile emulsions.
  • compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the pharmaceutical compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
  • Suitable inner matrixes include, but are not limited to,
  • Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
  • compositions comprising romidepsin and paclitaxel can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference.
  • Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- release.
  • controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • drug active ingredient
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • romidepsin is formulated for injection as a sterile lyophilized white powder and is supplied in a single -use vial containing 10 mg romidepsin and 20 mg povidone, USP.
  • the diluent is a sterile clear solution and is supplied in a single-use vial containing a 2 ml deliverable volume.
  • the diluent for romidepsin contains 80% (v/v) propylene glycol, USP and 20% (v/v) dehydrated alcohol, USP.
  • Romidepsin is supplied as a kit containing two vials.
  • Romidepsin for injection is intended for intravenous infusion after reconstitution with the supplied Diluent and after further dilution with 0.9%> Sodium Chloride, USP.
  • TAXOL paclitaxel
  • TAXOL paclitaxel
  • TAXOL paclitaxel
  • TAXOL is formulated for injection as a clear, colorless to slightly yellow viscous solution. It is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion.
  • TAXOL is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose vials. Each mL of sterile nonpyrogenic solution contains
  • compositions such as pharmaceutical compositions
  • medicine such as medicine, kits, and unit dosages useful for methods described herein.
  • unit dosages useful for methods described herein. Also provided are any use described herein whether in the context of use as a medicament and/or use for manufacture of a medicament.
  • Kits of the invention include one or more containers comprising taxane - containing compositions (or unit dosage forms and/or articles of manufacture) and/or at least one other agent that modifies the epigenetics in a cell, and in some
  • kits of the invention further comprise instructions for use in accordance with any of the methods described herein.
  • the kit may further comprise a description of selection an individual suitable or treatment.
  • Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
  • the kit comprises a) a composition comprising a taxane (such as paclitaxel), and b) an effective amount of at least one other agent that modifies the epigenetics in a cell.
  • the kit comprises a) a composition comprising a taxane (such as paclitaxel), b) an effective amount of at least one other agent that modifies the epigenetics in a cell, and c) instructions for administering the composition and the other agents simultaneously, sequentially, or concurrently for treatment of a proliferative disease (such as cancer).
  • the taxane is any of paclitaxel, docetaxel, and ortataxel.
  • the kit comprises a) a composition comprising paclitaxel, b) an effective amount of at least one other agent that modifies the epigenetics in a cell, and c) instructions for administering the composition and the other agents simultaneously, sequentially, and/or concurrently, for the effective treatment of a proliferative disease (such as cancer).
  • a proliferative disease such as cancer
  • the kit comprises a) a composition comprising a taxane (such as paclitaxel), b) a composition comprising at least one other agent that modifies the epigenetics in a cell and a carrier protein (such as albumin), and c) instructions for administering the compositions simultaneously, sequentially, and/or concurrently, for treatment of a proliferative disease (such as cancer).
  • a taxane such as paclitaxel
  • a composition comprising at least one other agent that modifies the epigenetics in a cell and a carrier protein (such as albumin)
  • a carrier protein such as albumin
  • the kit comprises a) a composition comprising paclitaxel, b) a composition comprising at least one other agent that modifies the epigenetics in a cell and a carrier protein (such as albumin), and c) instructions for administering the compositions simultaneously, sequentially, and/or concurrently, for the effective treatment of a proliferative disease (such as cancer).
  • a proliferative disease such as cancer
  • the other agents can be present in separate containers or in a single container. It is understood that the kit may comprise one distinct composition or two or more compositions wherein one composition comprises paclitaxel and one composition comprises an other agent.
  • kits of the invention are in suitable packaging.
  • suitable packaging include, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information.
  • the present application thus also provides articles of manufacture, which include vials (such as sealed vials), bottles, jars, flexible packaging, and the like.
  • the instructions relating to the use of the compositions generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • the containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of the taxane (such as taxane) as disclosed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the taxane and pharmaceutical compositions and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
  • the medicine comprises a) a composition comprising a taxane (such as paclitaxel), and b) at least one other agent that modifies the epigenetics in a cell.
  • the taxane is any of paclitaxel, docetaxel, and ortataxel.
  • the kit comprises a) a composition comprising paclitaxel, and b) at least one other agent that modifies the epigenetics in a cell, and c) instructions for administering the composition and the other agents simultaneously, sequentially, and/or concurrently, for the effective treatment of a proliferative disease (such as cancer).
  • the medicine comprises a) a composition comprising a taxane (such as paclitaxe), and b) at least one other agent that modifies the epigenetics in a cell.
  • a taxane such as paclitaxe
  • the taxane is any of paclitaxel, docetaxel, and ortataxel.
  • the at least one other agent that modifies the epigenetics in a cell is azacitidine.
  • kits comprising a) a composition comprising paclitaxel, and b) azacitidine, and c) instructions for administering the nanoparticles and the azacitidine simultaneously, sequentially, and/or concurrently, for the effective treatment of lymphoid neoplasm (for example, CLL/SLL or lymphoma, such as refractory DLBC lymphoma).
  • lymphoid neoplasm for example, CLL/SLL or lymphoma, such as refractory DLBC lymphoma.
  • the at least one other agent that modifies the epigenetics in a cell is decitabine.
  • kits comprising a) a composition comprising paclitaxel, and b) decitabine, and c) instructions for administering the compositions and the decitabine simultaneously, sequentially, and/or concurrently, for the effective treatment of lymphoid neoplasm (for example, CLL/SLL or lymphoma, such as refractory DLBC lymphoma).
  • lymphoid neoplasm for example, CLL/SLL or lymphoma, such as refractory DLBC lymphoma.
  • the medicine comprises a) a composition comprising a taxane (such as paclitaxel), and b) at least one other agent that modifies the epigenetics in a cell.
  • a taxane such as paclitaxel
  • the taxane is any of paclitaxel, docetaxel, and ortataxel.
  • the at least one other agent that modifies the epigenetics in a cell is azacitidine.
  • kits comprising a) a composition comprising paclitaxel, and b) azacitidine, and c) instructions for administering the nanoparticles and the azacitidine simultaneously, sequentially, and/or concurrently, for the effective treatment of ovarian cancer.
  • the at least one other agent that modifies the epigenetics in a cell is decitabine.
  • a kit comprising a) a composition comprising paclitaxel, and b) decitabine, and c) instructions for administering the composition and the decitabine simultaneously, sequentially, and/or concurrently, for the effective treatment of ovarian cancer.
  • the medicine comprises a) a composition comprising a taxane (such as paclitaxel), and b) at least one other agent that modifies the epigenetics in a cell.
  • a taxane such as paclitaxel
  • the taxane is any of paclitaxel, docetaxel, and ortataxel.
  • the at least one other agent that modifies the epigenetics in a cell is azacitidine.
  • kits comprising a) a composition comprising paclitaxel, and b) azacitidine, and c) instructions for administering the composition and the azacitidine simultaneously, sequentially, and/or concurrently, for the effective treatment of endometrial cancer (e.g. uterine cancer).
  • the at least one other agent that modifies the epigenetics in a cell is decitabine.
  • a kit comprising a) a composition comprising paclitaxel, and b) decitabine, and c) instructions for administering thecomposition and the decitabine simultaneously, sequentially, and/or concurrently, for the effective treatment of endometrial cancer (e.g. uterine cancer).
  • the medicine comprises a) a composition comprising a taxane (such as paclitaxel), and b) at least one other agent that modifies the epigenetics in a cell.
  • a taxane such as paclitaxel
  • the taxane is any of paclitaxel, docetaxel, and ortataxel.
  • the at least one other agent that modifies the epigenetics in a cell is azacitidine.
  • a kit comprising a) a composition comprising paclitaxel, b) azacitidine, and c) instructions for administering the composition and the azacitidine simultaneously, sequentially, and/or concurrently, for the effective treatment of lung cancer.
  • the at least one other agent that modifies the epigenetics in a cell is decitabine.
  • a kit comprising a) a composition comprising paclitaxel, b) decitabine, and c) instructions for administering the composition and the decitabine
  • the medicine comprises a) a composition comprising a taxane (such as paclitaxel), and b) at least one other agent that modifies the epigenetics in a cell.
  • a taxane such as paclitaxel
  • the taxane is any of paclitaxel, docetaxel, and ortataxel.
  • the at least one other agent that modifies the epigenetics in a cell is azacitidine.
  • a kit comprising a) a composition comprising paclitaxel, b) azacitidine, and c) instructions for administering the composition and the azacitidine simultaneously, sequentially, and/or concurrently, for the effective treatment of sarcoma.
  • the at least one other agent that modifies the epigenetics in a cell is decitabine.
  • kits comprising a) a composition comprising paclitaxel, b) decitabine, and c) instructions for administering the composition and the decitabine simultaneously, sequentially, and/or concurrently, for the effective treatment of sarcoma.
  • the medicine comprises a) a composition comprising a taxane (such as paclitaxel), and b) at least one other agent that modifies the epigenetics in a cell.
  • a taxane such as paclitaxel
  • the taxane is any of paclitaxel, docetaxel, and ortataxel.
  • the at least one other agent that modifies the epigenetics in a cell is azacitidine.
  • kits comprising a) a composition comprising paclitaxel, b) azacitidine, and c) instructions for administering the composition and the azacitidine simultaneously, sequentially, and/or concurrently, for the effective treatment of pancreatic cancer.
  • the at least one other agent that modifies the epigenetics in a cell is decitabine.
  • a kit comprising a) a composition comprising paclitaxel, b) decitabine, and c) instructions for administering the ciomposition and the decitabine simultaneously, sequentially, and/or concurrently, for the effective treatment of pancreatic cancer.
  • the medicine comprises a) a composition comprising a taxane (such as paclitaxel), and b) at least one other agent that modifies the epigenetics in a cell.
  • a taxane such as paclitaxel
  • the taxane is any of paclitaxel, docetaxel, and ortataxel.
  • the at least one other agent that modifies the epigenetics in a cell is romidepsin.
  • kits comprising a) a composition comprising paclitaxel, b) romidepsin, and c) instructions for administering the composition and the romidepsin simultaneously, sequentially, and/or concurrently, for the effective treatment of breast cancer (for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer).
  • breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer.
  • the at least one other agent that modifies the epigenetics in a cell is azacitidine
  • a kit comprising a) a composition comprising paclitaxel, b) azacitidine, and c) instructions for administering the composition and the azacitidine simultaneously, sequentially, and/or concurrently, for the effective treatment of breast cancer (for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer).
  • the at least one other agent that modifies the epigenetics in a cell is decitabine.
  • kits comprising a) a composition comprising paclitaxel, b) decitabine, and c) instructions for administering the composition and the decitabine simultaneously, sequentially, and/or concurrently, for the effective treatment of breast cancer (for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer).
  • breast cancer for example, HER2 negative breast cancer or for example, triple negative breast cancer, or for example, inflammatory breast cancer.
  • compositions and the other agents can be present in separate containers or in a single container. It is understood that the medicine may comprise one distinct composition or two or more compositions wherein one composition comprises paclitaxel and one composition comprises another agent.
  • kits, medicines, and compositions of this invention may include any one or more aspects or parameters described herein.
  • Example 1 The Combined Effect of Romidepsin and Paclitaxel on IBC cells in Vitro
  • SUM 149 and SUM 190 cell lines Two cell lines available for studies focused on IBC are the SUM 149 and SUM 190 cell lines.
  • human breast cancer cell lines of different molecular subtypes were included, i.e, breast cancer cells that differ with respect to hormone receptor (ER/PR) and Her-2 oncogene status.
  • the cell lines included were MDA-MB-231 breast cancer cells and SUM 149 IBC cells, which are both basal like (triple negative; ER/PR7Her-2 ⁇ ), AU565 cells, which are Her-2 amplified (ER/PR7Her-2 + ), SUM190 IBC cells which are luminal B subtype (ER/PR + /Her-2 + ), and MCF-7 cells, which are luminal A (ER/PR + /Her-2 ⁇ ).
  • the characterization of molecular subtypes of breast cancer cell lines is provided in Table 1 below. Table 1
  • Cell proliferation Cell were seeded in six-well culture dish, harvested at 24-120 hrs after plating and cell proliferation was determined by total live cell counts and by MTT [3-(4,5-dimethylthiazol-2-yi)-2,5-diphenyltetrazolium bromide; Life Technologies/Invitrogen] assay. MTT solution (5 mg/ml) was added to ceils and incubated at 37°C until the appearance of colored formazan product, which then was dissolved in DMSO, and subjected to colorimetric measurement at 570 nm using a plate reader. DMSO will be used as the solvent control. The IC 50 value was defined as the drug concentration at which half of the maximum growth inhibition is achieved and was determined using Calcusyn v 2.0 software (Biosoft). Agents tested is in stock solutions in DMSO or appropriate solvents depending upon chemical
  • Anchorage-independent growth was assessed based on the ability of cells to grow as colonies in soft agar. This assay was performed in six-well plates with a base of 2 ml of medium containing 1% fetal bovine serum and 0.5% Bacto agar. Breast cancer cell lines described above (5 x 104 cell concentration) were layered onto the base in 2 ml of medium containing 1% fetal bovine serum and 0.35% agar. The experiments were performed in triplicate and repeated twice.
  • SUM 149 cells and Mary-X tumor spheroids were engineered to contain a luciferase construct which imparts a bioluminescent signal to the cells, allowing for in vivo live imaging to identify tumor location and relative volume in real time during the time course of the in vivo studies.
  • 10 6 SUM 149 cells were injected into the left lower mammary fat pad (i.m.) using using 26 gauge needle and 1 cc tuberculin syringe following euthanasia using isoflurane.
  • the injection of SUM149 cells resulted in development of primary SUM 149 tumors within the mammary fat pad.
  • mice were euthanized using C0 2 and cervival dislocation. Based on IUCAC guidelines, mice bearing primary tumors that reached a size greater than 10% body mass of mouse were euthanized.
  • mice Primary tumors were initiated in mice as follows: SUM 149 cells [10 6 ] were injected into intramammary fat pad of Nod.Scid mice; and Mary-X tumor spheroids [10 6 ] were injected into the hind flank of Nod.Scid mice. At the time the tumors were 200-300 mm 3 , mice were randomly assigned to one of the treatment groups, with the total numbers of mice as described below.
  • Treatment groups consisted of the following:
  • Romidepsin treatment group romidepsin was injected with 100 ul 10%> polyethylated hydrogenated castor oil in physiological saline (Cremophor EL; BASF) at a concentration of 2.5 mg/kg via the i.p. 3 times weekly into Nod.Scid mice bearing primary SUM 149 xenografts and Nod.Scid mice bearing Mary-X tumor spheroids injected subcutaneously into the right hind flank of mice.
  • Paclitaxel treatment group paclitaxel at a concentration of 15 mg/kg in
  • Cremophor was injected via the i.p. route 3 times weekly into Nod.Scid mice bearing primary SUM 149 xenografts and Nod.Scid mice bearing Mary-X tumor spheroids injected subcutaneously into the right hind flank of mice.

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Abstract

L'invention concerne des procédés de polythérapie pour le traitement du cancer (tel qu'un cancer du sein inflammatoire), comprenant l'administration à un individu d'une quantité efficace de paclitaxel et d'une quantité efficace de romidepsine. L'invention concerne également des compositions pharmaceutiques et des coffrets les comprenant.
PCT/US2012/067759 2011-12-05 2012-12-04 Procédés de polythérapie pour le traitement d'un cancer du sein inflammatoire WO2013085902A1 (fr)

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