WO2002015921A2 - Methodes de traitement du lymphome cutane a cellules t et du lymphome peripherique a cellules t (non specifie) par l'administration d'un inhibiteur de l'histone deacetylase - Google Patents

Methodes de traitement du lymphome cutane a cellules t et du lymphome peripherique a cellules t (non specifie) par l'administration d'un inhibiteur de l'histone deacetylase Download PDF

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Publication number
WO2002015921A2
WO2002015921A2 PCT/US2001/025827 US0125827W WO0215921A2 WO 2002015921 A2 WO2002015921 A2 WO 2002015921A2 US 0125827 W US0125827 W US 0125827W WO 0215921 A2 WO0215921 A2 WO 0215921A2
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WO
WIPO (PCT)
Prior art keywords
administering
histone deacetylase
deacetylase inhibitor
nsc
systemically
Prior art date
Application number
PCT/US2001/025827
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English (en)
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WO2002015921A3 (fr
Inventor
Susan E. Bates
Antonio T. Fojo
Richard Piekarz
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The Governement Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services
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Publication date
Application filed by The Governement Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services filed Critical The Governement Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services
Priority to AU2001285042A priority Critical patent/AU2001285042A1/en
Publication of WO2002015921A2 publication Critical patent/WO2002015921A2/fr
Publication of WO2002015921A3 publication Critical patent/WO2002015921A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/15—Depsipeptides; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to methods of treating cutaneous T-cell lymphoma and peripheral T-cell lymphoma (unspecified).
  • the methods comprise administering a histone deacetylase inhibitor.
  • Cutaneous T-cell lymphoma is an indolent disorder of malignant, relatively mature T-cells which frequently involves the skin, bloodstream, regional lymph nodes and spleen. Approximately 800-1,000 new cases are diagnosed per year in the U.S. There are several clinical variants of the disease. The condition causes severe skin itching, pain and edema. Currently, cutaneous T-cell lymphoma is treated topically with steroids, photochemotherapy and chemotherapy. Radiotherapy is also utilized.
  • Peripheral T-cell lymphomas originate from mature or peripheral (not central or thymic) T-cell lymphocytes as a clonal proliferation from a single T-cell and are usually either predominantly nodal or extranodal tumors. They have T-cell lymphocyte cell-surface markers and clonal rearrangements of the T-cell receptor genes.
  • the present invention seeks to provide new methods of treating cutaneous T- cell lymphoma and peripheral T-cell lymphoma, unspecified.
  • the present inventive method of treating cutaneous T-cell lymphoma offers advantages over currently available methods by effectively treating the severe skin itching, pain and edema that accompany the disease without causing side effects.
  • the present invention provides methods of treating cutaneous T-cell lymphoma and peripheral T-cell lymphoma, unspecified, in a mammal.
  • the methods comprise administering to the mammal an effective amount of a histone deacetylase inhibitor.
  • the histone deacetylase inhibitor is a depsipeptide, in particular the depsipeptide known as NSC 630176.
  • the methods can further comprise (i) administering a steroid, a P-glycoprotein multiple drug resistance (MDR) antagonist, an active agent targeted to a T-cell receptor and/or a retinoid, (ii) the use of chemotherapy, and/or (iii) the use of photochemotherapy.
  • MDR P-glycoprotein multiple drug resistance
  • the present invention is predicated on the surprising and unexpected discovery that NSC 630176, a depsipeptide that inhibits histone deacetylase, effectively treats cutaneous T-cell lymphoma and peripheral T-cell lymphoma, unspecified.
  • the present invention provides methods of treating cutaneous T- cell lymphoma and peripheral T-cell lymphoma in a mammal.
  • the methods comprise administering to the mammal an effective amount of a histone deacetylase inhibitor.
  • Histone deacetylase inhibitors are known in the art.
  • histone deacetylase inhibitors include, but are not limited to, trapoxin A, trapoxin B, trichostatin A, amide analogues of trichostatin A (see, e.g., Jung et al., J. Med. Chem.
  • trichostatin C sodium butyrate (including derivatives thereof, such as phenyl butyrate), phenyl acetate, 3-bromopropionate, HC toxin, apicidin, and depsipeptides, such as (E)-(1S, 4S, 10S, 21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2- oxa- 12, 13-dithia-5,8,20,23-tetraazabicyclo [8,7,6]-tricos- 16-ene-3,6, 19,22-pentanone (NSC 630176, which is also known as FR901228), and the cyclic depsipeptides didemnin B and sandramycin.
  • the histone deacetylase inhibitor is a depsipeptide. More preferably, the depsipeptide is NSC 630176.
  • the histone deacetylase inhibitor is administered in the form of a pharmaceutically acceptable composition (see, e.g., Remington's Pharmaceutical
  • a formulation suitable for topical application can be in the form of creams, ointments, or lotions in which the inhibitor can be mixed with conventional oleoginous or emulsifying excipients.
  • the histone deacetylase inhibitor is systemically administered. If the histone deacetylase inhibitor is systemically administered, preferably it is administered orally or by intravenous infusion.
  • Compositions suitable for oral and intravenous infusion are also known in the art.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluent, such as water, saline, or orange juice; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or granules; (c) suspensions in an appropriate liquid; and (d) suitable emulsions.
  • Tablet forms can include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth.
  • Pastilles can comprise the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients/carriers as are known in the art.
  • an inert base such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients/carriers as are known in the art.
  • Formulations suitable for parenteral administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the histone deacetylase inhibitor is administered systemically, preferably the administration is intermittent.
  • the histone deacetylase inhibitor NSC 630176 is administered by intravenous infusion, it can be administered at the maximum tolerated dose of 17.8 mg/m over 4 hours on days 1 and 5 of a 21-day cycle, for example, although other doses and schedules can be effective and can be determined in accordance with methods known in the art.
  • an effective amount is meant an amount of histone deacetylase inhibitor sufficient to treat the cutaneous T-cell lymphoma or peripheral T-cell lymphoma, unspecified, in the mammal, in particular a human, over a reasonable time frame.
  • the determination of an effective amount is within the ordinary skill in the art.
  • the dose administered to a mammal, particularly a human, in the context of the present invention will vary with the inliibitor administered (e.g., its potency), the composition employed, the route of administration, the severity of the disease state, the body weight and age of the infected individual, the extent of contact, and the particular site being treated.
  • the size of the dose also will be determined by the existence of any adverse side effects that can accompany the use of the particular inhibitor employed. It is always desirable, whenever possible, to keep adverse side effects to a minimum.
  • an above-described inhibitor when administered to an animal, such as a mammal, in particular a human, it is preferable that the inhibitor is administered in a dose of from about 1 to about 1,000 micrograms of the inhibitor per kg of the body weight of the host per day when given parenterally.
  • this dosage range is merely preferred, and higher or lower doses may be chosen in appropriate circumstances.
  • the actual dose and schedule can vary depending on whether the composition is administered in combination with other pharmaceutical compositions, or depending on interindividual differences in pharmacokinetics, drug disposition, and metabolism.
  • the maximum tolerated dose of NSC 630176 is 17.8 mg/m 2 .
  • the methods can further comprise (i) administering a steroid, a P-glycoprotein multiple drug resistance (MDR) antagonist, a retinoid and/or an active agent targeted to a T-cell receptor, (ii) the use of chemotherapy, and/or (iii) the use of photochemotherapy.
  • MDR P-glycoprotein multiple drug resistance
  • steroids examples include, but are not limited to, glucocorticoids.
  • a steroid is administered topically.
  • P-glycoprotein antagonists are also known in the art and include, but are not limited to, cyclosporin A, verapamil, quinidine, dihydro-pyridines, calcium channel blockers, cyclosporin analogues (e.g., PSC833 (Novartis, East Hanover, NJ)), phenothiazines, thioxanthenes, XR9576 (Xenova, Flough, United Kingdom), GG918 (glaxo), VX710 (Vertex), and others of similar or greater potency.
  • a P- glycoprotein antagonist is administered topically or systemically.
  • Retinoids include agents that bind to the retinoic acid receptor, such as 9-cis- retinoic acid, 4-hydroxy-retinoic acid, all tr ⁇ r ⁇ -retinoic acid, (E)-4-[2-(5,6,7,8- tetrahydro-2-naphthylenyl)-l -propenyl]-benzoic acid, 3-methyl-(E)-4-[2-(5,6,7,8- tetrahydro-2-naphthylenyl)-l-propenyl]-benzoic acid), and the like as known in the art.
  • a retinoid is preferably administered topically or systemically.
  • An active agent that is targeted to a T-cell receptor can be any suitable agent that is targeted to a T-cell receptor, such as the IL-2 receptor, and has an effect, which, desirably, is an anti-cancer effect.
  • the active agent can be an antibody (or an antigenically reactive fragment thereof) to a T-cell receptor, such as the IL-2 receptor.
  • a commercially available antibody to a T-cell receptor is Zenapax, which is available from Hoffinan-LaRoche, Inc., Nutley, NJ. The antibody is preferably administered systemically.
  • the active agent can be a fusion protein or a conjugate of a means of targeting a T-cell receptor, such as an antibody (or an antigenically reactive fragment thereof) to a T-cell receptor or a ligand to a T-cell receptor, and an active agent, such as a drug (or a prodrug or derivative or pharmaceutically acceptable salt thereof) or a toxin as are known in the art.
  • a drug or a prodrug or derivative or pharmaceutically acceptable salt thereof
  • the drug is an anti-cancer drug and the toxin is an anti-cancer toxin.
  • An example of such an agent is an anti-IL- 2 antibody fused to a toxin, such as the agent known as Ontak TM (Ligand Pharmaceuticals, San Diego, CA).
  • This example describes the treatment of cutaneous T-cell lymphoma in four adult human males.
  • the male had skin (nodules on elbows, buttocks, sole of right foot (4 cm in size) and legs), lymph node and bone marrow involvement, retroperitoneal adenopathy, sinusitis, and mild erythroderma. He had previously received one course of EPOCH chemotherapy and the disease progressed after the course of treatment. He then was treated with five cycles of an infusion of depsipeptide (17.8 mg/m 2 on days 1 and 5 of a 21 day cycle). No change was noticed after the first cycle. The sinusitis improved after the second cycle as did the erythroderma and the skin nodules.
  • the patient began treatment after a 4-5 year history of pruritic skin lesions that started behind the ears and gradually spread to encompass his entire body.
  • Skin biopsies indicated mycosis fungoides. Disease progressed following three cycles of CVP (cyclophosphamide, vincristine and prednisone).
  • CVP cyclophosphamide, vincristine and prednisone
  • his peripheral white blood cell count was greater than 40,000 and comprised mostly Sezary cells.
  • a decline in white blood cells was noted.
  • a decrease in skin edema and thickening and a continued improvement in Sezary cell count were observed with marked relief of symptoms.
  • the patient had been treated with CHOP for approximately 3 1/2 months and with Yttrium-labeled Zenapax for approximately six weeks. He had severe erythroderma and lymphadenopathy. After the first cycle of treatment (as indicated for patient A), there was a marked decrease in skin edema, redness and itching. After three cycles of treatment, a decrease in skin edema and thickening and a continued improvement in Sezary cell count (decreased from 80,000 to 6,000) were observed with marked relief of symptoms.
  • This example describes the treatment of peripheral T-cell lymphoma, unspecified, in an adult human male.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des méthodes de traitement du lymphome cutané à cellules T et du lymphome périphérique à cellules T, non spécifié, chez un mammifère. Les méthodes consistent à administrer une quantité efficace d'un inhibiteur de l'histone déacétylase à un mammifère.
PCT/US2001/025827 2000-08-18 2001-08-17 Methodes de traitement du lymphome cutane a cellules t et du lymphome peripherique a cellules t (non specifie) par l'administration d'un inhibiteur de l'histone deacetylase WO2002015921A2 (fr)

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AU2001285042A AU2001285042A1 (en) 2000-08-18 2001-08-17 Methods of treating cutaneous and peripheral t-cell lymphoma by a histone deacetylase inhibitor

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US22623400P 2000-08-18 2000-08-18
US60/226,234 2000-08-18

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Cited By (19)

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US7148257B2 (en) 2002-03-04 2006-12-12 Merck Hdac Research, Llc Methods of treating mesothelioma with suberoylanilide hydroxamic acid
WO2008002634A1 (fr) * 2006-06-28 2008-01-03 Novartis Ag Utilisation d'inhibiteurs de la hdac pour le traitement des lymphomes
US7399787B2 (en) 2002-03-04 2008-07-15 Merck Hdac Research, Llc Methods of treating cancer with HDAC inhibitors
US7456219B2 (en) 2002-03-04 2008-11-25 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US7604939B2 (en) 2005-03-01 2009-10-20 The Regents Of The University Of Michigan Methods of identifying active BRM expression-promoting HDAC inhibitors
US7683185B2 (en) 2002-11-18 2010-03-23 Queen Mary & Westfield College Histone deacetylase inhibitors
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7879865B2 (en) 2001-10-16 2011-02-01 Sloan-Kettering Institute For Cancer Research Treatment of cancer of the brain using histone deacetylase inhibitors
US8093295B2 (en) 2005-05-20 2012-01-10 Merck Sharp & Dohme Corp. Formulations of suberoylanilide hydroxamic acid and methods for producing the same
WO2012009336A1 (fr) * 2010-07-12 2012-01-19 Gloucester Pharmaceuticals, Inc. Formes solides de la romidepsine et leurs utilisations
US8110577B2 (en) 2006-10-19 2012-02-07 Queen Mary & Westfield College Histone deacetylase inhibitors
WO2012128709A1 (fr) * 2011-03-21 2012-09-27 Valcuria Ab Composition pharmaceutique comprenant un inhibiteur des hdac et un stéroïde, et son utilisation
US8691534B2 (en) 2006-12-29 2014-04-08 Celgene Corporation Preparation of romidepsin
US8859502B2 (en) 2010-09-13 2014-10-14 Celgene Corporation Therapy for MLL-rearranged leukemia
US8957027B2 (en) 2006-06-08 2015-02-17 Celgene Corporation Deacetylase inhibitor therapy
US9101579B2 (en) 2012-11-14 2015-08-11 Celgene Corporation Inhibition of drug resistant cancer cells
US9134325B2 (en) 2012-09-07 2015-09-15 Celgene Corporation Resistance biomarkers for HDAC inhibitors
US9463215B2 (en) 2013-12-27 2016-10-11 Celgene Corporation Romidepsin formulations and uses thereof
US9539303B2 (en) 2006-04-24 2017-01-10 Celgene Corporation Treatment of Ras-expressing tumors

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Cited By (42)

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US7879865B2 (en) 2001-10-16 2011-02-01 Sloan-Kettering Institute For Cancer Research Treatment of cancer of the brain using histone deacetylase inhibitors
US7851509B2 (en) 2002-03-04 2010-12-14 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US7847122B2 (en) 2002-03-04 2010-12-07 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US7399787B2 (en) 2002-03-04 2008-07-15 Merck Hdac Research, Llc Methods of treating cancer with HDAC inhibitors
US7456219B2 (en) 2002-03-04 2008-11-25 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US8067472B2 (en) 2002-03-04 2011-11-29 Merck Hdac Research, Llc Methods of treating Hodgkin's and non-Hodgkin's lymphoma
US7652069B2 (en) 2002-03-04 2010-01-26 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US7375137B2 (en) 2002-03-04 2008-05-20 Merck Hdac Research, Llc Methods of treating cancer with HDAC inhibitors
US7732490B2 (en) 2002-03-04 2010-06-08 Merck Hdac Research, Llc Methods of treating cancer
US8101663B2 (en) 2002-03-04 2012-01-24 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US7148257B2 (en) 2002-03-04 2006-12-12 Merck Hdac Research, Llc Methods of treating mesothelioma with suberoylanilide hydroxamic acid
US7683185B2 (en) 2002-11-18 2010-03-23 Queen Mary & Westfield College Histone deacetylase inhibitors
US7604939B2 (en) 2005-03-01 2009-10-20 The Regents Of The University Of Michigan Methods of identifying active BRM expression-promoting HDAC inhibitors
US8288440B2 (en) 2005-05-20 2012-10-16 Merck Sharp & Dohme Corp. Formulations of suberoylanilide hydroxamic acid and methods for producing same
US8450372B2 (en) 2005-05-20 2013-05-28 Merck Sharp & Dohme Corp. Formulations of suberoylanilide hydroxamic acid and methods for producing same
US8093295B2 (en) 2005-05-20 2012-01-10 Merck Sharp & Dohme Corp. Formulations of suberoylanilide hydroxamic acid and methods for producing the same
US7741494B2 (en) 2005-07-14 2010-06-22 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
US9539303B2 (en) 2006-04-24 2017-01-10 Celgene Corporation Treatment of Ras-expressing tumors
US8957027B2 (en) 2006-06-08 2015-02-17 Celgene Corporation Deacetylase inhibitor therapy
US9259452B2 (en) 2006-06-08 2016-02-16 Gelgene Corporation Deacetylase inhibitor therapy
WO2008002634A1 (fr) * 2006-06-28 2008-01-03 Novartis Ag Utilisation d'inhibiteurs de la hdac pour le traitement des lymphomes
US8110577B2 (en) 2006-10-19 2012-02-07 Queen Mary & Westfield College Histone deacetylase inhibitors
US8691534B2 (en) 2006-12-29 2014-04-08 Celgene Corporation Preparation of romidepsin
WO2012009336A1 (fr) * 2010-07-12 2012-01-19 Gloucester Pharmaceuticals, Inc. Formes solides de la romidepsine et leurs utilisations
CN103108648A (zh) * 2010-07-12 2013-05-15 细胞基因公司 罗米地辛固体形式及其用途
US9624271B2 (en) 2010-07-12 2017-04-18 Celgene Corporation Romidepsin solid forms and uses thereof
US8980825B2 (en) 2010-07-12 2015-03-17 Celgene Corporation Romidepsin solid forms and uses thereof
RU2607634C2 (ru) * 2010-07-12 2017-01-10 Селджин Корпорейшн Твердые формы ромидепсина и их применение
US9518094B2 (en) 2010-07-12 2016-12-13 Celgene Corporation Romidepsin solid forms and uses thereof
US8859502B2 (en) 2010-09-13 2014-10-14 Celgene Corporation Therapy for MLL-rearranged leukemia
EP2688572A1 (fr) * 2011-03-21 2014-01-29 Valcuria AB Composition pharmaceutique comprenant un inhibiteur des hdac et un stéroïde, et son utilisation
EP2688572A4 (fr) * 2011-03-21 2014-08-20 Valcuria Ab Composition pharmaceutique comprenant un inhibiteur des hdac et un stéroïde, et son utilisation
WO2012128709A1 (fr) * 2011-03-21 2012-09-27 Valcuria Ab Composition pharmaceutique comprenant un inhibiteur des hdac et un stéroïde, et son utilisation
KR101909313B1 (ko) 2011-03-21 2018-10-17 발큐리아 에이비 Hdac 저해제 및 스테로이드를 포함하는 약학적 조성물 및 이의 용도
CN110279861A (zh) * 2011-03-21 2019-09-27 瓦尔库里亚公司 包括hdac抑制剂以及类固醇的药用组合物及其用途
US9134325B2 (en) 2012-09-07 2015-09-15 Celgene Corporation Resistance biomarkers for HDAC inhibitors
US9101579B2 (en) 2012-11-14 2015-08-11 Celgene Corporation Inhibition of drug resistant cancer cells
US9463215B2 (en) 2013-12-27 2016-10-11 Celgene Corporation Romidepsin formulations and uses thereof
US9468664B2 (en) 2013-12-27 2016-10-18 Celgene Corporation Romidepsin formulations and uses thereof
US9782451B2 (en) 2013-12-27 2017-10-10 Celgene Corporation Romidepsin formulations and uses thereof
US9795650B2 (en) 2013-12-27 2017-10-24 Celgene Corporation Romidepsin formulations and uses thereof

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AU2001285042A1 (en) 2002-03-04

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