WO2004022044A1 - Traitement du cancer au moyen de taxane - Google Patents

Traitement du cancer au moyen de taxane Download PDF

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Publication number
WO2004022044A1
WO2004022044A1 PCT/CA2003/001334 CA0301334W WO2004022044A1 WO 2004022044 A1 WO2004022044 A1 WO 2004022044A1 CA 0301334 W CA0301334 W CA 0301334W WO 2004022044 A1 WO2004022044 A1 WO 2004022044A1
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WO
WIPO (PCT)
Prior art keywords
chemotherapeutic agent
taxane
administered
patient
diphenyl compound
Prior art date
Application number
PCT/CA2003/001334
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English (en)
Inventor
Lorne J. Brandes
Original Assignee
The University Of Manitoba
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The University Of Manitoba filed Critical The University Of Manitoba
Priority to AU2003269620A priority Critical patent/AU2003269620A1/en
Publication of WO2004022044A1 publication Critical patent/WO2004022044A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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 the treatment of cancer using taxanes.
  • chemotherapeutic treatments are that of malignant growth (cancer) in humans.
  • the objective of chemotherapy is the total extermination of clonogenic tumor or malignant cells, with minimal damage to the patient.
  • cancer malignant growth
  • Anti-neoplastic agents have the lowest therapeutic indicies of any class of drugs used in humans and hence produce significant and potentially life-threatening toxicities. Certain commonly-used anti-neoplastic agents have unique and acute toxicities for specific tissues.
  • the vinca alkaloids possess significant toxicity for nervous tissues, while adriamycin has specific toxicity for heart tissue and bleomycin has for lung tissue.
  • adriamycin has specific toxicity for heart tissue
  • bleomycin has for lung tissue.
  • almost all members of the major categories of anti-neoplastic agents have considerable toxicities for normal cells of gastrointestinal, epidermal and myelopoietic tissues.
  • the dose-limiting consideration for chemical management of cancer in humans is the toxicity that anti-neoplastic agents have for the pluripotent stem cells of myelopoietic tissue. This toxicity arises from the fact that most anticancer drugs function preferentially against proliferating cells but with no significant capacity to discriminate between cycling normal and cycling tumor tissues.
  • DPPE N,N-diethyl-2- [4-(phenylmethyl)-phenoxy]ethanamine, abbreviated herein as DPPE.
  • Taxol trademark of Bristol-Myers Squibb for paclitaxel
  • Taxotere trademark of Aventis Pharma for docetaxel
  • administration of taxanes causes a potentially life-threatening allergic reaction.
  • potent HI and H2 receptor blockers to the cancer patient, usually prior to administration of the taxane.
  • the HI blocker usually used in diphenhydramine and the H2 blocker usually used in ranitidine.
  • the present invention provides a method of chemotherapeutic treatment of cancer with a taxane, which comprises:
  • X and Y are each fluorine, chlorine or bromine
  • phenyl groups are joined to form a tricyclic ring
  • o and p are 0 or 1
  • Ri and R are each an alkyl group containing 1 to 3 carbon atoms or are joined together to form a heterocyclic ring with the nitrogen atom and n is 1, 2 or 3, or pharmaceutically-acceptable salts thereof, in the absence of any conventional potent HI and H2 blockers, and
  • the diphenyl compound and the taxane chemotherapeutic agent are generally administered by intravenous irrfusion.
  • a solution of the diphenyl compound is administered to the patient over a desired period of time prior to administration of the taxane chemotherapeutic agent and a solution of the taxane chemotherapeutic agent in combination with the diphenyl compound then is administered for the period of administration of the taxane chemotherapeutic agent.
  • a solution of the diphenyl compound is administered after completion of the administration of the taxane chemotherapeutic agent for a desired period of time to ameliorate side effects from the taxane chemotherapeutic agent administration.
  • a diphenyl compound which is a potent antagonist of histamine binding at the intracellular histamine receptor and is administered in an amount sufficient to inhibit the binding of intracellular histamine at the intracellular binding site (H ⁇ _) in normal cells.
  • Such compounds exhibit a pKi of at least about 5, preferably at least about 5.5.
  • X and Y are each fluorine, chlorine or bromine
  • o and p are 0 or 1
  • R] and R 2 are each alkyl groups containing 1 to 3 carbon atoms or are joined together to form a hetero-ring with the nitrogen atom and n is 1, 2 or 3.
  • Pharmaceutically-acceptable salts of the diphenyl compounds may be employed.
  • the benzene rings may be joined to form a tricyclic ring, in accordance with the structure:
  • o and p are usually 0 when Z is an alkylene group and n may be 2. In one particularly preferred embodiment, Z is -CH 2 -, n is 2, o and p are each 0 and
  • R 2 is a diethylamino group.
  • This compound namely N,N-diethyl-2-[4-(phenylmethyl)- phenoxy]ethanamine, which may be in the form of the free base or in the form of its hydrochloride or other pharmaceutically-acceptable salt, is abbreviated herein as DPPE.
  • DPPE N,N-diethyl-2-[4-(phenylmethyl)- phenoxy]ethanamine
  • DPPE diphenylmethyl-2-[4-(phenylmethyl)- phenoxy]ethanamine
  • DPPE hydrochloride or other pharmaceutically-acceptable salt
  • Other substitutents may be provided on the benzene rings in addition to the halogen atoms, for example, an imidazole group.
  • the diphenyl compound employed in the present invention is administered to the patient in any convenient manner, such as by intravenous injection of a solution thereof in an aqueous pharmaceutically-acceptable vehicle.
  • the diphenyl compound is administered to the patient over a period of time before administration of the taxane chemotherapeutic agent.
  • the taxane chemotherapeutic agent employed herein preferably is Taxol or Taxotere.
  • the use of the taxane chemotherapeutic agent may be combined with the use of another chemotherapeutic agent which is active in the cancer under treatment.
  • Such latter materials include anthracyclines, such as doxorubicin and epirubicin, active in the treatment of breast cancer.
  • the taxane chemotherapeutic agent, or a mixture of taxanes and anthracyclines is administered in any manner consistent with its normal manner of administration in conventional breast cancer therapy, namely by intravenous infusion of a solution thereof.
  • the administration of the diphenyl compound to the patient prior to administration of the taxane chemotherapeutic agent is necessary in order to permit the diphenyl compound to inhibit the binding of intracellular histamine in normal and malignant cells and thereby, in effect, shut down the proliferation of the normal cells, but increase proliferation of malignant cells.
  • This result allows the use of taxane-based chemotherapy without the necessity for conventional potent HI and H2 blockers to prevent acute allergic reaction to the taxane.
  • DPPE potentiates the efficacy of taxanes or taxane/anthracycline combinations in the treatment of cancer, including breast cancer, an effect not observed with the pre-administration of HI and/or H2 blockers.
  • the length of time prior to administration of the chemotherapeutic agent that the diphenyl compound is administered depends on the diphenyl compound, its mode of administration and the size of the patient. Generally, the diphenyl compound is administered to the patient for about 30 to about 90 minutes, preferably about 60 minutes, prior to administration of the taxane chemotherapeutic agent.
  • the quantity of diphenyl compound administered to the patient depends on the side effects to be ameliorated, but should be at least sufficient to inhibit binding of intracellular histamine in normal cells. The quantity required to achieve the beneficial effects of the present invention depends upon the diphenyl compound employed, the taxane chemotherapeutic agent employed and the quantity of such agent employed.
  • the quantity of diphenyl compound employed in humans is from about 8 to about 320 mg/M 2 of human to which the diphenyl compound is administered, with about 8 and 240 mg/M 2 being the optimal dose for gastro-intestinal and bone marrow protection, respectively.
  • the present invention is able to achieve an enhanced chemotherapeutic effect on breast cancer cells while, at the same time, also protecting normal cells from damage by the taxane chemotherapeutic agent in a wide variety of circumstances where traditional chemotherapy leads to damage of normal cells or tissues not involved in the disease process.
  • the need for potent HI and H2 blockers is eliminated.
  • the diphenyl compound preferably is used in an amount of about 3 to about 10 mg/kg of patient administered intravenously over a period of about 30 to about 90 minutes prior to administration of the taxane chemotherapeutic agent and continuing for the period of administration of the chemotherapy agent.
  • a second regimen for DPPE/Taxotere is the intravenous administration of an aqueous solution of DPPE for 80 minutes, with the last 20 minutes being accompanied by infusion of the Taxotere, followed by infusion of Taxotere alone for 40 minutes.
  • the taxane chemotherapy agent which is employed herein preferably is used in an amount of about 75 to about 275 mg/M of patient consistent with the identity of the taxane chemotherapy agent.
  • 175 mg/M 2 of Taxol or 75 mg/M 2 of Taxotere administered over the last 20 minutes of infusion of the DPPE solution and over a further 180 minutes for Taxol or 60 minutes for Taxotere, accompanied by infusion of a 2.5 mg/kg of DPPE solution.
  • the taxane chemotherapy was combined with anthracycline chemotherapy, there was employed 50 mg/M 2 of doxorubicin or epirubicin in combination with the recited amounts of Taxol and Taxotere.
  • Patients usually are subjected to a number of cycles of chemotherapy at predetermined intervals.
  • the number of cycles for each patient is generally about 5 to about 10 cycles, with about 21 to about 28 days between each cycle.
  • Example 1 This Example illustrates the chemotherapy of patients with metastatic breast cancer and ovarian cancer using DPPE and Taxol or Taxotere.
  • DPPE was administered at a dose of 6 mg/kg over 80 minutes with Taxol at a dose of 175 mg/M 2 or Taxotere at a dose of 75 mg/M 2 over the last 20 minutes and over 180 minutes for Taxol and 60 minutes for Taxotere accompanied by infusion of a dose of 2.5 mg/kg of DPPE.
  • Example 2 [0027] This Example describes a Phase II clinical trial involving patients with metastatic breast cancer.
  • DPPE was administered at a dose of 6 mg/Kg over 80 minutes with a combination of epirubicin or doxorubicin administered at a dose of 50 mg/M and Taxol at a dose of 175 mg/M 2 or Taxotere at a dose of 75 mg/M 2 over the last 20 minutes and during a further 180 minutes for Taxol and a 60 minutes for Taxotere, at a dose of 3.5 mg/kg.
  • the treatment was repeated at 21 day intervals for 8 to 10 cycles.
  • the 29 patients with metastatic breast cancer had not been previously treated_wiflL taxanes .but. may have had anthracyclines,-. or may have had previous adjuvant chemotherapy or tamoxifen.
  • the patients had the demographics shown in Table III.
  • Example 3 This Example illustrates the neoadjuvant treatment of inflammatory or
  • DPPE was administered at a dose of 6 mg/M 2 over 80 minutes with a combination of epirubicin or doxorubicin at a dose of 50 mg/M 2 and Taxol at a dose of 175 mg/M or Taxotere at a dose of 75 mg/M over the last 20 minutes and during a further 180 minutes for Taxol and a 60 minutes for Taxotere, at a dose of 3.5 mg/kg.
  • the treatment was repeated at 21 day intervals for 7 cycles.
  • the eight patients with inflammatory or T3 to T4 breast cancer had no previous chemo-or radiotherapy. When the chemotherapy cycles were complete, the cancerous tissue was removed and the patients observed.
  • Example 4 This Example describes the toxicity results obtained. [0036] In each of the experiments described in Examples 1 to 3, no H1/H2 blocker was administered prior to the taxane administration. Over 410 cycles of taxanes, alone or in combination with anfhracyclines have been safely administered with DPPE to 70 patients with breast or ovarian cancer. In no case was an acute allergic reaction to the taxanes observed, in contrast to conventional taxane chemotherapy, where such acute allergic reactions are observed in approximately 2% of patients.
  • HI e.g. diphenhydramine
  • H2 e.g. ranitidine
  • DPPE potent HI blockers
  • H1/H2 blockers completely prevented allergic reaction to taxanes, despite the fact that it has only 1/10,000 of the potency of diphenhydramine as an HI blocker and does not bind the H2 receptor.
  • the DPPE potentiated the efficacy of taxanes or anthracycline/taxane combinations in breast cancer treatment, an effect not observed with pretreatment with H1/H2 blockers.
  • DPPE administered with taxanes in the treatment of cancer, prevents allergic reaction to the taxanes, while potentiating the effect of taxane chemotherapy agents. Modifications are possible within the scope of the invention.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le traitement au taxane du cancer nécessite de traiter préalablement le patient avec des agents bloquants puissants H1 et H2 afin d'empêcher une réaction allergique aiguë au taxane. On utilise DPPE à la place de ces agents bloquants puissants H1 et H2 et on a observé aucune réaction allergique aiguë et, simultanément, ceci permet de potentialiser le traitement du cancer au moyen de taxane. On a également observé aucun effet à la suite de l'utilisation des agents bloquants H1/H2.
PCT/CA2003/001334 2002-09-03 2003-09-02 Traitement du cancer au moyen de taxane WO2004022044A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003269620A AU2003269620A1 (en) 2002-09-03 2003-09-02 Use of a combination of a taxane with dppe for the treatment of cancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US40724302P 2002-09-03 2002-09-03
US60/407,243 2002-09-03

Publications (1)

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WO2004022044A1 true WO2004022044A1 (fr) 2004-03-18

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037318A1 (fr) * 2001-11-01 2003-05-08 Ym Biosciences, Inc. Utilisation de n,n-diethyl-2-[-4-(phenylmethyl)-phenoxy]ethanamine monohydrochloride (dppe) dans la therapie du cancer

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037318A1 (fr) * 2001-11-01 2003-05-08 Ym Biosciences, Inc. Utilisation de n,n-diethyl-2-[-4-(phenylmethyl)-phenoxy]ethanamine monohydrochloride (dppe) dans la therapie du cancer

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BRANDES LORNE J ET AL: "N,N-diethyl-2-(4-(phenylmethyl)phenoxyl) ethanamine (DPPE), a chemopotentiating and cytoprotective agent in clinical trials: Interaction with histamine at cytochrome P450 3A4 and other isozymes that metabolize antineoplastic drugs", CANCER CHEMOTHERAPY AND PHARMACOLOGY, vol. 45, no. 4, April 2000 (2000-04-01), pages 298 - 304, XP002268479, ISSN: 0344-5704 *
MENENDEZ A T ET AL: "Mechanism of action of DPPE, a chemosensitizing agent", PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL, vol. 39, March 1998 (1998-03-01), 89th Annual Meeting of the American Association for Cancer Research;New Orleans, Louisiana, USA; March 28-April 1, 1998, March, 1998, pages 509, XP001184767, ISSN: 0197-016X *
MUGGIA FRANCO M ET AL: "Modulation of taxanes in breast cancer", CANCER INVESTIGATION, vol. 18, no. SUPPL. 1, 2000, XVII Symposium of the Chemotherapy Foundation: Innovative Cancer Therapy for Tomorrow.;New York, NY, USA; November 03-06, 1999, pages 64 - 66, XP008027009, ISSN: 0735-7907 *

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