Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/243—Platinum; Compounds thereof
• • 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
  • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
  • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to a method for treating patients afflicted with cancer, and will have application to a combination drug treatment possessed of fewer and less severe unwanted toxic adverse effects.
• Combination chemotherapy is a common, accepted treatment for many types of cancers.
• the synergistic effects of combining two or more agents can be the difference between successful and unsuccessful treatment of the patient.
• MOPP an acronym for mechlorethamine, vincristine, procarbazine, prednisone
• MOPP an acronym for mechlorethamine, vincristine, procarbazine, prednisone
• Several different combination regimens (which all include cisplatin, vinblastine and bleomycin) are accepted in the treatment of testicular cancer, which is curable in up to 98% of diagnosed cases. In all, more than 300 different combination regimens have been used.
• paclitaxel Another consideration of importance in combination chemotherapy is the order in which the antineoplastic agents are administered. For instance, where cisplatin, or carboplatin (or any platinum complex antineoplastic agent) and paclitaxel are administered as a part of a combination treatment regimen, it has been shown that due to toxicity considerations, paclitaxel must be administered first, followed by administration of cisplatin. If the order of administration is reversed, the combination is highly toxic to the patient. The manifestation of such severe schedule dependent toxicity precludes the administration of the cisplatin followed by paclitaxel combination because of the risk of serious toxicities, morbidity and even death.
• Disodium 2 , 2' -dithiobis ethane sulfonate (also referred to in the literature as Dimesna and BNP7787) has been shown to reduce the unwanted toxic effects associated with the administration of single agent cisplatin, and of single agent paclitaxel in human patients.
• Dimesna is generally regarded as extremely safe and efficacious for these uses and others, and has been shown not to interfere with the cytotoxic effects of the antineoplastic agent (s) with which it is co-administered.
• This invention relates to methods of treating patients with cancer by administering combination chemotherapy wherein effective amounts and schedules of administration of two or more antineoplastic agents are administered to the patient, together with a toxicity reducing amount of a protective agent of the following formula I : (I)
• RT is hydrogen, Ci-C ⁇ alkyl, or -S-X 2 -R 3 ; R 2 and R 3 are each individually sulfonate or phosphonate; and Xi and X 2 are each individually Ci-C ⁇ alkyl, optionally substituted by one or more hydroxy, sulfhydryl or alkoxy moieties .
• Preferred antineoplastic agents include platinum based chemotherapy drugs (cisplatin, carboplatin, oxaliplatin, and others) and taxanes (including, but not limited to paclitaxel, docetaxel), and/or epothilones, and or vinca alkaloids, and/or oxazaphosphorines or other agents used in the chemotherapy of cancer, though the method of this invention is contemplated as useful in any of a vast number of combination chemotherapy regimens.
• platinum based chemotherapy drugs cisplatin, carboplatin, oxaliplatin, and others
• taxanes including, but not limited to paclitaxel, docetaxel
• epothilones include vinca alkaloids, and/or oxazaphosphorines or other agents used in the chemotherapy of cancer, though the method of this invention is contemplated as useful in any of a vast number of combination chemotherapy regimens.
• Another object of this invention is to provide a new method of treating patients with cancer through combination chemotherapy along with a toxicity-preventing agent.
• Another object is to provide for novel, safer, more effective methods of treating patients with cancer.
• combination chemotherapy involves administering two or more different antineoplastic agents using a schedule of administration to the patient that results in reduced toxicity and increased antitumor efficacy as a result of the administration of a toxicity reducing agent.
• the method of this invention specifically includes in addition to the antineoplastic agents, the administration of a toxicity- reducing amount of a protective agent of formula I:
• Ri is hydrogen, Ci-C ⁇ alkyl, or -S-X 2 -R 3 ; R 2 and R 3 are each individually sulfonate or phosphonate; and
• X ⁇ and X 2 are each individually Ci-C ⁇ alkyl, optionally substituted by one or more hydroxy, sulfhydryl or alkoxy moieties.
• the preferred protective agents of formula I include various thiols, disulfides and thioethers .
• Some preferred compounds of formula I include, but are not limited to mesna, dimesna, S-methyl mesna, and various analogues and derivatives of each wherein the alkylene bridge (s) include one to four -CH 2 - moieties, and may or may not be substituted by hydroxy or alkoxy moieties.
• Most preferred compounds of formula I include mesna and dimesna.
• antineoplastic agents include combinations of taxanes and platinum complex agents; electrophilic alkylating agents and vinca alkaloids, oxazaphosphorines, platinum and vinca alkaloids or bleomycin, with or without steroidal antineoplastic compounds; platinum complexes and vinca alkaloids, with or without antineoplastic antibiotics; and others, some of which are shown in the following tables .
• the dose, the duration of drug infusion, the route of administration, and the order of administration of the antineoplastic agents can determine the outcome of treatment and to significantly affect the toxicity, drug related morbidity and death of a patient due to drug treatment.
• the timing between doses and the duration of infusion of each agent has an effect on the safety and the efficacy outcome of treatment.
• the current protocol for paclitaxel/cisplatin combination therapy calls for each cycle of treatment to involve the administration of paclitaxel from 3 hours to 96 hours of the drug followed by the administration of cisplatin. Each cycle is repeated at approximately 3-week intervals.
• Administration of toxicity reducing amounts and novel schedules of administration of a formula I compound in conjunction with the administration of the combination of antineoplastic agents is postulated to improve the antitumor efficacy and safety throughout the course of treatment of the patient.
• adherence to the method of this invention may allow the physician to safely administer higher amounts of the antineoplastic agents, at shorter time intervals, thus improving the probability of success of a particular course of treatment.
• a preferred course of treatment under the method of this invention is the administration of effective amounts of a taxane/platinum combination, in conjunction with a formula I compound.
• the preferred course for platinum followed by taxanes includes the administration, every 1-21 days of: a) 10 mg/m 2 -300 mg/m 2 of a platinum drug over 15 minutes to 96 hours, followed by the administration of b) 10 mg/m 2 -400 mg/m 2 of a taxane; administered over 15 minutes to 96 hours; and c) 2 g/m 2 -50 g/m 2 of a compound of formula I that is administered over 15 minutes to 96 hours preceding the platinum administration and the provisional administration of the formula I compound over 15 minutes to 96 hours as a single or divided dose before, during or after the administration of the taxane.
• the preferred course of treatment includes the IV infusion of first, a formula I compound, followed by IV infusion of the platinum drug, followed by the administration of the taxane.
• This is an entirely novel schedule of platinum and taxane administration in combination with a toxicity reducing agent.
• conventional pre-medication for nausea and vomiting may be administered as per accepted medical practices .
• Cisplatin is preferably administered by IV infusion over an extended period, generally from 1-12 hours, most preferably from 1-4 hours
• Dimesna may be administered by IV push or infusion, or may be administered orally, and is preferably administered immediately or up to 90 minutes prior to the commencement of the IV cisplatin infusion.
• the duration of the dimesna infusion can be from 15 minutes to continuous infusion for as long as needed to prevent toxicity.
• a patient suffering from cancer is treated as follows : a) 4 g/m 2 -80 g/m 2 of dimesna is administered either by intravenous infusion over 15-90 minutes, or by oral administration route; b) within one hour of completion of a) 15 mg/m 2 -250 mg/m 2 of a platinum complex agent is administered either by intravenous infusion at a rate of 0.5 mg/min-2 mg/min; c) within 2 hours of completion of b) 20 mg/m 2 -250 mg/m 2 of a taxane agent is administered by either intravenous infusion over 15 minutes-96 hours, or by oral administration route.
• a patient suffering from cancer is treated as follows: a) 4 g/m 2 -80 g/m 2 of dimesna is administered either by intravenous infusion over 15-90 minutes, or by oral administration route; b) within one hour of completion of a) 15 mg/m 2 -250 mg/m 2 of a platinum complex agent is administered either by intravenous infusion at a rate of 0.5 mg/min-2 mg/min; c) within one hour of completion of b) 4 g/m 2 -80 g/m 2 of dimesna is again administered either by intravenous infusion over 15-90 minutes, or by oral administration route; d) within 2 hours of completion of c) 20 mg/m 2 -250 mg/m 2 of a taxane agent is administered by either intravenous infusion over 15 minutes-96 hours, or by oral administration route.
• a patient suffering from cancer is treated as follows: a) 4 g/m 2 -80 g/m 2 of dimesna is administered either by intravenous infusion over 15-90 minutes, or by oral administration route; b) within one hour of completion of a) 15 mg/m 2 -250 mg/m 2 of a platinum complex agent is administered either by intravenous infusion at a rate of 0.5 mg/min-2 mg/min; c) within 24 hours of completion of b) 4 g/m 2 -80 g/m 2 of dimesna is again administered either by intravenous infusion over 15-90 minutes, or by oral administration route; d) within 2 hours of completion of c) 20 mg/m 2 -250 mg/m 2 of a taxane agent is administered by either intravenous infusion over 15 minutes-96 hours, or by oral administration route; e) within 2 hours of completion of d) 4 g/m 2 -80 g/m 2 of dimesna is again administered either by intravenous infusion

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• 2002
  • 2002-01-11 AU AU2002251763A patent/AU2002251763B2/en not_active Ceased
  • 2002-01-11 WO PCT/US2002/000943 patent/WO2002056755A2/en active Application Filing
  • 2002-01-11 CA CA002434270A patent/CA2434270A1/en not_active Abandoned
  • 2002-01-11 JP JP2002557269A patent/JP2004523518A/ja active Pending
  • 2002-01-11 EP EP02720788A patent/EP1351677A4/en not_active Withdrawn
  • 2002-01-11 MX MXPA03006359A patent/MXPA03006359A/es active IP Right Grant
• 2009
  • 2009-09-14 JP JP2009212441A patent/JP2009292837A/ja active Pending

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