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WO2008135793A1 - Combinaison d'aplidine et de carboplatine dans des traitements anticancéreux - Google Patents

Combinaison d'aplidine et de carboplatine dans des traitements anticancéreux Download PDF

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Publication number
WO2008135793A1
WO2008135793A1 PCT/GB2008/050331 GB2008050331W WO2008135793A1 WO 2008135793 A1 WO2008135793 A1 WO 2008135793A1 GB 2008050331 W GB2008050331 W GB 2008050331W WO 2008135793 A1 WO2008135793 A1 WO 2008135793A1
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WO
WIPO (PCT)
Prior art keywords
carboplatin
aplidine
pharmaceutically acceptable
cancer
acceptable salt
Prior art date
Application number
PCT/GB2008/050331
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English (en)
Inventor
Jose Antonio Lopez Martin
Alan Hilary Calvert
Original Assignee
Pharma Mar S.A.
Williams, Gareth
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
Priority claimed from GB0708693A external-priority patent/GB0708693D0/en
Priority claimed from GB0710043A external-priority patent/GB0710043D0/en
Application filed by Pharma Mar S.A., Williams, Gareth filed Critical Pharma Mar S.A.
Publication of WO2008135793A1 publication Critical patent/WO2008135793A1/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
    • A61K31/33—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
    • 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 the treatment of cancers and, in particular, to the effective treatment of human cancers using Aplidine in combination with another drug, specifically Carboplatin.
  • Cancer develops when cells in a part of the body begin to grow out of control. Although there are many kinds of cancer, they all start because of out-of-control growth of abnormal cells. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body. There are several main types of cancer. Carcinoma is cancer that begins in the skin or in tissues that line or cover internal organs. Epithelial cells, which cover internal and external surfaces of the body, including organs and lining of vessels, may give rise to a carcinoma. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system.
  • cancer is invasive and tends to metastasise to new sites. It spreads directly into surrounding tissues and also may be disseminated through the lymphatic and circulatory systems.
  • Chemotherapy in its classic form, has been focused primarily on killing rapidly proliferating cancer cells by targeting general cellular metabolic processes, including DNA, RNA, and protein biosynthesis.
  • Chemotherapy drugs are divided into several groups based on how they affect specific chemical substances within cancer cells, which cellular activities or processes the drug interferes with, and which specific phases of the cell cycle the drug affects.
  • the most commonly used types of chemotherapy drugs include: D NA- alkylating drugs (such as cyclophosphamide, ifosfamide, cisplatin, carboplatin, dacarbazine), antimetabolites (5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine) , mitotic inhibitors (such as paclitaxel, docetaxel, vinblastine, vincristine), anthracyclines (such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone) , topoisomerase II inhibitors (such as topotecan, irinotecan, etoposide, ten
  • the ideal antitumor drug would kill cancer cells selectively, with a wide index relative to its toxicity towards non-cancer cells and it would also retain its efficacy against cancer cells, even after prolonged exposure to the drug.
  • none of the current chemotherapies with these agents posses an ideal profile. Most posses very narrow therapeutic indexes and, in addition, cancerous cells exposed to slightly sublethal concentrations of a chemotherapeutic agent may develop resistance to such an agent, and quite often cross-resistance to several other antitumor agents.
  • Aplidine (Dehydrodidemnin B) is a cyclic depsipeptide that was isolated from a Mediterranean marine tunicate, Aplidium albicans, and it is the subject of WO 91/04985. It is related to compounds known as didemnins, and has the following structure:
  • DDB Dehydrodidemnin B
  • L-carnitine was given as a 24 hour pretreatment or co-administered to prevent myelotoxicity, see for example WO 02/30441. Co-administration of L-carnitine was proven to be able to improve the recovery of the drug induced muscular toxicity and has allowed for dose escalation of Aplidine.
  • Carboplatin is a chemotherapy drug that belongs to the same family as cisplatin, specifically to the family of DNA alkylating agents.
  • This compound is a platinum coordination complex with the following structural formula:
  • cisplatin Like cisplatin, it contains a platinum atom surrounded in a plane by two ammonia groups and two other ligands in the cis position. The other two ligands in carboplatin are present in a ring structure rather than as two chloride atoms in cisplatin. This difference makes carboplatin more stable and has less nephrotoxicity, neurotoxicity, ototoxicity and emetogenesis (Go R. S. et al. J. Clin. Oncol. 1999, 17(1), 409-22; McEvoy GK, editor. AHFS 2000 Drug Information). The exact mechanism of action of Carboplatin is not known.
  • Carboplatin undergoes intracellular activation to form reactive platinum complexes which are believed to inhibit DNA synthesis by forming interstrand and intrastrand cross-linking of DNA molecules.
  • Carboplatin is radiation-sensitizing agent (Atagi S. et al. Jpn. J. Clin. Oncol. 2000, 30(2), 59- 64; Groen H.J. et al. Br. J. Cancer, 1995, 72(4), 992-7) and cycle-phase nonspecific (McEvoy GK, editor. AHFS 2000 Drug Information).
  • platinum coordination complex such as cisplatin or carboplatin, has increased substantially in the last decade.
  • Carboplatin has proved to be useful in the treatment of some types of cancer, mainly brain tumors, endometrial cancer, germ cell tumors, head and neck cancer, and ovarian cancer.
  • the present invention provides a new method for treating a human patient afflicted with cancer, comprising administering to said patient Carboplatin in combination with Aplidine.
  • the invention further provides a method for treating a human patient afflicted with cancer, which involves administering Carboplatin and Aplidine, in which the amount of Carboplatin is at least 50%, at least 75%, at least 85%, at least 90%, at least 95% or at least 100% of the Recommended Dose for Carboplatin given as monotherapy, that is in the absence of Aplidine.
  • the invention provides a method of treating a human patient afflicted with cancer, which involves administering Carboplatin and wherein Aplidine is administered as a combination therapy without a compensating drop in the dose of Carboplatin.
  • the present invention is directed to a method for treating a human patient afflicted with cancer which involves administering Aplidine in combination with Carboplatin, characterised in that the combination overcomes resistance to Carboplatin without increasing the toxicity of the therapy.
  • the present invention provides a method of reducing resistance to Carboplatin in an individual having cancer comprising administering to the individual Aplidine and Carboplatin in a dose range for Carboplatin which is the same as the dosage given if Carboplatin was administered alone.
  • the present invention provides a combination therapy for the treatment of cancer in humans which comprises administering Aplidine and Carboplatin, using a cyclical protocol. Typical dosing protocols for the combination therapy are provided.
  • the administration of Aplidine in combination with Carboplatin in humans in accordance with the methods and compositions of this invention is tolerable and provides antitumor activity at the dosage and regimens given.
  • this invention provides a method of treating cancer in humans, which method comprises administering Aplidine and Carboplatin in a specific sequence and with a predetermined cycle.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of Aplidine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the procedures and methods of this invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of Carboplatin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the procedures and methods of this invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of Aplidine, or a pharmaceutically acceptable salt thereof, an effective therapeutic amount of Carboplatin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the procedures and methods of this invention.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, in the preparation of a composition for use in the procedures and methods of this invention. Additionally, the invention also provides for the use of Carboplatin, or a pharmaceutically acceptable salt thereof, in the preparation of a composition for use in the procedures and methods of this invention.
  • a medical kit for administering Aplidine in combination with Carboplatin comprising printed instructions for administering Aplidine according to the procedures and methods of treatment set forth herein, and a supply of Aplidine in dosage units for at least one cycle, wherein each dosage unit comprises the appropriate amount of Aplidine for the treatments as defined above and a pharmaceutically acceptable carrier.
  • a medical kit for administering Carboplatin in combination with Aplidine comprising printed instructions for administering Carboplatin according to the procedures and methods of treatment set forth herein, and a supply of Carboplatin in dosage units for at least one cycle, wherein each dosage unit comprises the appropriate amount of Carboplatin for the treatments as defined above and a pharmaceutically acceptable carrier.
  • Aplidine is a cyclic depsipeptide with the following structure:
  • Aplidine is intended here to cover any pharmaceutically acceptable salt, ester, solvate, hydrate or any other compound which, upon administration to the patient is capable of providing (directly or indirectly) the compound as described herein.
  • non- pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts and prodrugs and derivatives can be carried out by methods known in the art.
  • compositions of Aplidine that can be used include solutions, suspensions, emulsions, lyophilised compositions, etc., with suitable excipients for intravenous administration.
  • Aplidine may be supplied and stored as a sterile lyophilized product, comprising Aplidine and excipients in a formulation adequate for therapeutic use.
  • a formulation comprising mannitol is preferred.
  • the present invention is directed to provide an efficacious treatment of cancer in humans based on the combination of Aplidine with Carboplatin.
  • the term "combination" as used throughout the specification, is meant to encompass the administration of the therapeutic agents in the same or separate pharmaceutical formulations, and at the same time or at different times.
  • Aplidine and Carboplatin may be provided as separate medicaments for administration at the same time or at different times.
  • Aplidine and Carboplatin are provided as separate medicaments for administration at different times.
  • either Aplidine or Carboplatin may be administered first; however, it is preferable to administer Aplidine followed by Carboplatin.
  • both drugs can be administered in the same day or at different days, and they can be administered using the same schedule or at different schedules during the treatment cycle.
  • Administration of the compounds or compositions of the present invention is by intravenous infusion.
  • Aplidine and Carboplatin are provided as separate medicaments for administration at different times, the infusion times for each may differ. Infusion times of up to 6 hours can be used, more preferably between 1 and 3 hours, with about 1 hour most preferred.
  • Intravenous infusion of Aplidine to the patient is typically repeated weekly on a cyclic basis.
  • the cyclic basis comprises a phase of weekly infusing and a phase of not infusing wherein patients are allowed to recover.
  • Aplidine is administered weekly during 3 weeks and the phase of not infusing consists in 1-2 additional weeks, being 1 week the most preferred.
  • the preferred diiration of each cycle for Aplidine is typically of 4-5 weeks, being 4 weeks the most preferred.
  • Intravenous infusion of Carboplatin is given to the patients typically the first day of each cycle and then the patients are allowed to recover for the remainder of the cycle.
  • a treatment cycle consists in the drug administration of Aplidine on day 1, 8, and 15, followed by Carboplatin on day 1, and treatment cycles are repeated every 4 weeks. Dose delays and/ or dose reductions and schedule adjustments are performed as needed depending on individual patient tolerance to treatments.
  • the invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient a therapeutically effective amount of Aplidine, or a pharmaceutical composition thereof, and a therapeutically effective amount of Carboplatin, or a pharmaceutical composition thereof, wherein Aplidine is administered by intravenous infusion and its administration is repeated weekly, preferably during 3 weeks out of 4, and wherein Carboplatin is preferably administered once every 4 weeks.
  • both drugs are administered by intravenous infusion with infusion times of up to 6 hours, preferably about 1 hour, and Aplidine is preferable first administered followed by Carboplatin.
  • Aplidine is administered at a dose below 3.0 mg/m 2 , preferably about 2.4 mg/m 2 .
  • the dose is at least about 2.4 mg/m 2 .
  • the dose is in the range of 2.4-3.0 mg/m 2 .
  • the dose is 2.4 mg/m 2 , 2.5 mg/m 2 , 2.6 mg/m 2 , 2.7 mg/m 2 , 2.8 mg/m 2 , 2.9 mg/m 2 , or 3.0 mg/m 2 .
  • the dose is 2.4 mg/m 2 .
  • the dosage amount of Carboplatin is the full dosage range used in monotherapy according to the type of schedule given.
  • GFR glomerular filtration rate
  • dose mg
  • AUC free carboplatin plasma concentration versus time curve
  • Dose (mg) target AUC x (GFR + 25) is now the recommended formula.
  • AUC values of 4 to 6 and 6 to 8 mg/ mL/min gave rise to manageable haematological toxicity in previously treated and untreated subjects, respectively, and hence target.
  • AUC values of 5 and 7 mg/ mL/min are recommended for single-agent carboplatin in these patient groups.
  • the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.
  • the dose of Carboplatin preferably targets an AUC of about 4-8 mg/mL/min, more preferably an AUC of about 4-6 mg/mL/min, and even more preferably an AUC of about 5 mg/mL/min.
  • the invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient Aplidine, or a pharmaceutical composition thereof, at a dose below 3.0 mg/m 2 , preferably about 2.4 mg/m 2 , followed by the administration of Carboplatin, or a pharmaceutical composition thereof, at a dose targeting an AUC of about 5 mg/mL/min.
  • both drugs are administered by intravenous infusion in infusion times of about 1 hour.
  • the administration of Aplidine is repeated weekly, preferably during 3 weeks out of 4, and Carboplatin is preferably administered once every 4 weeks.
  • the present invention is directed to a medical kit for administering Aplidine in combination with Carboplatin, comprising printed instructions for administering Aplidine according to the dosages and schedules set forth above, and a supply of Aplidine in dosage units for at least one cycle, wherein each dosage unit comprises the appropriate amount of Aplidine for the treatments as defined above and a pharmaceutically acceptable carrier.
  • the present invention is directed to a medical kit for administering Carboplatin in combination with Aplidine, comprising printed instructions for administering Carboplatin according to the dosages and schedules set forth above, and a supply of Carboplatin in dosage units for at least one cycle, wherein each dosage unit comprises the appropriate amount of Carboplatin for the treatments as defined above and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of Aplidine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the procedures and methods as defined herein.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of Carboplatin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the procedures and methods as defined herein.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of Aplidine, or a pharmaceutically acceptable salt thereof, an effective therapeutic amount of Carboplatin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the procedures and methods as defined herein.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, in the preparation of a composition for use in the procedures and methods as defined herein.
  • the invention further provides for the use of Carboplatin, or a pharmaceutically acceptable salt thereof, in the preparation of a composition for use in. the procedures and methods as defined herein.
  • the invention also provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, and Carboplatin, or a pharmaceutically acceptable salt thereof, in the preparation of a composition for use in the procedures and methods as defined herein.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, in combination therapy with Carboplatin.
  • the invention further provides for the use of Carboplatin, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, in combination therapy with Aplidine.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof in combination with Carboplatin, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in combination therapy with Carboplatin.
  • the invention further provides for the use of Carboplatin, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in combination therapy with Aplidine.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof in combination with Carboplatin, or a pharmaceutically acceptable salt thereof, for the treatment of cancer.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, as a medicament, in combination therapy with Carboplatin.
  • the invention further provides for the use of Carboplatin, or a pharmaceutically acceptable salt thereof, as a medicament, in combination therapy with Aplidine.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof in combination with Carboplatin, or a pharmaceutically acceptable salt thereof, as a medicament.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, as a medicament for the treatment of cancer, in combination therapy with Carboplatin.
  • the invention further provides for the use of Carboplatin, or a pharmaceutically acceptable salt thereof, as a medicament for the treatment of cancer, in combination therapy with Aplidine.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof in combination with Carboplatin, or a pharmaceutically acceptable salt thereof, as a medicament for the treatment of cancer.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, as a medicament formulated to be provided in a dosage and/ or schedule as defined herein for the treatment of cancer, in combination therapy with Carboplatin.
  • the invention further provides for the use of Carboplatin, or a pharmaceutically acceptable salt thereof, as a medicament formulated to be provided in a dosage and/ or schedule as defined herein for the treatment of cancer, in combination therapy with Aplidine.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, as a medicament formulated to be provided/ suitable to administered at a dosage and/ or schedule as defined herein in combination with Carboplatin, or a pharmaceutically acceptable salt thereof, as a medicament formulated to be provided in a dosage and/ or schedule as defined herein for the treatment of cancer.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament formulated to be provided /suitable to administered at a dosage and/ or schedule as defined herein for the treatment of cancer, in combination therapy with Carboplatin.
  • the invention further provides for the use of Carboplatin, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament formulated to be provided /suitable to administered at a dosage and/ or schedule as defined herein for the treatment of cancer, in combination therapy with Aplidine.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof and Carboplatin, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament formulated to be provided/ suitable to administered at a dosage and/ or schedule as defined herein for the treatment of cancer.
  • the invention further provides for the formulation of one or more dosage units of Aplidine, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, said dosage units formulated to be provided in a dosage and/ or schedule as defined herein for the treatment of cancer, in combination therapy with Carboplatin.
  • the invention further provides for the formulation of one or more dosage units of Carboplatin, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, said dosage units formulated to be provided in a dosage and/ or schedule as defined herein for the treatment of cancer, in combination therapy with Aplidine.
  • the invention further provides for the formulation of one or more dosage units of Aplidine, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more dosage units of Carboplatin, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, said dosage units formulated to be provided in a dosage and/ or schedule as defined herein for the treatment of cancer.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, in the preparation of a composition, formulated to be provided in a dosage and/ or schedule as defined herein for use in the procedures and methods as defined herein, in combination therapy with Carboplatin.
  • the invention further provides for the use of Carboplatin, or a pharmaceutically acceptable salt thereof, in the preparation of a composition, formulated to be provided in a dosage and/ or schedule as defined herein for use in the procedures and methods as defined herein, in combination therapy with Aplidine.
  • the invention further provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, in the preparation of a composition, and Carboplatin, or a pharmaceutically acceptable salt thereof, in the preparation of a composition, both formulated to be provided in a dosage and/ or schedule as defined herein for use in the procedures and methods as defined herein.
  • the invention further provides a medicament, dosage unit(s), formulation or composition of Aplidine, or a pharmaceutically acceptable salt thereof, specifically configured to the dosages and/ or schedules given herein, the Aplidine being given in combination therapy with Carboplatin.
  • This specific configuration is carried out during the preparation process of the final medicament, and is not part of the actions carried out by the doctor when treating the patient.
  • the invention further provides a medicament, dosage unit(s), formulation or composition of Carboplatin, or a pharmaceutically acceptable salt thereof, specifically configured to the dosages and/ or schedules given herein, the Carboplatin being given in combination therapy with Aplidine.
  • This specific configuration is carried out during the preparation process of the final medicament, and is not part of the actions carried out by the doctor when treating the patient.
  • the invention further provides a medicament, dosage unit(s), formulation or composition of Aplidine, or a pharmaceutically acceptable salt thereof, specifically configured to the dosages and/ or schedules given herein, together with a medicament, dosage unit(s), formulation or composition of Carboplatin, or a pharmaceutically acceptable salt thereof, specifically configured to the dosages and/ or schedules given herein.
  • This specific configuration is carried out during the preparation process of the final medicament, and is not part of the actions carried out by the doctor when treating the patient.
  • the invention provides a dosage unit(s), medicament, formulation or composition comprising Aplidine, or a pharmaceutically acceptable salt thereof, specifically adapted to be administered in the dosages and/ or schedules given herein, the Aplidine being given in combination therapy with Carboplatin.
  • the invention provides a dosage unit(s), medicament, formulation or composition comprising Carboplatin, or a pharmaceutically acceptable salt thereof, specifically adapted to be administered in the dosages and/ or schedules given herein, the Carboplatin being given in combination therapy with Aplidine.
  • the invention provides a dosage unit(s), medicament, formulation or composition comprising Aplidine, or a pharmaceutically acceptable salt thereof, and a dosage unit(s), medicament, formulation or composition comprising Carboplatin, or a pharmaceutically acceptable salt thereof, specifically adapted to be administered in the dosages and/ or schedules given herein.
  • the invention provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, in a medicament for the treatment of cancer wherein the medicament is configured for administration at the dosages and/ or schedules given herein, the Aplidine being given in combination therapy with Carboplatin.
  • the invention provides for the use of Carboplatin, or a pharmaceutically acceptable salt thereof, in a medicament for the treatment of cancer wherein the medicament is configured for administration at the dosages and/ or schedules given herein, the Carboplatin being given in combination therapy with Aplidine.
  • the invention provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, and Carboplatin, or a pharmaceutically acceptable salt thereof, in a medicament for the treatment of cancer wherein the medicament is configured for administration at the dosages and/ or schedules given herein.
  • the invention provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer wherein the medicament is configured for administration at the dosages and/ or schedules given herein, the Aplidine being given in combination therapy with Carboplatin.
  • the invention provides for the use of Carboplatin, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer wherein the medicament is configured for administration at the dosages and/ or schedules given herein, the Carboplatin being given in combination therapy with Aplidine.
  • the invention provides for the use of Aplidine, or a pharmaceutically acceptable salt thereof, and Carboplatin, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer wherein the medicament is configured for administration at the dosages and/ or schedules given herein.
  • the invention provides Aplidine or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein Aplidine is administered in combination therapy with Carboplatin or a pharmaceutically acceptable salt thereof.
  • the invention provides Carboplatin or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein Carboplatin is administered in combination therapy with Aplidine or a pharmaceutically acceptable salt thereof.
  • Example 1 it is showed the results of a phase I clinical trial wherein Aplidine is administered intravenously as a 1-hour infusion on days 1 , 8, and 15 every 4 weeks, followed by the intravenous administration of Carboplatin, at a dose targeting an AUC of about 5 mg/mL/min, as 1-hour infusion on day 1 every 4 weeks.
  • MTD maximum tolerated dose
  • RD recommended dose
  • Premedication and supportive medication can be given.
  • a premedication using Glucocorticoids (dexamethasone or equivalent), 5-HT3-receptor antagonists (ondansetron, granisetron, tropisetron, or equivalent), Hi-receptor antagonist (difenhydramine hydrochloride or equivalent), and H2-receptor antagonist (ranitidine or equivalent) can be useful to avoid the side effects due to the administration of the chemotherapeutic agents.
  • metoclopramide can be also administered.
  • the treatments of the invention are useful in promoting tumor regression, in stopping tumor growth and/or in preventing metastasis.
  • the method of the invention is suited for human patients, especially those who are relapsing or refractory to previous chemotherapy. First line therapy is also envisaged.
  • the method of the invention is used according to the above schedules and dosages for the treatment of colorectal cancer, malignant melanoma, ovarian cancer, cholangiocarcinoma, liver cancer (hepatocarcinoma), hepatobiliary cancer, esophageal carcinoma (esophagus carcinoma), carcinoma of esophagogastric junction, adenocarcinoma of stomach, bladder cancer, neuroendocrine gallbladder carcinoma and pancreas cancer.
  • a phase I trial combining Aplidine with Carboplatin was conducted.
  • the main objective of this study was to determine the safety, tolerability and to identify the maximum tolerated dose (MTD) and the recommended dose (RD) of Aplidine administered in combination with Carboplatin to subjects with advanced malignant solid tumours or lymphoma, for whom no standard therapy is left.
  • Other secondary objectives of the trial were to study drug- drug pharmacokinetic interactions between Aplidine and Carboplatin, and to evaluate the preliminary antitumor activity of Aplidine when administered in combination with Carboplatin.
  • Aplidine was administered intravenously (IV) over 1 hour, on days 1, 8, and 15, every 4 weeks, and Carboplatin was administered intravenously (IV) over 1 hour at a fixed dose targeting an AUC of about 5 mg/mL/min, immediately after the infusion of Aplidine, once every 4 weeks (on day 1).
  • the maximum tolerated dose relates to the highest dose at which at least 2 out of 3-6 subjects experience a dose limiting toxicity (DLT) at any given dose level, being this dose level considered the MTD.
  • the recommended dose is intended to relate to the highest dose at which less than 2 of 6 subjects experience DLT during the cycles 1 or 2.
  • Glucocorticoids diexamethasone 8 mg IV or equivalent
  • 5-HT3-receptor antagonists ondansetron 8 mg IV, granisetron 3 mg IV, tropisetron 5 mg IV, or equivalent
  • Hi -receptor antagonist doenhydramine hydrochloride 25 mg IV or equivalent
  • H2- receptor antagonist randomitidine 50 mg IV or equivalent
  • Aplidine drug product was provided as a lyophilized powder containing Aplidine and mannitol, and it was reconstituted with a reconstitution solution containing Cremophor EL/ Ethanol/ Water for injection (15%/ 15%/ 70%).
  • Carboplatin was provided in the form of Carboplatin Solution for Injection and supplied in individually packed clear glass containing sterile solutions of Carboplatin 10 mg/ml.
  • Subjects enrolled in this clinical trial were adult patients with confirmed malignant solid tumor or lymphoma for which no standard therapy would reasonable be expected to result in cure or palliation.
  • Inclusion criteria included recovery from any drug-related adverse event derived from previous therapies excluding alopecia and NCI-CTCAE grade ⁇ 2 symptomatic peripheral neuropathy, life expectancy of at least 3 months, adequate cardiac function (Left ventricular ejection fraction (LVEF) within normal limits), adequate renal, liver and bone marrow functions, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0, 1 or 2, no evidence of progressive central nervous system metastasis or any symptomatic brain or leptomeningeal metastases, no active infection or serious intercurrent illness, and no active cardiac disease, no chemotherapy, radiotherapy, hormonal therapy or biological therapy within four weeks prior to entry (8 weeks in case of extensive radiotherapy and 6 weeks in case of previous nitrosourea, mitomycin C or high dose chemotherapy), and measurable or non measurable disease using the RECIST criteria.
  • Dose limiting toxicities were defined as follows: ⁇ Haemato logical drug-related adverse events: - Grade 4 neutropenia (absolute neutrophil count (ANC) ⁇ 0.5 x 10 9 /L) lasting more than 5 days
  • Grade 4 neutropenia concomitant with fever i.e. body temperature ⁇ 38.5°C
  • fever should not be disease-related Grade 4 neutropenia and sepsis or other severe infection Platelets (thrombocytopenia) ⁇ 25 x 10 9 /L
  • cancers such as colorectal cancer (6), malignant melanoma (4), ovarian cancer (2), cholangiocarcinoma (1), liver cancer (hepatocarcinoma) (1), neuroendocrine gallbladder carcinoma (1), pancreas cancer (1), esophageal carcinoma (esophagus carcinoma) (1), carcinoma of esophagogastric junction (gastroesophageal junction carcinoma) (1) and adenocarcinoma of stomach (1).
  • cancers such as colorectal cancer (6), malignant melanoma (4), ovarian cancer (2), cholangiocarcinoma (1), liver cancer (hepatocarcinoma) (1), neuroendocrine gallbladder carcinoma (1), pancreas cancer (1), esophageal carcinoma (esophagus carcinoma) (1), carcinoma of esophagogastric junction (gastroesophageal junction carcinoma) (1) and adenocarcinoma of stomach (1).
  • Table I it is summarised the dose cohorts, patients and adverse events (DLTs) observed during the study.
  • Table V summarises the antitumor activity observed assessed by RECIST criteria.

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Abstract

L'invention propose des procédés de traitement d'un patient humain atteint d'un cancer, qui comporte l'administration audit patient d'une quantité efficace du point de vue thérapeutique d'aplidine en combinaison avec de la carboplatine.
PCT/GB2008/050331 2007-05-04 2008-05-06 Combinaison d'aplidine et de carboplatine dans des traitements anticancéreux WO2008135793A1 (fr)

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GB0708693A GB0708693D0 (en) 2007-05-04 2007-05-04 Anticancer treatments
GB0708693.7 2007-05-04
GB0710043A GB0710043D0 (en) 2007-05-25 2007-05-25 Anticancer treatments
GB0710043.1 2007-05-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029415A1 (fr) 2009-09-10 2011-03-17 Univerzita Palackeho Complexes cyclobutane-1,1-dicarboxylato de platine avec des dérivés de n6-benzyladénine, leur procédé de préparation et leur application en tant que médicaments dans un traitement antitumoral
US8258098B2 (en) 2006-02-28 2012-09-04 Pharma Mar, S.A. Antitumoral treatments
US20210268028A1 (en) * 2018-07-02 2021-09-02 Cellectis Chimeric antigen receptors (car)-expressing cells and combination treatment for immunotherapy of patients with relapse refractory adverse genetic risk aml

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080421A2 (fr) * 2003-03-12 2004-09-23 Pharma Mar, S.A. Traitement antitumoraux ameliores
WO2007101235A2 (fr) * 2006-02-28 2007-09-07 Pharma Mar, S.A. Traitements antitumoraux perfectionnés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080421A2 (fr) * 2003-03-12 2004-09-23 Pharma Mar, S.A. Traitement antitumoraux ameliores
WO2007101235A2 (fr) * 2006-02-28 2007-09-07 Pharma Mar, S.A. Traitements antitumoraux perfectionnés

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8258098B2 (en) 2006-02-28 2012-09-04 Pharma Mar, S.A. Antitumoral treatments
WO2011029415A1 (fr) 2009-09-10 2011-03-17 Univerzita Palackeho Complexes cyclobutane-1,1-dicarboxylato de platine avec des dérivés de n6-benzyladénine, leur procédé de préparation et leur application en tant que médicaments dans un traitement antitumoral
US20210268028A1 (en) * 2018-07-02 2021-09-02 Cellectis Chimeric antigen receptors (car)-expressing cells and combination treatment for immunotherapy of patients with relapse refractory adverse genetic risk aml

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