WO2004035033A2 - Combinaison chimiotherapeutique de clofarabine et de camptothecine - Google Patents

Combinaison chimiotherapeutique de clofarabine et de camptothecine Download PDF

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Publication number
WO2004035033A2
WO2004035033A2 PCT/US2003/032515 US0332515W WO2004035033A2 WO 2004035033 A2 WO2004035033 A2 WO 2004035033A2 US 0332515 W US0332515 W US 0332515W WO 2004035033 A2 WO2004035033 A2 WO 2004035033A2
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WIPO (PCT)
Prior art keywords
cancer
clofarabine
cell
dose
cancer cell
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Application number
PCT/US2003/032515
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English (en)
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WO2004035033A3 (fr
Inventor
Sean T. Wilson
Steven D. Weitman
Katherine Stephenson
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Ilex Products, Inc.
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Priority to AU2003301245A priority Critical patent/AU2003301245A1/en
Publication of WO2004035033A2 publication Critical patent/WO2004035033A2/fr
Publication of WO2004035033A3 publication Critical patent/WO2004035033A3/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to the use of clofarabine in cancer therapy. More particularly, it relates to the use of a combination of clofarabine and a camptothecin analogue in the treatment of cancer.
  • Cancer remains a major world-wide health problem. Although many advances have been made in cancer detection and therapy, no universally successful method for treatment or prevention is currently available. Cancer therapy currently relies on a combination of early diagnosis and treatment, which may include radiotherapy, chemotherapy or hormone therapy. The toxicity of such treatments often imposes limits on the use of presently available anticancer agents. The high mortality rate for many cancers indicates that improvements are needed in cancer prevention and treatment.
  • Clofarabine (2-chloro-9-(2-deoxy-2-fluoro- ⁇ -D-arabinofuranosyl)adenine) is a synthetic nucleoside analog that incorporates the favorable properties of fludarabine and cladarabine.
  • clofarabine has a chlorine atom at the purine C-2 position that confers resistance to deamination and a fluorine at the C-2' of the arbinofuranosyl moiety that decreases the susceptibility to phosphorolytic cleavage.
  • Clofarabine has shown potent cytotoxicity in human cell lines (Secrist et al, 1988; Carson et al, 1992) and therapeutic activity in murine tumor models (Montgomery et al., 1992).
  • the dose-limiting toxicity for clofarabine is myelosuppression in solid tumors and hepatic and skin toxicity in leukemias, the maximum tolerated dose being reported as 2-4 mg/kg for solid tumors when given daily for five days (Kozuch et al., 1999), while the maximum tolerated doses for leukemias are at least an order of magnitude higher (Gandi et al., 2002; Jeha et al., 2002).
  • Use of clofarabine in combination regimens with other chemotherapeutic agents may enhance the benefits of both clofarabine and the combined chemotherapeutic agent, thereby facilitating the treatment of a variety of tumor types while maintaining an acceptable toxicological profile.
  • This invention provides for the use of clofarabine in combination with a camptothecin analogue, wherein such combinations enhances the efficacy relative to either agent alone, thereby potentially reducing the amount of clofarabine and/or camptothecin analogue required to elicit an anticancer effect when used in combination.
  • One aspect of the present invention is a method for inhibiting the growth of a tumor cell, comprising contacting the tumor cell with clofarabine and a camptothecin analogue, wherein the dose of clofarabine, when combined with the dose of the camptothecin analogue, is effective to inhibit tumor cell growth.
  • the camptothecin analogue is irinotecan (CPT- 11, CAMPTOSAR) or topotecan.
  • the tumor cell is selected from the group consisting of a skin cancer cell, a prostate cancer cell, a lung cancer cell, a brain cancer cell, a breast cancer cell, an ovarian cancer cell, a cervical cancer cell, a liver cancer cell, a pancreatic cancer cell, a colon cancer cell, a stomach cancer cell, a leukemia cell and a lymphoma cell.
  • the present invention provides for a method of killing tumor cells, comprising contacting the tumor cell with clofarabine and a camptothecin analogue, wherein the dose of clofarabine, when combined with the dose of the camptothecin analogue, is effective to kill said tumor cell.
  • a further aspect of the present invention provides for a method for treating cancer in a human patient comprising administering clofarabine and a camptothecin analogue, wherein the dose of clofarabine, when combined with the dose of the camptothecin analogue, is effective to treat the cancer.
  • the camptothecin analogue is irinotecan or topotecan.
  • the cancer is selected from the group consisting of skin cancer, prostate cancer, lung cancer, brain cancer, breast cancer, ovarian cancer, cervical cancer, liver cancer, pancreatic cancer, colon cancer, stomach cancer, leukemia and lymphoma.
  • FIG. 1 is a graphical depiction of the response of subcutaneous human HT-29 colorectal tumors to a combination treatment of 4 mg/kg/dose clofarabine and 27 mg/kg/dose CPT-11.
  • FIG. 2 is a graphical depiction of the response of subcutaneous human HT-29 colorectal tumors to a combination treatment of 2 mg/kg/dose clofarabine and 60 mg/kg/dose CPT-11.
  • FIG. 3 is a graphical depiction of the response of subcutaneous human HT-29 colorectal tumors to a combination treatment of 1 mg/kg/dose clofarabine and 40 mg/kg/dose CPT-11.
  • ⁇ control group
  • • clofarabine 1 mg/kg/dose single agent
  • ⁇ CPT-11 40 mg/kg/dose single agent
  • A clofarabine 1 mg/kg/dose and CPT-11 40 mg/kg/dose combination.
  • FIG. 4 is a graphical depiction of the response of subcutaneous human HT-29 colorectal tumors to a combination treatment of 2 mg/kg/dose clofarabine and 60 mg/kg/dose CPT-11.
  • • control group
  • ⁇ clofarabine 2 mg/kg/dose single agent
  • ⁇ CPT-11 60 mg/kg/dose single agent
  • V clofarabine 2 mg/kg/dose and CPT-11 60 mg/kg/dose combination.
  • FIG. 5 is a graphical depiction of the response of subcutaneous human HT-29 colorectal tumors to a combination treatment of 2 mg/kg/dose clofarabine and 40 mg/kg/dose CPT-11.
  • • control group;
  • ⁇ clofarabine 2 mg/kg/dose single agent;
  • ⁇ CPT-11 40 mg/kg/dose single agent;
  • V clofarabine 2 mg/kg/dose and CPT-11 40 mg/kg/dose combination.
  • FIG. 6 is a graphical depiction of the response of subcutaneous human HT-29 colorectal tumors to a combination treatment of 2 mg/kg/dose clofarabine and 20 mg/kg/dose CPT-11.
  • • control group;
  • ⁇ clofarabine 2 mg/kg/dose single agent;
  • ⁇ CPT-11 20 mg/kg/dose single agent;
  • V clofarabine 2 mg/kg/dose and CPT-11 20 mg/kg/dose combination.
  • Clofarabine is disclosed and claimed as a composition in U.S. Patent 5,384,310 and disclosed and claimed as a method of killing cancer cells in U.S. Patent 5,661,136, both herein incorporated by reference.
  • Camptothecin analogues are defined generally as analogues of 20(S)-can ⁇ ptothecin:
  • the molecular target of camptothecin analogues is the type I topoisomerase (Liu et al,
  • camptothecin analogue topoisomerase inhibitors are reviewed in Kehrer et al.
  • camptothecin analogues are known in the art and are disclosed, e.g., in U.S.
  • the therapeutic agents of the present invention can be formulated in a variety of conventional pharmaceutical formulations and administered to cancer patients, in need of treatment, by any one of the drug administration routes conventionally employed including oral, intravenous, parental or intrapenitoneal.
  • the preferred routes of administration include intravenous (IV), intraperitoneal (IP) and oral (PO).
  • the therapeutic agents of the present invention may be formulated, for example, with an inert diluent or with an assimiable edible carrier, or enclosed in hard or soft shell gelatin capsules, or compressed into tablets, or incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of the unit. The amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder, a gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder such as a gum tragacanth, acacia, cornstarch, or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added
  • compositions of the therapeutic agents of the present invention that are suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that each syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the therapeutic agent in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the composition.
  • camptothecin analogues such as irinotecan and topotecan are known in the art (Stewart & Ratain, 2001; Verschraegen et al, 2000, both incorporated herein by reference).
  • the clinical dosage of clofarabine may be optimized for the tumor type as may be determined by one of skill in the art by routine experimentation.
  • Administration regimens include single weekly intravenous administration of 4 to 50 mg/m 2 , given in cycles of three weeks of dosing with one week of no administration.
  • Other administration regimens include daily intravenous dosing about 15 to about 50 mg/m 2 , wherein such dosing may be given in cycles of 5 consecutive days.
  • the treatment with clofarabine may precede or follow treatment with camptothecin analog by intervals ranging from seconds to weeks and/or be administered concurrently with such treatments.
  • steps should be taken to ensure that a period of time does not expire between the time of each delivery, such that the combination of the treatments would not be able to exert an advantageously combined therapeutic effect.
  • Tumors that can be suitably treated with the methods of the present invention include; but are not limited to, tumors of the brain (glioblastomas, medulloblastoma, astrocytoma, oligodendroglioma, ependymomas), lung, liver, spleen, kidney, lymph node, small intestine, pancreas, blood cells, colon, stomach, breast, endometrium, prostate, testicle, ovary, skin, head and neck, esophagus, bone marrow, blood and other tissue.
  • the tumor may be distinguished as metastatic and non-metastatic.
  • clofarabine and irinotecan was tested in an HT29 human colorectal adenocarcinoma xenograft model.
  • Tumors were implanted subcutaneously ("sc") with 30-40 mg trocar fragments into athymic nude mice housed in microinsulator cages in a 12 hr light/dark cycle. The animals receive filter-sterilized water and sterile rodent food ad libitum.
  • the tumor implants were allowed to increase in size to approximately 119 to 2184 mg (mm 3 ) median group size before treatment began on day 10 post-implantation. Mice were treated according to the study design summarized in Table 1.
  • T-C days
  • T-C is the difference in the median of times postimplant for tumors of the treated groups to attain an evaluation size compared to the medium of the control group.
  • Vehicle 1 Clofarabine vehicle (Saline with 0.5% Tween 80)
  • Vehicle 2 CPT-ll vehicle (D5W)
  • Q4Hx3, QlDx9 Administered three times daily for nine consecutive days.
  • Q4Dx3 administered every fourth day three times.
  • the dosage of clofarabine was 2 mg/kg/dose and the doses of CPT-11 were 60, 40 and 20 mg/kg/dose. The agents were given alone and in combination. Treatment began on day 11 when the median tumor size ranged from 144 to 196 mg. The results are summarized in Table 4 and FIGS. 4, 5 and 6.
  • the dosage of clofarabine was tolerated with a maximum loss in body weight of 9% (control group experienced a 13% loss in body weight).
  • the dosages of CPT-11 were tolerated with maximum losses in body weight of 17, 13 and 9% for dosages of 60, 40 and 20 mg/kg/dose respectively.
  • Clofarabine exhibited good activity against the HT29 tumor, as evidenced by a delay in tumor growth of (T-C) of 12.6 days for a dosage of 2 mg/kg/dose.
  • CPT-11 exhibited less activity with T-C values of 9.9, 10.1 and 7.9 days for dosages of 60, 40 and 20 mg/kg/dose respectively.
  • the combination groups exhibited better activity with T-C values of 17, 18.9 and 13 days than observed for either single agent. The combination appears to be additive with respect to the single agents.
  • Vehicle 2 CPT-l l vehicle (D5W)
  • Q4Hx3, QlDx9 Administered three times daily for nine consecutive days.
  • Q4Dx3 administered every fourth day three times.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne une combinaison de clorafabine et d'un analogue de camptothécine utilisée dans le traitement des cancers.
PCT/US2003/032515 2002-10-16 2003-10-14 Combinaison chimiotherapeutique de clofarabine et de camptothecine WO2004035033A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003301245A AU2003301245A1 (en) 2002-10-16 2003-10-14 Clofarabine and camptothecin chemotherapy combination

Applications Claiming Priority (4)

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US41906502P 2002-10-16 2002-10-16
US60/419.065 2002-10-16
US45947603P 2003-04-01 2003-04-01
US60/459.476 2003-04-01

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WO2004035033A3 WO2004035033A3 (fr) 2004-07-22

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Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BERAN M ET AL: "Results of combination chemotherapy with topotecan and high-dose cytosine arabinoside (ara-C) in previously untreated patients with high-risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML)" BLOOD, vol. 90, no. 10 SUPPL. 1 PART 1, 15 November 1997 (1997-11-15), page 583A XP009027996 39th Annual Meeting of the American Society of Hematology;San Diego, California, USA; December 5-9, 1997 ISSN: 0006-4971 *
CERSOSIMO R J: "IRINOTECAN: A NEW ANTINEOPLASTIC AGENT FOR THE MANAGEMENT OF COLORECTAL CANCER" ANNALS OF PHARMACOTHERAPY, XX, XX, vol. 32, no. 12, December 1998 (1998-12), pages 1324-1333, XP008018483 ISSN: 1060-0280 *
KANTARJIAN HAGOP M ET AL: "Phase I and pharmacology study of clofarabine (2-Cl-2'-F-deoxy-9-D-arabino-furanosyladen ine) in solid and hematologic cancers" BLOOD, vol. 98, no. 11 Part 2, 16 November 2001 (2001-11-16), page 214b XP009027998 43rd Annual Meeting of the American Society of Hematology, Part 2;Orlando, Florida, USA; December 07-11, 2001 ISSN: 0006-4971 *
KEHRER D F S ET AL: "MODULATION OF CAMPTOTHECIN ANALOGS IN THE TREATMENT OF CANCER: A REVIEW" ANTI-CANCER DRUGS, RAPID COMMUNICATIONS, OXFORD, GB, vol. 2, no. 12, February 2001 (2001-02), pages 89-105, XP008002866 ISSN: 0959-4973 cited in the application *
KOLLMANNSBERGER C ET AL: "TOPOTECAN-A NOVEL TOPOISOMERASE I INHIBITOR: PHARMACOLOGY AND CLINICAL EXPERIENCE" ONCOLOGY, S. KARGER AG, BASEL, CH, vol. 1, no. 56, 1999, pages 1-12, XP001064576 ISSN: 0030-2414 *
RIZZIERI D A ET AL: "Phase I trial of continuously infused gemcitabine with CPT-11 for refractory hematologic malignancies" BLOOD, vol. 96, no. 11 Part 2, 16 November 2000 (2000-11-16), page 216b XP009027999 42nd Annual Meeting of the American Society of Hematology;San Francisco, California, USA; December 01-05, 2000 ISSN: 0006-4971 *
WEITMAN STEVEN D ET AL: "Antitumor effect of combination treatment with clofarabine and CPT-11 in the HT-29 human colorectal tumor xenograft model." PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL, vol. 44, July 2003 (2003-07), page 161 XP001180279 94th Annual Meeting of the American Association for Cancer Research;Washington, DC, USA; July 11-14, 2003, July 2003 ISSN: 0197-016X *

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AU2003301245A1 (en) 2004-05-04
AU2003301245A8 (en) 2004-05-04

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