Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/32—Thymopoietins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/21—Interferons [IFN]
  • A61K38/212—IFN-alpha
• • 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
  • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/2292—Thymosin; Related peptides
• • 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
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • 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

• the present invention relates to the use of thymosin alpha 1 in combination with dacarbazine and optionally Interferon alpha, for preparing a medicament for the treatment of malignant melanoma on stage IV.
• Melanoma is a malignant tumor of melanocytes, which are cells derived from the neural crest.
• Melanomas are found primarily in normal areas of the skin, but may also occur in other mucosal surfaces.
• Skin nevi may be suspected of undergoing malignant changes if they appear darker or have variable discoloration, or there is itching, an increase in size, or development of satellites.
• Melanoma is unusual in that it is far more likely to metastasize than other types of cancer and can spread to regional or distant lymph nodes, or to any of the major organ systems of the body.
• the most common sites of metastasis other than the skin are the lung, liver, brain, and lymph nodes.
• stage IV malignant melanoma (“high- risk melanoma” or "H-RM”) will vary depending on the stage and site(s) of systemic involvement. Melanoma occurs more frequently in males and is found in adults of all ages.
• ACS American Cancer Society
• HR-M accounts for approximately 22% of all cutaneous malignant melanoma cases and is associated with a high mortality rate.
• melanoma Other known risk factors for melanoma include: genetics, where 5 - 10% of melanoma patients have a family history of the disease; dysplastic/ atypical nevi; complexion (fair-skinned, red-headed or blond individuals, and individuals with a high tendency to freckle are at higher risk for developing melanoma); and history of severe blistering sunburn.
• Patients diagnosed with H-RM have a strikingly worse prognosis than patients whose tumor are of minimal thickness/invasion and are locally confined.
• prognostic indicators for melanoma including: age; sex; characteristics of the primary tumor (e.g., anatomic location, size, Clark's level, Breslow's thickness, histopathological type, ulceration, inflammatory reaction); and lymph node involvement.
• H-RM is generally a fatal disease due to the absence of adequate therapeutic options.
• H-RM is characterized by tumors of the skin that metastasize to virtually every organ.
• the clinical presentation of H-RM varies according to the stage and site(s) of systemic involvement.
• stage IV malignant melanoma characterized by distant unresectable metastases
• Thymosin alpha 1 is a compound well known in the medical field.
• NSCLC non-small cell lung cancer
• Pulmonary metastases in mice with methylcholanthrene-induced fibrosarcoma were also reduced by thymosin alpha 1 , and local sarcoma growth as well as liver and lung metastases of lymphosarcoma cells were significantly reduced in BALB /c mice treated with thymosin alpha 1.
• Adjuvant immunotherapy agents designed to augment the immune response are under development and include melanoma vaccines, interferons ("IFNs”), interleukin-2 (“IL-2”), and tumor-infiltrating lymphocytes, and plasmid-based DNA vaccines.
• IFNs interferons
• IL-2 interleukin-2
• tumor-infiltrating lymphocytes tumor-infiltrating lymphocytes
• drugs investigated for use alone or in combination with dacarbazine include: alkylating agents and nitrosureas; vinca alkaloids; platinum compounds; hormonal agents; and plant-derived agents (paclitaxel (Taxol), coumarin). None of these drugs, either alone or in combination with dacarbazine and/ or Interferon alpha have been shown to be any more effective than dacarbazine alone (Cancer Medicine, Ed. 5 2000; pp. 1849-69) and are considered useful only for symptomatic relief.
• thymosin alpha 1 in combination with dacarbazine, and optionally Interferon alpha, are useful for treating malignant melanoma on stage IV characterized by distant unresectable metastases, particularly on patients having normal serum level of LDH (lactate dehydrogenase).
• the phrase "relatively high doses" as it pertains to thymosin alpha 1 shall be understood to mean doses in excess of about 1 mg per parenteral, e.g. subcutaneous, administration.
• low serum level of LDH lactate dehydrogenase
• LDH lactate dehydrogenase
• thymosin alpha 1 is administered in a dose from 1.1 to 7 mg/day/s.c; the preferred dose is from 1.6 to 6.4 mg/day/s.c; the most preferred dose are 1.6; 3.2; and 6.4 mg/day/s.c; dacarbazine is administered in a dose from 500 to 1100 mg/m 2 /day/i.v.; the preferred dose is 800 mg/m 2 /day/i.v.; and
• Interferon alpha is administered in a dose from 2 to 4 MIU/day/s.c; the preferred dose is 3 MIU/day/s.c.
• the method includes administering a combination of thymosin alpha 1 and dacarbazine, and optionally
• Interferon alpha to a patient in need thereof.
• the combination of thymosin alpha 1 and dacarbazine in the amounts described herein provide therapeutic advantages over the administration of either agent alone or prior art combinations of the ingredients in the treatment of melanomas, including malignant melanomas.
• Those of ordinary skill will appreciate that although the methods described herein speak of combinations of the two primary therapeutic agents, it is contemplated that each of the therapeutic agents can and preferably will be administered to the patient separately rather than as part of a single pharmaceutical dosage form or even simultaneously to the patient in need thereof. It will also be understood that the inventive methods of use and treatment contemplate administration of the synergistic combinations as part of treatment protocols as such protocols are understood by those of ordinary skill.
• Such treatment protocols can call for administration of the combinations according to a schedule which can be repeated, as needed. See, for example, the 28 day cycle described in Example 1 below. Further cycles and protocols will be apparent to those of ordinary skill based upon the description provided herein and clinical expense, without undue experimentation.
• Other protocols for treating malignant melanoma in a patient include administering a synergistic combination of thymosin alpha 1 and dacarbazine to patient in need thereof, wherein the combination is administered according to a protocol in which the dacarbazine is administered on day 1 thereof and the thymosin alpha 1 is administered between about one week and about two weeks thereafter.
• An alternative protocol for treating malignant melanoma in a patient includes administering a synergistic combination of thymosin alpha 1, dacarbazine and Interferon alpha to patient in need thereof, wherein the combination is administered according to a protocol in which the dacarbazine is administered on day 1 thereof, the thymosin alpha 1 is administered about between one week and about two weeks thereafter and the Interferon alpha is administered about 10- 12 days and optionally about 18 days after the dacarbazine is administered.
• a still further aspect of the invention includes a kit for treating melanomas such as malignant melanoma.
• the kits include effective amounts of thymosin alpha 1, dacarbazine, and optionally Interferon alpha.
• kits are contemplated wherein the two principal agents, i.e. thymosin alpha 1 and dacarbazine are present, as described above.
• the kit will preferably include directions for the administration of the separate components.
• the kit form is particularly advantageous when the separate components can be administered in different dosage forms (e.g., oral and parenteral) or are administered at different dosage intervals as will most commonly be the case herein where the components are administered on different days.
• effective amount shall be understood to mean an amount which achieves a desired clinical result, i.e.
• the five groups were analyzed independently one another within the so-called "pick the winner” strategy.
• the randomized patients were stratified according to the disease site: M Ia, MIb or M Ic level.
• M Ic Patients with other visceral metastases and/ or with serum LDH value out of normal range were classified as M Ic.
• M Ib patients notoriously have worse prognosis than M Ia patients while the M Ic patients have the worst prognosis.
• Tables 1 /A-5/A relate to patients treated without considering their LDH serum levels.
• Tables 1 /B-5/B relate to patients with a serum level of LDH between 96 to 460 U/L (this is a sub population of the patients treated/present in Tables 1/A- 5/A.
• the daily dose of the active ingredients to be administered will depend, according to the judgement of the primary care physician, on the subject's weight, age or general condition.
• Thymosin alpha 1 dacarbazine and Interferon alpha are well known active ingredients used in the medical field.

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

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• 2007
  • 2007-04-12 US US11/734,592 patent/US8017129B2/en active Active
  • 2007-04-17 EP EP07728177A patent/EP2032153A1/en not_active Withdrawn
  • 2007-04-17 AU AU2007260145A patent/AU2007260145A1/en not_active Abandoned
  • 2007-04-17 KR KR1020087031799A patent/KR20090020646A/ko not_active Withdrawn
  • 2007-04-17 WO PCT/EP2007/053712 patent/WO2007144218A1/en not_active Ceased
  • 2007-04-17 CA CA002652516A patent/CA2652516A1/en not_active Abandoned
  • 2007-04-17 MX MX2008015145A patent/MX2008015145A/es not_active Application Discontinuation
  • 2007-04-17 RU RU2009101026/15A patent/RU2009101026A/ru not_active Application Discontinuation
  • 2007-04-17 HR HR20090010A patent/HRP20090010A2/xx not_active Application Discontinuation
  • 2007-04-17 JP JP2009514721A patent/JP2009539916A/ja not_active Withdrawn
  • 2007-04-23 TW TW096114301A patent/TW200808327A/zh unknown
  • 2007-06-13 AR ARP070102577A patent/AR061352A1/es unknown
• 2008
  • 2008-12-15 IL IL195955A patent/IL195955A0/en unknown
• 2009
  • 2009-01-14 NO NO20090238A patent/NO20090238L/no not_active Application Discontinuation
  • 2009-03-31 US US12/415,589 patent/US8029799B2/en not_active Expired - Fee Related

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