Classifications

• • 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
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
  • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
• • 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 subject matter described herein relates to a method of treating advanced ovarian cancer in subjects previously treated with platinum/paclitaxel-based chemotherapy. More specifically, the subject matter relates to a method of treating advanced ovarian cancer in treatment-experienced patients with liposome-entrapped doxorubicin.
• Ovarian carcinoma is the leading cause of death in patients with gynecologic malignancies.
• the estimated incidence and mortality for 2005 are 22,220 and 16,210 respectively (Jemal A., et al., CA Cancer J. Clin., 55(1):10-30 (2005)).
• the majority of women diagnosed with advanced epithelial ovarian cancer will demonstrate a clinically-defined response to platinum/paclitaxel chemotherapy (Cannistra, S.A., N. Engl. J. Med., 351.(24) :2519-29 (2004)).
• the overall response rates can exceed 70% with complete clinical response rates of approximately 30-50% for patients with suboptimally resected disease (McGuire, WP. et al., N. Engl. J. Med.
• the anthracycline antibiotic doxorubicin possesses a broad spectrum of antineoplastic action that has been used in multiple solid tumors such as breast, ovary, bladder and thyroid.
• the conventional formulation of doxorubicin is rapidly cleared from the bloodstream and has a large distribution volume.
• a liposome- entrapped doxorubicin, Doxil ® provides an increased blood circulation time of the drug, reduces the nonspecific delivery to normal tissues, and avoids high plasma levels responsible for toxicity. These pharmacologic activities improve the specificity for tumors by allowing higher drug levels to eventually extravasate through the abnormally permeable vessels characteristic of many tumors.
• the liposome entrapped doxorubicin Doxil ® has demonstrated activity in epithelial ovarian cancer as a first or second line agent (Gordon, A.N. et al., Gynecol. Oncol., 95(1):1-8 (2004); Rose, P.G. et al., Abstract No. 1531 , ASCO 2000; Gibbs et al. Abstract No. 1539, ASCO 2000).
• a method of treating advanced ovarian cancer in a patient previously treated with platinum/paclitaxel-based chemotherapy and having a defined complete response to such treatment comprises administering an anthracycline entrapped in liposomes, optionally having an outer surface coating of hydrophilic polymer chains.
• a consolidation treatment strategy for a patient diagnosed with advanced ovarian cancer comprises treating the patient with platinum/paclitaxel-based chemotherapy to achieve a complete response and subsequently treating the patient with an anthracycline entrapped in liposomes, optionally having an outer surface coating of hydrophilic polymer chains.
• Fig. 1 shows the overall survival, in months, for patients treated with liposome- entrapped doxorubicin as detailed in Example 1.
• the present treatment method is based on the discovery that patients with suboptimally resected disease and a complete clinical response to initial chemotherapy can be treated with an anthracycline entrapped in a liposome to extend overall survival time.
• Ovarian cancer can be staged according to the AJCC/TNM System that describes the extent of the primary fumor (T), the absence or presence of metastasis to nearby lymph nodes (N), and the absence or presence of distant metastasis (M). This closely resembles the system that is actually used by most gynecologic oncologists, called the FIGO system.
• “Advanced epithelial ovarian cancer” intends patients with stage III or stage IV ovarian cancer. More particularly, and in one embodiment, the term intends patients with stage IMc or stage IV ovarian cancer, determined according to a recognized staging technique such as the AJCC/TMN or FIGO system.
• stage III ovarian cancer In patients diagnosed with stage III ovarian cancer the cancer involves one or both ovaries, and one or both of the following are present: (1) cancer has spread beyond the pelvis to the lining of the abdomen; (2) cancer has spread to lymph nodes. In stage INC patients, the cancer is in one or both ovaries, and one or both of the following are present: (1) cancer has spread to lymph nodes, and (2) deposits of cancer larger than 2 cm across are present in the abdomen. Patients diagnosed with stage IV have cancer in one or both ovaries. Distant metastasis (spread of the cancer to the inside of the liver, the lungs, or other organs located outside of the peritoneal cavity) has occurred. A finding of ovarian cancer cells in pleural fluid (from the cavity that surrounds the lungs) is also evidence of stage IV disease.
• a patient that has been "optimally debulked” is defined as a patient having a residual tumor with a diameter of 2 cm or less, more preferably of 1 cm or less.
• “Suboptimally debulked” intends a residual tumor, i.e, tumor after surgical debulking, with a diameter of greater than about 2 cm, more preferably of greater than about 1 cm.
• the current treatment protocol for stage III and stage IV ovarian cancer patients includes chemotherapy that includes a platinum chemotherapeutic agent, such as cisplatin or carboplatin. It will be appreciated that the platinum agent may be used in combination with one or more chemotherapeutic agents, such as a taxane like paclitaxel. In one embodiment, patients that have received six courses of platinum-based chemotherapy are selected for treatment.
• a platinum chemotherapeutic agent such as cisplatin or carboplatin.
• the platinum agent may be used in combination with one or more chemotherapeutic agents, such as a taxane like paclitaxel.
• patients that have received six courses of platinum-based chemotherapy are selected for treatment.
• Advanced ovarian patients treated with surgical debulking and chemotherapy comprised of a platinum-based agent may achieve a complete response.
• a clinically defined complete response intends (i) no evidence of cancer on physical exam within fourteen days after completion of initial chemotherapy, (ii) no evidence of residual tumor on a CT scan of the abdomen/pelvis within 60 days of completion of initial chemotherapy, and (iii) a cancer antigen-125 (CA-125) level that is less than or equal to 35 units/mL, measured in the blood or fluid from the abdominal or chest cavities.
• CA-125 cancer antigen-125
• Fig. 1 shows the overall survival after treatment with liposome-entrapped doxorubicin as a consolidation agent.
• the patients had a progression-free interval (PFI) of about 15 months.
• PFI progression-free interval
• the results show that therapy using liposome-entrapped doxorubicin is well-tolerated as a consolidation agent with an acceptable toxicity profile and provided a continued response in patients with advanced ovarian cancer.
• doxorubicin is an exemplary anthracycline compound, and that other anthracyclines are contemplated, such as daunorubicin, epirubicin, and idarubicin.
• composition of the liposomal platform can be widely varied, including but not limited to, the presence or absence of an external surface coating of hydrophilic polymer chains, the polymer forming the hydrophilic polymer chains when present, the lipids forming the liposomal bilayer.
• the various components to form liposomes and techniques for preparation are well known in the art.
• the dose, dosing regimen, and route of administration of the liposome-entrapped anthracycline can be varied to optimize the response.
• the dose can be increased or decreased from that exemplified as deemed suitable for a medical provider.
• the interval between doses and the number of doses or 'cycles' of treatment can also be varied.
• Intravenous injection is a preferred route of administration, but any parenteral mode of delivery is contemplated.
• PEGylated liposomes Patients received doxorubicin entrapped in PEGylated liposomes (Doxil ® ) at a one-hour infusion dose of 40 mg/m 2 every 28 days for four cycles. Dose reductions of 25% and treatment delays of 1-2 weeks were allowed for drug-related toxicities. Patients were followed every three months for the first two years, and then every six months until documentation of disease. Patients were removed from treatment for unacceptable toxicities. Progression-free interval (PFI) was calculated as the date of completion of primary platinum/paclitaxel-based chemotherapy to the date of recurrence. Survival analysis was calculated using the Kaplan-Meier method. Twenty-three (23) of the 29 evaluable patients (79%) completed all four cycles of consolidation therapy with Doxil ® .
• PFI Progression-free interval

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• 2006
  • 2006-04-20 BR BRPI0609939-4A patent/BRPI0609939A2/pt not_active IP Right Cessation
  • 2006-04-20 KR KR1020077026950A patent/KR20080008367A/ko not_active Withdrawn
  • 2006-04-20 CN CNA2006800130738A patent/CN101163485A/zh active Pending
  • 2006-04-20 WO PCT/US2006/015528 patent/WO2006116341A1/en not_active Ceased
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• 2007
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