Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• • 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

Definitions

• the present invention relates to a method of treating a warm-blooded animal, especially a human, having a cancer disease selected from hepatoma; primary fallopian tube cancer; primary peritoneal cancer; breast cancer progressing after treatment with hormonal agents or radiotherapy; renal cell carcinoma progressing after treatment with a cytokine, radiotherapy and/or nephrectomy; melanoma progressing after radiotherapy; prostate cancer progressing after orchiectomy; ovarian cancer progressing after treatment with a platinum compound or radiotherapy; and colorectal cancer progressing after radiotherapy and/or treatment with oxaliplatin or irinotecan;and metastasis thereof comprising administering to said animal a therapeutically effective amount of an epothilone derivative of formula I as defined below.
• a cancer disease selected from hepatoma; primary fallopian tube cancer; primary peritoneal cancer; breast cancer progressing after treatment with hormonal agents or radiotherapy; renal cell carcinoma progressing after treatment with a cytokine, radiotherapy and
• epothilones especially epothilones A, B and D, represent a new class of microtubule stabilizing cytotoxic agents (see Gerth, K. et al., J. Antibiot. 49, 560-3 (1996); or Hoefle et al., DE 41 38042).
• A represents O or NR N , wherein R N is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, produce a beneficial effect in the treatment of a cancer disease selected from hepatoma; primary fallopian tube cancer; primary peritoneal cancer; breast cancer progressing after treatment with hormonal agents or radiotherapy; renal cell carcinoma progressing after treatment with a cytokine, radiotherapy and/or nephrectomy; melanoma progressing after radiotherapy; prostate cancer progressing after orchiectomy; ovarian cancer progressing after treatment with a platinum compound or radiotherapy; and colorectal cancer progressing after radiotherapy and/or treatment with oxaliplatin or irinotecan; and metastasis thereof.
• a cancer disease selected from hepatoma; primary fallopian tube cancer; primary peritoneal cancer; breast cancer progressing after treatment with hormonal agents or radiotherapy; renal cell carcinoma progressing after treatment with a cytokine, radiotherapy and/or nep
• the invention relates to a method of treating a warm-blooded animal, preferably a human, having a cancer disease as mentioned above comprising administering a therapeutically effective amount of an epothilone derivative of formula I in which A represents O or NR Nl wherein R N is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, or a pharmaceutically acceptable salt thereof to a warm-blooded animal in need thereof.
• hepatoma as used herein means a cancer disease characterized by at least one liver tumor arising from malignant hepatocytes. Hepatoma is an important cause of death in certain areas of Africa and Southeast Asia. Symptoms for the disease are abdominal pain, weight loss, a right upper quadrant mass and unexplained deterioration in a previously stable patient with cirrhosis. Sometimes systemic metabolic manifestation occurs, including hypoglycemia, erythrocytosis, hypercalcemia and hyperlipidemia. An elevated level of ⁇ - fetoprotein is another indicator used in diagnosis. Abdominal US, CT and MRI are important diagnostic aids and can sometimes detect subclinical carcinomas. The treatment of hepatoma is generally unsatisfactory, since the tumor is not radiosensitive and chemotherapy is usually unsuccessful.
• primary fallopian tube cancer includes, but is not limited to, a cancer disease that can be limited to one or both fallopian tubes with or without pelvic extension, but also a cancer involving peritoneal implants outside the pelvis and/or metastases.
• radiotherapy includes, but is not limited to, the treatment of a disease by ionizing radiation.
• cytokine as used herein includes, but is not limited to IL-2 and IFN- ⁇ .
• orchiectomy means the excision of one of both testes.
• platinum compound as used herein includes, but is not limited to carboplatin, cis- platin and oxaliplatin.
• treatment comprises the treatment of patients having hepatoma, being in a pre-stage of said disease or were subject to a surgical resection of a liver tumor, which treatment effects a complete response, partial response or stable disease in said patients.
• partial response means in particular a greater than or equal to 50 % reduction in measurable or evaluable disease in the absence of progression in any particular disease site.
• stable disease means in particular a less than 50 % decrease or less than 25 % increase in measurable or evaluable disease.
• standard anti-diarrheal include, but is not limited to, natural opiods, such as tincture of opium, paregoric, and codeine, synthetic opoids, such as diphenoxylate, difenoxin and loperamide, bismuth subsalicylate, octreotide, especially in the form as marketed under the tradename SANDOSTATIN LARTM, motilin antagonists and traditional antidiarrheal remedies, such as kaolin, pectin, berberine and muscarinic agents.
• the antidiarrheal agent is administered as a preventative measure throughout the treatment cycle or as needed when diarrhea occurs.
• the antidiarrheal agent is administered to prevent, control or eliminate diarrhea that is sometimes associated with the administration of epothilones, especially epothilone B.
• organic radicals and compounds designated "lower” contain not more than 7, preferably not more than 4, carbon atoms.
• a compound of formula I in which A represents O, R is hydrogen and Z is O is known as epothilone A; a compound of formula I wherein A represents O, R is methyl and Z is O is known as epothilone B; a compound of formula I wherein A represents O, R is hydrogen and Z is a bond is known as epothilone C; a compound of formula I wherein A represents O, R is methyl and Z is a bond is known as epothilone D.
• epothilone derivatives of formula I can be administered as described in the publications cited above, e.g., epothilone B, can be administered as part of pharmaceutical compositions which are disclosed in WO 99/39694, in particular epothilone B can be used formulated in polyethylene glycol 300 (PEG 300) which composition has to be pre-diluted in 0.9% sodium chloride solution to obtain a concentration of 1 mg/mL
• PEG 300 polyethylene glycol 300
• references to the active ingredients are meant to also include the pharmaceutically acceptable salts. If these active ingredients have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
• the active ingredients having an acid group (for example COOH) can also form salts with bases.
• the active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.
• the invention also provides the use of a compound of formula I for the preparation of a medicament for the treatment of a cancer disease selected from hepatoma; primary fallopian tube cancer; primary peritoneal cancer; breast cancer progressing after treatment with hormonal agents or radiotherapy; renal cell carcinoma progressing after treatment with a cytokine, radiotherapy and/or nephrectomy; melanoma progressing after radiotherapy; prostate cancer progressing after orchiectomy; ovarian cancer progressing after treatment with a platinum compound or radiotherapy; and colorectal cancer progressing after radiotherapy and/or treatment with oxaliplatin or irinotecan; and metastasis
• a cancer disease selected from hepatoma; primary fallopian tube cancer; primary peritoneal cancer; breast cancer progressing after treatment with hormonal agents or radiotherapy; renal cell carcinoma progressing after treatment with a cytokine, radiotherapy and/or nephrectomy; melanoma progressing after radiotherapy; prostate cancer progressing after orchiectomy; ova
• an epothilone derivative of formula I is employed wherein A represents O, R is lower alkyl, especially methyl, ethyl or n-propyl, or hydrogen and Z is O or a bond. More preferably, an epothilone derivative of formula I is employed wherein A represents O, R is methyl and Z is O, which compound is also known as epothilone B.
• the present invention relates to a method of treating a warm-blooded animal having hepatoma comprising administering a therapeutically effective amount of an epothilone derivative of formula I or a pharmaceutically acceptable salt thereof, especially hepatoma which is progressing after radiotherapy and/or cannot be controlled by surgical resection.
• One embodiment of the invention pertains to the treatment of breast cancer progressing after treatment with hormonal agents or radiotherapy.
• One embodiment of the invention pertains to the treatment of ovarian cancer progressing after treatment with a platinum compound or radiotherapy.
• One embodiment of the invention pertains to the treatment of primary fallopian tube cancer, especially such cancer progressing after treatment with a platinum compound, a taxane or radiotherapy, preferably fallopian tube cancer which is a papillary serous adenocarcinoma.
• One embodiment of the invention pertains to the treatment of primary peritoneal cancer progressing after treatment with a platinum compound, a taxane or radiotherapy.
• One embodiment of the invention pertains to the treatment of renal cell carcinoma progressing after treatment with a cytokine, radiotherapy and/or nephrectomy
• One embodiment of the invention pertains to the treatment of melanoma progressing after radiotherapy.
• One embodiment of the invention pertains to the treatment of prostate cancer progressing after orchiectomy.
• One embodiment of the invention pertains to the treatment of colorectal cancer progressing after treatment with oxaliplatin or irinotecan.
• One embodiment of the invention pertains to the treatment of colorectal cancer progressing after radiotherapy.
• the method of treating a warm-blooded animal having a cancer disease as disclosed herein can be employed in the form of a monotherapy or in addition to other therapy forms, e.g., radiation or, in particular, together with the administration of a standard anti-diarrheal.
• a compound of formula I in particular epothilone B
• epothilone B The pharmacological activity of a compound of formula I, in particular epothilone B, can be demonstrated, e.g., in a study wherein patients suffering from hepatoma are treated with continuous 4-week cycles (three weeks on/one week off) of epothilone B until either disease progression or unacceptable side effects occur.
• Response initially can be evaluated after the first two cycles, and can be determined, e.g., by one of the diagnostic methods mentioned above and/or stabilization or improvement in clinical symptoms. Evaluations for response can be performed, e.g., every two cycles thereafter.
• the present invention relates also to pharmaceutical preparations that contain a compound of formula I as active ingredient and that can be used especially in the treatment of the diseases mentioned above.
• the preparations contain the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.
• the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
• the invention relates also to pharmaceutical preparations for use in a method for the prophylactic or especially therapeutic treatment of the human or animal body, to a process for the preparation thereof (especially in the form of compositions for the treatment of tumours) and to a method of treating the above-mentioned diseases, primarily neoplastic diseases, especially those mentioned above.
• the invention relates also to processes and to the use of compounds of formula I for the preparation of pharmaceutical preparations which contain compounds of formula I as active component (active ingredient).
• a pharmaceutical composition that is suitable for administration to a warm-blooded animal, especially a human or commercially useful mammal, suffering from a disease that is responsive to the inhibition of microtubule depolymerisation, for example psoriasis or especially a neoplastic disease, comprising a correspondingly effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof when salt-forming groups are present, together with at least one pharmaceutically acceptable carrier.
• a pharmaceutical composition for the prophylactic or especially therapeutic treatment of neoplastic and other proliferative diseases of a warm-blooded animal, especially a human or a commercially useful mammal requiring such treatment, especially suffering from such a disease, comprising a new compound of formula I, or a pharmaceutically acceptable salt thereof, as active ingredient in a quantity that is prophylactically or especially therapeutically active against said diseases, is likewise preferred.
• compositions contain from about 0.000001 % to 95 % of the active ingredient, whereby single-dose forms of administration preferably have from approximately 0.00001 % to 90 % and multiple-dose forms of administration preferably have from approximately 0.0001 to 0.5 % in the case of preparations for parenteral administration or 1 % to 20 % active ingredient in the case of preparations for enteral administration.
• Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories or capsules.
• Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions, etc. Examples are capsules containing from about 0.0002 g to about 1.0 g active ingredient.
• the pharmaceutical preparations of the present invention are prepared in a manner known perse, for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes.
• solutions of the active ingredient and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilised preparations which contain the active ingredient on its own or together with a carrier, for example mannitol, can be made up before use.
• the pharmaceutical preparations may be sterilised and/or may contain excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilising processes.
• the said solutions or suspensions may contain viscosity-increasing agents, typically sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatin, or also solubilisers, for example ⁇ Tween 80 [polyoxyethylene(20)sorbitan mono-oleate; trademark of ICI Americas, Inc. USA].
• Suspensions in oil contain as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes.
• liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, be- henic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
• antioxidants for example vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
• the alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a mono- or polyhydric, for example a mono-, di- or trihydric, alcohol, for example me-hanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol.
• fatty acid esters therefore, the following are mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375” (polyoxyethylene glycerol trioleate from Gattefosse, Paris), “Labrafil M 1944 CS” (unsaturated polyglycolised glycerides prepared by alcoholysis of apricot seed oil and consisting of glycerides and polyethylene glycol ester; Gattefosse, France), “Labrasol” (saturated polyglycolised glycerides prepared by alcoholysis of TCM and consisting of glycerides and polyethylene glycol ester; Gattefoss ⁇ , France), and/or "Miglyol 812” (triglyceride of saturated fatty acids of chain length C 8 to C ⁇ 2 from Hi-ls AG, Germany), but especially vegetable oils such as olive oil, cottonseed oil, almond oil, castor oil, sesame oil,
• injectable preparations are usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
• compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, if need be granulating a resulting mixture, and processing the mixture or granules, if desired, to form tablets or tablet cores, if need be by the inclusion of additional excipients.
• Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example trical- cium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example com, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
• Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
• Tablet cores may be provided with suitable, if need be enteric, coatings, using inter alia concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
• suitable, if need be enteric, coatings using inter alia concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
• Orally administrable pharmaceutical compositions also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol.
• the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as com starch, binders, and/or glidants, such as talc or magnesium stearate, and if need be stabilisers.
• the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilisers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
• suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilisers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
• Suitable rectally administrable pharmaceutical preparations are, for example, suppositories that consist of a combination of the active ingredient and a suppository base.
• Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
• the formulations suitable for parenteral administration are primarily aqueous solutions ([or example in physiological saline, obtainable by diluting solutions in polyethylene glycol, such as polyethylene glycol (PEG) 300 or PEG 400] of an active ingredient in water-soluble form, e.g. a water-soluble salt, or aqueous injectable suspensions containing viscosity-increasing agents, e.g. sodium carboxymethyl cellulose, sorbitol and/or dextran, and where appropriate stabilisers.
• the active ingredient if need be together with excipients, can also be in the form of a lyophilisate and can be made into a solution before parenteral administration by the addition of suitable solvents.
• Solutions such as those used, for example, for parenteral administration can also be employed as infusion solutions.
• Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbici- des, such as sorbic acid or benzoic acid.
• the effective dosage of a compound of formula I may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the severity of hepatoma being treated. Thus, the dosage regimen is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient. A physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of a compound of formula I required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites.
• the dosage of a compound of formula I is preferably in the range of about 0.1 to 75 mg/m, preferably 0.25 to 50 mg/m, e.g. 2.5 or 6 mg/m 2 , once weekly for two to four, e.g. three, weeks, followed by 6 to 8 days off in the case of an adult patient.
• Epothilone B is preferably administered in a dose that allows for the treatment of the cancer diseases mentioned herein and which dose is calculated according to the formula (I)
• N is the number of weeks between treatments and y is 6, wherein epothilone B is administered in more than one treatment cycle after an interval of one week to six weeks after the preceding treatment.
• epothilone B is administered weekly in a dose that is between about 0.1 to 6 mg/m 2 , preferably between 0.1 and 3 mg/m 2 , e.g. 2.5 or 3.0 mg/m 2 , for three weeks after an interval of one to six weeks, especially an interval of one week, after the preceding treatment.
• said epothilone B is preferably administered to a human every 18 to 24 days in a dose that is between about 0.3 and 12 mg/m 2 .
• the present invention also provides the use of a compound of formula I as defined herein for the treatment of a cancer disease as mentioned herein and for the preparation of a medicament for the treatment of such a cancer disease.
• the present invention provides a commercial package comprising as active ingredients a compound of formula I together with instructions for use thereof in the treatment of a cancer disease.
• Chemotherapies other than taxane/platinum or an additional agent to this regimen will not be allowed.
• the study population for this trial consists of ovarian, primary Fallopian, or primary peritoneal cancer patients who have either failed to respond to first-line therapy of taxane/platinum (or a combination using these agents), or patients who initially responded but have relapsed within six months of completing therapy.
• a third therapeutic agent administered as part of the taxane/platinum therapy is permitted for refractory disease if all other criteria are met.
• Patients may, at any time, have their dose reduced to 2.0 mg/m2 if in the investigator's opinion the original dose is either intolerable or unsafe for any given patient, and without such a dose reduction the patient would be forced to withdraw from the study. All dose modifications are captured on the dose administration record CRF.
• the study period for efficacy evaluation is up to six cycles. The study will enroll patients with histologically confirmed transitional cell carcinoma of the kidney. Mixed histology with a transitional cell carcinoma component is allowed. Patients may have either progressive regional disease or metastatic disease. This trial is currently ongoing. Several patients show a positive response in this study.
• the study period for efficacy evaluation is up to six cycles.
• the study population for this trial consists of colorectal cancer patients who have failed prior chemotherapy containing fluoropyrimidine (such as 5-FU and Xeloda) and either Irinotecan or oxaliplatin either administered in combination or sequentially (one regimen containing 5- flurouracil and one subsequent regimen containing either Irinotecan or oxaliplatin).
• fluoropyrimidine such as 5-FU and Xeloda
• Irinotecan or oxaliplatin either administered in combination or sequentially (one regimen containing 5- flurouracil and one subsequent regimen containing either Irinotecan or oxaliplatin).
• the prior chemotherapy may have been administered either as adjuvant therapy or as treatment for metastatic disease. Patients who have received only adjuvant therapy for their disease are eligible, as long as they have relapsed within six months of completing such therapy, and that therapy contained 5-FU and Irinotecan or oxaliplatin administered in combination as part of an investigational protocol. This trial is ongoing. Several patients shown a positive response in this trial.
• the study period for efficacy evaluation is up to nine cycles.
• the study population for this trial consists of colorectal cancer patients who have failed prior chemotherapy containing fluoropyrimidine (such as 5-FU and Xeloda) and either Irinotecan or oxaliplatin either administered in combination or sequentially (one regimen containing 5- flurouracil and one subsequent regimen containing either Irinotecan or oxaliplatin).
• the prior chemotherapy may have been administered either as adjuvant therapy or as treatment for metastatic disease.
• Patients who have received only adjuvant therapy for their disease are eligible, as long as they have relapsed within six months of completing such therapy and that therapy contained 5-FU and Irinotecan or oxaliplatin administered in combination as part of an investigational protocol.
• Each four-week period is considered one cycle. Patients are evaluated for tumor response one week after their last dose of every other cycle, starting with Cycle 2. Patients may, at any time, have their dose reduced to 2.0 mg/m 2 if in the investigator's opinion the original dose is either intolerable or unsafe for any given patient, and without such a dose reduction the patient will be forced to withdraw from the study. All dose modifications are captured on the dose administration record CRF. The study period for efficacy evaluation is up to six cycles.
• the study population for this trial consists of androgen-independent prostate cancer patients who have demonstrated evidence of progressive disease.
• Preparation process The pulverised active ingredient is suspended in Lauroglykol ® (propylene glycol laurate, Gattefosse S.A., Saint Priest, France) and ground in a wet pulverizer to a grain size of approximately 1 to 3 ⁇ m. Portions each containing 0.419 g of the mixture are then filled into soft gelatin capsules by a capsule filling machine.
• Lauroglykol ® propylene glycol laurate, Gattefosse S.A., Saint Priest, France
• the compound of example 1 , 2, 3 or 4 is dissolved at a concentration of 1 mg/ml in polyethylene glycol 300 (PEG 300) and filled into 2 ml vials. For infusion, this solution is diluted with 50 to 100 ml of 0.9% saline according to US Pharmacopoeia.
• PEG 300 polyethylene glycol 300

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