Method of administering a cationic liposomal preparation

Abstract

The present invention relates to the use of pharmaceutical preparations comprising paclitaxel for administration to a human patient in need thereof.

Claims

1. A method of treating a human subject suffering from cancer comprising administering to the human subject a pharmaceutical composition comprising a cationic liposomal formulation comprising: at least one cationic lipid from about 30 mole % to about 99.9 mole %, paclitaxel in an amount of at least about 0.1 mole %, and optionally a neutral and/or anionic lipid, wherein the cationic liposomal formulation has a positive zeta potential in about 0.05 M KCI solution at about pH 7.5 at room temperature, wherein the composition is administered at a schedule of: (i) once a week, (ii) twice a week, or (iii) a combination of (i) and (ii), wherein the pharmaceutical composition is administered at a dose of paclitaxel from about 0.05 mg/kg to about 1.88 mg/kg body weight (bw) of the subject, wherein a total monthly dose of paclitaxel administered is from about 0.1 mg/kg to about 15 mg/kg bw of the subject, and wherein the cancer is pancreatic cancer, liver cancer, prostate cancer, breast cancer, lung cancer, gastrointestinal cancer, or melanoma.

2. The method of claim 1, wherein the pharmaceutical composition is administered at a dose of paclitaxel from about 0.25 mg/kg to about 1.54 mg/kg bw of the subject, about 0.25 mg/kg to about 1.25 mg/kg bw of the subject, about 0.25 to about 1.13 mg/kg bw of the subject, about 0.28 to about 1.13 mg/kg bw of the subject, about 0.28 to about 0.94 mg/kg bw of the subject, or about 0.28 mg/kg bw to about 0.75 mg/kg bw of the subject.

3. The method of claim 1, wherein the pharmaceutical composition is administered at a dose of paclitaxel of about 0.28 mg/kg bw of the subject, about 0.56 mg/kg bw of the subject, about 1.13 mg/kg bw of the subject, or about 1.54 mg/kg bw of the subject.

4. The method of claim 1, wherein the total monthly dose is from about 1 mg/kg to about 15 mg/kg bw of the subject, about 0.5 mg/kg to about 7.5 mg/kg bw of the subject, about 1.1 mg/kg to about 6.2 mg/kg bw of the subject, about 1.1 mg/kg to about 4.5 mg/kg bw of the subject, about 2.2 mg/kg to about 6.2 mg/kg bw of the subject, or about 2.2 mg/kg to about 4.5 mg/kg bw of the subject.

5. The method of claim 1, wherein the pharmaceutical composition is administered at a schedule of once a week.

6. The method of claim 1, wherein the method further comprises administering to the human subject at least one further active agent and/or heat and/or radiation and/or cryotherapy.

7. The method of claim 6, wherein the pharmaceutical composition and the at least one further active agent and/or heat and/or radiation and/or cryotherapy are administered simultaneously, separately, or sequentially.

8. The method of claim 6, wherein the further active agent is a chemotherapeutic agent.

9. The method of claim 6, wherein the further active agent is an alkylating agent, a DNA topoisomerase inhibiting agent, a RNA/DNA antimetabolite, an anti-endothelial cell active agent, an anti-tumor active agent, an immunological active agent, or a chemosensitizer.

10. The method of claim 9, wherein the immunological active agent is a compound that reduces or eliminates a hypersensitivity reaction.

11. The method of claim 10, wherein the compound that reduces or eliminates a hypersensitivity reaction is ranitidine, dexamethasone, diphenhydramine, famotidine, hydrocortisone, clemastine, cimetidine, prednisolone, chlorphenamine, dimethindene maleate, or promethazine.

12. The method of claim 9, wherein the chemosensitizer is a cell cycle modulator, a substance that reverts drug resistance, and a vasoactive substance.

13. The method of claim 1, wherein the cationic liposomal formulation comprises paclitaxel in an amount of about 2 mole % to about 8 mole %.

14. The method of claim 13, wherein the cationic liposomal formulation comprises paclitaxel in an amount of about 2.5 mole % to about 3.5 mole %.

15. The method of claim 1, wherein the cationic liposomal formulation comprises 50:47:3 mole % of DOTAP, DOPC, and paclitaxel.

16. The method of claim 1, wherein the cationic liposomal formulation comprises liposomes having an average particle diameter from about 25 nm to about 500 nm, or about 100 nm to about 300 nm.

17. The method of claim 1, wherein the pharmaceutical composition is administered systemically.

18. The method of claim 7, wherein the further active agent is cisplatin, carboplatin, camptothecin, doxorubicin, 5-flurouracil, gemcitabine, thalidomide, discodermolide, laulimalide, isolaulimalide, eleutherobin, sarcodictyin A, or sarcodictyin B.

19. The method of claim 1, wherein the cationic lipid is selected from the group consisting of N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethyl ammonium salt (DOTAP); dimethyldioctadecyl ammonium bromide (DDAB); 1,2-diacyloxy-3-trimethylammonium propane N-[1-(2,3-dioloyloxy)propyl]-N, N-dimethyl amine (DODAP); 1,2-diacyloxy-3-dimethylammonium propane; N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA); 1,2-dialkyloxy-3-dimethylammonium propane; dioctadecylamidoglycylspermine (DOGS); 3β-[N-(N′,N′-dimethylamino-ethane)carbamoyl]cholesterol (DC-Chol); 2,3-dioleoyloxy-N-(2-(sperminecarboxamido)-ethyl)-N, N-dimethyl-1-propanaminium trifluoroacetate (DOSPA); β-alanyl cholesterol; cetyl trimethyl ammonium bromide (CTAB); diC14-amidine; N-tert-butyl-N′-tetradecyl-3-tetradecylamino-propionamidine; 14Dea2; N-(alpha-trimethylammonioacetyl)didodecyl-D-glutamate chloride (TMAG); O,O′-ditetradecanoyl-N-(trimethylammonioacetyl)diethanolamine chloride; 1,3-dioleoyloxy-2-(6-carboxy-spermyl)-propylamide (DOSPER); N,N,N′,N′-tetramethyl-N,N′-bis(2-hydroxylethyl)-2,3-dioleoyloxy-1,4-butanediammonium iodide; 1-[2-(acyloxy)ethyl]-alkyl (alkenyl)-3-(2-hydroxyethyl)-imidazolinium chloride; 1,2-dioleoyl-3-dimethyl-hydroxyethylammonium bromide (DORI); 1,2-dioleyloxypropyl-3-dimethylhydroxyethylammonium bromide (DORIE); 1,2-dioleyloxypropyl-3-dimethylhydroxypropylammonium bromide (DORIE-HP); 1,2-dioleyloxypropy-3-dimethylhydroxybutylammonium bromide (DORIE-HS); 1,2-dioleyloxypropyl-3-dimethylhydroxypentylammonium bromide (DORIE-Hpe); 1,2-dimyristyloxypropyl-3-dimethylhydroxylethylammonium bromide (DMRIE); 1,2-dipalmityloxypropyl-3-dimethylhydroxyethylammonium bromide (DPRIE); 1,2-disteryloxypropyl-3-dimethylhydroxyethylammonium bromide (DSRIE); and 1,2-diacyl-sn-glycerol-3-ethylphosphocholine.

20. The method of claim 19, wherein the 1-[2-(acyloxy)ethyl]2-alkyl (alkenyl)-3-(2-hydroxyethyl)-imidazolinium chloride is 1-[2-(9(Z)-octadecenoyloxy)ethyl]-2-(8(Z)-heptadecenyl-3-(2-hydroxyethyl)-imidazoliniumchloride (DOTIM) or 1[2-(hexadecanoyloxy)ethyl]-2-pentadecyl-3-(2-hydroxyethyl)imidazolinium chloride (DPTIM).

21. The method of claim 1, wherein the neutral lipid is selected from the group consisting of cholesterol, phospholipid, lysolipid, sphingolipid, and pegylated lipid with a neutral charge.

22. The method of claim 21, wherein the neutral lipid is lysophospholipid.

23. The method of claim 1, wherein the neutral lipid is selected from the group consisting of 1,2-diacyl-sn-glycero-3-phosphoethanolamine, 1,2-diacyl-sn-glycero-3-phosphocholine, and sphingomyelin.

24. The method of claim 23, wherein 1,2-diacyl-sn-glycero-3-phosphoethanolamine is 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE).

25. The method of claim 23, wherein 1,2-diacyl-sn-glycero-3-phosphocholine is 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC).

26. The method of claim 1, wherein the cationic liposomal formulation comprises DOTAP, DOPC, and paclitaxel.

27. The method of claim 1, wherein the cationic liposomal formulation further comprises an anionic lipid in an amount of 30 mole % to 55 mole %.

28. The method of claim 9, wherein the RNA/DNA antimetabolite is 5-fluorouracil or gemcitabine.

29. The method of claim 17, wherein the pharmaceutical composition is administered intravenously.

30. The method of claim 1, wherein the pharmaceutical composition is administered for at least one month, at least seven weeks, at least three months, at least four months, at least six months, at least twelve months, or at least 24 months.

31. The method of claim 30, wherein the pharmaceutical composition is administered for up to six months, up to twelve months, up to eighteen months, or up to 24 months.

Description

FIGURE LEGENDS

(1) FIG. 1: Cationic liposomal paclitaxel (EndoTAG®-1) in twice weekly dosing schedule.

(2) Schematic of the dose schedule for twice weekly application of liposomal paclitaxel. Cationic liposomal paclitaxel (EndoTAG®-1) is applied twice weekly (days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 43, and 46) in three different doses: (low dose: 11 mg/m.sup.2 lipid complexed paclitaxel); (medium dose: 22 mg/m.sup.2 lipid complexed paclitaxel); (high dose: 44 mg/m.sup.2 lipid complexed paclitaxel).

(3) FIG. 2: Cationic liposomal paclitaxel (EndoTAG®-1) in a pancreatic cancer study.

(4) Schematic of the dose schedule for twice weekly application of liposomal paclitaxel in combination with gemcitabine (Gemzar®) once weekly. The control group of patients receives 1: gemcitabine monotherapy. The other patients receive gemcitabine in combination with cationic liposomal paclitaxel (EndoTAG®-1) at three doses: 2: gemcitabine+EndoTAG®-1 (low dose: 11 mg/m.sup.2 lipid complexed paclitaxel); 3: gemcitabine+EndoTAG®-1 (medium dose: 22 mg/m.sup.2 lipid complexed paclitaxel); 4: gemcitabine+EndoTAG®-1 (high dose: 44 mg/m.sup.2 lipid complexed paclitaxel).

(5) Gemcitabine is applied at a dose of 1000 mg/m.sup.2 body surface once a week (Mon; =days 4, 11, 18, 25, 32, 39, and 46). Cationic liposomal paclitaxel (EndoTAG®-1) is applied twice weekly (days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 43, and 46).

(6) The following examples should be illustrative only but are not meant to be limiting to the scope of the invention. Other generic and specific configurations will be apparent to those skilled in the art.

EXAMPLES

Example 1

Human Therapy Treatment Protocol

(7) This example is concerned with human treatment protocols using the formulations disclosed. Treatment will be of use preventing and/or treating various human diseases and disorders associated with enhanced angiogenic activity. It is considered to be particularly useful in anti-tumor therapy, for example, in treating patients with solid tumors and hematological malignancies or in therapy against a variety of chronic inflammatory diseases such as rheumatoid arthritis or psoriasis.

(8) A feature of the invention is that several classes of diseases and/or abnormalities may be treated by directly targeting angiogenic epithelial cells without directly targeting the tissue or cells involved in the abnormality, e.g. by inhibiting angiogenesis the blood supply to a tumor is cut off and the tumor is killed without directly targeting the tumor cells in any manner. Other classes of diseases and/or abnormalities may be treated by directly targeting angiogenic endothelial cells and by directly targeting the tissue or cells involved in the abnormality.

(9) In another application, drug resistant cells such as drug resistant cancer cells or highly proliferative synoviocytes in rheumatoid arthritis can be affected directly.

(10) The various elements of conducting a clinical trial, including patient treatment and monitoring, will be known to those skilled in the art in light of the present disclosure.

(11) For regulatory approval purposes, it is contemplated that patients chosen for a study are either anti-neoplastic treatment naive or would have failed to respond to at least one course of conventional therapy and would have objectively measurable disease as determined by physical examination, laboratory techniques, or radiographic procedures. Such patients would also have no history of clinically relevant cardiac or renal disease and any chemotherapy should be stopped at least 2 weeks before entry into the study.

(12) Prior to application, the formulation can be reconstituted in an aqueous solution in the event that the formulation was freeze dried. As outlined above, the required application volume is calculated from the patient's body weight and the dose schedule.

(13) The disclosed formulations may be administered over a short to medium infusion time. The infusion given at any dose level should be dependent upon the toxicity achieved after each. Thus, if Grade II toxicity was reached after any single infusion, or at a particular period of time for a steady rate infusion, further doses should be withheld or the steady rate infusion stopped unless toxicity improved. Increasing doses should be administered to groups of patients until approximately 60% of patients showed unacceptable Grade III or IV toxicity in any category. Doses that are ⅔ of this value would be defined as the safe dose.

(14) Physical examination, tumor measurements and laboratory tests should, of course, be performed before treatment and at intervals of about 3-4 weeks later. Laboratory tests should include complete blood cell counts, serum creatinine, creatine kinase, electrolytes, urea, nitrogen, SGOT, bilirubin, albumin and total serum protein.

(15) Clinical responses may be defined by acceptable measure or changes in laboratory values e.g. tumor markers. For example, a complete response may be defined by the disappearance of all measurable disease for at least a month, whereas a partial response may be defined by a 50% or greater reduction.

(16) All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the composition, methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

(17) Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by the FDA Office of Biologics standards.

(18) The present invention includes a method of delivery of a pharmaceutically effective amount of the inventive formulation of an active agent to a target site such as an angiogenic vascular target site of a subject in need thereof. A “subject in need thereof” refers to a mammal, e. g. a human.

(19) The route of administration preferably comprises peritoneal or parenteral administration.

(20) For use with the present invention the “pharmacologically effective amount” of a compound administered to a subject in need thereof will vary depending on a wide range of factors. The amount of the compound will depend upon the size, age, sex, weight, and condition of the patient, as well as the potency of the substance being administered. Having indicated that there is considerable variability in terms of dosing, it is believed that those skilled in the art can, using the present disclosure, readily determine appropriate dosing by first administering extremely small amounts and incrementally increasing the dose until the desired results are obtained. Although the amount of the dose will vary greatly based on factors as described above, in general, the present invention makes it possible to administer substantially smaller amounts of any substance as compared with delivery systems which only target the pathologic tissue, e. g. target the tumor cells themselves.

Example 2

Twice Weekly Administration Protocol for Cationic Liposomal Paclitaxel (FIG. 1)

(21) Indication: Pancreatic Cancer; adenocarcinoma of the pancreas

(22) Study Design:

(23) A controlled, -three armed, randomized, open label clinical phase II trial 1st line treatment with twice weekly administration of lipid complexed paclitaxel (EndoTAG®-1) in three dose levels compared with gemcitabine monotherapy in patients with measurable locally advanced and/or metastatic adenocarcinoma of the pancreas is performed.

(24) The four treatment arms consist of (see FIG. 1): Arm 1: Gemcitabine monotherapy (control group): 1000 mg/m.sup.2 (=25.67 mg/kg body weight) Arm 2: EndoTAG®-1 (low dose: 11 mg/m.sup.2 (=0.28 mg/kg body weight) lipid complexed paclitaxel) Arm 3: EndoTAG®-1 (medium dose: 22 mg/m.sup.2(=0.56 mg/kg body weight) lipid complexed paclitaxel) Arm 4: EndoTAG®-1 (high dose: 44 mg/m.sup.2 (=1.13 mg/kg body weight) lipid complexed paclitaxel)

(25) Patients with advanced and/or metastatic adenocarcinoma of the pancreas that are considered unresectable are eligible to enter the study after signing informed consent and having undergone baseline evaluation. Those patients meeting study eligibility criteria will either receive a standardized chemotherapy regime (i.e. gemcitabine) as a monotherapy or EndoTAG®-1 infusions. Seven weekly applications of gemcitabine will be administered in arm 1 (gemcitabine monotherapy control arm without EndoTAG®-1). In arms 2, 3 and 4 seven weeks of fourteen twice weekly applications of EndoTAG®-1 (days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 43, and 46) are performed. In summary, one complete cycle of this new regimen comprises fourteen applications of EndoTAG®-1, which then consists of seven weeks (arms 2, 3, and 4).

Example 3

Combination Therapy of Cationic Liposomal Paclitaxel (EndoTAG®-1) Twice Weekly in Combination with Gemcitabine Once Weekly (FIG. 2)

(26) Study No. Indication

(27) CT4001 Pancreatic Cancer; adenocarcinoma of the pancreas

(28) Study Design CT 4001:

(29) A controlled, -four armed, randomized, open label clinical phase II trial 1st line combination treatment with weekly infusions of gemcitabine and twice weekly administration of lipid complexed paclitaxel (EndoTAG®-1) in three single dose levels compared with gemcitabine monotherapy in patients with measurable locally advanced and/or metastatic adenocarcinoma of the pancreas is performed.

(30) The four treatment arms consist of (see FIG. 2): Arm 1: Gemcitabine monotherapy (control group): 1000 mg/m.sup.2 (=25.67 mg/kg body weight) Arm 2: Gemcitabine+EndoTAG®-1 (low dose: 11 mg/m.sup.2 (=0.28 mg/kg body weight) lipid complexed paclitaxel) Arm 3: Gemcitabine+EndoTAG®-1 (medium dose: 22 mg/m.sup.2 (=0.56 mg/kg body weight) lipid complexed paclitaxel) Arm 4: Gemcitabine EndoTAG®-1 (high dose: 44 mg/m.sup.2 (=1.13 mg/kg body weight) lipid complexed paclitaxel)

(31) Patients with advanced and/or metastatic adenocarcinoma of the pancreas that are considered unresectable are eligible to enter the study after signing informed consent and having undergone baseline evaluation. Those patients meeting study eligibility criteria will either receive a standardized chemotherapy regime (i.e. gemcitabine) as a monotherapy or gemcitabine preceded by EndoTAG®-1 infusions. Seven weekly applications of gemcitabine will be administered in arm 1 (gemcitabine monotherapy control arm without EndoTAG®-1). In arms 2, 3, and 4 seven weeks of gemcitabine treatment (days 4, 11, 18, 25, 32, 39, and 46) will be combined with a total of fourteen twice weekly applications of EndoTAG®-1 (days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 43, and 46). In summary, one complete cycle of this new regimen comprises seven applications of gemcitabine (all arms) and fourteen applications of EndoTAG®-1, which then consists of seven weeks (arms 2, 3, and 4).

(32) Conclusion

(33) Treatments with high doses of EndoTAG®-1 can be replaced by using low doses at a higher frequency. There is a correlation between treatment density (no. of treatments per week) and treatment efficacy. The optimised dosing regimen potentially reduces toxic side effects caused by high dose treatments and reduces physical burden of the patient, which leads to an improved quality of life.

Example 4

Treatment of Liver Cancer (Hepatocellular Carcinoma)

(34) Study Design:

(35) A controlled, two-armed, randomized, open label clinical phase II trial, comparing TACE therapy only to TACE (transarterial chemoembolization) therapy combined with once weekly administration of lipid complexed paclitaxel (EndoTAG®-1) is performed.

(36) The two treatment arms consist of: Arm 1: TACE therapy alone (control group); Arm 2: TACE therapy in combination with once weekly EndoTAG®-1 (44 mg/m.sup.2 lipid complexed paclitaxel).

(37) Patients with irresectable histological/cytological proven hepatocellular carcinoma (HCC) who have shown responsiveness to TACE therapy are eligible to enter the study after signing informed consent and having undergone baseline evaluation. Those patients meeting study elegibility criteria are randomized and either receive TACE therapy or TACE therapy in combination with a once a week administration of 44 mg/m.sup.2 EndoTAG®-1, an interim analysis determining progression or response based on DCE-MRI and MRI scans is performed. Progression-free-survival (PFS) is determined as the primary efficacy parameter in the study.

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