WO2002002078A2 - Improved liposomal camptothecins and uses thereof - Google Patents
Improved liposomal camptothecins and uses thereof Download PDFInfo
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- WO2002002078A2 WO2002002078A2 PCT/CA2001/000981 CA0100981W WO0202078A2 WO 2002002078 A2 WO2002002078 A2 WO 2002002078A2 CA 0100981 W CA0100981 W CA 0100981W WO 0202078 A2 WO0202078 A2 WO 0202078A2
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- 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—Liposomes
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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
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- 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
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- 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—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
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- 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—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
- A61K9/1278—Post-loading, e.g. by ion or pH gradient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- This invention relates to improved liposomal camptothecin compositions and methods of manufacturing and using such compositions for treating neoplasia and for inhibiting angiogenesis.
- camptothecins such as Topotecan (9- dimethylaminomethyl-10-hydroxy-camptothecin; HycamtinTM), and Irinotecan, are a semi- synthetic, water soluble derivative of camptothecin, an alkaloid extracted from the stem wood of the Chinese tree Camptotheca acuminata (Wall, et al, J. Am. Chem. Soc. 88:3888-3890 (1966)). Camptothecins belong to the topoisomerase inhibitor class of antineoplastic agents, specifically inhibiting the action of the nuclear enzyme topoisomerase I which is involved in DNA replication (Hsiang, et al., Cancer Res. 48:1722-1726 (1988)).
- topotecan exhibits a cell cycle-specific mechanism of action, acting during S-phase (DNA replication) to cause irreversible double strand breaks in DNA that ultimately lead to G2 cell cycle arrest and apoptosis.
- the drug has a broad spectrum of activity against a range of tumor cell lines and murine allograft and human xenograft tumor models (McCabe, F. L. et al, Cancer Invest 12:308-313 (1994); Emerson, et al, Cancer Res. 55:603-609 (1995); Thompson, Biochim. Biophys.
- topotecan has been approved for second-line therapy in ovarian and small cell lung cancer (SCLC) and is currently the focus of extensive clinical evaluation.
- SCLC ovarian and small cell lung cancer
- Lipid formulations of camptothecins have been proposed as therapeutic agents (see, U.S. Patent No. 5,552,156 and PCT Publication No. WO 95/08986.
- not all lipid formulations are equal for drug delivery purposes and extensive research continues into formulations which demonstrate preferred characteristics for drug loading and storage, drug administration, pharmacokinetics, biodistribution, leakage rates, tumor accumulation, toxicity profile, and the like.
- camptothecins the field is further complicated because dose limiting toxicities in humans may be 10-fold lower than in mice (Erickson-Miller, et al, Cancer Chemother. Pharmacol 39:467-472 (1997)).
- camptothecins are a promising class of anti-neoplastic agents, and lipid formulations of these drugs could prove very useful.
- lipid formulations have not provided sufficiently remarkable activity to warrant clinical advancement. It is an object of the instant invention to provide novel lipid formulated camptothecins having novel clinical utility.
- the present invention provides improved liposomal camptothecin (e.g. , topotecan) compositions having surprisingly increased clinical efficacy and decreased collateral toxicity.
- the present invention provides methods of using such liposomal camptothecin compositions to treat neoplasia and to inhibit angiogenesis.
- the present invention provides a liposomal camptothecin unit dosage form comprising a camptothecin dosage of from about 0.015 mg/M ⁇ /dose to about 1 mg/M 2 /dose and a lipid, wherein the liposomal camptothecin unit dosage form has a drug:lipid ratio (by weight) of about 0.005 to about 0.01.
- the unit dosage form comprises a camptothecin dosage of from about 0.15 mg/M 2 /dose to about 0.5 mg/M 2 /dose.
- the present inveniton provides a liposomal topotecan unit dosage form is about 0.01 mg/M 2 /dose to about mg/M 2 /dose and a lipid and having a drug ipid ratio (by weight) of about 0.05 to about 0.2.
- the drug:lipid ratio (by weight) is about 0.05 to about 0.15.
- the liposomal topotecan unit dosage form is about 1 mg/M /dose to about 4 mg/M 2 /dose of topotecan.
- the present invention provides liposomal topotecan unit dosage forms.
- the lipid comprises a mixture of sphingomyelin and cholesterol, preferably at a spingomyelin: cholesterol ratio (by weight) of about 30:70 to about 60:40.
- the present invention provides a liposomal camptothecin (e.g., topotecan) formulation, wherein the formulation retains greater than 50% of the camptothecin as the active lactone species after 12 hours in blood circulation. In a preferred embodiment, the formulation retains greater than 80% of the camptothecin as the active lactone species after 12 hours in blood circulation.
- the present invention provides a lipid formulation of a camptothecin (e.g. , topotecan), comprising a camptothecin, sphingomyelin, cholesterol and a divalent ionophore, such as a divalent cation ionophore.
- the divalent ionophore is present in trace amounts. In another preferred embodiment, the ionophore is present in greater than trace amounts.
- the present invention provides a method of treating a solid tumor in a human afflicted therewith, the method comprising administering to the human an effective amount of a liposomal camptothecin unit dosage form in a pharmaceutically acceptable carrier.
- a liposomal camptothecin unit dosage form in a pharmaceutically acceptable carrier.
- the solid tumor to be treated is selected from the group consisting of solid tumors of the lung, mammary, colon and prostate.
- the method further comprises co-administration of a treatment or active agent suitable for treating neutropenia or platelet deficiency.
- the camptothecin dosage in the liposomal camptothecin unit dosage form ranges from 0.015 mg/M 2 /dose to about 1 mg/M 2 /dose.
- the liposomal camptothecin unit dosage form has a drug:lipid ratio (by weight) of about 0.005 to about
- the unit dosage form comprises a camptothecin dosage of from about 0.15 mg/M /dose to about 0.5 mg/M /dose.
- camptothecin dosage of from about 0.15 mg/M /dose to about 0.5 mg/M /dose.
- a liposomal topotecan unit dosage form is used to treat the solid tumors.
- any of a variety of lipids can be used to form the liposomal compositions of the present invention.
- the liposomal unit dosage form comprises a mixture of sphingomyelin and cholesterol, preferably at a spingomyelin-.cholesterol ratio (by weight) of about 30:70 to about 60:40.
- FIG. 1 Pharmacokinetics and drug leakage of topotecan encapsulated in SM/CH vesicles.
- Topotecan was encapsulated in 100 nm SM/CH (55/45 mol/mol) vesicles using the Mg-A23187 ionophore method as described in the Example section.
- Topotecan was assayed by a fluorescence assay (see, the Example section) and lipid was determined through the incorporation of a lipid marker, [ H]-CHE. Data points represent the mean ⁇ SD of 4 mice.
- the SM/CH formulation prepared by the Mn-A23187 ionophore method is included in the bottom panel for comparison (from Tardi et al, Cancer Res., 2000 submitted).
- FIG. 14 Figure 2. Influence of mouse strain, dose schedule and hposome- encapsulation on topotecan tolerability in mice.
- Balb/c mice (CT-26); Single Dose (A); NCr nude mice. (LX-1); Single Dose (B); NCr nude mice (MX-1); q3dx4 (C); and NCr nude mice (MX-1); q7dx3 (D).
- FIG. 3 Efficacy of free (A) and encapsulated (B) topotecan in an intravenous L1210 murine leukemia model - single dose.
- L1210 cells (10 5 cells in 200 ⁇ l) were injected i.v. into the tail vein of BDF-1 mice on day 0.
- Topotecan was encapsulated in SM:CH (55:45) vesicles at a drug-to-lipid ratio of 0.10 (w/w) using the Mg-A23187 method as described in Experimental. All dilutions were made in sterile 0.9% saline immediately prior to injection. Drug administration was made via the lateral tail vein at 1 day post-tumor cell injection. Each group consisted of 8 animals.
- FIG. 7 Efficacy of free and encapsulated topotecan in subcutaneous MX-1 xenografts - q3dx4 schedule.
- Topotecan was encapsulated in SM:CH (55:45) vesicles at a drug-to-lipid ratio of 0.10 (w/w) using the Mg-A23187 method as described in Experimental. All dilutions were made in sterile 0.9% saline immediately prior to injection.
- Liposome, vesicle and liposome vesicle will be understood to indicate structures having lipid-containing membranes enclosing an aqueous interior.
- the structures can have one or more lipid membranes unless otherwise indicated, although generally the liposomes will have only one membrane.
- Such single-layered liposomes are referred to herein as "unilamellar.”
- Multilayer liposomes are referred to herein as "multilamellar.”
- the liposomes that are used in the present invention are preferably formed from lipids which when combined form relatively stable vesicles. An enormous variety of lipids are known in the art which can be used to generate such liposomes.
- Preferred lipids include, but are not limited to, neutral and negatively charged phospholipids or sphingolipids and sterols, such as cholesterol.
- the selection of lipids is generally guided by consideration of, e.g., liposome size and stability of the liposomes in the bloodstream.
- Preferred liposome compositions for use in the present invention include those comprising sphingomyelin and cholesterol.
- the ratio of sphingomyelin to cholesterol in the liposome composition can vary, but generally is in the range of from about 75/25 mol %/mol % sphingomyelin/cholesterol to about 30/50 mol %/mol % sphingomyelin/cholesterol, more preferably about 70/30 mol %/mol % sphingomyelin cholesterol to about 40/45 mol %/mol % sphingomyelin/cholesterol, and even more preferably about 55/45 mol %/mol % sphingomyelin/cholesterol.
- lipids can be included in the liposome compositions of the present invention as may be necessary, such as to prevent lipid oxidation or to attach ligands onto the liposome surface. Generally, if lipids are included, the other inclusion of such lipids will result in a decrease in the sphingomyelin/cholesterol ratio. Liposomes of this type are known as sphingosomes and are more fully described in U.S. Patent No. 5,814,335, the teachings of which are incorporated herein by reference.
- the protocol for generating liposomes generally includes: mixing of lipid components in an organic solvent; drying and reconstituting liposomes in aqueous solvent; and sizing of liposomes (such as by extrusion), all of which are well known in the art.
- Preparation of liposomal camptothecins requires loading of the drug into the liposomes. Loading can be either passive or active. Passive loading generally requires addition of the drug to the buffer at the time of the reconstitution step. This allows the drug to be trapped within the liposome interior, where it will remain if it is not lipid soluble, and if the vesicle remains intact (such methods are employed, for example, in PCT Publication No. WO 95/08986, the teachings of which are incorporated herein by reference).
- Active loading is in many ways preferable, and a wide variety of therapeutic agents can be loaded into liposomes with encapsulation efficiencies approaching 100%) by using a transmembrane pH or ion gradient (see, Mayer, et al, Biochim. Biophys. Ada 1025:143-151 (1990) and Madden, et al, Chem. Phys. Lipids 53:37-46 (1990)).
- Numerous ways of active loading are known to those of skill in the art. All such methods involve the establishment of some form of gradient that draws lipophilic compounds into the interior of liposomes where they can reside for as long as the gradient is maintained. Very high quantities of the desired drug can be obtained in the interior, so much that the drug may precipitate out on the interior and generate a continuing uptake gradient.
- ionophore mediated loading as disclosed and claimed in U.S. Patent No. 5,837,282, the teachings of which are incorporated by reference herein. Basically, this method employs an ionophore in the liposome membrane to drive the generation of a pH gradient from a previously existing monovalent or divalent ion gradient.
- Drug:lipid ratios can be established in two ways: 1) using homogenous liposomes each containing the same drug:lipid ratio; or 2) by mixing empty liposomes with liposomes having a high drug:lipid ratio to provide a suitable average drug:lipid ratio. For different applications, different drug:lipid ratios may be desired. Techniques for generating specific drug:lipid ratios are well known in the art. Drug:lipid ratios can be measured on a weight to weight basis, a mole to mole basis or any other designated basis. Preferred drug:lipid ratios range from about .005 drug:lipid (by weight) to about .2 drug:lipid (by weight) and, more preferably, from about .01 drug:lipid (by weight) to about .02 drug:lipid (by weight).
- a further important characteristic is the size of the liposome particles.
- liposomes having a size of from about 0.05 microns to about 0.15 microns are preferred.
- the present invention also provides liposomal camptothecin compositions in kit form.
- the kit can comprise a ready-made formulation, or a formulation which requires mixing of the medicament before administration.
- the kit will typically comprise a container that is compartmentalized for holding the various elements of the kit.
- the kit will contain the liposomal compositions of the present invention or the components thereof, possibly in dehydrated form, with instructions for their rehydration and administration
- compositions prepared, for example, by the methods described herein can be administered either alone or in a mixture with a physiologically- acceptable carrier (such as physiological saline or phosphate buffer) selected in accordance with the route of administration and standard pharmaceutical practice.
- physiologically- acceptable carrier such as physiological saline or phosphate buffer
- suitable carriers include, e.g., water, buffered water, 0.4% saline, 0.3%> glycine, and the like, including glycoproteins for enhanced stability, such as albumin, lipoprotein, globulin, etc.
- These compositions may be sterilized by conventional, well known sterilization techniques.
- compositions may be packaged for use or filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration.
- the compositions may also contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, etc.
- the composition may include lipid-protective agents which protect lipids against free-radical and lipid-peroxidative damages on storage. Lipophilic free-radical quenchers, such as ⁇ .- tocopherol and water-soluble iron-specific chelators, such as ferrioxamine, are suitable. [35] Exemplary methods of making specific formulations of liposomal camptothecins and, in particular, liposomal topotecan are set out in the examples below.
- Liposomal camptothecins are used, according to this invention, in the treatment of solid tumors in an animal, such as a human.
- the examples below set out key parameters of the drug ipid ratios, dosages of camptothecin and lipid to be administered, and preferred dose scheduling to treat different tumor types.
- the pharmaceutical compositions are administered parenterally, i.e., intraarticularly, intravenously, intraperitoneally, subcutaneously or intramuscularly. More preferably, the pharmaceutical compositions are administered by intravenous drip or intraperitoneally by a bolus injection.
- the concentration of liposomes in the pharmaceutical formulations can vary widely, i.e., from less than about 0.05%, usually at or at least about 2-5% to as much as 10 to 30% by weight and will be selected primarily by fluid volumes, viscosities, etc. , in accordance with the particular mode of administration selected. For example, the concentration can be increased to lower the fluid load associated with treatment. Alternatively, liposomes composed of irritating lipids can be diluted to low concentrations to lessen inflammation at the site of administration.
- the amount of liposomes administered will depend upon the particular camptothecin used, the disease state being treated and the judgement of the clinician, but will generally, in a human, be between about 0.01 and about 50 mg per kilogram of body weight, preferably between about 5 and about 40 mg/kg of body weight. Higher lipid doses are suitable for mice, for example, 50 - 120 mg/kg.
- Dosage for the camptothecin will depend on the administrating physician's opinion based on age, weight, and condition of the patient, and the treatment schedule.
- a recommended dose for free topotecan in Small Cell Lung Cancer is 1.5 mg/M 2 per dose, every day for 5 days, repeated every three weeks. Because of the improvements in treatment now demonstrated in the examples, below, doses of topotecan in liposomal topotecan in humans will be effective at ranges as low as from 0.015 mg/M 2 /dose and will still be tolerable at doses as high as 15 to 75 mg/M 2 /dose, depending on dose scheduling.
- Doses may be single doses or they may be administered repeatedly every 4h, 6h, or 12h or every Id, 2d, 3d, 4d, 5d, 6d, 7d, 8d, 9d, lOd or combination thereof.
- Preferred scheduling may employ a cycle of treatment that is repeated every week, 2 weeks, three weeks, four weeks, five weeks or six weeks or combination thereof.
- treatment is given once a week, with the dose typically being less than 1.5 mg/M 2 .
- the interval regime is at least once a week.
- interval regime is at least once every two week, or alternatively, at least once every three weeks.
- Topotecan was encapsulated in SM:CH (55:45, mol/mol) liposomes using the Mg-A23187 ionophore method according to U.S. Patent No. 5,837,282.
- the initial drug-to-lipid ratio was 0.10 (w/w) and drug loading was typically 95-100%.
- the external buffer consisted of 10 mM PBS, pH 7.5 and 300 mM sucrose. All formulations were analyzed with respect to particle size, drug loading efficiency, pH, and drug and lipid concentration. [44] 4. Drug preparation and dosing.
- Each vial of topotecan was encapsulated in SM:CH (55:45, mol/mol) liposomes using the Mg-A23187 ionophore method according to U.S. Patent No. 5,837,282.
- the initial drug-to-lipid ratio was 0.10 (w/w) and drug loading was typically 95-100%.
- the external buffer consisted of 10 mM PBS, pH
- HycamtinTM (HycamtinTM) was hydrated in 1.0 ml of sterile water, giving a topotecan concentration of 4.0 mg/ml. Subsequent dilutions were ⁇ l made in 0.9% sterile saline to maintain the low pH required for the lactone species of the drug. Unused drug in the water stock solution (4.0 mg/ml) was stored at 4°C in the absence of light. Liposome encapsulated topotecan was diluted in 0.9% saline to the required concentration for administration. All drug administrations were at 10 ml/kg (200 ⁇ l/20 g mouse) via the lateral tail vein.
- Total topotecan in blood was determined by a fluorescence assay preceded by precipitation of plasma proteins. Topotecan was quantified by spectrofluorimetry at an excitation (2.5 nm slit width) and emission wavelength (2.5 nm slit width) of 380 and 518 nm, respectively. Lipid levels in plasma were determined by liquid scintillation counting of the [ 3 H]-CHE label. [46] 6. MTD studies. MTD studies were performed in the host mouse strain corresponding to each tumor model. Single dose and multidose MTD were determined by monitoring weight loss over time. The MTD was defined as the dose that resulted in 20% weight loss.
- CT-26 murine colon metastases model were employed as in standard protocols.
- Human MX- 1 and LX-1 cell lines were obtained fro the.
- DCTD-Tumor -Repository in Frederick,- MD. These cell lines were received as tumor fragments and were propagated in NCr nude mice by serial transplantation of 3 x 3 mm fragments. Experiments were not initiated until the cell lines had been through 3 passages in nude mice and the tumor lines were restarted when the passage number reached 10.
- therapeutic index is defined as:
- MTD MTD/MED.
- MTD the maximum tolerated dose, defined as that dose that causes a mean weight loss of 20%> in a group of animals
- MED is the minimal effective dose, defined as the dose that produces an optimal %T/C value of ⁇ 40 in the solid tumor models or an %>ILS of 50 + 10% in the survival models.
- Liposomal topotecan has been shown to exhibit exceptional anti-tumor activity, even at very low drug doses (0.5 mg/kg; drug-to-lipid ratio, 0.10, wt/wt). At these drug doses and drug-to-lipid ratio, liposome elimination from the plasma is expected to be rapid. Therefore, to determine whether the pharmacokinetics of topotecan at low doses could be improved, a low drug-to- lipid ratio (0.02, wt/wt) formulation of topotecan was investigated. Interestingly, in this study, the low drug-to-lipid ratio formulation released the drug much faster than the higher drug-to-lipid ratio (0.11, wt wt) formulation. This result was unexpected.
- humans are more sensitive than mice to myelosuppression and can only tolerate 11% of the MTD in mice (1.5 vs 14 mg/M 2 ).
- dogs have been shown to be a much better predictor of topotecan myelosuppression in humans (Burris, et al, J. Natl. Cancer Inst. 84:1816-1820 (1992)).
- mice should be suitable for comparing the relative myelosuppressive effects of free and liposome encapsulated topotecan.
- L1210 Murine Leukemia The intravenous L1210 murine leukemia model has been used extensively to evaluate differential activity between free and liposome encapsulated chemotherapeutic agents and was one of the original (1955-1975) models in the in vivo NCI screen of novel chemotherapeutic agents (Plowman, et al, Human tumor xenograft models in NCI drug development. In "Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval” (B. Teicher, Ed), Humana Press Inc., Totowa (1997); Waud, Murine L1210 andP388 leukemias.
- CT-26 Murine Colon Carcinoma The murine CT-26 colon cell line is useful for drug screening since it readily grows as subcutaneous solid tumors or can be administered intravenously and used as a survival model.
- the tumor cells are administered by intrasplenic injection, followed by splenectomy, the cells seed to the liver and give rise to an experimental metastases model that more closely resembles the clinical progression of colorectal cancer.
- the model has been used extensively and is described, for example, in detail elsewhere.
- MX-1 Human Breast Carcinoma.
- MX-1 is an experimental model of human breast cancer and has a reported doubling time of 3.9 days (NCI); in this study, the median doubling time was consistently 3.6-3.7 days.
- the tumor cell line was derived from the primary tumor of a 29-year-old female with no previous history of chemotherapy and is provided by the DCTD (NCI) tumor repository as a tumor fragment that is serially passaged in nude mice. Histologically, MX-1 is a poorly differentiated mammary carcinoma with no evidence of gland formation or mucin production.
- MX-1 was one of 3 xenograft models (MX-1, LX-1, CX-1) that comprised the NCI in vivo tumor panel and prescreen (1976-1986) for evaluating novel chemotherapeutic agents (Plowman, et al, Human tumor xenograft models in NCI drug development.
- MX-1 has been incorporated into a larger panel of breast tumor models (12 in total) to reflect a shift in NCI strategy from "compound- oriented" discovery to "disease-oriented” discovery.
- staged (100-300 mm ) MX-1 tumors free topotecan exhibited dose- dependent inhibition of tumor growth (see, Figure 5; Table I).
- At the highest dose (40 mg/kg) an optimal % T/C of 24% was obtained; while optimal % T/C values for 10 and 5 mg/kg were 66% and 78%, respectively.
- %T/C Liposome encapsulation of topotecan had a marked impact on %T/C, with optimal %T/C values of 8%, -49%> and -62% following a single administration of the drug at 2, 5 or 10 mg/kg, respectively.
- a negative % T/C value is indicative of tumor volume regression from the original staged tumor size (100-300 mm 3 ).
- an optimal %> T/C ⁇ 10%> is considered significant activity, while values ⁇ 42% are the minimum acceptable limits for advancing a drug further in development (Corbett, T. et al, In vivo methods for screening and preclinical testing.
- Liposome encapsulation increased the toxicity of topotecan, reducing the MTD to 10 mg/kg from > 40 mg/kg for free topotecan.
- LX-1 Human Lung Carcinoma.
- LX-1 is an experimental model of human small cell lung cancer (SCLC).
- SCLC small cell lung cancer
- the tumor cell line was derived from the surgical explant of a metastatic lesion found in a 48 year old male and is provided by the DCTD (NCI) tumor repository as a tumor fragment that is serially passaged in nude mice.
- the LX-1 model was part of the NCI in vivo tumor panel from 1976-1986 (Plowman, J. et al , Human tumor xenograft models in NCI drug development. In "Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval" (B. Teicher, Ed), Humana Press Inc., Totowa (1997)) and, although used less frequently now, remains a useful xenograft model for comparative activity studies between free and liposomal drugs because of its rapid growth rate.
- the LX-1 model was less sensitive to the effects of topotecan than the MX-1 model, for both free and liposome-encapsulated drug (see, Figure 6; Table I).
- Optimal % T/C values for free topotecan were 43%, 55%> and 67%> for doses of 30, 10 or 5 mg/kg, respectively.
- Anti-tumor activity was improved through encapsulation, resulting in %T/C values of 8%, 11% and 13% for doses of 30, 10, or 5 mg/kg, respectively.
- all of the liposomal topotecan doses exhibited similar activity. This was an early study and subsequent studies in other models (see, Figures 4-6) indicate dose response beginning at doses ⁇ 5 mg/kg.
- camptothecin-class compounds can exhibit "self-limiting" efficacy whereby, at doses above a critical threshold dose, no further activity benefits are observed (Thompson, Biochim. Biophys. Ada 1400:301-319 (1998)). This situation could conceivably occur if the drug has limited tumor cell access or if the drug is acting on, and destroying, the tumor vasculature (i.e., has anti-angiogenic activity). In both instances, a higher dose of drug would be expected to have negligible benefit.
- MX-1 Human Breast Carcinoma To address the effectiveness of multiple administration and prolonged exposure of the tumors to drug, two multiple dose protocols were examined in MX-1 xenografts - q3dx4 and q7dx3 schedules. On the q4dx3 schedule, free topotecan exhibited moderate activity at 2.5 and 10 mg/kg/dose and minimal activity at 1.25 mg/kg/dose (see, Figure 7; Table II). Optimal % T/C values for free topotecan on this dosing schedule were 55%>, 30% and 27% for 1.25, 2.5 and 10 mg/kg/dose, respectively.
- % T/C values were - 15%, - 100%, - 100%, and - 100% for 0.5, 1.25, 2.5 and 5 mg/kg dose, respectively. All regressed tumors were monitored for 60 days. At the end of this period, all animals treated with > 1.25 mg/kg/dose of liposomal topotecan were considered tumor free.
- CT-26 (murine colon) i.s. single 1.0 (1.5) b 5.0 5 (3.3) b
- Topotecan is an excellent candidate for liposome encapsulation. Briefly, topotecan is cell-cycle specific (S-phase) and activity is greatly enhanced with prolonged exposure, topotecan exhibits rapid plasma pharmacokinetics and the drug needs to be maintained below pH 6.0 to retain biological activity. This is an ideal scenario for using a relatively non-leaky liposome formulation (such as SM:CH, 55:45) that has an acidic aqueous core. The required acidic interior can be produced, for example, by pH-loading or ionophore loading methodology.
- Therapeutic index (TI) is a useful parameter of drug activity, as it is measure of the ratio of toxicity (MTD) to biological activity (user defined endpoint, i.e., MED, ED 50 , or ED 80 ). In general, the lower the TI, the greater the risk of toxicity since the dose of drug required to elicit a biological effect approaches the MTD. Therapeutic index is particularly useful for the evaluation of liposomal drugs since the relative change in TI can be used to define the benefit (or lack thereof) of encapsulation. As demonstrated herein, the TI improved from 3-18 fold depending on the model and dose schedule used. Therefore, the improvement in biological activity observed following liposome encapsulation of topotecan more than compensates for any increases in toxicity.
- the lactone plasma concentration for liposomal drug was 5.4 ⁇ g/ml compared to 1.5 ⁇ g/ml at 5 minutes for free drug - still 3.5 -fold greater than the peak lactone concentration for free topotecan.
- TCS 30 8 9.9 22 0.93 0/6 4/6 - 29.0
- DRD Drug-related death A death was considered drug-related if the animal died or was euthanized within 15 days following the final treatment with drug AND its tumor weight was less than the lethal burden on control mice, or its weight loss was greater than 20%> that of the control animals.
- T and T 0 are the optical densities at 48 and 0 h, respectively;
- C is the control (cell count) optical density at 0 h.
- % ILS Increase in lifespan (in percent). For survival models this is calculated using the median survival times for the treated (Tu-ea t ) and control (T con t) animals, according to:
- Net log cell kill can be calculated by subtracting the duration of treatment from the tumor growth delay (T - C) parameter as follows:
- a log cell kill of 0 indicates that the cell population at the end of treatment is the same as it was at the onset of treatment. However, a log cell kill of 4, for example, indicates a 99.99% reduction in the initial cell population.
- MBWL Maximum body weight loss (in percent). The animals are weighed prior to the first administration of the drug (Wi) and on various days during the study (Wd). The percent change in body weight is calculated by:
- % T/C range -50 to -100 4 % T/C range -50 to -100 and > 30% tumor-free mice
- TGD Tumor growth delay (also represented as T - C). This parameter expresses the difference in time (in days) for treated and control tumors to attain an arbitrary size (typically 500 or 1000 mm 3 ).
- Therapeutic index is the ratio of a toxicity parameter (i.e. LD 50 , LD I Q, MTD) and a biological activity parameter (i.e. ED 50 - the dose that causes a defined biological response in 50% of the treatment group).
- a toxicity parameter i.e. LD 50 , LD I Q, MTD
- a biological activity parameter i.e. ED 50 - the dose that causes a defined biological response in 50% of the treatment group.
- TI describes the margin of safety for a drug. For animal model studies this is traditionally described by the formula:
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CA2412795A CA2412795C (en) | 2000-06-30 | 2001-06-29 | Improved liposomal camptothecins and uses thereof |
EP01949169A EP1299085B1 (en) | 2000-06-30 | 2001-06-29 | Improved liposomal camptothecins and uses thereof |
DE60115045T DE60115045T2 (en) | 2000-06-30 | 2001-06-29 | IMPROVED LIPOSOMAL CAMPTOTHECINE AND ITS USES |
AU2001270413A AU2001270413A1 (en) | 2000-06-30 | 2001-06-29 | Improved liposomal camptothecins and uses thereof |
AT01949169T ATE309787T1 (en) | 2000-06-30 | 2001-06-29 | IMPROVED LIPOSOMAL CAMPTOTHECINS AND USES THEREOF |
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PCT/CA2001/000925 WO2002002077A2 (en) | 2000-06-30 | 2001-06-29 | Liposomal antineoplastic drugs and uses thereof |
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