CONTINUOUS DELIVERY OF LENALIDOMID

Description

TECHNICAL FIELD

[0001] The present subject matter generally relates to lenalidomide for use in a method of treating multiple myeloma, the method comprising continuous delivery of lenalidomide to a subject in need thereof. Surprisingly, this method of continuous delivery improved anti-cancer activity of the drug with reduced toxicities (such as neutropenia) when compared with a standard pulsatile dosing regimen.BACKGROUND

[0002] Immunomodulatory imide compounds include thalidomide and thalidomide analogues (collectively the thalidomide family of compounds), which possess pleiotropic anti-myeloma properties including immune-modulation, anti-angiogenic, anti-inflammatory and antiproliferative effects. The thalidomide analogues include lenalidomide, pomalidomide, iberdomide, and apremilast.

[0003] Lenalidomide (3-(4-amino-1-3-dihydro-1-oxo-2H-isoindol-2yl)-2,6-piperidinedione), as shown in Formula I below, is an FDA approved drug which is available in the form of an oral capsule. Lenalidomide is indicated, for example, for treatment of patients with multiple myeloma (MM) in combination with dexamethasone, MM as maintenance following autologous hematopoietic stem cell transplantation (auto-HSCT), transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities, mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib, previously treated follicular lymphoma (FL) in combination with a rituximab product, or previously treated marginal zone lymphoma (MZL) in combination with a rituximab product. Lenalidomide is available in an oral dosing form in strengths of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg.

[0004] Pomalidomide (4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione), shown as Formula II below, is also a FDA approved drug, which is available in the form of oral capsules. Pomalidomide, is typically used, often in combination with dexamethasone, for patients with multiple myeloma who have received prior therapy (such as lenalidomide) and have demonstrated disease progression upon completion (or shortly thereafter) of the last therapy. Pomalidomide is available in an oral dosage form at strengths of 1mg, 2mg, 3mg, and 4mg.

[0005] Thalidomide (2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione) shown as Formula III below, is a FDA approved drug, which is available in the form of oral capsules. Thalidomide, is typically used, often in combination with dexamethasone, for the treatment of patients with newly diagnosed multiple myeloma. Thalidomide is available in an oral dosage form at strengths of 50 mg, 100 mg, 150 mg, and 200 mg.

[0006] Apremilast (N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide) shown as Formula IV below, is a FDA approved drug, which is available in the form of tablets. Apremilast is indicated for the treatment of patients with active psoriatic arthritis. Apremilast is available in an oral dosage form at strengths of 10,mg, 20mg, and 30 mg.

[0007] Iberdomide ((3S)-3-[7-[[4-(morpholin-4-ylmethyl)phenyl]methoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione), which is shown below as Formula V, is under development for treating refractory multiple myeloma. Bruno Gonçalves Pereira et al disclose "Evaluation of the effects of thalidomide-loaded biodegradable devices in solid Ehrlich tumor", in BIOMEDICINE AND PHARMACOTHERAPY., vol. 67, no. 2, 1 March 2013 (2013-03-01), FR, pages 129 - 132, XP055709198, ISSN: 0753-3322, DOI: 10.1016 / j.biopha.2012.08.006 Mandac Inga et al disclose "Lenalidomide induced good clinical response in a patient with multiple relapsed and refractory Hodgkin's lymphoma", in JOURNAL OF HEMATOLOGY & ONCOLOGY, BIOMED CENTRAL LTD, LONDON UK, vol. 3, no. 1, 28 May 2010 (2010-05-28), pages 20, XP021083346, ISSN: 1756-8722, DOI: 10.1186 / 1756-8722-3-20 WO2005046593 discloses continuous oral and intravenous infusion of thalidomide to treat multiple myeloma. WO2018138737 discloses topical administration of apremilast and PEG 400 for use in treating skin cancers and inflammation. BRIEF SUMMARY

[0008] Provided is an immunomodulatory imide compound comprising lenalidomide for use in a method of treating multiple myeloma, the use comprising: continuously administering to a subject in need of the treatment a formulation comprising the immunomodulatory imide compound and a pharmaceutically acceptable carrier, wherein the use further comprises continuously administering the formulation to the subject via subcutaneous infusion; and wherein the pharmaceutically acceptable carrier comprises water and PEG 400 at a ratio of 5:1 (v / v).

[0009] According to certain embodiments, the immunomodulatory imide compound is present in the range of 0.01%-95%w / w of the total weight of the formulation.

[0010] According to embodiments provided herein, a continuous delivery platform comprises a formulation consisting of a liquid formulation. The embodiments are intended to be formulated to provide a continuous, sustained delivery to mitigate the peak and valley pharmacokinetic behavior associated with standard immediate release oral delivery forms.

[0011] In liquid embodiments, the formulation is selected from the group consisting of solutions, dispersions, suspensions, emulsions which includes micro-emulsions, nano-emulsions, self-emulsifying, depot preparations, or micelles.

[0012] In some embodiments, the method comprises administering the immunomodulatory imide compound continuously to a subject at a predetermined hourly rate for a predetermined number of days.BRIEF DESCRIPTION OF FIGURES

[0013] FIG. 1 demonstrates the tumor volume as a function of time, in days post continuous administration of lenalidomide at a various hourly rate (µg / h) comparing with a vehicle and intraperitoneal injection of lenalidomide once a day. FIG. 2 demonstrates the body weight as a function of time, in days post continuous administration of lenalidomide at various hourly rate (µg / hour) comparing with a vehicle and intraperitoneal injection of lenalidomide once a day. FIG. 3 and 4 demonstrates plasma concentration of lenalidomide 25 mg daily oral dose compared to three continuous delivery rates. FIG. 5 demonstrates plasma concentration of lenalidomide 10 mg daily oral dose compared to three continuous delivery rates. FIG. 6 demonstrates plasma concentration of lenalidomide 5 mg daily oral dose compared to three continuous delivery rates. FIG. 7 is a Kaplan-Meier Plot displaying the survival percentages of mice xenografted with multiple myeloma as a function of time, in days post continuous administration of lenalidomide at various hourly rate (µg / hour) comparing with a vehicle and intraperitoneal injection of lenalidomide once a day. DETAILED DESCRIPTION

[0014] As used herein, the term "pharmaceutically acceptable salts" includes acid addition salts or addition salts of free bases. The term "pharmaceutically acceptable salts" within its scope include each of all the possible isomers and their mixtures, and any pharmaceutically acceptable metabolite, bioprecursor and / or pro-drug, such as, for example, a compound which has a structural formula different from the one of the compounds recited or described, yet is directly or indirectly converted in vivo into such a compound upon administration to a subject, such as a mammal, and particularly a human being.

[0015] As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, the term "patient" refers to an animal, preferably a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats etc.) and a primate (e.g., monkey and human), and most preferably a human. In some embodiments, the subject is a non-human animal such as a farm animal (e.g., a horse, pig, or cow) or a pet (e.g., a dog or cat). In a specific embodiment, the subject is an elderly human. In another embodiment, the subject is a human adult. In another embodiment, the subject is a human child. In yet another embodiment, the subject is a human infant.

[0016] As used herein, the term "active", "agent", or "therapeutic agent" refers to any molecule, compound, methodology and / or substance that is used for the prevention, treatment, management and / or diagnosis of a disease, disorder or condition.

[0017] As used herein, the term "effective amount" refers to the amount of a therapy or agent that is sufficient to result in the prevention of the development, recurrence, or onset of a disease or condition, the prevention, treatment, reduction or amelioration of one or more symptoms thereof, the enhancement or improvement of the prophylactic effect(s) of another therapy, the reduction of the severity or the duration of a disease or condition, the amelioration of one or more symptoms of a disease or condition, the prevention of the advancement of a disease or condition, the regression of a disease or condition or one or more of its symptoms, and / or the enhancement or improvement of the therapeutic effect(s) of another therapy.

[0018] As used herein, the phrase "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia, Chinese Pharmacopeia, or other generally recognized pharmacopeia for use in animals, and more particularly, in humans.

[0019] As used herein, the term "treat", "treating", "treatment", or "therapy" of a disease or disorder refers to ameliorating the disease or disorder; for example slowing, arresting or reducing the disease, its development, or one or more clinical symptom thereof; the term also refers to alleviating or ameliorating one or more physical parameter, whether or not discernible by the patient; the term also refers to physically and / or physiologically modulating the disease or disorder (e.g. by stabilization of a discernible symptom and / or physical parameter). Methods of treatment are not claimed.

[0020] As used herein, the term "prevention" of a disease or disorder refers to the administration of the compounds of the invention to a subject before any symptoms of that disease or disorder are apparent.

[0021] As used herein, a patient or subject is "in need of" a treatment if the patient or subject would benefit biologically, medically or in quality of life from such treatment.

[0022] The term "analog," "derivative" or "derivatized" as used herein includes chemical modification of a compound, or pharmaceutically acceptable salts thereof or mixtures thereof. That is, a "derivative" may be a functional equivalent of a compound which is capable of inducing the functional activity of the compound in a given subject or application.

[0023] As used herein, the terms "composition" and "formulation" may be used interchangeably, unless otherwise indicated. Generally, a formulation may be used as a stand-alone non-occlusive transdermal composition for application to the skin, or may be used in form of or to prepare a transdermal patch for application to the skin (patch formulation).

[0024] As used herein, the term "transdermal delivery" means delivery of drug into systemic circulation through the skin, which includes occlusive and non-occlusive delivery by a transdermal composition or a patch.

[0025] As used herein, the term "topical delivery" means delivery of a drug not into the systemic circulation through the skin, which includes occlusive and non-occlusive delivery by a topical composition or a patch.

[0026] As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g. "such as", "for example", "illustrative", "e.g.") provided herein is intended merely to better illustrate the invention and is not intended to limit the scope of the invention.

[0027] As used herein, the term "continuous delivery," "continuously administering," or "continuous administration" refers to essentially uninterrupted administration to a subject of a medication or drug. The administration is non-stop (uninterrupted) except when it is necessary to refill the medication or drug supply or to administer the next dose in the regimen. "Continuous delivery" means there is an uninterrupted administration of the medication or drug, and that the dosing rate or absorbance rate may fluctuate over the dosing interval.

[0028] As used herein, the term "therapeutic agent" refers to any molecule, compound, and / or substance that is used for the purpose of treating and / or managing a disease or disorder.

[0029] As used herein, the terms "therapies" and "therapy" can refer to any method(s), composition(s), and / or agent(s) that can be used in the prevention, treatment and / or management of a disease or condition, or one or more symptoms thereof. In certain embodiments, the terms "therapy" and "therapies" refer to small molecule therapy.

[0030] In an aspect, a method of providing continuous delivery of a therapeutically effective amount of a pharmaceutical composition or formulation comprising lenalidomide is provided. In some embodiments, the method delivers lenalidomide continuously at a predetermined hourly rate. In some embodiments, the predetermined hourly rate may range from 16 to 1400 µg / hour for example from 30 µg to 750 µg / hour, from 30 µg to 145 µg / hour, from 70 µg to 285 µg / hour, or from 185 µg to 725 µg / hour, such as 35 µg / hour, 75 µg / hour, 90 µg / hour, 140 µg / hour, 180 µg / hour, 190 µg / hour, 275 µg / hour, 450 µg / hour, or 700 µg / hour, or is an hourly rate between any two of these recited rates (inclusive), e.g., between 35-140 µg / hour or 75-280 µg / hour or 190 to 700 µg / hour.

[0031] In some embodiments, the method delivers lenalidomide continuously to achieve a steady state plasma level of the immunomodulatory imide compound in a range of 3-140 µg / L, such as 3.5-140 µg / L, 3-75 µg / L,,3.5-75 µg / L, 3.5 - 14 µg / L, 7.5-28 µg / L, 19-70 µg / L,9 µg / L, 18 µg / L,or 45 µg / L.

[0032] In some embodiments, the method delivers the immunomodulatory imide compound continuously for a predetermined number of days. In some embodiments, the predetermined number of days is one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten day, eleven days, twelve day, thirteen days, or fourteen days. In other embodiments, the predetermined number of days is between 1-14 days, 1-12 days, 1-10 days, 1-7 days, 1-5 days, 1-3 days, 2-14 days, 2-12 days, 2-10 days, 2-7 days, 2-5 days, 2-3 days, 3-14 days, 3-12 days, 3-10 days, 3-7 days, 3-5 days, 4-14 days, 4-10 days, 7-14 days or 7-10 days.

[0033] In some embodiments, the hourly rate is selected to achieve a plasma concentration comparable to the immunomodulatory imide compound plasma concentration provided by an oral dose between 0 to 24 hours, such as from about 1 to 24 hrs, further such as between about 5 and 24 hrs, and even further such as between about 5 hours and 23 hours or between about 10 hours and 16 hours after ingestion. The oral dose can be from 2.5 to 50 mg once daily, for example, 2.5 mg, 4.0 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 50 mg of the immunomodulatory imide compound once daily or once every two days. The phrase "comparable to plasma concentration of an oral dose between 0 and 24 hours" can be understood from the description of Examples 6-9. For example, the area of the time concentration curve (AUC) calculated by the trapezoidal rule for the interval 0-24 hours from a graph of plasma concentration versus time of an oral dose divided by the hours (24 hours) is the hourly blood concentration associated with the AUC. The hourly AUC that can be achieved by the hourly rate of the continuous delivery method described herein would produce similar drug exposure over time exhibited by the oral dose. Such hourly rate of the continuous delivery method described herein is the one which achieves a plasma concentration comparable to the 0 hour to 24 hours blood level of an oral dose. In another embodiment, the continuous delivery method described herein achieves an AUC comparable to the AUC from an oral dose of the same compound in the 0-24 hour post dosing period.

[0034] In some embodiments, the method delivers the immunomodulatory imide compound continuously in a manner where the AUC thereof is between 10-60% of the exposure obtained from a standard of care treatment. The standard of care treatment can be intraperitoneal injection of, for example, 500 mcg once per day, or can be from 2.5 to 50 mg oral once daily, such as 2.5 mg, 4.0 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 50 mg of the immunomodulatory imide compound once daily or once every two days via oral administration. In another embodiment, the method herein provides for continuous administration of the lenalidomide to provide an AUC that is between about 10 and 60% of the AUC provided by a standard of care treatment. In some embodiments, the standard of care treatment is an oral dose of lenalidomide from 2.5 mg to 50 mg once daily, such as at 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg or 50 mg once daily or once every two days.

[0035] In some embodiments, the method delivers the immunomodulatory imide compound (lenalidomide) continuously at a dose rate that provides a blood level (µg / L) equivalent to the blood level at a time point from 10 hours to 16 hours obtained from daily oral dose of 2.5 -50 mg once daily (e.g., 2.5 mg, 5 mg, 10 mg, or 25 mg of lenalidomide once per day). In the most preferred embodiments, the method delivers the immunomodulatory imide compound continuously at a dose rate that provides a blood level equivalent to the blood level at 12 hours obtained from daily oral dose of 2.5 to 50 mg once daily (e.g. 5 mg, 10 mg, or 25 mg of lenalidomide once per day). In some embodiments, the method is for treating newly diagnosed multiple myeloma and the daily oral dose of lenalidomide is 25 mg. In some embodiments, the method is for maintenance treatment of multiple myeloma and the daily oral dose of lenalidomide is 10 mg. In some embodiments, the method is for treating chronic lymphocytic leukemia and the daily oral dose of lenalidomide is 5 mg.

[0036] In some embodiments, the method delivers the immunomodulatory imide compound (lenalidomide) continuously at a dose rate such that the daily dose of the method is 10-75%, such as 15-70%, 15-25%, 40-50%, 10-45%, 45%-70%, 60-70%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% of the daily dose of a standard of care treatment. In some embodiments, the standard of care treatment is intraperitoneal injection of, for example, 500 mcg once daily. In some embodiments, the standard of care treatment is FDA-approved once daily oral dose of the immunomodulatory imide compound such as at 5 mg, 10 mg, or 25 mg of lenalidomide oral once per day.

[0037] All pharmaceutically acceptable forms of immunomodulatory imide compound, including, for example, free base, salts, polymorphs, solvates, solutions, isomers, amorphous, crystalline, co crystalline, solid solution, prodrugs, analogs, derivatives, and metabolites are contemplated for use in the methods described herein. The compound may be in the form of a pharmaceutically acceptable salt, such as an acid addition salt or a base salt, or a solvate thereof, including a hydrate thereof. Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts.

[0038] The formulation for continuous delivery of the immunomodulatory imide compound comprises the immunomodulatory imide compound and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier should be compatible with other ingredients of the formulation, if any, and not harmful for the subject's health. Where the continuous delivery comprise infusion, the formulation ingredients may be selected to facilitate the infusion of the formulation. The pharmaceutically acceptable carrier comprises water and PEG 400 at a ratio of 5:1 (v / v). .. The immunomodulatory imide compound is present, in some embodiments, at a concentration of between about 0.01-20 mg / mL, 0.05-5 mg / mL, 0.05-3 mg / mL, 0.1-4 mg / mL, 0.1 - 2.0 mg / mL or between about 0.1-1 mg / mL.

[0039] The continuous delivery of the immunomodulatory imide compound in the form of a formulation is achieved through infusion therapy via subcutaneous application. Infusion therapy administers medication through the use of a sterile thin tube such as catheter that is inserted into the body and secured. A pump delivery system and any other delivery system that would deliver a continuous infusion such as depot injection and ambulatory pumps can be used for this purpose.

[0040] One study as described in Example 1 demonstrated that administration route has a role in the anti-cancer activity of the compound. In this study, a composition comprising lenalidomide was continuously delivered via subcutaneous infusion or was delivered once a day via intraperitoneal injection to SCID mice wherein the mice were implanted with a H929 multiple myeloma xenograft. This study unexpectedly showed that the continuous infusion route effectively reduced the tumor size in all animals treated at 6 mcg / hr while the intraperitoneal injection at a higher dose slowed progression but did not inhibit the growth of the tumor size. See FIG. 1. This study also showed that the continuous infusion route did not result in substantial loss of body weight or hematologic toxicity. See FIG. 2 and Table 1.

[0041] In the study described in Example 1, the SCID mice in Group 2 were given the standard of care treatment which is a daily intraperitoneal dose of 25 mg / kg (500 mcg for 20gm mouse) administered once a day. The pharmacokinetic profile of Group 2 displayed blood level Cmax of 2.9 mcg / mL at 0.08 hours and 0.013 mcg / mL at 18 hours. Further data demonstrated continuous blood levels of greater than those observed at 8 hours or 0.29 mcg / mL and lower than those observed at 18 hours or 0.013 mcg / mL were either toxic or ineffective. For example, if the continuous blood level is greater than that observed at 16 hours but less than that observed at 10 hours in daily intraperitoneal dose of 500 mcg administered once a day, it is effective and non-toxic. The maintenance of continuous dose specific blood levels in terms of their time range are predicted to be safe and effective and result in activity in humans.

[0042] In a comparative example, the continuous delivery of the thalidomide compound can also be achieved through a transdermal delivery system. The continuous infusion model described above is used to emulate the application of a transdermal drug delivery. Both continuous infusion and transdermal delivery bypasses the first pass metabolic extraction, which can be observed with oral drug delivery. The blood level targets observed in a continuous infusion delivery are equivalent to those, which are produced by a transdermal patch. Transdermal patch drug delivery can be quantitated in terms of unit of drug (dose) per unit of time (hour). This delivery rate is then adjusted by the surface area of the transdermal patch to deliver an adequate amount of drug to achieve a specific blood level of drug. This specific blood level, in this embodiment, is the target level which was observed to be effective as a continuous infusion.

[0043] Lenalidomide is administered in an Immediate Release (IR) dosage form (tablet) which does not consider the need for a reduced onset or lower therapeutic window. In general, the intent of an IR tablet is to provide sufficient drug to obtain a therapeutic level in a therapeutic window for some period after initial absorption. In consideration of this therapeutic window, between 10 and 24 hours, the reduced onset refers to the initial absorption of the drug for up to about 10 hours where the maximum blood level is observed between 0.5 to 3 hours post-dose from the IR tablet. The therapeutic window for efficacious dose is considered between about 10 hours to about 24 hours. Thereby, as disclosed herein, the maximum observed blood level would not exceed the upper level of the therapeutic window for a given dose. By reducing the dose further, an IR tablet regimen to effectively reduce the potential for toxicity, the actual dose obtained in the therapeutic window between 10 and 24 hours is likely not achieved and this suggests efficacy from the current standard of care treatment, IR tablet, is not probable. The embodiments described herein provide for an increasing slow drug release and delivery up to the therapeutic window without significantly exceeding the therapeutic blood levels within the therapeutic window.

[0044] The method of delivery provides a steady state release of lenalidomide via stated routes of administration. A delivery rate of about 16 µg / hour to about 1400 µ / hour of lenalidomide, and more preferably about 38 µg / hour to about 700 µg / hour is needed to achieve a therapeutically effective dose in a patient. The current administration of lenalidomide is provided orally from about 2.5 to 25 mg per day with limited consideration given to the actual therapeutic efficacy window between about 1 to 24 hours.

[0045] Examples 6 and 7 exemplify the dose ranges of continuously administered lenalidomide predicted to be at a biologically equivalent dose to once oral daily lenalidomide at 25 mg a day (treating newly diagnosed multiple myeloma). Lenalidomide can be continuously administered at a dose equivalent to the blood level at a time point from 10 hours to 16 hours obtained from once daily lenalidomide at 25 mg a day. For example, the lenalidomide can be continuously administered at a dose providing blood level equivalent to the blood level at 12 hours obtained from once daily lenalidomide at 25 mg a day.

[0046] Example 8 exemplifies the dose ranges of continuously administered lenalidomide predicted to be at a biologically equivalent dose to once oral daily lenalidomide at 10 mg a day (multiple myeloma maintenance treatment). Lenalidomide can be continuously administered at a dose equivalent to the blood level at a time point from 10 hours to 16 hours obtained from once daily lenalidomide at 10 mg a day. For example, the lenalidomide can be continuously administered at a dose providing blood level equivalent to the blood level at 12 hours obtained from once daily lenalidomide at 10 mg a day.

[0047] Example 9 exemplifies the dose ranges of continuously administered lenalidomide predicted to be at a biologically equivalent dose to once oral daily lenalidomide at 5 mg a day (treating chronic lymphocytic leukemia). Lenalidomide can be continuously administered at a dose equivalent to the blood level at a time point from 10 hours to 16 hours obtained from once daily lenalidomide at 5 mg a day. For example, the lenalidomide can be continuously administered at a dose providing blood level equivalent to the blood level at 12 hours obtained from once daily lenalidomide at 5 mg a day.

[0048] Examples 6-9 used lenalidomide as an example to determine the hourly delivery rate and steady state plasma concentration of lenalidomide to be achieved for continuous administration of lenalidomide based on the PK profile of oral dose of lenalidomide. The hourly delivery rate and steady state plasma concentration of other immunomodulatory imide compounds for continuous administration of other immunomodulatory imide compounds can be similarly determined based on the PK profile of the corresponding immunomodulatory imide compound.

[0049] In further embodiments, provided is a simplified and improved therapeutic regimen by decreasing dosing frequency and maintaining blood serum levels within a predetermined range.

[0050] Transdermal delivery systems (TDS) described herein for comparative purposes include transdermal formulations which may be in form of a liquid or semi-solid form of a desired degree of viscosity, for example, a solution, suspension, nano suspension, micro suspension, dispersion, emulsion, micro emulsion, nano emulsion, gel, ointment, cream, paste, lotion, mousse, or balm. Alternatively the transdermal formulation may form part of a TDS that comprises the transdermal formulation. Exemplary TDS include, without limitation, topical formulations (e.g. for occlusive or non-occlusive application to the skin or mucous membrane), gels, lotions, sprays, metered dose transdermal sprays, aerosols, suppositories, magma, transdermal patches, bilayer matrix patches, multilayer matrix patches, monolithic matrix patches with or without adhesive, drug-in-adhesive patches, matrix reservoir patches (with a separate matrix reservoir optionally surrounded by adhesive), microreservoir patches, hydrogel matrix patches, mucoadhesive patches, adhesive systems, transdermally applicable tape, microneedle systems, iontophoresis systems, or combinations thereof. In further embodiments, the formulations provided herein provide for stable formulations of the active components in the formulations. For example, the formulations are shelf stable and maintain at least 90% of their activity over a predetermined time period, when stored under standard ambient conditions. In further embodiments, the formulations are shelf stable for at least 3 months, 6 months, 9 months, or a year.

[0051] Various formulations of immunomodulatory imide compounds for administration are prepared as described in the general embodiments of various platforms below.SPECIFIC EXAMPLES Example 1: Efficacy of lenalidomide continuous infusion in myeloma xenograft model

[0052] Six groups of female CB.17 SCID mouse, each containing ten mice, were subcutaneously injected with 1x10 7< H929 multiple myeloma tumor cells in 50% Matrigel. After the tumor reached an average size of 100 - 150 mm 3< , an iPrecio pump was surgically implanted into each of the mice. Dosing began twenty-four hours post pump implantation. Group 1, the control group, was treated with vehicle via intraperitoneal injection once a day day. Group 2 was treated with lenalidomide via intraperitoneal injection once a day. Each of Groups 3-6 was treated lenalidomide via continuous subcutaneous infusion at different hourly rate. The dosing lasted 14 days followed by one day off the treatment and lasted for another 14 days. The iPrecio pump was replaced after 14 days. The formulation used in Groups 2-6 contains 20% PEG400 in water as the carrier. Blood was drawn at predetermined time points and analyzed

[0053] The table below lists the daily dose and schedule for each of the six groups. Gr. N Agent Active dose (daily) Active dose (hourly) iPrecio Pump Flow Rate Route Schedule 1 #< 10vehiclenanaNaipqdx 14 / 1 day off / qdx 14210lenalidomide25 mg / kg 1< naNaipqdx 14 / 1 day off / qdx 14310lenalidomide144 µg / day6 µg / hr4 µL / hrsc iPrecio pumpcontinuous for 14 days / 1 day off / continuous for 14 days410lenalidomide48 µg / day2 µg / hr4 µL / hrsc iPrecio pumpcontinuous for 14 days / 1 day off / continuous for 14 days510lenalidomide24 µg / day1 µg / hr4 µL / hrsc iPrecio pumpcontinuous for 14 days / 1 day off / continuous for 14 days610lenalidomide12 µg / day.5 µg / hr4 µL / hrsc iPrecio pumpcontinuous for 14 days / 1 day off / continuous for 14 days 1< The mice weighed 20 g on average, the daily dose of 25 mg / kg corresponds to 500 µg / day.

[0054] FIG. 1 displays the normalized tumor volume as a function of time, in days post the treatment (day 1 is the day when the treatment begins) for each of the six groups. Group 3 with the daily dose of 144 µg of lenalidomide via continuous subcutaneous infusion is the only group having tumor volume reduced during the treatment schedule. Group 2 with a much higher daily dose, i.e., 500 µg of lenalidomide, via Intraperitoneal injection failed to inhibit the growth of the tumor volume. FIG. 2 displays the normalized body weight as a function of time, in days post the treatment (day 1 is the day when the treatment begins). Group 3 had insignificant weight loss.

[0055] FIG. 7, a Kaplan-Meier Plot, displays the survival percentage of the mice as a function of time, in day 1 to day 95 post the treatment (day 1 is the day when the treatment begins) for each of the six groups. Group 3 with the daily dose of 144 µg of lenalidomide via continuous subcutaneous infusion is the only group having mice survived for 95 days. Group 2 with a much higher daily dose, i.e., 500 µg of lenalidomide, via Intraperitoneal injection failed to inhibit the growth of the tumor volume and has no mouse survived at day 52.

[0056] Table 1 below lists the white blood cell count (WBC), platelet count (PLT), and absolute neutrophil count (ANC) for each group at day 8 post the treatment, which indicates no substantial hematologic toxicity for Groups 3-6. Table 1: WBC, PLT, and ANC for each group at day 8 post the treatmentGr. WBC (10 3< cells / µL) (normal range: 1.4-5.4) PLT (10 3< cells / µL) (normal range: 733-1441) ANC (10 3< cells / µL) (normal range: 0.77-2.5) 11.98301.321.88501.232.813602.442.413451.953.314102.863.215352.5

[0057] The multiple myeloma study in SCID mice provides pharmacokinetically modeled data to support three treatment paradigms. The standard of care treatment in the mouse model study is a daily intraperitoneal dose of 500 mcg administered once a day (see Group 2). This produced blood levels at Cmax of 2.9 mcg / mL and a trough of 0.002 mcg / mL. The range of tolerable and effective blood levels ranged from the blood level at 10 hours to the blood level at 16 hours. Continuous blood levels of greater than those observed at 8 hours or 0.29 mcg / mL and lower than those observed at 18 hours or 0.013 mcg / mL were either toxic or ineffective, respectfully. The maintenance of continuous dose specific blood levels in terms of their time range are predicted to be safe and effective and result in activity in humans.Example 2: Preparing a lenalidomide topical formulation (reference only)

[0058] A lenalidomide formulation is prepared by mixing a pharmaceutically acceptable form of lenalidomide, with one or more excipients (or enhancers), and a solvent. The proportions of each by %w / w are shown below. Formulation % w / wlenalidomide1-95%Excipient 10-95%Excipient 20-95%Solvent1-95%Total100 Example 3: Forming a pomalidomide topical formulation (reference only)

[0059] A pomalidomide formulation is prepared by mixing a pharmaceutically acceptable form of pomalidomide, with one or more excipients ((or enhancers), and a solvent. The proportions of each by %w / w are shown below. Formulation %w / wpomalidomide1-95%Excipient 10-95%Excipient 20-95%Solvent1-95%Total100 Example 4: Forming a thalidomide topical formulation (reference only)

[0060] A thalidomide formulation is prepared by mixing a pharmaceutically acceptable forms of thalidomide, with one or more excipients (or enhancers), and a solvent. The proportions of each by %w / w are shown below. Formulation %w / wthalidomide0.5-95%Excipient10-95%Excipient 20-95%Solvent1-95%Total100 Example 5: Preparation of a Transdermal Patch (reference only)

[0061] A patch may be formed from a drug-in-adhesive polymer blend by casting the material onto a release liner, curing the adhesive and laminating the adhesive to a backing layer. The resulting laminate may be die cut into a fixed area patch. Formulation %w / wlenalidomide0.5-95%Pressure sensitive adhesive / Polymer0-95%Excipient 10-95%Excipient 20-95%Process Solvent1-95%Total100% Example 6: Blood Plasma Concentration (1) - based on 25 mg lenalidomide once daily orally (reference only)

[0062] A standard lenalidomide dose of 25 mg orally once a day is used to calculate the pharmacokinetic profile for the projected blood levels of lenalidomide over 7 days of dosing. As shown in FIG. 3, the lenalidomide blood levels of the oral dose (as shown in the Oral Cp-line) range from a Cmax of 522 to a Cmin of 5.2 mcg / L over the dose interval of 24 hours. The area of the time concentration curve (AUC) calculated by the trapezoidal rule is 2609 mcg / L / hr for the interval 0-24 hours. The plasma concentration associated with the arithmetic mean of the hourly AUC over the dose interval is 108 mcg / L (mean (X) AUC / hr RLD line). That is, a constant blood level of 108 mcg / L would produce the same drug exposure over time exhibited by the oral dose regimen, but without the high peak and low trough. A second method of establishing an AUC target is to identify the blood level (mcg / L) point estimate with oral administration where half of the dose interval is above the point estimate and half of the dose interval is below the point estimate. In this example, the blood level at the mid-point of the 24-hour dosing interval is 52 mcg / L (PO 12h Value line). Further, in this example, the TDS flux blood levels which might be targeted is determined from experimental data where efficacy is maintained but toxicity is lower than the oral treatment.

[0063] In one example, the target blood concentration for the TDS delivery would be around 108 mcg / L to provide the same drug exposure as an oral dosing regimen at 25 mg a day. In this example the TDS would provide an equivalent AUC 2600 mcg / L / hr as the oral dailyAUC.

[0064] In a second example, the target blood concentration for the TDS delivery would be around 52 mcg / L to provide the drug exposure equivalent to the mid-point of the dosing interval observed with an oral dosing regimen at 25 mg a day. In this example the TDS would provide an AUC of 1248 mcg / L / hr.

[0065] In a third example, the target blood concentration for the TDS delivery would be based on a lenalidomide dose of 15 mg every other day which is commonly used in the presence of hematologic toxicity and is still considered effective. At this dose, the AUC of lenalidomide over 48 hours is 1536 mcg / L / hr with an average blood level of 32 mcg / L. The TDS blood level over the dosing period would approximate the 32 mcg / L plasma concentration at its zenith TDS Cp line).Example 7: Blood Plasma Concentration (2)- based on 25 mg lenalidomide once daily orally (reference only)

[0066] The first line treatment of multiple myeloma usually involves the administration of lenalidomide at dose of 25 mg a day orally. That treatment regimen results in maximum plasma concentrations of ~ 500 mcg / L at the Cmax of 1 hour and trough values of ~ 4 mcg / L at 24 hours. In this embodiment, continuous administration of lenalidomide from 697 mcg / hour (10 hour equivalent) to 191 mcg / hr (16 hour equivalent) represent the effective and safe range for the treatment of first line primary therapy in multiple myeloma in adults (See the table below). The blood level targets range from a low of 19.1 mcg / L to a high of 69.7 mcg / L. In one embodiment, the blood level target is 45 mcg / L (12 hour equivalent) produced by the continuous administration of 453 mcg / hr. In the way, the actual daily dose of lenalidomide is reduced by 56% compared to a once a day 25 mg pulsatile daily dose. Also, the total exposure in a weekly continuous administration treatment cycle compared to once daily dosing for 7 days measured in area-under-the-time-concentration- curve (AUC 0-168 ) is 68% lower than that observed with oral dosing of lenalidomide.

[0067] Blood level and dose ranges of continuously administered lenalidomide in adults at a biologically equivalent dose to once daily lenalidomide at 25 mg a day TEMPORAL EQUIVALENT BLOOD LEVEL WITH A 25MG DOSE10 hr12 hr16 hrSTEADY STATE PLASMA LEVEL MCG / L69.745.319.1AVERAGE DOSE NEEDED MCG / HR697453191DOSE / DAY MCG16729108614577% DOSE OF ORAL67%43%18%AUC MCG / L / HR1771870872045% AUC OF ORAL49%32%13%

[0068] The graphic representation of the plasma concentration over time curves of a weekly cycle of lenalidomide for this embodiment are provided in FIG. 4. FIG. 4 displays blood levels of pulsatile and continuous lenalidomide emulating a once daily 25 mg oral dose compared to 3 unique continuous infusion rates.Example 8: Blood Plasma Concentration (3) - based on 10 mg lenalidomide once daily orally (reference only)

[0069] The maintenance treatment of multiple myeloma usually involves the administration of lenalidomide at dose of 10 mg a day orally. That treatment regimen results in maximum plasma concentrations of ~ 200 mcg / L at the Cmax of 1 hour and trough values of ~ 1.4 mcg / L at 24 hours. In this embodiment, continuous administration of lenalidomide from 279 mcg / hour (10 hour equivalent) to 76 mcg / hr (16 hour equivalent) represent the effective and safe range for the treatment of first line maintenance therapy in multiple myeloma in adults (See the table below). The blood level targets range from a low of 7.6 mcg / L to a high of 27.9 mcg / L. In one embodiment, the blood level target is 18.1 mcg / L produced by the continuous administration of 181 mcg / hr (12 hour equivalent). In this way, the actual daily dose of lenalidomide is reduced by 57% compared to a once a day 10 mg pulsatile daily dose. Also, the total exposure in a weekly continuous administration treatment cycle compared to once daily dosing for 7 days measured in area-under-the-time-concentration- curve (AUC 0-168 ) is 68% lower than that observed with oral dosing of lenalidomide.

[0070] Blood level and dose ranges of continuously administered lenalidomide in adults at a biologically equivalent dose to once daily lenalidomide at 10 mg a day TEMPORAL EQUIVALENT BLOOD LEVEL WITH A 10MG DOSE10 hr12 hr16 hrSTEADY STATE PLASMA LEVEL MCG / L27.918.17.6AVERAGE DOSE NEEDED MCG / HR27918176DOSE / DAY MCG669243441831% DOSE OF ORAL67%43%18%AUC MCG / L / HR460929841253% AUC OF ORAL49%32%13%

[0071] The graphic representation of the plasma concentration over time curves of a weekly cycle of lenalidomide for this embodiment are provided in FIG. 5. FIG. 5 displays blood levels of pulsatile and continuous lenalidomide emulating a once daily 10 mg oral dose compared to 3 unique continuous infusion rates.Example 9: Blood Plasma Concentration (4) - based on 5 mg lenalidomide once daily orally (reference only)

[0072] The treatment of chronic lymphocytic leukemia (CLL) usually involves the administration of lenalidomide at dose of 5 mg a day orally. That treatment regimen results in maximum plasma concentrations of ~ 100 mcg / L at the Cmax of 1 hour and trough values of ~ 0.6 mcg / L at 24 hours. In this embodiment, continuous administration of lenalidomide from 139 mcg / hour (10 hour equivalent) to 38 mcg / hr (16 hour equivalent) represent the effective and safe range for the treatment of CLL in adults (See the table below). The blood level targets range from a low of 3.8 mcg / L to a high of 13.9 mcg / L. In one embodiment, the blood level target is 9.1 mcg / L (12 hour equivalent) produced by the continuous administration of 91 mcg / hr. In this way, the actual daily dose of lenalidomide is reduced by 58% compared to a once a day 5 mg pulsatile daily dose. Also, the total exposure in a weekly continuous administration treatment cycle compared to once daily dosing for 7 days measured in area-under-the-time-concentration- curve (AUC 0-168 ) is 68% lower than that observed with oral dosing of lenalidomide.

[0073] Blood level and dose ranges of continuously administered lenalidomide in adults at a biologically equivalent dose to once daily lenalidomide at 5 mg a day TEMPORAL EQUIVALENT BLOOD LEVEL WITH A 5MG DOSE10 hr12 hr16 hrSTEADY STATE PLASMA LEVEL MCG / L13.99.13.8AVERAGE DOSE NEEDED MCG / HR1399138DOSE / DAY MCG33462172915% DOSE OF ORAL67%43%18%AUC MCG / L / HR2310.41498.2626.7% AUC OF ORAL50%32%14%

[0074] The graphic representation of the plasma concentration over time curves of a weekly cycle of lenalidomide for this embodiment are provided in FIG. 6. FIG. 6 displays blood levels of pulsatile and continuous lenalidomide emulating a once daily 5 mg oral dose compared to 3 unique continuous infusion rates.

[0075] The invention is defined by the appended claims.

Claims

1. An immunomodulatory imide compound comprising lenalidomide for use in a method of treating multiple myeloma, the use comprising: continuously administering to a subject in need of the treatment a formulation comprising the immunomodulatory imide compound and a pharmaceutically acceptable carrier, wherein the use further comprises continuously administering the formulation to the subject via subcutaneous infusion; and wherein the pharmaceutically acceptable carrier comprises water and PEG 400 at a ratio of 5:1 (v / v).

2. The compound for use of any of the preceding claims, wherein continuous administration of the formulation comprising the immunomodulatory imide compound and the pharmaceutically acceptable carrier comprises continuous administration of the formulation to the subject for one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, thirteen days, or fourteen days.

3. The compound for use of claim 1, wherein the continuous administration comprises continuous administration of lenalidomide to the subject at a rate of about 16-1400 µg / hour.