KR20130020943A - Compositions and methods for treating myelodysplastic syndrome - Google Patents

Abstract

PURPOSE: A composition and a method using ezatiostat or its pharmacologically acceptable salt thereof are provided to treat patients with myelodysplastic syndrome. CONSTITUTION: A composition for treating myelodysplastic syndrome contains ezatiostat or its salt thereof, lenalidomide, and a pharmaceutically acceptable excipient. A kit for treating myelodysplastic syndrome contains a first composition containing lenalidomide, and a second composition containing ezatiostat or its salt thereof.

Description

Compositions and Methods for Treating Myelodysplastic Syndrome {COMPOSITIONS AND METHODS FOR TREATING MYELODYSPLASTIC SYNDROME}

The present invention relates to compositions and methods for treating myelodysplastic syndromes.

Myelodysplastic syndrome (s) (MDS) is a heterogeneous group of heterogeneous groups characterized by various risks of invalid hematopoiesis (blood cell production) and conversion to acute myeloid leukemia (AML), including one or more cell lines (erythrocytes, leukocytes or platelets). Refers to clonal hematopoietic stem cell disorders. The syndrome is more common with age. It is estimated that around 300,000 people have MDS worldwide. According to the American Cancer Society, 10,000 to 20,000 new cases of MDS are diagnosed annually in the United States alone. Survival using current therapies ranges from six months to six years for patients who often require blood transfusions to manage the disease.

Currently, there are three drugs for the treatment of MDSs approved by the Food and Drug Administration (FDA). Lenalidomide is shown in the treatment of transfusion-dependent MDS patients with del (5q) and low risk diseases, while azacytidine and decitabine are approved in all categories. Except for del (5q) patients, the response rate is about 50%, highlighting the need for clinical trials of new agents.

Ezatiostat and its salts are disclosed in US Pat. No. 5,763,570. Ezathiostat is ethyl ( 2S ) -2-amino-5-[[( 2R ) -3-benzylsulfanyl-1-[[( 1R ) -2-ethoxy-2-oxo-1-phenylethyl] amino ] -1-oxopropan-2-yl] amino] -5-oxopentanoate has the IUPAC chemical name.

One example of a salt of ezathiostat is the hydrochloride salt ezathiostat hydrochloride (USAN), whose molecular weight is 566.1 and the trade name is Telintra? CAS registration number is 286942-97-0. US patent application Ser. No. 13 / 041,136, filed March 4, 2011, describes polymorphs and ansolvates of ezathiostat hydrochloride.

2005 Annual Meeting of the American Society for Hematology (Abstract # 2250) and in Raza et al. in Journal of Hematology & Oncology, 2: 20 (published online on May 13, 2009), the liposome formulations, as reported on by the (US Patent No. 7,029,695) I-IIa studies; And in the 2007 Annual Meeting of the American Society for Hematology (Abstract # 1454) and in Raza et al. in Blood , 113 : 6533-6540 (published online on April 27, 2009), Phase I studies using tablet formulations, and Quddus et al. in Journal of Hematology & Oncology, 3: 16 (published online on April 23, 2010) reported a single case of a patient in to evaluate the eja Tio start hydrochloride for the treatment of MDS.

The entire disclosure of each patent, patent application, and publication mentioned in that application is incorporated herein by reference.

Summary of the Invention

In one embodiment, the invention is a method of treating MDS in a patient pre-exposed to lenalidomide, the method comprising treating the patient with ezathiostat or a pharmaceutically acceptable salt thereof. .

In one embodiment, the present invention is a method of treating MDS by administering ezaziostat or salts thereof and lenalidomide.

In another embodiment, the present invention is a method of treating MDS by administering ezathiostat or a salt thereof and lenalidomide, followed by administration of ezathiostat or a salt thereof alone.

In some embodiments, the ezathiostat or salt thereof is administered daily for at least two weeks. In some embodiments, ezathiostat or a salt thereof is administered daily for at least 3 weeks.

In the method of the present invention, U.S. Patent Application No. 13 / 108,752, entitled "COMPOSITIONS AND METHODS FOR TREATING MYELODYSPLASTIC SYNDROME," filed May 16, 2011, which is incorporated herein by reference. Ezathiostat or salts thereof may be administered by the dosing regimen described in US application No. 61 / 352,371, filed June 7, 2010, which is incorporated by reference in its entirety. For example, ezathiostat or a salt thereof may be orally 3 g / day for 2 weeks on or 1 week off or 2 g / day for 2 weeks on / 1 week off It can be administered in a cycle of. The same amount of ezathiostat dosage may also be used for ezathiostat itself or for other ezathiostat salts or for other routes of administration.

In another aspect, the present invention provides the use of ezathiostat or a salt thereof for the preparation of an agent for the treatment of myelodysplastic syndromes in a patient who has been previously exposed to lenalidomide.

In another aspect, the present invention provides the use of ezathiostat or a salt thereof for the manufacture of a medicament for the treatment of myelodysplastic syndromes in a patient, wherein the ezathiostat or salt thereof is administered with lenalidomide.

In another aspect, the present invention provides a composition comprising lenalidomide and ezathiostat or a salt thereof. Such compositions preferably comprise a pharmaceutically acceptable excipient which facilitates administration.

In another aspect, the present invention provides a kit for the treatment of MDS comprising a first composition comprising lenalidomide and a second composition comprising ezathiostat or a salt thereof.

These and other embodiments of the invention are further described in the following paragraphs.

Before describing the present invention in more detail, the following terms are first defined.

It is to be understood that the invention is not limited to the specific embodiments described, as the invention may, of course, vary. Moreover, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural unless the context clearly dictates otherwise. Thus, for example, to refer to "pharmaceutically acceptable excipients" includes a plurality of pharmaceutically acceptable excipients.

1. Definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the following terms have the following meanings.

The term "comprising" or "comprising" means that the compositions and methods include the elements cited but do not exclude others. "Consisting essentially of" when used in defining compositions and methods should mean excluding any essentially important other elements for the combination for the purposes stated. Thus, a composition consisting essentially of the elements as defined herein will not exclude other materials or steps that do not substantially affect the basic and novel property (s) of the claimed invention. "Consisting of" means excluding more than traces of substantial process steps and other ingredients. Embodiments defined with each of these transitions are within the scope of the present invention.

When used before a numerical specification, eg, temperature, time, amount and concentration, and range, the term "about" is an approximation that may vary from (+) or (-) to 15%, 10%, 5% or 1%. Indicates.

"Renalimidide" (also known as Revamid in the UK) is an immunomodulator with antiangiogenic and antineoplastic properties. It is 3- (4-amino-1-oxoisoindolin-2-yl) piperidine-2,6-dione or 1-oxo-2- (2,6-dioxopiperidin-3-yl) -4 Has the chemical name of -aminoisoindolin or 3- (7-amino-3-oxo-1H-isoindol-2-yl) piperidine-2,6-dione, and the CAS Registry Number is 191732-72-6. Lenalidomide has been shown in the treatment of blood transfusion dependent patients due to low- or medium-1 risk MDS associated with deletion 5q cytogenetic abnormalities. Lenalidomide is available in 5 mg, 10 mg, 15 mg and 25 mg capsules for oral administration.

The term “therapeutically effective amount” refers to an amount of lenalidomide or ezathiostat or salts, or combinations thereof (“together”), ie when administered to a subject in need of such treatment, as defined herein. As well as sufficient amount to induce treatment. In one embodiment, the therapeutically effective amount of ezathiostat or salt thereof administered will be no greater than 3.5 g per day. Preferably, ezathiostat or a salt thereof is administered in an amount of 2 g per day, more preferably twice a day in the same 1 g dose. This therapeutically effective amount is particularly appropriate when the treatment regimen has not administered the drug for one week after the administration of ezathiostat or its salts for three weeks. In another embodiment, the therapeutically effective amount of ezathiostat or a salt thereof administered in a single dose will be 3 g or 1.5 g in two equivalent daily doses. Such a therapeutically effective amount is particularly appropriate when the treatment regimen has not administered the drug for one week after the administration of ezathiostat or its salts for two weeks. Preferably, the dosing regimen utilizes 2 g of ezathiostat or salts thereof in a 1 g dose twice daily, with or without drug administration for 1 week after continuous administration or for 3 weeks.

In one embodiment, a therapeutically effective amount will provide an efficacy result in at least about 10%, preferably at least about 15%, of the treatment population.

As used herein, the term “treatment” or “treating” means any treatment of MDS in a patient, representing one or more of the following:

Inhibiting MDS, ie, arresting or inhibiting the onset of clinical symptoms (eg, need for blood transfusion, abnormal blood count, etc.); And / or

● Relieve MDS, ie induce regression of symptoms.

As used herein, the term “patient” refers to a mammal and includes human or non-human mammals.

2. Method

In one of the method embodiments, the present invention relates to a method for treating myelodysplastic syndrome (MDS) in a patient in need thereof, wherein the patient has been previously exposed to lenalidomide, the method being ezathio Treating said patient with a start or a pharmaceutically acceptable salt thereof.

Unexpectedly, it has been found that patients treated with lenalidomide prior to treatment with ezathiostat hydrochloride have a higher response rate and / or duration of response compared to patients not pretreated with lenalidomide. For example, as shown in Table 2, the response rate in patients who were not pretreated with lenalidomide was about 22%, and in patients who were pretreated with lenalidomide, the response rate was about 46% and the response rate was 100. Rises above%

Pre-exposure to lenalidomide may be administered ezathiostat or salts thereof any time after the administration of lenalidomide to the patient. A typical lenalidomide treatment schedule involves a 28-day-cycle, during which time lenalidomide is administered once daily for 21 days (3 weeks), followed by 7 days (1 week) (Does not receive lenalidomide). The 28-day-cycle can be repeated for a period of up to 6 months. Lenalidomide capsules have four different intensities: 5 mg, 10 mg, 15 mg, and 25 mg.

In some embodiments of the invention, the patient has been treated with the administration of one or more lenalidomides. In some embodiments, the patient is treated with lenalidomide for at least 2 days, 3 days, 4 days, 5 days or 6 days. In some embodiments, the patient has been treated with lenalidomide for at least 1 week, 2 weeks or 3 weeks. In some embodiments, the patient has completed 1, 2, 3, 4, 5 or 6 lenalidomide treatment cycles. In some embodiments, the patient has completed a full 6 month lenalidomide treatment plan.

In some embodiments of the present invention, after being treated with lenalidomide, the patient receiving ezathiostat or a salt thereof showed intolerance to lenalidomide, and was treated with lenalidomide. After discontinuing treatment or changing to a low lenalidomide dose, administration of ezathiostat or salts thereof is initiated. Depending on the patient's resistance to lenalidomide, it is understood that the patient can switch to a low lenalidomide dose or stop using lenalidomide after completion of the cycle or during the cycle.

As derivatives of thalidomide, lenalidomide can cause a number of side effects, such as birth defects and other adverse reactions. Reported adverse reactions include, but are not limited to:

Blood and lymphatic disorders such as thrombocytopenia, neutropenia, eg febrile neutropenia, leukopenia, anemia, hemolytic anemia, eg warm typ hemolytic anemia, splenic infarction, myelosuppression, coagulopathy , Hemolysis and refractory anemia;

Skin and subcutaneous tissue disorders such as rash, dry skin, bruises, night sweats, increased sweating, ecchymosis and erythema;

Gastrointestinal disorders such as diarrhea, constipation, nausea, abdominal pain, vomiting, upper abdominal pain, dry mouth, stool, gastrointestinal bleeding, ischemic colitis, intestinal perforation, rectal bleeding, colon polyps, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease Obstructive inguinal hernia, irritable bowel syndrome, bleeding, pancreatitis due to bile duct obstruction, pancreatitis, rectal abscess, small intestine obstruction and upper gastrointestinal bleeding;

Breathing, chest and mediastinal disorders such as nasopharyngitis, cough, dyspnea, pharyngitis, nosebleeds, dyspnea, rhinitis and bronchitis;

Musculoskeletal and connective tissue disorders such as arthralgia, low back pain, muscle spasms, limb pain, myalgia, and peripheral edema, arthritis, exacerbated arthritis, gouty arthritis, neck pain and chondrocalcification pyrophosphate;

Benign or malignant tumors such as acute leukemia, acute myeloid leukemia, alveolar adenocarcinoma, lung cancer, lymphoma and prostate cancer;

Neurological disorders such as dizziness, headache, hypoesthesia, taste disorders and peripheral neuropathy;

Infections and parasitics such as pneumonia, urinary tract infections, sinusitis, cellulitis, infections, bacteremia, central vein infections, clostridial infections, ear infections, enterobacter sepsis, fungal infections, herpes virus infections, influenza, kidney infections , Klebsiella pneumonia, lobe pneumonia, local infection, oral infection, pseudomonas infection, septic shock, acute sinusitis, sinusitis, staphylococcal infection and uremia;

Metabolic and nutritional disorders such as hypokalemia, anorexia, hypomagnesemia, dehydration, gout, hypernatremia and hypoglycemia;

Psychiatric disorders such as insomnia, chaos and depression;

Renal and urinary disorders such as difficulty urinating, kidney failure, hematuria, acute renal failure, nitremia, ureters and kidney masses;

Reproductive and breast disorders such as pelvic pain;

Vascular and cardiac disorders such as hypertension, palpitations, congestive heart failure, atrial fibrillation, angina pectoris, cardiac arrest, heart failure, cardio-respiratory arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, exacerbated atrial fibrillation, bradycardia, psychogenic shock, pulmonary edema, Ventricular arrhythmia, tachyarrhythmia and ventricular dysfunction;

Endocrine disorders, such as acquired hypothyroidism;

Ear and maze disorders such as dizziness;

Hepatobiliary disorders such as hyperbilirubinemia, acute cholecystitis, cholecystitis and hepatic insufficiency;

Endocrine disorders such as Basedow's disease;

Immune system disorders such as hypersensitivity;

General disorders such as disease progression, fallout, abnormal gait, intermittent fever, nodules, stiffness and sudden death;

Administrative site conditions, such as femoral fractures, transfusion reactions, cervical fractures, femoral neck fractures, fracture pelvis, hip fractures, overdose, postoperative bleeding, rib fractures, road traffic accidents, and spinal compression fractures; And

Other observations, such as increased blood creatinine, decreased hemoglobin, abnormal liver function tests, increased alanine aminoconvertase and increased troponin I.

The most common and / or serious adverse reactions are neutropenia, thrombocytopenia, pneumonia, rash, anemia, leukopenia, fatigue, shortness of breath, low back pain, febrile neutropenia, nausea, diarrhea, fever, sepsis, dizziness, granulocytopenia, chest pain, Pulmonary embolism, shortness of breath, itching, pancytopenia, muscle spasm, airway infection, upper respiratory tract infection, lethargy, manifold failure, nosebleeds, hypoxia, pleural effusion, pneumonia, pulmonary arterial hypertension, vomiting, increased sweating, arthralgia, pain in the extremities, Includes headaches and fainting.

In certain patient populations, one or more adverse reactions are so severe that either lenalidomide can no longer be administered to the patient or the lenalidomide should be administered at a reduced dose. Under such circumstances, replacing lenalidomide with ezathiostat or salts thereof, or adding ezathiostat or salts thereof, not only avoids adverse reactions but also the ezathiostat or salts thereof will provide a better therapeutic effect. Can be.

In some embodiments of the present invention, a patient treated with lenalidomide prior to administration of ezathiostat or a salt thereof does not respond to lenalidomide or responds to lenalidomide with continuous lenalidomide treatment. Does not last. It has been reported that about 50% of patients receiving lenalidomide show a clinically recognizable response. Under such circumstances, treating patients who do not or have stopped responding to lenalidomide with ezathiostat hydrochloride unexpectedly lead to better therapeutic effects and reduction of clinical symptoms. In such instances, the treatment with lenalidomide may be continued or the treatment with lenalidomide may be stopped by administering the ezathiostat or salts thereof at the same or reduced dose. .

In some embodiments, ezathiostat or a pharmaceutically acceptable salt thereof is administered daily for at least two weeks. In some embodiments, ezathiostat or a pharmaceutically acceptable salt thereof is administered daily for at least 3 weeks.

In another of the aspects of the method, the present invention provides a method of treating myelodysplastic syndrome (MDS) in a patient, the method comprising administering to said patient a combination of lenalidomide and ezathiostat or a pharmaceutically acceptable salt thereof. It provides a method comprising the. In some embodiments, ezathiostat or a pharmaceutically acceptable salt thereof is administered daily for at least two weeks. In some embodiments, ezathiostat or a pharmaceutically acceptable salt thereof is administered daily for at least 3 weeks. In such cases, the patient may or may not be treated with lenalidomide prior to administration of ezathiostat hydrochloride. The former includes the situations described above.

When administered in combination, lenalidomide and ezathiostat or salts thereof can be administered in any manner in which the pharmacological effects of both are simultaneously present in the patient. Thus, co-administration of lenalidomide and ezathiostat or a pharmaceutically acceptable salt thereof may result in the use of a single pharmaceutical composition, the same dosage form, the same route of administration in two formulations, and simultaneous administration of the two formulations. Do not require administration of the two agents for a similar period of time. When administered in the same dosage form and in the same route of administration, it can proceed substantially simultaneously, by delivering both active ingredients simultaneously in a single novel pharmaceutical composition according to the invention. In addition to the above, it is understood that the present invention is contemplated that concurrent administration may be administration of first and second pharmaceutical compositions comprising lenalidomide and ezathiostat, or pharmaceutically acceptable salts thereof, respectively. The term “combination” includes sequential delivery as well as simultaneous delivery of both, with each drug being administered separately in a manner that simultaneously provides both drugs at the serum level to the patient.

As mentioned above, clinicians who utilize only lenalidomide in their patients to treat MDS will be able to add ezathiostat or their pharmaceutically acceptable salts as additional ingredients to treat the patient in their treatment planning. Can be. This subsequent addition of ezathiostat or a pharmaceutically acceptable salt thereof in combination with lenalidomide constitutes a combination administration for the purposes of the present invention, since both effects will occur simultaneously in the patient.

In another embodiment, the present invention is a method of treating MDS by administering ezathiostat or a salt thereof and lenalidomide, followed by administration of ezathiostat or a salt thereof alone.

In some embodiments of the invention, when administered in combination with ezathiostat or a pharmaceutically acceptable salt thereof, lenalidomide is administered in a typical 28-day-cycle as described above and provided in any dosage strength. Can be. In some embodiments, lenalidomide is administered at a reduced dosage and / or frequency, eg, lenalidomide may be administered once every three, four, five or six days every other day. have. Alternatively, it may be administered or discontinued once a week while continuing treatment with ezathiostat or a pharmaceutically acceptable salt thereof.

Typically, ezathiostat or a salt thereof is administered in a therapeutically effective amount. In some embodiments, US patent application Ser. No. 13 / 108,752, entitled "COMPOSITIONS AND METHODS FOR TREATING MYELODYSPLASTIC SYNDROME," filed May 16, 2011, which is incorporated herein in its entirety. Ezathiostat or its salts are administered according to the dosing regime described in

In some embodiments, up to about 3.5 g of ezathiostat hydrochloride per day, or an equivalent amount of ezathiostat itself or ezathiostat, based on the ezathiostat or salt thereof, Administration with other salts. In a preferred embodiment, the administration of ezathiostat or a salt thereof is about 1.5 g or less when administered twice a day (b.i.d.).

In an embodiment of the invention, the ezathiostat or salt thereof is administered in a 1 g dose twice daily for three weeks, followed by one week of discontinuation (without administering the ezathiostat or salt thereof). After the interruption, the plan can be repeated as needed. The plan may be referred to as a “three week plan”.

In an embodiment of the invention, the ezathiostat or salt thereof is administered at a 1.5 g dose twice daily for two weeks, followed by one week of discontinuation (no administration of the ezathiostat or salt thereof). After the interruption, the plan can be repeated as needed. The plan may be referred to as a "two week plan".

In another embodiment of the invention, the patient is continuously treated with a therapeutically effective amount of ezathiostat or its salt at 3 g or less per day, preferably at a dose of 1.5 g or less twice daily. . In this embodiment, the ezathiostat or salt thereof may be administered as long as the patient requires and can withstand such treatment. In such embodiments, it is contemplated that a therapeutically effective amount of ezathiostat or salts thereof may be lower or higher than when the treatment plan is interrupted. Such a plan may be referred to as a "continuous plan".

While twice daily administration is preferred, it is contemplated that once daily administration or three times daily administration may be utilized. In the former case, once daily administration aids patient compliance; In the latter case, smaller tablets may be used in patients who have difficulty swallowing larger tablets. The dose of drug will be adjusted such that the total drug administered per day is a therapeutically effective amount.

Treatment with ezathiostat or salts thereof may comprise one or a combination of two or more of the dosage regimes described above. The following illustrates the dosing schedule for ezathiostat hydrochloride:

For a total dose of 42 g, dosing 1.5 g ezathiostat hydrochloride twice per day for 2 weeks, followed by no ezathiostat or salt for 1 week;

For a total dose of 42 g, dosing 1 g ezathiostat hydrochloride twice per day for 3 weeks, followed by no ezathiostat or salt for 1 week;

Continually administering 1 g of ezathiostat hydrochloride twice per day until the primary clinician deems it appropriate for the patient to withdraw from the administration;

Administering a therapeutically effective amount of up to 3 g of ezathiostat hydrochloride per day divided by 1, 2 or 3 doses for 2 weeks, followed by no ezathiostat or salt for 1 week;

Administering a therapeutically effective amount of up to 2 g of ezathiostat hydrochloride per day in three divided doses of 1, 2 or 3 times, followed by no ezathiostat or salt for 1 week; And / or

• Continuously administer a therapeutically effective amount of up to 2 g of ezathiostat hydrochloride per day in divided doses of 1, 2 or 3 until the physician considers it appropriate to withdraw from the administration.

The above dose of ezathiostat hydrochloride may be replaced with an equivalent amount (based on the ezathiostat content) of the ezathiostat itself or another salt of the ezathiostat.

If the administration of ezathiostat or salts thereof is twice daily, the interval between the first and second administrations is preferably about 6 to 14 hours, preferably about 8 to 14 hours.

In one embodiment, ezathiostat or a salt thereof, such as ezathiostat hydrochloride, is administered intravenously as those described in lipid formulations such as US Pat. No. 7,029,695, which is incorporated by reference in its entirety. can do.

In another embodiment, ezathiostat or salts thereof, such as ezathiostat hydrochloride, can be administered orally. In one embodiment, ezathiostat or a salt thereof, such as ezathiostat hydrochloride, may be administered as a tablet formulation. Such tablet formulations are disclosed in US patent application Ser. No. 13 / 075,116, filed Mar. 29, 2011, entitled "TABLET FORMULATION OF EZATIOSTAT", which is incorporated by reference in its entirety. Included.

3. Composition

In another aspect, the present invention provides a composition comprising lenalidomide and ezathiostat or a pharmaceutically acceptable salt thereof.

In some embodiments, ezathiostat or a salt thereof and lenalidomide are present together in a therapeutically effective amount.

In some embodiments, lenalidomide and / or ezathiostat or salts thereof are present in a therapeutically effective amount. In some embodiments, the composition comprises about 5 mg, 10 mg, 15 mg or 25 mg of lenalidomide and about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg Or 1000 mg ezathiostat or salts thereof.

In one embodiment, lenalidomide may be added to ezathiostat, or a salt thereof, which is a lipid formulation described in US Pat. No. 7,029,695.

In another embodiment, lenalidomide may be added to the tablet formulation ezathiostat or salts thereof. Such tablet formulations are disclosed in US patent application Ser. No. 13 / 075,116, filed Mar. 29, 2011, under the heading "TABLET FORMULATION OF EZATIOSTAT", which is incorporated by reference in its entirety. Included.

4. Kit

In another aspect, the invention provides a kit for the treatment of MDS, comprising a first composition comprising lenalidomide and a second composition comprising ezathiostat or a salt thereof, and those described herein. .

In some embodiments, ezathiostat or a salt thereof and lenalidomide are present together in a therapeutically effective amount.

In some embodiments, the kit administers a first dose of lenalidomide one, two, three, four, five, six days prior to the first administration of ezathiostat or a salt thereof. Include a label with instructions for In some embodiments, the kit comprises a rabbet with instructions for administering lenalidomide one week, two weeks, three weeks, four weeks, five weeks, or six weeks prior to administering ezathiostat or salts thereof. Includes additional. In some embodiments, the kit further comprises a label with instructions for administering lenalidomide in combination with ezathiostat or a salt thereof. In some embodiments, the kit further comprises a label with instructions for administering lenalidomide and ezathiostat or salts thereof according to any dosing schedule described herein.

Example

The invention is further defined with reference to the following examples. It will be apparent to those skilled in the art that numerous modifications to both materials and methods can be made without departing from the scope of the present invention.

International prognosis scoring system International Prognostic System Score  ( IPSS )) Low to medium -1 risk Myelodysplasia  syndrome In patients Eza Tiostat Hydrochloride  refine

87 patients were randomized and treated at 23 irradiation sites. After the initial administration in 14 patients, two dose levels were selected for further study. 37 patients were then treated with 3 g per day for 2 weeks, followed by a 1 week rest period, and 36 patients were treated with 2 g per day for 3 weeks, followed by a 1 week rest period. Data for the 73 patients were pooled for the preliminary analysis.

The median age was 72 years and the patient population distribution was IPSS low risk (23 patients, 32%) and medium-1 risk (50 patients, 68%). Patients received the intermediate of three prior MDS treatments (34 patients (47%) were pretreated with Revlimid® (lenalidomide) and 28 patients (38%) were DNA methyltransferase inhibitors (DMTIs)). [Azacitidine, Decitabine].

In preliminary analysis, eight patients were on treatment to sustain clinical benefit. Total blood improvement-erythrocyte (HI-E) rate was 22% (13 of 60 evaluable patients) (95% CI, 12.1-34.2). The median duration of HI-E response was 46 weeks (range 2-51). Median hemoglobin levels increased 2.0 g / dL in respondents. Eleven of 38 red blood cell (RBC) transfusion-dependent patients had a clinically significant decrease in RBC transfusion (4U / 8 week reduction, IWG 2006), with four patients (11%) independent of RBC transfusion independence. Was achieved, and 3 patients continued the treatment. One patient lasted full relief for more than 12 months after discontinuation of treatment (Quddus et. Al., J. Hem. And Onc. Apr. 2010, 3:15).

Telintra? Consistently indicates multisystem blood improvement. A 15% blood improvement-neutrophil (HI-N) rate was observed in 3 of 20 patients (95% CI, 3.2-37.9) and bilateral HI rate (HI-E and HI-N) was 11% (19 Of 2 patients) (95% CI, 1.3-33.1).

There are three cytogenetic complete responses, and one of the patients with 45X, -Y [4], 46, XY [16] abnormal cytogenes returned to normal after 4 cycles of treatment. Of the 4 patients enrolled in the study with a Dell 5q minus, 2 had a complete cytogenetic response, which was determined by prior Revlimid? Includes one who did not receive treatment.

Telintra? By evaluating all known prognostic characteristics using planned logistic regression analysis. Patients with an increased likelihood of responding to HI-E were defined. Advance DMTI Treatment Is Telintra? Predict a 5-fold decrease in the probability for the HI-E response to (p = 0.023). Dictionary Revlimid? Does Telintra? It has been observed to improve the HI-E response to.

● Dictionary Revlimid? The HI-E rate in patients treated but not pre-DMTI was 40% (6 of 15 patients, 95% CI, 16.3% -67.7%). Within this patient group, 5 of 11 patients (45%) achieved significant RBC transfusion reductions and 3 of these patients (27%) achieved transfusion independence.

● Dictionary Revlimid? HI-E rates in untreated and pre-DMTI untreated patients were 26% (6 of 23 patients, 95% CI, 10.2% -48.4%). Within this group, 5 out of 11 patients (45%) achieved significant reductions in RBC transfusion.

● Dictionary Revlimid? The HI-E rate in untreated but pre-DMTI treated patients was 0% (0 of 17 patients, 95% CI, 0% -19.5%).

Telintra over 403 cycles? Treatment was administered. Safety data is based on all patients treated. The most common non-blood adverse events (AEs) were nausea (45%, 16%), diarrhea (25%, 7%) and vomiting (30%, 12%), which are grade 1 and 2 gastrointestinal (GI), respectively. . Grade 3 cases were rare: nausea (1%), diarrhea (3%) and vomiting (2%). Prior DMTI treatment is associated with an increased incidence of GI AEs.

Telintra? Treatment may lead to clinically significant blood improvement in patients with MDS and may provide an alternative to RBC transfusion. These results are Telintra? Consistent with the level of efficacy observed in prior studies with (the first GST P1-1 enzyme inhibitor tested in MDS patients).

Tables 1 and 2 summarize the results of these clinical studies.

As shown in Table 2, Telintra? Response rate for, Revlimid? From about 22.2% of patients who were not pretreated with Revlimid? After being treated with Telintra? Increased to about 46.2% in patients receiving.

Table 1

Blood improvement-red blood cells (HI-E): time to response and duration of response

Initiated Telintra? Dose 3,000 mg / day (1.5 g b.i.d.) or 2,000 mg / day (1 g b.i.d.)

(Efficacy evaluation group)

[1] 1 divided by 7 plus the number of days from the first administration of the test agent to the day on which the response was first recorded.

[2] The total number of days for which the response was shown divided by seven.

Table 2

Blood Improvement-Red Blood Cells (HI-E)

(Efficacy evaluation group)

[3] reduction in RBC transfusion from baseline => 4 units per 8 weeks; Or achieve hemoglobin increase of hemoglobin <11 g / dL,> = 1.5 g / dL maintained for a period of 8 weeks in patients with symptomatic anemia that is not transfusion dependent.

Claims (13)

An agent comprising ezathiostat or a salt thereof for treating myelodysplastic syndrome in a patient who has been previously exposed to lenalidomide, wherein the ezathiostat or salt thereof is administered daily for at least two weeks. The agent according to claim 1, wherein the patient exhibits intolerance to lenalidomide. The agent according to claim 1, wherein the patient experiences a decrease or lack of therapeutic effect with continuous lenalidomide treatment. 4. A medicament according to any one of claims 1 to 3, wherein the ezathiostat or salt thereof is administered in a therapeutically effective amount. An agent comprising ezathiostat or a salt thereof for treating myelodysplastic syndrome in a patient, wherein the ezathiostat or a salt thereof is administered together with lenalidomide. 6. A medicament according to claim 5, wherein the ezathiostat or salt thereof and lenalidomide are administered together in a therapeutically effective amount. The agent according to any one of claims 1, 2, 3, 5 and 6, which is orally administered. 8. The method of claim 7, wherein the ezathiostat or salt thereof is administered according to a treatment schedule comprising a one-week discontinuance of not administering the ezathiostat or the salt after administration of 2 g of the daily dose for three weeks. drugs. The method of claim 7, wherein the ezathiostat or salt thereof is administered according to a treatment schedule comprising a one-week discontinuance of not administering the ezathiostat or the salt after administration of 3 g of the daily dose for two weeks. drugs. A composition for treating myelodysplastic syndromes comprising ezathiostat or salts thereof and lenalidomide, and optionally a pharmaceutically acceptable excipient. The composition of claim 10, wherein the ezathiostat or salt thereof and lenalidomide are present together in a therapeutically effective amount. A kit for treating MDS, comprising a first composition comprising lenalidomide and a second composition comprising ezathiostat or a salt thereof. 13. The kit of claim 12, wherein the ezathiostat or salt thereof and lenalidomide are present together in a therapeutically effective amount.