MX2011009305A - Compositions and methods for treating myelodysplastic syndrome. - Google Patents

Abstract

The invention generally relates to compositions for use in the treatment of myelodysplastic syndrome. In one embodiment, the invention relates to methods for treating myelodysplastic syndrome with ezatiostat or a salt thereof and lenalidomide.

Description

COM POSITION IS AND M ETHODS TO TREAT IF N DROM E MY LASITIC ELODISP Field of the invention This invention relates to compositions and methods for treating myelodysplastic syndrome.

State of the art Myelodysplastic syndrome (s) (MDS) refers to a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis (production of blood cells) involving one or more cell lineages (red blood cells, white blood cells or platelets) ) and a variable risk of transformation to acute myeloid leukemia (AML). This syndrome becomes more common with age. It is estimated that MDS affects approximately 300,000 people around the world. According to the American Cancer Society, 10,000 to 20,000 new cases of MDS are diagnosed each year in the United States alone. Survival rates using current therapy vary from 6 months to 6 years with patients frequently requiring blood transfusions to manage their disease.

Currently, there are three drugs approved to treat MDS by the U.S. Food and Drug Administration (FDA). Lenalidomide is indicated for the treatment of transfusion-dependent MDS patients with (5q) and lower risk of disease, while azacitidine and decitabine are approved for all categories. With the exception of patients of (5q), the response rate is approximately 50%, highlighting the need for clinical trials of new agents.

Ezatiostat and its salts are described in U.S. Pat. 5,763, 570. Ezatiostat has the chemical name of I UPAC of (2S) -2-amino-5 - [[(2R) -3-benzylsulfanyl-1 - [[(1 R) -2-ethoxy-2-oxo- 1-phenylethyl] amino] -1-oxopropan-2-yl] amino] -5-oxopentanoate.

An example of an ezatiostat salt is the hydrochloride salt, ezatiostat hydrochloride (USAN), which has the molecular weight of 566.1, the Telintra® trademark and the CAS registry number of 286942-97-0. The US patent application no. 1 3/041, 1 36, filed on March 4, 201 1, discloses a solvate and polymorphs of ezatiostat hydrochloride.

Ezatiostat hydrochloride has been evaluated for the treatment of MDS, in a Phase II study using a liposomal formulation (US Patent No. 7,029,695), as reported in the 2005 Annual Meeting of the American Society for Hematology (Abstract # 2250 ) and by Raza et al. , in Journal of Hematology & Oncology, 2:20 (published online May 1, 2009); and in a Phase I study using a tablet formulation, as reported in the 2007 Annual Meeting of the American Society for Hematology (Abstract # 1454) and by Raza et al. in Blood, 1 13: 6533-6540 (pre-published online on April 27, 2009), and in a single-patient case report by Quddus et al. in Journal of Hematology & Oncology, 3: 16 (published online on 23 April 201 0).

The full descriptions of each of the patents, patent applications and publications referred to in this application are incorporated in this application by reference.

Brief description of the invention In one embodiment, this invention is a method of treating MDS in a patient, wherein the patient has prior exposure to lenalidomide, said method comprising treating said patient with ezatiostat or a pharmaceutically acceptable salt thereof.

In one embodiment, this invention is a method for treating MDS by administration of ezatiostat or a salt thereof and lenalidomide.

In another embodiment, this invention is a method of treating MDS by administration of ezatiostat or a salt thereof and lenalidomide followed by administration of ezatiostat or a salt thereof alone.

In some modalities, ezatiostat or a salt thereof is administered daily for at least 2 weeks. In some modalities, ezatiostat or a salt thereof is administered daily for at least 3 weeks.

In the methods of this invention, ezatiostat or a salt thereof is administered by a dosage regimen described in U.S. patent application no. 13 / 108,752, entitled "COMPOSITIONS AND METHODS FOR TREATING M YE LODYS PLASTIC SYNDROME" (Compositions and methods for treating myelodysplastic syndrome), filed May 16, 201 1, which is incorporated by reference in its entirety and claims priority to provisional US application no. 61 / 352,371, filed June 7, 201 0. For example, ezatiostat or a salt thereof can be administered in cycles of 2 gram / day orally for 3 weeks yes / 1 week no, or cycles of 3 grams / day orally for 2 weeks yes / 1 week no. Equivalent dosages of ezatiostat for ezatiostat by itself or other salts of ezatiostat, or for other routes of administration may also be used.

In yet another aspect, this invention provides the use of ezatiostat or a salt thereof for the preparation of a medicament for treating a myelodysplastic syndrome in a patient who has had prior exposure to lenalidomide.

In yet another aspect, this invention provides the use of ezatiostat or a salt thereof for the preparation of a medicament for treating a myelodysplastic syndrome in a patient, wherein the ezatiostat or a salt thereof is administered with lenalidomide.

In another aspect, this invention provides a composition comprising lenalidomide and ezatiostat or a salt thereof. Such compositions preferably contain a pharmaceutically acceptable excipient to facilitate administration.

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

These and other embodiments of this invention are further described in the text that follows.

Detailed description of the invention Before describing this invention in greater detail, the following terms will be defined first.

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

It should be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the," include plural referents unless the context clearly dictates otherwise. . Thus, for example, the reference to "a pharmaceutically acceptable excipient" includes a plurality of pharmaceutically acceptable excipients. 1 . Definitions 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 pertains. As used herein, the following terms have the following meanings.

The term "comprising" or "comprises" means that the compositions and methods include the declared elements, but do not exclude others. "Consists essentially of" when used to define compositions and methods, shall mean that it excludes other elements of any essential importance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consists of" means that it excludes more than trace elements of other ingredients and substantial method steps. The modalities defined for each of these transition terms are within the scope of this invention.

The term "approximately" when used before a numerical designation, for example, temperature, time, quantity and concentration, including range, indicates approximations which may vary by (+) or (-) 1 5%, 10%, 5% or 1%.

"Lenalidomide" (Revlimid®, also known as Revamid in the UK) is an immunomodulatory agent with antiangiogenic and antineoplastic properties. It has the chemical name of 3- (4-amino-1-oxoisoindolin-2-yl) piperidin-2,6-dione or 1 -oxo-2- (2,6-dioxopiperidin-3-yl) -4-aminoisoindoline or 3- (7-amino-3-oxo-1 H-isoindol-2-yl) piperidine-2,6-dione and CAS registry number of 191732-72-6. Lenalidomide is indicated for the treatment of patients with transfusion-dependent MDS due to low or intermediate-1 risk associated with a cytogenetic abnormality of suppression 5q. Lenalidomide is available in capsules of 5 milligrams (mg), 10 mg, 15 mg and 25 mg for oral administration.

The term "therapeutically effective amount" refers to the amount of either lenalidomide or ezatiostat or a salt thereof, or the combination ("together"), which is a sufficient amount to effect treatment, as defined herein, when it is administered to a subject in need of such treatment. In one embodiment, the therapeutically effective amount will be up to 3.5 grams (g) of ezatiostat or a salt thereof administered per day. Preferably, ezatiostat or a salt thereof is administered in an amount of 2 grams per day and, more preferably, is administered twice a day in doses equal to 1 gram. Such a therapeutically effective amount is particularly relevant when the treatment regimen is for 3 weeks of administration of ezatiostat or a salt thereof, followed by a week without administration of the drug. In another embodiment, the therapeutically effective amount will be up to 3 grams of ezatiostat or a salt thereof administered in a single dose, or in 2 equal daily doses of up to 1.5 grams. Such a therapeutically effective amount is particularly relevant when the treatment regimen is for 2 weeks of administration of ezatiostat or a salt thereof followed by a week without administration of the drug. Preferably, the dosing regimen employs 2 grams of ezatiostat or a salt thereof administered in a dose amount of 1 gram twice a day either under continuous administration or with administration for 3 weeks followed by a week without administration of the drug.

In a preferred embodiment, the therapeutically effective amount will provide effective results in at least about 10% of the treated population and preferably at least about 15%.

As used herein, the term "treatment" or "treating" means any treatment of MDS in a patient that produces one or more of the following: • Inhibit MDS; that is, stopping or suppressing the development of clinical symptoms (e.g., need for blood transfusion, abnormal blood count and the like); I • Relieve MDS, that is, cause regression of symptoms.

As used herein, the term "patient" refers to mamphers and includes humans and non-human mammals. 2. Methods In one of its aspects of method, this invention is directed to a method for treating a myelodysplastic syndrome (MDS) in a patient in need thereof, wherein the patient has previous exposure to lenalidomide, said method comprises treating said patient with ezatiostat or a pharmaceutically acceptable salt thereof.

It has been unexpectedly discovered that patients who were treated with lenalidomide before treatment with ezatiostat hydrochloride, exhibited a higher response rate and / or duration as compared to patients who were not pre-treated with lenalidomide. For example, as shown in Table 2, the response rate in patients who were not pre-treated with lenalidomide is approximately 22% and in patients who were pre-treated with lenalidomide the response rate is approximately 46%, 100%. % increase above the response rate.

Previous exposure to lenalidomide may be administration of lenalidomide to the patient at any time prior to the administration of ezatiostat or a salt thereof. A typical lenalidomide treatment program involves a 28-day cycle, during which lenalidomide is administered once a day, every day, for 21 days (3 weeks) followed by an interruption of 7 days (1 week) when no lenalidomide is administered. This 28-day cycle can be repeated for a duration of up to 6 months. The lenalidomide capsules have four different strengths: 5 mg, 10 mg, 15 mg and 25 mg.

In some embodiments of this invention, the patient has been treated with at least one dosage of lenalidomide. In some modalities, the patient has been treated with lenalidom ida for at least 2 days, 3 days, 4 days, 5 days or 6 days. In some modalities, the patient has been treated with lenalidomide for at least a week, two weeks or three weeks. In some modalities, the patient has completed 1, 2, 3, 4, 5 or 6 treatment cycles of lenalidomide. In some modalities, the patient has completed the full 6-month lenalidomide treatment regimen.

In some embodiments of this invention, the patient being treated with lenalidomide prior to the administration of ezatiostat or a salt thereof has developed intolerance to lenolidomide and stopped treatment with lenalidomide or switched to a lower dosage of lenalidomide prior to the administration of ezatiostat or a salt of it begins. It is understood that a patient may stop using lenalidomide or switch to a lower dosage of lenalidomide after completing a cycle or during the cycle dependent on the tolerance of the patient to lenalidomide.

As a thalidomide derivative, lenalidomide can cause many side effects, such as birth defects and other adverse events. Adverse events reported include but are not limited to those related to: • Disorders of the circulatory and lymphatic system, such as thrombocytopenia, neutropenia, for example, febrile neutropenia, leukopenia, anemia, hemolytic anemia, for example, warm-type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis and refractory anemia; • Subcutaneous and skin tissue disorders, such as rash, dry skin, bruising, night sweats, increased sweating, bruising and erythema; • Gastrointestinal disorders, such as diarrhea, constipation, nausea, abdominal pain, vomiting, upper abdominal pain, dry mouth, loose stools, gastrointestinal bleeding, ischemic colitis, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis, peri-rectal abscesses, small bowel obstruction, and upper gastrointestinal hemorrhage; Respiratory, thoracic and mediastinal disorders, such as nasopharyngitis, cough, dyspnea, pharyngitis, epistaxis, dyspnea on exertion, rhinitis and bronchitis; Disorders of musculoskeletal and connective tissue, such as arthralgia, back pain, muscle cramps, pain in the extremities, myalgia and peripheral swelling, arthritis, aggravated arthritis, gouty arthritis, neck pain and pyrophosphate chondrocalcinosis; Benign or malignant neoplasms, such as acute leukemia, acute myeloid leukemia, bronchioalveolar carcinoma, lung cancer, lymphoma and prostate cancer; Nervous system disorders, such as dizziness, headache, hypostasis, dysgeusia and peripheral neuropathy; Infestations and infestations, such as pneumonia, urinary tract infection, sinusitis, cellulitis, infection, bacteremia, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, viral herpes infection, influenza, infection of the kidney, sepsis due to Klebsiella, lobar pneumonia, localized infection, oral infection, pseudomonas infection, septic shock, acute sinusitis, sinusitis, staphylococcal infection, and urosepsis; Disorders of metabolism and nutrition, such as hypokalemia, anorexia, hypomagnesemia, dehydration, gout, hypernatremia and hypoglycemia; Psychiatric disorders, such as insomnia, confusion and depression; Kidney and urinary disorders, such as dysuria, renal failure, hematuria, acute renal failure, azotemia, ureteric stones and renal mass; Disorders of the reproductive system and breast, 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, aggravated atrial fibrillation, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia and ventricular dysfunction; Endocrine disorders, such as acquired hypothyroidism; Ear and labyrinth disorders, such as vertigo; Hepatobiliary disorders, such as hyperbilirubinemia, acute cholecystitis, cholecystitis, and liver failure; Endocrine disorders, such as Basedow's disease; Immune system disorders, such as hypersensitivity; General disorders, such as progression of disease, fall, alteration of gait, intermittent pyrexia, nodule, rigors and sudden death; • Administrative site conditions, such as femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis, chain fracture, overdose, post-procedure haemorrhage, rib fracture, road traffic accident and fracture of spinal compression; Y • Other observations, such as increased blood creatinine, decreased hemoglobin, abnormal liver function tests, increased alanine aminotransferase and increased troponin I.

Most common and / or severe adverse events include neutropenia, thrombocytopenia, pneumonia, rash, anemia, leukopenia, fatigue, dyspnea, back pain, febrile neutropenia, nausea, diarrhea, pyrexia, sepsis, dizziness, granulocytopenia, chest pain, pulmonary embolism , respiratory distress, pruritus, pancytopenia, muscle cramp, respiratory tract infection, upper respiratory tract infection, asthenia, multiple organ failure, epistaxis, hypoxia, ple effusion, pneumonitis, pulmonary hypertension, vomiting, increased sweating, arthralgia, pain in extremities, headache and syncope.

In certain patient populations, one or more of the adverse events are so severe that lenalidomide can no longer be administered to the patient or lenalidomide must be administered in a reduced dosage. Under such circumstances, switching from lenalidomide to ezatiostat or a salt thereof or addition of ezatiostat or a salt thereof not only avoids the adverse effect, but may also provide better therapeutic effect for ezatiostat or a salt thereof. same.

In some embodiments of this invention, the patient being treated with lenalidomide prior to administration of ezatiostat or a salt thereof does not respond to lenalidomide or the response to lenalidomide does not continue with continued lenalidomide treatment. It is reported that approximately 50% of the patient administered with lenalidomide exhibited a clinically recognizable response. Under such circumstances, treating patients who did not respond or stopped responding to lenalidomide with ezatiostat hydrochloride results in a better unexpected therapeutic effect and reduction of clinical symptoms. In this case, the treatment with lenalidomide can continue with the administration of ezatiostat or a salt thereof at the same dosage or at a reduced dosage, or treatment with lenalidomide can be stopped completely.

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

In another aspect of the method, this invention provides a method for treating a myelodysplastic syndrome (MDS) in a patient, said method comprising administering to said patient concurrently lenalidomide and ezatiostat or a pharmaceutically acceptable salt thereof. In some embodiments, ezatiostat or a pharmaceutically acceptable salt thereof is administered daily for at least two weeks. In some embodiments, ezatiostat or a pharmaceutically acceptable salt thereof is administered daily for at least three weeks. In these cases, the patient may or may not have been treated with lenalidomide before the administration of ezatiostat hydrochloride. The above includes situations described above.

When administered concurrently, lenalidomide and ezatiostat or a salt thereof can be administered in any manner in which the pharmacological effects of both are manifested in the patient at the same time. Thus, the concurrent administration of lenalidomide and ezatiostat or a pharmaceutically acceptable salt thereof does not require that a single pharmaceutical composition, the same dosage form, the same route of administration to be used for the two agents, the two agents are administered at the same time or both agents are administered during a similar period. When administered by the same dosage form and the same route of administration, in substantially the same time, it could proceed to deliver both active ingredients simultaneously into a single novel pharmaceutical composition according to the present invention. It is understood that in addition to the above, this invention contemplates that a concurrent administration may be the administration of a first and second pharmaceutical composition comprising lenalidomide and ezatiostat or a pharmaceutically acceptable salt thereof, respectively. The term "concurrent" includes both simultaneous delivery and delivery sequential, wherein each drug is administered separately in a manner that provides serum levels of both drugs in the patient at the same time.

As noted above, a clinician who employs lenalidomide alone in a patient to treat MDS may, at a point in that treatment regimen, add ezatiostat or a pharmaceutically acceptable salt thereof as an additional component to treat that patient. Such subsequent addition of ezatiostat or a pharmaceutically acceptable salt thereof in combination with lenalidomide constitutes concurrent administration for the purposes of this invention as the effects of both will be manifested in the patient at the same time.

In another embodiment, this invention is a method for treating MDS by the administration of ezatiostat or a salt thereof and lenalidomide, followed by administration of ezatiostat or a salt thereof alone.

In some embodiments of this invention, when administered concurrently with ezatiostat or a pharmaceutically acceptable salt thereof, lenalidomide is administered in the typical 28-day cycle as described above and may occur at any of the dosage strengths. In some embodiments, lenalidomide is administered at a reduced dosage and / or frequency, for example, lenalidomide can be administered once every third day, once every 3, 4, 5 or 6 days. Or it may be administered once a week or it may be discontinued while treatment with ezatiostat or a pharmaceutically acceptable salt thereof continues.

Normally, ezatiostat or a salt thereof is administered in a therapeutically effective amount. In some embodiments, ezatiostat or a salt thereof is administered by a dosage regimen described in U.S. patent application no. 1 3/108, 752, entitled "COMPOSITONS AND METHODS FOR TREATI NG MYELODYS PLASTIC SYN DROME" (Compositions and Methods for Treating Myelodysplastic Syndrome) "presents May 1, 201 1, which is incorporated by reference in its entirety.

In some embodiments, ezatiostat or a salt thereof is administered up to about 3.5 grams per day of ezatiostat hydrochloride, or an equivalent amount (in terms of ezatiostat content) of ezatiostat by itself or another salt of ezatiostat. In a preferred embodiment, the dosage of ezatiostat or a salt thereof is a therapeutically effective amount of up to about 1.5 gram administered twice daily (b. I.d.).

In one embodiment of this invention, ezatiostat or a salt thereof is administered in dosages of 1 gram twice a day for three weeks followed by a one week break, where ezatiostat or a salt thereof is not administered. After the interruption, the regimen can be repeated as necessary. This regimen can be referred to as the "three-week regimen".

In one embodiment of this invention, ezatiostat or a salt thereof is administered in dosages of 1.5 grams twice a day for two weeks followed by a one-week break where ezatiostat or a salt thereof is not administered. After the interruption, the regimen can be repeated as necessary. This regimen can be referred to as the "two week regimen".

In another embodiment of this invention, the patient is continuously treated with a therapeutically effective amount of ezatiostat or a salt thereof of up to 3 grams per day, preferably administered up to dosages of 1.5 grams twice a day. In this modality, ezatiostat or a salt thereof can be administered as long as the patient is in need of and can tolerate such treatment. It is contemplated that in this embodiment, the therapeutically effective amount of ezatiostat or a salt thereof may be less or more than that when there is an interruption in the treatment regimen. This regime can be referred to as the "continuous regime".

Although administration twice a day is preferred, it is contemplated that administration once a day or administration of 3 times a day could be employed. In the first case, administration once a day would help the patient's condescension; while in the latter case, smaller tablets could be used for those patients who have difficulty swallowing larger tablets. The amount of drug administered would be adjusted so that the total medication administered per day is a therapeutically effective amount.

Treatment with ezatiostat or a salt thereof may involve one or a combination of two or more of the dosage regimens described herein. The following are example dosing schedules of ezatiostat hydrochloride: • 1.5 grams of ezatiostat hydrochloride administered twice daily for 2 weeks during an aggregate total dosage of 42 grams, followed by a week when no g of ezatiostat or a salt is administered; • 1 gram of ezatiostat hydrochloride given twice a day for 3 weeks for an aggregate total dosage of 42 grams followed by a week when ezatiostat or a salt is not administered; • 1 gram of ezatiostat hydrochloride given twice a day continuously until the attending physician considers it appropriate to withdraw the patient from administration; • A therapeutically effective amount of up to 3 grams of ezatiostat hydrochloride per day given in one, two or three divided doses for 2 weeks followed by a week when ezatiostat or a salt is not administered; • A therapeutically effective amount of up to 2 grams of ezatiostat hydrochloride per day administered in one, two or three divided doses for 3 weeks, followed by one week without administration of ezatiostat or a salt; I • A therapeutically effective amount of up to 2 grams of ezatiostat hydrochloride per day given in one, two or three divided doses continuously until the attending physician deems it appropriate to withdraw the patient from administration.

The ezatiostat hydrochloride in the above dosages can be replaced with an equivalent amount of ezatiostat by itself or another salt of ezatiostat (in terms of content of ezatiostat).

When the administration of ezatiostat or a salt thereof is twice a day, it is preferred that the interval between the first and second doses be from about 6 to 14 hours and preferably between about 8 and 14 hours.

In one embodiment, ezatiostat or a salt thereof, for example, ezatiostat hydrochloride, can be administered intravenously as a lipid formulation, such as those described in U.S. Pat. 7, 029,695, which is incorporated by reference in its entirety.

In one embodiment, ezatiostat or a salt thereof, for example, ezatiostat hydrochloride, can be administered orally. In one embodiment, ezatiostat or a salt thereof can be administered as a tablet formulation. Such a tablet formulation is described in U.S. patent application no. 1 3/075, 1 16, filed on March 29, 201 1, entitled "TABLET FORMU LATION OF EZATIOSTAT" (Formulation of ezatiostat tablets), which is incorporated by reference in its entirety. 3. Composition In another aspect, this invention provides a composition comprising lenalidomide and ezatiostat or a pharmaceutically acceptable salt thereof.

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

In some embodiments, the lenalidomide and / or ezatiostat or a salt thereof is 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 of ezatiostat or a salt thereof.

In one embodiment, lenalidomide can be added to the ezatiostat formulation or a salt thereof described in U.S. Pat. 7,029,695.

In another embodiment, the lenalidomide can be added to a tablet formulation of ezatiostat or a salt thereof. Such a tablet formulation is described in U.S. patent application no. 13/075, 1 16, filed on March 29, 201 1, entitled "TABLET FORMU LATION OF EZATIOSTAT" (Formulation of ezatiostat tablets), which is incorporated by reference in its entirety. 4. Kit In still another aspect, this invention provides a kit for the treatment of MDS comprising a first composition comprising lenalidomide and a second composition comprising ezatiostat or a salt thereof, including those described herein.

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

In some embodiments, the kit further comprises a label with instructions for administering the first dose of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days of lenalidomide before the first administration of ezatostat or a salt thereof. . In some embodiments, the kit further comprises a label with instructions for administering 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks of lenalidomide before the administration of ezatiostat or a salt thereof. In some embodiments, the kit further comprises a label with instructions for administering lenalidomide concurrently with ezatiostat or a salt thereof. In some embodiments, the kit further comprises a label with instructions for administering lenalidomide and ezatiostat or a salt thereof according to any of the dosage schedules described herein.

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

Ezatiostat hydrochloride tablets in patients with a low-risk myelodysplastic syndrome to intermediate-1 international prognostic system rating (I PSS) Eighty-seven patients were randomized and treated in 23 research sites. After varying the initial dose in 14 patients, two dose levels were selected for further study. Subsequently, 37 patients were treated with 3 grams daily for two weeks followed by a one-week rest period, and 36 patients were treated at 2 grams daily for three weeks followed by a one-week rest period. Data on these 73 patients were deposited for this preliminary analysis.

The median age was 72 years, with a population distribution of patients at low risk of I PSS (23 patients, 32%) and intermediate risk-1 (50 patients, 68%). The patients had received a median of three previous MDS therapies, including 34 patients (47%) with previous Reviimid® (lenalidomide) and 28 patients (38%) with previous DNA methyltransferase inhibitors (ITEM) [azacitidine, decitabine].

At the time of preliminary analysis, 8 patients remained in treatment to continue the clinical benefit. The overall hematologic-erythroid (HL-E) improvement rate was 22%, 13 of 60 evaluable patients (95% Cl, 12.1 -34.2). The median duration of Hl-E response was 46 weeks (range 2-51). The median hemoglobin level increased by 2.0 gram / dl in responders. Eleven of 38 patients dependent on red blood cell transfusion (RBC) (29%) had clinically significant reductions in RBC transfusion (reduction of 4U / 8 weeks, IWG 2006) with 4 patients (11%) achieving independence of RBC transfusion and 3 patients continuing treatment. One patient continued in complete remission for more than 12 months, following discontinuation of therapy (Quddus, et al., J. Hem. And Onc. Apr. 201 0, 3: 1 5).

Telintra® continues to demonstrate the multilineage hematologic improvement. There was a haematological-neutrophil (H lN) improvement rate of 1 5% observed in 3 of 20 patients (95% Cl, 3.2-37.9) and the H l rate of bilinexation (Hl-E and H lN) was 1 1% , 2 of 19 patients (95% Cl, 1 .3-33.1).

There were three complete cytogenetic responses, one in a patient with 45X, and [4], 46, XY [16] abnormal cytogenetics that became normal after four cycles of therapy. Of the four patients enrolled in this study with the 5q minus, two had a complete cytogenetic response, including one that had failed previous Revlimid® therapy.

A planned logistic regression analysis was used to evaluate all the known prognostic characteristics in order to define those patients who had an increased probability of Hl-E response to Telintra®. The treatment of previous ITIM predicts a fivefold decrease in the possibilities of an Hl-E response to Telintra® (p = 0.023). It was observed that the previous Revlimid® treatment intensifies the response of Hl-E to Telintra®.

• There was an HL-E rate of 40% (6 of 15 patients, 95% CI, 16.3% - 67.7%) in patients who had had previous Revlimid® treatment, but without previous TIMM treatment. Within this group of patients, five of 1 1 patients (45%) achieved a reduction of transfusion of significant RBC with three of those patients (27%) achieving independence of transfusion.

• There was an HL-E rate of 26% (6 out of 23 patients, 95% Cl, 1 0.2% - 48.4%) in patients who did not have prior Revlimid® treatment and no previous TIMM treatment. Within this group, five of 11 patients (45%) achieved a significant reduction in RBC transfusion.

• There was a Hl-E rate of 0% (0 of 1 7 patients, 95% C l, 0% - 19.5%) in patients who did not have previous Revlimid® treatment but who had received previous TIMM treatment.

More than 403 Telintra® therapy cycles have been administered. The safety data are based on all treated patients. The most common non-haematological adverse events (AEs) were gastrointestinal (Gl) grade 1 and 2 respectively, nausea (45%, 16%), diarrhea (25%, 7%) and vomiting (30%, 1 2%). Grade 3 events were not common: nausea (1%), diarrhea (3%) and vomiting (2%). Previous DMT treatment was associated with an increased incidence of Gl AEs.

The treatment of Telintra® may result in clinically significant hematologic improvement in patients with MDS and may offer an alternative to TB transfusions. These results are consistent with levels of efficacy observed in previous studies with Telintra®, the first inhibitor of GST P1 -1 enzyme tested in MDS patients.

Tables 1 and 2 summarize the results of the clinical study.

As shown in Table 2, the Telintra® response rate increased from approximately 22.2% for patients who had not previously been treated with Revlimid® to approximately 46.2% in patients who were treated with Revlimid® before the administration of Telintra®.

Table 1 Haematological-erythroid improvement (H I-E): Response time and response duration starting with Telintra® dose of 3,000 mg / day (1 .5 g b.i.d.) or 2, 000 mg / day (1 g b.i.d.) (Efficacy of evaluable population) [1] Days from the date of the first dose of study medication to the date of the first response documentation plus one divided by 7. [2] Total number of days where the response is seen divided by 7.

Table 2 Hematological improvement - erythroid (HL-E) (Efficacy of evaluable population) [3] Reduced RBC transfusion from the baseline = > 4 units for eight weeks; or patient with symptomatic anemias not dependent on transfusion with hemoglobin < 1 1 g / dl before treatment, achieving an increase in hemoglobin by > = 1.5 g / dl sustained over a period of eight weeks.

Claims (13)

1. CLAIMS 1. The use of ezatiostat or a salt thereof for the preparation of a medicament for treating a myelodysplastic syndrome in a patient who has had previous exposure to lenalidomide, wherein the ezatiostat or the salt thereof is administered daily for at least 2 weeks. 2. The use of claim 1, wherein the patient has developed intolerance to lenalidomide. 3. The use of claim 1, wherein the patient experiences a reduced therapeutic effect or lack of therapeutic effect with continued lenalidomide treatment. The use of any of claims 1-3, wherein the ezatiostat or the salt thereof is administered in a therapeutically effective amount. 5. The use of ezatiostat or a salt thereof for the preparation of a medicament for treating a myelodysplastic syndrome in a patient, wherein the ezatiostat or a salt thereof is administered with lenalidomide. 6. The use of claim 5, wherein the ezatiostat or salt thereof and lenalidomide are administered together in a therapeutically effective amount. 7. The use of any of claims 1-6, wherein the ezatiostat or salt thereof is administered orally. 8. The use of claim 7, wherein the ezatiostat or the salt thereof is administered according to a treatment program comprising the administration of a daily dosage of 2 grams for three weeks followed by a one-week break, wherein no ezatiostat or salt thereof is administered. 9. The use of claim 7, wherein the ezatiostat or salt thereof is administered in accordance with a treatment program comprising the administration of a daily dosage of 3 grams for two weeks followed by a one-week break, wherein nothing of ezatiostat or the salt thereof is administered. 10. A composition comprising ezatiostat or a salt thereof and lenalidomide, and optionally a pharmaceutically acceptable excipient. eleven . The composition of claim 10, wherein the ezatiostat or the salt thereof and the lenalidomide together are in a therapeutically effective amount. 12. A kit for the treatment of MDS comprising a first composition comprising lenalidomide and a second composition comprising ezatiostat or a salt thereof. 13. The kit of claim 12, wherein the ezatiostat or the salt thereof and the lenalidomide together are in a therapeutically effective amount.