TW201306834A - Compositions and methods for treating myelodysplastic syndrome - Google Patents

Abstract

This invention generally relates to compositions and methods for treating myelodysplastic syndrome. In one embodiment, this invention relates to methods for treating myelodysplastic syndrome with ezatiostat or a salt thereof and lenalidomide.

Description

Composition and method for treating myelodysplastic syndrome

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

Myelodysplastic syndrome (MDS) refers to a group of heterogeneous pure hematopoietic stem cell disorders characterized by ineffective hematopoiesis (blood cell production) associated with one or more cell lineages (red blood cells, white blood cells or platelets) and conversion to acute bone marrow Variable risk of leukemia (AML). The syndrome becomes more common with age. It is estimated that approximately 300,000 people worldwide are affected by MDS. 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 therapies range from 6 months to 6 years and patients often require blood transfusions to control their disease.

Currently, there are three drugs that have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS. Lenalidomide is indicated for the treatment of patients with transfusion-dependent MDS with del(5q) and lower risk, while azacytidine and decitabine are approved for use in all category. In addition to del(5q) patients, the response rate is approximately 50%, highlighting clinical trials requiring new agents.

Ezatiostat and its salts are disclosed in U.S. Patent No. 5,763,570. The IUPAC chemical name of Ezstat is ( 2S )-2-amino-5-[[( 2R )-3-phenylmethylsulfonyl-1-[[( 1R )-2-ethoxy-) 2-Phenoxy-1-phenylethyl]amino]-1-oxoylpropan-2-yl]amino]-5-oxoethoxyvalerate.

An example of a salt of Ezstat is the hydrochloride salt, Ezstat Hydrochloride (USAN), which has a molecular weight of 566.1 and is trademarked Telintra. The CAS Registry No. 286942-97-0. U.S. Patent Application Serial No. 13/041,136, filed on March 4, 2011, describes the solvates and polymorphs of Ezstat hydrochloride.

Liposomal formulations (U.S. Patent No. 7,029,695) have been used in Phase I-IIa studies (e.g., 2005 Annual Meeting of the American Society for Hematology (Abstract #2250) and by Raza et al. in Journal of Hematology & Oncology , 2 : 20 (reported online on May 13, 2009); and use of tablet formulations in Phase I studies (eg 2007 Annual Meeting of the American Society for Hematology (Abstract #1454) and by Raza et al. in Blood , 113: 6533-6540 (April 27, 2009 online pre-published) reported) and in a single case reports of patients (Quddus et al., Journal of Hematology & Oncology, 3: 16 (2010 Nian 4 Yue 23 on line open) Medium) Evaluation of treatment of MDS with Ezstat hydrochloride.

The entire disclosure of each of the patents, patent applications, and publications in

In one embodiment, the invention is a method of treating a patient's MDS, wherein the patient has previously been exposed to lenalidomide, the method comprising treating the patient with Ezast or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention is a method of treating MDS by administering Ezast or a salt thereof and lenalidomide.

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

In some embodiments, the Ezstat or its salt is administered daily for at least 2 weeks. In some embodiments, the Ezstat or its salt is administered daily for at least 3 weeks.

In the method of the present invention, the dosage regimen described in U.S. Patent Application Serial No. 13/108,752, entitled "COMPOSITIONS AND METHODS FOR TREATING MYELODY SPLASTIC SYNDROME", filed on May 16, 2011, is assigned to Ezter. Or a salt thereof, which is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in its entirety in the the the the the the the the the the For example, it can be administered orally by a dose of 2 g/day for 3 weeks/stop for 1 week or by oral administration of 3 g/day for 2 weeks/stop for 1 week. salt. It is also possible to use Ezast itself or other Ezstat salts or other routes of administration equivalent to the Ezstat dose.

In yet another aspect, the invention provides the use of Ezstat or a salt thereof for the manufacture of a medicament for treating a myelodysplastic syndrome of a patient previously exposed to lenalidomide.

In still another aspect, the present invention provides the use of Ezstat or a salt thereof for the preparation of a medicament for treating a myelodysplastic syndrome of a patient, wherein the Ezast or its salt and the genus The amine is administered together.

In another aspect, the invention provides a composition comprising lenalidomide and Ezstat or a salt thereof. These compositions preferably contain a pharmaceutically acceptable excipient to aid in administration.

In still another aspect, the present invention provides a kit for treating MDS comprising a first composition comprising a lenalidomide and a second composition comprising Ezra Ster or its salt.

These and other specific examples of the invention are further described below.

Before describing the invention in more detail, the following terms will first be defined.

It will be appreciated that the invention is not limited to the specific embodiments described, which may of course vary. It is also understood that the terminology used herein is for the purpose of describing the particular embodiments and is not intended to

It must be noted that the singular forms "a" and "the" Thus, for example, reference to "pharmaceutically acceptable excipient" includes a plurality of pharmaceutically acceptable excipients.

1. Definition

Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning The following terms as used herein have the following meanings.

The term "comprising" means that the composition and method include the elements, but does not exclude other elements. When used to define a composition and method, "consisting essentially of" shall mean the exclusion of other elements having any necessary meaning for the combination for the purpose. Therefore, a composition consisting essentially of the elements defined herein will not exclude other substances or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" means not including other constituent elements and substantial method steps beyond trace amounts. Specific examples defined by each of these terms are within the scope of the invention.

When used before a numerical symbol (eg, temperature, time, amount, and concentration (including range)), the term "about" indicates an approximation that may vary (+) or (-) by 15%, 10%, 5%, or 1%.

"Lenlimid" (Revlimid , also known as Revamid in the UK, is an immunomodulator with anti-angiogenic properties and anti-neoplastic properties. Its chemical name is 3-(4-amino-1-oxoisoindoline-2-yl)piperidine-2,6-dione or 1-o-oxo-2-(2,6-di Oleoxypiperidin-3-yl)-4-aminoisoindoline or 3-(7-amino-3-oxo-1H-isoindol-2-yl)piperidine-2,6 - Diketone and CAS registration number is 191732-72-6. Lenalidomide is indicated for the treatment of patients with blood transfusion dependence caused by low or moderate-1 risk MDS associated with a genetic abnormality in the absence of 5q cells. Lenalidomide can be used in the form of 5 mg (mg), 10 mg, 15 mg and 25 mg capsules for oral administration.

The term "therapeutically effective amount" refers to an amount of lenalidomide or Ezstat or a salt or combination thereof ("common") as defined herein sufficient to effect an individual in need of treatment. In one embodiment, the therapeutically effective amount will be administered up to 3.5 grams (g) of Ezstat or a salt thereof per day. Preferably, Ezstat or a salt thereof is administered in an amount of 2 grams per day and more preferably twice a day in an equivalent dose of 1 gram. Such a therapeutically effective amount is especially appropriate when the treatment regimen is administration of Ezastast or its salt for 3 weeks followed by discontinuation of administration of the drug for 1 week. In another embodiment, the therapeutically effective amount will be 3 grams of Ezstat or a salt thereof administered in a single dose or in two equal daily doses of 1.5 grams. Such a therapeutically effective amount is particularly appropriate when the treatment regimen is administration of Ezstat or its salt for 2 weeks followed by discontinuation of administration of the drug for 1 week. In the case of continuous administration or administration for 3 weeks and then discontinuation of administration for 1 week, the administration scheme preferably uses 2 g of Ezast or a salt thereof twice a day in an amount of 1 g.

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

As used herein, the term "treatment" means any treatment that produces one or more of the following effects on a patient's MDS:

‧ inhibit MDS, that is, block or inhibit clinical symptoms (such as the need for blood transfusion, abnormal blood counts and the like); and / or

‧ Relieve MDS, which causes symptoms to subside.

As used herein, the term "patient" refers to mammals and includes both human and non-human mammals.

2. Method

In one aspect of the invention, the invention relates to a method of treating a myelodysplastic syndrome (MDS) in a patient in need thereof, wherein the patient has previously been exposed to lenalidomide, the method comprising using Ezart The patient or a pharmaceutically acceptable salt thereof is used to treat the patient.

Surprisingly, patients who had been treated with lenalidomide prior to treatment with ezetamide hydrochloride exhibited a higher response rate and/or longer duration than patients who did not previously received lenalidomide treatment. For example, as shown in Table 2, the response rate of patients not pre-treated with lenalidomide was about 22% and the response rate of patients previously treated with lenalidomide was about 46%, and the reaction rate increased more than 100%.

Previous exposure to lenalidomide may be administered to the patient at any time prior to administration of Ezstat or its salt. A typical lenalidomide treatment consisted of a 28-day cycle in which lenalidomide was administered once daily for 21 days (3 weeks), followed by discontinuation of lenalidomide for 7 days (1 week). This 28 day cycle can be repeated for up to 6 months. Lenazamide capsules have four different strengths: 5 mg, 10 mg, 15 mg, and 25 mg.

In some embodiments of the invention, the patient has been treated with at least one dose of lenalidomide. In some embodiments, the patient has been 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 at least 1, 2, 3, 4, 5 or 6 lenalidomide treatment cycles. In some embodiments, the patient has completed a complete 6-month lenalidomide treatment regimen.

In some embodiments of the invention, the patient for lenalidomide treatment exhibits lenalidomide intolerance prior to administration of Ezstat or a salt thereof and ceases to be administered prior to initiation of administration of Ezstat or its salt. The lenalidomide treatment or the use of a lower lenalidomide dose. It will be appreciated that depending on the patient's tolerance to lenalidomide, the patient may discontinue the use of lenalidomide or switch to a lower lenalidomide dose after completion of the cycle or during the cycle.

As a derivative of thalidomide, lenalidomide causes many side effects such as birth defects and other adverse events. Adverse events reported include, but are not limited to, adverse events related to:

‧ Blood and lymphatic disorders such as thrombocytopenia, neutropenia (eg, febrile neutropenia), leukopenia, anemia, hemolytic anemia (eg warm hemolytic anemia), spleen infarction , bone marrow depression, coagulopathy, hemolysis and refractory anemia;

‧ skin and subcutaneous tissue disorders such as rash, dry skin, contusion, night sweats, increased sweating, ecchymoses 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 bleeding, colon polyps, diverticulitis, dysphagia, Gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, large intestine irritability, black feces, pancreatitis caused by biliary obstruction, pancreatitis, periorectal abscess, small bowel obstruction and upper gastrointestinal bleeding;

‧ respiratory, chest and mediastinal conditions such as nasopharyngitis, cough, dyspnea, pharyngitis, nosebleeds, exertional dyspnea, rhinitis and bronchitis;

‧ Musculoskeletal and connective tissue disorders such as joint pain, back pain, muscle cramps, limb pain, myalgia and peripheral swelling, arthritis, arthritis exacerbations, gouty arthritis, neck pain and pyrophosphate cartilage calcium Sedative disease

‧ benign or malignant neoplasms, such as acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer, lymphoma and prostate cancer;

‧ neurological disorders such as dizziness, headache, dysesthesia, dysgeusia and peripheral neuropathy;

‧ infection and infection, such as pneumonia, urinary tract infection, sinusitis, cellulitis, infection, bacteremia, central line infection, Clostridium infection, ear infection, Enterobacter sepsis , fungal infection, herpes virus infection, influenza, kidney infection, Klebsiella sepsis, lobar pneumonia, local infection, oral infection, pseudomonas infection, septic shock , acute sinusitis, sinusitis, Staphylococcal infection and urinary sepsis;

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

‧ mental illnesses such as insomnia, mental disorders and depression;

‧ nephropathy and urinary disorders such as dysuria, renal failure, hematuria, acute renal failure, nitroxemia, calculus ureteric and renal mass;

‧ reproductive system 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, cardiac-respiratory arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, atrial fibrillation , bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia and ventricular dysfunction;

‧ endocrine disorders, such as acquired hypothyroidism;

‧ ear disease and labyrinth disorder, such as dizziness;

‧ hepatobiliary disorders such as hyperbilirubinemia, acute cholecystitis, cholecystitis and liver failure;

‧ endocrine disorders such as Basedow's disease;

‧ immune system disorders, such as allergies;

‧ systemic conditions such as disease progression, falls, abnormal gait, intermittent fever, nodules, stiffness and sudden death;

‧ conditions that can be administered to the site, such as femoral fractures, transfusion reactions, cervical spine fractures, femoral neck fractures, pelvic fractures, hip fractures, overdose, postoperative bleeding, rib fractures, road traffic accidents, and spinal compression fractures; and

‧ Other observations, such as increased serum creatinine, hemoglobin reduction, abnormal liver function tests, increased alanine transaminase, and increased troponin I.

The most common and/or serious adverse events include neutropenia, thrombocytopenia, pneumonia, rash, anemia, leukopenia, fatigue, dyspnea, back pain, febrile neutropenia, nausea, diarrhea , fever, sepsis, dizziness, globular globule reduction, chest pain, pulmonary embolism, respiratory distress, itching, total hematocytopenia, muscle spasm, respiratory infection, upper respiratory tract infection, weakness, multiple organ failure, nosebleeds, hypoxia, Pleural effusion, pneumonia, high blood pressure in the pulmonary circulation, vomiting, increased sweating, joint pain, limb pain, headache and syncope.

In certain patient populations, one or more adverse events are too severe to allow the patient to be re-administered with lenalidomide or lenalidomide must be administered at a reduced dose. In such cases, the conversion of lenalidomide to Ezstat or its salt or the addition of Ezast or its salt not only avoids side effects, but also provides a preferred therapeutic effect of Ezstat or its salt.

In some embodiments of the invention, a patient treated with lenalidomide prior to administration of Ezstat or a salt thereof does not respond to lenalidomide or does not react with lenalidomide. Treatment continues and continues to occur. Approximately 50% of patients who received lenalidomide reported a clinically identifiable response. In such cases, patients treated with Ezstat hydrochloride did not respond to lenalidomide or stopped responding to lenalidomide with unexpectedly better therapeutic effects and reduced clinical symptoms. In this case, lenalidomide treatment may be continued at the same dose or at a reduced dose while administering Ezstat or its salt, or lenalidomide treatment may be completely stopped.

In some embodiments, Ezast or a pharmaceutically acceptable salt thereof is administered daily for at least 2 weeks. In some embodiments, Ezast or a pharmaceutically acceptable salt thereof is administered daily for at least 3 weeks.

In another aspect of the invention, the invention provides a method of treating a patient's myelodysplastic syndrome (MDS), the method comprising administering to the patient lenalidomide and Ezstat or its medicinal Acceptable salt. In some embodiments, Ezast or a pharmaceutically acceptable salt thereof is administered daily for at least 2 weeks. In some embodiments, Ezast or a pharmaceutically acceptable salt thereof is administered daily for at least 3 weeks. In such cases, the patient may or may not have been treated with lenalidomide prior to administration of Ezstat hydrochloride. The former case includes the above situation.

When administered simultaneously, lenalidomide and ezastatin or a salt thereof can be administered in any manner that allows the pharmacological effects of both to appear simultaneously in the patient. Therefore, simultaneous administration of lenalidomide and ezastatin or a pharmaceutically acceptable salt thereof does not require the use of a single pharmaceutical composition, the same dosage form, the same administration route, simultaneous administration of two agents, or similar persistence. Two doses of the drug were administered over time. When administered in the same dosage form and the same route of administration at substantially the same time, it can be carried out by simultaneously delivering the two active ingredients in the form of a single novel pharmaceutical composition of the invention. It will be appreciated that in addition to the above, the present invention contemplates simultaneous administration of a first pharmaceutical composition and a second pharmaceutical composition comprising lenalidomide and ezastatin or a pharmaceutically acceptable salt thereof, respectively. The term "simultaneously" includes both simultaneous delivery and sequential delivery, wherein each drug is administered separately in a manner that provides serum levels of both drugs simultaneously in the patient.

As described above, a clinician who uses only lenalidomide to treat a patient's MDS may add Ezast or a pharmaceutically acceptable salt thereof as a further component for treating the patient at some point in the treatment regimen. . This operational composition, which is later added with a combination of Ezstat or a pharmaceutically acceptable salt thereof and lenalidomide, is administered simultaneously for the purpose of the present invention, since the effects of both will be manifested simultaneously in the patient.

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

In some embodiments of the invention, when administered concurrently with Ezstat or a pharmaceutically acceptable salt thereof, lenalidomide is administered in a typical 28 day cycle as described above and may be administered in any dosage. Strength is given. In some embodiments, lenalidomide is administered at a reduced dose and/or frequency, for example, once every other day, every 3 days, every 4 days, every 5 days, or every 6 days. Give lenalidomide once. The lenalidomide may be administered once a week or lenalidomide may be discontinued and continued to be treated with Ezast or a pharmaceutically acceptable salt thereof.

Typically, a therapeutically effective amount of Ezstat or a salt thereof is administered. In some specific examples, the administration regimen described in U.S. Patent Application Serial No. 13/108,752, entitled "COMPOSITIONS AND METHODS FOR TREATING MYELODY SPLASTIC SYNDROME", filed on May 16, 2011, is assigned to Ezast or Salt, the patent application is incorporated herein by reference in its entirety.

In some embodiments, Ezast is administered in the form of Ezast hydrochloride or equivalent (by Ezart content) of Ezter itself or another Ezstat salt in an amount of up to about 3.5 grams per day. Or its salt. In a preferred embodiment, Ezstat or a salt thereof is administered in a therapeutically effective amount administered up to about 1.5 grams per day (b.i.d.).

In one embodiment of the invention, Ezast or a salt thereof is administered twice daily at a dose of 1 gram for 3 weeks, followed by discontinuation of administration of Ezstat or its salt for 1 week. After the suspension period, the program can be repeated as needed. This program can be called a "3 week plan."

In one embodiment of the invention, Ezast or a salt thereof is administered twice daily at a dose of 1.5 grams for 2 weeks, followed by discontinuation of administration of Ezstat or its salt for 1 week. After the suspension period, the program can be repeated as needed. This program can be called a "two-week plan."

In another embodiment of the invention, the patient is continuously treated with a therapeutically effective amount of Ezast or a salt thereof (preferably administered twice daily at a dose of up to 1.5 grams) of up to 3 grams per day. In this particular example, Ezstat or a salt thereof can be administered as long as the patient desires and can tolerate the treatment. It is contemplated that in this particular embodiment, the therapeutically effective amount of Ezstat or a salt thereof can be less than or greater than the therapeutically effective amount when there is a discontinuation period in the treatment regimen. This program can be called a "continuous plan."

Although it is preferred to administer the drug twice a day, it is expected to be administered once a day or three times a day. In the former case, administration once a day will help the patient to be compliant; in the latter case, a smaller lozenge may be used for patients who have difficulty swallowing a larger lozenge. The dosage will be adjusted such that the total daily dose is a therapeutically effective amount.

Treatment with Ezstat or a salt thereof can involve one or a combination of two or more of the dosage regimens described herein. The following is an example of the administration schedule of Ezstat hydrochloride:

‧ 1.5 g of Ezstat hydrochloride twice a day for 2 weeks (total 42 g), followed by a suspension of Ezstat or its salt for 1 week;

‧ 2 g of Ezstat hydrochloride twice a day for 3 weeks (total 42 g), followed by a suspension of Ezstat or its salt for 1 week;

‧ 1 g of Ezstat hydrochloride is administered twice a day until the attending clinician considers the patient to be suitable for discontinuation;

‧ administering up to 3 grams of therapeutically effective amount of Ezstat hydrochloride for 2 weeks per day in 1, 2 or 3 divided doses, followed by discontinuation of administration of Ezstat or its salt for 1 week;

‧ administering up to 2 grams of therapeutically effective amount of Ezstat hydrochloride for 3 weeks per day in 1, 2 or 3 divided doses, followed by discontinuation of administration of Ezast or its salt for 1 week; and/or

‧ Continuously deliver up to 2 grams of therapeutically effective amount of Ezstat hydrochloride daily in 1, 2 or 3 divided doses until the attending clinician considers the patient to be eligible to discontinue medication.

The equivalent amount of Ezstat itself or another Ezstat salt (associated according to the Ezart content) can be used to replace Ezstat hydrochloride in the above dosing schedule.

When Ezast or a salt thereof is administered twice daily, the time interval between the first dose and the second dose is preferably from about 6 to 14 hours and preferably between about 8 hours and 14 hours.

In one embodiment, Ezstat or a salt thereof (e.g., Ezstat hydrochloride) can be administered intravenously in the form of a lipid formulation, such as the lipid formulation described in U.S. Patent No. 7,029,695, which is incorporated by reference in its entirety The way is incorporated in this article.

In another embodiment, Ezstat or a salt thereof, such as Ezstat hydrochloride, can be administered orally. In one embodiment, Ezstat or a salt thereof (e.g., Ezstat hydrochloride) can be administered as a tablet formulation. Such a tablet formulation is disclosed in U.S. Patent Application Serial No. 13/075,116, filed on Mar. 29, 2011, which is incorporated herein by reference.

3. Composition

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

In some embodiments, Ezstat or a salt thereof and lenalidomide are a therapeutically effective amount.

In some embodiments, lenalidomide and/or ezastatin or a salt thereof is 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 Ezast or its salt.

In one embodiment, lenalidomide can be added to a lipid formulation of Ezstat or a salt thereof (described in U.S. Patent No. 7,029,695).

In another embodiment, lenalidomide can be added to the formulation of the Ezast or its salt lozenge. Such a tablet formulation is disclosed in U.S. Patent Application Serial No. 13/075,116, filed on Mar. 29, 2011, which is incorporated herein by reference.

4. Set

In still another aspect, the present invention provides a kit for treating MDS comprising a first composition comprising a lenalidomide and a second composition comprising Ezra Or its salt (including the salts described herein).

In some embodiments, Ezstat or a salt thereof and lenalidomide are a therapeutically effective amount.

In some embodiments, the kit further comprises administering a first dose of lenalidomide 1 day, 2 days, 3 days, 4 days, 5 days, 6 days prior to the first administration of Ezast or its salt. Description label. In some embodiments, the kit further includes instructions for administering lenalidomide at 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks prior to administration of Ezstat or its salt. In some embodiments, the kit further includes an instructional label for simultaneous administration of lenalidomide and Ezstat or a salt thereof. In some embodiments, the kit further includes instructions for administering lenalidomide and ezastatin or a salt thereof according to any of the dosing schedules described herein.

Example

The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that various modifications may be made in the materials and methods without departing from the scope of the invention.

The role of Ezstat hydrochloride in patients with low to moderate-1 risk of myelodysplastic syndrome in the International Prognostic Score System (IPSS)

Eighty-seven patients were randomly selected and treated at 23 study sites. After an initial dose range study in 14 patients, two doses were selected for further study. Next, 37 patients were treated with a daily dose of 3 grams for 2 weeks, followed by a one-week suspension period, and 36 patients were treated with a 2 gram dose per day for 3 weeks, followed by a one-week suspension period. The data of these 73 patients were combined for this preliminary analysis.

The median age was 72 years and the patient population was low risk for IPSS (23 patients, 32%) and moderate-1 risk (50 patients, 68%). The patient has received one of three previous MDS therapies, including 34 patients (47%) who received the previous Revlimid (Lenalidomide) treatment and 28 patients (38%) received prior DNA methyltransferase inhibitor (DMTI) [azacitidine, decitabine] treatment.

At the time of the initial analysis, 8 patients continued to receive treatment to continue to receive clinical benefit. The overall hematologic improvement-red blood cell (HI-E) improvement rate was 13% (95% CI, 12.1-34.2) in 13 of the 60 evaluable patients. The median duration of the HI-E reaction was 46 weeks (range 2-51 weeks). The median hemoglobin content in the responders increased by 2.0 g/dl. Eleven of the 38 red blood cell (RBC) infusion-dependent patients (29%) had a clinically significant reduction in RBC infusion (4 U/8 weeks reduction, IWG 2006), of which 4 patients (11%) were no longer dependent on RBC The infusion and 3 patients continued to receive treatment. One patient continued to achieve complete remission for more than 12 months after discontinuation of treatment (Quddus et al, J. Hem. and Onc. April 2010, 3:15).

Telintra Continuous display of multilineage hematologic improvement. Fifteen patients with hematologic improvement-neutrophil (HI-N) improvement rate (95% CI, 3.2-37.9) were observed in 3 of 20 patients, and 2 of the 19 patients were doubled. The line HI rate (HI-E and HI-N) was 11% (95% CI, 1.3-33.1).

There are three complete cytogenetic responses, one occurring with 45X, -Y[4], 46, XY[16] cytogenetic abnormalities and these cytogenetic abnormalities are converted to normal after 4 treatment cycles Among patients. Of the 4 del 5q-deficient patients enrolled in the study, 2 patients had a complete cytogenetic response, including 1 in the previous Revlimid A patient who fails under therapy.

Use the planned logistic regression analysis to evaluate all known prognostic characteristics to define the relationship to Telintra A patient with an increased likelihood of a HI-E response. Previous DMTI treatments have been shown to appear on Telintra The likelihood of a HI-E response was reduced by a factor of 5 (p=0.023). Observed the previous Revlimid Treatment enhanced for Telintra HI-E reaction.

‧ Previously used Revlimid The HI-E rate was 40% in patients who were previously treated without DMTI (6 of 15 patients, 95% CI, 16.3%-67.7%). In this patient population, 5 of 11 patients (45%) achieved a significant reduction in RBC infusion, and 3 of these patients (27%) were no longer dependent on infusion.

‧ Previously not used Revlimid The HI-E rate was 26% in patients treated and previously not treated with DMTI (6 of 23 patients, 95% CI, 10.2% - 48.4%). In this cohort, 5 of 11 patients (45%) achieved a significant reduction in RBC infusion.

‧ Previously not used Revlimid The HI-E rate was 0% in patients treated with previous DMTI (0 of 17 patients, 95% CI, 0%-19.5%).

More than 403 Telintra Treatment cycle. Safety data is based on all patients treated. The most common non-hematologic adverse events (AEs) were grade I gastrointestinal events (GI) and grade II gastrointestinal events, namely nausea (45%, 16%), diarrhea (25%, 7%), and vomiting (30). %, 12%). Grade III events were uncommon: nausea (1%), diarrhea (3%), and vomiting (2%). Previous DMTI treatments have been associated with an increased incidence of GI AE.

Telintra Treatment may result in a clinically significant improvement in the hematology profile of MDS patients and may provide an alternative to RBC infusion. These results are related to the observations in the previous study of Telintra The level of efficacy of the first GST P1-1 enzyme inhibitor tested in patients with MDS was consistent.

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

As shown in Table 2, for Telintra Reaction rate since the previous use of Revlimid About 22.2% of patients treated were added to the administration of Telintra Before using Revlimid About 46.2% of patients treated.

Claims (22)

Use of ezatiostat or a salt thereof for the preparation of a medicament for treating a myelodysplastic syndrome of a patient who has previously been exposed to lenalidomide, wherein the ectopic dose is administered daily Zarst or its salt lasts for at least 2 weeks. The use of the first aspect of the patent application wherein the patient has developed lenalidomide intolerance. For example, the use of the scope of claim 1 wherein the patient experiences a decrease or deficiency in the therapeutic effect when continuing the treatment with lenalidomide. The use of any one of clauses 1 to 3, wherein the Ezastast or a salt thereof is administered in a therapeutically effective amount. A use of Ezstat or a salt thereof for the preparation of a medicament for treating a myelodysplastic syndrome of a patient, wherein the Ezastast or a salt thereof is administered together with lenalidomide. The use of claim 5, wherein the Ezastast or a salt thereof and the lenalidomide are administered together in a therapeutically effective amount. The use of any one of claims 1 to 6, wherein the Ezstat or its salt is administered orally. The use of the seventh aspect of the patent application, wherein the Ezast or its salt is administered according to a course of treatment comprising administering a daily dose of 2 g for 3 weeks, followed by suspending the administration of the Zarst or its salt for 1 week. . The use of the seventh aspect of the patent application, wherein the Ezast or its salt is administered according to a course of treatment comprising administering a daily dose of 3 grams for 2 weeks, followed by suspending the administration of the Zarst or its salt for 1 week. . A composition comprising ezastatin or a salt thereof and lenalidomide and, optionally, a pharmaceutically acceptable excipient. The composition of claim 10, wherein the Ezastast or a salt thereof and the lenalidomide are together in a therapeutically effective amount. A kit for treating MDS comprising a first composition comprising a lenalidomide and a second composition comprising Ezastast or a salt thereof. A kit of claim 12, wherein the Ezastast or a salt thereof and the lenalidomide are together in a therapeutically effective amount. A pharmaceutical composition for treating a myelodysplastic syndrome of a patient who has previously been exposed to lenalidomide, comprising a therapeutically effective amount of ezastatin or a salt thereof for daily administration of the ezastatin or a salt thereof Continue for at least 2 weeks. For example, the pharmaceutical composition of claim 14 wherein the patient has developed lenalidomide intolerance. For example, the pharmaceutical composition of claim 14 wherein the patient experiences a decrease or deficiency in therapeutic effect while continuing to receive lenalidomide treatment. A pharmaceutical composition according to any one of claims 14 to 16, which is for administering a therapeutically effective amount of the Ezstat or a salt thereof. A pharmaceutical composition for treating a myelodysplastic syndrome of a patient comprising Ezast or a salt thereof and lenalidomide. A pharmaceutical composition according to claim 18, which is for co-administering a therapeutically effective amount of the Ezstat or a salt thereof and the lenalidomide. The pharmaceutical composition according to any one of claims 14 to 19, which is for oral administration of the Ezstat or a salt thereof. A pharmaceutical composition according to claim 20, which is for administering the Eza according to a course of treatment comprising administering a daily dose of 2 g for 3 weeks, followed by suspending the administration of the Zarst or its salt for 1 week. Ster or its salt. The pharmaceutical composition of claim 20, which is for administering the Eza according to a course of treatment comprising administering a daily dose of 3 grams for 2 weeks, followed by suspending the administration of the Zarst or its salt for 1 week. Ster or its salt.