MXPA00003346A - Chronic myeloid leukemia (cml) therapy - Google Patents

Abstract

Methods for treating treatment-naive as well as treatment-experienced patients having CML to achieve at least a partial cytogenetic response involving administering a therapeutically effective amount of pegylated interferon-alfa, e.g. , pegylated interferon alfa-2b as monotherapy or in association with a therapeutically effective amount of Ara-C are disclosed.

Description

THERAPY FOR LEUKEMIA M.ELOCIT.CA CHRONICLE BACKGROUND OF THE INVENTION This invention relates to an improved therapy for treating patients having chronic mejeocytic leukemia ("CML") by administering a therapeutically effective dose of PEG-modified interferon-alpha for a sufficient time to achieve at least a partial cytogenetic response. Guilhot, F. et al described in N. Engl. J. Med., 1997, Volume 337, pages 223-229 that the combination of interferon alfa-2b and cytarabine increased the speed of main cytogenetic response and prolonged the survival in patients in the chronic phase of CML. It should be noted that daily injections were required to achieve these results. In addition, interferon alfa-2b has many side effects that find a number of patients unacceptable, and the adequacy of the patient to daily injections of interferon alfa-2b becomes a problem. Allogeneic bone marrow transplantation ("BMT") may be an alternative for CML patients with identical HLA relatives. However, many patients are very old or lack adequate donors and, therefore, BMT can not be performed for most of these patients. (See the Goldman Publisher, John M. In N. Engl. J. Med. 1997, volume 337, pages 270-271).

Accordingly, there is a need for improved therapy to treat patients with CML.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a method for treating a patient having chronic myelogenous leukemia comprising administering to said patient a therapeutically effective amount of PEG-modified interferon alpha for a period of time sufficient to obtain at least a partial cytogenetic response. The present invention also provides a method for treating a patient having chronic phase chronic myelocytic leukemia comprising administering to said patient an effective amount of PEG-modified interferon-alpha once a week for a period of time sufficient to achieve at least a partial cytogenetic response. The present invention further provides a method for a patient who is in the chronic phase of chronic melanogenic leukemia comprising administering to said patient between about 4.5 micrograms / kg and about 9.0 micrograms / kg of interferon alfa-2b modified with PEG once a week for a period of time sufficient to achieve at least a partial cytogenetic response.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an improved method for treating patients with CML, especially those in the chronic phase of CML. The improved method provides a safer, more effective and tolerable treatment for CML through the use of weekly injections of alpha-interferon modified with PEG alone or in combination with chemotherapeutic agents such as, for example, cytarabine. Patients with CML include those recently diagnosed with this disease, as well as those patients who can not tolerate or are resistant to interferon alfa. Normally, hydroxyurea is given if necessary to patients with CML before starting the method of the present invention to reduce the white blood cell count. Treatment with alpha-interferon modified with PEG according to the present invention will continue for a minimum of six months, and preferably for at least twelve months, unless there is clinical evidence of disease progression, unacceptable toxicity or the patient requires discontinue therapy. When PEG-modified interferon-alpha is administered is a PEG-modified interferon alpha-2b, the therapeutically effective amount of PEG-modified interferon alpha-2b administered is within a range between about 4.5 and about 9.0 micrograms per kilogram of interferon alfa-2b modified with PEG administered once a week (QW), preferably between about 4.5 and about 6.5 micrograms per kilogram of PEG-modified interferon alfa-2b once a week, more preferably between about 5.5 and about 6.5 micrograms per kilogram of interferon alfa-2b modified with PEG administered once a week, and more preferably about 6.0 micrograms per kilogram of interferon alfa-2b modified with PEG administered once a week. When PEG-modified interferon is administered it is PEG-modified alga-2a interferon, the therapeutically effective amount of PEG-modified interferon alfa-2a administered is within a range between about 50 micrograms and about 500 micrograms once a week ("QW"), preferably between about 200 micrograms and about 250 micrograms once a week. The term "alpha-interferon modified with PEG" as used herein refers to modified polyethylene glycol conjugates of interferon alpha, preferably interferon alpha-2a and -2b. The preferred polyethylene glycol-interferon alpha-2b conjugate is PEG? 2u-interferon alpha 2b. The phrases "alpha-interferon conjugated with polyethylene glycol of 12,000 molecular weight" and "PEG12000-IFN alpha" as used herein, refer to conjugates as prepared according to the methods of International Application No. WO 95/13090 and contain urethane linkages between the interferon alpha-2a or 2b groups and the polyethylene glycol having a molecular weight of 12,000. The preferred PEGi2ooo-interferon alpha-2b is prepared by linking a PEG polymer to the epsilon amino group of a lysine residue in the IFN alpha-2b molecule. A simple PEG? 2ooo molecule is conjugated to free amino groups on an IFN alpha-2b molecule by means of a urethane linkage. This conjugate is characterized by the molecular weight of PEG-α 2 or annexed. The PEG12000-IFN alpha-2b conjugate is formulated as a lyophilized powder for injection. The goal of conjugation of IFN alpha with PEG is to improve the distribution of the protein by means of the significant prolongation of the useful life of plasma, and thus providing prolonged activity of IFN alpha. The term "interferon alpha" as used herein refers to the specific family of proteins of highly homologous species that inhibit viral replication and cell proliferation and modulate the immune response. Typical suitable interferon-alphas include, but are not limited to, recombinant interferon alpha-2b such as, for example, interferon interferon-A marketed by Schering Corporation, Kenilworth, NJ, recombinant alpha-2a interferon such as, for example, interferon Roferon. marketed by Hoffmann-La Roche, Nutley, NJ, recombinant interferon alpha-2c such as, for example, interferon Berofor alpha 2 marketed by Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, CT., interferon alpha-n1, a purified mixture of natural alpha interferons such as, for example, Sumiferon marketed by Sumitomo, Japan or interferon alfa-n1 Wellferon (INS) marketed by Glaxo-Wellcome Ltd., London, Great Britain, or a consensual alpha interferon such as those described in US Patent No. 4,897,471 and the U.S. Patent No. 4,695,623 (especially in Examples 7, 8 or 9) and the specific product distributed by Amgen Inc., Newbury Park, CA, or interfer alpha-n3 a mixture of natural alpha interferons prepared by Interferon Sciences and marketed by Purdue Frederick Co., Norwalk, Ct, under the trade name Alferon. The use of interferon alpha-2a or alpha-2b is preferred. Since interferon alfa-2b, among all interferons, has the widest global approval for the treatment of chronic hepatitis C infection, it is the most preferred. The manufacture of interferon alpha-2b is described in U.S. Patent No. 4,530,901. Other alpha interferon conjugates can be prepared by linking an alpha interferon to a water soluble polymer. A non-limiting list of these polymers includes other polyalkylene oxide homopolymers such as, for example, polypropylene glycols, polyoxyethylenated polyols, their copolymers and their block copolymers. As an alternative to the polyalkylene oxide-based polymers, effectively non-antigenic materials can be used such as, for example, dextran, polyvinylpyrrolidones, polyacrylamides, polyvinyl alcohols, carbohydrate-based polymers and the like. These interferon alpha-polymer conjugates are described in U.S. Patent No. 4,766,106, U.S. Patent No. 4,917,888, European Patent Application No. 0,236,987, European Patent Application No. 0,510,356, 0,593,868 and 0,809,996 (interferon alfa-2a modified with PEG) and International Publication No. WO 95/13090. The pharmaceutical composition of interferon alpha modified with PEG suitable for parenteral administration can be formulated with a suitable regulator, for example, Tris-CHI, acetate or phosphate such as, for example, a sodium basic phosphate regulator / sodium phosphate monobasic, and pharmaceutically acceptable excipients (e.g. sucrose), carriers (e.g., human serum albumin), agents for toxicity (e.g., NaCl), preservatives (e.g., thimerosol, cresol or benylalcohol), and surfactants (e.g., Tween or polysorbates) in sterile water for injection. PEG-modified interferon alpha can be stored as lyophilized powder under refrigeration at 2-8 ° C. The reconstituted aqueous solutions are stable when stored at 2 ° to 8 ° C and are used within 24 hours of reconstitution. See, for example, U.S. Patent No. 4,492,537; U.S. Patent No. 5,762,923 and U.S. Patent No. 5,766,582. Reconstituted aqueous solutions can also be stored in pre-filled multi-dose syringes, such as those used to distribute drugs such as insulin. Typical suitable syringes include systems comprising a pre-filled vial attached to a pencil-type syringe such as NOVOLET Novo Pen marketed by Novo Nordisk, as well as pre-filled pencil-type syringes that allow easy self-application by the user. Other syringe systems include the pencil-type syringe comprising a glass cartridge containing a diluent and powder of interferon alpha modified with freeze-dried PEG in a separate behavior. CML (chronic myelogenous leukemia) is a clonal myeloproliferative disorder that is a neoplastic proliferation of the pluripotent stem cell. In CML, leukemia cells retain some ability to differentiate. Therefore, at the time CML is diagnosed, the white blood cell count in CML may be within a range between 10000 and > 200,000 cells / mm3 with 90% cells in the granulocyte series. Hematocrit, hemoglobin, and platelet counts are usually normal, although the platelet count and the number of basophils can be increased. CML was the first cancer associated with a specific cytogenetic abnormality, the Philadelphia chromosome (Ph1), a reciprocal displacement that includes chromosomes 22 and 9. A segment of the long arm of chromosome 9 that contains the c-abl oncogene moves to the position q11 on chromosome 22 within a specified segment designated as the region of breakpoint grouping (bcr). This produces a new gene, bcr / abl, on chromosome 22 within an associated abnormal messenger RNA, which can be detected by means of RT-PCR (reverse polymeric reverse transcriptase chain reaction), and an abnormal protein product. A rearrangement of the bcr / abl gene is the main pathogenic mechanism underlying the development of CML. The term "cryogenic response" as used herein refers to the reduction or elimination of Philadelphia chromosome positive cells ("Ph1 + cells") in the bone marrow. A complete cytogenetic response refers to no Ph1 + cells; a major cytogenetic response refers to that there are between about 1 and about 34% of said cells i.e., < about 35% of Ph1 + cells. A minor response refers to that between about 25 and about 90% of these cells and the treatment fail in between about 91 and about 100% of these cells, ie, > about 90% of Ph1 + cells.). Doctors have suggested that the achievement of a greater cytogenic response is to say < About 35% of Ph + cells in the bone marrow after one year of therapy for CML is predictive of long-term survival. The term "patient suffering from chronic myelogenous leukemia or CML" as used herein refers to any patient suffering from CML and includes patients without prior treatment, as well as patients who underwent some treatment in the chronic phase of CML. The term "untreated patients" as used herein refers to patients with CML, including patients with recently diagnosed CML, who have never been treated with any chemotherapeutic drug, including, but not limited to, for example, busulfan ( "BU"), hydroxyurea ("HU"), homoharringtonine ("HHT"), cytarabine ("Ara-C"), Idadubicin ("I"), Etoposide ("E") or chemotherapeutic drug combinations, ie, I + Ara-C + E, that is, "ICE" as well as any interferon, including but not limited to interferon alfa or interferon modified with PEG. The term "patients who experienced some treatment" as used herein refers to patients who have initiated some form of therapy with a chemotherapeutic drug that includes, but is not limited to, busulfan ("BU"), hydroxyurea ("HU" ), homoharringtonine ("HHT"), cytarabine ("Ara-C"), Idadubicin ("I"), Etoposide ("E") or combinations of chemotherapeutic drugs, for example, "ICE". The term "hematological response" as used herein refers to the improvement in WBC and platelets. A complete haematological response refers to WBC less than 10000 per microliter and a platelet count less than 450000 per microliter and normal differential in peripheral blood and non-palpable spleen. A partial haematological response refers to a WBC less than about 20,000 per microliter, or at least a reduction of about 50% in the WBC baseline (evaluated before treatment). In a preferred embodiment of the present invention, hydroxyurea is administered to patients with CML before the initiation of the treatment with alpha-interferon modified with PEG and preferably around two weeks and about three months before the initiation with the interferon alfa modified with PEG. Formulations of PEG-modified interferon alpha are not effective when administered orally, therefore, the preferred mode of administration of PEG-modified interferon alpha is parenterally, preferably by means of a subcutaneous, IV, or IM injection. Of course, other types of administration of both drugs are contemplated, for example, by nasal spray, transdermally, by suppository, by means of the sustained release dosage form, and by pulmonary inhalation. Any form of administration will work as long as the proper doses are administered without destroying the active ingredient. The following Clinical Study Design can be used to treat patients with CML according to the method of the present invention. Many modifications to this Clinical Study Design protocol will be obvious to the trained clinician, and the following Clinical Study Design should not be construed as limiting the scope of the method of this invention which is defined by the claims below.

Clinical Study Design In a preferred embodiment of the method for the treatment of CML of the present invention, subjects newly diagnosed with CML, hydroxyurea, may be administered for a maximum of up to 3 months to control WBC counts. This treatment is not necessary in subjects presenting WBC of 50000 μl. The "date of diagnosis" will be considered as the date on which the subject is confirmed to be Ph1 + by means of the cytogenetic test (performed in any laboratory using RT-PCR). The randomization in this study should take place within 3 months from the initial diagnosis, and after WBC of 50000 μl. Subjects who do not reach a WBC of 50000 μl or who have progressive splenomegaly after pre-treatment with hydroxyurea will not be randomly chosen to receive the study drug. Subjects who do not reach a WBC of 50000 μl without progressive splenomegaly after up to about 3 months of hydroxyurea therapy will be randomly chosen in one of the two treatment groups A and B as follows: subjects will receive interferon alfa 2b modified with PEG, ie PEG-? 20o-interferon alfa 2b in doses of 6.0 micrograms per kilogram of subcutaneous injection once a week (Group B) or interferon alfa-2b in doses of 5 million international units per square meter of body surface area per day "5 MIU / m2 / day) (Group A) Group A: INTRON® (interferon alfa-2b, recombinant) 5 MIU / m2 daily per injection SC Group B: US Patent PEG Intron (PEG12uoo - recombinant alfa-2b interferon) 6.0 μg / kg weekly by SC injection Duration of the Study and Outline of visits The duration of this study is based on achieving a therapeutic response, and will be determined by each subject individually. Treatment with either PEG Intron or INTRON® A will continue for a minimum of 6 months unless there is evidence of disease progression, unacceptable toxicity, or the subject requests to discontinue therapy. The haematological response will be evaluated in months 3, 6, 9, and 12 and the cytogenetic response will be evaluated in months 6 and 12 during the first year of study treatment. The subjects who achieve a complete hematologic response in three months must have the cytogenetic response evaluated in 3 months. The pharmacokinetics of the population will be carried out in several points of the study. In addition, the quality of life and the total life data will be reported. Subjects who achieve a complete hematologic response in 6 months will continue treatment for another 6 months. At the end of the six months of treatment, the subject's hematologic response will be evaluated to determine whether the subject has achieved a complete hematologic response. Subjects who achieve a complete hematologic response can continue treatment. Criteria for complete blood response: • WBC < 10,000 / μl • Platelets < 450000 / μl • Normal differential in peripheral blood (PB) • No palpable spleen Treatment failure will be considered in subjects who do not achieve a complete hematologic response after 6 months of treatment. The realization of another treatment for this group will be at the discretion of the doctor. Subjects can continue to receive their medication assigned by the study for an additional 6 months according to that protocol. The addition of Ara-C will be allowed to subjects who failed treatment. These subjects will continue the evaluations assigned for the study, including the 12-month cytogenetic evaluation.

• After one year of treatment, the subject who has achieved at least a partial cytogenetic response (90% Ph1 +) can continue the treatment of the study until the progression of the disease. For subjects who do not achieve a minor cytogenetic response after 1 year of treatment, it will be considered a failed treatment and the study treatment will be discontinued. After 2 years of treatment, subjects who have achieved a major cytogenetic response (35% of ph1 + cells) can continue the treatment until the progression of the disease. Subjects who have not achieved a major cytogenic response will discontinue the study. All subjects will be followed up on their life, regardless of whether they left the study or not. After 12 months of treatment, subjects who obtained a minor cytogenetic response (ie, 90% of Ph1 + cells) will be accepted to continue treatment for an additional 12 months. After 2 years of treatment, subjects with a partial or complete cytogenetic response (ie, <35% of Ph1 + cells) can continue with the treatment until the progression of the disease. The goal of the improved CML therapy of the present invention is to achieve at least a partial cytogenetic response (<90% of Ph1 + cells) after 6 to 12 months of treatment and preferably to achieve a partial or complete cytogenetic response (< 35% of Ph1 + cells) after 12 to 24 months of treatment.

The following clinical protocol can be used to administer the CML therapy of the present invention. The study population will include male and female patients with recently diagnosed CML without prior treatment and will be included if they meet the following inclusion or exclusion criteria.

Inclusion criteria a) Subjects who were diagnosed with CML in the chronic phase within three months prior to enrollment in the study. The date of diagnosis is the date of the first documentation of the presence of the chromosome Philadephia (Ph1 +) confirmed by means of a cytogenetic test, performed by a central laboratory. b) Subjects must have chronic phase CML that is positive in Ph1 + cells confirmed by cytogenetic studies, performed in a central laboratory. c) Subjects must meet or exceed the following hematological criteria • Platelet count > 50000 / μl • Hemoglobin > 9.0 g / dL • WBC count > 2000 / μl but 50.00 / μl d) Subjects should have adequate liver and kidney function defined by the following parameters, obtained within 14 days before the start of study treatment: • SGOT and SGPT < 2 times the upper limit of the laboratory normal (ULN) • Bilirubin in plasma < 2 times ULN • Plasma creatinine < 2.0 mg / dL e) Subjects must be fully recovered from any previous major surgery and must have been at least 4 weeks post-operative. f) Subjects must be between 18-70 years old g) Subjects must have an ECOG performance status of 0-2 h) Subjects must sign in writing, voluntary consent before beginning the study, confirming that they wish to participate in this study and who wish to complete all follow-up evaluations.

Exclusion criteria a) Subjects with accelerated or blast phase CML defined by the following criteria.

Criterion for accelerated phase CML (any of the following): Myeloblasts in peripheral blood 15% Basophils in peripheral blood 20% Myeloblasts in peripheral blood plus proyelocytes 30% Platelets < 100000 / μL not related to therapy Criterion for CML of the blasto: 30% of myeloblasts in peripheral blood or bone marrow b) Subjects who are candidates for and plan to receive bone marrow transplantation allogeneic, syngeneic or derived from itself (BMT) within the next 12 months. c) Subjects who have received previous treatment for their CML, except for hydroxyurea. d) Subjects who have severe cardiovascular disease, for example, arrhythmias that require chronic treatment, congestive heart failure (NYHA Class III or IV), symptomatic ischemic coronary disease. e) Subjects with a history of neuropsychiatric disorders requiring hospitalization. f) Subjects with thyroid dysfunction who do not respond to therapy g) Subjects with uncontrolled diabetes mellitus h) Subjects who have a history of seropositivity for HIV) Subjects with active and / or uncontrolled infection, including active hepatitis j) Subjects with a medical condition requiring chronic systemic corticosteroids k) Subjects with a history of previous malignancies within the last 5 years, except for cancer of non-melanoma skin surgically cured, or cervical carcinoma in situ. I) Subjects who have received any experimental therapy within 30 days before enrolling in this study m) Subjects that are known to actively abuse alcohol and drugs. n) Women who are pregnant, breastfeeding, or have a reproductive potential and who do not practice an effective means of contraception.

Discontinuation criteria It is the right and duty of the investigator to interrupt the treatment of any subject whose health or well-being may be threatened by the continuity of the study. Subjects may discontinue before completing the study due to any of the following reasons: a) Experience the onset of CML in accelerated phase or blasto. b) The WBC rises to 100000 / μl after 3 months of treatment with both INTRON® A or PEG intron despite treatment with hydroxyurea.

Treatment with hydroxyurea is prohibited after 3 months of study. C) Has a significant clinical adverse event determined by the principal investigator. d) Does not achieve the desired therapeutic responses in months 6 and 12 e) Requests to be withdrawn from the study f) Can not meet the requirements for evaluations / visits of the study g) Develop circumstances that prevent evaluations / views of the study h) Develop other conditions by which, according to the opinion of the researcher, the best thing for the subject is to withdraw from the study i) Develop a severe depression or any other psychiatric disorder that requires hospitalization j) Experience a serious allergic response to the study drug manifested by angioedema, bronconstriction or anaphylaxis k) Experiences recurrent toxicities despite dose reductions I) Receives a treatment with a prohibited medication Analysis of primary and secondary endpoints The endpoint of primary efficacy will be the cytogenetic response in 12 months. The primary analysis will be the comparison of the treatment groups with respect to the proportion of the treatment groups with respect to the proportion of subjects with greater cytogenetic response in 12 months using the Cochran Mantel-Haenszel test adjusting for the strata. A summary of the relationship by differences and the 95% safety intervals for the relationship by differences will be made. The analysis will be made on the treatment-based basis. The primary analysis will be based on the cytogenetic response where those who respond are those subjects who did not have failures in the treatment and those who had a main cytogenetic response (<35% of Ph1 + cells) in 12 months. In this analysis, subjects who failed treatment at 6 months will be eliminated in the cytogenetic evaluation. In a secondary analysis of cytogenetic response, subjects will be analyzed according to their cytogenetic response in 12 months, regardless of whether or not they failed treatment. The secondary end points of the study will be the cytogenetic response at 6 months, the haematological response at 3, 6 and 12 months, and the total life expectancy. The cytogenetic response at 6 months and the haematological response at 3, 6 and 12 months will be analyzed using the Cochran Mantel-Haenszel test. The total lifetime will be analyzed using the log rank statistic. The Kaplan-Meier estimates of the over-life curves will be provided. The relationship between the risk and the 95% safety interval for the risk ratio will be obtained using the Cox proportional hazards model.

Claims (20)

NOVELTY OF THE INVENTION. . . » CLAIMS

1. The use of PEG-modified interferon alfa for the manufacture of a medicament for treating a patient with chronic melanogic leukemia, wherein said PEG-modified interferon alpha is administered for a sufficient period to obtain at least a partial cytogenic response.

2. The use of claim 1, wherein the PEG modified interferon is interferon alfa-2 a modified with PEG or interferon alfa-2b modified with PEG.

3. The use of claim 2, wherein the patient is a patient without prior treatment.

4. The use of claim 3, wherein the patient who was not treated is someone who was recently diagnosed with chronic myelogenous leukemia.

5. The use of claim 1, wherein the patient is a patient who underwent some treatment.

6. The use of claim 5, wherein the patient who underwent some treatment does not tolerate interferon alfa or is resistant to interferon alfa.

7. - The use of claim 1, wherein the period is at least 6 months.

8. The use of claim 1, wherein the cytogenetic response is a complete cytogenetic response.

9. The use of PEG-modified interferon alfa for the manufacture of a medicament for treating a patient who is chronically in chronic melogenic leukemia where said PEG-modified interferon alfa is administered once a week for a sufficient period to obtain at least a partial cytogenic response.

10. The use of claim 9, wherein the PEG-modified interferon alfa is interferon alfa-2b modified with PEG and said medicament provides from about 4.5 micrograms / kg to about 6.5 micrograms / kg of interferon alfa-2b modified with PEG to the patient when said medication is administered once a week.

11. The use of claim 9, wherein the PEG-modified interferon alpha is interferon alfa-2a modified with PEG and the effective amount is within a range between about 200 micrograms and about 250 administered once a week. .

12. The use of claim 9, wherein the period is at least 6 months.

13. The use of claim 9, wherein the cytogenetic response is a complete cytogenetic response.

14. The use of claim 9, further comprising administering an effective amount of cytarabine.

15. The use of PEG-modified interferon alfa-2b for the manufacture of a medicament for treating a patient who is chronically in chronic myelogenous leukemia once a week for a sufficient period to obtain at least a partial cytogenetic response wherein said medicament provides from about 4.5 micrograms / kg to about 9.0 micrograms / kg of interferon alfa-2b misfed with PEG to the patient when said medicament is administered.

16. The use of claim 15, wherein the period is at least 6 months.

17. The use of claim 15, wherein the period is at least 12 months.

18. The use of claim 15, wherein said medicament provides from about 4.5 micrograms / kg to about 6.5 micrograms / kg of PEG-modified interferon alfa-2b to the patient when said medicament is administered once a week. .

19. The use of claim 15, wherein a complete cytogenetic response is obtained.

20. The use of claim 15 which further comprises administering an effective amount of cytarabine.