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  Pharmaceutical Patents  

 

Title:  Combination therapy for the treatment of acute leukemia and myelodysplastic syndrome
United States Patent: 
7,727,968
Issued: 
June 1, 2010

Inventors:
 Feingold; Jay Marshall (Wynnewood, PA), Sherman; Matthew L. (Newton, MA), Leopold; Lance H. (Dresher, PA), Berger; Mark (Merion Station, PA)
Assignee:
  Wyeth LLC (Madison, NJ)
Appl. No.:
 11/811,626
Filed:
 June 11, 2007


 

George Washington University's Healthcare MBA


Abstract

Methods of treatment and pharmaceutical combinations are provided for the treatment of acute leukemia, such as acute myelogenous leukemia, and myelodysplastic syndrome. The methods of treatment and pharmaceutical combinations employ an anti-CD33 cytotoxic conjugate in combination with at least one compound selected from the group consisting of an anthracycline and a pyrimidine or purine nucleoside analog. Preferred methods of treatment and pharmaceutical combinations employ gemtuzumab ozogamicin, daunorubicin, and cytarabine.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention provides a method of treating acute leukemia or MDS comprising administering to a patient in need of said treatment an anti-CD33 cytotoxic conjugate in combination with at least one compound selected from the group consisting of an anthracycline and a pyrimidine or purine nucleoside analog in an amount effective to ameliorate the symptoms of said acute myelogenous leukemia or said myelodysplastic syndrome. The acute leukemia being treated is preferably AML.

In a preferred embodiment, the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin.

In another preferred embodiment, the anthracycline is selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin.

In another preferred embodiment, the pyrimidine or purine nucleoside analog is selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin.

The present invention further provides a method of treatment of a patient having acute leukemia or MDS, comprising administering to the patient: (a) gemtuzumab ozogamicin in an amount of about 3 mg/m.sup.2 to about 9 mg/m.sup.2 per day; (b) daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m.sup.2 to about 60 mg/m.sup.2 per day; and (c) cytarabine in an amount of about 100 mg/m.sup.2 to about 200 mg/m.sup.2 per day.

In a preferred embodiment, the gemtuzumab ozogamicin is in an amount of about 6 mg/m.sup.2 per day.

In another preferred embodiment, the daunorubicin, preferably daunorubicin hydrochloride, is in an amount of 45 mg/m.sup.2 per day.

In another preferred embodiment, the cytarabine is in an amount of 100 mg/m.sup.2 per day.

The present invention further provides a method of treating acute leukemia or MDS syndrome comprising administering to a patient in need of treatment thereof: (a) gemtuzumab ozogamicin in an amount of about 3 mg/m.sup.2 to 9 mg/m.sup.2 for one day; (b) daunorubicin in an amount of about 45 mg/m.sup.2 to 60 mg/m.sup.2 per day for three days; and (c) cytarabine in an amount of about 100 mg/m.sup.2 to 200 mg/m.sup.2 per day for at least seven days.

In a preferred embodiment, the daunorubicin is administered on the first three days that cytarabine is administered, preferably in an amount of 45 mg/m.sup.2 per day.

In another preferred embodiment, the cytarabine is administered for ten days, more preferably for seven days, and preferably in an amount of 100 mg/m.sup.2 per day.

In another preferred embodiment, the gemtuzumab ozogamicin is administered to the patient on the fourth day that cytarabine is administered to the patient, preferably in an amount of 6 mg/m.sup.2.

In another preferred embodiment, the cytarabine is administered by continuous infusion, the daunorubicin, preferably daunorubicin hydrochloride, is administered by intravenous bolus, and the gemtuzumab ozogamicin is administered by 2-hour infusion.

The present invention further provides a pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or MDS comprising: (a) an anti-CD33 cytotoxic conjugate, wherein the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin; (b) an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin; and (c) a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin.

The present invention further provides a pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or MDS comprising gemtuzumab ozogamicin in an amount of about 3 mg/m.sup.2 to about 9 mg/m.sup.2 per day, preferably 6 mg/m.sup.2 per day, daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m.sup.2 to about 60 mg/m.sup.2 per day, preferably 45 mg/m.sup.2 per day, and cytarabine in an amount of about 100 mg/m.sup.2 to about 200 mg/m.sup.2 per day, preferably 100 mg/m.sup.2 per day.

The present invention further provides a method of treating acute leukemia or MDS comprising:

(a) administering a first course of therapy to a patient in need of treatment comprising (i) administering an anti-CD33 cytotoxic conjugate for one day, wherein the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin; (ii) administering an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days; and (iii) administering a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin for up to ten days;

(b) administering a second course of therapy to a patient in need of treatment comprising: (i) administering an anti-CD33 cytotoxic conjugate for one day, wherein the cytotoxin in the anti-CD33 cytotoxic conjugate is selected from the group consisting of a calicheamicin and an esperamicin; (ii) administering an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days; and (iii) administering a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin for up to ten days; and

(c) administering a third course of therapy to a patient in need of treatment comprising: (i) administering an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days; and (ii) administering a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin for up to ten days.

The present invention further provides a method of treating acute leukemia or MDS comprising:

(a) administering a first course of therapy to a patient in need of treatment comprising (i) gemtuzumab ozogamicin in an amount of about 3 mg/m.sup.2 to about 9 mg/m.sup.2, preferably 6 mg/m.sup.2, per day for one day; (ii) daunorubicin in an amount of about 45 mg/m.sup.2 to about 60 mg/m.sup.2, preferably 45 mg/m.sup.2, per day for up to three days; and (iii) cytarabine in an amount of about 100 mg/m.sup.2 to about 200 mg/m.sup.2, preferably 100 mg/m.sup.2, per day for up to ten days;

(b) administering a second course of therapy to a patient in need of treatment comprising: (i) gemtuzumab ozogamicin in an amount of about 3 mg/m.sup.2 to about 9 mg/m.sup.2, preferably 6 mg/m.sup.2, per day for one day; (ii) daunorubicin in an amount of about 45 mg/m.sup.2 to about 60 mg/m.sup.2, preferably 45 mg/m.sup.2, per day for up to three days; and (iii) cytarabine in an amount of about 100 mg/m.sup.2 to about 200 mg/m.sup.2, preferably 100 mg/m.sup.2, per day for up to ten days; and

(c) administering a third course of therapy to a patient in need of treatment comprising: (i) daunorubicin in an amount of about 45 mg/m.sup.2 to about 60 mg/m.sup.2, preferably 45 mg/m.sup.2, per day for up to three days; and (ii) cytarabine in an amount of about 100 mg/m.sup.2 to about 200 mg/m.sup.2, preferably 100 mg/m.sup.2, per day for up to ten days.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides advantageous pharmaceutical combinations and methods of treatment for acute leukemia, such as AML, and for myelodysplastic syndrome (MDS) which employ an anti-CD33 cytotoxic conjugate, an anthracycline, and a pyrimidine or purine nucleoside analog. The method of treatments and pharmaceutical combinations described herein provide a better rate of complete remission and improved quality of life in such patients than the standard 3+7 regimen of daunorubicin and cytarabine. Surprisingly, a preferred embodiment employing gemtuzumab ozogamicin, daunorubicin, and cytarabine provides a higher rate of complete remission than the standard 3+7 regimen of daunorubicin and cytarabine.

The patients to be treated with the methods of treatment and pharmaceutical combinations provided herein are those who have been untreated for acute leukemia such as AML and are being treated de novo, those who are being treated with induction therapy, those who are being treated with consolidation therapy, those who are being treated after one or more relapses, and those who have MDS.

One composition used in the present invention is an anti-CD33 cytotoxic conjugate in which an anti-CD33 antibody is conjugated with a cytotoxic antitumor or antibiotic, such as a calicheamicin isolated from fermentation of a bacterium, Micromonospora echinospora ssp. calichensis, or an esperamicin. Calicheamicins are described in U.S. Pat. Nos. 4,970,198; 5,037,651; and 5,079,233. Esperamicins are described in U.S. Pat. Nos. 4,675,187; 4,539,203; 4,554,162; and 4,837,206. The antibody portion of the conjugate binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein found on the surface of leukemic blasts and immature normal cells of myelomonocytic lineage, but not on normal hematopoietic stem cells, and acts as a targeting unit to deliver the cytotoxic agent to these targeted cells. This antibody is linked to the calicheamicin or esperamicin. When N-acetyl-gamma calicheamicin is used, it is preferred to link the antibody by a bifunctional linker. Such conjugates and methods for making them are described in U.S. Pat. Nos. 5,733,001; 5,739,116; 5,767,285; 5,877,296; 5,606,040; 5,712,374; and 5,714,586, which are incorporated by reference herein in their entirety.

A preferred form of the anti-CD33 cytotoxic conjugate for use in the present invention is gemtuzumab ozogamicin, a chemotherapy agent composed of a recombinant humanized IgG4, kappa antibody conjugated with calicheamicin. Gemtuzumab ozogamicin is available commercially as Mylotarg.RTM. (Wyeth Pharmaceuticals, Philadelphia, Pa.). The antibody portion of gemtuzumab ozogamicin binds specifically to the CD33 antigen. Gemtuzumab ozogamicin contains amino acid sequences of which approximately 98.3% are of human origin. The constant region and framework regions contain human sequences while the complementarity-determining regions are derived from a murine antibody (p67.6) that binds CD33. This antibody is linked to N-acetyl-gamma calicheamicin via a bifunctional linker. Gemtuzumab ozogamicin has approximately 50% of the antibody loaded with 4-6 moles calicheamicin per mole of antibody. The remaining 50% of the antibody is not linked to the calicheamicin derivative. Gemtuzumab ozogamicin has a molecular weight of 151 to 153 kDa. Gemtuzumab ozogamicin and methods for making it are described in U.S. Pat. Nos. 5,733,001; 5,739,116; 5,767,285; 5,877,296; 5,606,040; 5,712,374; and 5,714,586, which are incorporated by reference herein in their entirety. When given as a single agent therapy for the treatment of AML, the recommended dose of gemtuzumab ozogamicin is 9 mg/m.sup.2, administered as a two-hour intravenous infusion. The recommended treatment course with gemtuzumab ozogamicin alone has been a total of two doses with fourteen days between the doses. In the combination therapy of the present invention, gemtuzumab ozogamicin is given in an amount ranging from about 3 mg/m.sup.2 to 9 mg/m.sup.2 per day.

U.S. Pat. No. 5,773,001, in col. 62, lines 37-46, and Example 112, describes dosage amounts of calicheamicin conjugates, including gemtuzumab ozogamicin, based on calicheamicin equivalents, i.e., 10 .mu.g calicheamicin/m.sup.2 protein, as compared to the clinical dose description based on mg/m.sup.2 body-surface. When calicheamicin is loaded onto the antibody, there is approximately 27 .mu.g calicheamicin/mg protein. A 9 mg/m.sup.2 dose of gemtuzumab ozogamicin is equivalent to 243 .mu.g calicheamicin/m.sup.2 protein. A 6 mg/m.sup.2 dose of gemtuzumab ozogamicin is equivalent to 162 .mu.g calicheamicin/m.sup.2 protein. A 3 mg/m.sup.2 dose of gemtuzumab ozogamicin is equivalent to 81 .mu.g calicheamicin/m.sup.2 protein.

Another composition used in the present invention is an anthracycline, an anticancer agent consisting of 3 moieties: a pigmented aglycone, an amino sugar, and a lateral chain. Anthracyclines include doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin. See Merck Index (13.sup.th ed. 2001).

A preferred anthracycline for use in the present invention is daunorubicin. Daunorubicin, also known as daunomycin, is an anthracycline cytotoxic antibiotic of the rhodomycin group obtained from Streptomyces peucetius, which is used in the treatment of acute leukemia. Stedman's Medical Dictionary (27.sup.th ed. 2002). Daunorubicin has a 4-ring anthracycline moiety linked by a glycosidic bond to daunosamine, an amino sugar. Daunorubicin may also be isolated from Streptomyces coeruleorubidus and has the following chemical name: (8S-cis)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-(alpha)-L-lyxo-hexopyranosy- l)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedio- ne hydrochloride. Daunorubicin is usually given as the hydrochloride, but doses are expressed in terms of the base.

A preferred form of daunorubicin used in the present invention is daunorubicin hydrochloride, the hydrochloride salt of daunorubicin. Daunorubicin hydrochloride is available commercially as Cerubidine.RTM. (Bedford Laboratories, Bedford Ohio). It may be described with the chemical name of (1 S,3 S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-diox- o-1-naphthacenyl 3-amino-2,3,6-trideoxy-(alpha)-L-lyxo-hexopyranoside hydrochloride. Its molecular formula is C.sub.27H.sub.29NO.sub.10.HCl with a molecular weight of 563.99. In the treatment of adult acute nonlymphocytic leukemia, such as AML and ALL, daunorubicin hydrochloride, used as a single agent, has produced complete remission rates of 40 to 50%, and in combination with cytarabine, has produced complete remission rates of 53 to 65%. Physician's Desk Reference (56.sup.th ed. 2002). Typically, daunorubicin is given daily for three days in an amount of 30 to 45 mg/m.sup.2 by intravenous infusion for two to three days. In high-dose regimens, daunorubicin is given daily in an amount of 50 mg/m.sup.2 for three days.

Daunorubicin is also available commercially in a daunorubicin citrate liposome injection as DaunoXome.RTM. (Gilead Sciences, Inc., Foster City, Calif.). DaunoXome.RTM. contains an aqueous solution of the citrate salt of daunorubicin encapsulated within lipid vesicles (liposomes) composed of a lipid bilayer of distearoylphosphatidylcholine and cholesterol (2:1 molar ratio), with a mean diameter of about 45 nm. The lipid to drug weight ratio is 18.7:1 (total lipid:daunorubicin base), equivalent to a 10:5:1 molar ratio of distearoylphosphatidylcholine:cholesterol:daunorubicin. Each vial of DaunoXome.RTM. contains daunorubicin citrate equivalent to 50 mg of daunorubicin base, encapsulated in liposomes consisting of 704 mg distearoylphosphatidylcholine and 168 mg cholesterol. The liposomes encapsulating daunorubicin are dispersed in an aqueous medium containing 2,125 mg sucrose, 94 mg glycine, and 7 mg calcium chloride dihydrate in a total volume of 25 ml/vial. The pH of the dispersion is between 4.9 and 6.0. DaunoXome.RTM. is administered intravenously over a 60 minute period at a dose of 40 mg/m.sup.2, with doses repeated every two weeks.

A third composition used in the present invention is a pyrimidine nucleoside analog or a purine nucleoside analog. Representative of such nucleoside analogs are cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin. See Merck Index (13.sup.th ed. 2001).

A preferred pyrimidine nucleoside analog used in the present invention is cytarabine, which is also known as arabinosylcytosine (aC, araC), arabinocytidine, or arabinofuranosylcytosine. Chemically, cytarabine is 4-amino-1-(beta)-D-arabinofuranosyl-2(1H)-pyrimidinone, also known as cytosine arabinoside (C.sub.9H.sub.13N.sub.3O.sub.5, molecular weight 243.22). Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase of cell division. It is a compound of arabinose and cytosine that inhibits the biosynthesis of DNA and is used as a chemotherapeutic agent because of its antiviral and tumor-growth-inhibiting properties. Typically, cytarabine is given in an amount of 100-200 mg/m.sup.2 daily for five to ten days by constant intravenous infusion, usually for seven days. Cytarabine can be given in an amount of 100 mg/m.sup.2 body-surface twice daily by rapid intravenous injection. However, cytarabine can be given in amounts of up to 3 g/m.sup.2 daily. In high-dose regimens, cytarabine is given in doses of up to 3 g/m.sup.2 by intravenous infusion for every 12 hours for up to six days.

Cytarabine is also available commercially in a cytarabine liposome injection as DEPOCYT.RTM. (Chiron Corporation, Emeryville, Calif.). DepoCyt.RTM. is a sterile, injectable suspension of the antimetabolite cytarabine, encapsulated into multivesicular lipid-based particles. Each vial contains 50 mg of cytarabine. Cytarabine, the active ingredient, is present at a concentration of 10 mg/ml and is encapsulated in the particles. Inactive ingredients at their respective approximate concentrations are cholesterol, 4.1 mg/ml; triolein, 1.2 mg/ml; dioleoylphosphatidylcholine (DOPC), 5.7 mg/ml; and dipalmitoylphosphatidylglycerol (DPPG), 1.0 mg/ml. The pH of the product falls within the range from 5.5 to 8.5. DepoCyt.RTM. is administered intrathecally.

The present invention provides several methods for treating acute leukemia or MDS. In one method, a patient is given an anti-CD33 cytotoxic conjugate in combination with at least one compound selected from the group consisting of an anthracycline and a pyrimidine or purine nucleoside analog in an amount effective to ameliorate the symptoms of the acute leukemia, such as AML, or MDS. Preferably, the cytotoxin in the anti-CD33 cytotoxic conjugate is a calicheamicin or an esperamicin. The anthracycline is preferably selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin. The pyrimidine or purine nucleoside analog is preferably selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercid. Most preferred is that the cytotoxin in the anti-CD33 conjugate is a calicheamicin, the anthracycline is daunorubicin or daunorubicin hydrochloride, and the pyrimidine nucleoside analog is cytarabine.

In another method of treatment, a patient having acute leukemia or MDS is given gemtuzumab ozogamicin in an amount of about 3 mg/m.sup.2 to about 9 mg/m.sup.2 per day; daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m.sup.2 to about 60 mg/m.sup.2 per day; and cytarabine in an amount of about 100 mg/m.sup.2 to about 200 mg/m.sup.2 per day. Preferably, the gemtuzumab ozogamicin is given in an amount of about 6 mg/m.sup.2 per day. The daunorubicin, preferably daunorubicin hydrochloride, is preferably given in an amount of 45 mg/m.sup.2 per day. The cytarabine is preferably given in an amount of 100 mg/m.sup.2 per day.

In another method of treatment, a patient having acute leukemia or MDS is given gemtuzumab ozogamicin in an amount of about 3 mg/m.sup.2 to 9 mg/m.sup.2 for one day; daunorubicin in an amount of about 45 mg/m.sup.2 to 60 mg/m.sup.2 per day for three days; and cytarabine in an amount of about 100 mg/m.sup.2 to 200 mg/m.sup.2 per day for at least seven days. Preferably, the daunorubicin is administered on the first three days that cytarabine is administered, and is preferably given in an amount of 45 mg/m.sup.2 per day. The cytarabine is preferably administered for ten days, more preferably for seven days, and is preferably given in an amount of 100 mg/m.sup.2 per day. The gemtuzumab ozogamicin is preferably administered to the patient on the fourth day that cytarabine is administered to the patient, and is preferably given in an amount of 6 mg/m.sup.2. In a preferred embodiment, the cytarabine is administered by continuous infusion, the daunorubicin, preferably daunorubicin hydrochloride, is administered by intravenous bolus, and the gemtuzumab ozogamicin is administered by 2-hour infusion.

Pharmaceutical combinations for enhanced induction of remission in a patient having acute leukemia or MDS are also provided by the present invention. One such pharmaceutical combination for enhanced induction of remission in a patient having acute leukemia or MDS comprises an anti-CD33 cytotoxic conjugate, an anthracycline, and a pyrimidine or purine nucleoside analog. The cytotoxin in the anti-CD33 cytotoxic conjugate may be selected from the group consisting of a calicheamicin and an esperamicin. The anthracycline may be selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin. The pyrimidine or purine nucleoside analog may be selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin.

Another pharmaceutical combination comprises gemtuzumab ozogamicin in an amount of about 3 mg/m.sup.2 to about 9 mg/m.sup.2 per day, preferably 6 mg/m.sup.2 per day, daunorubicin, preferably daunorubicin hydrochloride, in an amount of about 45 mg/m.sup.2 to about 60 mg/m.sup.2 per day, preferably 45 mg/m.sup.2 per day, and cytarabine in an amount of about 100 mg/m.sup.2 to about 200 mg/m.sup.2 per day, preferably 100 mg/m.sup.2 per day.

The nature of acute leukemias and myelodysplastic syndrome calls for the administration of intensive chemotherapy to induce remission in patients having these diseases. In one embodiment of the present invention, a single course of combination therapy comprises administering to the patient a therapeutically effective amount of an anti-CD33 cytotoxic conjugate, together with one or more chemotherapeutic agents, such as anthracycline, and a pyrimidine or purine nucleoside analog. The present invention also provides treatment regimens in which multiple courses of combination therapy, which include an anti-CD33 cytotoxic conjugate and other chemotherapeutic agents, are administered. Such treatment regimens may be administered from at least two to five courses of treatment, depending upon the drugs being administered, the severity of the disease, and the condition of the patient.

In another method of treatment of the present invention, a patient having acute leukemia or MDS is given three courses of therapy. In the first course of therapy, the patient is given an anti-CD33 cytotoxic conjugate for one day; an anthracycline for up to three days; and a pyrimidine or purine nucleoside analog for up to ten days. The cytotoxin in the anti-CD33 cytotoxic conjugate may be selected from the group consisting of a calicheamicin and an esperamicin. The anthracycline may be selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin. The pyrimidine or purine nucleoside analog may be selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin. The first course of therapy is repeated as a second course of therapy in which the patient is given an anti-CD33 cytotoxic conjugate for one day, an anthracycline for up to three days, and a pyrimidine or purine nucleoside analog for up to ten days. A third course of therapy may be given to the patient which comprises the administration to the patient of an anthracycline selected from the group consisting of doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, and valrubicin for up to three days, and a pyrimidine or purine nucleoside analog selected from the group consisting of cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabine, floxuridine, fludarabine, gougerotin, puromycin, tegafur, tiazofurin, and tubercidin for up to ten days.

In another such method of treatment of acute leukemia or MDS, a patient is given a first course of therapy comprising gemtuzumab ozogamicin in an amount of about 3 mg/m.sup.2 to about 9 mg/m.sup.2, preferably 6 mg/m.sup.2, per day for one day; daunorubicin in an amount of about 45 mg/m.sup.2 to about 60 mg/m.sup.2, preferably 45 mg/m.sup.2, per day for up to three days; and cytarabine in an amount of about 100 mg/m.sup.2 to about 200 mg/m.sup.2, preferably 100 mg/m.sup.2, per day for up to ten days. A second course of therapy is given to the patient comprising gemtuzumab ozogamicin in an amount of about 3 mg/m.sup.2 to about 9 mg/m.sup.2, preferably 6 mg/m.sup.2, per day for one day; daunorubicin in an amount of about 45 mg/m.sup.2 to about 60 mg/m.sup.2, preferably 45 mg/m.sup.2, per day for up to three days; and cytarabine in an amount of about 100 mg/m.sup.2 to about 200 mg/m.sup.2, preferably 100 mg/m.sup.2, per day for up to ten days. A third course of therapy may be administered to the patient comprising daunorubicin in an amount of about 45 mg/m.sup.2 to about 60 mg/m.sup.2, preferably 45 mg/m.sup.2, per day for up to three days, and cytarabine in an amount of about 100 mg/m.sup.2 to about 200 mg/m.sup.2, preferably 100 mg/m.sup.2, per day for up to ten days.

The surprising and unexpected result disclosed herein is the ability of the anti-CD33 cytotoxic conjugate, the anthracycline, and the pyrimidine or purine nucleoside analog to act synergistically in the treatment of various symptoms associated with acute leukemia or MDS. Synergistically" is used herein to refer to a situation where the benefit conveyed by the administration of these antineoplastic compositions in combination is greater than the algebraic sum of the effects resulting from the separate administration of the components of the combination. As shown in the Examples below, the combination treatment of an anti-CD33 cytotoxic conjugate, an anthracycline, and an pyrimidine or purine nucleoside analog is synergistic with respect to treating acute leukemia and increasing the efficacy as measured by complete remission. This combined treatment has the advantage of achieving the same result with a lower dose of the anti-CD33 cytotoxic conjugate, thereby reducing any toxic effect from the conjugate, providing an improved quality of life, and increasing the chances for survival of the patient.

As with the use of other chemotherapeutic drugs, the individual patient will be monitored in a manner deemed appropriate by the treating physician. The combination therapy agents described herein may be administered with immunosuppressive agents, potentiators and side-effect relieving agents as deemed necessary by the treating physician.

In therapeutic applications, the dosages of the agents used in accordance with the invention may vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in complete remission as previously defined. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. It is especially advantageous to formulate compositions of these antineoplastic compounds in dosage unit form for ease of administration and uniformity of dosage. "Dosage unit form" as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated, each unit containing a predetermined quantity of anti-neoplastic compounds calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like which are compatible with the active ingredient and with the mode of administration and other ingredients of the formulation and not deleterious to the recipient.

The pharmaceutical compositions of this invention which are found in the combination may also include, depending on the formulation desired, pharmaceutically-acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like. Effective amounts of such diluent or carrier will be those amounts which are effective to obtain a pharmaceutically acceptable formulation in terms of solubility of components, or biological activity, and the like.

For parenteral therapeutic administration, each antineoplastic compound may be incorporated with a sterile injectable solution. The sterile injectable solution may be prepared by incorporating the antineoplastic compound in the required amount in an appropriate pharmaceutically acceptable carrier, with various other ingredients, followed by filtered sterilization. In the case of dispersions, each may be prepared by incorporating the additional antineoplastic compound into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated herein. In the case of sterile injectable solutions, each may be prepared by incorporating a powder of the additional antineoplastic compound and, optionally, any additional desired ingredient from a previously sterile-filtered solution thereof, wherein the powder is prepared by any suitable technique (e.g., vacuum drying and freeze drying). The use of such media and agents is well known in the art (see for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990), Mack Publishing Co., Easton, Pa. 18042, pages 1435-1712, the disclosure of which is hereby incorporated by reference). Supplementary active ingredients can also be incorporated into the compositions. The specific dose of the antineoplastic compound is calculated according to the approximate body weight or surface area of the patient. Other factors in determining the appropriate dosage can include the stage of the acute myelogenous leukemia or myelodysplastic syndrome (de novo or relapse), the severity of the disease, the route of administration and the age, sex and medical condition of the patient. Further refinement of the calculations necessary to determine the appropriate dosage for treatment involving each of the herein-mentioned formulations is routinely made by those skilled in the art. Dosages can also be determined through the use of known assays for determining dosages used in conjunction with appropriate dose-response data. Thus, for example, it is within the scope of the invention that doses of the antineoplastic compounds used in the present invention for treating acute myelogenous leukemia or myelodysplastic syndrome can be varied to achieve a desired therapeutic effect.

If oral therapeutic administration is an option, the antineoplastic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixers, suspensions, syrups, wafers and the like, or it may be incorporated directly with the food in the diet. The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; or a flavoring agent such as peppermint, oil of wintergreen or cherry or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to material of the type described herein, a liquid carrier. Various other materials may be present as a coating or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the antineoplastic compound may be incorporated into a sustained-release preparation and formulation. The amount of the antineoplastic compound in such therapeutically useful composition is such that a suitable dosage will be obtained.
 

Claim 1 of 20 Claims

1. A method of treating acute leukemia or myelodysplastic syndrome consisting essentially of administering to a patient in need of treatment thereof: (a) gemtuzumab ozogamicin in an amount of about 3 mg/m.sup.2 to about 9 mg/m.sup.2 per day; (b) daunorubicin in an amount of about 45 mg/m.sup.2 to about 60 mg/m.sup.2 per day; and (c) cytarabine in an amount of about 100 mg/m.sup.2 to about 200 mg/m.sup.2 per day.

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