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Link:  Pharm/Biotech Resources


Title:  Method of cancer treatment

United States Patent:  6,929,802

Issued:  August 16, 2005

Inventors:  Andreeff; Michael (Houston, TX); Estey; Elihu H. (Houston, TX)

Assignee:  Board of Regents, The University of Texas System (Austin, TX)

Appl. No.:  419025

Filed:  April 18, 2003

Abstract

This invention comprises a method of treating a subject having relapsed or refractory cancer such as leukemia with liposomal annamycin including the steps of

bullet(a) evaluating the subject to determine if the subject has relapsed or refractory cancer;
bullet(b) administering a high-dose amount of liposomal-annamycin for at least 3 days in a 7 day period. First line cancer therapy with particular reference to leukemia is both contemplated and useful.

SUMMARY OF THE INVENTION

This invention includes a method of treating a subject having relapsed or refractory cancer such as leukemia with liposomal annamycin by the steps of

(a) evaluating the subject to determine if the subject has relapsed or refractory cancer;

(b) administering a high-dose amount of liposomal-annamycin for at least 3 days in a 7 day period. In some embodiments administration is for one or multiple consecutive days in a seven day period, with particular reference to 2, 3, 4, 5, 6 or 7 days. In some embodiments administration comprises a cycle of at least about 2 or more courses of administering a therapeutically effective amount of liposomal-annamycin for at least 2, or 3 or more days in a 7 day period, with a recovery period between courses. Periods of about 1, 2, 3 or more weeks are contemplated between courses. In some embodiments the high-dose amount of liposomal annamycin is at least about 280 mg/m2, or at least about 350 mg/m2, or at least about 500 mg/m2 and up to about 1000 mg/m2 or more. In some embodiments the method of claim further comprises administration of an adjunct antineoplastic drug such as all-trans retinoic acid, with particular reference to all-trans retinoic acid is in liposomal form. Note is made of adjunct treatment with all-trans retinoic acid administered at a dose of about 15 to 300 or more mg/m2. Particularly noted is all-trans retinoic acid is administered at a dose of at least about 90 mg/m2 in free or liposomal form.

This invention also comprises a method of treating a subject having cancer with particular reference to leukemia by the step of administering a high-dose amount of liposomal-annamycin for one or multiple consecutive days in a seven day period, with particular reference to 2, 3, 4, 5, 6 or 7 days. In some embodiments administration comprises a cycle of at least about 2 or more courses of administering a therapeutically effective amount of liposomal-annamycin for at least 2, or 3 or more days in a 7 day period, with a recovery period between courses. Periods of about 1, 2, 3 or more weeks are contemplated between courses. In some embodiments the high-dose amount of liposomal annamycin is at least about 280 mg/m2, or at least about 350 mg/m2, or at least about 500 mg/m2 and up to about 1000 mg/m2 or more.

In some embodiments the method of claim further comprises administration of an adjunct antineoplastic drug such as all-trans retinoic acid, with particular reference to all-trans retinoic acid is in liposomal form. Note is made of adjunct treatment with all-trans retinoic acid administered at a dose of about 15 to 300 or more mg/m2. Particularly noted is all-trans retinoic acid administered at a dose of at least about 90 mg/m2 in free or liposomal form.

Neoplasms are also usefully treated by the methods of this invention.

DETAILED DESCRIPTION OF THE INVENTION

Liposomal annamycin has surprisingly been found to overcome cross-resistance to anthracycline drugs. Liposomal annamycin has been the subject of a clinical study of cancer patients with refractory or relapsed cancer. Particular reference is made to refractory or relapsed acute promyelocytic leukemia (AML).

This invention will be better understood with reference to the following definitions:

A. Relapsed and refractory are significant indications for liposomal annamycin cancer therapy.

Relapsed shall be understood to mean the presence of about ≧10% leukemic blast cells in blood or bone marrow in patients previously in complete remission.

Refractory shall be understood to mean the presence of about ≧5% of leukemic blast cells in blood or marrow of patients following chemotherapy, four weeks after initiation of such therapy, or persistence of leukemic blasts in blood or marrow 14 days after therapy started, with no evidence of decrease to <30%.

B. Evaluating as related to establishing whether or not a subject has relapsed or refractory cancer shall mean comparing a subjects presenting condition with the standards of relapsed and refractory as defined above. It is understood that clinical presentation is accompanied by a degree of variability, but the evaluation of subjects as relapsed or refractory is within the skill of an oncology medical Particular note is made of patients with refractory or relapsed AML, myelodysplastic syndrom (MDS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), chronic myelomonocytic leukemia (CMML), ALL or blast crisis of chronic myelogenous leukemia (CML) (lymphoid, myeloid and megakaryocytic).

C. High-dose liposomal annamycin shall mean at least about 250 mg/m2, and further at least about 280 mg/m2, or about 350 mg/m2, and further at least about 500 mg/m2, and further about 1 gm/m2 or more. Reference to "m2" is to skin surface area in square meters. Calculated dosage is based on pure, anhydrous solvent free Annamycin.

Particular note is made of doses of 240 mg/m2 which exhibited dose limiting thrombocytopenia accompanying treatment of solid tumors. In some instances, Grade IV plate counts were also noted, which was present in some instances even at doses of 210 mg/m2.

It is understood that while high-dose annamycin is therapeutically effective as to liposomal anthracycline therapy in that slowing or stasis of cancer progression and, in some embodiments therapeutically effective dosing further includes regression and complete remission of cancer.

D. Complete remission shall mean normalization of the peripheral blood and bone marrow with 5% or less blasts, normocellular or hypercellular marrow, a granulocyte count of 1000 or above, and a platelet count of 100×109/L or above. CR in both acute leukemia and CML-BP does not require disappearance of abnormal karyotype. In CML-BP, a return to chronic phase will be defined as CR, except for an elevation of WBC 10×109/L or more with a CML differential.

E. Partial Remission shall mean the same as complete remission except for the presence of 6-25% blast. All other responses are considered failures.

F. A cycle as applied to therapy of the present invention shall mean administration of antineoplastic drug at least 3 times in a seven day period with at least about one week intervening between repeated doses. By way of example, administering a dosage of 280 mg/m2 over about 1 to 2 hours each day for 3 consecutive days constitutes a course of administration and, and repeating the procedure 3 to 4 weeks later, and again 3 to 4 weeks later and then ceasing treatment for at least 8 weeks constitutes one treatment cycle.

Administration of liposomal annamycin by a variety or regimens is contemplated. In some embodiments, intravenous dosing is over a period of from about 30 minutes to about 4 hours, with particular reference to 1 to 2 hours. Dosing daily or every other day is anticipated with particular reference to dosing for 3 consecutive days with a hiatus between 3 day cycles. A hiatus or recovery period of from about 2 to about 6 weeks is noted with particular reference to about 3 to 4 weeks. In some embodiments recovery is characterized by a return of WBC, usually followed by rising platelet counts. In one embodiment, 3 dosage cycles are administered.

G. Leukemia is a condition which is usefully treated with L-annamycin. Particular reference is made to AML, myelodysplastic syndrom (MDS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), chronic myetomonocytic leukemia (CMML), ALL or blast crisis of chronic myelogenous leukemia (CML) (lymphoid, myeloid and megakaryocytic), hairy cell leukemia.

Beyond resistant or refractory subjects, high-dose L-annamycin is a useful first line treatment. High-dose L-Annamycin treatment is usefully combined with other antineoplastic drugs.

MDR-1 mRNA Testing

In some embodiments, levels of MDT-1 mRNA were established by RT-PCR after the method of Drach D. et al., "Subpopulations of normal peripheral blood and bone marrow cells express a functional:multidrug resistant phenotype," Blood 1:80(11):2729-34 (1992), the teachings of which are incorporated by reference. The multidrug-resistance gene, MDR1 is expressed in many normal tissues. Using the monoclonal antibody C219 and flow cytometric analysis, P-glycoprotein (P-gp) was found to be expressed in all peripheral blood (PB) subpopulations (CD4, CD8, CD14, CD19, CD56) except granulocytes. To specifically determine MDR1 gene expression, these PB subpopulations were isolated by fluorescence-activated cell sorting (FACS) and analyzed for MDR1 mRNA by polymerase chain reaction (PCR). All subsets were positive by PCR, but only minimal MDR1 mRNA was detected in monocytes and granulocytes. Significant efflux of Rhodamine-123 (Rh-123), a measure of P-gp function, was detected in CD4+, CD8+, CD14+CD19+, and CD56+ cells but not in granulocytes. Next, PCR-analysis was performed on FACS-sorted bone marrow (BM) cells to assess MDR1 expression in different maturational stages. Precursors (CD34+), early and late myeloid cells (CD33+/CD34+, CD33+/CD34-;) as well as lymphocytes of the B-cell lineage (CD19+/CD10+, CD19+/CD10-;) expressed the MDR1 gene. BM monocytic cells (CD33++/CD34-;) were negative, and a very weak signal was detected in erythroid cells (glycophorin A+). Significant Rh-123 efflux was found in CD34+, CD10+, CD33+, and CD33++BM cells, but not in glycophorin A+ cells. By this method expression of MDR1mRNA and a functional P-gp is determined in PB and BM lymphocytes, PB monocytes, BM progenitors, and immature myeloid cells. These results have to be taken into account when MDR1 expression is determined in tumor samples containing normal blood cells such that selection does not include MDR1 as contained in the normal cells. This method also was useful for testing of P-gp of CD34*blasts.

Liposomal-Annamycin

Liposomal Annamycin (2′-Iodo, 3′-hydroxy, 4′-epi, 4-demethoxy doxorubicin) was used in one embodiment of the present invention. Annamycin is a lipophilic anthracycline antibiotic that incorporates 4 structural modifications from doxorubicin: 2′-Iodo, 3′-hydroxy, 4′-epi, 4-demethoxy.

L-Annamycin is conveniently provided in the form of a preliposomal lyophilized powder containing a mixture of phospholipids, in one embodiment this is supplied as 20 mL vials containing 10 mg of Annamycin, or 100 mL vials containing 50 mg of Annamycin.

As a 50 mg vial one formulation is 50 mg Annamycin, dimysteroyl phosphatidyl choline (DMPC) 1750 mg, dimyristoyl phosphatidyl glycerol (DMPG) 750 mg and Tween 20, 85 mg. "Tween™" refers to a commercially available nonionic surfactant (ICI Americas Inc.) consisting of a mixture of different length chains of polyoxyethylene linked to a common sorbitan sugar. These polyoxyethylene sugars are also linked to a fatty acid. In the case of Tween™ 20, the composition is polyoxyethylene sorbitan monolaurate (MW approximately 1300).

As a 10 mg vial, one formulation is 10 mg Annamycin, DMPC 350 mg, DMPG 150 mg and Tween 20, 17 mg.

The lyophilate is conveniently reconstituted on the day of use. The drug is prepared by reconstituting the drug with saline (0.9% Sodium Chloride, Injection U.S.P.) at room temperature. It is useful to tap the vials prior to reconstitution to break up any dry cake. Reconstitute the 10 mg vial with 10 mL of saline, and the 50 mg vial with 50 mL of saline. Shake each vial back and forth for 2 minutes, or until suspended, to form liposomes (final Annamycin concentration approximately 1 mg/mL). If foaming occurs, allow vial to stand for a few minutes until foam subsides. Gently invert vial one more time to ensure against settling of the contents, and then transfer the reconstituted product to an empty IV bag for infusion. Take care to avoid transferring any foam.
 

Claim 1 of 11 Claims

1. A method of treating a human subject having relapsed or refractory leukemia with liposomal annamycin by the steps of:

(a) evaluating the subject to determine of the subject has relapsed or refractory leukemia;

(b) administering an amount of at least about 280 mg/m2 of liposomal annamycin for at least 3 days in a 7 day period.


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