Formulation of oral compositions comprising arsenic trioxide and methods of use thereof Number:7,521,071 from the United States Patent and Trademark Office (PTO) owispatent The present invention provides an oral formulation of arsenic trioxide (As.sub.2O.sub.3) for the treatment of a variety of hematological malignancies, including acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL). The present invention also provides methods for making the oral arsenic trioxide formulation. Methods of using the oral arsenic trioxide formulation are also described.<H compositions, Formulation, Formulation, of, , 7521071.html, Patent, pto, 7521071

Title: Formulation of oral compositions comprising arsenic trioxide and methods of use thereof

Abstract: The present invention provides an oral formulation of arsenic trioxide (As.sub.2O.sub.3) for the treatment of a variety of hematological malignancies, including acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL). The present invention also provides methods for making the oral arsenic trioxide formulation. Methods of using the oral arsenic trioxide formulation are also described.

Patent Number: 7,521,071 Issued on 04/21/2009 to Kumana, et al.

Inventors: Kumana; Cyrus Rustam (Pokfulam, HK), Kwong; Yok-Lam (Pokfulam, HK)
Assignee: Versitech Limited (HK)

Appl. No.: 10/669,869

Filed: September 23, 2003

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
60417200	Oct., 2002
60483014	Jun., 2003

Current U.S. Class: 424/623

Current International Class: A61K 33/36 (20060101); A61P 35/02 (20060101); A61P 7/00 (20060101)

Field of Search: 424/623

References Cited [Referenced By]

U.S. Patent Documents


6723351	April 2004	Warrell et al.
6875451	April 2005	Ellison et al.
2004/0126434	July 2004	Kumana et al.

Foreign Patent Documents


WO 9924029	May., 1999	WO

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Primary Examiner: Richter; Johann R
Assistant Examiner: Choi; Frank I
Attorney, Agent or Firm: Pabst Patent Group LLP

Parent Case Text

This application claims priority benefit to U.S. provisional application No. 60/417,200, filed Oct. 9, 2002; and U.S. provisional application No. 60/483,014, filed Jun. 25, 2003, each of which is incorporated herein by reference in its entirety.

Claims

What is claimed:

1. A method of treating hematological malignancies in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of at least 90% pure arsenic trioxide to produce a lower peak plasma concentration with less prolongation of the QT interval and ventricular tachycardia than observed when the same amount of arsenic trioxide is administered intravenously.

2. The method of claim 1, wherein the arsenic trioxide is a powder.

3. The method of claim 2, wherein the arsenic trioxide powder has at least 97%, 98% or 99% purity.

4. The method of claim 1, wherein the arsenic trioxide is incompletely dissolved or dispersed in a solution.

5. The method of claim 1, wherein the arsenic trioxide is administered in a dosage of 5 to 10 mg/day.

6. The method of claim 1, wherein the arsenic trioxide is in a solution having a pH of 8.0.

7. The method of claim 1, wherein the arsenic trioxide is in a solution having a pH of 7.2.

8. The method of claim 1, wherein the arsenic trioxide is orally administered to the subject daily at intervals for periods of weeks, a month or longer.

9. The method of claim 1, wherein the therapeutically effective amount is 10 mg per day.

10. The method of claim 1, wherein the hematological malignancies is selected from the group consisting of acute myeloid leukemia, acute nonlymphocytic leukemia, myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemia, myelodysplastic syndrome, acute promyclocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, polycythemia vera, Hodgkin's lymphoma, non-Hodgkin's lymphomas, myeloma, giant cell myeloma, indolent myeloma, localized myeloma, multiple myeloma, plasma cell myeloma, sclerosing myeloma, solitary myeloma, smoldering multiple myeloma, nonsecretary myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma.

11. The method of claim 1, wherein the hematological malignancies is acute myeloid leukemia.

12. The method of claim 1, wherein the hematological malignancies is acute promyclocytic leukemia.

13. The method of claim 1 further comprising administering one or more additional chemotherapeutic agents.

14. The method of claim 1 wherein the arsenic trioxide is a in a tablet, capsule, dispersion or suspension.

Description

1. INTRODUCTION

The present invention relates to an oral formulation of arsenic trioxide (As.sub.2O.sub.3) for the treatment of various hematological malignancies, including acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL). The formulation provides the systemic bioavailability comparable to that of intravenous (IV) administration of arsenic trioxide currently practiced. The oral formulation of the present invention exhibits the shelf life of more than three (3) months and provides a much more convenient, less risky and less expensive method of administering arsenic trioxide than the intravenous administration methods. The present invention also relates to a method for preparing the oral formulation of the present invention and a method for treating a subject with hematological malignancies using the oral formulation.

2. BACKGROUND OF THE INVENTION

2.1 Hematological Malignancies

Hematological malignancies are cancers of the body's blood-forming and immune systems. Hematological malignancies include leukemia, lymphoma (both Hodgkin's disease and non-Hodgkin's lymphoma), and myeloma. The abnormal cell growth interferes with the body's production of healthy blood cells, thus making the body unable to protect itself against infections.

New cases of hematological malignancies account for 9 percent of cancer cases diagnosed in the United States, and about 59,200 persons are killed by the diseases each year. Many of these disease occur in children.

2.1.1 Leukemia

Leukemia is a cancer of the bone marrow and blood. It is characterized by the uncontrolled growth of blood cells. About 30,000 new cases of leukemia in the United States are reported each year. Most cases occur in older adults, though leukemia is the most common type of childhood cancer.

Leukemia is either acute or chronic. In acute leukemia, the abnormal blood cells are blasts that remain very immature and cannot carry out their normal functions. The number of blasts increases rapidly, and the disease gets worse quickly. In chronic leukemia, some blast cells are present, but in general, these cells are more mature and can carry out some of their normal functions. Also, the number of blasts increases less rapidly than in acute leukemia. As a result, chronic leukemia gets worse gradually.

Leukemia can arise in either of the two main types of white blood cells--lymphoid cells (lymphocytic leukemia) or myeloid cells (myeloid or myelogenous leukemia). Common types of leukemia include acute lymphocytic leukemia (ALL); acute myeloid leukemia (AML) (sometimes called acute nonlymphocytic leukemia (ANLL)) such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome; chronic lymphocytic leukemia (CLL); chronic myeloid (granulocytic) leukemia (CML); chronic myelomonocytic leukemia (CMML); hairy cell leukemia; and polycythemia vera.

2.1.2 Lymphoma

There are two main types of lymphoma--Hodgkin's disease and non-Hodgkin's lymphoma. Hodgkin's disease, also known as Hodgkin's lymphoma, is a special form of lymphoma in which there is a particular cell known as the Reed Sternberg (R-S) cell. This cell is not usually found in other lymphomas.

The cause for Hodgkin's disease is unknown. Hodgkin's disease, like other cancers, is not infectious and cannot be passed onto other people. It is not inherited. The first symptom of Hodgkin's disease is usually a painless swelling in the neck, armpits or groin. Other symptoms may include night sweats or unexplained fever, weight loss and tiredness, cough or breathlessness, and persistent itch all over the body.

There are about 20 different types of non-Hodgkin's lymphoma. Non-Hodgkin's lymphomas are categorized according to their appearance under the microscope and the cell type (B-cell or T-cell). Risk factors include old age, female, weakened immune system, human T-lymphotropic virus type 1 (HTLV-1) and Epstein-Barr virus infection, and exposure to chemicals such as pesticides, solvents, and fertilizers.

2.1.3 Myeloma

Myeloma is a malignant tumor composed of plasma cells of the type normally found in the bone marrow. Myeloma cells tend to collect in the bone marrow and in the hard, outer part of bones. Sometimes they collect in only one bone and form a single mass, or tumor, called a plasmacytoma. In most cases, however, the myeloma cells collect in many bones, often forming many tumors and causing other problems. When this happens, the disease is called multiple myeloma such as but not limited to giant cell myeloma, indolent myeloma, localized myeloma, multiple myeloma, plasma cell myeloma, sclerosing myeloma, solitary myeloma, smoldering multiple myeloma, nonsecretary myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma.

Myelodysplastic syndromes are disorders in which the bone marrow produces ineffective and abnormal looking cells on one or more types (white blood cells, red blood cells or platelets). The majority of patients are men over sixty. Secondary myelodysplastic syndromes are seen following the use of chemotherapy and irradiation.

Signs and symptoms depend on the types of cells that are affected. Abnormal white cells make people more susceptible to infections; abnormal platelets make people more susceptible to bruising and spontaneous hemorrhages; and abnormal red blood cells causes anemia and fatigue.

While chemotherapy and radiation are useful in the treatment of hematological malignancies, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to hematological malignancies therapy and management of the disease by using an oral composition comprising arsenic trioxide.

2.2 Arsenic

Arsenic has been used medicinally for over 2,000 years. In the 18th century, a solution of arsenic trioxide (empirical formula As.sub.2O.sub.3) in 1% w/v potassium bicarbonate (Fowler's solution) was developed to treat a variety of infectious and malignant diseases. Its efficacy in suppressing white cells was first described in 1878 (Kwong Y. L. et al. Delicious poison: arsenic trioxide for the treatment of leukemia, Blood 1997;89:3487-8). Arsenic trioxide was therefore used to treat chronic myelogenous leukemia, until more potent cytotoxic drugs superseded it in the 1940s. However, there was a resurgence of interest in such therapy, when arsenic trioxide was found to induce apoptosis and differentiation in acute promyelocytic leukemia (APL) cells (Chen G. Q. et al. Use of arsenic trioxide (As.sub.2O.sub.3) in the treatment of acute promyelocytic leukemia (APL): I. As.sub.2O.sub.3 exerts dose-dependent dual effect on APL cells in vitro and in vivo, Blood 1997;89:3345-53; Soignet S. L. et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852-60). The clinical implications of these in vitro observations have since been verified, as arsenic trioxide induces remissions in over 90% of such patients (Shen Z. X. et al. Use of arsenic trioxide (As.sub.2O.sub.3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients, Blood 1997;89:3354-60; Soignet S. L. et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide, N Engl J Med 1998;339:1341-8; Niu C. et al., Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients, Blood 1999;94:3315-24).

A typical course of arsenic trioxide involves daily intravenous (IV) administration for 4 to 8 weeks and the attendant inconvenience, risks and expense of maintaining suitable vascular access and prolonged hospitalization. Currently, there is no oral arsenic trioxide for clinical use. Fowler's solution is no longer detailed in modem pharmacopoeias or listed in formularies (1941, Arsenum. Martindale, The Extra Pharmacopoeia 22:209-15; British Pharmacopoeia. London: Her Majesty's Stationery Office, 1988; Appendix 1A, p A12). Formulation of arsenic trioxide for oral administration could therefore offer distinct advantages. The inventors have recently developed an oral preparation of arsenic trioxide useful for achieving total blood cell and plasma levels of elemental arsenic comparable with those of intravenous arsenic trioxide (Kumana C. R. et al. Systemic availability of oral arsenic-trioxide used for treatment of patients with haematological malignancies. Eur J Clin Pharmacol. 2002;58:521-526, which is incorporated by reference herein in its entirety).

3. SUMMARY OF THE INVENTION

The present invention provides an oral preparation of arsenic trioxide (As.sub.2O.sub.3) for the treatment of patients with hematological malignancies, in particular, relapsed acute myeloid leukemia (AML) such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome, and relapsed acute promyelocytic leukemia (APL). A primary objective was to test whether the systemic bioavailability of the oral formulation was comparable to intravenous administration. A secondary objective was to delineate the extent of As.sub.2O.sub.3 accumulation in the cellular components of blood and by inference bone marrow cells (the presumed site of action).

In certain embodiments, the invention relates to an oral composition comprising arsenic trioxide useful for treating hematological malignancies. In one embodiment, the oral arsenic trioxide composition is prepared by the steps of: (1) adding arsenic trioxide to sterile water to form a first solution; (2) adding sodium hydroxide to the first solution to form a second solution; (3) adding sterile water to the second solution to form a third solution; (4) adding hydrochloric acid to the third solution to form a fourth solution; and (5) adding diluted hydrochloric acid and sterile water to the fourth solution to form a final solution. In a specific embodiment, the arsenic trioxide is a powder that has at least 90%, 95%, 96%, 97%, 98% or 99% purity. Preferably, the arsenic trioxide powder is completely dissolved prior to adding the hydrochloric acid. In another specific embodiment, the pH of the final arsenic trioxide solution is about 6.0, 6.5, 7.0, 7.5, or 8.0, preferably about 7.2. In another specific embodiment, the final solution has an arsenic trioxide concentration of 1 mg/ml.

The invention also relates to methods of making the oral arsenic trioxide composition. In a preferred embodiment, the method for making the arsenic trioxide composition comprises the steps of: (1) adding 500 mg of arsenic trioxide to 150 ml of sterile water to form a first solution; (2) adding 3M sodium hydroxide to the first solution to form a second solution; (3) adding 250 ml of sterile water to the second solution to form a third solution; (4) adding 6M hydrochloric acid to the third solution to form a fourth solution; and (5) adding dilute hydrochloric acid and sterile water to the fourth solution to form a final solution.

The invention further relates to methods of using the oral arsenic trioxide composition to treat hematological malignancies in a subject. The subject is selected from the group consisting of a cow, a pig, a horse, a sheep, a dog, a cat, a chicken, a duck, a monkey, a rat, a mouse, and a human. Preferably, the subject is a mammal, more preferably a primate, and most preferably a human.

In preferred embodiments, the arsenic trioxide composition is orally administered to a subject with hematological malignancies. The arsenic trioxide composition can be administered to the subject prior to, during, or after conventional treatments for hematological malignancies (e.g., chemotherapy, radiation).

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a representative estimation of arsenic level versus time curve (AUC) attributed to intravenous and oral dosing with arsenic trioxide in a single patient. All AUCs were computed using the trapezoid rule. The net 24 h AUC attributable to oral dosing was calculated as the difference between the gross 24-48 h AUC on day 2 and the corresponding AUC attributable to intravenous dosing. The latter AUC was calculated using the extrapolated arsenic level derived from estimates of that patient's elimination pharmacokinetics on day 1 (see Table IV). FIG. 1 is adopted from Kumana et al., Eur J Clin Pharmacol. (2002) 58:521-6, which is incorporated herein by reference in its entirety.

FIGS. 2a-2i show the arsenic concentrations of all nine (9) patients in plasma and whole blood arsenic concentrations on day 1 and day 2. FIGS. 2a-2i are also adopted from Kumana et al., supra., which is incorporated herein by reference in its entirety.

FIG. 3 shows the clinicopathologic features and outcome of 12 consecutive patients with relapsed acute promyelocytic leukemia (APL) treated with oral As.sub.2O.sub.3. FIG. 3 is adopted from Au et al., Blood (2003) 102:407-8, which is incorporated herein by reference.

5. DETAILED DESCRIPTION OF THE INVENTION

5.1 Preparation of the Oral Arsenic Trioxide Composition

In the absence of commercially available pharmacopoeial grade As.sub.2O.sub.3, a powder of good chemical quality (minimum purity 99%) was obtained from Sigma Chemical Company (St Louis, Mo., USA). As.sub.2O.sub.3 powder is sparingly and extremely slowly soluble in cold water; even in boiling water it is only soluble in a 1:15 ratio (Arsenic Trioxide, In: Budavari S O'Neil M J (Eds), The Merck Index. An encyclopedia of chemicals, drugs and biologicals. NJ: Merck & Co., Inc. 11th Ed., Rahway, N.J., USA. 1989. Monograph 832, p 127). It was eventually dissolved as follows.

Accurately weighed 500 mg aliquots of As.sub.2O.sub.3 powder were poured into a beaker containing 150 ml of sterile water. The resulting suspension was dissolved by drop-wise addition of 3M Sodium Hydroxide. When the powder was completely dissolved, a further 250 ml of sterile water were added. Using a pH meter, the ensuing solution was adjusted to pH 8.0 by slow titration with 6M Hydrochloric acid (HCl). Subsequent adjustment of the pH to 7.2 was carried out with dilute HCl and sterile water added to make up a final volume of 500 ml. Due to the extremely poisonous nature of the raw material and the known liability of such solutions to support fungal growths, the entire process was conducted in a pharmaceutical isolator. Contrary to general recommendations in Pharmacopoeias, no fungicidal agent was added. The resulting clear solution was developed to contain As.sub.2O.sub.3 at a concentration of 1 mg/ml. Moreover, samples submitted to the Hong Kong Government Laboratory were assayed and confirmed to contain 1 mg of As.sub.2O.sub.3 per ml and there was no fungal growth after incubation for 1 month in a sample submitted to the Department of Microbiology. The shelf-life of the solution was in excess of 3 months and for purpose of this study, no patient received formulations that had been stored for longer periods.

5.2 Methods of Use

5.2.1 Use in Subjects with Hematological Malignancies

The present invention further provides methods of using the oral arsenic trioxide compositions of the invention. In one embodiment, the arsenic trioxide composition is used as a medicament for treatment of hematological malignancies (e.g., leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, and myeloma). The methods comprise administering an effective amount of the arsenic trioxide composition to a subject in need. The arsenic trioxide composition may be administered orally, in liquid or solid form, or enterally through a feeding tube. As used herein, the term "an effective amount" means an amount sufficient to provide a therapeutic or healthful benefit in the context of hematological malignancies.

In one embodiment, the arsenic trioxide composition can produce a healthful benefit in a subject suffering from hematological malignancies. Preferably, the subject is a human being. The subject in need is one who is diagnosed with hematological malignancies, with or without metastasis, at any stage of the disease. As used herein, the term "hematological malignancies" include but are not limited to leukemia, lymphoma, and myeloma. As used herein, the term "leukemia" includes but is not limited to acute lymphocytic leukemia (ALL); acute myeloid leukemia (AML) (sometimes called acute nonlymphocytic leukemia (ANLL)) such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome; chronic lymphocytic leukemia (CLL); chronic myeloid (granulocytic) leukemia (CML); chronic myelomonocytic leukemias (CMML); hairy cell leukemia; and polycythemia vera. As used herein, the term "lymphoma" includes but is not limited to Hodgkin's disease and non-Hodgkin's lymphoma. As used herein, the term "myeloma" includes but is not limited to giant cell myeloma, indolent myeloma, localized myeloma, multiple myeloma, plasma cell myeloma, sclerosing myeloma, solitary myeloma, smoldering multiple myeloma, nonsecretary myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma.

The subject may be a patient who is receiving concurrently other treatment modalities against the hematological malignancies. The subject can be a patient with hematological malignancies who had undergone a regimen of treatment (e.g., chemotherapy and/or radiation) and whose cancer is regressing. The subject may be a patient with hematological malignancies who had undergone a regimen of treatment and who appears to be clinically free of the hematological malignancies. The arsenic trioxide composition of the invention can be administered adjunctively with any of the treatment modalities, such as but not limited to chemotherapy and/or radiation. For example, the arsenic trioxide composition can be used in combination with one or more chemotherapeutic or immunotherapeutic agents, such as amsacrine (AMSA), busulfan (Myleran.RTM.), chlorambucil (Leukeran.RTM.), cladribine (2-chlorodeoxyadenosine; "2-CDA"; Leustatin.RTM.), cyclophosphamide (Cytoxan.RTM.), cytarabine (ara-C;Cytosar-U.RTM.), daunorubicin (Cerubidine.RTM.), doxorubicin (Adriamycin.RTM.), etoposide (VePesid.RTM.), fludarabine phosphate (Fludara.RTM.), hydroxyurea (Hydrea.RTM.), idarubicin (Idamycin.RTM.), L-asparaginase (Elspar.RTM.), methotrexate sodium plus 6-mercaptopurine (6-MP; Purinethol.RTM.), mitoxantrone (Novantrone.RTM.), pentostatin (2-deoxycoformycin; "DCF"; Nipent.RTM.), prednisone, retinoic acid (ATRA), vincristine sulfate (Oncovin.RTM.), 6-thioguanine (Tabloid.RTM.), cyclosporin A, Taxol.RTM.), Cisplatin.RTM., Carboplatin.RTM., Doxil.RTM., Topotecan.RTM., Methotrexate.RTM., Bleomycin.RTM., and Epirubicin.RTM.. The arsenic trioxide composition can also be used after other regimen(s) of treatment is concluded.

The subject may be one who has not yet been diagnosed with hematological malignancies but are predisposed to or at high risk of developing hematological malignancies as a result of genetic factors and/or environmental factors.

Depending on the subject, the therapeutic and healthful benefits range from inhibiting or retarding the growth of the hematological malignancies and/or the spread of the hematological malignancies to other parts of the body (i.e., metastasis), palliating the symptoms of the cancer, improving the probability of survival of the subject with the cancer, prolonging the life expectancy of the subject, improving the quality of life of the subject, and/or reducing the probability of relapse after a successful course of treatment (e.g., chemotherapy, radiation). The symptoms associated with hematological malignancies include but are not limited to a weakened immune system, infections, fevers, decrease in red blood cells and platelets, weakness, fatigue, loss of appetite, loss of weight, swollen or tender lymph nodes, liver, or spleen, easy bleeding or bruising, tiny red spots (called petechiae) under the skin, swollen or bleeding gums, sweating (especially at night), bone or joint pain, headaches, vomiting, confusion, loss of muscle control, and seizures.

In particular, the invention provides a method for complete remission of the hematological malignancies in a subject, such as a human, comprising administering orally to the subject an arsenic trioxide composition of the invention. In other embodiments, the invention provides at least 10%, 20%, 40%, 60%, 80%, and 95% remission of the hematological malignancy. The invention also provide a method for prolonging the time of survival of a subject inflicted with hematological malignancies, preferably a human patient, comprising administering orally to the subject an arsenic trioxide composition of the invention.

The effective dose will vary with the subject treated and the route of administration. The effective dose for the subject will also vary with the condition to be treated and the severity of the condition to be treated. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual subject. In general, the total daily dose range of the arsenic trioxide composition for a subject inflicted with hematological malignancies is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, or 25 mg per day; preferably, about 10 mg per day, administered in single or divided doses. Preferably, the arsenic trioxide composition is administered to the subject orally.

The length of time for a course of treatment should be at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 7 weeks, at least 10 weeks, at least 13 weeks, at least 15 weeks, at least 20 weeks, at least 6 months, or at least 1 year. It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. In certain embodiments, the arsenic trioxide compositions can be administered for a period of time until the symptoms are under control, or when the disease has regressed partially or completely. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate use of the arsenic trioxide composition as a medication in conjunction with individual patient response.

The effect of the arsenic trioxide compositions of the invention on development and progression of hematological malignancies can be monitored by any methods known to one skilled in the art, including but not limited to measuring: a) changes in the size and morphology of the tumor using imaging techniques such as a computed tomographic (CT) scan or a sonogram; and b) changes in levels of biological markers of risk for hematological malignancies.

In certain embodiments, toxicity and efficacy of the prophylactic and/or therapeutic protocols of the instant invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD.sub.50 (the dose lethal to 50% of the population) and the ED.sub.50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD.sub.50/ED.sub.50. Prophylactic and/or therapeutic agents that exhibit large therapeutic indices are preferred. While prophylactic and/or therapeutic agents that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such agents to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

In other embodiments, the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage of the prophylactic and/or therapeutic agents for use in humans. The dosage of such agents lies preferably within a range of circulating concentrations that include the ED.sub.50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any agent used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC.sub.50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

The anti-cancer activity of the therapies used in accordance with the present invention also can be determined by using various experimental animal models for the study of cancer such as the scid mouse model or transgenic mice. The following are some assays provided as examples and not by limitation.

5.2.2 Formulation

The compositions of the present invention comprise arsenic trioxide prepared as described above in Section 5.1, as active ingredient, and can optionally contain a pharmaceutically acceptable carrier or excipient, and/or other ingredients provided that these ingredients do not compromise (e.g., reduce) the efficacy of the arsenic trioxide compositions. Other ingredients that can be incorporated into the arsenic trioxide compositions of the present invention, may include, but are not limited to, herbs (including traditional Chinese medicine products), herbal extracts, vitamins, amino acids, metal salts, metal chelates, coloring agents, flavor enhancers, preservatives, and the like.

Any dosage form may be employed for providing the subject with an effective dosage of the oral composition. Dosage forms include tablets, capsules, dispersions, suspensions, solutions, and the like. In one embodiment, compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, blisters, cachets, or tablets, each containing a predetermined amount of activated and conditioned yeast cells, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. In preferred embodiments, the oral composition is in the form of a solution. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. Such products can be used as pharmaceuticals or dietary supplements, depending on the dosage and circumstances of its use.

The oral compositions of the present invention may additionally include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); binders or fillers (e.g., lactose, pentosan, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets or capsules can be coated by methods well known in the art.

Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. The temperature of the liquid used to reconstitute the dried product should be less than 65.degree. C. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). As described below, the preparations can also be made to resemble foods or beverages, containing buffer salts, flavoring, coloring and sweetening agents as appropriate.

In certain embodiments, the arsenic trioxide composition is a suspension comprising about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10 or 15 mg of arsenic trioxide per ml. The arsenic trioxide composition can be diluted or concentrated using methods well known to those skilled in the art. In less preferred embodiments, the arsenic trioxide composition is a suspension containing about 0.1 to 100 mg arsenic trioxide per ml. In preferred embodiments, the arsenic trioxide composition is a suspension containing about 0.5 to 10 mg arsenic trioxide per ml. In more preferred embodiments, the arsenic trioxide composition is a suspension containing about 1 mg arsenic trioxide per ml. In most preferred embodiments, the arsenic trioxide composition is a suspension containing 1 mg arsenic trioxide per ml. The arsenic trioxide composition can be formulated as a health drink and packaged in liquid containers, each containing a predetermined amount of the liquid yeast culture. Standard methods of quality control and packaging are applied to produce in one embodiment of the invention, arsenic trioxide compositions packaged in liquid containers each comprising about 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 10 ml, 15 ml, 20 ml, 30 ml, 40 ml, 50 ml, 75 ml, 100 ml, 150 ml, 200 ml, 250 ml, 500 ml, 750 ml, or 1,000 ml of the arsenic trioxide composition. The number of container to be taken each day to obtain the total daily dose in a subject depends on the concentration of the arsenic trioxide compositions contained within each container.

Generally, because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers as described above are employed. In a preferred embodiment, the composition is a capsule. The capsules can be formulated by any commercially available methods. In certain embodiments, the composition is a capsule containing 0.25 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, or 50 mg of the arsenic trioxide compositions in powder form.

Additional examples of anti-cancer agents that can be used in the various embodiments of the invention, including pharmaceutical compositions and dosage forms and kits of the invention, include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2); interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagoni