Fixed drug ratios for treatment of hematopoietic cancers and proliferative disorders

Abstract

Provided herein are methods for treating cancer by administering a pharmaceutical composition comprising a fixed, non-antagonistic molar ratio of cytarabine and an anthracycline. Such methods are particularly useful in the treatment of patients with advanced hematologic cancers or proliferative disorders.

Description

RELATED APPLICATIONS[0001]The application claims benefit of U.S. Application Ser. No. 60 / 901,772 filed 16 Feb. 2007, and U.S. Application Ser. No. 60 / 965,196 filed 17 Aug. 2007, each of which is incorporated herein by reference in its entirety.TECHNICAL FIELD[0002]The invention relates to methods for improved delivery and therapeutic effectiveness of a combination of therapeutic agents. More particularly, the inventions relates to delivery of a fixed ratio combination of cytarabine and an anthracycline, e.g., daunorubicin.BACKGROUND ART[0003]In vitro studies have shown that antitumor activity can be enhanced when cytotoxic drugs are used in combination. This has led, over the years, to the use of drug combinations in the clinic such that cytotoxic drug combinations are now standard in many forms of cancer chemotherapy. New anticancer drugs are typically first introduced in patients as single agents. After a maximum tolerated dose is determined for one agent, a second agent is added ...

AI Technical Summary

Benefits of technology

[0013]In one aspect, provided herein is a method to reduce the toxicity of cytarabine / anthracycline combination chemotherapy treatments in a subject by administering to said patient a pharmaceutical composition comprising delivery vehicles having stably associated therewith a fixed, non-antagonistic molar ratio of cytarabine and anthracycline, wherein the toxicity resulting from administration of said composition is less than the toxicity that results from administration of the same amount of cytarabine and anthracycline when not present in delivery vehicles. In some embodiments, reduction in toxicity is measured as a reduction in non-hematopoietic toxicities such as, for example, mucositis or alopecia. A reduction in such toxicities can in turn lead to a reduction in hospitalization, supportive care, morbidity and / or a reduction in induction mortality particularly in patients over 60 years of age and more specifically in patients over the age of 75.

Problems solved by technology

However, in vitro, where the molar ratio of drugs used in combination can be controlled, it has been demonstrated that drug combinations providing synergy at one ratio may be simply additive or even antagonistic at other ratios (Mayer, L. D., et al., Mol. Cancer. Ther.

When individual free drugs are administered in chemotherapy “cocktails”, each agent is handled differently by the body, resulting in varying distribution and elimination of each drug, which can result in drug ratios that are suboptimal or ineffective for some or most of the time.

Daunorubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA.

While combinations of these two drugs administered as drug cocktails have provided some benefit, there are various drawbacks that limit their therapeutic use.

For instance, administration of free drug cocktails typically results in rapid clearance of one or all of the drugs before reaching the disease site.

If the individual drugs in the cocktail are only optimally effective within a narrow ratio to one another, a rapid clearance of one drug but not the other can reduce overall efficacy of the combination while increasing toxicity.

Such long infusional administration results in increased complexity, hospitalization time, and expense as well as increased risk of infusion complications.

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