Use of dianhydrogalactitol and analogs or derivatives thereof in combination with platinum-containing antineoplastic agents to treat non-small-cell carcinoma of the lung and brain metastases

Abstract

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of non-small-cell lung carcinoma (NSCLC) and ovarian cancer, as well as other types of malignancy, including brain metastases of NSCLC. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N7 methylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide, cisplatin, and tyrosine kinase inhibitors; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol can be used together with other anti-neoplastic agents and can possess additive or super-additive effects.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of PCT Patent Application Serial No. PCT / US2015 / 0244562 by J. A. Bacha et al., filed Apr. 6, 2015 and entitled “Use of Dianhydrogalactitol and Analogs and Derivatives Thereof to Treat Non-Small-Cell Carcinoma of the Lung and Ovarian Cancer,” which in turn claimed the benefit of U.S. Provisional Patent Application Ser. No. 61 / 975,587 by J. A. Bacha et al., filed Apr. 4, 2014 and entitled “Use of Dianhydrogalactitol and Analogs and Derivatives Thereof to Treat Non-Small-Cell Carcinoma of the Lung” and claimed the benefit of U.S. Provisional Patent Application Ser. No. 62 / 062,246 by J. Bacha et al., filed Oct. 10, 2014 and entitled “Use of Dianhydrogalactitol and Analogs and Derivatives Thereof to Treat Non-Small-Cell Carcinoma of the Lung.” The contents of the above-identified PCT application and both of these United States provisional patent applications are incorporated herein in their entirety by this r...

AI Technical Summary

Benefits of technology

[0011]The use of a substituted hexitol derivative to treat non-small-cell lung carcinoma (NSCLC) provides an improved therapy for NSCLC and ovarian cancer that yields increased survival and is substantially free of side effects. In general, the substituted hexitols usable in methods and compositions according to the present invention include galactitols, substituted galacitols, dulcitols, and substituted dulcitols. Typically, the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol. A particularly preferred substituted hexitol derivative is dianhydrogalactitol (DAG). The substituted hexitol derivative can be employed together with other therapeutic modalities for these malignancies. Dianhydrogalactitol is particularly suited for the treatment of these malignancies because it can suppress the growth of cancer stem cells (CSC), and because it is resistant to drug inactivation by O6-methylguanine-DNA methyltransferase (MGMT). The substituted hexitol derivative yields increased response rates and improved quality of life for patients with NSCLC and ovarian cancer.

[0015](2) modifying the factor or parameter to improve the efficacy and / or reduce the side effects of the administration of the substituted hexitol derivative for treatment of NSCLC or ovarian cancer.

[0052](36) use with an agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier to treat brain metastases of NSCLC or ovarian cancer.

[0055](i) a therapeutically effective quantity of a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative, wherein the modified substituted hexitol derivative or the derivative, analog or prodrug of the substituted hexitol derivative or modified substituted hexitol derivative possesses increased therapeutic efficacy or reduced side effects for treatment of NSCLC as compared with an unmodified substituted hexitol derivative;

[0060](iv) a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is incorporated into a dosage kit and packaging, wherein the substituted hexitol derivative, the modified substituted hexitol derivative or the derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative incorporated into the dosage kit and packaging possesses increased therapeutic efficacy or reduced side effects for treatment of NSCLC as compared with an unmodified substituted hexitol derivative; and

[0061](v) a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is subjected to a bulk drug product improvement, wherein substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative subjected to the bulk drug product improvement possesses increased therapeutic efficacy or reduced side effects for treatment of NSCLC as compared with an unmodified substituted hexitol derivative.

Problems solved by technology

While many advances have been made from basic scientific research to improvements in practical patient management, there still remains tremendous frustration in the rational and successful discovery of useful therapies particularly for life-threatening diseases such as cancer, inflammatory conditions, infection, and other conditions.

However, from the tens of billions of dollars spent over the past thirty years supporting these programs both preclinically and clinically, only a small number of compounds have been identified or discovered that have resulted in the successful development of useful therapeutic products.

Unfortunately, many of the compounds that have successfully met the preclinical testing and federal regulatory requirements for clinical evaluation were either unsuccessful or disappointing in human clinical trials.

In other cases, chemical agents where in vitro and in vivo studies suggested a potentially unique activity against a particular tumor type, molecular target or biological pathway were not successful in human Phase II clinical trials where specific examination of particular cancer indications / types were evaluated in government sanctioned (e.g., U.S. FDA), IRB approved clinical trials.

In addition, there are those cases where potential new agents were evaluated in randomized Phase III clinical trials where a significant clinical benefit could not be demonstrated; such cases have also been the cause of great frustration and disappointment.

Finally, a number of compounds have reached commercialization but their ultimate clinical utility has been limited by poor efficacy as monotherapy (<25% response rates) and untoward dose-limiting side-effects (Grade III and IV) (e.g., myelosuppression, neurotoxicity, cardiotoxicity, gastrointestinal toxicities, or other significant side effects).

In many of those cases, the results did not realize a significant enough improvement to warrant further clinical development toward product registration.

Even for commercialized products, their ultimate use is still limited by suboptimal performance.

With so few therapeutics approved for cancer patients and the realization that cancer is a collection of diseases with a multitude of etiologies and that a patient's response and survival from therapeutic intervention is complex with many factors playing a role in the success or failure of treatment including disease indication, stage of invasion and metastatic spread, patient gender, age, health conditions, previous therapies or other illnesses, genetic markers that can either promote or retard therapeutic efficacy, and other factors, the opportunity for cures in the near term remains elusive.

For difficult to treat cancers, a patient's treatment options are often exhausted quickly resulting in a desperate need for additional treatment regimens.

Although smoking is apparently the most frequent cause of squamous cell carcinoma, when lung cancer occurs in patients without any history of prior tobacco smoking, it is frequently adenocarcinoma.

However, chemotherapy and radiation therapy are frequently attempted, particularly if the diagnosis cannot be made at an early stage of the malignancy.

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