Method for treating female non-smokers with non-small cell lung cancer

Abstract

To provide a method of treating a female patient suffering from non-small cell lung cancer.SOLUTION: The present invention provides a method that includes the step of administering to the patient in need thereof a composition of 2,2'-dithio-bis-ethane sulfonate or a pharmaceutically-acceptable salt thereof. The method can include other primary therapies.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] This application relates to pharmaceutical compositions, methods, and kits used in the treatment of cancer and other medical conditions. More specifically, this application relates to pharmaceutical compositions, methods, and kits containing medicaments used in the treatment of non-small cell lung cancer, advanced non-small cell lung cancer, adenocarcinoma, and other medical conditions, particularly in women and non-smokers or never-smokers. [Background technology]

[0002] Tavocept or 2'-dithio-bis-ethane disodium (CAS number 16208-51-8) is water soluble, can be delivered intravenously, and has the following structure: [ka] It is a small molecule (approximately 326 Da) having the following structure:

[0003] Tavocept demonstrated positive subgroup responses with a significant improvement in overall survival, but did not meet clinical efficacy endpoints.

[0004] Worldwide, lung cancer is the most common cancer in terms of both incidence and mortality.

[0005] Lung cancer is the leading cause of cancer death for both men and women worldwide, and the cost of treating lung cancer in the United States in 2015 was $13.4 billion. The American Cancer Society estimates that of the 234,030 new lung cancer cases in the United States in 2018, 112,350 were women. NSCLC is the most common form of lung cancer (approximately 85% of lung cancers) and has three subtypes in descending order of prevalence: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Approximately 10–15% of all lung cancers occur in never smokers, and lung cancer in never smokers is one of the leading causes of cancer-related mortality. Given the impact of this disease, it is surprising that little information is available on the descriptive epidemiology of lung cancer in never smokers. Neither cancer registries nor routinely collected death certificates provide reliable information on lifetime smoking history, so general demographic statistics are largely uninformative. Furthermore, reports of smoking from next of kin or in medical records are often incomplete and unreliable. Only large cohort studies allow for the measurement of age- and sex-specific lung cancer rates in never smokers with reasonable accuracy, and these generally study mortality rather than incidence. There are currently no treatments specifically approved for the growing indication of non-smokers with non-small cell lung cancer, or NSCLC.

[0006] Approximately 40% of all NSCLCs are adenocarcinomas, and more than half occur in women. Today, the majority of people diagnosed with lung cancer are not active smokers, and despite recent declines in lung cancer overall, lung cancer has increased significantly in one group of people: women who never smoke. The prevalence of lung cancer in nonsmokers has increased over time, with more than half occurring in current nonsmokers.

[0007] Recent data suggest that lung cancer mortality in women is projected to rise by 43% globally by 2030, surpassing breast cancer mortality. Although it has been argued that lung cancer in female non-smokers is a distinct type of cancer, few studies have reported on this population. This population remains underserved, and lung cancer in female non-smokers is rightly classified as a rare disease. The poor prognosis of advanced non-small cell lung cancer (NSCLC) is likely due to tumor resistance to chemotherapy.

[0008] Thus, there is a need for treatments for non-smoking female NSCLC patients with adenocarcinoma, and it is to this need, among others, that the present application is directed. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 shows a retrospective subgroup analysis of NSCLC adenocarcinoma patients who received cisplatin and / or paclitaxel.

[0010] [Diagram 2] FIG. 2 shows that the percentage of patients who experienced treatment failure was lowest in non-smokers who received 2,2′-dithio-bis-ethanesulfonate. [Diagram 3] FIG. 3 shows that the percentage of patients who experienced treatment failure was lowest in female non-smokers who received 2,2′-dithio-bis-ethanesulfonate. Summary of the Invention

[0011] The present disclosure provides methods, devices, and compositions for delivering a combination of a cytostatic drug (e.g., cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II)) and 2'-dithio-bis-ethane disodium to patients with non-small cell lung cancer, adenocarcinoma.

[0012] One embodiment of the present application provides a combination therapy of 2'-dithio-bis-ethane disodium for treating non-small cell lung cancer, particularly in female non-smokers. In some embodiments, the therapeutic agent is one or more chemotherapeutic agents selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatinum, carboplatin, melphalam, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and Raf kinase inhibitors.

[0013] Another embodiment includes a method of treating advanced and / or metastatic non-small cell lung cancer in a female patient, comprising administering to a human patient having second-line or higher line of treatment non-small cell lung cancer a pharmaceutical composition of 2,2'-dithio-bis-ethanesulfonate or a pharma- ceutical acceptable salt thereof and a second therapeutic agent. The non-small cell lung cancer can be lung adenocarcinoma.

[0014] Another embodiment includes a method of treating a female patient suffering from non-small cell lung cancer, comprising administering to the patient in need of treatment a composition of 2,2'-dithio-bis-ethanesulfonate or a pharma- ceutically acceptable salt thereof. The patient may be a non-smoker or a never-smoker. The method may include the additional step of co-administering to the patient in need thereof a second therapeutic agent useful in the treatment of non-small cell lung cancer.

[0015] Another embodiment includes a method of treating a female non-smoking patient suffering from or susceptible to non-small cell lung cancer, comprising determining whether the patient is a non-smoker and administering to the non-smoker a composition of 2,2'-dithio-bis-ethanesulfonate or a pharma- ceutically acceptable salt thereof. The method may include a second therapeutic agent, paclitaxel or cisplatin. Additionally, the method may include an additional step of co-administering a second therapeutic agent useful in the treatment of non-small cell lung cancer to a patient in need thereof. The second therapeutic agent may be selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatinum, carboplatin, melphalam, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, and cetuximab.

[0016] Another embodiment includes a method comprising determining whether the non-small cell lung cancer is an ALK, ROS, MET, EGFR mutation-positive non-small cell lung cancer. In an example, the non-small cell lung cancer includes fusions / rearrangements of the ALK and ROS1 genes, mutations / deletions of the EGFR gene, and amplifications of the MET / HGFR genes.

[0017] The details of the invention are set forth in the drawings and description which follow. Other features, objects, and advantages of the invention will become apparent from the description and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Detailed Description One embodiment includes a method of increasing survival time in a female patient with non-small cell lung carcinoma or non-small cell lung carcinoma, in which 2,2'-dithio-bis-ethanesulfonate or a salt is administered to the patient with non-small cell lung carcinoma in a therapeutically effective amount. In one example, 2,2'-dithio-bis-ethanesulfonate or a salt thereof may be administered prior to, simultaneously with, or subsequent to administration of one or more chemotherapeutic agents. In one example, the female patient is a non-smoker. In another particular embodiment, the method is used to treat a female non-smoker patient suffering from non-small cell lung cancer.

[0019] The composition is a therapeutically effective amount of a compound of formula (I) that affects oxidative metabolism, including, but not limited to, 2,2'-dithio-bis-ethanesulfonic acid disodium salt or a pharma- ceutically acceptable salt or analog thereof. 2,2'-dithio-bis-ethanesulfonic acid disodium salt is also referred to in the literature as 2,2'-dithio-bis-ethanesulfonate. Various salts and analogs of 2,2'-dithio-bis-ethanesulfonate, as well as other dithioethers, can also be synthesized, as outlined in U.S. Pat. No. 5,808,160, U.S. Pat. No. 6,160,167, and U.S. Pat. No. 6,504,049, the disclosures of which are incorporated herein by reference in their entirety. Additionally, the composition of the present invention also includes a medically sufficient dose of a metabolite of 2,2'-dithio-bis-ethanesulfonic acid disodium, also known as sodium 2-mercaptoethanesulfonate.

[0020] In another embodiment, any of the above treatment methods includes the further step of co-administering one or more second therapeutic agents to the patient. The selection of the drug or combination of second therapeutic agents can be made from any second therapeutic agent known to be useful for co-administration with 2,2'-dithio-bis-ethanesulfonate or salt. The selection of the second therapeutic agent also depends on the particular disease or condition to be treated. Examples of second therapeutic agents that can be used in the methods of the present application are those described above for use in the combination composition comprising the compound of the present invention and a second therapeutic agent.

[0021] In another embodiment, the second therapeutic agent is one or more chemotherapeutic agents selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatinum, carboplatin, melphalam, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and a Raf kinase inhibitor.

[0022] In another embodiment, the second therapeutic agent is one or more chemotherapeutic agents selected from paclitaxel or cisplatinum.

[0023] The methods detailed herein also include methods in which a patient is identified as needing a particular routine treatment. Identifying a patient as needing such treatment may be at the discretion of the patient or a medical professional and may be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method). 2,2'-dithio-bis-ethanesulfonate may target molecular pathways that are more prevalent in female non-smokers than other groups. c-Met, also known as tyrosine-protein kinase Met / MET mesenchymal epithelial transition / hepatocyte growth factor receptor (HGFR) / anaplastic lymphoma kinase (ALK), ROS-1 (orphan receptor tyrosine kinase), and epidermal growth factor receptor (EGFR) genetic alterations are most commonly found in female, non-smokers presenting with advanced stage adenocarcinoma. In certain embodiments, patients may be initially screened using one or more tests for EGFR and c-Met / ALK status. A high percentage of adenocarcinoma patients appear to have EGFR gene mutations or are c-Met / ALK positive or ROS-1.A method of treating advanced and / or metastatic non-small cell lung cancer in a female patient, comprising administering to a human patient with non-small cell lung cancer who has received second line or higher line therapy a pharmaceutical composition of 2,2'-dithio-bis-ethanesulfonate or a pharma- ceutical acceptable salt thereof and a second therapeutic agent.

[0024] In one embodiment, an effective amount of the compound of the present application may range from 10 to 40 grams per dose. In one embodiment, an effective amount of the compound of the present application may range from 1 to 500 grams per dose. In some embodiments, an effective amount ranges from 0.01 to 10 grams per dose. In other embodiments, an effective amount ranges from 10 to 60 grams per dose. It is not necessary to provide equal daily or weekly dosages.

[0025] The therapeutically effective dose may vary depending on the disease being treated, the severity of the disease, the route of administration, the age and general health of the patient, the use of excipients, the possibility of co-administration with other therapeutic treatments such as the use of other drugs, and the judgment of the treating physician, as will be recognized by those skilled in the art. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information or journal review for 2,2'-dithio-bis-ethanesulfonate.

[0026] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents.The formulations may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0027] The aforementioned injection solutions may be in the form of, for example, a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable excipients and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma- ceutical acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0028] Alternatively, 2,2'-dithio-bis-ethanesulfonate may be delivered orally using a formulation that protects the compound from oxidation in an acidic environment and allows for intestinal absorption.

[0029] "Non-smoker" refers to an individual who is not a smoker at the time of evaluation. Non-smokers include individuals who have never smoked and individuals who have smoked in the past but have not used tobacco products within the past year. In one example, the term "non-smoker" refers to a person who has smoked for 15 pack-years or less or has not smoked for 25 years or more. The appropriate category can be selected by those skilled in the art with only routine experimentation. In certain embodiments, the test subject is a non-smoker. "Non-smoker" refers to an adult who has never smoked or has smoked less than 100 cigarettes in his / her lifetime.

[0030] The term "effective amount" as used herein refers to the amount of drug required to alleviate at least one or more symptoms of a disease or disorder, and relates to a sufficient amount of a pharmacological composition to provide a desired effect. Thus, the term "therapeutically effective amount" refers to an amount of drug that is sufficient to provide a particular effect when administered to a typical subject. As used herein, an effective amount will also include an amount sufficient to delay the onset of a disease symptom, alter the course of a disease symptom (such as, but not limited to, slowing the progression of a disease symptom), or reverse a disease symptom in various circumstances. Thus, it is generally not feasible to specify an exact "effective amount". However, for any given case, an appropriate "effective amount" can be determined by one of ordinary skill in the art using only routine experimentation.

[0031] Dosage ranges for administration of agents according to the methods described herein vary, for example, depending on the form of the agent, its potency, and the degree to which it is desired to reduce the symptoms, markers, or indicators of the conditions described herein, e.g., the desired rate of reduction in tumor growth. The dosage should not be so large as to cause adverse side effects. In general, dosages will vary according to the age, condition, and sex of the patient, and can be determined by one of skill in the art. Dosages can also be adjusted by the individual physician in the event of any complications.

[0032] For example, the efficacy of the agents described herein in treating a condition described herein or in inducing a response described herein (e.g., in lung cancer) can be determined by one of skill in the art. However, as the term treatment is used herein, a treatment is considered to be "effective treatment," if one or more of the signs or symptoms of a condition described herein are modified in a beneficial manner, if other clinically acceptable symptoms are improved or even alleviated, or if a desired response is induced, for example, by at least 10% after treatment by a method described herein. Efficacy can be evaluated, for example, by measuring markers, indicators, symptoms and / or incidence of a condition treated according to a method described herein, or any other suitable measurable parameter, for example, tumor size and / or growth rate. Efficacy can also be measured by failure of an individual to deteriorate as assessed by hospitalization, or the need for medical intervention (i.e., progression of the disease is halted). Methods for measuring these indicators are known to those of skill in the art and / or described herein. Treatment includes any treatment of a disease in an individual or animal (some non-limiting examples include humans or animals), including (1) inhibiting the disease, e.g., preventing the worsening of symptoms (e.g., pain or inflammation), or (2) reducing the severity of the disease, e.g., causing regression of symptoms. An effective amount for the treatment of a disease means an amount that, when administered to a subject in need thereof, is sufficient to provide effective treatment for the disease, as that term is defined herein. The efficacy of an agent can be determined by assessing physical indicators of the condition or desired response. It is well within the capabilities of one of ordinary skill in the art to monitor the efficacy of administration and / or treatment by measuring any one of the aforementioned parameters, or any combination of parameters. Efficacy can be assessed in the treatment of lung cancer in an animal model of the condition described herein, e.g., a mouse model. When using an experimental animal model, the efficacy of the treatment is demonstrated when a statistically significant change in a marker, e.g., tumor size and / or growth rate, is observed.A method for treating advanced and / or metastatic non-small cell lung cancer in a female patient, comprising administering to a human patient having non-small cell lung cancer who has received second-line or higher-line therapy a pharmaceutical composition of 2,2'-dithio-bis-ethanesulfonate or a pharma- ceutical acceptable salt thereof and a second therapeutic agent.

[0033] As used herein, the term "pharmaceutical acceptable" refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutical acceptable salt" means any non-toxic salt that is capable of providing, directly or indirectly, a compound of the invention upon administration to a recipient. A "pharmaceutical acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

[0034] The term "treating" is used and includes both therapeutic and prophylactic treatment (reducing the likelihood of occurrence). Both terms refer to the reduction, suppression, attenuation, reduction, arrest or stabilization of the onset or progression of a disease (e.g., a disease or disorder detailed herein), the lessening of the severity of a disease, or the amelioration of symptoms associated with a disease. EXAMPLES

[0035] example The following examples are included for illustrative purposes and are not intended to limit the scope of the invention.

[0036] Example 1 There are several pathways in NSCLC adenocarcinoma whose targets are often overexpressed in women and are regulated by 2,2'-dithio-bis-ethanesulfonic acid disodium salt. Thus, 2,2'-dithio-bis-ethanesulfonic acid disodium salt targets within the following important pathways: 1) kinases involved in important signaling pathways (ALK, ROS, MET, EGFR), 2) enzymes important for DNA synthesis and repair (ERCC1, RNR1, RNR2), and 3) enzymes and proteins important for regulating the redox state of cells (Trx, Prx, Grx, PDI). The mutations and overexpressions targeted and regulated by 2,2'-dithio-bis-ethanesulfonic acid disodium salt appear to be more frequent in women with lung adenocarcinoma, especially in non-smokers.

[0037] Results of clinical trials of 2,2'-dithio-bis-ethanesulfonic acid disodium salt showed increased survival from 13 to 25 months in female non-smokers, but the increase in survival was small in all gender and smoking status groups. Results of the study showed an overall survival of 25.0 months and a 2-year survival rate of 51.4% in women with advanced lung adenocarcinoma treated with paclitaxel / cisplatin. The observed results were statistically significant (p value = 0.0477; HR = 0.579) and were observed in a subgroup of 114 female patients upon retrospective analysis. Consistent statistically significant results were observed in a prospective double-blind, placebo-controlled trial of 2,2'-dithio-bis-ethanesulfonic acid disodium salt in female adenocarcinoma patients conducted in Japan.

[0038] 2,2'-Dithio-bis-ethanesulfonic acid disodium salt exhibited chemoprotective properties and reduced anemia, both of which disproportionately affect women. A Phase III pulmonary study also demonstrated significant safety / toxicity profile benefits by protecting against chemotherapy-induced nephrotoxicity and reducing anemia. These data complement previous clinical findings with 2,2'-dithio-bis-ethanesulfonic acid disodium salt protecting against neuropathy and other chemotherapy-induced toxicities.

[0039] Example 2 FIG. 1 shows a retrospective subgroup analysis of NSCLC adenocarcinoma patients receiving cisplatin / paclitaxel from the Phase III clinical trial ID DMS32212R (ClinicalTrials.gov Identifier: NCT00966914), showing significantly better survival for women, non-smokers, and female non-smokers in the 2,2′-dithio-bis-ethanesulfonate-treated group, as indicated by improved overall survival.

[0040] FIG. 2 shows that the percentage of patients experiencing treatment failure was lowest in non-smokers in the 2,2′-dithio-bis-ethanesulfonate treatment group.

[0041] FIG. 3 shows that the percentage of patients experiencing treatment failure was lowest in female non-smokers in the 2,2′-dithio-bis-ethanesulfonate treatment group.

[0042] Although the description refers to specific example embodiments, it will be apparent to one skilled in the art that example embodiments in accordance with the present invention may be practiced by varying these specific details, and therefore, the example embodiments should not be construed as being limited to the embodiments set forth herein.

Claims

1. 1. A method of treating a female patient suffering from non-small cell lung cancer, comprising administering a composition of 2,2'-dithio-bis-ethanesulfonate or a pharma- ceutical acceptable salt thereof to a patient in need thereof.

2. The method of claim 1 , wherein the patient is a non-smoker.

3. The method of claim 2, wherein the non-small cell lung cancer is lung adenocarcinoma.

4. 10. The method of claim 1, further comprising the further step of co-administering a second therapeutic agent useful in the treatment of non-small cell lung cancer to a patient in need thereof.

5. 5. The method of claim 4, wherein the second therapeutic agent is paclitaxel or cisplatin.

6. 5. The method of claim 4, wherein the second therapeutic agent is selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatinum, carboplatin, melphalam, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, and cetuximab.

7. The method of claim 4, wherein the non-small cell lung cancer is EGFR mutation-positive non-small cell lung cancer.

8. 10. The method of claim 1, wherein 10 to 40 grams of 2,2'-dithio-bis-ethanesulfonate or a pharma- ceutically acceptable salt is administered to the patient per dose.

9. The method of claim 1 , wherein the patient is a never-smoker.

10. A method of treating advanced and / or metastatic non-small cell lung cancer in a female patient, comprising administering to a human patient having non-small cell lung cancer who has received second line or higher line therapy a pharmaceutical composition of 2,2'-dithio-bis-ethanesulfonate or a pharma- ceutical acceptable salt thereof and a second therapeutic agent.

11. The method of claim 10, wherein the non-small cell lung cancer is EGFR mutation-negative non-small cell lung cancer.

12. 11. The method of claim 10, wherein the second therapeutic agent is paclitaxel or cisplatin.

13. 1. A method of treating a female, non-smoking patient suffering from non-small cell lung cancer, comprising: a. determining whether the patient is a non-smoker; and b. administering to said non-smoker a composition of 2,2'-dithio-bis-ethanesulfonate, or a pharma- ceutically acceptable salt thereof. The method includes:

14. 14. The method of claim 13, further comprising testing for EGFR mutations.

15. 14. The method of claim 13, further comprising the further step of co-administering to a patient in need thereof a second therapeutic agent useful in the treatment of non-small cell lung cancer.

16. 16. The method of claim 15, wherein the second therapeutic agent is paclitaxel or cisplatin.

17. 16. The method of claim 15, wherein the second therapeutic agent is selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatinum, carboplatin, melphalam, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, and cetuximab.

18. 17. The method of claim 16, wherein the effective amount of 2,2'-dithio-bis-ethanesulfonate or a pharma- ceutically acceptable salt thereof ranges from 0.01 to 10 grams per dose.

19. The method of claim 13, further comprising determining that the non-small cell lung cancer is ALK, ROS, MET, EGFR mutation-positive non-small cell lung cancer for ALK, ROS, MET, EGFR.

20. 14. The method of claim 13, comprising determining that the non-small cell lung cancer comprises a fusion / rearrangement of the ALK and ROS1 genes, a mutation / deletion of the EGFR gene, and an amplification of the MET / HGFR genes.

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