Combination of dimesna and pemetrexed to treat non-small cell lung cancer (NSCLC)

Abstract

A method of treating advanced non-small cell lung adenocarcinoma in a patient includes administering dimesna in combination with pemetrexed and carboplatin and transitioning to a monotherapy regimen with pemetrexed for maintenance of disease control. This methodology provides applications in personalized oncology, addressing the need for durable and manageable treatment regimens for advanced NSCLC.

Description

Combination of Dimesna and Pemetrexed to Treat Non-Small Cell Lung Cancer (NSCLC)TECHNICAL FIELD

[0001] This application relates to pharmaceutical compositions, methods, and kits designed for the treatment of cancer and various medical conditions. More specifically, it focuses on pharmaceutical compositions, methods, and kits that include medicaments for treating non-small cell lung cancer, advanced non-small cell lung cancer, adenocarcinoma, and other forms of lung cancer.BACKGROUND

[0002] Disodium 2’-dithio-bis-ethane (CAS No. 16208-51-8) or dimesna is a small molecule (about 326 Da) that is water soluble, that can be delivered intravenously, and that has following structure:Dimesna showed promising results in certain subgroups, notably with significant enhancements in overall survival rates. However, it fell short of meeting the clinical efficacy endpoints. Presently, there is no therapy explicitly approved for the increasingly recognized category of nonsmokers afflicted with NSCLC (Non-Small Cell Lung Cancer).

[0003] Lung cancer in non-smokers (LCINS) is the seventh leading cause of death among solid tumors. LCINS is more frequent in women, and the histological incidence of adenocarcinoma is higher among non-smokers. NSCLC is the most common form of lung cancer (app. 85% of lung cancers), with adenocarcinoma, squamous cell and large cell carcinoma as the three subtypes in decreasing prevalence order. Approximately 40% of all NSCLC are adenocarcinomas, while more than half are in women. The majority of people diagnosed with lung cancer today are not activesmokers, and unlike the recent decrease in lung cancer in general, lung cancer is significantly increasing in one group of people: women who do not smoke. The prevalence of lung cancer in non-smokers has been increasing over time with over half occurring in current non-smokers. Recent data suggest that lung cancer mortality rates among women are projected to rise globally by 43% by 2030 and exceed deaths from breast cancer. It has been argued that lung cancer in female non-smokers is a distinct entity, but studies describing this population are scant. This population remains under-served and lung cancer in female non-smokers should be classified as a rare disease.

[0004] Accordingly, there is a need for a treatment for nonsmoking female NSCLC patients with adenocarcinoma. It is to this need, among others, that this application is directed.SUMMARY

[0005] The application discloses a method and composition for using dimesna in combination with pemetrexed as a maintenance therapy in cancer treatment. This combination is particularly useful in prolonging remission and preventing relapse in patients who have responded to initial cancer therapy. This application provides a effective approach for managing advanced NSCLC, demonstrating the clinical benefit of integrating LP-300 / dimesna into combination and maintenance therapy regimens. This therapeutic method can achieve durable responses and improved survival outcomes in patients with advanced- stage disease.

[0006] One aspect provides a multi-phase treatment strategy tailored to patients with advanced- stage NSCLC. The treatment begins with a combination therapy phase, where LP-300 / dimesna is administered alongside pemetrexed and carboplatin. LP-300 / dimesna, a chemoprotective agent, is given at a dosage of approximately 18.4 mg / m2, administered intravenously every three weeks. This combination is designed to leverage the cytotoxic effects of standard chemotherapy agents while providing protective and therapeutic benefits through LP-300 / dimesna.

[0007] Baseline assessments can be conducted to identify target lesions, measure disease burden, and establish clinical performance status. Imaging studies, such as CT and PET / CT scans, are used to assess tumor size and metabolic activity, while performance status is evaluated using the Eastern Cooperative Oncology Group (ECOG) scale. The combination therapy can be administered in repeated three-week cycles, with response assessments conducted after every third cycle.

[0008] Following initial combination therapy, subjects can transition to a maintenance phase involving pemetrexed monotherapy. This phase can be initiated once the patient achieves a stable disease state, with significant reductions in tumor size or resolution of secondary lesions. The maintenance therapy is continued in repeated cycles, with periodic imaging to monitor disease status. Patients who achieve non-FDG avid disease status on PET / CT scans during maintenance therapy demonstrate sustained responses, with no evidence of active tumor growth or recurrence.

[0009] Another aspect includes include pharmaceutical compositions combining dimesna and pemetrexed for the treatment of non-small cell lung cancer (NSCLC). These compositions can be tailored with specific dosage ranges, such as 100-500 mg for dimesna and 50-100 mg for pemetrexed, and can be formulated for intravenous administration. The combination exhibits synergistic effects, enhancing treatment efficacy and reducing the toxicity typically associated with pemetrexed. This approach is further extended to therapeutic methods that involve concurrent or sequential administration of the two agents, providing options for personalized treatment strategies based on patient-specific biomarkers or genetic profiles. The methods demonstrate potential in reducing tumor size and increasing survival rates, particularly among nonsmokers and those with certain genetic mutations.

[0010] Another aspect is a maintenance therapy in cancer patients, utilizing combinations of dimesna with pemetrexed or cisplatin. These therapies can be designed to prolong remission and prevent recurrence following initial treatment. Doses can be administered continuously or intermittently, with adjustments based on patient response and side effect monitoring. The maintenance regimens incorporate strategies for patients with partial or complete responses to initial cancer treatments, including surgery, radiation, or chemotherapy. Additionally, the use of specific biomarkers to predict positive outcomes ensures the personalized efficacy of the maintenance therapy.

[0011] Another aspect includes the development of kits comprising separately packaged doses of dimesna and pemetrexed or cisplatin, alongside detailed administration instructions. These kits can be intended for both active NSCLC treatment and maintenance therapy, ensuring ease of use and adherence to recommended protocols. The kits often incorporate provisions for patient monitoring and dosage adjustments, reflecting a commitment to safety and efficacy. The combinations are also highlighted for their role in reducing the toxicity of cisplatin and pemetrexed therapies, providing a well-rounded, patient-centric approach to cancer management.DETAILED DESCRIPTION

[0012] Specific examples provide a method for treating cancer, particularly NSCLC, using a combination of dimesna and pemetrexed or cisplatin. This method includes administering these agents in therapeutically effective amounts to achieve initial remission and continuing the administration as maintenance therapy to prevent relapse. A specific embodiment includes combining dimesna with pemetrexed for maintenance therapy as a treatment for certain cancers, such as non-small cell lung cancer (NSCLC). By using dimesna alongside pemetrexed or cisplatin in a maintenance therapy setting, the aim of sustained remission can be achieved from initial treatments, thereby prolonging patient survival and improving quality of life. This maintenance strategy is particularly valuable as it targets the period post-remission, a critical phase where the risk of cancer recurrence is significant. The synergy of dimesna and pemetrexed in this context could lead to better outcomes in terms of delaying or preventing the recurrence of cancer, while also managing side effects more effectively, making the maintenance phase more tolerable for patients.

[0013] One embodiment includes a method for increasing survival time in patients with non-small cell lung carcinoma or non-small cell lung carcinoma, in which 2,2'-dithio-bis-ethane sulfonate or its salt is administered in a therapeutically effective amount to the patient with non-small cell lung carcinoma, together with pemetrexed or cisplatin. In one example, 2,2'-dithio-bis-ethane sulfonate or its salt may be administered either prior to, concomitantly with, or subsequent to the administration of pemetrexed with a chemotherapeutic agent or agents, including cisplatin or pemetrexed. In one example, the patients can be nonsmokers. In another particular embodiment, the method is used to treat a female, nonsmoker patient suffering from or susceptible to non-small cell lung cancer.

[0014] Maintenance therapy in the context of cancer treatment refers to a continued treatment approach used after the primary treatment (such as surgery, chemotherapy, or radiation) has been completed, especially when the cancer is in remission or the disease progression has been halted. The primary goals of maintenance therapy can be to prolong remission, prevent or delay the cancer's recurrence, and manage any chronic conditions related to the cancer or its treatment. Maintenance therapy can involve the long-term use of medication, e.g., a prolonged treatment phase that can last for months or even years, depending on the patient's response and the type ofcancer. The intensity of maintenance therapy may be lower compared to initial treatment regimens - in such cases, the treatment can be less toxic and more tolerable, allowing patients to maintain a better quality of life while managing the disease. Regular monitoring can be included during maintenance therapy to assess the effectiveness of the treatment, watch for signs of recurrence, and manage side effects.

[0015] Maintenance therapy after the achievement of a response from initial chemotherapy may represent an approach to provide clinical benefit by delaying disease progression side effects, delaying the need for toxic chemotherapy and prolonging overall survival. In some embodiments, 2,2'-dithio-bis-ethane sulfonate or a pharmaceutically acceptable salt or analog is administered as a maintenance therapy.

[0016] One embodiment includes methods for the treatment and management of advanced-stage non-small cell lung adenocarcinoma (NSCLC) using a novel combination of therapeutic agents followed by maintenance therapy. More specifically, this embodiment includes the use of LP- 300 / dimesna, a chemoprotective agent with anti-cancer properties, in combination with standard care agents such as pemetrexed and carboplatin during initial treatment phases, followed by a transition to monotherapy for maintenance of disease control. This approach leverages the synergistic effects of the combination therapy to induce a significant initial tumor response while utilizing monotherapy to sustain disease control and prevent progression. The method can be particularly effective for patients who exhibit disease progression after prior lines of treatment, including targeted therapies tailored to the tumor’s genomic profile.

[0017] This embodiment can be applicable to a variety of clinical settings, as demonstrated by its effectiveness in patients with measurable disease progression and multiple target lesions. Baseline assessments, including imaging and clinical performance evaluations, inform the initiation of combination therapy, which is administered in repeated cycles over several weeks. Response assessments conducted at regular intervals reveal a reduction in tumor size and, in many cases, complete resolution of secondary lesions. Upon achieving a stabilized disease state, patients transition to monotherapy to maintain these responses. The embodiment significantly extends progression-free survival, as evidenced by durable non-FDG avid disease status on imaging studies, and provides a viable treatment strategy for patients with limited therapeutic options. This methodology provide personalized oncology, addressing the need for durable and manageable treatment regimens for advanced NSCLC.

[0018] The compositions can be a therapeutically effective dose of an oxidative metabolismaffecting Formula (I) compound, including, but not limited to, the disodium salt of 2,2'-dithio-bis- ethane sulfonate or a pharmaceutically acceptable salt or analog thereof. The disodium salt of 2,2'- dithio-bis-ethane sulfonate has also been referred to in the literature as dimesna. Various salts and analogs of 2,2'-dithio-bis-ethane sulfonate, as well as other dithioethers, may 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 hereby incorporated by reference in their entirety. Additionally, the compositions of the present invention also comprise a medically sufficient dose of the metabolite of disodium 2,2'-dithio-bis-ethane sulfonate, known as 2-mercapto ethane sulfonate sodium (also known in the literature as mesna).

[0019] Pemetrexed is a chemotherapeutic agent used primarily in the treatment of certain types of lung cancer, including non-small cell lung cancer (NSCLC), and in the treatment of mesothelioma, a type of cancer usually associated with asbestos exposure. As a multitargeted antifolate, pemetrexed works by inhibiting several key enzymes required for the synthesis of nucleotides. This inhibition disrupts the ability of cells, particularly rapidly dividing cancer cells, to replicate DNA and RNA, leading to cell death. By targeting the rapidly dividing cells, pemetrexed can help slow down or stop the growth of cancer cells. In one example, the treatment of non-small cell lung cancer can include cisplatin.

[0020] The administration of pemetrexed typically involves intravenous infusion. Its use can be associated with a range of side effects, some of which can be significant. These side effects may include fatigue, nausea, loss of appetite, rash, and blood count abnormalities. To mitigate some of these side effects, patients can be often advised to take folic acid supplements and vitamin B12 injections before and during treatment with pemetrexed.

[0021] The typical dosage of pemetrexed varies depending on several factors, including the type of cancer being treated, the patient's body surface area (BSA), kidney function, overall health, and whether it's being used alone or in combination with other chemotherapy agents. For the treatment of NSCLC, pemetrexed is commonly administered at a dose of 500 mg per square meter of body surface area (mg / m2). This dosage is usually given once every 3 weeks.

[0022] In another embodiment, any of the above methods of treatment comprises the further step of co-administering to the patient additional therapeutic agents. The choice of the second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examplesof second therapeutic agents that may be employed in the methods of this application are those set forth above for use in combination compositions comprising a compound of this invention and a second therapeutic agent.

[0023] In one embodiment, an effective amount of a compound of this application can range from 10-40 grams per dose. In another embodiment, an effective amount of a compound of this application can range from 1-500 grams per dose. In some embodiments, an effective amount ranges from 0.01-10 grams per dose. In other embodiments, an effective amount ranges from 10- 60 grams per dose. It is not necessary to provide an equal dosage per day or per week.

[0024] Therapeutically effective doses can vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents, and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for 2,2'-dithio-bis-ethane sulfonate.

[0025] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0026] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This 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, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may beemployed 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 pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[0027] Alternatively, 2,2'-dithio-bis-ethane sulfonate may be delivered orally using formulations that protect the compound from oxidation in acidic environments and allow intestinal absorption.

[0028] “Nonsmoker" means an individual who, at the time of the evaluation, is not a smoker. This includes individuals who have never smoked as well as individuals who in the past have smoked but have not used tobacco products within the past year. In one example, the term "nonsmoker" means a human that has a smoking history of 15 pack-years or less, or who has not smoked for over 25 years. Appropriate categories can be selected with no more than routine experimentation by those of ordinary skill in the art. In certain embodiments, the test subject is a nonsmoker.

[0029] The term "pharmaceutically acceptable," as used herein, 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, and are commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

[0030] The term "treat" is used and includes both therapeutic treatment and prophylactic treatment (reducing the likelihood of development). Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.

[0031] EXAMPLES

[0032] The following examples are included for purposes of illustration and are not intended to limit the scope of the invention.Example 1

[0033] This example is set in a clinical setting. The patient is a 68-year-old Caucasian male diagnosed with stage 4 non-small cell lung adenocarcinoma. He initially started treatment with carboplatin, pemetrexed, and Keytruda, and was later switched to osimertinib therapy based on the genomic profile of his tumor. Subsequently, he developed disease progression with a new cancer lesion on the left adrenal gland.

[0034] He had a baseline CT scan, which showed two target lesions as follows: a 24mm nodule in the upper lobe of the left lung and a 23mm nodule in the left adrenal gland (total sum of 47mm). He weighed 262.8 lb with an ECOG Performance Status of one at baseline. He started treatment with LP-300 / dimesna (18.4mg / m2) in combination with standard care (pemetrexed and carboplatin), administered every 3 weeks.

[0035] A response assessment with a PET / CT scan conducted at the end of cycle three of treatment showed that the patient had a partial response. The nodule in the upper lobe of the left lung measured 22mm, and the nodule in the left adrenal gland was completely cleared (total sum of 22mm). The patient continued treatment, and a re-evaluation of the disease done with a PET / CT scan at the end of Cycle 6 showed maintained partial response with a slight decrease in the size of the left lung upper lobe nodule to 20mm, and no evidence of new disease sites.

[0036] The patient has been receiving treatment with pemetrexed monotherapy starting with Cycle 7. Cycle 9 began about 6 weeks later. His duration of time during and after treatment, in which the cancer has not grown or spread further, exceeds that typically observed in NSCLC cases.

[0037] PET / CT scan at the end of Cycle 21 showed partial response. PET / CT done at the end of Cycle 21 showed no evidence of FDG avid disease, indicating no active tumor disease. Notably, the non-FDG avid disease status was first observed at the end of Cycle 15 and persisted through the last scan six months later. The evidence shows that there was no demonstration of an active tumor. After more than one year on therapy, the patient is still living.

[0038] Although the disclosure has been described with reference to various some embodiments, it should be understood that various modifications can be made without departing from the spirit of the disclosure. Accordingly, the scope of the disclosure should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. Throughout this application, various publications are referenced by author name and date, or by Patent No. or Patent Publication No. The disclosure of these publications are hereby incorporatedin their entireties by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an acknowledgement that such reference is prior art to the present invention.

Claims

CLAIMS1. A method of treating advanced non-small cell lung adenocarcinoma in a patient, comprising: administering dimesna in combination with pemetrexed and carboplatin; and transitioning to a monotherapy regimen with pemetrexed for maintenance of disease control.

2. The method of claim 1, wherein the treatment results in sustained non-FDG avid disease status, indicative of no active tumor disease.

3. The method of claim 1, wherein the dimesna dosage is 18.4 mg / m2, administered every three weeks.

4. A method of treating NSCLC in a patient, comprising administering a therapeutically effective amount of a combination of dimesna and pemetrexed.

5. The method of claim 4, wherein the dimesna and pemetrexed are administered concurrently.

6. The method of claim 1, wherein the patient achieves progression-free survival exceeding one year..

7. A kit for treating NSCLC, comprising separately packaged doses of dimesna and pemetrexed.

8. The kit of claim 7, further comprising instructions for the administration of dimesna and pemetrexed.

9. The method of claim 4, wherein the administration of dimesna and pemetrexed results in a reduction of tumor size in patients with NSCLC.

10. The method of claim 4, further comprising monitoring the patient for side effects of the treatment and adjusting the dosage of dimesna and / or pemetrexed accordingly.

11. The composition of claim 1, wherein the dimesna and pemetrexed are formulated for intravenous administration.

12. A use of dimesna in combination with pemetrexed for the manufacture of a medicament for treating NSCLC.

13. The method of claim 4, wherein the treatment increases overall survival rates in patients with NSCLC compared to patients treated with pemetrexed alone.

14. The composition of claim 1, wherein the dimesna and pemetrexed are part of a chemotherapy regimen that includes at least one additional chemotherapeutic agent.

15. A method for improving the efficacy of pemetrexed in treating N SCLC, comprising administering dimesna in combination with pemetrexed.

16. The method of claim 4, wherein the treatment is particularly effective for NSCLC patients who are nonsmokers.

17. The method of claim 4, wherein the treatment is effective for NSCLC patients with a specific genetic mutation or biomarker.

18. The use of dimesna for reducing the toxicity associated with pemetrexed therapy in the treatment of NSCLC.

19. A pharmaceutical composition comprising dimesna and pemetrexed, wherein the composition exhibits synergistic effects in the treatment of NSCLC.

20. The method of claim 19, further comprising the step of determining the presence of a biomarker indicative of a positive response to the combination of dimesna and pemetrexed in a patient before administering the treatment.

21. A method for maintenance therapy in cancer treatment, comprising administering a combination of dimesna and cisplatin or pemetrexed to a patient in remission from cancer.

22. The method of claim 21, wherein the cancer is non-small cell lung cancer (NSCLC).

23. A pharmaceutical composition for use in maintenance therapy of cancer, comprising a therapeutically effective amount of dimesna and cisplatin.

24. The method of claim 23, wherein the dimesna is administered in a dose range of 100 mg to 500 mg.

25. The method of claim 1, wherein the cisplatin or pemetrexed is administered in a dose range of 50 mg to 100 mg.

26. The method of claim 23, wherein the dimesna and cisplatin or pemetrexed are administered concurrently at regular intervals post cancer remission.

27. A use of a combination of dimesna and cisplatin or pemetrexed for the manufacture of a medicament intended for maintenance therapy in cancer patients.

28. The method of claim 27, wherein the maintenance therapy is designed to prevent the recurrence of cancer post initial treatment.

29. A kit for the maintenance therapy of cancer, comprising separately packaged doses of dimesna and cisplatin or pemetrexed, along with instructions for their administration.

30. The method of claim 29, further including monitoring the patient for side effects of the combination therapy and adjusting the dosage of dimesna and / or cisplatin or pemetrexed accordingly.

31. The composition of claim 29, wherein the dimesna and cisplatin or pemetrexed are formulated for intravenous administration.

32. The method of claim 29, wherein the administration of dimesna and cisplatin or pemetrexed is continuous or intermittent over a predefined period for maintaining remission in cancer patients.

33. The method of claim 29, further comprising assessing the patient for specific biomarkers indicative of a positive response to the combination of dimesna and cisplatin or pemetrexed.

34. The composition of claim 33, wherein the combination of dimesna and cisplatin or pemetrexed exhibits synergistic effects in prolonging the remission phase in cancer patients.

35. The method of claim 33, wherein the dimesna is utilized to reduce the toxicity associated with cisplatin or pemetrexed therapy during the maintenance phase.

36. The method of claim 33, tailored for patients who have shown a partial or complete response to initial cancer therapy.

37. The method of claim 33, wherein the maintenance therapy is particularly effective for patients who have undergone surgery, radiation, or chemotherapy as initial cancer treatment.

38. A method of extending the disease-free interval in cancer patients in remission, involving the administration of a combination of dimesna and cisplatin or pemetrexed.

39. The method of claim 38, wherein the maintenance therapy is part of a comprehensive treatment plan that includes regular monitoring and reassessment of the cancer status.