Use of a novel tyrosine kinase inhibitor in renal cancer

Abstract

The present application relates to a novel tyrosine kinase inhibitor in the application of kidney cancer, more particularly relates to the use of a dioxane and quinoline compound and its pharmaceutically acceptable salt in the preparation of a medicament for treating kidney cancer, especially for treating locally advanced or metastatic kidney cancer.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology. Specifically, this invention relates to the use of a dioxanequinoline compound and its pharmaceutically acceptable salt in the preparation of a medicament for treating renal cell carcinoma. Background Technology

[0002] Renal cell carcinoma is one of the most common malignant tumors of the genitourinary system, with its global incidence and mortality rates showing an increasing trend year by year, accounting for 2-3% of the total cancer incidence. The most common subtype of renal cell carcinoma is clear cell renal cell carcinoma (ccRCC), accounting for approximately 70-85% of all renal cell carcinoma patients. About 25-30% of ccRCC patients are diagnosed with metastasis at initial diagnosis, and the 5-year survival rate for metastatic ccRCC is only 32%. Papillary renal cell carcinoma (pRCC) is the second most common subtype of renal cell carcinoma after clear cell renal cell carcinoma, accounting for 10-15% of renal cell carcinomas, and currently lacks a standard treatment method.

[0003] If a patient is diagnosed with kidney cancer in its early stages (e.g., stage I), it can be treated with surgical resection. However, 20-25% of patients have already metastasized at initial diagnosis, causing them to miss the optimal time for surgery. On the other hand, because kidney cancer often lacks early signs and is also radioresistant, it is not sensitive to traditional chemotherapy and radiotherapy. Furthermore, traditional immunotherapy, primarily based on interleukin (IL)-2 or interferon (IFN), has a low response rate, with an efficacy of approximately 10-20%, and is accompanied by significant drug toxicity.

[0004] After sorafenib was approved for advanced renal cell carcinoma in 2005, systemic targeted therapy gradually became the standard treatment for renal cell carcinoma, following the development of tyrosine kinase inhibitors (TKIs) such as pazopanib, sunitinib, axitinib, and cabozantinib. In recent years, immune checkpoint inhibitors, represented by PD-1 / PD-L1 inhibitors, have shown very good efficacy in patients with advanced refractory renal cell carcinoma, with a 5-year survival rate as high as 26% for nivolumab as second-line therapy. However, overall, TKIs and the latest immune checkpoint inhibitors still have significant toxic side effects. The overall efficacy of PD-1 monoclonal antibodies as monotherapy is not ideal, and the objective response rate of TKI inhibitors is not high. Furthermore, patients who initially respond to treatment often experience disease progression later, resulting in a poor prognosis. Therefore, there is still a lack of effective new methods for treating renal cell carcinoma in clinical practice.

[0005] WO2019154133 (Application No. PCT / CN2019 / 073260, Application Date 2019.01.25) discloses a class of compounds that can effectively inhibit VEGFR-2 and c-MET tyrosine kinases, representing a novel class of anti-tumor drugs targeting multiple kinases. Recent research results indicate that these compounds hold promise for the treatment of renal cell carcinoma, demonstrating excellent efficacy in patients with locally advanced renal cell carcinoma and those whose disease has progressed after prior targeted therapy, immunotherapy, or combined targeted and immunotherapy. Summary of the Invention

[0006] On the one hand, this application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for renal cancer.

[0007] On the other hand, this application provides a method for treating renal cell carcinoma, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0008] In some embodiments, the renal cell carcinoma is clear renal cell carcinoma or non-clear renal cell carcinoma, and non-clear renal cell carcinoma includes, but is not limited to, papillary renal cell carcinoma.

[0009] In some implementations, the renal cell carcinoma is advanced (locally advanced), metastatic, or unresectable clear or non-clear renal cell carcinoma.

[0010] In some implementations, the renal cell carcinoma is renal cell carcinoma that has not previously received conventional treatment, or has failed conventional treatment, or for which there is no standard treatment.

[0011] In some implementations, the conventional treatment includes, but is not limited to, radiotherapy, chemotherapy, targeted therapy and / or immunotherapy, and any combination thereof, especially the combination of targeted therapy and immunotherapy.

[0012] In some implementations, the chemotherapy includes, but is not limited to, treatment with platinum complexes (e.g., cisplatin, carboplatin, nedaplatin, oxaliplatin), taxanes (e.g., paclitaxel, docetaxel), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, fluorouracil, difuranofluorouracil, deoxyfluorouridine, tegafur, carmoflu), pemetrexed, vinorelbine, etoposide, vinblastine, etc.

[0013] In some implementations, the targeted therapy is treatment using, but not limited to, apatinib, axitinib, lenvatinib, sorafenib, sunitinib, pazopanib, fruquintinib, anlotinib, erlotinib, lenvatinib, cabozantinib, voronib, abexistat, bezotifan, sirolimus, everolimus, bevalizumab, and certain investigational drugs (APG115), as well as any combination thereof.

[0014] In some implementations, the immunotherapy includes, but is not limited to, conventional immunotherapy (such as interleukins, interferons), immune checkpoint inhibitor therapy (such as PD-1 / PD-L1), and other immunotherapeutic agents (such as CTLA-4 inhibitors, LAG-3 inhibitors, OX40 agonists, etc.).

[0015] In some implementations, the immunotherapy is treatment with one or more selected from PD-1 and PD-L1, including but not limited to camrelizumab, toripalimab, tislelizumab, nivolumab, pembrolizumab, sintilimab, slulimab, and the investigational TQB2450.

[0016] The compound of formula (I) may be in its free base form, or in the form of its salt, hydrate, or prodrug, which is converted in vivo into the free base form of the compound of formula (I). For example, pharmaceutically acceptable salts of the compound of formula (I) within the scope of this invention may be produced by various organic and inorganic acids according to methods known in the art.

[0017] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a p-toluenesulfonate, mucilage, or phosphate of the compound of formula (I), preferably a p-toluenesulfonate. In some embodiments, it is in the crystalline form of a p-toluenesulfonate, mucilage, or phosphate of the compound of formula (I). In a more specific embodiment, it is in the crystalline form of a p-toluenesulfonate of the compound of formula (I).

[0018] Compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered via a variety of routes, including but not limited to: oral, parenteral, intraperitoneal, intravenous, intra-arterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, local, subcutaneous, intra-fat, intra-articular, intraperitoneal, and intrathecal. In some specific embodiments, oral administration is preferred.

[0019] In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered, by weight of compound (I), is from 60 mg to 220 mg daily. In some embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered, by weight of compound (I), is from 100 mg to 180 mg daily.

[0020] Compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once or more daily. In some embodiments, compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, it is administered once daily as an oral solid dosage form.

[0021] The method of administration can be determined comprehensively based on the drug's activity, toxicity, and patient tolerability. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an intermittent manner. The intermittent administration includes a dosing period and a withdrawal period. During the dosing period, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once or more daily. For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered daily during the dosing period, followed by a withdrawal period during which administration is stopped for a period of time, then another dosing period, and then another withdrawal period, and so on, which can be repeated multiple times. The ratio of the dosing period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, and more preferably 2:0.5 to 1.

[0022] In some implementations, the drug is administered continuously for 2 weeks and then stopped for 2 weeks. In some implementations, the dosing pattern of once-daily administration followed by a 2-week dosing and 2-week stop-dosing can be repeated multiple times.

[0023] In some implementations, the drug is administered continuously for 3 weeks and then stopped for 1 week. In some implementations, the once-daily dosing regimen of 3 weeks followed by a 1-week break can be repeated multiple times.

[0024] In some implementations, the drug is administered continuously for 2 weeks and then stopped for 1 week. In some implementations, the dosing interval of once daily administration for 2 weeks followed by a 1-week stop can be repeated multiple times.

[0025] In some implementation schemes, the drug is administered continuously for 5 days and then stopped for 2 days. In other implementation schemes, the dosing pattern of once-daily administration for 5 days followed by a 2-day break can be repeated multiple times.

[0026] In another aspect, this application provides a pharmaceutical composition for treating renal cell carcinoma, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0027] In some embodiments of the present invention, the pharmaceutical composition is a formulation suitable for oral administration, including tablets, capsules, powders, granules, pellets, pastes, powders, etc., preferably tablets and capsules. The tablets may be ordinary tablets, dispersible tablets, effervescent tablets, sustained-release tablets, controlled-release tablets, or enteric-coated tablets, and the capsules may be ordinary capsules, sustained-release capsules, controlled-release capsules, or enteric-coated capsules. The oral formulation can be prepared using pharmaceutically acceptable carriers known in the art through conventional methods. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc.

[0028] In some embodiments, the pharmaceutical composition is a solid dosage form suitable for oral administration. The composition may be in the form of tablets or capsules, for example. In some specific embodiments, the pharmaceutical composition is a tablet. Invention Details

[0030] Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below. In this application, unless otherwise stated, the use of “or” or “and” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “having” is not restrictive. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter.

[0031] Unless otherwise stated, the dosages and ranges provided herein are based on the molecular weight of the free base form of the compound of formula (I).

[0032] In this document, the crystal forms of the p-toluenesulfonate, mucilage, or phosphate of the compounds of formula (I) include, but are not limited to, the crystal forms of the corresponding salts disclosed in Chinese patent application CN117986267. In some embodiments, the p-toluenesulfonate of the compounds of formula (I) is in crystal form A-II.

[0033] "Patient" or "subject" refers to a mammal, preferably a human. In some embodiments, the patient is a patient who has failed or is without standard treatment.

[0034] "Pharmaceutical acceptable" means that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes that it is acceptable for human pharmaceutical use.

[0035] "Pharmaceutically acceptable salts" refer to the organic and inorganic salts of the compounds of this invention, which are suitable for human and lower animal use, without excessive toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. These salts can be formed by reacting the compounds of this invention with a suitable free base or acid. This includes, but is not limited to, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or by using methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glycerophosphate, gluconate, hemisulfate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, dihydroxynaphthalate, pectate, persulfate, per-3-phenylpropionate, phosphate, picrate, propionate, stearate, sulfate, thiocyanate, p-toluenesulfonate, undecanoate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include suitable non-toxic ammonium, quaternary ammonium, and amino cations formed using halogen ions, hydroxide ions, carboxyl ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonates, and aryl sulfonates.

[0036] "Therapeutic effective amount" refers to the amount of a compound that, when given to a person to treat a disease, is sufficient to achieve the therapeutic effect on that disease.

[0037] Overall survival (OS): from the randomization date to the date of death from any cause. For subjects still alive at the last follow-up, OS is calculated from the time of the last follow-up. For subjects lost to follow-up, OS is calculated from the time of the last confirmed survival prior to loss to follow-up.

[0038] Objective response rate (ORR): The proportion of subjects whose tumors shrink to a certain extent and remain so for a certain period of time, including cases with complete response (CR) and partial response (PR).

[0039] Objective response to tumors was assessed using the Solid Tumor Response Assessment Criteria. Subjects had measurable tumor lesions at baseline. Response assessment criteria were based on RECIST 1.1, categorized as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). For solid tumors, target lesions were measured using the long diameter; for pathological lymph nodes, target lesions were measured using the short diameter.

[0040] Complete remission (CR): All target lesions disappear and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10mm.

[0041] Partial remission (PR): The sum of the diameters of the target lesions is reduced by at least 30% compared to the baseline level.

[0042] Stable (SD): The sum of the diameters of the target lesions does not shrink to achieve partial response (PR) or increases to achieve partial response (PD).

[0043] Progression (PD): The sum of the diameters of the target lesions increases by at least 20% compared to the minimum sum of the diameters of the target lesions measured previously, and the absolute value of the sum of the diameters increases by at least 5 mm (the appearance of one or more new lesions is also considered disease progression).

[0044] Disease control rate (DCR): The percentage of subjects with confirmed complete remission, partial remission, or stable disease (more than 8 weeks) among those with evaluable efficacy.

[0045] Progression-free survival (PFS): The time from the start of randomization to disease progression or death from any cause, whichever comes first.

[0046] Duration of Response (DOR): The time interval from the initial assessment of CR or PR to the initial assessment of PD or death of the subject from any cause.

[0047] 12-month survival rate (OS) 12m ): The percentage of subjects who survived 12 months after treatment with the investigational drug out of the total number of subjects. Detailed Implementation

[0048] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0049] Preparation of compound of formula (I)

[0050]

[0051] The preparation of this compound was carried out in accordance with the disclosure in WO2019154133.

[0052] The preparation of p-toluenesulfonate of compound (I) was carried out in accordance with Chinese patent application CN117986267.

[0053] Example 1. Phase Ib / II clinical trial of the efficacy and safety of compound (I) in patients with advanced renal cell carcinoma.

[0054] Trial objective: To evaluate the efficacy and safety of compound (I) in the treatment of patients with advanced renal cell carcinoma. The primary objective was to evaluate the objective response rate (ORR), and the secondary objective was to evaluate safety.

[0055] Inclusion criteria:

[0056] 1. ECOG=0 or 1

[0057] 2. Expected survival time is greater than 3 months.

[0058] 3. Appropriate organ function

[0059] 4. Unresectable, locally advanced, or metastatic renal cell carcinoma

[0060] 5. Failure of conventional treatment, lack of a standard treatment plan, unsuitability for standard treatment at this stage, or refusal of standard treatment.

[0061] 6. Previous treatment with at least an immune checkpoint inhibitor and / or a TKI followed by disease progression (dose expansion phase).

[0062] As of October 2024, a total of 60 patients (subjects) were enrolled in this clinical trial for evaluation. The baseline characteristics of the subjects are shown in Table 1 below, and the dosage and cancer type distribution are shown in Table 2 below.

[0063] Table 1. Baseline characteristics of the subjects:

[0064]

[0065] Table 2. Sample size and distribution of subjects:

[0066]

[0067] Treatment (administration) regimen:

[0068] Eligible renal cell carcinoma subjects were treated with tablets containing p-toluenesulfonate of formula (I) as the active ingredient (100 mg / 120 mg / 140 mg / 160 mg / 180 mg / 220 mg, QD, continuous administration, 21 days per cycle) on an empty stomach until intolerable toxicity, disease progression, withdrawal of informed consent, death, loss to follow-up, or initiation of a new antitumor regimen (whichever occurs first).

[0069] Validity evaluation:

[0070] Dosage discussion: The test compound showed some efficacy at a dose of 100 mg, with most subjects experiencing lesion shrinkage and a disease control rate of 100%; the overall fitted mPFS was approximately 204 days.

[0071] Eight patients (14.3%) achieved partial response (PR), including six with clear renal cell carcinoma (ccRCC) and two with papillary renal cell carcinoma (pRCC). Nine patients with ccRCC had previously received only TKI therapy, with an objective response rate (ORR) of 22.2% (2 PR, 5 SD). Thirty-eight patients with ccRCC had previously received targeted immunotherapy, with an ORR of 10.5% and a disease control rate (DCR) of 89.5% (4 PR, 30 SD). Detailed results are shown in Table 3 below.

[0072] Table 3. Evaluation of treatment effectiveness in subjects

[0073]

[0074] In typical ccRCC subjects who had previously received targeted therapy or combined immunotherapy and targeted therapy, the test compound (100 mg) showed positive efficacy as a single agent.

[0075] Table 4-6 below shows the specific treatment process of three typical subjects.

[0076] Table 4. Treatment status of Subject 1

[0077]

[0078] Table 5. Treatment status of Subject 2

[0079]

[0080] Table 6. Treatment status of Subject 3

[0081]

[0082] Note: 1L represents first-line treatment, and so on.

[0083] Median PFS: The median PFS for each dose group of the test compound has not yet been reached. Based on the existing data, the fitted mPFS is approximately 204 days. Compared with bezouterine, the test drug significantly prolongs PFS. In ccRCC subjects who have failed 1-4 lines of targeted immunotherapy, the median PFS of bezouterine was 168 days. Other data: bezouterine ORR=21.9%, DCR=61.3%. The previous lines of treatment for the test compound included 1-9 lines. In the 180 mg dose group: ORR=15.4%, DCR=92.3%.

[0084] There is currently no standard treatment for advanced / metastatic papillary RCC (pRCC), and the CSCO guidelines recommend that patients enter clinical trials. Due to its lower incidence than ccRCC, it receives less attention in current clinical drug development studies. The test compound showed positive efficacy signals in first-line treatment of pRCC and in second-line treatment after prior immunotherapy ± targeted therapy. Two subjects achieved partial response (PR), and six subjects had stable disease (SD).

[0085] Security assessment:

[0086] The investigational compound showed good overall safety in treating patients with locally advanced or metastatic renal cell carcinoma, with a grade ≥3 adverse event incidence of 67.3%. Details of adverse events are shown in Table 7 below, and the incidence is comparable to that of similar products. Specific data are shown in Table 8.

[0087] Table 7. Occurrence of Adverse Events (N=55)

[0088]

[0089] Table 8. Comparison of the Occurrence of Common Adverse Events

[0090]

[0091] Conclusion: The investigational compound showed positive efficacy in advanced renal cell carcinoma (ccRCC), with a dose of 100 mg demonstrating positive effects and lesion shrinkage in most subjects. It also showed preliminary efficacy in subjects with papillary renal cell carcinoma (ccRCC) for which there is currently no standard treatment. There is a significant unmet clinical need for ccRCC patients who have failed prior targeted immunotherapy, and the investigational compound demonstrated good efficacy in these patients. Overall, the safety profile was good, with adverse reaction types similar to those of similar drugs.

[0092] The above description represents the preferred embodiments of the present invention. It should be noted that, for those skilled in the art, various improvements and modifications can be made to the embodiments of the present invention without departing from the principles described herein, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of renal cell carcinoma. Formula (I).

2. The use according to claim 1, wherein, The renal cell carcinoma is either clear renal cell carcinoma or non-clear renal cell carcinoma, and non-clear renal cell carcinoma includes, but is not limited to, papillary renal cell carcinoma.

3. The use according to claim 2, wherein, The renal cell carcinoma is an advanced (locally advanced), metastatic, or unresectable clear or non-clear renal cell carcinoma.

4. The use according to claim 1, wherein, The kidney cancer referred to is kidney cancer that has not previously received conventional treatment, or whose conventional treatment has failed, or for which there is no standard treatment.

5. The use according to claim 4, wherein, The conventional treatments include radiotherapy, chemotherapy, targeted therapy and / or immunotherapy, and any combination thereof.

6. The use according to claim 5, wherein, The immunotherapy mentioned refers to treatment using one or more of PD-1 and PD-L1.

7. The use according to claim 1, wherein, The pharmaceutically acceptable salt is p-toluenesulfonate, mucilage, or phosphate, preferably p-toluenesulfonate.

8. The use according to claim 1, wherein, The daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, calculated as the compound of formula (I), is 60-220 mg, preferably 100-180 mg.

9. The use according to claim 1, wherein, The compound of formula (I) or its pharmaceutically acceptable salt is administered daily.

10. The use according to claim 1, wherein, The compound of formula (I) or its pharmaceutically acceptable salt is administered by an interval dosing method, wherein the interval dosing includes a dosing period and a withdrawal period, wherein the ratio of the dosing period to the withdrawal period in days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, and more preferably 2:0.5-1; as a preferred interval dosing method, one of the following is: dosing continuously for 2 weeks and then stopping for 2 weeks, dosing continuously for 3 weeks and then stopping for 1 week, dosing continuously for 2 weeks and then stopping for 1 week, and dosing continuously for 5 days and then stopping for 2 days, and the above interval dosing methods can be repeated multiple times.

11. The use according to any one of claims 1 to 10, wherein, The compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a composition, the composition further comprising a pharmaceutically acceptable carrier.

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