Use of KRAS g12d inhibitor in combination with chemotherapy in preparation of drug for treating solid tumors

Abstract

The use of a KRAS G12D inhibitor in combination with chemotherapy in the preparation of a drug for treating solid tumors, specifically the use of the KRAS G12D inhibitor in combination with a chemotherapeutic agent in the preparation of a drug for treating KRAS G12D-mutated solid tumors. The KRAS G12D inhibitor is selected from compounds represented by formula (I) or pharmaceutically acceptable salts thereof.

Description

Use of KRAS G12D inhibitors in combination with chemotherapy in the preparation of drugs for treating solid tumors Technical Field

[0001] This disclosure relates to the pharmaceutical field, specifically to the use of a combination of a KRAS G12D inhibitor and a chemotherapeutic agent in the preparation of a medicament for the treatment of KRAS G12D-mutant solid tumors. Background Technology

[0002] RAS (Rapid Acid Spectroscopy) genes are among the most frequently mutated oncogenes in tumors, with approximately 30% of human malignancies associated with RAS gene mutations. The RAS family includes KRAS, NRAS, and HRAS, with KRAS mutations being the most common, accounting for about 85%. KRAS mutations are common in solid tumors, showing high frequency in the three leading causes of cancer death in humans—lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). In KRAS gene mutations, 97% involve mutations at amino acid residue 12 or 13, with G12D being a significant mutation. Data analysis of European and American populations shows that G12D mutations account for 36%, 12%, and 4% of patients with pancreatic cancer, colorectal cancer, and non-small cell lung cancer, respectively.

[0003] Once activated, KRAS regulates various functions of cell proliferation, survival, migration, and metabolism through numerous downstream signaling pathways, including RAF-MEK-ERK, PI3K-AKT-mTOR, and TIAM1-RAc. Mutations in the KRAS gene result in a persistently activated protein, leading to continued activation of downstream signaling pathways and promoting tumorigenesis.

[0004] Because the KRAS protein lacks traditional small-molecule binding sites on its surface and has an extremely high affinity for guanosine monophosphate (GMP), making it extremely difficult to inhibit, it has long been considered an untreatable drug target. However, based on the importance and prevalence of abnormal KRAS activation in cancer progression, KRAS has always been a target of great interest in drug development. Currently, apart from KRAS G12C inhibitors, there is still a lack of effective KRAS inhibitors against other mutations, leaving most patients with KRAS mutations without a cure. G12D, as a mutant widely and highly expressed in various tumors, makes the development of inhibitors of it of significant clinical importance. WO2022268051A discloses an effective KRAS G12D inhibitor and its preparation method, the structure of which is shown in formula (I). This compound has significant pharmacodynamic advantages.

[0005] Clinically, commonly used chemotherapy drugs for treating unresectable locally advanced or metastatic pancreatic cancer include gemcitabine, albumin-bound paclitaxel, 5-FU / LV, cisplatin, oxaliplatin, irinotecan, tegafur, and capecitabine. Among these, the AG regimen and the FOLFIRINOX regimen are both recommended by the NCCN guidelines as first-line systemic treatment for pancreatic cancer.

[0006] This disclosure provides the use of a KRAS G12D inhibitor as shown in Formula (I) in combination with a chemotherapeutic agent in the preparation of a medicament for treating KRAS G12D-mutant solid tumors, and demonstrates good antitumor effects. Summary of the Invention

[0007] This disclosure provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a chemotherapeutic agent in the preparation of a medicament for treating KRAS G12D-mutant solid tumors, wherein the chemotherapeutic agent is selected from: 1) albumin-bound paclitaxel and gemcitabine; or 2) irinotecan liposomes, oxaliplatin, 5-fluorouracil, and leucovorin calcium.

[0008] In an optional embodiment, this disclosure provides the use of the compound shown in (I) or a pharmaceutically acceptable salt thereof in combination with a chemotherapeutic agent in the preparation of a medicament for treating KRAS G12D-mutant solid tumors, wherein the chemotherapeutic agent is albumin-bound paclitaxel and gemcitabine.

[0009] In an optional embodiment, this disclosure provides the use of the compound shown in (I) or a pharmaceutically acceptable salt thereof in combination with a chemotherapeutic agent in the preparation of a medicament for treating solid tumors with KRAS G12D mutations, wherein the chemotherapeutic agent is irinotecan liposome, oxaliplatin, 5-fluorouracil, and leucovorin calcium.

[0010] In some embodiments, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from 50-2000 mg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, or twice every three weeks.

[0011] In an optional embodiment, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt may be 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg or any value between any two, and the dosing frequency may be selected from once a week, once every two weeks, once every three weeks or twice every three weeks.

[0012] In optional embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at least once during one cycle. In optional embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at least twice during one cycle. In optional embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at least three times during one cycle. In optional embodiments, one cycle is 14 days. In optional embodiments, one cycle is 21 days. In optional embodiments, one cycle is 28 days. In optional embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at least once a week. In optional embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at least once every two weeks. In optional embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at least once every three weeks. In optional embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at least twice every three weeks. In optional embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at least once every four weeks. In optional embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at least twice every four weeks. In an optional embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered at least three times every four weeks. In an optional embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered on days 1, 8, and 15 of a 28-day cycle. In an optional embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered on days 1 and 8 of a 21-day cycle.

[0013] In an optional implementation, the compound of formula (I) or its pharmaceutically acceptable salt is administered at 200-600 mg on day 1 of a 21-day cycle and at 800-1200 mg on day 8.

[0014] In an optional embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered at 500 mg on day 1 and 1200 mg on day 8 of a 21-day cycle.

[0015] In an optional embodiment, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt may be 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg, and the dosing frequency may be selected from once a week, once every two weeks, once every three weeks, or twice every three weeks.

[0016] In an optional embodiment, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 200-600 mg, and the frequency of administration is selected from once a week, specifically, for example, a dosage of 300 mg once a week, a dosage of 400 mg once a week, a dosage of 500 mg once a week, or a dosage of 600 mg once a week.

[0017] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 400 mg once a week, or at a dose of 800 mg once every 2 weeks, or at a dose of 1200 mg once every 3 weeks.

[0018] In an optional implementation, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 800 mg once every 2 weeks.

[0019] In an optional implementation, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 1200 mg once every 3 weeks.

[0020] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 600 mg once a week, or at a dose of 1200 mg once every two weeks.

[0021] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 1200 mg once every 2 weeks. In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered...

[0022] In some embodiments, the dosage of the albumin-bound paclitaxel is selected from 50-200 mg / m². 2 The dosing frequency is selected from twice a week, twice every two weeks, twice every three weeks, twice every four weeks, or three times every four weeks.

[0023] In an optional implementation, the dosage of albumin-bound paclitaxel may be 50 mg / m². 2 55mg / m 2 60mg / m 2 65mg / m2 70mg / m 2 75mg / m 2 80mg / m 2 85mg / m 2 90mg / m 2 95mg / m 2 100mg / m 2 105mg / m 2 110mg / m 2 115mg / m 2 120mg / m 2 125mg / m 2 130mg / m 2 135mg / m 2 140mg / m 2 150mg / m 2 155mg / m 2 160mg / m 2 165mg / m 2 170mg / m 2 175mg / m 2 180mg / m 2 185mg / m 2 190mg / m 2 195mg / m 2 200mg / m 2 Or any value between any two numbers; the dosing frequency is selected from twice a week, twice every 2 weeks, twice every 3 weeks, twice every 4 weeks, or three times every 4 weeks.

[0024] In optional embodiments, albumin-bound paclitaxel is administered at least once during one cycle. In optional embodiments, albumin-bound paclitaxel is administered at least twice during one cycle. In optional embodiments, albumin-bound paclitaxel is administered at least three times during one cycle. In optional embodiments, one cycle is 14 days. In optional embodiments, one cycle is 21 days. In optional embodiments, one cycle is 28 days. In optional embodiments, albumin-bound paclitaxel is administered at least once a week. In optional embodiments, albumin-bound paclitaxel is administered at least once every two weeks. In optional embodiments, albumin-bound paclitaxel is administered at least once every three weeks. In optional embodiments, albumin-bound paclitaxel is administered at least twice every three weeks. In optional embodiments, albumin-bound paclitaxel is administered at least once every four weeks. In optional embodiments, albumin-bound paclitaxel is administered at least twice every four weeks. In optional embodiments, albumin-bound paclitaxel is administered at least three times every four weeks. In an optional embodiment, albumin-bound paclitaxel is administered on days 1, 8, and 15 of a 28-day cycle. In an optional embodiment, albumin-bound paclitaxel is administered on days 1 and 8 of a 21-day cycle.

[0025] In an optional implementation, the dosage of albumin-bound paclitaxel is selected from 80 mg / m². 2 100mg / m 2 125mg / m 2 The dosing frequency is twice every 3 weeks or three times every 4 weeks.

[0026] In an optional implementation, the dosage of albumin-bound paclitaxel is 125 mg / m². 2 The dosing frequency is twice every 3 weeks. Alternatively, albumin-bound paclitaxel may be administered twice every 3 weeks, on day 1 and day 8, respectively.

[0027] In an optional implementation, the dosage of albumin-bound paclitaxel is 125 mg / m². 2 The dosing frequency is three times every four weeks. In an optional embodiment, albumin-bound paclitaxel is administered three times every four weeks, on days 1, 8, and 15. In some embodiments, the gemcitabine dosage is selected from 300-2000 mg / m². 2 The dosing frequency is selected from twice a week, twice every two weeks, twice every three weeks, twice every four weeks, or three times every four weeks.

[0028] In an optional implementation, the dosage of gemcitabine may be 300 mg / m². 2 350mg / m 2 400mg / m 2450mg / m 2 500mg / m 2 550mg / m 2 600mg / m 2 650mg / m 2 700mg / m 2 750mg / m 2 800mg / m 2 850mg / m 2 900mg / m 2 950mg / m 2 1000mg / m 2 1100mg / m 2 1200mg / m 2 1300mg / m 2 1400mg / m 2 1500mg / m 2 1600mg / m 2 1700mg / m 2 1800mg / m 2 1900mg / m 2 2000mg / m 2 Or any value between any two numbers; the dosing frequency is selected from twice a week, twice every 2 weeks, twice every 3 weeks, twice every 4 weeks, or three times every 4 weeks.

[0029] In optional embodiments, gemcitabine is administered at least once during a cycle. In optional embodiments, gemcitabine is administered at least twice during a cycle. In optional embodiments, gemcitabine is administered at least three times during a cycle. In optional embodiments, a cycle is 14 days. In optional embodiments, a cycle is 21 days. In optional embodiments, a cycle is 28 days. In optional embodiments, gemcitabine is administered at least once a week. In optional embodiments, gemcitabine is administered at least once every two weeks. In optional embodiments, gemcitabine is administered at least once every three weeks. In optional embodiments, gemcitabine is administered at least twice every three weeks. In optional embodiments, gemcitabine is administered at least once every four weeks. In optional embodiments, gemcitabine is administered at least twice every four weeks. In optional embodiments, gemcitabine is administered at least three times every four weeks. In optional embodiments, gemcitabine is administered on days 1, 8, and 15 of a 28-day cycle. In optional embodiments, gemcitabine is administered on days 1 and 8 of a 21-day cycle.

[0030] In an optional implementation, the dosage of gemcitabine is selected from 500 mg / m². 2 750mg / m 21000mg / m 2 The dosing frequency is twice every 3 weeks or three times every 4 weeks.

[0031] In an optional implementation, the dosage of gemcitabine is 1000 mg / m². 2 The dosing frequency is twice every 3 weeks. Alternatively, gemcitabine is administered twice every 3 weeks, on day 1 and day 8, respectively.

[0032] In an optional implementation, the dosage of gemcitabine is 125 mg / m². 2 The dosing frequency is three times every four weeks. In an optional implementation, gemcitabine is administered three times every four weeks, on day 1, day 8, and day 15, respectively.

[0033] In some embodiments, the dosage of the irinotecan liposomes is selected from 10-100 mg / m². 2 The dosing frequency is once a week, once every two weeks, once every three weeks, or once every four weeks.

[0034] In an optional implementation, the dosage of irinotecan liposomes may be 10 mg / m². 2 15mg / m 2 20mg / m 2 25mg / m 2 30mg / m 2 35mg / m 2 40mg / m 2 45mg / m 2 50mg / m 2 55mg / m 2 60mg / m 2 65mg / m 2 70mg / m 2 75mg / m 2 80mg / m 2 85mg / m 2 90mg / m 2 95mg / m 2 100mg / m 2 Or any value between any two numbers; the dosing frequency is once a week, once every 2 weeks, or once every 3 weeks.

[0035] In an optional implementation, the dosage of irinotecan liposomes is selected from 35 mg / m². 2 43mg / m 2 50mg / m 2 60mg / m 2 The administration frequency is once every 2 weeks.

[0036] In some embodiments, the dosage of oxaliplatin is selected from 10-100 mg / m². 2 The dosing frequency is once a week, once every two weeks, once every three weeks, or once every four weeks.

[0037] In an optional implementation, the dosage of oxaliplatin may be 10 mg / m². 2 15mg / m 2 20mg / m 2 25mg / m 2 30mg / m 2 35mg / m 2 40mg / m 2 45mg / m 2 50mg / m 2 55mg / m 2 60mg / m 2 65mg / m 2 70mg / m 2 75mg / m 2 80mg / m 2 85mg / m 2 90mg / m 2 95mg / m 2 100mg / m 2 Or any value between any two numbers; the dosing frequency is once a week, once every 2 weeks, or once every 3 weeks.

[0038] In an optional implementation, the dosage of oxaliplatin is 50 mg / m². 2 60mg / m 2 85mg / m 2 The dosing frequency is selected as once every 2 weeks.

[0039] In some embodiments, the dosage of the calcium folinate is selected from 50-600 mg / m². 2 The dosing frequency can be selected from once a week, once every two weeks, once every three weeks, or once every four weeks.

[0040] In an optional embodiment, the dosage of the calcium leucovorin may be 50 mg / m². 2 60mg / m 2 70mg / m 2 80mg / m 2 90mg / m 2 100mg / m 2 110mg / m 2 120mg / m 2 130mg / m2 、140mg / m 2 、150mg / m 2 、160mg / m 2 、170mg / m 2 、180mg / m 2 、190mg / m 2 、200mg / m 2 、210mg / m 2 、220mg / m 2 、230mg / m 2 、240mg / m 2 、250mg / m 2 、260mg / m 2 、270mg / m 2 、280mg / m 2 、290mg / m 2 、310mg / m 2 、320mg / m 2 、330mg / m 2 、340mg / m 2 、350mg / m 2 、360mg / m 2 、370mg / m 2 、380mg / m 2 、390mg / m 2 、400mg / m 2 、410mg / m 2 、420mg / m 2 、430mg / m 2 、440mg / m 2 、450mg / m 2 、460mg / m 2 、470mg / m 2 、480mg / m 2 、490mg / m 2 、500mg / m 2 、510mg / m 2 、520mg / m 2 、530mg / m 2 、540mg / m 2 、550mg / m 2 、560mg / m 2 、570mg / m 2 、580mg / m 2 、590mg / m 2 、600mg / m 2Or any value between any two numbers; the dosing frequency is selected from once a week, once every 2 weeks, or once every 3 weeks.

[0041] In an optional embodiment, the dosage of leucovorin calcium is 400 mg / m². 2 The medication should be administered once every two weeks.

[0042] In some embodiments, the dosage of the 5-fluorouracil is selected from 1000-4000 mg / m². 2 The dosing frequency is once a week, once every two weeks, once every three weeks, or once every four weeks.

[0043] In an optional embodiment, the dosage of 5-fluorouracil may be 1000 mg / m². 2 1100mg / m 2 1200mg / m 2 1300mg / m 2 1400mg / m 2 1500mg / m 2 1600mg / m 2 1700mg / m 2 1800mg / m 2 1900mg / m 2 2000mg / m 2 2100mg / m 2 2200mg / m 2 2300mg / m 2 2400mg / m 2 2500mg / m 2 2600mg / m 2 2700mg / m 2 2800mg / m 2 2900mg / m 2 3000mg / m 2 3500mg / m 2 3600mg / m 2 3700mg / m 2 3800mg / m 2 3900mg / m 2 4000mg / m 2 Or any value between any two numbers; the dosing frequency is once a week, once every 2 weeks, or once every 3 weeks.

[0044] In an optional embodiment, the dosage of 5-fluorouracil is 1400 mg / m². 2 2100mg / m 2 2800mg / m2 The administration frequency is once every 2 weeks.

[0045] In some implementations, the KRAS G12D-mutated solid tumor is selected from advanced solid tumors.

[0046] In some implementations, the KRAS G12D-mutated solid tumor is selected from pancreatic cancer.

[0047] In some implementations, the KRAS G12D-mutated solid tumor is selected from advanced pancreatic cancer.

[0048] In some implementations, the KRAS G12D-mutated solid tumor is selected from recurrent or metastatic pancreatic cancer.

[0049] In some implementations, the pancreatic cancer is selected from pancreatic ductal adenocarcinoma.

[0050] In some implementation schemes, the pancreatic cancer patients have previously received at most first-line standard treatment (including but not limited to systemic chemotherapy, molecularly targeted therapy, immunotherapy, biotherapy and other investigational treatments) and have not previously received KRAS inhibitor treatment.

[0051] In some implementations, the pancreatic cancer patient has not previously received systemic antitumor therapy.

[0052] Another aspect of this disclosure provides a pharmaceutical composition comprising the compound of formula (I) above or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel and gemcitabine, and one or more pharmaceutically acceptable carriers.

[0053] Another aspect of this disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, irinotecan, oxaliplatin, 5-fluorouracil, and leucovorin calcium, and one or more pharmaceutically acceptable carriers.

[0054] This disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12D-mutant solid tumors, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with albumin-bound paclitaxel and gemcitabine.

[0055] This disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12D-mutant solid tumors, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with irinotecan, oxaliplatin, leucovorin calcium and 5-fluorouracil.

[0056] This disclosure also provides a method for treating KRAS G12D-mutated solid tumors, comprising administering a subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel and gemcitabine.

[0057] This disclosure also provides a method for treating KRAS G12D-mutated solid tumors, comprising administering a subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof with irinotecan liposomes, oxaliplatin, 5-fluorouracil, and leucovorin calcium.

[0058] The combination therapy disclosed herein increases the potency of KRAS G12D inhibitors, enhances their antitumor activity, and improves the treatment outcomes of cancer diseases, providing patients with improved clinical benefits compared to treatment using the KRAS G12D inhibitors disclosed herein as monotherapy.

[0059] definition

[0060] To facilitate understanding of this disclosure, certain techniques and scientific methods are specifically defined below. Unless otherwise expressly defined in this disclosure, all other techniques and scientific methods used in this disclosure have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0061] This disclosure incorporates the entire contents of application WO2024022507A.

[0062] Unless the context clearly requires otherwise, throughout the specification and claims, the words “comprising,” “having,” “including,” etc., should be understood as having an inclusive meaning, rather than an exclusive or exhaustive meaning; that is, the meaning of “including but not limited to.”

[0063] The values ​​in this disclosure are instrument measurements or calculated values ​​after instrument measurement, and are subject to a certain degree of error. Generally speaking, ±10% is within the reasonable error range. Of course, the context in which the value is used needs to be considered. For example, for the content of total impurities, the value is defined as having an error variation of no more than ±10% after measurement, and can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0064] "Effective amount" includes an amount sufficient to improve or prevent the symptoms or condition of a medical condition. Effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount used on a subject may vary depending on factors such as the condition to be treated, the subject's overall health, the route and dosage of administration, and the severity of side effects. Effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity. Subjects in this disclosure may be animal or human subjects.

[0065] The term "pharmaceutical composition" refers to a mixture containing one or more of the active ingredients described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0066] The terms “pharmaceuticalally acceptable excipient” or “pharmaceuticalally acceptable carrier” include any material that, when combined with an active ingredient, allows that ingredient to retain its biological activity and does not react with the subject’s immune system. Examples include, but are not limited to, any standard pharmaceutical carrier, such as phosphate-buffered saline solution, water, emulsions such as oil / water emulsions, and various types of wetting agents. In some embodiments, the diluent for aerosol or parenteral administration is phosphate-buffered saline (PBS) or physiological (0.9%) saline. Compositions containing such carriers are formulated using well-known conventional methods (see, for example, Remington’s Pharmaceutical Sciences, 18th edition, A. Gennaro, editor, Mack Publishing Co., Easton, PA, 1990; and R. Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing, 2000).

[0067] The terms “cancer,” “cancerous,” “proliferative disorder,” and “tumor” are not mutually exclusive when used in this disclosure.

[0068] The terms “give,” “apply,” and “treat,” when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid, such as in therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Cellular treatment includes contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cell. “Give,” “apply,” and “treat” also mean treatment, such as of cells, by means of a reagent, diagnostic agent, conjugate composition, or by means of another cell in vitro and ex vivo. When applied to humans, veterinary, or research subjects, it refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0069] The term "treatment" means administering a therapeutic agent, such as a fusion protein or insulin analog comprising any of the present disclosure, to a subject who has, is suspected of having, or is predisposed to having one or more diabetes or hyperglycemia-related diseases or their symptoms, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, a therapeutic agent is administered in a treated subject or population in an amount that effectively relieves symptoms of one or more diseases by preventing or delaying the onset of symptoms or complications, reducing symptoms or complications, or eliminating the disease, condition, or symptom to any clinically measurable degree. The amount of a therapeutic agent that effectively relieves symptoms of any specific disease (also referred to as a "therapeuticly effective amount") can vary depending on a variety of factors, such as the subject's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the subject. Whether the disease symptoms have been relieved can be evaluated using any clinical test that a physician or other healthcare professional typically uses to assess the severity or progression of the symptoms. Although the embodiments of this disclosure (e.g., treatment methods or products) may be ineffective in alleviating the symptoms of the target disease in a particular subject, they should alleviate the symptoms of the target disease in a statistically significant number of subjects, as determined by any statistical test known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test. The patients to be treated are mammals, and preferably humans.

[0070] The terms “subject” and “patient” refer to mammals, especially primates, and particularly humans.

[0071] The “combination” described in this disclosure refers to a route of administration in which at least one dose of the compound of formula (I), and at least one dose of albumin-bound paclitaxel and at least one dose of gemcitabine are administered within a specified time period; or at least one dose of the compound of formula (I), and at least one dose of irinotecan liposomes, at least one dose of oxaliplatin, at least one dose of leucovorin calcium, and at least one dose of 5-fluorouracil are administered within a specified time period, wherein all administered drugs exhibit pharmacological effects. The specified time period can be within a dosing cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours, more preferably within 12 hours. The compound of formula (I), albumin-bound paclitaxel, and gemcitabine can be administered simultaneously or sequentially, or the compound of formula (I), irinotecan liposomes, oxaliplatin, leucovorin calcium, and 5-fluorouracil can be administered simultaneously or sequentially. This duration includes treatments in which the compound of formula (I), albumin-bound paclitaxel, and gemcitabine are administered via the same or different routes of administration; and the compound of formula (I), irinotecan liposomes, oxaliplatin, leucovorin calcium, and 5-fluorouracil are administered via the same or different routes of administration. The combined administration methods described in this disclosure are selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.

[0072] Progression-free survival (PFS): from randomization to the date of first recorded objective progression of adenocarcinoma or to death from any cause, whichever comes first.

[0073] Overall survival (OS) refers to the period from randomization to death from any cause. For subjects still alive at the last follow-up, the OS is defined as the time to the last follow-up, indicating data loss. For subjects lost to follow-up, the OS is defined as the time to the last confirmed survival prior to loss to follow-up, indicating data loss. OS with data censoring is defined as the time from randomization to censoring.

[0074] The objective response rate (ORR) refers to the proportion of patients whose tumors shrink to a certain extent and remain so for a certain period of time, including cases of complete response (CR) and partial response (PR). The RECIST 1.1 criteria are used to assess objective response. Subjects must have measurable tumor lesions at baseline. The efficacy assessment criteria, according to RECIST 1.1, are divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).

[0075] The Disease Control Rate (DCR) is the percentage of patients with confirmed complete remission, partial remission, and stable disease (≥8 weeks) among those with evaluable efficacy.

[0076] 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 <10 mm.

[0077] Partial remission (PR): The sum of the diameters of the target lesions is reduced by at least 30% compared to the baseline level.

[0078] Disease progression (PD): The minimum sum of the diameters of all target lesions measured throughout the entire experimental study is used as a reference, with a relative increase of at least 20% in the sum of diameters (or the baseline value if the baseline measurement is the minimum); in addition, the absolute value of the sum of diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered disease progression).

[0079] Disease stability (SD): The degree of reduction in target lesions does not reach the PR level, nor does the degree of increase reach the PD level; it falls between the two. The minimum value of the sum of diameters can be used as a reference in studies. Detailed Implementation

[0080] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the disclosure. Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions, such as those described in Cold Spring Harbor Laboratory's *Antibody Technology Laboratory Manual* and *Molecular Cloning Handbook*; or under conditions recommended by the raw material or commercial manufacturer. Reagents whose specific source is not specified are commercially available, conventional reagents.

[0081] Example 1: Phase IB / II clinical study of the safety, tolerability, and efficacy of compound (I) in combination with AG or FOLFIRINOX chemotherapy regimens in subjects with KRAS G12D-mutated advanced pancreatic cancer.

[0082] I. Test Drugs

[0083] The preparation method of the injection solution of the compound shown in formula (I) can be referred to WO2024022507A, specification: 10ml:30mg.

[0084] Albumin-bound paclitaxel, strength: 100mg / vial

[0085] Gemcitabine, available in 200mg / vial and 1000mg / vial specifications.

[0086] Irinotecan hydrochloride liposome injection, specification: 8ml: 37.66mg (as per C) 33 H 38 (N4O6)

[0087] Oxaliplatin for injection, strength: 50mg / 100mg

[0088] 5-Fluorouracil, specification: 10ml:0.1g

[0089] Leucovorin calcium injection, specification: 10ml:0.1g

[0090] II. Enrolled Population

[0091] Patients with unresectable locally advanced or metastatic solid tumors with confirmed KRAS G12D mutations.

[0092] The Phase IB cohort enrolled patients with recurrent or metastatic pancreatic cancer who had previously received at most first-line standard treatment (including but not limited to systemic chemotherapy, molecularly targeted therapy, immunotherapy, biotherapy, and other investigational therapies) and had not previously received KRAS inhibitor therapy; the Phase II pancreatic cancer cohort enrolled patients with pancreatic cancer who had not previously received systemic anti-tumor therapy.

[0093] III. Dosing Regimen

[0094] Qualified subjects were given the appropriate medication.

[0095] 1. IB phase (dose escalation):

[0096] This phase aims to evaluate the tolerability of the compound shown in Formula (I) in combination with AG or FOLFIRINOX in patients with advanced pancreatic cancer and KRAS G12D mutation, determine the recommended dose for Phase II (RP2D), and assess safety and preliminary efficacy.

[0097] The compound combined with the AG scheme shown in formula (I)

[0098] The compound shown in formula (I) is administered at doses of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1200 mg, with each dosing cycle consisting of 3 weeks. The compound is administered via intravenous infusion on the first and eighth days of each cycle.

[0099] Albumin-bound paclitaxel: The starting dose is 125 mg / m². 2 Each dosing cycle consists of 3 weeks, with intravenous infusion administered on days 1 and 8 of each cycle.

[0100] Gemcitabine: Starting dose is 1000 mg / m² 2 Each dosing cycle consists of 3 weeks, with intravenous infusion administered on days 1 and 8 of each cycle.

[0101] The compound shown in formula (I) is combined with the FOLFIRINOX scheme.

[0102] The compound shown in formula (I) is administered at doses of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1200 mg, by intravenous infusion, once a week, once every 2 weeks or once every 3 weeks;

[0103] The dosage of irinotecan liposomes is 60 mg / m². 2 Intravenous infusion, once every 2 weeks;

[0104] The dosage of oxaliplatin is 85 mg / m². 2 Intravenous infusion, once every 2 weeks;

[0105] The dosage of calcium leucovorin is 400 mg / m². 2 Intravenous infusion, once every 2 weeks;

[0106] The dosage of 5-fluorouracil is 400 mg / m² via intravenous bolus. 2 Followed by 2400 mg / m² 2 Intravenous infusion is maintained for 46-48 hours, once every 2 weeks.

[0107] If the relevant dose groups of the above two combination regimens are not tolerated, the dosing cycle, dosing sequence, and dosage of the study drug can be adjusted as needed.

[0108] 2. Phase II (Therapeutic Effect Expansion)

[0109] The dosage of the compound shown in formula (I) was determined in the IB phase RP2D and administered by intravenous infusion once weekly, every 2 weeks or every 3 weeks.

[0110] The AG scheme and the FOLFIRINOX scheme are consistent with the IB phase.

[0111] IV. Test Results

[0112] A total of 31 patients with pancreatic ductal adenocarcinoma mutated by KRAS G12D were enrolled and treated with the compound shown in formula (I) in combination with the AG regimen. The specific dosing regimen for the compound shown in formula (I) was as follows: each dosing cycle was 3 weeks, with 500 mg and 1200 mg administered intravenously on day 1 and day 8 of each cycle, respectively.

[0113] The results showed that the confirmed ORR for first-line treatment patients was 63.3%, the DCR was 93.3%, and the 6-month PFS rate was 89.3%.

[0114] Example 2: A randomized, controlled, double-blind, multicenter phase III clinical trial comparing compound (I) in combination with AG regimen versus placebo in combination with AG regimen as first-line treatment for advanced or metastatic pancreatic cancer with KRAS G12D mutation.

[0115] I. Test Drugs

[0116] The preparation method of the injectable solution of the compound shown in formula (I) can refer to WO2024022507A, and the specifications are 10mL:30mg and 40mL:120mg.

[0117] Paclitaxel for Injection (Albumin-Bound), 100mg / vial, Jiangsu Hengrui Medicine Co., Ltd.

[0118] Gemcitabine hydrochloride for injection, in C9H 11 1.0g of F2N3O4, Jiangsu Hansoh Pharmaceutical Group Co., Ltd.

[0119] II. Enrolled Population

[0120] Subjects with advanced or metastatic pancreatic cancer carrying the KRAS G12D gene mutation who have not previously received systemic anti-tumor therapy for advanced or metastatic pancreatic cancer and whose histological pathology confirms adenocarcinoma.

[0121] III. Dosing Regimen

[0122] Experimental group: Compound (I) combined with AG scheme

[0123] Compound (I): 500 mg on day 1 and 1200 mg on day 8, administered intravenously by infusion, with each cycle lasting 3 weeks. The first infusion should last at least 60 minutes. If no infusion-related reaction occurs after the first administration, the duration of each subsequent infusion may be appropriately shortened.

[0124] AG regimen: Gemcitabine 1000 mg / m² 2 Administered intravenously on days 1 and 8, with each cycle lasting 3 weeks; albumin-bound paclitaxel 125 mg / m². 2 , d1 and d8, intravenous injection, every 3 weeks as one cycle.

[0125] The general order of administration is to first use compound (I) followed by chemotherapy drugs. The order of administration in the chemotherapy regimen should be consistent with clinical practice. Considering the cumulative toxicity of long-term chemotherapy, it is recommended that the total chemotherapy course be 6-8 cycles, followed by maintenance therapy. Maintenance therapy may involve compound (I) in combination with gemcitabine chemotherapy until disease progression, intolerable toxicity, the subject voluntarily requests to terminate the trial or withdraw from the trial, or the investigator determines that the subject needs to withdraw from the trial.

[0126] Control group: Placebo plus AG regimen

[0127] The dosage and administration of placebo are the same as those of compound (I), and the dosage and administration of AG regimen drugs are the same as those of the experimental group. Considering the cumulative toxicity of long-term chemotherapy, it is recommended that the total chemotherapy be 6-8 cycles, followed by maintenance therapy. Maintenance therapy can be a combination of placebo and gemcitabine chemotherapy. Treatment continues until disease progression, intolerable toxicity, the subject voluntarily requests to terminate the trial or withdraw from the trial, or the investigator determines that the subject needs to withdraw from the trial.

[0128] If the relevant doses of the above combined treatment regimens in the experimental and control groups are not tolerated, the dosing cycle, dosing sequence, and dosage of the study drug can be adjusted as needed.

Claims

1. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a chemotherapeutic agent in the preparation of a medicament for the treatment of KRAS G12D-mutant solid tumors, wherein the chemotherapeutic agent is selected from: 1) albumin-bound paclitaxel and gemcitabine; or 2) irinotecan liposomes, oxaliplatin, 5-fluorouracil, and leucovorin calcium.

2. The use according to claim 1, wherein the dosage of the compound shown in (I) or its pharmaceutically acceptable salt is selected from 50-2000 mg, preferably administered once a week, once every two weeks, once every three weeks, or twice every three weeks.

3. The use according to claim 1, wherein the dosage of the albumin-bound paclitaxel is selected from 50-200 mg / m². 2 The preferred dosing frequency is twice a week, twice every two weeks, twice every three weeks, twice every four weeks, or three times every four weeks.

4. The use according to claim 1, wherein the dosage of gemcitabine is selected from 300-2000 mg / m². 2 The preferred dosing frequency is twice a week, twice every two weeks, twice every three weeks, twice every four weeks, or three times every four weeks.

5. The use according to claim 1, wherein the dosage of oxaliplatin is selected from 10-100 mg / m². 2 The preferred dosing frequency is once a week, once every two weeks, or once every three weeks.

6. The use according to claim 1, wherein the dosage of the irinotecan liposomes is selected from 10-100 mg / m². 2 The preferred dosing frequency is once a week, once every two weeks, or once every three weeks.

7. The use according to claim 1, wherein the dosage of leucovorin calcium is selected from 100-600 mg / m². 2 The preferred dosing frequency is once a week, once every two weeks, or once every three weeks.

8. The use according to claim 1, wherein the dosage of 5-fluorouracil is selected from 1000-4000 mg / m². 2 The preferred dosing frequency is once a week, once every two weeks, or once every three weeks.

9. The use according to any one of claims 1-8, wherein the solid tumor is selected from advanced solid tumors, preferably pancreatic cancer, more preferably recurrent or metastatic pancreatic cancer.

10. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel and gemcitabine, and one or more pharmaceutically acceptable carriers.

11. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, irinotecan, oxaliplatin, 5-fluorouracil, and leucovorin calcium, and one or more pharmaceutically acceptable carriers.

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