Use of KRAS inhibitor in preparing drug for treating advanced solid tumor

Abstract

The present invention pertains to the technical field of drug application and particularly relates to clinical use of a KRAS G12D inhibitor. The inhibitor can be clinically used to effectively treat patients with advanced solid tumors carrying the KRAS G12D mutation and can produce beneficial effects.

Description

Use of a KRAS inhibitor for the manufacture of a medicament for the treatment of advanced solid tumors

[0001] This application claims priority to Chinese Patent Application No. CN202410417643X, filed on April 8, 2024, and Chinese Patent Application No. CN2024117552826, filed on November 29, 2024, and Chinese Patent Application No. CN2025103966892, filed on March 31, 2025. This application incorporates the entire text of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application belongs to the technical field of drug application, and specifically relates to a clinical use of a KRAS G12D inhibitor, which can effectively treat patients with advanced (metastatic or unresectable) solid tumors carrying KRAS G12D mutations in a clinical setting and produce beneficial effects. BACKGROUND

[0003] Malignant tumors have seriously threatened human life and health. According to estimates by the International Agency for Research on Cancer of the World Health Organization, there were about 19.3 million new cases and about 1 million deaths worldwide in 2020. In terms of incidence, the incidence of malignant tumors in low-income countries is much higher than that in developed countries. China has the highest number of new cancer cases and cancer deaths worldwide, and the anti-cancer situation is grim. KRAS is a frequently mutated proto-oncogene in human cancers and belongs to the rat sarcoma (RAS) superfamily. RAS genes (KRAS, HRAS, and NRAS) are the most common mutated oncogenes in cancers, and RAS mutations can lead to increased downstream signaling, driving persistent cell proliferation and tumorigenesis.

[0004] KRAS gene mutations are the most common mutation subtype among RAS mutations, accounting for 85% of the total number of RAS gene mutations. KRAS mutations are common in a variety of tumors, with a mutation rate of about 90% in pancreatic cancer, about 50% in colorectal cancer, and about 25% in lung cancer. KRAS gene mutations are also found in cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, and breast cancer, among other cancer types.

[0005] KRAS mutations are mainly single base missense mutations, more than 80% of which are mutations of the 12th (G12) amino acid residue. Common mutation types include G12C, G12D and G12V, etc. KRAS G12D mutation is one of the most common KRAS mutation types, and its incidence is 2.5 times that of G12C mutation. Studies have shown that in KRAS mutant patients with pancreatic cancer, G12D mutation accounts for as high as 45% (in contrast, G12C mutation is only 1%). In colorectal cancer, which is the third most common disease in the world, G12D mutation accounts for 45% of KRAS mutations. In addition, in KRAS mutant lung adenocarcinoma patients, G12D mutation also accounts for 18.1% of KRAS mutations.

[0006] In patients with KRAS mutations, the proportion of G12D mutations is about 26%, the proportion of G12V mutations is about 20.7%, and the proportion of G12C mutations is about 13%. Although the listing of AMG510 has broken the cognition that KRAS target cannot be drugged, most of the current KRAS targeted drugs are targeted at G12C mutants. G12D mutants still lack targeted drugs. At present, no KRAS G12D targeted drug has been approved for marketing at home and abroad, and only a few drugs are in the preclinical stage or in the first clinical research stage, and there are substantial differences in the pharmacodynamic test model, animal species, type of cancer disease, disease progression stage, tumor metastasis and diffusion between the pharmacodynamic test of these preclinical candidate drug molecules and the human clinical trials in the present application. Therefore, there is a great unmet need for KRAS G12D mutant tumors in the clinic, and therefore it is urgent to explore drugs that are effective for the human body and target KRAS G12D, to change the poor survival status of patients with KRAS G12D mutant advanced solid tumors, to improve the quality of life of patients, and to improve the survival time of patients. SUMMARY

[0007] The first aspect of the present application provides the use of a compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a KRAS G12D mutant carrying advanced solid tumor.

[0008] In any of the technical solutions of the first aspect of the present application, the solid tumor is non-small cell lung cancer, colorectal cancer, or pancreatic cancer.

[0009] In any of the technical solutions of the first aspect of the present application, the solid tumor is non-small cell lung cancer.

[0010] In any of the technical solutions of the first aspect of the present application, the solid tumor is colorectal cancer.

[0011] In any of the technical solutions of the first aspect of the present application, the solid tumor is pancreatic cancer, for example, pancreatic ductal adenocarcinoma.

[0012] In any of the technical solutions of the first aspect of the present application, the carrying KRAS G12D mutation can be determined by histological detection or by genetic detection.

[0013] In any of the technical solutions of the first aspect of the present application, the solid tumor is metastatic or unresectable solid tumor.

[0014] In any of the technical solutions of the first aspect of the present application, the patient with advanced solid tumor carrying KRAS G12D mutation fails or cannot tolerate standard treatment, has no standard treatment or refuses to accept standard treatment.

[0015] In any of the technical solutions of the first aspect of the present application, the patient with advanced solid tumor carrying KRAS G12D mutation has received first-line treatment, second-line treatment, third-line treatment or fourth-line treatment.

[0016] In any of the technical solutions of the first aspect of the present application, the use is to administer an effective dose of Compound I or a pharmaceutically acceptable salt thereof (based on the weight of Compound I) to the patient in the implementation of treatment; wherein the effective dose is 200-4000 mg / day orally; preferably, the effective dose is 100-2000 mg / time orally for administration, twice a day or once in the morning and once in the evening; more preferably, the effective dose is 100 mg / time, or 200 mg / time, or 300 mg / time, or 400 mg / time, or 500 mg / time, or 600 mg / time, or 900 mg / time, or 1200 mg / time, or 1300 mg / time, or 1400 mg / time, or 1500 mg / time, or 1600 mg / time, or 1700 mg / time, or 1800 mg / time, or 1900 mg / time, or 2000 mg / time orally, with a frequency of twice a day, preferably once in the morning and once in the evening; preferably, the patient is ≥18 years old.

[0017] In any of the technical solutions of the first aspect of the present application, the use is to administer an effective dose of Compound I or a pharmaceutically acceptable salt thereof (based on the weight of Compound I) to the patient in the implementation of treatment; wherein the effective dose is 200-2400 mg / day orally; preferably, the effective dose is 100-1200 mg / time orally for administration, once in the morning and once in the evening; more preferably, the effective dose is 100 mg / time, or 200 mg / time, or 300 mg / time, or 400 mg / time, or 500 mg / time, or 600 mg / time, or 900 mg / time, or 1200 mg / time orally, once in the morning and once in the evening; preferably, the patient is preferably ≥18 years old.

[0018] In any of the technical solutions of the first aspect of the present application, the administration dose of the compound of formula I or its pharmaceutically acceptable salt (calculated by the weight of compound I) is 200-4000 mg / day, preferably 100-2000 mg / time, twice a day or once a day in the morning or evening; more preferably, 100 mg / time, or 200 mg / time, or 300 mg / time, or 400 mg / time, or 500 mg / time, or 600 mg / time, or 900 mg / time, or 1200 mg / time, or 1300 mg / time, or 1400 mg / time, or 1500 mg / time, or 1600 mg / time, or 1700 mg / time, or 1800 mg / time, or 1900 mg / time, or 2000 mg / time, once a day in the morning or evening.

[0019] In any of the technical solutions of the first aspect of the present application, the drug is in the form of oral administration.

[0020] In any of the technical solutions of the first aspect of the present application, the compound of formula I or its pharmaceutically acceptable salt is administered in a treatment cycle of 1 week every 3 weeks.

[0021] In any of the technical solutions of the first aspect of the present application, the patient with advanced solid tumor carrying KRAS G12D mutation is preferably ≥18 years old.

[0022] In any of the technical solutions of the first aspect of the present application, the patient with advanced solid tumor carrying KRAS G12D mutation is not a patient who has previously received an inhibitor against KRAS G12D mutation.

[0023] In a technical solution of the first aspect of the present application, the use of a compound of formula I or its pharmaceutically acceptable salt in the preparation of a drug for treating non-small cell lung cancer carrying KRAS G12D mutation is provided.

[0024] In a technical solution of the first aspect of the present application, the use of a compound of formula I or its pharmaceutically acceptable salt in the preparation of a drug for treating colorectal cancer carrying KRAS G12D mutation is provided.

[0025] In a technical solution of the first aspect of the present application, the use of a compound of formula I or its pharmaceutically acceptable salt in the preparation of a drug for treating pancreatic cancer carrying KRAS G12D mutation is provided.

[0026] In a technical solution of the first aspect of the present application, the use of a compound of formula I or its pharmaceutically acceptable salt in the preparation of a drug for treating metastatic or unresectable non-small cell lung cancer carrying KRAS G12D mutation is provided.

[0027] In a first aspect of the present application, there is provided a use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating metastatic or unresectable colorectal cancer carrying KRAS G12D mutation.

[0028] In a first aspect of the present application, there is provided a use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating metastatic or unresectable pancreatic cancer carrying KRAS G12D mutation.

[0029] In a second aspect of the present application, there is provided a method for treating a patient with advanced solid tumor carrying KRAS G12D mutation, the method comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0030] In any of the embodiments of the second aspect of the present application, the solid tumor is non-small cell lung cancer, colorectal cancer, or pancreatic cancer.

[0031] In any of the embodiments of the second aspect of the present application, the solid tumor is non-small cell lung cancer.

[0032] In any of the embodiments of the second aspect of the present application, the solid tumor is colorectal cancer.

[0033] In any of the embodiments of the second aspect of the present application, the solid tumor is pancreatic cancer, for example, pancreatic ductal adenocarcinoma.

[0034] In any of the embodiments of the second aspect of the present application, the carrying KRAS G12D mutation means that the KRAS G12D mutation is confirmed by histological detection.

[0035] In any of the embodiments of the second aspect of the present application, the solid tumor is metastatic or unresectable solid tumor.

[0036] In any of the embodiments of the second aspect of the present application, the patient with advanced solid tumor carrying KRAS G12D mutation has failed or is intolerant to standard treatment, has no standard treatment, or refuses to accept standard treatment.

[0037] In any of the embodiments of the second aspect of the present application, the patient with advanced solid tumor carrying KRAS G12D mutation has received first-line treatment, second-line treatment, third-line treatment, or fourth-line treatment.

[0038] In any of the technical solutions of the second aspect of the present application, the effective dose is 200-4000 mg per day orally, preferably 200-3200 mg per day orally; more preferably, the effective dose is 100-2000 mg per time orally, twice a day; more preferably, the effective dose is 100 mg per time orally, or 200 mg per time orally, or 300 mg per time orally, or 400 mg per time orally, or 500 mg per time orally, or 600 mg per time orally, or 900 mg per time orally, or 1200 mg per time orally, or 1300 mg per time orally, or 1400 mg per time orally, or 1500 mg per time orally, or 1600 mg per time orally, or 1700 mg per time orally, or 1800 mg per time orally, or 1900 mg per time orally, or 2000 mg per time orally, twice a day, preferably once in the morning and once in the evening.

[0039] In any of the technical solutions of the second aspect of the present application, the effective dose is 200-2400 mg per day orally; preferably, the effective dose is 100-1200 mg per time orally, once in the morning and once in the evening; more preferably, the effective dose is 100 mg per time orally, or 200 mg per time orally, or 300 mg per time orally, or 400 mg per time orally, or 500 mg per time orally, or 600 mg per time orally, or 900 mg per time orally, or 1200 mg per time orally, once in the morning and once in the evening.

[0040] In any of the technical solutions of the second aspect of the present application, the effective dose is 200-4000 mg per day; preferably, the effective dose is 100-2000 mg per time, twice a day or once in the morning and once in the evening; more preferably, the effective dose is 100 mg per time, or 200 mg per time, or 300 mg per time, or 400 mg per time, or 500 mg per time, or 600 mg per time, or 900 mg per time, or 1200 mg per time, or 1300 mg per time, or 1400 mg per time, or 1500 mg per time, or 1600 mg per time, or 1700 mg per time, or 1800 mg per time, or 1900 mg per time, or 2000 mg per time, once in the morning and once in the evening.

[0041] In any of the technical solutions of the second aspect of the present application, the compound of formula I or the pharmaceutically acceptable salt thereof is administered in a treatment cycle of 1 week every 3 weeks.

[0042] In any of the technical solutions of the second aspect of the present application, the treatment method is administered orally.

[0043] In any of the technical solutions of the second aspect of the present application, the patient with advanced solid tumors carrying KRAS G12D mutation is not a patient who has previously received an inhibitor against KRAS G12D mutation.

[0044] In any of the technical solutions of the second aspect of the application, the patient is ≥ 18 years old.

[0045] Definitions and explanations

[0046] In the application, the standard treatment refers to a treatment method that is recognized by experts and has been accepted and widely used, and is a treatment mode for the purpose of controlling tumor growth, improving the quality of life of patients, and prolonging the survival period of patients.

[0047] In the application, the number of treatment lines experienced by the patient refers to the number of different treatment regimens the patient has experienced before receiving the clinical trial.

[0048] In the application, the intolerance refers to the occurrence of obvious adverse reactions in patients after receiving treatment, which seriously affects the normal life activities of patients and even affects the safety of life.

[0049] In the application, the abbreviations that can be used are shown in the following table: DETAILED DESCRIPTION

[0050] The trial scheme of the application is carried out under the condition that the safety, informed consent, and treatment opportunity of the subjects are fully guaranteed, the subjects sign the informed consent form, and the ethical committee approval is obtained. The clinical trial scheme of the implementation of the application is formulated in accordance with the relevant guiding principles for clinical trials published by CDE, and meets the relevant requirements for clinical trials. The clinical trial scheme of the application is implemented as follows:

[0051] I. Selection criteria for the research population of the clinical trial

[0052] Each subject participating in the research must meet all of the following selection criteria:

[0053] 1. The subject voluntarily signs the informed consent form (ICF), can understand and follow the requirements of the research, has good compliance, and cooperates with follow-up;

[0054] 2. The age of the subject on the date of signing the ICF is ≥ 18 years old, and the sex is not limited;

[0055] 3. The patient with advanced (metastatic or unresectable) solid tumor carrying KRAS G12D is confirmed by histology. Local institution test results (including test results from hospitals and institutions other than research centers) are allowed. For subjects who have not been tested, tumor tissue (puncture or resection, archived specimens within 2 years) needs to be sent to the central laboratory for detection using NGS detection method before medication.

[0056] The following requirements need to be met for the cohort expansion phase (phase Ib-drug preliminary anti-tumor activity test):

[0057] a) Cohort 1: Patients with advanced non-small cell lung cancer harboring KRAS G12D mutation;

[0058] b) Cohort 2: Patients with advanced colorectal cancer harboring KRAS G12D mutation;

[0059] c) Cohort 3: Patients with advanced pancreatic cancer harboring KRAS G12D mutation;

[0060] d) Cohort 4: Patients with other advanced solid tumors harboring KRAS G12D mutation.

[0061] 4. Failed standard treatment or unable to tolerate standard treatment, no standard treatment or refused to accept standard treatment;

[0062] 5. Able to swallow and retain oral medication and must not have any gastrointestinal abnormalities of clinical significance that could alter absorption;

[0063] 6. Subject has at least one measurable lesion documented by computed tomography (CT) and / or magnetic resonance imaging (MRI) according to the investigator's assessment by RECIST vl. l. (Ia phase monotherapy dose escalation phase also allows enrollment with evaluable lesions);

[0064] Note: Measurable lesions that can be used for efficacy assessment must meet the following criteria: a) not in an area previously irradiated, or b) with evidence of radiographic progression since completion of radiotherapy and prior to study entry;

[0065] 7. ECOG PS score: 0 or 1;

[0066] 8. Life expectancy > 3 months;

[0067] 9. Adequate organ function at screening: (No use of any blood components, cell growth factors, leukocyte-boosting drugs, platelet-boosting drugs, anemia-correcting drugs, etc. within 7 days prior to obtaining laboratory tests):

[0068] a) Hematology: white blood cell count (WBC) > 3.5 x 109 / L, neutrophil count (ANC) > 1.5 x 109 / L, platelet count (PLT) > 100 x 109 / L, hemoglobin (Hb) > 90 g / L;

[0069] b) Liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x upper limit of normal (ULN), < 5 x ULN for liver cancer / liver metastasis subjects; serum total bilirubin (TBIL) < 1.5 x ULN, < 3 x ULN for Gilbert syndrome subjects;

[0070] c) Kidney function: creatinine clearance (CCr) > 60 mL / min (using standard Cockcroft-Gault formula);

[0071] d) Coagulation function: activated partial thromboplastin time (APTT) < 1.5 x ULN, international normalized ratio (INR) < 1.5, and prothrombin time (PT) < 1.5 x ULN;

[0072] e) Left ventricular ejection fraction (LVEF) > 50%;

[0073] 10. Female subjects of childbearing potential must be non-lactating, and must have a negative serum pregnancy test result within 3 days prior to first dose;

[0074] 11. Female subjects with childbearing potential and male subjects who are not surgically sterile must agree to use effective contraception from the time of signing the ICF until at least 180 days after the last dose.

[0075] II. Exclusion Criteria for the Study Population

[0076] Any subject who meets any of the following criteria is not eligible for the study.

[0077] 1. Prior receipt of an inhibitor against KRAS G12D mutation;

[0078] 2. Received > 30 Gy of non-thoracic radiation within 28 days prior to first dose or > 30 Gy of thoracic radiation within 24 weeks prior to first dose or < 30 Gy of palliative radiation within 14 days prior to first dose;

[0079] 3. Must have at least 28 days between prior major surgery, medical device treatment, and first dose of trial drug; at least 28 days or 5 half-lives, whichever is longer, between prior cytotoxic chemotherapy, immunotherapy, biologic, and first dose of trial drug; at least 21 days or 5 half-lives, whichever is longer, between prior small molecule targeted agents and first dose of trial drug; at least 14 days between prior Chinese medicine with anti-tumor indication and first dose of trial drug; at least 14 days between prior endocrine therapy and first dose of trial drug; at least 5 half-lives between prior any drug with anti-tumor effect (including trial drug) and first dose of trial drug;

[0080] 4. Received strong or moderate CYP3A, P-gp inhibitors within 1 week prior to first dose, or is using these drugs within 5 half-lives, whichever is longer, or is required to continue using these drugs during the study; received strong CYP3A inducers within 4 weeks prior to first dose;

[0081] 5. AEs from prior antitumor therapy have not recovered to Grade ≤1 (alopecia, cancer-related fatigue, pigmentation, etc. can be excluded, and neurotoxicity is relaxed to Grade ≤2) or have not reached a stable state as assessed by the investigator;

[0082] 6. Significant trauma or elective surgery requiring during the trial is anticipated within 4 weeks prior to first use of the trial drug;

[0083] 7. Known immediate or delayed hypersensitivity or idiosyncratic reactions to components of the agents used in the trial;

[0084] 8. Presence of other active malignancies in addition to the primary tumor; skin basal cell or squamous cell carcinoma, superficial bladder cancer, cervical carcinoma in situ, breast ductal carcinoma in situ, and thyroid papillary carcinoma that can be treated locally and cured, are excluded; patients with a history of malignancy that has been cured for > 2 years can be enrolled;

[0085] 9. Presence of brain metastases (asymptomatic brain metastases or symptomatic brain metastases that have been stable for > 4 weeks after treatment can be included) and / or carcinomatous meningitis or leptomeningeal disease that, in the judgment of the investigator, are not suitable for inclusion;

[0086] 10. Severe lung disease in the screening phase, including but not limited to active lung inflammation, tuberculosis (active or history of active tuberculosis infection < 48 weeks prior to screening), radiation pneumonitis, drug-induced pneumonitis, pulmonary fibrosis, or other diseases, symptoms, or signs of severely impaired lung function;

[0087] 11. Clinically significant gastrointestinal disease or other conditions that severely interfere with drug absorption, including but not limited to a history of severe gastrointestinal ulceration, gastrointestinal perforation, obstruction, fistula formation, intra-abdominal inflammation / abscess, intra-abdominal gas not resulting from puncture or surgery, macroscopic gastrointestinal bleeding / melena (except for hemorrhoids), hemoptysis (> 3 mL) within 6 months prior to first dose;

[0088] 12. Severe genetic or acquired bleeding diathesis or coagulopathy;

[0089] 13. Presence of clinically significant cardiovascular disease, including but not limited to:

[0090] a) myocardial infarction or unstable angina within 6 months prior to first dose;

[0091] b) stroke or transient ischemic attack within 6 months prior to first dose;

[0092] c) clinically significant cardiac arrhythmias that have been stable for > 14 days prior to first dose, and the patient can be enrolled;

[0093] d) Hypertension that is uncontrolled after optimal antihypertensive therapy: systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg;

[0094] e) Congestive heart failure (New York Heart Association [NYHA] class III-IV);

[0095] f) Pericarditis or clinically significant pericardial effusion;

[0096] g) Myocarditis;

[0097] h) 12-lead ECG showing mean QT interval (QTcF) > 450 ms (male) or > 470 ms (female) prior to first dose of study drug;

[0098] i) Subjects who cannot discontinue use of medications that can cause prolongation of the QTc interval or torsades de pointes (e.g., antiarrhythmics) during the study;

[0099] 14. Presence of ascites that requires drainage (drainage frequency > 1 per month) that is uncontrolled;

[0100] 15. Presence of active infection or fever > 38.5°C of unknown origin requiring treatment during the screening period (confirmed to be cancer-related fever can be included in the screening);

[0101] 16. HIV infection, positive for Treponema pallidum antibodies (positive for Treponema pallidum specific antibodies requires additional non-specific antibodies, subjects with negative non-specific antibodies can be included in the screening) or other acquired or congenital immunodeficiency disease;

[0102] 17. Positive for hepatitis B surface antigen (HBsAg) and hepatitis B virus deoxyribonucleic acid (HBV-DNA) > 104copies / mL (approximately equivalent to 2000 IU / mL) or positive for anti-HCV antibodies and HCV-RNA;

[0103] 18. History of allogeneic hematopoietic stem cell transplantation or organ transplantation (except corneal transplantation);

[0104] 19. Known presence of psychiatric illness, epilepsy, dementia, or alcohol or drug abuse that can potentially affect compliance with the requirements of the trial;

[0105] 20. Other history or evidence of disease, treatment or laboratory values that are abnormal that can potentially confound the results of the trial or prevent the subject from participating in the trial for the entire duration of the study, or that the investigator considers to be not in the best interest of the subject to participate in the trial.

[0106] 21. For subjects participating in the food effect trial:

[0107] a) Consumption of any medication that alters liver enzyme activity within 28 days prior to screening;

[0108] b) subjects who are unable to tolerate a standard meal;

[0109] c) have ingested chocolate, any food or beverage containing caffeine or xanthines within 48 hours prior to taking the study drug;

[0110] d) have ingested any alcoholic beverage or smoked any tobacco product within 48 hours prior to taking the study drug;

[0111] e) have ingested any food or beverage containing pitaya, mango, grapefruit, pomelo, papaya, pomegranate, starfruit or other food or beverage that affects drug absorption, distribution, metabolism, excretion, etc. within 48 hours prior to taking the study drug.

[0112] III. Study Drug and Dosing

[0113] The compound of Formula I is administered at the specified dose of 200-2400 mg / day, twice daily (BID), morning and evening. Each 3 weeks is a treatment cycle. The time difference between two consecutive administrations is preferably 12 hours, with a window of ± 4 hours.

[0114] The Phase II recommended dose (RP2D) of Compound I in subjects is determined based on safety, tolerability, PK, preliminary anti-tumor activity, and any other relevant data obtained from the dose escalation phase and the PK study case expansion phase. After the RP2D dose is obtained, dose expansion studies are conducted in specific tumor types and in a pan-tumor population, with the tumor types and groups enrolled as follows:

[0115] 1. subjects with advanced non-small cell lung cancer harboring KRAS G12D mutation;

[0116] 2. subjects with advanced colorectal cancer harboring KRAS G12D mutation;

[0117] 3. subjects with advanced pancreatic cancer harboring KRAS G12D mutation;

[0118] 4. subjects with other advanced solid tumors harboring KRAS G12D mutation;

[0119] Among them, the subjects enrolled in groups 1-4 are given Compound I for monotherapy at the RP2D dose, with each 3 weeks as a treatment cycle, until disease progression (unless the investigator considers that there is a sustained clinical benefit, until the trial drug is discontinued), intolerable toxicity, voluntary withdrawal, loss to follow-up, initiation of other anti-tumor treatment, death, or the investigator's judgment that treatment should be ended, or the longest medication time since the first medication is 2 years, whichever occurs first. Each tumor type is expected to enroll 30-60 subjects.

[0120] The RP2D dose can be a dose of 200-2400 mg / day; preferably, 100-1200 mg per oral administration, once in the morning and once in the evening, more preferably, 100 mg per oral administration, or 200 mg per oral administration, or 300 mg per oral administration, or 400 mg per oral administration, 500 mg per oral administration, or 600 mg per oral administration, or 900 mg per oral administration, or 1200 mg per oral administration, or 1300 mg per oral administration, or 1400 mg per oral administration, or 1500 mg per oral administration, or 1600 mg per oral administration, or 1700 mg per oral administration, or 1800 mg per oral administration, or 1900 mg per oral administration, or 2000 mg per oral administration, once in the morning and once in the evening.

[0121] IV. Tumor and Efficacy Assessments

[0122] 1. Assessment Methods

[0123] Tumor imaging assessments will be performed within 28 days prior to the first dose of study drug. Results of standard tests or examinations performed at the same study center prior to obtaining informed consent, if assessed to be applicable for screening, do not need to be repeated. The investigator will assess the tumor according to RECIST vl. l (see EUROPEAN JOURNAL OF CANCER, 45 (2009): 228-247) criteria, and the subjects will be evaluated for tumor imaging every 6 weeks (± 7 days) starting with C1D1 for the first 48 weeks, and every 9 weeks (± 7 days) thereafter until the subject has PD by imaging. The assessment frequency will not be changed due to subject delay or interruption of treatment. The efficacy assessment is classified as CR, PR, SD, or PD. Subjects with a response (CR or PR) will need to be re-evaluated for confirmation of response 4-6 weeks after the first assessment of CR or PR.

[0124] 2. Efficacy Measures

[0125] Objective response rate (ORR): defined as the percentage of subjects with a best overall response of CR and PR during the study.

[0126] Duration of response (DoR): defined as the time from the first assessment of CR or PR (whichever is recorded first) to the first imaging assessment of progressive disease or death.

[0127] Disease control rate (DCR): defined as the percentage of subjects with a best overall response of "CR + PR + SD".

[0128] Progression-free survival (PFS): defined as the time from the first dose of study drug to the first imaging assessment of progressive disease or death from any cause, whichever occurs first.

[0129] Time to disease progression (TTP): The time between the first dose of study drug and the occurrence of objective tumor progression in a subject.

[0130] Overall survival (OS): The time from the first dose of study drug to death from any cause in a subject.

[0131] Progression-free survival at 6 / 12 months: The proportion of subjects who are alive and have not experienced disease progression at 6 / 12 months from the first dose of study drug.

[0132] Overall survival at 1 / 2 year: The proportion of subjects who are alive at 1 / 2 year from the first dose of study drug.

[0133] Five, Statistics of the trial data

[0134] 1. General principles

[0135] In this study, if not otherwise specified, data will be summarized using descriptive statistics. Continuous data will be summarized using non-missing number, mean, standard deviation, median, maximum, and minimum. Count data will be summarized using frequency and percentage. ORR and DCR will be summarized using frequency, percentage, and 95% confidence interval (CI). Time-to-event data will be summarized using Kaplan-Meier estimates of survival and survival curves. Plasma concentration data will be summarized using number, number below the lower limit of quantification (BLQ), geometric mean, geometric coefficient of variation, mean, standard deviation, coefficient of variation, median, maximum, and minimum. PK parameters will be summarized using number, mean, standard deviation, coefficient of variation, geometric mean, geometric coefficient of variation, median, maximum, and minimum. Statistical methods will be described in detail in the statistical analysis plan.

[0136] 2. Efficacy analysis

[0137] Efficacy will be analyzed based on the full analysis set (FAS). The full analysis set refers to subjects who have taken the study drug at least once. The efficacy evaluation will be divided into CR (complete remission), PR (partial remission), SD (stable disease), or PD (disease progression) according to the RECIST v1.1 standard. Some of the data collected are shown in Tables 1 and 2, and the summary of the optimal tumor efficacy exhibited by patients enrolled under the condition of 100-1200 mg / each, twice a day is shown in Table 3.

[0138] If the data permit, each efficacy endpoint will be summarized by study phase, dose group, and cohort.

[0139] For ORR and DCR, their point estimates and two-sided 95% CIs will be calculated.

[0140] The Kaplan-Meier method was used to estimate the TTP, DoR, PFS and OS curves, respectively; the median DoR, TTP, PFS and OS time and 95% CI were calculated, and the 6-month and 12-month progression-free survival rates and 95% CI, 1-year and 2-year overall survival rates and 95% CI were calculated.

[0141] Table 1 Part of the information of the enrolled patients

[0142] Table 2 Changes in tumors after the compound of the present application is used to treat patients

[0143] Note: WK6 is the tumor condition at the time of 6 weeks of administration;

[0144] Table 3 Summary of tumor efficacy of enrolled subjects

[0145] The above test results show that the compound I of the present application exhibits obvious inhibitory and therapeutic effects in the clinical treatment of patients with pancreatic cancer, non-small cell lung cancer and colorectal cancer.

[0146] 3. Safety analysis

[0147] The adverse reactions in this test were mainly concentrated in diarrhea and vomiting, and the grades were not more than G2. The severity of adverse events was graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v5.0).

[0148] Preparation Example 1: Preparation of compound I;

[0149] Step 1: Preparation of intermediate 2-2

[0150] Intermediate 2-1 (50 g, 418.09 mmol) was dissolved in dichloromethane (500 mL), triethylamine (84.61 g, 836.17 mmol) was added, followed by di-tert-butyl dicarbonate (100.37 g, 459.90 mmol), and the reaction was carried out at 25°C for 16 hours. The reaction solution was added with 100 mL of water, and the liquid was separated. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1-50 / 1) to obtain intermediate 2-2. MS: m / z = 206.1 [M+Na] + .

[0151] Step 2: Preparation of intermediate 2-3

[0152] Intermediate 2-2 (25 g, 136.43 mmol) was dissolved in anhydrous tetrahydrofuran (350 mL), 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonane (37.31 g, 177.36 mmol) was added, cooled to -65 °C, and sec -butyllithium (1.3 M, 157.42 mL) was added dropwise slowly. After 1 h, methyl chloroformate (15.73 g, 166.44 mmol) was added dropwise, and the reaction was allowed to proceed for 2 h at -65 °C. The reaction was quenched by the dropwise addition of saturated ammonium chloride (20 mL), extracted with ethyl acetate (300 mL*2), and the organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (PE / EA = 50 / 1-25 / 1) to give intermediate 2-3. MS: m / z = 186.0 [M-tBu+H] + .

[0153] Step 3: Preparation of intermediate 2-4

[0154] Intermediate 2-3 (12 g, 49.73 mmol) was dissolved in tetrahydrofuran (120 mL), 3-chloro-2-chloromethylpropene (24.87 g, 198.94 mmol) was added, and the reaction was cooled to -40 °C. Lithium bis(trimethylsilyl)amide (1 M, 99.47 mL) was added dropwise slowly, and the reaction was allowed to proceed for 2 h while gradually warming to 20 °C. The reaction was quenched by the dropwise addition of saturated ammonium chloride (20 mL), extracted with ethyl acetate (150 mL*2), and the organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1-10 / 1) to give a mixture of relative configurations of intermediate 2-4. TLC (petroleum ether:acetone = 5:1) was developed twice, and the Rf value of 2-4 was 0.5, and the Rf value of its isomer was 0.55. The retention time of 2-4 on LCMS (column: Agilent Poroshell 120 EC-C18 2.7 μm 3.0*30 mm, mobile phase: A: water (0.037% formic acid)-B: acetonitrile (0.0187% formic acid); gradient: B: 5%-95%) was 0.776 min, and the retention time of its isomer was 0.801 min. MS: m / z = 274.0 [M-tBu+H] + .

[0155] Step 4: Preparation of intermediate 2-5

[0156] Intermediate 2-4 (3.6 g, 10.92 mmol) was dissolved in hydrogen chloride / ethyl acetate (4 M, 27.29 mL), and the reaction was allowed to proceed for 2 h at 20 °C. The reaction was concentrated under reduced pressure to give the hydrochloride salt of crude intermediate 2-5. MS: m / z = 230.1 [M+H]+ .

[0157] Step 5: Preparation of intermediate 2-6

[0158] The hydrochloride salt of intermediate 2-5 (2.9 g) was dissolved in methanol (100 mL), and potassium carbonate (4.52 g, 32.69 mmol) was added. The reaction was stirred at 20 °C for 2 h. The reaction was filtered and concentrated. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-5 / 1) to give intermediate 2-6. MS: m / z = 194.1 [M+H] + .

[0159] Step 6: Preparation of intermediate 2-7

[0160] Intermediate 2-6 (1.6 g, 8.28 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and lithium aluminum hydride (628.51 mg, 16.56 mmol) was added. The reaction was stirred at 0 °C for 2 h. The reaction was diluted with ethyl acetate (10 mL) and water (0.63 mL) was added dropwise. The reaction was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude intermediate 2-7. MS: m / z = 166.1 [M+H] + .

[0161] Step 7: Preparation of intermediate 1-2

[0162] Intermediate 1-1 (25 g, 99.03 mmol) was dissolved in dichloromethane (200 mL) and cooled to -30 °C. N,N-diisopropylethylamine (38.40 g, 297.08 mmol) and 1-1B (21.02 g, 99.03 mmol) were added sequentially. The reaction was stirred at -30 °C for 2 h. The reaction was directly concentrated under reduced pressure to give crude intermediate 1-2. MS: m / z = 428.1 [M+1] + .

[0163] Step 8: Preparation of intermediate 1-3A

[0164] Intermediate 1-2 (23 g) and intermediate 2-7 (9.76 g) were dissolved in anhydrous toluene (300 mL), and sodium tert-butoxide (13.93 g, 145.00 mmol) was slowly added at 0 °C. The reaction was carried out at 0 °C for 0.5 h and then at 20 °C for 0.5 h. The reaction solution was diluted with ethyl acetate (200 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product 1-3. The crude product 1-3 was purified by preparative SFC (Chromatographic column: DAICEL CHIRALCEL OD (250 mm*50 mm, 10 μm); Mobile phase: [A (supercritical carbon dioxide), B (ethanol containing 0.1% ammonia water)]; B: 40%) to give single isomer 1-3A and its isomer. The retention time of 1-3A under the condition of analytical SFC (Chromatographic column: Cellulose 2 100 mm*4.6 mm, 3 μm) mobile phase: [A (supercritical carbon dioxide), B (methanol (0.05% diethylamine))] ; B: 40%) was 4.964 min, and the ee value was 95.7%, 1 H NMR (400 MHz, CD3OD) δ 8.76 (s, 1H), 4.98-4.87 (m, 2H), 4.51-4.48 (m, 3H), 4.34-4.29 (m, 1H), 4.27 (br s, 2H), 4.23-4.18 (m, 1H), 3.61-3.58 (m, 3H), 3.12 (d, J = 9.5 Hz, 1H), 2.78 (br d, J = 16.8 Hz, 1H), 2.71 (dd, J = 4.0, 9.6 Hz, 1H), 2.45 (br d, J = 16.8 Hz, 1H), 1.83-1.72 (m, 2H), 1.75-1.62 (m, 3H), 1.55-1.51 (m, 1H), 1.42 (s, 9H), 0.60 (q, J = 4.2 Hz, 1H), 0.47-0.42 (m, 1H). MS: m / z = 557.2 [M+1] + . The retention time of its isomer under the same condition was 8.382 min, and the ee value was 96.5%.

[0165] Step 9: Synthesis of intermediate 1-4

[0166] Intermediate 1-3A (11.3 g, 20.29 mmol) was added to water (60 mL) and anhydrous dioxane (240 mL), followed by the addition of methanesulfonic acid [n- butyldi(1-adamantyl)phosphine]palladium(II)(2-amino-1,1'-biphenyl-2-yl) (1.48 g, 2.03 mmol) and intermediate 1-4A (15.38 g, 24.34 mmol), cesium carbonate (13.22 g, 40.57 mmol), and the reaction was stirred at 87 °C for 2 h. The reaction was diluted with ethyl acetate (200 mL), washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated by column chromatography (mobile phase: dichloromethane:methanol = 50:1 to 20:1) to give intermediate 1-4. MS (ESI) m / z: 862.4 [M+H2O-Ph2CO+1] + .

[0167] Step 10: Synthesis of intermediate 1-5

[0168] Intermediate 1-4 (8.4 g, 8.18 mmol) was added to ethyl acetate (30 mL) and water (10 mL), followed by the addition of hydrochloric acid / ethyl acetate (4 M, 62.37 mL), and the reaction was stirred at 20 °C for 2 h. The reaction was diluted with water (30 mL), and the organic phase was washed with water (30 mL x 2), the combined aqueous phases were adjusted to pH 7-8 with saturated sodium bicarbonate, and the product was extracted with ethyl acetate (80 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product 1-5. MS (ESI) m / z: 762.3 [M+1] + .

[0169] Step 11: Synthesis of compound of formula (I)

[0170] Intermediate 1-5 (6.2 g) was added to acetonitrile (70 mL), followed by the addition of tetramethylammonium fluoride (2.29 g, 13.83 mmol), and the reaction was stirred at 60 °C for 1 h. The reaction was diluted with 100 mL of ethyl acetate, washed with 30 mL of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane (10% ammonia in methanol):methanol = 20:1 to 10:1) to give compound I. MS (ESI) m / z: 606.3 [M+1] + ; 1H NMR (400 MHz, CD3OD) δ = 9.01 (s, 1H), 7.76 (dd, J = 5.6, 9.2 Hz, 1H), 7.28 - 7.19 (m, 2H), 7.15 (d, J = 2.3 Hz, 1H), 5.08 (br s, 1H), 5.01 (br s, 1H), 4.70 - 4.54 (m, 3H), 4.43 (dd, J = 7.3, 10.0 Hz, 1H), 4.32 (dd, J = 6.3, 10.3 Hz, 1H), 3.78 - 3.65 (m, 5H), 3.39 - 3.34 (m, 1H), 3.23 (d, J = 9.5 Hz, 1H), 2.93 (br d, J = 17.3 Hz, 1H), 2.82 (dd, J = 4.0, 9.3 Hz, 1H), 2.56 (br d, J = 17.1 Hz, 1H), 1.91 - 1.76 (m, 5H), 1.64 (td, J = 3.6, 6.9 Hz, 1H), 0.72 (q, J = 4.0 Hz, 1H), 0.61 - 0.53 (m, 1H).

Claims

1. Use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating advanced solid tumors carrying a KRAS G12D mutation:

2. The use according to claim 1, wherein the solid tumor is non-small cell lung cancer, colorectal cancer, or pancreatic cancer; the pancreatic cancer is, for example, pancreatic ductal adenocarcinoma.

3. The use according to claim 1, wherein the solid tumor is a metastatic or unresectable solid tumor.

4. The use according to claim 1, wherein the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is 200-4000 mg / day, or 200-3200 mg / day, calculated on the weight of compound I.

5. The use according to claim 4, wherein the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is 100-2000 mg / time, calculated on the weight of compound I, twice daily or once in the morning and once in the evening.

6. The use according to claim 4, wherein the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is, based on the weight of compound I, 100 mg / time, or 200 mg / time, or 300 mg / time, or 400 mg / time, or 500 mg / time, or 600 mg / time, or 900 mg / time, or 1200 mg / time, or 1300 mg / time, or 1400 mg / time, or 1500 mg / time, or 1600 mg / time, or 1700 mg / time, or 1800 mg / time, or 1900 mg / time, or 2000 mg / time, once in the morning and once in the evening.

7. The use according to claim 1, wherein the use is to administer an effective dose of Compound I or a pharmaceutically acceptable salt thereof to a patient during treatment; wherein, The effective dose is 200-4000 mg / day for oral administration; preferably, the effective dose is 100-2000 mg / time for each oral administration, twice a day; more preferably, the effective dose is 100 mg / time, or 200 mg / time, or 300 mg / time, or 400 mg / time, or 500 mg / time, or 600 mg / time, or 900 mg / time, or 1200 mg / time, or 1300 mg / time, or 1400 mg / time, or 1500 mg / time, or 1600 mg / time, or 1700 mg / time, or 1800 mg / time, or 1900 mg / time, or 2000 mg / time, and the frequency of administration is twice a day, preferably once in the morning and once in the evening.

8. The use according to claim 1, wherein the solid tumor is metastatic or unresectable non-small cell lung cancer carrying a KRAS G12D mutation, metastatic or unresectable colorectal cancer carrying a KRAS G12D mutation, or metastatic or unresectable pancreatic cancer carrying a KRAS G12D mutation.

9. The use according to claim 1, wherein the patient with advanced solid tumor carrying KRAS G12D mutation is not a patient who has previously received an inhibitor targeting KRAS G12D mutation.

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