Use of hetrombopag or its medicinal salts for treating thrombocytopenia caused by cancer chemotherapy

Abstract

The present disclosure relates to the use of hetrombopag or a medicinal salt thereof for treating thrombocytopenia caused by tumor chemotherapy. Specifically, the present disclosure relates to a method for treating the disease, which comprises administering hetrombopag or a medicinal salt thereof to a patient, and can significantly improve the platelet count of the subject.

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 2022113138298, filed on October 25, 2022, and Chinese Patent Application No. 2023102887574, filed on March 22, 2023. The above-mentioned Chinese patent applications are incorporated herein by reference in their entirety.

[0002] (Technical field) The present disclosure relates to the use of hetrombopag or a pharmaceutical salt thereof in the treatment of thrombocytopenia caused by chemotherapy of malignant tumors. [Background technology]

[0003] Thrombocytopenia is characterized by a lower-than-normal platelet count in peripheral blood, resulting in bleeding or bleeding risk of varying degrees, and severe platelet depletion is associated with a relatively high mortality rate. Depending on the etiology, thrombocytopenia can be divided into decreased thrombopoiesis (e.g., leukemia, bone metastasis of malignant tumors, chemotherapy, radiation, aplastic anemia, megaloblastic anemia, etc.), increased destruction or increased consumption (including immune-mediated destruction such as immune thrombocytopenia [ITP] and systemic lupus erythematosus, and non-immune destruction such as thrombotic thrombocytopenic purpura and vasculitis), abnormal distribution (splenomegaly due to various causes), and platelet loss (e.g., bleeding, hemodialysis, etc.). Chemotherapy-induced thrombocytopenia (CIT) is a clinically common dose-limiting toxic reaction of chemotherapy drugs. It is caused by the inhibitory effect of antitumor chemotherapy drugs on the bone marrow, particularly megakaryocytes, which leads to insufficient thrombopoiesis and excessive destruction of platelets, resulting in a decrease in the number of platelets in the peripheral blood (<100 × 10 9 / L). The time to the appearance of the nadir platelet count and the extent of the platelet decline associated with CIT depend on the chemotherapy drug, dose, presence or absence of concomitant medications, individual patient variability, and the number of chemotherapy treatments. The incidence of CIT ranges from approximately 10% to 36% in solid tumors, but can reach as high as 75% in hematological tumors. Direct harm from CIT includes bleeding, such as mucocutaneous bleeding, epistaxis, gingival bleeding, hemoptysis, hematemesis, hematuria, increased menstrual flow in women, and cerebral hemorrhage. Indirect harms include increased platelet transfusion requirements, reduced chemotherapy drug doses, delayed chemotherapy, and even the termination of chemotherapy, thereby affecting the progress and efficacy of chemotherapy and increasing mortality, as well as prolonging patient hospitalization, increasing medical costs, and affecting long-term clinical outcomes. Severe thrombocytopenia is associated with poor clinical outcomes, including increased bleeding risk and mortality.

[0004] In chemotherapy regimens, platinum-based drugs and gemcitabine (used to treat lung cancer, bladder cancer, ovarian cancer, cervical cancer, and gastrointestinal tumors) are prone to CIT, especially grade 3 / 4 CIT. CIT generally indicates that platelet counts begin to decline between days 3 and 7 after chemotherapy, reach a nadir on day 14, then gradually increase, and return to baseline levels between days 28 and 35. Furthermore, the incidence of CIT gradually increases with the number of chemotherapy cycles. In a large-scale epidemiological study of outpatient cancer patients conducted in the United States over a 7-year period (2000-2007), 11.1% of 43,995 patients with evaluable platelet counts initially experienced thrombocytopenia. After initial chemotherapy, thrombocytopenia varied depending on the regimen: 64.2% with gemcitabine-based regimens, 55.4% with platinum-based regimens, 37.8% with anthracycline-based regimens, and 21.9% with taxol-based regimens. The incidence of grade 3 / 4 thrombocytopenia was 11.2% for gemcitabine-based regimens, 10.6% for platinum-based regimens, 5.2% for anthracycline-based regimens, and 1.9% for taxol-based regimens. Among various tumors, the incidence of thrombocytopenia was 61.7% for colorectal cancer, 50.5% for NSCLC, 45.6% for ovarian cancer, and 37.6% for breast cancer. Furthermore, the incidence of grade 3 / 4 thrombocytopenia was highest in NSCLC at 10.7%. Among all cancer chemotherapy patients, the platelet transfusion rate was 2.5%, and the chemotherapy delay rate reached 22.7%, with a mean delay of 17 days. Elias et al. also reported that in patients with advanced sarcoma treated with doxorubicin, ifosfamide, and dacarbazine, grade 3 / 4 thrombocytopenia occurred in 48% of patients. In patients with NSCLC treated with chemotherapy containing carboplatin, ifosfamide, and etoposide, CIT occurred in over 50% of patients.In patients with ovarian cancer treated with chemotherapy containing taxol, ifosfamide, and cisplatin, the incidence of CIT was 24% to 33%. Summary of the Invention [Problem to be solved by the invention]

[0005] Currently, there is no clinically available oral, safe, and effective thrombopoiesis-promoting drug that can rapidly increase platelet count while maintaining the relative dose intensity of chemotherapy. [Means for solving the problem]

[0006] (Summary of the Invention) The present disclosure provides the use of hetrombopag or a medicinal salt thereof in the preparation of a medicament for treating thrombocytopenia caused by tumor chemotherapy, wherein the hetrombopag or a medicinal salt thereof is a unit dose formulation containing 7.5 mg of hetrombopag.

[0007] In some embodiments, patients with oncology chemotherapy-induced thrombocytopenia have a platelet count of <75×10 9 / L.

[0008] In some embodiments, the patient with oncology chemotherapy-induced thrombocytopenia is one in which chemotherapy is delayed by ≥ 1 week from the prescribed time due to thrombocytopenia and the platelet count is < 75 x 10 9 / L.

[0009] In some embodiments, the chemotherapy regimen for patients with thrombocytopenia due to tumor chemotherapy is a platinum-containing drug combination treatment regimen, where the platinum-based drugs include, but are not limited to, carboplatin, nedaplatin, cisplatin, lobaplatin, platin oxalate, oxaliplatin, and the like.

[0010] In another aspect, in some embodiments, after administering hetrombopag or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is 100×10 9 / L or more and 200 x 10 9 If the dose is less than 1 / L, administer the original dose.

[0011] In some embodiments, after the patient has been given hetrombopag or a pharmaceutical salt thereof for 14 days, the patient's platelet count is 100×10 9 / L or more and 200 x 10 9 If the dose is less than 1 / L, administer the original dose.

[0012] In some other embodiments, after administering hetrombopag or a medicinal salt thereof to the patient, the patient's platelet count is greater than or equal to 400×10 9 / L, temporarily interrupt administration and 9 / L, administration is resumed and the daily dose is reduced by 2.5 mg; if the lowest dose used at this time is 2.5 mg / day, administration is continued without treatment.

[0013] In some embodiments, after the patient has been given hetrombopag or a pharmaceutical salt thereof for 14 days, the patient's platelet count is greater than or equal to 400×10 9 / L, temporarily interrupt administration and 9 / L, administration is resumed and the daily dose is reduced by 2.5 mg; if the lowest dose used at this time is 2.5 mg / day, administration is continued without treatment.

[0014] In some other embodiments, after administering hetrombopag or a medicinal salt thereof to the patient, the patient's platelet count is greater than or equal to 200×10 9 / L and greater than 400 x 10 9 / L or less, reduce the daily dose by 2.5 mg.

[0015] In some embodiments, after the patient has been given hetrombopag or a pharmaceutical salt thereof for 14 days, the patient's platelet count is greater than or equal to 200×10 9 / L and greater than 400 x 10 9 / L or less, reduce the daily dose by 2.5 mg.

[0016] In another aspect, in some embodiments, after administering hetrombopag or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is 100×10 9 / L or more and 250 x 10 9 If the dose is less than 1 / L, administer the original dose.

[0017] In some embodiments, after the patient has been given hetrombopag or a pharmaceutical salt thereof for 14 days, the patient's platelet count is 100×10 9 / L or more and 250 x 10 9 If the dose is less than 1 / L, administer the original dose.

[0018] In some other embodiments, after administering hetrombopag or a medicinal salt thereof to the patient, the patient's platelet count is greater than or equal to 400×10 9 / L, temporarily interrupt administration and 9 / L, administration is resumed and the daily dose is reduced by 2.5 mg; if the lowest dose used at this time is 2.5 mg / day, administration is continued without treatment.

[0019] In some embodiments, after the patient has been given hetrombopag or a pharmaceutical salt thereof for 14 days, the patient's platelet count is greater than or equal to 400×10 9 / L, temporarily interrupt administration and 9 / L, administration is resumed and the daily dose is reduced by 2.5 mg; if the lowest dose used at this time is 2.5 mg / day, administration is continued without treatment.

[0020] In some other embodiments, after administering hetrombopag or a medicinal salt thereof to the patient, the patient's platelet count is greater than or equal to 250×10 9 / L and greater than 400 x 10 9 / L or less, reduce the daily dose by 2.5 mg.

[0021] In some embodiments, after the patient has been given hetrombopag or a pharmaceutical salt thereof for 14 days, the patient's platelet count is greater than or equal to 250×10 9 / L and greater than 400 x 10 9 / L or less, reduce the daily dose by 2.5 mg. In some embodiments, after the patient receives hetrombopag or a medicinal salt thereof, the patient's platelet count is <100 x 109 / L, increase the daily dose by 2.5 mg to a maximum of 15 mg / day.

[0022] In some embodiments, after the patient has received hetrombopag or a pharmaceutical salt thereof for 14 days, the patient has a platelet count of <100×10 9 / L, increase the daily dose by 2.5 mg to a maximum of 15 mg / day.

[0023] The present disclosure further provides a method for treating thrombocytopenia due to tumor chemotherapy, comprising administering to a patient a therapeutically effective amount of hetrombopag or a pharmaceutical salt thereof.

[0024] The present disclosure further provides a method for treating tumor chemotherapy-induced thrombocytopenia with hetrombopag or a medicament salt thereof.

[0025] In some embodiments, the starting dose of hetrombopag or a pharmaceutical salt thereof is 2.5 to 10.0 mg, preferably 2.5 mg, 3.75 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg.

[0026] In some embodiments, the starting dose of hetrombopag or a pharmaceutical salt thereof is 7.5 mg.

[0027] In some embodiments, in the method for treating tumor chemotherapy-induced thrombocytopenia with hetrombopag or a medicament salt thereof, the dosage is 7.5 mg.

[0028] In some embodiments, patients with oncology chemotherapy-induced thrombocytopenia have a platelet count of <75×10 9 / L.

[0029] In some embodiments, the patient with oncology chemotherapy-induced thrombocytopenia is one in which chemotherapy is delayed by ≥ 1 week from the prescribed time due to thrombocytopenia and the platelet count is < 75 x 10 9 / L.

[0030] In some embodiments, hetrombopag or a pharmaceutical salt thereof is present in a unit dose formulation.

[0031] In some other embodiments, the unit dose formulation contains at least 2.5 mg of hetrombopag. In some other embodiments, the unit dose formulation contains at least 3.75 mg of hetrombopag. In some embodiments, the unit dose formulation contains 5 mg of hetrombopag. In some embodiments, the unit dose formulation contains 7.5 mg of hetrombopag.

[0032] In some embodiments, the platelet count should be monitored periodically during the course of the methods or uses described herein, and the dose should be adjusted according to the platelet count status until the minimum dose that maintains the platelet response and obtains effective treatment is reached. Before each dose adjustment, it is preferable to maintain the current dose for at least one or two weeks to clarify the relevant therapeutic effect.

[0033] In some embodiments, the methods described herein include administering hetrombopag or a pharmaceutically acceptable salt thereof to a patient for at least 14 days, followed by adjusting the dose depending on the patient's platelet count.

[0034] In some other embodiments, the methods described herein include administering hetrombopag or a pharmaceutically acceptable salt thereof to a patient for at least seven days, followed by adjusting the dose depending on the patient's platelet count.

[0035] In some embodiments, after administering hetrombopag or a medicinal salt thereof to the patient, the patient's platelet count is greater than or equal to 400×10 9 / L, temporarily interrupt administration and 9 / L, administration is resumed and the daily dose is reduced by 2.5 mg, and if the lowest dose used at this time is 2.5 mg / day, administration is continued to be discontinued, preferably after the patient has received hetrombopag or a pharmaceutically acceptable salt thereof for at least 14 days.

[0036] In some embodiments, after administering hetrombopag or a medicinal salt thereof to the patient, the patient's platelet count is greater than or equal to 200×10 9 / L and greater than 400 x 10 9 / L or less, reduce the daily dose by 2.5 mg, preferably after the patient has received hetrombopag or a pharmaceutical salt thereof for at least 14 days.

[0037] In some embodiments, after administering hetrombopag or a pharmaceutically acceptable salt thereof to the patient, the patient's platelet count is 100×10 9 / L or more and 200 x 10 9 If the dose is less than 1 / L, administer the original dose.

[0038] In some other embodiments, after administering hetrombopag or a medicinal salt thereof to the patient, the patient's platelet count is greater than or equal to 400×10 9 / L, temporarily interrupt administration and 9 / L, administration is resumed and the daily dose is reduced by 2.5 mg, and if the lowest dose used at this time is 2.5 mg / day, administration is continued to be discontinued, preferably after the patient has received hetrombopag or a pharmaceutically acceptable salt thereof for at least 14 days.

[0039] In some other embodiments, after administering hetrombopag or a medicinal salt thereof to the patient, the patient's platelet count is greater than or equal to 250×10 9 / L and greater than 400 x 10 9 / L or less, reduce the daily dose by 2.5 mg, preferably after the patient has received hetrombopag or a pharmaceutical salt thereof for at least 14 days.

[0040] In some other embodiments, after administering hetrombopag or a medicinal salt thereof to the patient, the patient's platelet count is greater than or equal to 100×10 9 / L or more and 250 x 10 9 / L, the original dose is administered. In some embodiments, after the patient receives hetrombopag or a pharmaceutically acceptable salt thereof, the patient's platelet count is <100 x 10 9 / L, increase the daily dose by 2.5 mg to a maximum of 15 mg / day, preferably after the patient has received hetrombopag or a pharmaceutical salt thereof for at least 7 days.

[0041] In some embodiments, after a patient is given hetrombopag or a pharmaceutically acceptable salt thereof, if the patient's platelet response rate / trend is predicted to cause a delay or reduction in the next cycle of chemotherapy, the dose is upregulated one week after dosing.

[0042] In another embodiment, the patient according to the present disclosure does not suffer from any other hematopoietic disorder other than chemotherapy-induced thrombocytopenia (CIT).

[0043] In some embodiments, the other hematopoietic disorder is selected from, but is not limited to, leukemia, primary immune thrombocytopenia, myeloproliferative disorders, multiple myeloma, and myelodysplastic syndromes.

[0044] In some embodiments, the method is therapeutically effective for the duration of the treatment.

[0045] The unit dose formulations of the present disclosure typically include a pharmaceutically acceptable excipient selected from, but not limited to, microcrystalline cellulose, lactose, low-substituted hydroxypropyl cellulose, or magnesium stearate.

[0046] Tumors according to the present disclosure include, but are not limited to, lung cancer (small cell or non-small cell), breast cancer, and bladder cancer.

[0047] A "treatment period" as used herein is generally defined as two consecutive chemotherapy cycles, which are based on drug half-life and tumor doubling time and can be adjusted depending on the chemotherapy drug.

[0048] In some embodiments, the chemotherapy cycle described in this disclosure is 21 days.

[0049] "Therapeutically effective" as defined in this disclosure is when the subject meets one of the following conditions or simultaneously meets the following conditions during the treatment period (two consecutive chemotherapy cycles): 1. Patients are able to resume chemotherapy for this cycle 14 days after starting treatment with the study drug, and have a platelet count of ≥ 100 x 10 9 / L or a platelet count of ≥ 100 × 10 within 14 days (including the 14th day) of initiating treatment with the study drug. 9 / L, 2. Able to complete two chemotherapy cycles while not adjusting the chemotherapy regimen due to thrombocytopenia (e.g., chemotherapy delay of ≥ 4 days, and / or chemotherapy dose reduction of ≥ 15%, termination of chemotherapy, etc.); 3. Able to complete the first chemotherapy cycle (C1) with the same treatment plan as before enrollment, and have a platelet count of ≥ 75 x 10 on C1D21 (window period: +4 days). 9 / L, 4. No platelet rescue therapy (platelet transfusion, interleukin-11, recombinant human thrombopoietin) was used during the treatment period.

[0050] Hetrombopag as described in the present disclosure has the structure of a compound of formula I [ka] is.

[0051] The pharmaceutically acceptable salt of hetrombopag described in the present disclosure may be a sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, arginine salt, lysine salt, methylamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, ethanolamine salt, piperazine salt, dibenzylethylenediamine salt, meglumine salt, tromethamine salt, tetramethyl quaternary ammonium salt, tetraethyl quaternary ammonium salt or choline salt, preferably a diethylamine salt, ethanolamine salt, choline salt, piperazine salt, meglumine salt or tromethamine salt, more preferably an ethanolamine salt, and most preferably a diethanolamine salt.

[0052] "Persistent oncology chemotherapy-induced thrombocytopenia" as defined in this disclosure refers to a condition in which chemotherapy-induced thrombocytopenia is delayed by ≥ 1 week from the prescribed time and platelet count is < 75 x 10 9 It is defined as / L.

[0053] In some embodiments, the administration frequency of the hetrombopag or a pharmaceutical salt thereof is once every other day, once a day, twice a day, or three times a day.

[0054] According to research data related to the present disclosure, hetrombopag or a medicinal salt thereof has a significant therapeutic effect on sustained oncology chemotherapy-induced thrombocytopenia, significantly increases the proportion of subjects who benefit from the treatment, and is safe and controllable. Further development and use of this drug is expected to significantly change the current state of treatment for oncology chemotherapy-induced thrombocytopenia. DETAILED DESCRIPTION OF THE INVENTION

[0055] The present disclosure will be further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure.

[0056] Example 1: Study of the efficacy and safety of hetrombopagethanolamine tablets in treating thrombocytopenia caused by cancer chemotherapy

[0057] 1. Research drug Test drug: Hetrombopag ethanolamine tablets (2.5 mg / tablet) manufactured and provided by Jiangsu Hengrui Pharmaceutical Co., Ltd. Control drug: 2.5 mg / tablet of trombopag ethanolamine imitation tablets (placebo) which are identical in shape, color and weight to the trombopag ethanolamine tablets and are manufactured and provided by Jiangsu Hengrui Pharmaceutical Co., Ltd.

[0058] 2. Registration criteria To be enrolled in this study, patients must meet all of the following entry criteria: 1. 18 to 75 years old (inclusive) with no gender restrictions. 2. Having been diagnosed with malignant tumors, including lung cancer (small cell or non-small cell), breast cancer, bladder cancer, etc., by histopathological or cytological examination. 3. The subject is currently receiving a 21-day cycle chemotherapy regimen (excluding chemotherapy cycles of other lengths) and is receiving one or more chemotherapy agents, e.g., Antimetabolites, including gemcitabine, Platinum-based drugs, including carboplatin, nedaplatin, cisplatin, lobaplatin, etc. Anthracyclines, including doxorubicin, daunorubicin, and epirubicin alkylating agents, including cyclophosphamide, ifosfamide, etc. that you need to use 4. Subject has delayed chemotherapy for ≥ 1 week due to thrombocytopenia and platelet count remains < 75 x 10 9 / L, 5. ECOG physical fitness score is 0-1 points. 6. Patients are expected to have a survival time of ≥ 12 weeks at screening and can be treated with at least two cycles of their current chemotherapy regimen. 7. Subjects of childbearing age must agree to use reliable contraceptive measures (including male or female condoms, contraceptive foams, rubber contraceptives, membranes, creams, plugs, abstinence, and intrauterine device placement) throughout the study period, excluding female subjects who have undergone hysterectomy, bilateral salpingectomy, bilateral tubal ligation, or are more than one year postmenopausal, and male subjects who have undergone bilateral vasectomy or ligation. 8. Voluntarily participate in this study, sign the informed consent form, and comply with the study.

[0059] Patients with any one of the following cannot enroll in this study: 1. Screening or baseline platelet count <30 x 10 9 / L, 2. Platelet count <75 x 10 before initial chemotherapy 9 / L, 3. Patients with hematopoietic diseases other than chemotherapy-induced thrombocytopenia (CIT), including but not limited to leukemia, primary immune thrombocytopenia, myeloproliferative disorders, multiple myeloma, and myelodysplastic syndromes. 4. Thrombocytopenia due to causes other than CIT within 6 months prior to screening, including but not limited to chronic liver disease, hypersplenism, infection, and bleeding. 5. Bone marrow invasion or bone marrow metastasis 6. Having received pelvic or spinal radiotherapy and extensive bone irradiation within 3 months prior to screening, or currently receiving / planning to receive radiotherapy; 7. A history of serious cardiovascular disease within 6 months prior to screening, such as congestive heart failure (NYHA cardiac function score III to IV), arrhythmias such as atrial fibrillation that are known to increase the risk of thromboembolism, or post-coronary stent implantation, angioplasty, or coronary artery bypass graft surgery. 8. History of any arterial or venous thrombosis within 6 months prior to screening, 9. Clinical symptoms of severe bleeding, such as gastrointestinal or central nervous system bleeding, within 2 weeks prior to screening. 10. Brain tumor or brain metastasis, 11. Emergency treatment is required, such as superior vena cava syndrome or spinal cord compression. 12. Absolute neutrophil count <1.0 × 10 9 / L, hemoglobin <80g / L, and treatment with granulocyte colony-stimulating factor, red blood cell, and EPO infusions according to clinical routine is acceptable. 13. Obvious liver function abnormalities: In patients without liver metastasis, ALT / AST > 3ULN (upper limit of normal), TBIL > 3ULN, and in patients with liver metastasis, ALT / AST ≥ 5ULN, TBIL ≥ 5ULN. 14. Renal function abnormalities: blood creatinine ≥ 1.5ULN or eGFR ≤ 60ml / min (Cockcroft-Gault formula), 15. Have received treatment with thrombopoietin receptor agonists (e.g., eltrombopag, romiplostim), human recombinant thrombopoietin (rhTPO), or recombinant human interleukin-11 (rhIL-11) within one month prior to screening. 16. Have received platelet transfusion within 3 days prior to randomization / first dose, 17. Patients with known or suspected hypersensitivity or intolerance to the active ingredients or excipients of Hetrombopagethanolamine Tablets (including cellulose-lactose, low-substituted hydroxypropyl cellulose, and magnesium stearate). 18. Being HIV positive; 19. Being a pregnant or breastfeeding woman; 20. Participation in any other clinical study of an investigational drug or device in the 3 months prior to screening; 21. Any other case where the investigator believes that participation in the trial poses a relatively large risk to the subject's health or safety or may affect the evaluation of the treatment's effectiveness.

[0060] 3. Dosage method: A stratified block randomization method was used to determine whether baseline platelet counts (≥ 50 × 10 9 / L vs <50×109 Patients were stratified by CI / L and randomly assigned in a 1:1 ratio to either the test group (Hetrombopag ethanolamine tablets 7.5 mg) or the placebo group (Hetrombopag ethanolamine imitation tablets) and received the corresponding treatment.

[0061] Drug dosage: During the treatment period, subjects randomly assigned to the study group were treated with Hetrombopag ethanolamine tablets, starting at 7.5 mg once daily. After 14 days, the dose was adjusted based on the subject's platelet response or investigator discretion, and the treatment could be continued for up to two chemotherapy cycles. Subjects randomly assigned to the control group were treated with corresponding placebo tablets. During the optional extension period, subjects in the Hetrombopag group could continue treatment, while subjects in the placebo group were treated with Hetrombopag ethanolamine tablets, starting at 7.5 mg once daily. The dose was adjusted based on the investigator discretion during the treatment period, and the treatment could be continued for up to four chemotherapy cycles.

[0062] During the optional extension period, the patients in the Hetrombopag group could continue to receive treatment, while the patients in the placebo group would receive treatment with Hetrombopag ethanolamine tablets, with a starting dose of 7.5 mg once daily. The drug dose could be adjusted based on the investigator's discretion during the treatment period, and patients could continue for up to four chemotherapy cycles.

[0063] Drug usage: It should be administered orally once daily on an empty stomach, and may be taken 2 hours after oral administration, provided that it is not administered with a meal.

[0064] Products containing dairy products (e.g., milk, yogurt, cheese, and ice cream) or mineral supplements containing polyvalent cations (e.g., aluminum, calcium, magnesium, iron, selenium, and zinc) should be used at least 2 hours after administration.

[0065] Medication adjustment Each dose adjustment should be maintained for 2 weeks to observe its effect, and the adjustment rules are as follows: Platelets <100×10 9 / L, increase the daily dose by 2.5 mg to a maximum of 15 mg / day; Platelets ≥ 200 × 10 9 / L and ≦400×10 9 / L, reduce the daily dose by 2.5 mg; Platelets >400 × 10 9 / L, administration should be temporarily interrupted and platelets should be <200 × 10 9 If the blood pressure is 100 / L, administration should be resumed and the daily dose reduced by 2.5 mg. If the lowest dose used is 2.5 mg / day, administration can be discontinued. If the investigator predicts that the subject's platelet response rate / trend will cause a delay or reduction in the next cycle of chemotherapy, the dose may be upregulated one week after dosing.

[0066] 4. Clinical endpoints: Primary Study Endpoints: The primary endpoint was the proportion of subjects with a therapeutic response, defined as meeting the following conditions simultaneously during the treatment period (two consecutive chemotherapy cycles): 1. 14 days after the start of treatment with the study drug, chemotherapy can be resumed for this cycle and platelets are ≥ 100 x 10 9 / L, 2. Able to complete two chemotherapy cycles while not adjusting the chemotherapy regimen due to thrombocytopenia (e.g., chemotherapy delay of ≥ 4 days, and / or chemotherapy dose reduction of ≥ 15%, termination of chemotherapy, etc.); 3. No platelet rescue therapy (platelet transfusion, interleukin-11, recombinant human thrombopoietin) was used during the treatment period.

[0067] 5. Research results: During the study period, 60 patients were enrolled, of whom 59 received at least one study drug and were randomly assigned to the test group (n=28) or placebo group (n=31). Seventeen patients in the test group reached the primary study endpoint (17 / 28 [60.7%, 95% CI 40.6-78.5]), while four patients in the placebo group reached the primary study endpoint (4 / 31 [12.9%, 95% CI 3.6-29.8]). The OR value was 10.44 [95% CI 2.82-38.65], p=0.0001, indicating a significant increase in patients in the test group who reached the primary study endpoint.

[0068] Although the incidence of adverse events was comparable between the test group and the placebo group, no treatment-related adverse events of grade 3 or higher or treatment-related serious adverse events were observed in the test group.

[0069] Example 2: Study of the efficacy and safety of hetrombopagethanolamine tablets in treating thrombocytopenia caused by cancer chemotherapy

[0070] 1. Research drug Test drug: Hetrombopag ethanolamine tablets (2.5 mg / tablet) manufactured and provided by Jiangsu Hengrui Pharmaceutical Co., Ltd.

[0071] Control drug: 2.5 mg / tablet of trombopag ethanolamine imitation tablets (placebo) which are identical in shape, color and weight to the trombopag ethanolamine tablets and are manufactured and provided by Jiangsu Hengrui Pharmaceutical Co., Ltd.

[0072] 2. Registration criteria To be enrolled in this study, subjects must meet all of the following criteria: 1. 18 to 75 years old (inclusive) with no gender restrictions. 2. Diagnosed as a malignant tumor by histopathological or cytological examination, including but not limited to gastric cancer, colorectal cancer, lung cancer (small cell or non-small cell), breast cancer, bladder cancer, etc. 3. The subject is currently receiving a 21-day cycle chemotherapy regimen (excluding chemotherapy cycles of other lengths), and the chemotherapy regimen must be a platinum-based combination regimen, including combination therapy with ≥ 2 chemotherapy drugs or combination therapy with ≥ 1 chemotherapy drug and immunotherapy and / or targeted therapy, etc. 4. Subjects have had chemotherapy delayed by CIT for ≥ 1 week from the scheduled time, and their platelet count during the delay and on the day of enrollment is < 75 x 10 9 / L, 5. ECOG PS score is 0 to 1. 6. The expected survival time is ≥ 12 weeks and the patient can be treated with the current chemotherapy regimen for at least 2 cycles. 7. Female subjects of childbearing potential must have a negative serum pregnancy test within 3 days prior to randomization and must be non-lactating. Female subjects of childbearing age or male subjects whose partners are women of childbearing age must agree to use acceptable contraception during study drug administration and within 30 days after the last dose of study drug. 8. Voluntarily participate in this study, sign the informed consent form, and comply with the study.

[0073] Subjects with any one of the following cannot enroll in this study: 1. Platelet count <30 × 10 9 / L, 2. At the current stage of antitumor treatment, the platelet count before the first chemotherapy is <75 × 10 9 / L, 3. Hematopoietic disorders, including but not limited to leukemia, primary immune thrombocytopenia, myeloproliferative disorders, multiple myeloma, and myelodysplastic syndromes; 4. Other diseases causing thrombocytopenia other than CIT within 6 months prior to randomization, including but not limited to chronic liver disease, hypersplenism, and infection. 5. Bone marrow invasion or bone marrow metastasis of the tumor. 6. Have received radiation therapy in the past, especially to long bones or flat bones (e.g., pelvis, sternum, etc.), or are currently receiving / planning to receive radiation therapy. 7. Serious cardiac clinical symptoms or diseases, such as New York Heart Association (NYHA) grade 3 or higher heart failure, unstable angina, myocardial infarction, and clinically significant supraventricular or ventricular arrhythmias, occurring within 6 months prior to randomization and requiring treatment or intervention. 8. Subjects with a tendency to thrombosis or receiving thrombolytic / anticoagulant therapy. 9. History of arterial or venous thrombotic events within 6 months prior to randomization, including, but not limited to, cerebrovascular accidents (e.g., transient ischemic attack, cerebral infarction), deep vein thrombosis (excluding intermuscular vein thrombosis not requiring treatment), and pulmonary embolism. 10. Clinically significant bleeding episodes within 2 weeks prior to randomization or clear clinical signs of bleeding tendency, e.g., gastrointestinal or central nervous system bleeding. 11. Brain tumor or brain metastasis of tumor. 12. Complications requiring emergency treatment, such as superior vena cava syndrome or spinal cord compression. 13. Absolute neutrophil count (ANC) <1.0 × 10 9 / L, hemoglobin (Hb) <80 g / L (allowing treatment with red blood cell, erythropoietin [EPO], and recombinant human granulocyte colony-stimulating factor [G-CSF] infusions according to clinical routine); 14. Obvious liver function abnormalities: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 3 × ULN (upper limit of normal), total bilirubin (TBIL) > 1.5 × ULN (those with liver metastases can be enrolled if ALT and AST are ≦ 5 × ULN, and TBIL is ≦ 3 × ULN). 15. Renal function abnormalities: blood creatinine ≥ 1.5 × ULN or creatinine clearance (CrCL) ≤ 50 mL / min (Cockcroft-Gault formula), 16. Have received treatment with rhIL-11, rhTPO, or thrombopoietin receptor agonists (e.g., eltrombopag, romiplostim, etc.) within 28 days prior to randomization, have received treatment with other drugs that affect platelet function (e.g., aspirin, caffeic acid tablets, nonsteroidal anti-inflammatory drugs, leucogen tablets, etc.) within 7 days prior to randomization, or have received a platelet transfusion within 3 days prior to randomization. 17. Known or anticipated hypersensitivity or intolerance to the active ingredients or excipients of Hetrombopagethanolamine Tablets; 18. Have a history of testing positive for human immunodeficiency virus (HIV) or are known to have acquired immunodeficiency syndrome (AIDS); 19. Participation in any other clinical study of an investigational drug or device within 28 days prior to randomization; 20. Factors that the investigator determines may affect the results of the study or force the termination of the study, such as alcoholism, drug addiction, substance abuse, or other serious illnesses (including psychiatric disorders) that require concomitant treatment, or serious laboratory abnormalities, and family or social factors that may affect medication safety.

[0074] 3. Dosage method: Hetrombopag ethanolamine tablets / hetrombopag ethanolamine simulant tablets are orally administered once daily on an empty stomach, and can be taken 2 hours after oral administration, so as not to be administered with food.

[0075] Products containing dairy products (e.g., milk, yogurt, cheese, and ice cream) or mineral supplements containing polyvalent cations (e.g., aluminum, calcium, magnesium, iron, selenium, and zinc) should be used at least 2 hours after administration.

[0076] Dose pauses and adjustments are permitted as required by the plan.

[0077] Drug dosage This study is divided into test group 1, test group 2, and test group 3 (control group).

[0078] During the orthodontic treatment period, subjects randomly assigned to study group 1 and study group 2 will be treated with hetrombopag ethanolamine tablets, with a starting dose of 7.5 mg administered orally once daily, and subjects randomly assigned to the control group will be treated with the corresponding dose of hetrombopag ethanolamine sham tablets.

[0079] During the maintenance treatment period, subjects randomly assigned to study group 1 will continue to receive treatment with hetrombopag ethanolamine tablets, while subjects randomly assigned to study group 2 and the control group will receive treatment with the corresponding dose of hetrombopag ethanolamine sham tablets.

[0080] During the extension treatment period, subjects randomly assigned to study group 1 will continue to receive treatment with Hetrombopag ethanolamine tablets, while subjects randomly assigned to study group 2 and the control group will also receive treatment with Hetrombopag ethanolamine tablets, starting at 7.5 mg, administered orally once daily for a maximum of two chemotherapy cycles. Subjects must enter the extension treatment period and begin continuous treatment with the study drug within one natural day after randomization. During the extension treatment period, subjects must achieve a platelet count of ≥ 100 x 10 within 14 days of receiving the study drug. 9 If the platelet count recovers to <100 × 10 / L, chemotherapy must be immediately restarted in the maintenance treatment period using the same combination treatment regimen as before enrollment, and the platelet count must remain <100 × 10 / L 14 days after the subject receives study drug. 9 If the patient is ≥18 years of age and has not yet started the first cycle of chemotherapy, platelet rescue therapy and / or chemotherapy resumption is permitted at the investigator's discretion.

[0081] When subjects enter the maintenance treatment period, they must complete two consecutive cycles of chemotherapy using the same combination treatment plan (including the same dose intensity and administration schedule) as before enrollment (excluding adjustment of the treatment plan for the second cycle by CIT). At the same time, subjects randomly assigned to test group 1 and control group will continue to receive treatment with Hetrombopag ethanolamine tablets or Hetrombopag ethanolamine sham tablets, respectively, while subjects randomly assigned to test group 2 will discontinue treatment with Hetrombopag ethanolamine tablets and switch to continuous oral administration of Hetrombopag ethanolamine sham tablets. Before the second cycle of chemotherapy in the maintenance treatment period, subjects must have a platelet count of ≥ 100 x 10 9 If the patient's platelet count is ≥ 4 days and the second cycle of chemotherapy is delayed due to thrombocytopenia, chemotherapy may be resumed at the investigator's discretion. During the maintenance treatment period, based on the change in the subject's platelet count, the investigator may adjust the study drug dose and / or administer platelet-increasing rescue therapy according to the study drug dose adjustment rules and platelet-increasing rescue therapy rules.

[0082] After the maintenance treatment period, a portion of the subjects may, at the investigator's discretion, enter the extension treatment period and receive up to two cycles of chemotherapy. After entering the extension treatment, subjects randomly assigned to study group 1 will continue to receive treatment with hetrombopagethanolamine tablets, while subjects randomly assigned to study group 2 and the control group will also begin treatment with hetrombopagethanolamine tablets, starting at 7.5 mg, administered orally once daily for up to two chemotherapy cycles. In addition, all subjects entering the extension treatment period will undergo one-on-one blinding. Based on changes in the subject's platelet count, investigators will adjust the study drug dose and / or perform platelet rescue therapy in accordance with the study drug dose adjustment rules and platelet rescue therapy rules.

[0083] Dose adjustment During the study, platelet counts should be monitored regularly, and the dose should be adjusted according to the platelet count status until the lowest dose that maintains platelet response and achieves effective treatment is reached. Before each dose adjustment, it is recommended to maintain the current dose for at least 2 weeks to clarify the relevant therapeutic effect. The specific adjustment rules are as follows: Platelet count <100×10 9 / L, upregulate one dose level in 2.5 mg increments depending on the current dose, not to exceed a maximum of 15 mg / day (if the investigator predicts that the subject's platelet response rate / trend will cause a delay in the next chemotherapy cycle or a reduction in the dose intensity of the chemotherapy drug, then upregulation of one dose level may occur one week after receiving treatment with the current dose); Platelet count ≥ 100 × 10 9 / L and <250×10 9 / L, maintain the current dose. Platelet count ≥ 250 × 10 9 / L and ≦400×10 9 / L, downregulate one dose level in 2.5 mg increments depending on the current dose, Platelet count >400 × 10 9 / L, administration can be temporarily interrupted and platelet counts <250 × 10 9 / L, downregulate and re-administer one dose level in 2.5 mg increments, depending on the dose before discontinuation.

[0084] 4. Clinical endpoints: Primary study endpoint: proportion of subjects with therapeutic benefit.

[0085] A therapeutic response is defined as a subject simultaneously meeting the following criteria after initiating treatment with the study drug: 1. A platelet count of ≥ 100 x 10 within 14 days (including the 14th day) of initiating treatment with the study drug. 9 / L, 2. Able to complete the first chemotherapy cycle (C1) with the same treatment plan as before enrollment, and have a platelet count of ≥ 75 x 10 on C1D21 (window period: +4 days). 9 / L, 3. Not have received platelet rescue therapy (e.g., platelet transfusion, administration of platelet proliferation-promoting drugs including injectable recombinant human interleukin-11 and recombinant human thrombopoietin) from the start of therapy with the study drug until C1D21 (window period: +4 days).

[0086] Key secondary study endpoint: platelet count ≥ 100 x 10 at the start of the first cycle of chemotherapy (C1D1 [window period: -1 day]) 9 The proportion of subjects who simultaneously meet the following conditions, i.e., the proportion of subjects who are effective during the maintenance treatment period: 1. Patients can complete the first chemotherapy cycle (C1) using the same treatment plan as before enrollment, and have a platelet count of ≥ 100 x 10 on C1D21 (window period: +4 days). 9 / L, and at the same time, the second chemotherapy cycle (C2) does not require any adjustment of the treatment plan due to thrombocytopenia (e.g., chemotherapy delay of ≥ 4 days, chemotherapy dose intensity reduction of ≥ 15%, and early termination of chemotherapy, etc.); 2. Not have received platelet rescue therapy (e.g., platelet transfusion, administration of platelet proliferation-promoting drugs including injectable recombinant human thrombopoietin and recombinant human interleukin-11) from the start of therapy with the study drug until C1D21 (window period: +4 days) period.

[0087] Secondary Efficacy Study Endpoints: 1. Initial platelet count ≥ 100 x 10 after treatment with study drug 9 Time to reach / L, 2. Platelet count ≥ 100 x 10 within 14 days after treatment with the study drug 9 / L, 3. The proportion of subjects who start the first cycle (C1) of chemotherapy within 14 days after treatment with the study drug, 4. Able to complete the first chemotherapy cycle (C1) using the same treatment regimen as before enrollment, with a platelet count of ≥ 75 x 10 on C1D21 (window period: +4 days). 9 / L, 5. Able to complete the first chemotherapy cycle (C1) using the same treatment regimen as before enrollment, with a platelet count of ≥ 100 x 10 on C1D21 (window period: +4 days). 9 / L, 6. The proportion of subjects who are able to complete two consecutive chemotherapy cycles (C1, C2) using the same treatment regimen as before enrollment, without any adjustment of the treatment regimen due to thrombocytopenia (e.g., chemotherapy delay of ≥ 4 days, chemotherapy dose intensity reduction of ≥ 15%, and early termination of chemotherapy), 7. Able to complete two consecutive chemotherapy cycles (C1, C2) using the same treatment regimen as before enrollment, with a platelet count of ≥ 75 × 10 on C2D21 (window period: +4 days). 9 / L, 8. The proportion of subjects who received at least one scheduled platelet rescue therapy after initiating treatment with the study drug, 9. Subject's platelet count at each time point visit after initiation of treatment with study medication.

Claims

1. Use of hetrombopag or a pharmaceutical salt thereof in the preparation of a medicament for treating thrombocytopenia caused by tumor chemotherapy, wherein the hetrombopag or a pharmaceutical salt thereof is a unit dose formulation containing 7.5 mg of hetrombopag. use.

2. Patients with thrombocytopenia due to oncology chemotherapy had a platelet count <75 × 10 ９ / L, 2. The use according to claim 1.

3. Patients with thrombocytopenia due to cancer chemotherapy were those whose chemotherapy was delayed by ≥1 week due to thrombocytopenia and whose platelet count was <75×10 ９ / L, 3. Use according to claim 1 or 2.

4. After administering hetrombopag or its medicinal salts to the patient, the patient's platelet count is 100 x 10 ９ / L or more and 250 x 10 ９ If the dose is less than 1 / L, administer the original dose. Use according to any one of claims 1 to 3.

5. After administering hetrombopag or its medicinal salt to the patient, the patient's platelet count increased to 400 x 10 ９ If platelets are greater than 250 × 10 / L, administration should be temporarily interrupted. ９ If the blood glucose level drops to 1.5 mg / L, administration will be resumed and the daily dose will be reduced by 2.5 mg. If the lowest dose used at this time is 2.5 mg / day, administration will continue to be discontinued. Use according to any one of claims 1 to 3.

6. After administering hetrombopag or its medicinal salts to the patient, the patient's platelet count increased to 250 x 10 ９ / L and 400 × 10 ９ / L or less, reduce the daily dose by 2.5 mg; Use according to any one of claims 1 to 3.

7. After the patient receives hetrombopag or its medicinal salts, the patient's platelet count is <100 x 10 ９ / L, increase the daily dose by 2.5 mg to a maximum of 15 mg / day; Use according to any one of claims 1 to 3.

8. The dosage of hetrombopag or its pharmaceutical salts is adjusted according to the platelet count, and if the patient's platelet response rate / trend is predicted to cause a delay or reduction in the next cycle of chemotherapy, the dose is upregulated one week after administration. Use according to any one of claims 1 to 7.

9. The use is therapeutically effective for a period of treatment. Use according to any one of claims 1 to 8.

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