Application of Hytrambopag or medicinal salt thereof in treatment of thrombocytopenia caused by tumor chemotherapy

Abstract

The invention relates to application of hitrombopag or medicinal salt thereof to treatment of thrombocytopenia caused by tumor chemotherapy. In particular, the present disclosure relates to a method of treatment of a disease comprising administering to a patient hitrombopag, or a pharmaceutically acceptable salt thereof, which can significantly increase platelet count in the subject.

Description

Use of hetromopag or its pharmaceutically acceptable salt in treating thrombocytopenia caused by tumor chemotherapy

[0001] This application claims priority to Chinese Patent Application No. 2022113138298 filed on October 25, 2022, and Chinese Patent Application No. 2023102887574 filed on March 22, 2023. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present disclosure relates to the use of hetromopag or a pharmaceutically acceptable salt thereof in treating thrombocytopenia caused by chemotherapy for malignant tumors. Background Art

[0003] Thrombocytopenia is characterized by a subnormal platelet count in peripheral blood, resulting in varying degrees of bleeding or bleeding risk. Severe thrombocytopenia is associated with a higher mortality rate. Thrombocytopenia can be categorized by etiology as decreased platelet production (e.g., leukemia, bone metastasis of malignant tumors, chemotherapy drugs, radiation, aplastic anemia, megaloblastic anemia), increased platelet destruction or consumption (including immune destruction such as immune thrombocytopenia [ITP] and systemic lupus erythematosus, and non-immune destruction such as thrombotic thrombocytopenic purpura and vasculitis), abnormal platelet distribution (e.g., splenomegaly due to various causes), and platelet loss (e.g., bleeding, hemodialysis). Chemotherapy-induced thrombocytopenia (CIT) is a common, dose-limiting toxicity of chemotherapy drugs. It results from the inhibitory effect of anticancer chemotherapy on the bone marrow, particularly megakaryocytes, leading to insufficient platelet production and excessive destruction, resulting in a low platelet count in peripheral blood (<100 × 109 / L). The timing of the platelet nadir and the magnitude of the platelet decline in CIT are related to the chemotherapy drug used, its dose, the presence of combined medications, individual patient variability, and the number of chemotherapy cycles. The incidence of CIT ranges from approximately 10% to 36% in solid tumors and as high as 75% in hematologic malignancies. Direct consequences of CIT include bleeding, such as mucocutaneous bleeding, epistaxis, gingival bleeding, hemoptysis, hematemesis, hematuria, increased menstrual flow, and intracerebral hemorrhage in women. Indirect consequences of CIT include increased platelet transfusion requirements, reduced chemotherapy doses, delayed chemotherapy, and even discontinuation of treatment, which can impact the progress and efficacy of chemotherapy and even increase mortality. It also prolongs hospitalization, increases medical costs, and compromises long-term clinical outcomes. Severe thrombocytopenia is associated with poor clinical outcomes, including increased bleeding risk and increased mortality.

[0004] Chemotherapy regimens containing platinum agents and gemcitabine (used to treat lung, bladder, ovarian, cervical, and gastrointestinal cancers) are prone to CIT, particularly grade 3 / 4 CIT. CIT typically manifests as a decrease in platelets starting 3-7 days after chemotherapy, reaching a nadir on day 14, then slowly rising, returning to baseline levels between days 28-35. The incidence of CIT increases with the number of chemotherapy cycles. A large-scale epidemiological survey of outpatient cancer patients in the United States, conducted over a seven-year period (2000-2007) and including evaluable platelet counts, found that 11.1% of patients had thrombocytopenia at baseline. The incidence of thrombocytopenia after initial chemotherapy varied by regimen: 64.2% for gemcitabine-based regimens, 55.4% for platinum-based regimens, 37.8% for anthracycline-based regimens, and 21.9% for paclitaxel-based regimens. The incidence of grade 3 / 4 thrombocytopenia was 11.2% with gemcitabine-based regimens, 10.6% with platinum-based regimens, 5.2% with anthracycline-based regimens, and 1.9% with paclitaxel-based regimens. Among various cancer types, the incidence of thrombocytopenia was 61.7% in colorectal cancer, 50.5% in NSCLC, 45.6% in ovarian cancer, and 37.6% in breast cancer. The highest incidence of grade 3 / 4 thrombocytopenia was in NSCLC, at 10.7%. Among all patients undergoing chemotherapy for cancer, the platelet transfusion rate was 2.5%, and the chemotherapy delay rate was 22.7%, with a mean delay of 17 days. Elias et al. also reported that 48% of patients with advanced sarcomas treated with doxorubicin, ifosfamide, and dacarbazine experienced grade 3 / 4 thrombocytopenia. Over 50% of patients with NSCLC treated with carboplatin, ifosfamide, and etoposide experienced CIT. The incidence of CIT in patients with ovarian cancer treated with paclitaxel, ifosfamide, and cisplatin is 24%-33%.

[0005] Currently, there is no oral platelet-stimulating drug in clinical practice that can quickly increase platelet counts and is safe and effective while maintaining the relative dose intensity of chemotherapy.

[0006] Summary of the Invention

[0007] The present disclosure provides a use of hetromopag or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating thrombocytopenia induced by tumor chemotherapy, wherein the hetromopag or a pharmaceutically acceptable salt thereof is a unit dose preparation containing 7.5 mg of hetromopag.

[0008] In some embodiments, the platelet count of a patient with thrombocytopenia caused by cancer chemotherapy is less than 75×10 9 / L.

[0009] In some embodiments, patients with thrombocytopenia caused by tumor chemotherapy are those whose chemotherapy is delayed by ≥1 week than expected due to thrombocytopenia and whose platelet count is <75×10 9 / L.

[0010] In some embodiments, the chemotherapy regimen for patients with thrombocytopenia induced by tumor chemotherapy is a combination therapy regimen containing platinum drugs, and the platinum drugs include but are not limited to carboplatin, nedaplatin, cisplatin, lobaplatin, oxaliplatin, and the like.

[0011] On the other hand, in some embodiments, after administering hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than or equal to 100×10 9 / L and less than 200×10 9 / L, maintain the original dose.

[0012] In some embodiments, after 14 days of administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than or equal to 100×10 9 / L and less than 200×10 9 / L, maintain the original dose.

[0013] In other embodiments, after administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 400×10 9 / L, suspend the drug and wait until the platelet count drops to <200×10 9 / L resume administration, reducing the daily dose by 2.5 mg. If the lowest dose used at this time is 2.5 mg / day, continue to withhold administration.

[0014] In some embodiments, 14 days after administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 400×10 9 / L, suspend the drug and wait until the platelet count drops to <200×10 9 / L resume administration, reducing the daily dose by 2.5 mg. If the lowest dose used at this time is 2.5 mg / day, continue to withhold administration.

[0015] In other embodiments, after administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 200×10 9 / L and less than or equal to 400×10 9 / L, reduce the daily dose by 2.5 mg.

[0016] In some embodiments, after 14 days of administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 200×10 9 / L and less than or equal to 400×10 9 / L, reduce the daily dose by 2.5 mg.

[0017] On the other hand, in some embodiments, after administering hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than or equal to 100×10 9 / L and less than 250×10 9 / L, maintain the original dose.

[0018] In some embodiments, after 14 days of administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than or equal to 100×10 9 / L and less than 250×10 9 / L, maintain the original dose.

[0019] In other embodiments, after administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 400×10 9 / L, suspend the drug and wait until the platelet count drops to <250×10 9 / L resume administration, reducing the daily dose by 2.5 mg. If the lowest dose used at this time is 2.5 mg / day, continue to withhold administration.

[0020] In some embodiments, 14 days after administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 400×10 9 / L, suspend the drug and wait until the platelet count drops to <250×10 9 / L resume administration, reducing the daily dose by 2.5 mg. If the lowest dose used at this time is 2.5 mg / day, continue to withhold administration.

[0021] In other embodiments, after administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 250×10 9 / L and less than or equal to 400×10 9 / L, reduce the daily dose by 2.5 mg.

[0022] In some embodiments, after 14 days of administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 250×10 9 / L and less than or equal to 400×10 9 / L, the daily dose is reduced by 2.5 mg. In some embodiments, after administering hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is less than <100×10 9 / L, the daily dose is increased by 2.5 mg, up to a maximum of 15 mg / day.

[0023] In some embodiments, after 14 days of administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is less than 100×10 9 / L, the daily dose is increased by 2.5 mg, up to a maximum of 15 mg / day.

[0024] The present disclosure also provides a method for treating thrombocytopenia induced by tumor chemotherapy, comprising administering a therapeutically effective amount of hetromopag or a pharmaceutically acceptable salt thereof to a patient.

[0025] The present disclosure also provides a method for treating thrombocytopenia caused by tumor chemotherapy by using hetromopag or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the starting dose of hetromopag or a pharmaceutically acceptable salt thereof is 2.5-10.0 mg, preferably 2.5 mg, 3.75 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg.

[0027] In some embodiments, the starting dose of hetromopag or a pharmaceutically acceptable salt thereof is 7.5 mg.

[0028] In some embodiments, the dosage of hetromopag or its pharmaceutically acceptable salt in the method for treating thrombocytopenia induced by tumor chemotherapy is 7.5 mg.

[0029] In some embodiments, the platelet count of a patient with thrombocytopenia caused by cancer chemotherapy is less than 75×10 9 / L.

[0030] In some embodiments, patients with thrombocytopenia caused by tumor chemotherapy are those whose chemotherapy is delayed by ≥1 week than expected due to thrombocytopenia and whose platelet count is <75×10 9 / L.

[0031] In some embodiments, hetromopag or a pharmaceutically acceptable salt thereof is present in a unit dosage formulation.

[0032] In other embodiments, the unit dose formulation contains at least 2.5 mg of haloperidol. In other embodiments, the unit dose formulation contains at least 3.75 mg of haloperidol. In some embodiments, the unit dose formulation contains 5 mg of haloperidol. In some embodiments, the unit dose formulation contains 7.5 mg of haloperidol.

[0033] In some embodiments, the methods or uses described herein require regular monitoring of platelet counts during implementation, and dosage adjustments should be made based on platelet counts until the lowest dose that maintains platelet response and achieves effective treatment is reached. Before each dose adjustment, it is recommended that the current dose be maintained for at least one or two weeks to determine its efficacy.

[0034] In some embodiments, the methods of the present disclosure comprise administering hetromopag or a pharmaceutically acceptable salt thereof to a patient for at least 14 days and then adjusting the dose based on the patient's platelet count.

[0035] In other embodiments, the methods of the present disclosure comprise administering hetromopag or a pharmaceutically acceptable salt thereof to a patient for at least 7 days and then adjusting the dose based on the patient's platelet count.

[0036] In some embodiments, after administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 400×10 9 / L, suspend the drug and wait until the platelet count drops to <200×10 9 / L resumes administration, reducing the daily dose by 2.5 mg. If the lowest dose used at this time is 2.5 mg / day, continues to stop administration; preferably, at least 14 days after administering hetromopa or a pharmaceutically acceptable salt thereof to the patient.

[0037] In some embodiments, after administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 200×10 9 / L and less than or equal to 400×10 9 / L, the daily dose is reduced by 2.5 mg; preferably after administering hetromopa or a pharmaceutically acceptable salt thereof to the patient for at least 14 days.

[0038] In some embodiments, after administering hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than or equal to 100×10 9 / L and less than 200×10 9 / L, maintain the original dose.

[0039] In other embodiments, after administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 400×10 9 / L, suspend the drug and wait until the platelet count drops to <250×10 9 / L resumes administration, reducing the daily dose by 2.5 mg. If the lowest dose used at this time is 2.5 mg / day, continues to stop administration; preferably, at least 14 days after administering hetromopa or a pharmaceutically acceptable salt thereof to the patient.

[0040] In other embodiments, after administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than 250×10 9 / L and less than or equal to 400×10 9 / L, the daily dose is reduced by 2.5 mg; preferably after administering hetromopa or a pharmaceutically acceptable salt thereof to the patient for at least 14 days.

[0041] In other embodiments, after administration of hetromopa or a pharmaceutically acceptable salt thereof to a patient, the patient's platelet count is greater than or equal to 100×10 9 / L and less than 250×10 9 / L, maintain the original dose. In some embodiments, after administering hetromopa or its pharmaceutically acceptable salt to the patient, the patient's platelet count is less than <100×10 9 / L, the daily dose is increased by 2.5 mg, up to 15 mg / day; preferably after administering hetromopa or a pharmaceutically acceptable salt thereof to the patient for at least 7 days.

[0042] In some embodiments, after administering hetromopag or a pharmaceutically acceptable salt thereof to a patient, if the patient's platelet response rate / trend is expected to result in a delay or reduction in the next cycle of chemotherapy, the dose is adjusted upward after 1 week of administration.

[0043] On the other hand, the patient described in the present disclosure does not suffer from other hematopoietic diseases except tumor chemotherapy drug-induced thrombocytopenia (CIT).

[0044] In some embodiments, the other hematopoietic disorder is selected from, but not limited to, leukemia, primary immune thrombocytopenia, myeloproliferative disorders, multiple myeloma, and myelodysplastic syndrome.

[0045] In some embodiments, the method is therapeutically effective during the treatment period.

[0046] The present disclosure relates to unit dose formulations including, generally, pharmaceutically acceptable excipients, selected from, but not limited to, microcrystalline cellulose, lactose, low-substituted hydroxypropyl cellulose, or magnesium stearate.

[0047] The tumors disclosed herein include, but are not limited to, lung cancer (small cell or non-small cell), breast cancer, and bladder cancer.

[0048] The "treatment period" described in this disclosure is generally defined as two consecutive chemotherapy cycles. The chemotherapy cycle is formulated based on the drug half-life and tumor doubling time, and the chemotherapy cycle can be adjusted according to different chemotherapy drugs.

[0049] In some embodiments, the chemotherapy cycle described herein is 21 days.

[0050] The term "effective treatment" as used herein is defined as the subject meeting one or both of the following conditions during the treatment period (two consecutive chemotherapy cycles):

[0051] 1. Able to resume chemotherapy in this cycle 14 days after starting trial drug treatment and platelet count ≥ 100×10 9 / L; or the platelet count can be ≥100×10 within 14 days (including 14 days) after starting the study drug treatment. 9 / L;

[0052] 2. Able to complete two cycles of chemotherapy without chemotherapy regimen adjustment due to thrombocytopenia (e.g., chemotherapy delay ≥4 days, and / or chemotherapy dose reduction ≥15%, chemotherapy termination, etc.);

[0053] 3. Able to complete the first chemotherapy cycle C1) using the same treatment regimen as before enrollment, and the platelet count is ≥75×10 on C1D21 (window period: +4 days) 9 / L;

[0054] 4. No platelet rescue therapy (platelet transfusion, interleukin-11, recombinant human thrombopoietin) was used during the treatment period.

[0055] The hetromopa described in the present disclosure is a compound structure shown in Formula I

[0056] The pharmaceutically acceptable salt of hetromopag described in the present disclosure can be a sodium salt, a lithium salt, a potassium salt, a calcium salt, a magnesium salt, an arginine salt, a lysine salt, a methylamine salt, a dimethylamine salt, a trimethylamine salt, an ethylamine salt, a diethylamine salt, a triethylamine salt, an ethanolamine salt, a piperazine salt, a dibenzylethylenediamine salt, meglumine, a tromethamine salt, a tetramethyl quaternary ammonium salt, a tetraethyl quaternary ammonium salt or a choline salt, preferably a diethylamine salt, an ethanolamine salt, a choline salt, a piperazine salt, a meglumine salt or a tromethamine salt, more preferably an ethanolamine salt, and most preferably a diethanolamine salt.

[0057] The “persistent thrombocytopenia caused by tumor chemotherapy” mentioned in this disclosure is defined as chemotherapy delayed by ≥1 week from the expected time due to thrombocytopenia, and the platelet count is less than 75×10 9 / L.

[0058] In some embodiments, the administration frequency of hetromopag or its pharmaceutically acceptable salt is once a day, once a day, twice a day, or three times a day.

[0059] According to the relevant research data disclosed in this disclosure, hetromopa or its pharmaceutically acceptable salt has outstanding efficacy in treating thrombocytopenia caused by continuous tumor chemotherapy, significantly increasing the proportion of subjects with effective treatment, and is safe and controllable. The further development and application of this drug is expected to greatly change the current treatment status of thrombocytopenia caused by tumor chemotherapy. DETAILED DESCRIPTION

[0060] The present disclosure is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present disclosure.

[0061] Example 1: Study on the efficacy and safety of hetrombopag ethanolamine tablets in the treatment of thrombocytopenia induced by chemotherapy for malignant tumors

[0062] 1. Study Drug

[0063] Experimental drug: Hetrombopag tablets, 2.5 mg / tablet, produced and provided by Jiangsu Hengrui Medicine Co., Ltd.

[0064] Control drug: Hetrombopag dummy tablets (placebo), 2.5 mg / tablet, which are exactly the same as Hetrombopag tablets in shape, color and weight, and are produced and provided by Jiangsu Hengrui Medicine Co., Ltd.

[0065] 2. Inclusion criteria

[0066] Patients must meet all of the following inclusion criteria to be enrolled in this study:

[0067] 1. Aged 18 to 75 (inclusive), regardless of gender;

[0068] 2. Malignant tumors confirmed by histopathological or cytological examination, including lung cancer (small cell or non-small cell), breast cancer, bladder cancer, etc.;

[0069] 3. The subject is currently receiving a 21-day chemotherapy regimen (excluding chemotherapy cycles of other lengths) and requires the use of one or more chemotherapy drugs, such as:

[0070] Antimetabolites, including gemcitabine;

[0071] Platinum drugs, including carboplatin, nedaplatin, cisplatin, lobaplatin, etc.

[0072] Anthracyclines, including doxorubicin, daunorubicin, and epirubicin;

[0073] Alkylating agents, including cyclophosphamide and ifosfamide;

[0074] 4. The subject's chemotherapy is delayed by ≥1 week due to thrombocytopenia, and the platelet count is still <75×10 9 / L;

[0075] 5. Physical status ECOG score of 0-1;

[0076] 6. The estimated survival time at screening is ≥12 weeks, and the patient can receive the current chemotherapy regimen for at least 2 cycles;

[0077] 7. Subjects of childbearing age agree to take reliable contraceptive measures (including male or female condoms, contraceptive foam, contraceptive gel, contraceptive diaphragm, contraceptive cream, contraceptive suppository, abstinence, and placement of intrauterine contraceptive device, etc.) throughout the study period; female subjects who have undergone hysterectomy, bilateral salpingectomy, bilateral tubal ligation, or who are postmenopausal for more than 1 year, and male subjects who have undergone bilateral vasectomy or ligation, are excluded;

[0078] 8. Voluntarily join this study, sign the informed consent form, and have good compliance.

[0079] Patients with any of the following conditions are not eligible for this study:

[0080] 1. Screening or baseline platelet count <30×10 9 / L;

[0081] 2. Platelet count <75×10 before the first chemotherapy 9 / L;

[0082] 3. Suffering from other hematopoietic diseases other than thrombocytopenia induced by tumor chemotherapy drugs (CIT), including but not limited to leukemia, primary immune thrombocytopenia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome;

[0083] 4. Thrombocytopenia caused by causes other than CIT within 6 months before screening, including but not limited to chronic liver disease, hypersplenism, infection, and bleeding;

[0084] 5. Bone marrow invasion or bone marrow metastasis;

[0085] 6. Patients who have received pelvic, spinal radiotherapy and large-field bone irradiation within 3 months before screening, or are currently receiving / expected to receive radiotherapy;

[0086] 7. History of severe cardiovascular disease within 6 months before screening, such as congestive heart failure (NYHA heart function score III-IV), arrhythmias known to increase the risk of thromboembolism such as atrial fibrillation, coronary artery stent implantation, angioplasty, and coronary artery bypass grafting;

[0087] 8. Any history of arterial or venous thrombosis within 6 months before screening;

[0088] 9. Severe bleeding clinical manifestations within 2 weeks before screening, such as gastrointestinal or central nervous system bleeding;

[0089] 10. Brain tumor or brain metastasis;

[0090] 11. Emergency treatment is required, such as superior vena cava syndrome and spinal cord compression;

[0091] 12. Neutrophil absolute value <1.0×10 9 / L, hemoglobin <80g / L, granulocyte colony-stimulating factor, red blood cell, and EPO infusion therapy in accordance with clinical routine are allowed;

[0092] 13. Significantly abnormal liver function: For patients without liver metastasis, ALT / AST>3ULN (upper limit of normal), TBIL>3ULN; for patients with liver metastasis, ALT / AST≥5ULN, TBIL≥5ULN;

[0093] 14. Abnormal renal function: serum creatinine ≥1.5ULN or eGFR ≤60ml / min (Cockcroft-Gault formula);

[0094] 15. Patients who have received thrombopoietin receptor agonist drugs (such as eltrombopag, romiplostim), or human recombinant thrombopoietin (rhTPO), or recombinant human interleukin-11 (rhIL-11) treatment within 1 month before screening;

[0095] 16. Received platelet transfusion within 3 days before randomization / first dose;

[0096] 17. Patients with known or anticipated allergy or intolerance to the active ingredients or excipients of hetromopar tablets (including cellulose-lactose, low-substituted hydroxypropyl cellulose, and magnesium stearate);

[0097] 18. HIV-infected persons;

[0098] 19. Pregnant or breastfeeding women;

[0099] 20. Participated in any other clinical study of research drugs or devices within 3 months before screening;

[0100] 21. The researcher believes that participation in the trial poses a significant risk to the health or safety of the subjects, or there are other circumstances that may affect the evaluation of efficacy.

[0101] 3. Dosage method:

[0102] The stratified block randomization method was used, and the baseline platelet count (≥50×10 9 / L vs<50×10 9 The patients were stratified by blood pressure (> 400 mg / L) and randomly assigned to the experimental group (7.5 mg hetrombopag tablets) or the placebo group (hetrombopag sham tablets) in a 1:1 ratio to receive corresponding treatment.

[0103] Drug dosage:

[0104] During the treatment phase, subjects randomly assigned to the experimental group will receive hetrombopag ethanolamine tablets at a starting dose of 7.5 mg once daily. After 14 days, the dose can be adjusted based on the subject's platelet response or at the investigator's discretion. The oral administration will continue until two chemotherapy cycles are completed. Subjects randomly assigned to the control group will receive the corresponding placebo tablets. During the optional extension phase, the hetrombopag group can continue treatment, while the placebo group will receive hetrombopag ethanolamine tablets at a starting dose of 7.5 mg once daily. The dose can be adjusted based on the investigator's discretion during treatment for a maximum of four chemotherapy cycles.

[0105] During the optional extension period, the haloperidol group could continue to receive treatment, and the placebo group received haloperidol ethanolamine tablets, with a starting dose of 7.5 mg once a day. During treatment, the drug dose could be adjusted according to the investigator's judgment, with a maximum duration of 4 chemotherapy cycles.

[0106] Drug usage:

[0107] Take orally once a day on an empty stomach. Eat 2 hours after taking the medicine. Avoid taking the medicine with meals.

[0108] The following products should be consumed at least 2 hours after taking medication, including dairy products (such as milk, yogurt, cheese, and ice cream) or mineral supplements containing multivalent cations (such as aluminum, calcium, magnesium, iron, selenium, and zinc).

[0109] Medication adjustments

[0110] It is recommended to maintain each dose adjustment for 2 weeks to observe its effect. The adjustment rules are as follows:

[0111] ·When platelets<100×10 9 / L, the daily dose is increased by 2.5 mg, up to a maximum of 15 mg / day;

[0112] ·When platelets ≥200×10 9 / L and ≤400×10 9 / L, the daily dose was reduced by 2.5 mg;

[0113] ·When platelets>400×10 9 / L, the drug can be suspended and the platelet count can be reduced to <200×10 9 / L resumes administration, reducing the daily dose by 2.5 mg; if the lowest dose of 2.5 mg / day is being used at this time, administration can be stopped;

[0114] If the investigator anticipates that the subject's platelet response rate / trend will result in a delay or dose reduction in the next cycle of chemotherapy, the dose may be increased after one week of treatment.

[0115] 4. Clinical endpoints:

[0116] Primary study endpoint:

[0117] The primary endpoint was the proportion of subjects with effective treatment, which was defined as meeting the following conditions simultaneously during the treatment period (two consecutive chemotherapy cycles):

[0118] 1. Able to resume chemotherapy in this cycle 14 days after starting trial drug treatment and platelet count ≥ 100×10 9 / L;

[0119] 2. Able to complete two cycles of chemotherapy without chemotherapy regimen adjustment due to thrombocytopenia (e.g., chemotherapy delay ≥4 days, and / or chemotherapy dose reduction ≥15%, chemotherapy termination, etc.);

[0120] 3. No platelet rescue therapy (platelet transfusion, interleukin-11, recombinant human thrombopoietin) was used during the treatment period.

[0121] 5. Research results:

[0122] During the study, 60 patients were enrolled, 59 of whom received at least one dose of study drug and were randomly assigned to either the experimental group (n=28) or the placebo group (n=31). Seventeen patients in the experimental group (17 / 28 [60.7%, 95% CI 40.6-78.5]) achieved the primary endpoint, compared with four patients in the placebo group (4 / 31 [12.9%, 95% CI 3.6-29.8]), with an OR of 10.44 [95% CI 2.82-38.65]; p=0.0001, indicating a significant increase in patients in the experimental group achieving the primary endpoint.

[0123] The incidence of adverse events was comparable between the trial and placebo groups, and no treatment-related adverse events of grade 3 or higher or treatment-related serious adverse events were observed in the trial group.

[0124] Example 2: Study on the efficacy and safety of hetrombopag ethanolamine tablets in the treatment of thrombocytopenia induced by tumor chemotherapy

[0125] 1. Study Drug

[0126] Experimental drug: Hetrombopag tablets, 2.5 mg / tablet, produced and provided by Jiangsu Hengrui Medicine Co., Ltd.

[0127] Control drug: Hetrombopag dummy tablets (placebo), 2.5 mg / tablet, which are exactly the same as Hetrombopag tablets in shape, color and weight, and are produced and provided by Jiangsu Hengrui Medicine Co., Ltd.

[0128] 2. Inclusion criteria

[0129] Subjects must meet all of the following conditions to be included in this study.

[0130] 1. Aged 18-75 (inclusive), regardless of gender;

[0131] 2. Malignant tumors confirmed 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.;

[0132] 3. The subject is currently receiving chemotherapy with a 21-day cycle (excluding chemotherapy cycles of other lengths). The chemotherapy regimen must be a platinum-containing combination therapy, including combination therapy of ≥2 chemotherapy drugs or ≥1 chemotherapy drug combined with immunotherapy and / or targeted therapy;

[0133] 4. The subject's chemotherapy is delayed by ≥1 week due to CIT, and the platelet count during the delay and on the day of enrollment is <75×10 9 / L;

[0134] 5. ECOG PS score of 0-1;

[0135] 6. Patients are expected to survive ≥12 weeks and can receive at least 2 cycles of current chemotherapy;

[0136] 7. Female subjects of childbearing potential must undergo a serum pregnancy test within 3 days before randomization, and the result must be negative; and they must not be breastfeeding. Female subjects of childbearing age or male subjects whose partners are women of childbearing age must agree to take acceptable contraceptive measures during the administration of the study drug and within 30 days after the last administration of the study drug;

[0137] 8. Voluntarily join this study, sign the informed consent form, and have good compliance.

[0138] Subjects with any of the following conditions are not eligible for inclusion in this study:

[0139] 1. Platelet count <30 × 10 9 / L;

[0140] 2. Current stage of anti-tumor treatment, platelet count <75×10 9 / L;

[0141] 3. Patients with hematopoietic system diseases, including but not limited to leukemia, primary immune thrombocytopenia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome;

[0142] 4. Other diseases causing thrombocytopenia other than CIT occurred within 6 months before randomization, including but not limited to chronic liver disease, hypersplenism, and infection;

[0143] 5. Tumor bone marrow invasion or bone marrow metastasis;

[0144] 6. Patients who have received radiotherapy in the past, especially to long bones or flat bones (such as the pelvis and sternum), or are currently receiving or are expected to receive radiotherapy;

[0145] 7. Severe cardiac clinical symptoms or diseases occurred within 6 months before randomization, such as New York Heart Association (NYHA) grade 3 or above heart failure, unstable angina, myocardial infarction, and clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention;

[0146] 8. Those with thrombotic tendencies or currently receiving thrombolytic / anticoagulant therapy;

[0147] 9. Arterial or venous thrombotic events occurred within 6 months before randomization, including but not limited to cerebrovascular accident (such as transient ischemic attack, cerebral infarction), deep vein thrombosis (except intermuscular vein thrombosis that does not require treatment) and pulmonary embolism;

[0148] 10. Significant clinical bleeding symptoms or clear clinical manifestations of bleeding tendency, such as gastrointestinal or central nervous system bleeding, occur within 2 weeks before randomization;

[0149] 11. Brain tumor or brain metastasis;

[0150] 12. Accompanied by complications requiring emergency treatment, such as superior vena cava syndrome, spinal cord compression, etc.;

[0151] 13. Absolute neutrophil count (ANC) <1.0×10 9 / L, hemoglobin (Hb) <80g / L (red blood cells, erythropoietin [EPO], and recombinant human granulocyte colony-stimulating factor [G-CSF] transfusion therapy in accordance with clinical routine is allowed);

[0152] 14. Significantly abnormal liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 3×ULN (upper limit of normal), total bilirubin (TBIL) > 1.5×ULN (patients with liver metastasis, ALT and AST ≤ 5×ULN, TBIL ≤ 3×ULN are allowed to enroll);

[0153] 15. Abnormal renal function: serum creatinine (Cr) ≥ 1.5 × ULN or creatinine clearance (CrCL) ≤ 50 ml / min (Cockcroft-Gault formula);

[0154] 16. Patients who have received rhIL-11, rhTPO, or thrombopoietin receptor agonists (e.g., eltrombopag, romiplostim, etc.) within 28 days before randomization; received other drugs that affect platelet function (e.g., aspirin, caffeic acid tablets, nonsteroidal anti-inflammatory drugs, levofloxacin tablets, etc.) within 7 days before randomization; received platelet transfusion within 3 days before randomization;

[0155] 17. Known or anticipated allergy or intolerance to the active ingredients or excipients of Hetrombopag Tablets;

[0156] 18. Known history of positive human immunodeficiency virus (HIV) test or acquired immunodeficiency syndrome (AIDS);

[0157] 19. Participated in any other clinical study of research drugs or devices within 28 days before randomization;

[0158] 20. The researcher judges that there are other factors that may affect the study results or force the termination of this study, such as alcoholism, drug abuse, substance abuse, other serious diseases (including mental illness) that require combined treatment; or serious laboratory abnormalities, and family or social factors that may affect the safety of medication.

[0159] 3. Dosage method:

[0160] Take Hetrombopag tablets / Hetromopag analog tablets once a day on an empty stomach. Eat 2 hours after taking the tablets and avoid taking the tablets with meals.

[0161] The following products should be consumed at least 2 hours after taking medication, including dairy products (such as milk, yogurt, cheese, and ice cream) or mineral supplements containing multivalent cations (such as aluminum, calcium, magnesium, iron, selenium, and zinc).

[0162] Dose interruptions and adjustments were allowed as per protocol.

[0163] Drug dosage

[0164] This experiment was divided into experimental group 1, experimental group 2 and experimental group 3 (control group).

[0165] During the correction period, subjects randomly assigned to trial groups 1 and 2 will receive hetrombopag tablets at a starting dose of 7.5 mg once daily for continuous oral administration; while subjects randomly assigned to the control group will receive the corresponding dose of hetrombopag sham tablets.

[0166] During the maintenance treatment period, subjects randomly assigned to trial group 1 will continue to receive hetrombopag tablets; while subjects randomly assigned to trial group 2 and the control group will receive corresponding doses of hetrombopag sham tablets.

[0167] During the extended treatment period, subjects randomly assigned to trial group 1 will continue to receive hetrombopag tablets; subjects randomly assigned to trial group 2 and the control group will also receive hetrombopag tablets, with a starting dose of 7.5 mg, once a day, orally for up to 2 chemotherapy cycles. Subjects must enter the correction treatment period within 1 natural day after randomization and begin continuous treatment with the study drug. During the correction treatment period, if the subject's platelet count recovers to ≥100×10 within 14 days of receiving the study drug, 9 / L must use the same combination therapy as before enrollment to enter the maintenance treatment period and resume chemotherapy in time; if the platelet count of the subject is still <100×10 9 Patients with platelet-raising leukemia / L who have not started the first cycle of chemotherapy are allowed to receive platelet-raising rescue therapy and / or resume chemotherapy at the discretion of the investigator.

[0168] After the subjects enter the maintenance treatment period, they must complete 2 consecutive cycles of chemotherapy using the same combination therapy (including the same dose intensity and administration schedule, etc.) as before enrollment (except for adjustments to the second cycle treatment schedule due to CIT). At the same time, the subjects randomly assigned to the experimental group 1 and the control group will continue to receive treatment with haloperidol tablets or haloperidol simulating tablets, respectively; while the subjects randomly assigned to the experimental group 2 will stop receiving haloperidol tablets and switch to continuous oral haloperidol simulating tablets. Before the second cycle of chemotherapy during the maintenance treatment period, the platelet count of the subjects must be ≥100×10 9 / L; if the second cycle of chemotherapy is delayed for ≥4 days due to thrombocytopenia, chemotherapy may be resumed at the investigator's discretion. During the maintenance treatment period, the investigator will adjust the study drug dose and / or administer platelet-raising rescue therapy based on changes in the subject's platelet count in accordance with the study drug dose adjustment rules and platelet-raising rescue therapy rules.

[0169] After the maintenance treatment period, some subjects may enter an extended treatment period at the investigator's discretion, receiving up to two cycles of chemotherapy. Subjects randomized to trial group 1 will continue to receive hetrombopag tablets, while subjects randomized to trial group 2 and the control group will also begin hetrombopag tablets, starting at a dose of 7.5 mg once daily for up to two cycles of chemotherapy. Furthermore, all subjects entering the extended treatment period will be unblinded on a case-by-case basis. Based on changes in the subject's platelet count, the investigator will adjust the study drug dose and / or administer platelet-raising rescue therapy according to the study drug dose adjustment rules and platelet-raising rescue therapy rules.

[0170] Dosage adjustments

[0171] During the study, platelet counts should be monitored regularly and dose adjustments should be made based on the platelet count 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 determine its efficacy. The specific adjustment rules are as follows:

[0172] Platelet count <100 × 10 9 / L, based on the current dose, increase the dose by one level in units of 2.5 mg, up to a maximum of 15 mg / day (if the researcher anticipates that the subject's platelet response speed / trend will result in a delay in the next chemotherapy cycle or a decrease in the dose intensity of chemotherapy drugs, the dose may be increased by one level after one week of treatment with the current dose);

[0173] Platelet count ≥100 × 10 9 / L and <250×10 9 / L, maintain the current dosage;

[0174] Platelet count ≥250 × 10 9 / L and ≤400×10 9 / L, based on the current dose, adjust down one dose level in units of 2.5 mg;

[0175] Platelet count >400 × 10 9 / L, the drug can be suspended and the platelet count can be reduced to <250×10 9 / L, adjust the dose down one level in units of 2.5 mg based on the dose before discontinuation and then resume the medication.

[0176] 4. Clinical endpoints:

[0177] The primary endpoint of the study was the proportion of subjects with effective treatment.

[0178] Effective treatment is defined as the subject meeting the following conditions simultaneously after starting treatment with the study drug:

[0179] 1. Ability to maintain platelet count ≥100×10 within 14 days (including 14 days) of starting study drug treatment; 9 / L;

[0180] 2. Able to complete the first chemotherapy cycle (C1) using the same treatment regimen as before enrollment, and the platelet count is ≥75×10 on C1D21 (window period: +4 days) 9 / L;

[0181] 3. After starting study drug treatment, patients did not receive platelet-raising rescue therapy (such as platelet transfusion, administration of platelet-promoting drugs including recombinant human interleukin-11 and recombinant human thrombopoietin for injection) until C1D21 (window period: +4 days).

[0182] Key secondary endpoint: platelet count ≥ 100 × 10-1 at the start of the first cycle of chemotherapy (C1D1 [window period: -1 day]) 9 The proportion of subjects with / L who meet the following conditions simultaneously - that is, the effective treatment proportion during the maintenance treatment period:

[0183] 1. Able to complete the first chemotherapy cycle (C1) using the same treatment regimen as before enrollment, and the platelet count is ≥100×10 on C1D21 (window period: +4 days) 9 / L, and the second chemotherapy cycle (C2) did not lead to treatment adjustment due to thrombocytopenia (such as chemotherapy delay ≥4 days, chemotherapy dose intensity reduction ≥15%, and early termination of chemotherapy, etc.);

[0184] 2. After starting the study drug treatment, the patient did not receive platelet-raising rescue treatment (such as platelet transfusion, administration of recombinant human thrombopoietin for injection, recombinant human interleukin-11 and other platelet-stimulating drugs) until C1D21 (window period: +4 days).

[0185] Secondary efficacy endpoints:

[0186] 1. After receiving study drug treatment, the platelet count is ≥100×10 9 / L time;

[0187] 2. Platelet count ≥100×10 within 14 days after receiving study drug treatment 9 / L proportion of subjects;

[0188] 3. The proportion of subjects who started the first cycle (C1) of chemotherapy within 14 days after receiving study drug treatment;

[0189] 4. Able to complete the first chemotherapy cycle (C1) using the same treatment regimen as before enrollment, with platelet count ≥ 75×10 on C1D21 (window period: +4 days) 9 / L proportion of subjects;

[0190] 5. Able to complete the first chemotherapy cycle (C1) using the same treatment regimen as before enrollment, with platelet count ≥ 100×10 on C1D21 (window period: +4 days) 9 / L proportion of subjects;

[0191] 6. The proportion of subjects who were able to complete two consecutive chemotherapy cycles (C1 and C2) using the same treatment regimen as before enrollment, without any treatment regimen adjustment due to thrombocytopenia (e.g., chemotherapy delay ≥4 days, chemotherapy dose intensity reduction ≥15%, and early termination of chemotherapy);

[0192] 7. Able to complete two consecutive chemotherapy cycles (C1, C2) using the same treatment regimen as before enrollment, with platelet count ≥ 75×10 on C2D21 (window period: +4 days) 9 / L proportion of subjects;

[0193] 8. The proportion of subjects who received at least one platelet-raising rescue treatment as prescribed in the protocol after starting study drug treatment;

[0194] 9. Platelet counts of subjects at various time points after starting study drug treatment.

Claims

1. A use of hetromopag or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating thrombocytopenia induced by tumor chemotherapy, wherein the hetromopag or a pharmaceutically acceptable salt thereof is a unit dose preparation containing 7.5 mg of hetromopag.

2. The use according to claim 1, wherein the platelet count of the patient with thrombocytopenia caused by tumor chemotherapy is less than 75×10 9 / L.

3. The use according to claim 1 or 2, wherein the patient with thrombocytopenia caused by tumor chemotherapy is a patient whose chemotherapy is delayed by ≥1 week compared with the expected time due to thrombocytopenia, and whose platelet count is less than 75×10 9 / L.

4. The use according to any one of claims 1 to 3, wherein After administering hetromopa or its pharmaceutically acceptable salt to the patient, the patient's platelet count is greater than or equal to 100×10 9 / L and less than 250×10 9 / L, maintain the original dose.

5. The use according to any one of claims 1 to 3, wherein After administration of hetromopa or its pharmaceutically acceptable salt to the patient, the patient's platelet count is greater than 400×10 9 / L, suspend the drug and wait until the platelet count drops to <250×10 9 / L resume administration, reducing the daily dose by 2.5 mg. If the lowest dose used at this time is 2.5 mg / day, continue to withhold administration.

6. The use according to any one of claims 1 to 3, wherein After administration of hetromopa or its pharmaceutically acceptable salt to the patient, the patient's platelet count is greater than 250×10 9 / L and less than or equal to 400×10 9 / L, reduce the daily dose by 2.5 mg.

7. The use according to any one of claims 1 to 3, wherein After administration of hetromopa or its pharmaceutically acceptable salt to the patient, the patient's platelet count is less than 100×10 9 / L, the daily dose is increased by 2.5 mg, up to a maximum of 15 mg / day.

8. The use according to any one of claims 1 to 7, wherein the dosage of hetromopag or a pharmaceutically acceptable salt thereof is adjusted according to the platelet count, and when it is expected that the patient's platelet response rate / trend will lead to a delay or reduction in the next cycle of chemotherapy, the dosage is increased after one week of medication.

9. The use according to any one of claims 1 to 8, which is therapeutically effective during the treatment period.