WO2020192506A1 - 西奥罗尼用于小细胞肺癌的治疗 - Google Patents

西奥罗尼用于小细胞肺癌的治疗 Download PDF

Info

Publication number
WO2020192506A1
WO2020192506A1 PCT/CN2020/079822 CN2020079822W WO2020192506A1 WO 2020192506 A1 WO2020192506 A1 WO 2020192506A1 CN 2020079822 W CN2020079822 W CN 2020079822W WO 2020192506 A1 WO2020192506 A1 WO 2020192506A1
Authority
WO
WIPO (PCT)
Prior art keywords
lung cancer
small cell
treatment
cell lung
cioroni
Prior art date
Application number
PCT/CN2020/079822
Other languages
English (en)
French (fr)
Inventor
鲁先平
山松
潘德思
宁志强
Original Assignee
深圳微芯生物科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳微芯生物科技股份有限公司 filed Critical 深圳微芯生物科技股份有限公司
Priority to CA3134156A priority Critical patent/CA3134156C/en
Priority to US17/442,631 priority patent/US20220184055A1/en
Priority to UAA202105888A priority patent/UA128539C2/uk
Priority to JP2021556944A priority patent/JP7278405B2/ja
Priority to AU2020248270A priority patent/AU2020248270B2/en
Priority to KR1020217033987A priority patent/KR102686264B1/ko
Priority to EP20776399.6A priority patent/EP3949966A4/en
Priority to BR112021018858A priority patent/BR112021018858A2/pt
Priority to MX2021011529A priority patent/MX2021011529A/es
Publication of WO2020192506A1 publication Critical patent/WO2020192506A1/zh
Priority to ZA2021/07342A priority patent/ZA202107342B/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the technical field of medicines, in particular to the application of the compound Cioroni in the treatment of small cell lung cancer.
  • SCLC Small cell lung cancer
  • Untreated patients often die within 2 to 4 months. Although newly-treated patients are more sensitive to chemotherapy, they are prone to drug resistance and relapse, and are relatively insensitive to second-line chemotherapy drugs, and the prognosis is poor. 30% to 40% of the patients diagnosed are in the limited stage, and 60% to 70% of the patients are in the extensive stage. The limited-period long-term survival rate is 20%, and the extensive period is only 2%.
  • Etoposide/cisplatin regimen is currently the main chemotherapy regimen for SCLC.
  • the results of the phase III clinical study showed that in patients with limited-stage SCLC, the 2-year and 5-year survival rate of the EP regimen was better than that of the cyclophosphamide/epirubicin/vincristine regimen (25% vs. 10%, 8% vs. 3 %); For patients with extensive-stage SCLC, the EP regimen can also bring survival benefits.
  • a series of subsequent studies have also confirmed the effectiveness of the EP regimen, so the EP regimen has become the standard first-line chemotherapy regimen for SCLC.
  • IP regimen Irinotecan/cisplatin
  • ORR objective response rates
  • SCLC still lacks effective treatment methods.
  • second-line options such as topotecan, paclitaxel, etc.
  • NCCN only recommend supportive treatment or clinical research, at this time there is a lack of available treatment options.
  • the toxicity of cisplatin often inhibits its efficacy, causing patients to influence treatment due to tolerance. Therefore, for small cell lung cancer, there is still a need to explore treatment options with better curative effects and/or fewer adverse reactions.
  • the purpose of the present invention is to provide a treatment plan for small cell lung cancer with better curative effect and/or fewer adverse reactions.
  • the inventors unexpectedly discovered in the research that the compound of formula (I) (its chemical name is N-(2-aminophenyl)-6-(7-methoxyquinoline-4-oxo)-1-naphthylamide,
  • the Chinese common name is Cioroni
  • can effectively treat small cell lung cancer has a satisfactory clinical benefit rate for small cell lung cancer, and is relatively significantly better than non-small cell lung cancer, colon cancer and other types of tumors. Tumor activity.
  • the application of Cioroni in the preparation of a medicine for the treatment of small cell lung cancer is provided.
  • the present invention also provides a method for treating small cell lung cancer, including administering Cioroni to a subject in need.
  • Cioroni can also be used in combination with other active pharmaceutical ingredients.
  • the small cell lung cancer is relapsed or refractory small cell lung cancer.
  • the relapsed or refractory small cell lung cancer refers to the progression or recurrence of small cell lung cancer that occurs after receiving one or two or more different treatments, especially systemic chemotherapy regimens (such as platinum-containing chemotherapy regimens) .
  • Sioroni is a small molecule anti-tumor targeted drug targeting multiple protein kinases. However, there is no report on the application of Cioroni against small cell lung cancer.
  • the present invention proposes the application of sioroni in patients with small cell lung cancer, including but not limited to the treatment of sioroni alone, as well as treatment in combination with other drugs or adjuvant drugs or therapeutic agents, including Treatment combined with other treatments (such as surgery, radiotherapy, etc.).
  • Figure 1 shows a waterfall chart of the efficacy of Cioroni on various tumors in the phase I clinical study
  • Figure 2 shows a waterfall chart of the efficacy of Cioroni on small cell lung cancer in a phase Ib clinical study.
  • the present invention discloses the application of Cioroni in the treatment of small cell lung cancer. Those skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve it. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
  • the application of the present invention has been described through the preferred embodiments. It is obvious that relevant personnel can make changes or appropriate changes and combinations to the applications described herein without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention .
  • Cioroni can be used in its prototype compound or salt form (pharmaceutically acceptable salt).
  • the pharmaceutically acceptable salt can be prepared by using, for example, the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, Glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, Methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.
  • the pharmaceutically acceptable salt of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in an organic solvent miscible with water (such as acetone, methanol, ethanol, and acetonitrile), and adding an excessive amount of organic acid or An aqueous inorganic acid solution is used to precipitate the salt from the resulting mixture, the solvent and the remaining free acid are removed therefrom, and then the precipitated salt is separated.
  • an organic solvent miscible with water such as acetone, methanol, ethanol, and acetonitrile
  • Cioro or a pharmaceutically acceptable salt thereof of the present invention may include a solvate form, and preferably, the solvate is a hydrate.
  • the additional therapeutic drug means that it has an effect on the treatment or prevention of cancer, including the ability to reduce, reduce, regulate, improve or eliminate its cause, or improve its cause. Symptoms or any compound or ingredient that contributes to the overall therapeutic effect of the patient.
  • the dosage of Cioroni may be 1 mg to 500 mg per day, such as 1 mg to 100 mg per day, preferably 5 mg to 80 mg per day, 5 mg to 70 mg per day, 5 mg to 60 mg per day or
  • the daily dose is 5 mg to 50 mg, and a more preferred daily dose may be, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg per day.
  • the specific application dose can be adjusted according to the actual situation of the patient, the treatment plan and the combination with other drugs.
  • Cioroni can be administered to the subject in the form of any suitable pharmaceutical composition.
  • the pharmaceutical composition may be a dosage form such as oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes), such as capsules, tablets, granules, powders, syrups, emulsions, microemulsions, solutions or suspensions .
  • Cioroni and the other therapeutic agent may be administered to the subject to be treated separately, simultaneously or sequentially; Cioroni and the other therapeutic agent may be present in the same pharmaceutical composition, or They are administered separately in the form of different pharmaceutical compositions (or kits or kits).
  • the application of Theoroni provided by the present invention will be further explained below.
  • Example 1 Phase I clinical trial of Cioroni in the treatment of patients with advanced solid tumors
  • Test drug Cioroni capsules, specifications: 5mg, 25mg. Produced by Shenzhen Microchip Biotechnology Co., Ltd.
  • Dosage regimen starting dose 10mg/day, after the starting dose, according to the modified Fibonacci method, the patients are enrolled in order from low to high.
  • the set dose groups are 20mg, 35mg, 50mg, 65mg...dose groups Until MTD is determined.
  • Cioroni capsules are administered orally, once a day in the morning. Before knowing the bioavailability analysis data of food effects, the drugs were taken on an empty stomach.
  • the body mass index is in the range of 18-28;
  • Age 18 to 65 years old, regardless of gender;
  • Hb hemoglobin
  • ANC absolute neutrophils
  • PHT platelets
  • Cioroni capsules The prescribed dose of Cioroni capsules was taken orally once every day, and every 28 days was a treatment cycle; there was no stopping interval during the treatment week, and all patients in the group received the trial drug treatment until the disease progressed or appeared intolerable toxicity.
  • the clinical benefits of tumor treatment include:
  • Safety assessment including physical examination, vital signs, ECOG fitness score, blood routine, urine routine, 12-lead ECG, blood biochemistry, electrolytes, coagulation function, myocardial enzymes, troponin, TSH, FT3, FT4, amylase, Echocardiography, 24-hour urine protein quantification (if necessary), adverse events.
  • Example 2 Phase Ib clinical trial of Cioroni single-drug treatment of relapsed and refractory small cell lung cancer
  • Test drug Cioroni capsules, specifications: 5mg, 25mg. Produced by Shenzhen Microchip Biotechnology Co., Ltd.
  • Cioroni capsules are administered at 50 mg/day, QD (no adjustments to body weight or body surface area). Take it on an empty stomach every morning, take it with water, and swallow whole capsules. Continuous administration for 28 days constitutes a treatment cycle, and there is no interval between each treatment cycle.
  • the disease has progressed or recurred after receiving at least 2 different systemic chemotherapy regimens (including platinum-containing chemotherapy regimens) in the past;
  • the lesions treated by radiotherapy or local area treatment must have imaging evidence of disease progression before they can be regarded as target lesions;
  • Coagulation function Prothrombin time-international normalized ratio (PT-INR) ⁇ 1.5.
  • test subjects took 50 mg of Cioroni capsules orally once a day, every 28 days as a treatment cycle, and there was no stopping interval during the treatment week. Throughout the trial period, all subjects continued treatment until any of the following conditions (whichever occurs first) occurred: disease progression, intolerable toxicity, death, withdrawal of informed consent, or loss to follow-up.
  • Efficacy evaluation According to the RECIST1.1 standard, it will be evaluated once in the baseline period and the 4th weekend after treatment, and repeated every 8 weeks until the disease progresses.
  • Tumor imaging examinations include CT or MRI of the neck, chest, whole abdomen, and pelvis. Examinations of other parts are carried out when necessary based on clinical indications.
  • the baseline and follow-up assessment and measurement of the lesion should use the same techniques and methods.
  • Safety assessment including physical examination, vital signs, ECOG fitness score, blood routine, urine routine, 12-lead ECG, blood biochemistry, electrolytes, coagulation function, myocardial enzymes, troponin, TSH, FT3, FT4, amylase, Echocardiography, 24-hour urine protein quantification (if necessary), adverse events.
  • Figure 1 is a waterfall chart of the curative effect of various tumors in Cioroni's Phase I clinical trial, including 15 patients with measurable lesions among the 18 patients enrolled in the group.
  • the tumor types included are colorectal cancer, non-small cell lung cancer, gastric cancer, Ovarian cancer, papillary thyroid cancer, poorly differentiated renal carcinoma.
  • After treatment there were no patients whose target lesions were reduced by more than 30% relative to the baseline, and the target lesions were reduced by 30% relative to the baseline as a criterion for clinical objective remission of tumor treatment.
  • Figure 2 is a waterfall chart of the curative effect of Sioroni's stage Ib treatment of small cell lung cancer, including 20 patients who have been evaluated for curative effect among the 25 patients enrolled. After treatment, 5 patients (25%) had target lesions reduced by more than 30% from baseline, and 4 patients were evaluated as partial remission (PR) in clinical efficacy.
  • PR partial remission
  • Cioroni has obvious advantages over other tumors in terms of objective remission, clinical benefit, and reduction of target lesions in small cell lung cancer.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

利用西奥罗尼治疗小细胞肺癌的方法以及西奥罗尼在制备用于治疗小细胞肺癌的药物中的应用。

Description

西奥罗尼用于小细胞肺癌的治疗
本申请要求于2019年3月25日提交到中国专利局的发明名称为“西奥罗尼用于小细胞肺癌的治疗”的中国专利申请201910229379.6的优先权，其内容通过引用以整体并入本文。
技术领域
本发明涉及药物技术领域，具体涉及化合物西奥罗尼在小细胞肺癌治疗中的应用。
背景技术
肺癌发病率及死亡率均高居恶性肿瘤第一位，小细胞肺癌(small cell lung cancer，SCLC)占肺癌总数的10％～15％，其临床特点和生物学行为异于其他类型肺癌，表现为倍增时间短，早期易发生转移，恶性程度极高。未接受治疗的患者常在2～4个月内死亡，尽管初治患者对化疗较敏感，但很容易产生耐药性和复发，且对二线化疗药物相对不敏感，预后较差。确诊30％～40％的患者处于局限期，60％～70％的患者处于广泛期。局限期长期生存率在20％，广泛期则仅在2％。
依托泊苷/顺铂方案(EP方案)是目前SCLC的主要化疗方案。III期临床研究结果显示，在局限期SCLC患者中，EP方案的2年和5年生存率优于环磷酰胺/表阿霉素/长春新碱方案(25％比10％，8％比3％)；对于广泛期SCLC患者，EP方案同样可以带来生存获益。后续的一系列研究亦证实了EP方案的有效性，因此EP方案成为SCLC的标准一线化疗方案。
伊立替康/顺铂(CPT-11/DDP)(IP方案)是治疗SCLC的另一个常规化疗方案。在一项对照研究中，同时设置IP方案组和EP方案组，结果显示，两组患者的客观缓解率(ORR)分别为84.4％、67.5％(P＝0.02)，中位生存期分别为12.8个月、9.4个月(P＝0.002)。
除了上述常规EP方案和IP方案外，还存在少数二线治疗方案，例如采用拓扑替康或紫杉醇的联合治疗。研究表明，拓扑替康联合最佳支持治疗组总生存期、生活质量及症状的改善均明显优于单用最佳支持治疗组，因此拓扑替康成为SCLC的二线化疗药物。
尽管存在上述治疗方案，但总体而言，SCLC仍缺乏有效的治疗手段，在常规EP或IP方案失败后，二线可选方案较少(如拓扑替康、紫杉醇等)，且二线治疗失败后，NCCN等指南只推荐支持治疗或临床研究，此时缺乏可用的治疗方案。另外，无论是EP方案还是IP方案，顺铂的毒性往往会抑制其疗效，导致患者因耐受性影响治疗。因此，对于小细胞肺癌而言，尚需要探寻具有更好疗效和/或较少不良反应的治疗方案。
发明内容
有鉴于此，本发明的目的在于提供一种具有更好疗效和/或较少不良反应的小细胞肺癌治疗方案。本发明人在研究中意外发现，式(I)化合物(其化学名为N-(2-氨基苯基)-6-(7-甲氧基喹啉-4-氧)-1-萘酰胺，中文通用名为西奥罗尼)可以有效治疗小细胞肺癌，对于小细胞肺癌有着令人满意的临床获益率，且具有相对明显优于对非小细胞肺癌、结肠癌等其他类型肿瘤的抑瘤活性。
Figure PCTCN2020079822-appb-000001
因此，在本发明的一个方面，提供了西奥罗尼在制备用于治疗小细胞肺癌的药物中的应用。
相应地，本发明还提供了一种治疗小细胞肺癌的方法，包括向有此需要的对象给予西奥罗尼。
在本发明的上述制药应用和治疗方法中，西奥罗尼还可以与另外的活性药物成分联用。
在本发明一些优选的实施方案中，所述小细胞肺癌为复发性或难治性小细胞肺癌。
所述复发性或难治性小细胞肺癌意指在接受过1种或2种或更多种不同的治疗尤其是系统化疗方案(例如含铂化疗方案)后出现的小细胞肺癌疾病进展或复发。
西奥罗尼是一个以多蛋白激酶为靶点的小分子抗肿瘤靶向药物。然而，目前还未有关于西奥罗尼针对小细胞肺癌的应用报道。
我们进行了西奥罗尼针对晚期实体瘤患者的I期临床试验，入组了包括结直肠癌、非小细胞肺癌、胃癌、卵巢癌、甲状腺乳头状癌、弥漫大B细胞型淋巴瘤、纤维肉瘤、肾低分化癌等8种肿瘤适应症的患者共18例，结果表明，未观察到临床主要疗效指标的客观缓解，包括全部缓解(CR)和部分缓解(PR)的病例。
我们还进行了西奥罗尼针对复发难治的小细胞肺癌的Ib期临床试验，入组小细胞肺癌患者25例，其中有疗效评价的患者20例。结果显示，有4例患者的最佳疗效评价为PR，客观缓解率(ORR)为20％。考虑到小细胞肺癌的治疗难度，该治理结果是相当鼓舞人心的。
上述试验结果显示，西奥罗尼在针对非小细胞肺癌、结肠癌等8种肿瘤的临床试验中，在临床主要疗效指标上还未观察到客观缓解患者。然而，西奥罗尼在小细胞肺癌的临床试验中显示出良好的疗效，客观缓解率(ORR)为20％。表明小细胞肺癌是西奥罗尼的有效肿瘤适应症。与针对其他类型肿瘤的治疗效果相比，西奥罗尼对于小细胞肺癌的疗效是意料之外的。
根据上述发现，本发明提出了西奥罗尼在小细胞肺癌患者中的应用，包括而不仅限于单独给予西奥罗尼治疗，以及与其它药物或辅助药物或治疗剂联合应用的治疗，也包括与其它治疗手段(如手术治疗、放疗等)联合应用的治疗。
附图说明
图1示出了I期临床研究中西奥罗尼对多种肿瘤的疗效瀑布图；
图2示出了Ib期临床研究中西奥罗尼对小细胞肺癌的疗效瀑布图。
具体实施方式
本发明公开了西奥罗尼在小细胞肺癌治疗中的应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明所述应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述应用进行改动或适当变更与组合，来实现和应用本发明技术。
在本发明中，西奥罗尼可以以其原型化合物或盐形式(可药用盐)或应用。所述可药用盐可以通过使用例如以下的无机酸或有机酸而制得：盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸或甲苯磺酸。
本发明的可药用盐可通过常规方法制备，例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)中，向其中添加过量的有机酸或无机酸水溶液，以使得盐从所得混合物中沉淀，从中除去溶剂和剩余的游离酸，然后分离所沉淀的盐即可。
本发明的西奥罗或其可药用盐可包括溶剂化物形式，优选地，所述溶剂化物为水合物。
在西奥罗尼与另外的治疗药物联合应用的治疗中，所述另外的治疗药物意指对癌症的治疗或预防有作用，包括可以减轻、减少、调节、改善或消除其病因，或改善其症状或有助于患者整体治疗效果的任何化合物或成分。
在本发明的治疗应用中，西奥罗尼的给药剂量可以是每日1mg至500mg，例如每日1mg至100mg，优选每日5mg至80mg、每日5mg至70mg、每日5mg至60mg或每日5mg至50mg，更优选的每日剂量可以是例如每日1mg、2mg、3mg、4mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg或50mg。其具体应用剂量可以根据患者的实际情况、治疗方案以及与其他药物联用的情况进行调整。
在本发明的治疗应用中，西奥罗尼可以以任何适合的药物组合物的形式给予对象。所述药物组合物可以是诸如口服施用或肠胃外施用(包括肌内、 静脉内和皮下途径)的剂型，例如胶囊、片剂、颗粒、粉末、糖浆、乳剂、微乳剂、溶液或混悬液。
在本发明的联合治疗应用中，西奥罗尼可以与另外的治疗剂分别、同时或依次给予待治疗的对象；西奥罗尼可以与另外的治疗剂可以存在于同一药物组合物中，或者以不同的药物组合物(或试剂盒或药盒)的形式分别施用。以下就本发明所提供的西奥罗尼的应用做进一步说明。
实施例1：西奥罗尼治疗晚期实体瘤患者的I期临床试验
试验药物：西奥罗尼胶囊，规格：5mg、25mg。由深圳微芯生物科技股份有限公司生产。
给药方案：起始剂量10mg/天，起始剂量后，依据改良的Fibonacci方法，剂量由低到高依次入组患者，设定的剂量组分别为20mg、35mg、50mg、65mg……剂量组，直到确定MTD。
西奥罗尼胶囊口服给药，每天早晨服药一次。在未获知食物影响的生物利用度分析数据前，均采用空腹服药方式。
病例数：入组18例。
入选标准：
1.经组织学或细胞学明确诊断的晚期实体瘤患者，包括非小细胞肺癌、结直肠癌、卵巢癌、肾细胞癌、胃肠道间质瘤、胃癌等；
2.经标准方案治疗失败或缺乏标准治疗方案的患者；
3.体重指数在18～28范围内；
4.年龄：18～65岁，性别不限；
5.ECOG评分：0或1分；
6.主要器官功能符合以下标准：
a)血常规检查：血红蛋白(Hb)≥100g/L(14天内未输血)；中性粒细胞绝对值(ANC)≥1.5×109/L；血小板(PLT)≥100×109/L；
b)生化检查：血清肌酐Cr≤正常值上限(ULN)；胆红素BIL≤1.25×ULN；谷丙转氨酶(ALT)、谷草转氨酶(AST)≤1.5×ULN；空腹甘油三酯(TG)≤3.0mmol/L，空腹总胆固醇(TC)≤7.75mmol/L；
c)凝血功能：国际标准化比率(INR)＜1.5。
7.女性必须在研究期间和研究结束后6个月内采用避孕措施，研究入组前的7天内血清或尿妊娠试验阴性，必须为非哺乳期患者；男性必须在研究期间和结束后6个月内采用避孕措施；
8.自愿签署书面知情同意书。
治疗计划：
每天空腹口服规定剂量的西奥罗尼胶囊一次，每28天为一个治疗周期；治疗周期间无停药间隔，所有入组患者均接受试验药物治疗至疾病进展或出现无法耐受的毒性。
疗效评估：肿瘤治疗临床获益包括:
完全缓解(CR)
部分缓解(PR)
判断标准：依据实体瘤RECIST 1.1版(2009年)标准进行疗效评价。
安全性评估：包括体格检查、生命体征、ECOG体能评分、血常规、尿常规、12导联ECG、血生化、电解质、凝血功能、心肌酶、肌钙蛋白、TSH、FT3、FT4、淀粉酶、超声心动图、24小时尿蛋白定量(必要时)、不良事件。
临床试验结果：
试验共入组18例患者，均纳入FAS、SS和PPS分析集。18例患者中，有7例(38.9％)结直肠癌，5例(27.8％)非小细胞肺癌，另有胃癌、卵巢癌、甲状腺乳头状癌、弥漫大B细胞型淋巴瘤、纤维肉瘤、肾低分化癌各1例。
结果表明，未观察到有临床主要疗效指标获得客观缓解的病例，所述客观缓解包括全部缓解(CR)和部分缓解(PR)。
实施例2：西奥罗尼单药治疗复发难治的小细胞肺癌的Ib期临床试验
试验药物：西奥罗尼胶囊，规格：5mg、25mg。由深圳微芯生物科技股份有限公司生产。
给药方案：西奥罗尼胶囊按50mg/天、QD给药(对体重或体表面积不做调整)。每天上午空腹服用，用水送服，完整吞服整粒胶囊。连续给药28天为1个治疗周期，每个治疗周期间无间隔。
病例数：入组25例。
入选标准：
1.年龄≥18岁，≤75岁，性别不限；
2.组织学或细胞学证实的小细胞肺癌；
3.既往至少接受过2种不同的系统化疗方案(其中包括含铂化疗方案)后均出现疾病进展或复发；
4.根据RECIST1.1标准，至少有一个可测量的靶病灶，放疗或局部区域治疗的病灶必须有疾病进展的影像学证据方可视为靶病灶；
5.ECOG体力评分0-1分；
6.主要器官功能符合以下标准：
a)血常规：中性粒细胞绝对值≥1.5×109/L，血小板≥75×109/L，血红蛋白≥80g/L；
b)血生化：总胆红素≤正常值上限的1.5倍，AST/ALT≤正常值上限的2.5倍(若肝转移，则≤正常值上限的5倍)，血清肌酐≤正常值上限的1.5倍；
凝血功能：凝血酶原时间-国际标准化比率(PT-INR)<1.5。
7.预期生存时间≥3个月；
8.自愿签署书面知情同意书。
治疗计划：
试验受试者每天口服西奥罗尼胶囊50mg一次，每28天为一个治疗周期，治疗周期间无停药间隔期。整个试验期间，所有受试者均持续治疗直至出现以下任一情况(以先发生者为准)：疾病进展、不能耐受的毒性反应、死亡、撤回知情同意或失访。
疗效评估：根据RECIST1.1标准，分别在基线期以及治疗后第4周末评估一次，后续每8周重复进行，直到疾病进展。肿瘤影像学检查包括颈部、 胸部、全腹、盆腔CT或MRI，其他部位检查根据临床指征，有需要时进行，病灶基线和后续评估测量应采用同样的技术和方法。
安全性评估：包括体格检查、生命体征、ECOG体能评分、血常规、尿常规、12导联ECG、血生化、电解质、凝血功能、心肌酶、肌钙蛋白、TSH、FT3、FT4、淀粉酶、超声心动图、24小时尿蛋白定量(必要时)、不良事件。
临床试验结果：
阶段性入组小细胞肺癌患者25例，其中有疗效评价的患者20例。结果表明，有4例患者的最佳疗效评价为PR，客观缓解率(ORR)为20％。这些结果显示西奥罗尼可有效用于治疗小细胞肺癌。
实施例3：西奥罗尼治疗其它肿瘤与小细胞肺癌的疗效对比
图1为西奥罗尼I期临床多种肿瘤疗效瀑布图，包含入组的18例患者中有可测量病灶的15例患者，包含的肿瘤类型有结直肠癌，非小细胞肺癌，胃癌、卵巢癌、甲状腺乳头状癌、肾低分化癌。在治疗后，没有出现靶病灶相对于基线缩小30％以上的患者，其中靶病灶相对于基线缩小30％是肿瘤治疗临床客观缓解的一个标准。
图2为西奥罗尼Ib期治疗小细胞肺癌疗效瀑布图，包含入组的25例患者中有疗效评价的20例患者。治疗后，有5例患者(25％)靶病灶相对于基线缩小30％以上，其中4例患者的临床疗效评价为部分缓解(PR)。
下表为西奥罗尼治疗小细胞肺癌及其它肿瘤的疗效对比，西奥罗尼在小细胞肺癌中客观缓解、临床获益、靶病灶缩小等疗效指标相对于其它肿瘤有明显优势。
对比项目 I期临床 Ib期临床
肿瘤类型 8种常见肿瘤 小细胞肺癌
评价患者人数 18 20
PR(％) 0 4(20)
靶病灶缩小30％以上(％) 0 5(25)
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (4)

  1. 式(I)化合物西奥罗尼在制备用于治疗小细胞肺癌的药物中的应用
    Figure PCTCN2020079822-appb-100001
  2. 如权利要求1所述式(I)化合物西奥罗尼与另外的活性药物化合物之联合在制备用于治疗小细胞肺癌的药物中的应用。
  3. 一种治疗小细胞肺癌的方法，包括向有此需要的对象给予如权利要求1所述式(I)化合物西奥罗尼。
  4. 权利要求3所述的治疗方法，还包括向所述对象给予另外的治疗药物。
PCT/CN2020/079822 2019-03-25 2020-03-18 西奥罗尼用于小细胞肺癌的治疗 WO2020192506A1 (zh)

Priority Applications (10)

Application Number Priority Date Filing Date Title
CA3134156A CA3134156C (en) 2019-03-25 2020-03-18 Chiauranib for treatment of small cell lung cancer
US17/442,631 US20220184055A1 (en) 2019-03-25 2020-03-18 Chiauranib for treatment of small cell lung cancer
UAA202105888A UA128539C2 (uk) 2019-03-25 2020-03-18 Чіаураніб для лікування дрібноклітинного раку легенів
JP2021556944A JP7278405B2 (ja) 2019-03-25 2020-03-18 小細胞肺がんの治療におけるキアウラニブの使用
AU2020248270A AU2020248270B2 (en) 2019-03-25 2020-03-18 Chiauranib for treatment of small cell lung cancer
KR1020217033987A KR102686264B1 (ko) 2019-03-25 2020-03-18 소세포폐암 치료용 치아우라닙
EP20776399.6A EP3949966A4 (en) 2019-03-25 2020-03-18 CHIAURANIB FOR THE TREATMENT OF SMALL CELL LUNG CANCER
BR112021018858A BR112021018858A2 (pt) 2019-03-25 2020-03-18 Chiauranibe para tratamento de câncer de pulmão de células pequenas
MX2021011529A MX2021011529A (es) 2019-03-25 2020-03-18 Chiauranib para el tratamiento de cáncer de pulmón microcítico.
ZA2021/07342A ZA202107342B (en) 2019-03-25 2021-09-29 Chiauranib for treatment of small cell lung cancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910229379 2019-03-25
CN201910229379.6 2019-03-25

Publications (1)

Publication Number Publication Date
WO2020192506A1 true WO2020192506A1 (zh) 2020-10-01

Family

ID=72611382

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/079822 WO2020192506A1 (zh) 2019-03-25 2020-03-18 西奥罗尼用于小细胞肺癌的治疗

Country Status (13)

Country Link
US (1) US20220184055A1 (zh)
EP (1) EP3949966A4 (zh)
JP (1) JP7278405B2 (zh)
KR (1) KR102686264B1 (zh)
CN (2) CN111728974B (zh)
AU (1) AU2020248270B2 (zh)
BR (1) BR112021018858A2 (zh)
CA (1) CA3134156C (zh)
MX (1) MX2021011529A (zh)
TW (2) TWI797426B (zh)
UA (1) UA128539C2 (zh)
WO (1) WO2020192506A1 (zh)
ZA (1) ZA202107342B (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111728974A (zh) * 2019-03-25 2020-10-02 深圳微芯生物科技股份有限公司 西奥罗尼用于小细胞肺癌的治疗

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023160647A1 (zh) * 2022-02-24 2023-08-31 康方药业有限公司 包含抗ctla4-抗pd-1双特异性抗体和西奥罗尼的药物组合

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101906076A (zh) * 2009-06-04 2010-12-08 深圳微芯生物科技有限责任公司 作为蛋白激酶抑制剂和组蛋白去乙酰化酶抑制剂的萘酰胺衍生物、其制备方法及应用
WO2019096194A1 (zh) * 2017-11-16 2019-05-23 江苏恒瑞医药股份有限公司 Pd-1抗体和vegfr抑制剂联合治疗小细胞肺癌的用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105481778B (zh) * 2014-09-16 2019-06-04 深圳微芯生物科技股份有限公司 嘧啶衍生物、其制备方法及其应用
TWI797426B (zh) * 2019-03-25 2023-04-01 大陸商深圳微芯生物科技股份有限公司 西奧羅尼用於小細胞肺癌的治療
TWI798532B (zh) 2019-03-25 2023-04-11 大陸商深圳微芯生物科技股份有限公司 Ｋｄｍ５ａ基因和ａｔｒｘ基因的應用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101906076A (zh) * 2009-06-04 2010-12-08 深圳微芯生物科技有限责任公司 作为蛋白激酶抑制剂和组蛋白去乙酰化酶抑制剂的萘酰胺衍生物、其制备方法及应用
WO2019096194A1 (zh) * 2017-11-16 2019-05-23 江苏恒瑞医药股份有限公司 Pd-1抗体和vegfr抑制剂联合治疗小细胞肺癌的用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
WANG, XINHAO: "Clinical Trials of Etoposide Capsules in Treating Relapsed/Refractory Small Cell Lung Cancer", DRUG CLINICAL TRIAL REGISTRATION AND INFORMATION DISCLOSURE PLATFORM: WWW.CHINADRUGTRIALS.ORG.CN, no. CTR20170765, 27 July 2017 (2017-07-27), CN, pages 1 - 6, XP009526139 *
ZHOU Y.ET AL.: "CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency.", CANCER SCIENCE, vol. 108, no. 3, 31 March 2017 (2017-03-31), XP055737667 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111728974A (zh) * 2019-03-25 2020-10-02 深圳微芯生物科技股份有限公司 西奥罗尼用于小细胞肺癌的治疗

Also Published As

Publication number Publication date
KR20210141643A (ko) 2021-11-23
AU2020248270A1 (en) 2021-10-28
AU2020248270B2 (en) 2023-05-18
CN115105501A (zh) 2022-09-27
BR112021018858A2 (pt) 2022-01-11
KR102686264B1 (ko) 2024-07-19
TW202034919A (zh) 2020-10-01
JP2022527702A (ja) 2022-06-03
CA3134156A1 (en) 2020-10-01
CN111728974B (zh) 2022-08-16
EP3949966A1 (en) 2022-02-09
CN111728974A (zh) 2020-10-02
CA3134156C (en) 2024-01-16
TWI797426B (zh) 2023-04-01
US20220184055A1 (en) 2022-06-16
EP3949966A4 (en) 2022-12-28
TW202332445A (zh) 2023-08-16
UA128539C2 (uk) 2024-08-07
MX2021011529A (es) 2021-12-15
ZA202107342B (en) 2023-03-29
JP7278405B2 (ja) 2023-05-19

Similar Documents

Publication Publication Date Title
Motzer et al. Phase I/II trial of dexverapamil plus vinblastine for patients with advanced renal cell carcinoma.
EP3443962B1 (en) Quinoline derivative for treating gastric cancer
TWI798199B (zh) 癌症治療
US20220193076A1 (en) Methods of treating breast cancer with tucatinib
WO2020192506A1 (zh) 西奥罗尼用于小细胞肺癌的治疗
CN104582706A (zh) 辅助癌症治疗的方法
WO2015172712A1 (zh) 维生素c与抗肿瘤药物协同作用的注射用药物组合物
TW202402290A (zh) 癌症治療
JP2012524078A (ja) 肝細胞癌の治療法
AU2011323832B2 (en) Method of treating neuroendocrine tumors
US20220241294A1 (en) Bisfluoroalkyl-1,4-benzodiazepinone compounds for treating notch-activated breast cancer
RU2784869C1 (ru) Чиаураниб для лечения мелкоклеточного рака легкого
AU2019236578B2 (en) Quinoline derivative for treatment of nasopharyngeal carcinoma
WO2021089005A1 (zh) 一种fgfr抑制剂的用途
WO2021185234A1 (zh) 作为c-Met激酶抑制剂的化合物的联用药物组合物及其用途
US11911374B2 (en) Methods and uses for treating cancer
WO2023169384A1 (zh) 西奥罗尼联合抗代谢化疗药物治疗乳腺癌的用途
WO2024022282A1 (zh) 吡啶胺化合物在特定ros1基因融合的非小细胞肺癌中的应用
US20130281528A1 (en) Method of treating gastric cancer
CN117956999A (zh) 杂芳基氧基萘类化合物的用途
WO2021219137A1 (zh) 用于治疗met基因异常疾病的氨基吡啶衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20776399

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3134156

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021556944

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112021018858

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 20217033987

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020248270

Country of ref document: AU

Date of ref document: 20200318

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020776399

Country of ref document: EP

Effective date: 20211025

REG Reference to national code

Ref country code: BR

Ref legal event code: B01E

Ref document number: 112021018858

Country of ref document: BR

Free format text: APRESENTE O COMPLEMENTO DO TEXTO EM PORTUGUES, ADAPTADO A NORMA VIGENTE, DO PEDIDOCONFORME DEPOSITO INTERNACIONAL INICIAL (RELATORIO DESCRITIVO E DESENHO, SE HOUVER), CONFORMEDETERMINA A RESOLUCAO INPI PR NO 77/2013 DE 18/03/2013, ART. 5O E 7O.

ENP Entry into the national phase

Ref document number: 112021018858

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20210922

REG Reference to national code

Ref country code: BR

Ref legal event code: B01Y

Ref document number: 112021018858

Country of ref document: BR

Kind code of ref document: A2

Free format text: ANULADA A PUBLICACAO CODIGO 1.5 NA RPI NO 2656 DE 30/11/2021 POR TER SIDO INDEVIDA.