CN118354772A - 治疗头颈癌的方法 - Google Patents
治疗头颈癌的方法 Download PDFInfo
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- CN118354772A CN118354772A CN202280075796.XA CN202280075796A CN118354772A CN 118354772 A CN118354772 A CN 118354772A CN 202280075796 A CN202280075796 A CN 202280075796A CN 118354772 A CN118354772 A CN 118354772A
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Abstract
本发明涉及一种治疗头颈癌的方法。该方法包括向有需要的患者施用有效量的gunagratinib，或其药学上可接受的盐。该方法提供一种有效治疗以口腔、鼻腔、咽、喉、鼻咽粘膜表面产生的鳞状细胞癌。口服是优选的给药途径。
Description
发明领域
本发明涉及一种通过向有需要的受试者施用有效量的gunagratinib或其可药用的盐，来治疗头颈癌的方法。
发明背景
头颈癌会导致疼痛、毁容、功能障碍、社会心理压力和死亡。2018年，头颈癌是全球第七种最常见的癌症(新增病例89万例，死亡45万例)，在美国占所有癌症病例的3％，占所有癌症死亡病例的1.5％以上(Chow L，N.Engl.J.Med.，382：1，60-72，2020)。
成纤维细胞生长因子受体(FGFR)为受体酪氨酸激酶(RTK)超家族的一员。FGFR结构由膜外配体结合域、单跨膜域和膜内酪氨酸激酶组成。FGFRs能与配体高亲和力结合，激活下游STAT3、MAPK和PI3K/AKT级联信号，参与多种生物学过程，如调节器官发育、新生血管生成、细胞增殖、迁移和抗凋亡等。FGFR信号通路的改变在肿瘤形成中起着重要的作用，是备受关注的药物靶点。由于FGF/FGFR通路异常是癌症的驱动因素，因此针对FGFR的靶向治疗已成为临床试验的新兴领域。
FGFR包括4种亚型，FGFR1、FGFR2、FGFR3和FGFR4，分布有组织特异性。FGFR1主要在中胚层起源的组织中表达，FGFR2在内胚层起源的组织中表达，FGFR3在神经发育和神经组织中高表达，FGFR4则分布于肝、胆、肺、肾、肌肉等组织，并在内胚层发育时高表达。FGF/FGFR异常激活发生在多种实体瘤和血液瘤中，FGFR失调已被视为胆管癌、膀胱癌、子宫内膜癌、乳腺癌、胃癌、肺癌和卵巢癌的一种驱动因素。
多种肿瘤与FGF/FGFR表达和激活密切相关，包括非小细胞肺癌、乳腺癌、胃癌、肝癌、膀胱癌、子宫内膜癌、前列腺癌、宫颈癌、结肠癌、食道癌、骨髓瘤和黑色素瘤等(Clin.Cancer Res.2012，18，1855)。研究表明FGFR1扩增占非小细胞肺癌的20％，FGFR2扩增占胃癌的约5％，FGFR3突变占非浸润性膀胱癌的约70％，FGFR4在肝癌中扩增(PloS One2012，7，e36713)。因此，开发靶向FGFR的抑制剂成为抗肿瘤药物研究的热点领域(DrugDisc.Today 2014，19，51)。
附图简要说明
图1显示了7名患有头颈癌的患者使用gunagratinib治疗至少两个周期的结果。一个周期是21天。
本发明的详细说明
定义
“头颈癌”是指主要解剖结构粘膜表面产生的鳞状细胞癌，包括口腔、鼻腔、咽、喉和鼻咽。口腔包括唇、颊粘膜、前舌、口底、硬腭、上下牙龈和磨牙后三角。咽包括鼻咽(位于鼻腔后面)，口咽(包括扁桃体区、舌根、软腭和咽后壁)，和下咽(包括梨状窦，喉后表面和环后区，咽后下壁和下外侧壁)。喉包括声门上喉、声门喉(真声带及前后连合)和声门下喉。鼻腔和鼻旁窦包括上颌窦、筛窦、蝶窦和额窦。
“异构体”是指分子式相同但原子键合的性质、顺序或原子空间排列不同的化合物，称为“异构体”。原子空间排列不同的异构体称为“立体异构体”。立体异构体包括光学异构体、几何异构体和构象异构体。
“同位素”包括具有相同原子序数但不同质量数的原子。适合掺入本发明化合物的同位素例子是氢、碳、氮、氧、磷、氟和氯，例如但不限于2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F和36Cl。本发明同位素标记化合物一般可通过本领域技术人员已知的常规技术手段制备，使用与所述实施例中描述的类似方法，并使用适当的同位素标记试剂代替非同位素标记试剂。诸如2H(氘)的稳定同位素可以更好地改变其生物学、药理学或药代动力学特性。
“前药”是指gunagratinib的衍生物，其可以在体内生理条件下转化为生物活性化合物，例如通过氧化、还原、水解等，其各自通过有或没有酶参与的条件下进行。前体药物的例子是具有氨基的本发明化合物被酰基化、烷基化或磷酸化，例如二十烷基氨基、丙氨酰氨基、新戊酰氧基甲基氨基；或羟基被酰基化、烷基化、磷酸化或转化为硼酸盐的化合物，例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙氨酰氧基等；或载体分子的羧基被酯化或酰胺化；或硫醇基形成二硫键，其选择性地将药物递送至靶点和/或细胞的胞质溶胶，比如肽。这些化合物可以根据已知方法用本发明化合物来制备。
“药学上可接受的盐”是指由药学上可接受的碱或酸制备得到的盐，包括无机碱或酸以及有机碱或酸制备的盐。例如，药学上可接受的盐包括碱金属盐、碱土金属盐或铵盐。此类盐的具体例子包括钠盐、钾盐、钙盐、镁盐或无机或有机酸加成盐。合适的酸的例子包括盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、新戊酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡萄糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域普通技术人员已知的其他酸。
本发明提供一种治疗头颈癌的方法。该方法包括向有需要的患者施用有效量的gunagratinib，或其前药、稳定同位素衍生物、药学上可接受的盐、立体异构体或其混合物。
Gunagratinib是一个INN(国际非专有药品名称)名称；其化学名称为(S)-1-(1-丙烯酰基吡咯烷-3-基)-3-((3，5-二甲氧基苯基)乙炔基)-5-(甲氨基)-1H-吡唑-4-甲酰胺，其结构如下所示：
有效量是指能够有效抑制FGFR功能并治疗头颈癌的gunagratinib的量。
药物成分
本发明提供包含一种或多种药学上可接受的载体和gunagratinib活性化合物的药物组合物。药物组合物中活性化合物量通常占注射剂约0.1-5％、片剂约1-90％和胶囊剂1-100％。
在一个实施例中，药物组合物可以为片剂、胶囊剂、颗粒剂、细颗粒剂、粉剂、糖浆剂、栓剂、注射溶液、贴剂等的剂型。药物组合物可以通过常规方法制备。
药学上可接受的载体，也称为非活性成分，可以由本领域技术人员可以使用常规标准选择。药学上可接受的载体包括但不限于非水性溶液、悬浮液、乳液、微乳液、胶束溶液和凝胶。药学上可接受的载体还可以包含以下成分，包括但不限于：盐水和水电解质溶液；离子和非离子渗透剂，如氯化钠、氯化钾、甘油和葡萄糖；pH调节剂和缓冲剂，例如氢氧化物、磷酸盐、柠檬酸盐、乙酸盐、硼酸盐；和三乙醇胺；抗氧化剂，例如亚硫酸氢盐、亚硫酸盐、焦亚硫酸盐、硫代亚硫酸盐、抗坏血酸、乙酰半胱氨酸、半胱氨酸、谷胱甘肽、丁基羟基茴香醚、丁基羟基甲苯、生育酚和抗坏血酸棕榈酸酯的盐、酸和/或碱；表面活性剂，如卵磷脂、磷脂，包括但不限于磷脂酰胆碱、磷脂酰乙醇胺和磷脂酰肌醇；泊洛沙姆和泊洛沙胺，聚山梨酯，例如聚山梨酯80、聚山梨酯60和聚山梨酯20，聚醚，如聚乙二醇和聚丙二醇；聚乙烯醇、聚维酮等聚乙烯类；纤维素衍生物如微晶纤维素、甲基纤维素、羟丙基纤维素、羟乙基纤维素、羧甲基纤维素和羟丙基甲基纤维素及其盐；石油衍生物，如矿物油和白凡士林；脂肪，如羊毛脂、花生油、棕榈油、豆油；甘油单酯、甘油二酯和甘油三酯；丙烯酸聚合物，例如羧基聚亚甲基凝胶，和疏水改性的交联丙烯酸酯共聚物；葡聚糖等多糖类和透明质酸钠等糖胺聚糖类；黄原胶和卡拉胶。这种药学上可接受的载体可以使用熟知的防腐剂来防止细菌污染，这包括但不限于苯扎氯铵、乙二胺四乙酸及其盐，苄索氯铵、氯己定、三氯叔丁醇、对羟基苯甲酸甲酯、硫柳汞和苯乙醇，或者可配制成单次或多次使用的非防腐制剂。
例如活性化合物的片剂或胶囊剂可以包含不具有生物活性且与该活性化合物不反应的其他赋形剂。片剂或胶囊的赋形剂可以包括填充剂、粘合剂、润滑剂和助流剂、崩解剂、润湿剂以及释放速调节剂。粘合剂促进制剂颗粒的粘附，对于片剂是重要的。片剂或胶囊的赋形剂的实例包括但不限于，羧甲基纤维素、纤维素、乙基纤维素、羟丙基甲基纤维素、甲基纤维素、刺梧桐树胶、淀粉、黄蓍胶、明胶、硬脂酸镁、二氧化钛、聚(丙烯酸)以及聚乙烯吡咯烷酮。例如，片剂可以含有一些非活性成分，例如胶体二氧化硅、交聚维酮、羟丙甲纤维素、硬脂酸镁、微晶纤维素、聚乙二醇、羟基乙酸淀粉钠和/或二氧化钛。胶囊剂可以含有一些非活性成分，例如明胶、硬脂酸镁和/或二氧化钛。
使用方法
本发明涉及治疗患者头颈癌的方法。Gunagratinib可以以额外包含药学可接受的载体的药物组合物的形式进行给药。该方法包括向有需要的患者施用有效剂量的gunagratinib，或前药，其稳定同位素衍生物、其药学上可接受的盐、其立体异构体或其混合物。
该方法包含首先确定患有头颈癌的受试者，以及向其施用有效剂量的gunagratinib。
该方法对治疗口腔、鼻腔、咽、喉、鼻咽粘膜表面产生的鳞状细胞癌有效。
该方法治疗由FGF/FGFR信号通路异常引起的头颈癌，包括但不限于基因突变、扩增、重排/融合、插入/缺失和蛋白质过表达。例如，该方法治疗FGF3、FGF4、和/或FGF19扩增、和/或FGFR(例如FGFR1/2/3/4)过表达。
本发明提供一种使用gunagratinib，或其前药、其稳定同位素衍生物、其药学上可接受的盐、其立体异构体或其混合物制备用于治疗患有头颈癌的患者的药物。
本发明提供一种gunagratinib，或其前药、其稳定同位素衍生物、其药学上可接受的盐、其立体异构体或其混合物用于治疗患有头颈癌的患者的用途。
本发明的药物组合物可以通过局部给药和系统给药施用。局部给药包括表皮给药。系统给药包括口服、胃肠外(例如静脉内、肌肉、皮下或直肠)以及其他系统性给药途径。在系统给药中，活性化合物首先到达血浆，然后分布到靶组织中。口服给药是本发明优选的给药途径。
根据损伤的程度和每个患者的个体反应，以及与其他治疗方法联合治疗的可能性，包括使用其他治疗剂，组合物的剂量可能有所不同。
一般而言，人受试者口服gunagratinib的有效剂量为每天约5-50mg，优选每天10-30mg。日剂量可以单次给药，或分2～4次以同样剂量给药。
在一个实施方式中，药物组合物被皮下注射给受试者。
以上述任何方法向受试者给于gunagratinib的时间范围可以是，例如从约1至2周至受试者的剩余寿命的范围内。gunagratinib可以给药，例如至少1、2、3、4、5、6、7、8、9、10、20、30、40或50周，或至少1、2、3、4、5、6、7、8、9、11或12个月，或至少1到2年。
本领域技术人员将认识到，多种给药装置也适用于本发明。
本发明可用于治疗哺乳动物受试者，例如人、马和狗。本发明特别适用于治疗人类。
以下实施例进一步说明本发明。这些实施例仅供示范，不应被解释为限制性。
实施例
实施例1.Gunagratinib治疗头颈癌患者
目的
本研究评估在头颈癌患者中gunagratinib口服给药的疗效。
主要入选标准：
进入研究的参与者必须达到所有以下标准：
1.患有组织病理学确认的不可切除或者转移的晚期恶性实体瘤的患者，其为难治性或复发性的，或其对所有标准治疗方案不耐受或没有可用的标准治疗(剂量递增阶段)。
2.患有组织或细胞病理学确认的不可切除、复发或转移的胆管癌(AJCC＜2017年第8版＞TNM分期IV期)患者，或其对一线化疗不耐受(需至少两个周期的化疗)，或其在新辅助/辅助化疗后6个月内进展/复发(剂量扩展阶段)。
3.已有检测报告确认FGFR2基因易位/融合或中心实验室检测到FGFR2基因易位/融合(剂量扩展阶段)。
4.年龄≥18周岁且≤75周岁。
5.根据实体瘤应答评估标准1.1版(RECIST 1.1)，至少有一个可评估病灶(剂量递增阶段)和至少有一个可测量病灶(剂量扩展阶段)。
6.ECOG表现状态0-1分(剂量递增阶段)；ECOG表现状态0-2分(剂量扩展阶段)。
7.预计生存期3个月以上。
8.必须具有下列所述的合适器官功能：
a)骨髓：中性粒细胞绝对计数(ANC)≥1.5×109/L(1500/mm3)，血小板≥75×109/L，血红蛋白≥90g/L(9g/dL)。
b)凝血功能：凝血酶原时间(PT)，国际标准化比值(INR)，和部分凝血活酶时间(APTT)均≤正常值上限(ULN)的1.5倍。
c)肝脏：血清总胆红素≤1.5×ULN(如果肿瘤转移到肝脏，则≤2.5×ULN)，天冬氨酸转氨酶(AST)和丙氨酸转氨酶(ALT)≤3×ULN(如果肿瘤转移到肝脏，则AST和ALT≤5×ULN)。
d)血清肌酐＜1.5×ULN或肌酐清除率＞60mL/min(根据Cockcroft-Gault公式计算)。
9.自愿入组，签署知情同意书，遵循试验治疗方案和访视计划。
主要排除标准：
达到以下任一标准的参与者从本研究中排除：
1.既往接受过选择性泛FGFR小分子抑制剂或抗体药物治疗(例如erdafitinib、pemigatinib、infrigatinib、rogaratinib、derazantinib、HMPL-453、3D185、ECO317、E7090等)。
2.在首次服用试验药物前2周内接受过口服氟尿嘧啶类化疗，前4周内接受过系统或局部抗癌治疗，包括化疗(口服氟尿嘧啶类化疗除外)、放疗、激素、靶向药物或生物免疫治疗。
3.在首次服用试验药物前6周内进行过大外科手术(开胸、开腹手术等)或2周内进行过小外科手术(浅表皮肤、淋巴结切除、疝修补术等)。
4.首次服用试验药物前2周内受试者的磷酸盐水平在治疗下仍持续大于ULN。
5.临床上明显的胃肠道功能异常，可能影响药物的摄入、转运或吸收的受试者(如无法吞咽、慢性腹泻、肠梗阻等)。
6.有已知症状的中枢神经系统转移。无症状的中枢神经系统转移或中枢神经系统转移症状经治疗后稳定≥4周者可以入选。
7.有既往病史或目前患有无法控制的心脑血管疾病，包括：
·首次给药前6个月内出现纽约心脏病协会(NYHA)II级及以上充血性心力衰竭、不稳定型心绞痛、或心肌梗塞。
·在筛选时有需要治疗的心律失常或左心室射血分数(LVEF)＜50％。
·有临床意义的QTc间期延长病史，或筛选期QTc间期女性＞470ms、男性＞450ms。
8.首次服用试验药物前6个月内有活动性出血病史，2个月内有门脉高压征象导致胃底食道静脉出血，或者研究者认为有明确的出血倾向(如食道静脉曲张、局部活动性溃疡病灶等)。
9.根据研究者判断，存在严重或不能控制的全身性疾病(如不稳定或不能代偿的呼吸、肝或肾脏疾病)的证据；或任何不稳定的系统性疾病(包括活动的临床严重感染、难以控制的高血压、肝、肾或代谢性疾病)。
10.存在间质性肺病、肺栓塞、深静脉栓塞病史(I期剂量递增阶段)。
11.在服用研究药物之前6个月内有中风或颅内出血病史。
12.有器官移植史或异基因造血干细胞移植病史(I期剂量递增阶段)。
13.可能增加眼部毒性的角膜或视网膜异常的情况，包括但不限于：
a)目前患有中心性浆液性视网膜病变(CSR)或视网膜静脉闭塞(RVO)疾病或有相关病史。
b)活动性湿性和老年性黄斑变性(AMD)。
c)伴有黄斑水肿的糖尿病性视网膜病。
d)无法控制的青光眼。
e)角膜病变，如角膜炎、角膜结膜炎、角膜病变、角膜磨损、发炎或溃疡。
14.存活的乙肝炎病毒(PCR法检测HBV DNA＞ULN)、存活的丙肝、HIV感染。
15.还没有从先前治疗的可逆毒性(＞一级)恢复(不包括脱发、可控的恶心、呕吐)。
16.妊娠或哺乳期女性、不愿或不能在本试验的整个治疗期间及研究药物末次给药后6个月内避孕的育龄妇女及不愿或不能在本试验的整个治疗期间及研究药物末次给药后12周内避孕的有生育能力的男性。
17.研究者认为其他不适合参加本研究的情况。
剂量和给药方式：
患者每天接受14mg、16mg、18mg或22mg的gunagratinib治疗，每日1次，每21天为一个周期。患者在每两个周期第21天进行评估。
评估方法
东部肿瘤协作组(ECOG)表现状况
ECOG表现状况是一种测量癌症患者功能状态的简单指标。
级别0：活动能力完全正常，与得病前活动能力无任何差异。
级别1：剧烈体力活动受到限制，但可以走动和能够进行轻度或久坐的工作，例如轻度家务、办公室工作。
级别2：能走动及生活自理，但已丧失工作能力。日间不少于一半时间可以起床活动。
级别3：生活仅能部分自理，日间一半以上时间卧床或坐轮椅。
级别4：完全残疾。生活不能自理。完全卧床或坐轮椅。
级别5：死亡。
实体瘤的应答评价标准。
在基线水平上，肿瘤病灶/淋巴结将按以下分为可测量和不可测量两种：
可测量病灶
肿瘤病灶：至少有一条可以精确测量的径线(记录为最大径)，其最小长度如下：
·CT扫描10mm(CT扫描层厚不大于5mm；影像学指导见附录II)。
·临床检查仪器10mm(病灶不能用测径仪器准确测量的应记录为不可测量)。
·胸部X-射线20mm
恶性淋巴结：定义为病理学增大且可测量，单个淋巴结CT扫描短径须≥15mm(CT扫描层厚推荐不超过5mm)。基线和随访中，仅测量和随访短径。有关淋巴结测量的信息，也见以下有关“靶病灶和非靶病灶的基线记录”的注解。
不可测量病灶
所有其他病灶，包括小病灶(最长径＜10mm或者病理淋巴结短径≥10mm且＜15mm)和无法测量的病灶。无法测量的病灶包括：脑膜疾病、腹水、胸膜或者心包积液、炎性乳腺疾病、皮肤/肺的癌性淋巴管累及、体检时发现的但无法通过可重复的影像学测量的腹部包块以及腹部器官肿大。
评价方法
临床病灶：临床病灶只有位于浅表且测量时直径≥10mm时才能认为是可测量病灶(如皮肤结节等)。对于有皮肤病灶的患者，建议用含有标尺测量病灶大小的彩色照片作为存档。当病灶可以同时使用影像学和临床检查评价时，应该选用影像学评价。
CT、MRI：CT是目前用于疗效评价最好的可用可重复的方法来测量病灶进行疗效评估。本指导原则对可测量性的定义建立在CT扫描层厚≤5mm的基础上。如果CT层厚大于5mm，可测量病灶最小应为层厚的2倍。MRI在部分情况下也可接受(如全身扫描)。
靶病灶评估
完全缓解(CR)：所有靶病灶消失，全部病理淋巴结(包括靶结节和非靶结节)短直径必须减少至＜10mm。
部分缓解(PR)：靶病灶直径之和比基线水平减少至少30％。
疾病进展(PD)：以整个实验研究过程中所有测量的靶病灶直径之和的最小值为参照，直径和相对增加至少20％(如果基线测量值最小就以基线值为参照)；除此之外，必须满足直径和的绝对值增加至少5mm。出现一个或多个新病灶也视为疾病进展。
疾病稳定(SD)：靶病灶减小的程度没达到PR，增加的程度也没达到PD水平，介于两者之间(研究时可以直径之和的最小值作为参考)。
客观缓解率的计算将采用完全缓解(CR)和部分缓解(PR)的患者人数除以患者总数。
疾病控制率(DCR)的计算将采用完全缓解(CR)、部分缓解(PR)和疾病稳定(SD)的患者人数除以患者总数。
头颈癌患者
7名头颈癌患者至少接受了2个治疗周期。结果如图1所示。
第23、28、37、38号患者有FGF3、4、19配体扩增。25号患者在FGFR2中有C383R突变。32号患者在FGFR2中有R450H突变。34号患者有FGFR1-P150S亚克隆。37号患者有FGF3/4/6/12/19/23扩增。
结果
7例患者的结果见图1。第25、34、37和38号患者的治疗仍在进行中。
25号患者在4-22治疗周期后始终显示出超过42％的癌症病变减少的部分缓解(PR)。
37号患者在2、4、8个治疗周期后显示出癌症病灶减少分别33.8％、30％和37％的PR。
34号患者在2-8治疗周期后表现出疾病稳定(SD)，在10治疗周期后表现出PR。
3名患者(23、28和38)在治疗后表现出疾病稳定(SD)。
32号患者显示疾病进展(PD)。
应当理解，前面描述了本发明的优选实施例，在不脱离如权利要求中所述的本发明的范围的情况下，可以对其进行修改。
Claims (6)
1.用Gunagratinib、其前药、其稳定同位素衍生物、其药学上可接受的盐、其立体异构体或其混合物制备用于治疗患者头颈癌的药物。
2.根据权利要求1，其中gunagratinib为口服制剂。
3.根据权利要求2，其中gunagratinib以10-30mg的日剂量给予患者。
4.根据权利要求1，其减少了患者癌症病灶的大小。
5.Gunagratinib、其前药、其稳定同位素衍生物、其药学上可接受的盐、其立体异构体或其混合物，用于治疗患者头颈癌的方法。
6.一种用于治疗头颈癌的方法，其包括向有需要的患者施用有效量的gunagratinib、其前药、其稳定同位素衍生物、其药学上可接受的盐、其立体异构体或其混合物。
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