CN110505880A - Her2阳性乳腺癌的治疗 - Google Patents
Her2阳性乳腺癌的治疗 Download PDFInfo
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- CN110505880A CN110505880A CN201780067414.8A CN201780067414A CN110505880A CN 110505880 A CN110505880 A CN 110505880A CN 201780067414 A CN201780067414 A CN 201780067414A CN 110505880 A CN110505880 A CN 110505880A
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- anthracycline antibiotic
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Abstract
提供了通过与基于蒽环类抗生素的化疗组合的帕妥珠单抗和曲妥珠单抗的新辅助施用来治疗HER2阳性乳腺癌的方法。具体地,该方法涉及通过在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的新辅助施用来治疗具有HER2阳性,局部晚期,炎性,或早期阶段乳腺癌的患者,其中帕妥珠单抗和曲妥珠单抗的组合施用相对于曲妥珠单抗作为单一药剂的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件,诸如心脏毒性。
Description
序列表
本申请含有序列表,已经以ASCII格式电子提交且据此通过援引完整收录。于2017年9月26日创建的所述ASCII拷贝命名为GNE-0425-WO_SL.txt且大小为32,642个字节。
发明领域
本发明涉及通过与基于蒽环类抗生素的化疗组合的帕妥珠单抗和曲妥珠单抗的新辅助施用来治疗HER2阳性乳腺癌。具体地,本发明涉及通过在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的新辅助施用来治疗具有HER2阳性,局部晚期,炎性,或早期阶段乳腺癌的患者,其中帕妥珠单抗和曲妥珠单抗的组合施用相对于曲妥珠单抗作为单一药剂的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件,诸如心脏毒性。
还涉及一种制品,其包含其中有帕妥珠单抗的管形瓶和其上提供安全性和/或功效数据的包装插页;一种制备所述制品的方法;和一种确保与其相关的,与曲妥珠单抗组合的帕妥珠单抗的安全和有效使用的方法。
发明背景
HER受体酪氨酸激酶家族的成员是细胞生长,分化和存活的重要介导物。该受体家族包括四种独特的成员,包括表皮生长因子受体(EGFR,ErbB1,或HER1),HER2(ErbB2或p185neu),HER3(ErbB3)和HER4(ErbB4或tyro2)。该受体家族的成员已牵连于多种类型的人恶性肿瘤。
鼠抗HER2抗体4D5的重组人源化型式(huMAb4D5-8,rhuMAb HER2,曲妥珠单抗或美国专利No.5,821,337)在患有过表达HER2的转移性乳腺癌,已接受过大量在前抗癌疗法的患者中是有临床活性的(Baselga等,J.Clin.Oncol.14:737-744(1996))。
曲妥珠单抗在1998年9月25日从食品药品管理局得到上市许可,用于治疗其肿瘤过表达HER2蛋白的转移性乳腺癌患者。目前,批准曲妥珠单抗在转移性背景中用作单一药剂或与化疗或激素治疗组合,和作为单一药剂或与化疗组合作为辅助治疗用于患有早期HER2阳性乳腺癌的患者。基于曲妥珠单抗的疗法现在是用于患有HER2阳性早期乳腺癌,不具有其使用禁忌证的患者的推荐治疗(处方信息;NCCN指南,版本2.2011)。曲妥珠单抗加多西他赛(或帕利他赛)是一线转移性乳腺癌(MBC)治疗背景中的经注册的标准医护(Slamon等,N Engl J Med.2001;344(11):783-792;Marty等,J Clin Oncol.2005;23(19):4265-4274)。
基于HER2表达为疗法选择用HER2抗体曲妥珠单抗治疗的患者。参见例如,WO99/31140(Paton等),US2003/0170234A1(Hellmann,S.)和US2003/0147884(Paton等);以及WO01/89566,US2002/0064785和US2003/0134344(Mass等)。亦参见美国专利No.6,573,043,美国专利No.6,905,830和US2003/0152987,Cohen等,其涉及用于检测HER2过表达和扩增的免疫组织化学(IHC)和荧光原位杂交(FISH)。如此,对转移性乳腺癌的最佳管理现在不仅考虑患者的一般状况,医学史,和受体状态,而且还考虑HER2状态。
帕妥珠单抗(亦称为重组人源化单克隆抗体2C4(rhuMAb 2C4);Genentech,Inc,South San Francisco)代表称为HER二聚化抑制剂(HDI)的一类新药剂中的第一种,且发挥抑制HER2与其他HER受体(如EGFR/HER1,HER2,HER3和HER4)形成活性异二聚体或同二聚体的能力的功能。参见例如,Harari和Yarden,Oncogene 19:6102-14(2000);Yarden和Sliwkowski,Nat Rev Mol Cell Biol 2:127-37(2001);Sliwkowski,Nat Struct Biol10:158-9(2003);Cho等,Nature 421:756-60(2003);和Malik等,Pro Am Soc CancerRes44:176-7(2003)。
已显示帕妥珠单抗对肿瘤细胞中HER2-HER3异二聚体形成的阻断抑制关键的细胞信号传导,其导致降低的肿瘤增殖和存活(Agus等,Cancer Cell 2:127-37(2002))。
帕妥珠单抗已在临床中进行作为单一药剂的试验,即患有晚期癌症的患者的Ia期试验和患有卵巢癌和乳腺癌以及肺癌和前列腺癌的患者中的II期试验。在I期研究中,将患有不能治愈的,局部晚期的,再发或转移性实体瘤,已在标准疗法期间或之后进展的患者用每3周静脉内给药的帕妥珠单抗治疗。帕妥珠单抗一般耐受较好。20位可评估应答的患者中有3位实现肿瘤消退。确认了2位患者的部分响应。在21位患者中有6位中观察到持续超过2.5个月的稳定疾病(Agus等,Pro Am Soc Clin Oncol 22:192(2003))。在2.0-15mg/kg的剂量,帕妥珠单抗的药动学为线性,且均值清除范围为2.69至3.74mL/d/kg,均值终末消除半衰期范围为15.3至27.6天。未检测到针对帕妥珠单抗的抗体(Allison等,Pro Am SocClin Oncol 22:197(2003))。
US 2006/0034842描述了用抗ErbB2抗体组合来治疗表达ErbB的癌症的方法。US2008/0102069描述了曲妥珠单抗和帕妥珠单抗在治疗HER2阳性转移性癌症如乳腺癌中的用途。Baselga等,J Clin Oncol,2007ASCO Annual Meeting Proceedings Part I,Col.25,No.18S(June 20Supplement),2007:1004报告了对患有经预治疗的HER2阳性乳腺癌,在用曲妥珠单抗治疗期间已进展的患者的治疗,其使用曲妥珠单抗和帕妥珠单抗的组合。Portera等,J Clin Oncol,2007ASCO Annual Meeting Proceedings Part I.Vol.25,No.18S(June20Supplement),2007:1028评估了曲妥珠单抗+帕妥珠单抗组合疗法在已在基于曲妥珠单抗的疗法上疾病进展的HER2阳性乳腺癌患者中的功效和安全性。作者得出结论,需要对该组合治疗的功效的进一步评估来定义该治疗方案的总体风险和益处。
帕妥珠单抗已在II期研究中与曲妥珠单抗组合在患有HER2阳性转移性乳腺癌,先前针对转移性疾病接受过曲妥珠单抗的患者中进行评估。一项由国家癌症研究院(NCI)进行的研究招募了11位患有先前治疗过的HER2阳性转移性乳腺癌的患者。11位患者中有2位展现出部分响应(PR)(Baselga等,J Clin Oncol 2007ASCO Annual MeetingProceedings;25:18S(June 20Supplement):1004。
在患有早期HER2阳性乳腺癌的女性中评估帕妥珠单抗和曲妥珠单抗加化疗(多西他赛)的新组合方案效果的II期新辅助研究的结果(2010年12月8-12日在CTRC-AACR圣安东尼奥乳腺癌学术会议(SABCS)上呈现)显示,在手术前的新辅助背景中给予两种HER2抗体加多西他赛将乳腺中完全肿瘤消失的比率(病理学完全响应率,pCR,45.8个百分数)相比于曲妥珠单抗加多西他赛(pCR,29.0个百分数)显著改进了超过一半,p=0.014。
帕妥珠单抗和曲妥珠单抗(CLEOPATRA)II期临床研究的临床评估评价作为具有局部复发,不可切除,或转移性HER2阳性乳腺癌的患者的一线治疗,与安慰剂加曲妥珠单抗加多西他赛相比,帕妥珠单抗加曲妥珠单抗加多西他赛的功效和安全性。当作为HER2阳性转移性乳腺癌的一线治疗使用时,与安慰剂加曲妥珠单抗加多西他赛相比,帕妥珠单抗加曲妥珠单抗加多西他赛的组合显著延长无进展存活,心脏毒性效应没有升高(Baselga等,NEng J Med 2012 366:2,109-119)。
II期临床研究NeoSphere评价帕妥珠单抗和曲妥珠单抗的新辅助施用在具有可手术,局部晚期,和炎性乳腺癌的未治疗女性(尚未接受任何在先癌症疗法的患者)中的功效和安全性。给予帕妥珠单抗和曲妥珠单抗加多西他赛的患者显示与给予曲妥珠单抗加多西他赛的患者相比显著改善的病理学完全响应率,而耐受性没有实质性差异(Gianni等,Lancet Oncol 201213(1):25-32)。报告了5年随访的结果(Gianni等,Lancet Oncol201617(6):791-800)。
涉及HER2抗体的专利公开文本包括:美国专利No.5,677,171;5,720,937;5,720,954;5,725,856;5,770,195;5,772,997;6,165,464;6,387,371;6,399,063;6,015,567;6,333,169;4,968,603;5,821,337;6,054,297;6,407,213;6,639,055;6,719,971;6,800,738;5,648,237;7,018,809;6,267,958;6,695,940;6,821,515;7,060,268;7,682,609;7,371,376;6,127,526;6,333,398;6,797,814;6,339,142;6,417,335;6,489,447;7,074,404;7,531,645;7,846,441;7,892,549;6,573,043;6,905,830;7,129,840;7,344,840;7,468,252;7,674,589;6,949,245;7,485,302;7,498,030;7,501,122;7,537,931;7,618,631;7,862,817;7,041,292;6,627,196;7,371,379;6,632,979;7,097,840;7,575,748;6,984,494;7,279,287;7,811,773;7,993,834;7,435,797;7,850,966;7,485,704;7,807,799;7,560,111;7,879,325;7,449,184;7,700,299;和US 2010/0016556;US 2005/0244929;US 2001/0014326;US 2003/0202972;US 2006/0099201;US 2010/0158899;US2011/0236383;US 2011/0033460;US 2005/0063972;US 2006/018739;US 2009/0220492;US 2003/0147884;US 2004/0037823;US 2005/0002928;US 2007/0292419;US 2008/0187533;US 2003/0152987;US 2005/0100944;US 2006/0183150;US2008/0050748;US2010/0120053;US 2005/0244417;US 2007/0026001;US 2008/0160026;US 2008/0241146;US 2005/0208043;US 2005/0238640;US 2006/0034842;US 2006/0073143;US 2006/0193854;US 2006/0198843;US 2011/0129464;US 2007/0184055;US 2007/0269429;US2008/0050373;US 2006/0083739;US 2009/0087432;US 2006/0210561;US 2002/0035736;US 2002/0001587;US 2008/0226659;US 2002/0090662;US 2006/0046270;US 2008/0108096;US 007/0166753;US 2008/0112958;US 2009/0239236;US 2004/008204;US2009/0187007;US 2004/0106161;US 2011/0117096;US 2004/048525;US 2004/0258685;US 2009/0148401;US 2011/0117097;US 2006/0034840;US 2011/0064737;US 2005/0276812;US 2008/0171040;US 2009/0202536;US 2006/0013819;US 2006/0018899;US2009/0285837;US 2011/0117097;US 2006/0088523;US 2010/0015157;US 2006/0121044;US 2008/0317753;US2006/0165702;US 2009/0081223;US 2006/0188509;US 2009/0155259;US 2011/0165157;US 2006/0204505;US 2006/0212956;US 2006/0275305;US2007/0009976;US 2007/0020261;US 2007/0037228;US 2010/0112603;US 2006/0067930;US 2007/0224203;US 2008/0038271;US 2008/0050385;2010/0285010;US 2008/0102069;US 2010/0008975;US 2011/0027190;US 2010/0298156;US 2009/0098135;US 2009/0148435;US 2009/0202546;US 2009/0226455;US 2009/0317387;和US 2011/0044977。
发明概述
估计占据美国每年大约6000-8000例死亡,欧洲每年12,000-15,000例死亡,和全球每年60,000-90,000例死亡(基于乳腺癌总体的死亡率),具有HER2阳性乳腺癌的患者需要新的积极的治疗(Levi等,Eur J Cancer Prev 2005;14:497-502;Estimates ofworldwide burden of cancer in 2008:GLOBOCAN 2008.Int J Cancer 2010;127:2893-917;SEER cancer statistics review,1975-2008[Internet].Bethesda,MD.NationalCancer Institute;November 2010[updated,2011];Malvezzi等,Ann Oncol 2013;24:792-800)。呈现HER2阳性乳腺癌的患者的中值年龄是50-60岁中段,比一般乳腺癌群体年轻大约5岁(Breast Cancer Res Treat 2008;110:153-9;Breast Cancer Res2009;11:R31)。当女性的保险精算存活>80年时,每位患者的寿命损失中值是大约20年。当疾病仍然局限于乳房和区域淋巴结时改善初始疗法的结果提供潜在治愈疾病,以及在没有治愈的患者中延迟疾病复发和死亡的机会。
已经报告了在新辅助设置中和化疗的组合的有希望的结果(Gianni等,Lancet Oncol 2012;13:25-32;Ann Oncol 2013;24:2278-84),导致在美国加速批准用于新辅助用途。虽然已经评估一定范围的组合方案,但是需要包括基于蒽环类抗生素的化疗的含有的新辅助治疗方案,特别是具有剂量密集的(dd)进度表,包括多柔比星(而非表柔比星)作为蒽环类抗生素的治疗方案的安全性和功效数据,因为此类治疗和进度表在具有乳腺癌的患者的辅助和新辅助治疗中广泛使用。具体地,多柔比星加环磷酰胺(AC)继以帕利他赛加(TH)是依照NCCN指导方针的HER2阳性乳腺癌的新辅助和辅助治疗的两种优选方案之一。
含有的新辅助方案也需要更多数据,其中完全在手术之前给予化疗成分,而不是在新辅助和辅助施用之间分拆化疗。
本发明至少部分基于对实施例1中描述的一项非随机化,开放标签,多中心,多国II期临床试验的分析,其设计成主要评估与和组合给予的两种新辅助基于蒽环类抗生素/紫杉烷的方案的心脏安全性。
在第一个方面,本发明涉及一种用于治疗乳腺癌的方法,其包括对具有HER2阳性局部晚期,炎性,或早期阶段乳腺癌的患者在基于蒽环类抗生素的化疗后新辅助施用有效量的帕妥珠单抗和曲妥珠单抗的组合,其中在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的组合施用相对于在基于蒽环类抗生素的化疗后曲妥珠单抗的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件。
在一个具体方面,在至少4个周期的基于蒽环类抗生素的化疗之后开始帕妥珠单抗和曲妥珠单抗的组合施用。
在另一个方面,该基于蒽环类抗生素的化疗包含多柔比星。
在又一个方面,该基于蒽环类抗生素的化疗包含多柔比星加环磷酰胺。
在仍有又一个方面,该基于蒽环类抗生素的化疗是多柔比星加环磷酰胺(AC)。
在仍有又一个方面,该基于蒽环类抗生素的化疗是剂量密集的多柔比星和环磷酰胺(ddAC)。
在一个另外的方面,与G-CSF支持一起施用该多柔比星加环磷酰胺。
在一个具体方面,每两周施用该基于蒽环类抗生素的化疗。
在另一个方面,在帕妥珠单抗和曲妥珠单抗的组合施用之前施用至少四个周期的该基于蒽环类抗生素的化疗。
在还有另一个方面,该基于蒽环类抗生素的化疗包含表柔比星。
在又一个方面,该基于蒽环类抗生素的化疗包含表柔比星,5-氟尿嘧啶和环磷酰胺。
在仍有又一个方面,该基于蒽环类抗生素的化疗是5-氟尿嘧啶,表柔比星加环磷酰胺(FEC)。
在一个另外的方面,每三周施用该基于蒽环类抗生素的化疗。
在另一个方面,在帕妥珠单抗和曲妥珠单抗的组合施用之前施用至少四个周期的该基于蒽环类抗生素的化疗。
在还有另一个方面,与紫杉烷的新辅助施用组合施用帕妥珠单抗和曲妥珠单抗,其中该紫杉烷可以是例如多西他赛或帕利他赛。
在又一个方面,在开始紫杉烷施用时开始帕妥珠单抗和曲妥珠单抗的组合施用。
在仍有又一个方面,该pCR是乳腺病理学完全响应(bpCR)。
在一个另外的方面,该pCR是总病理学完全响应(tpCR)。
在另一个方面,该不良事件包括心脏副作用。
在一个具体方面,该不良事件是心脏副作用。
在一个方面,该心脏副作用包含左心室射血分数(LVEF)下降。
在另一个方面,该LVEF下降是无症状的。
在还有另一个方面,该心脏副作用包含左心室收缩功能障碍(LVSD)。
在一个方面,该LVSD是有症状的。
在另一个方面,该HER2阳性乳腺癌特征在于免疫组织化学(IHC)得分3+或2+或通过通过荧光原位杂交测定的≥2.0的扩增比。
在又一个方面,该HER2阳性乳腺癌是通过PAM50RT-qPCR测定法测定的腔A,腔B,HER2富集(HER2-E)或基样亚型的。
在仍有又一个方面,该HER2阳性乳腺癌是HER2-E亚型。
在一个另外的方面,该HER2阳性乳腺癌特征在于异常PI3K途径。
在一个不同方面,该HER2阳性乳腺癌呈乙酰基丹参酮IIA(ATA)阳性。
在又一个方面,该新辅助施用继以确定性手术。
在仍有又一个方面,在至少八个周期的新辅助疗法之后实施确定性手术。
在另一个方面,确定性手术继以帕妥珠单抗加曲妥珠单抗的辅助施用。
在还有另一个方面,pCR与无进展存活(PFS)有关联。
在又一个方面,本发明涉及一种通过在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的组合的新辅助施用在具有HER2-阳性,局部晚期,炎性,或早期阶段乳腺癌的患者中相对于在含有蒽环类抗生素的化疗后曲妥珠单抗的施用延长病理学完全响应(pCR)的方法,而不相对于新辅助含有蒽环类抗生素的化疗显著增加不良事件。
在一个不同方面,本发明涉及一种制品,其包含其中有帕妥珠单抗的管形瓶和包装插页,其中该包装插页提供图10-15中显示的安全性数据的至少部分。
在一个方面,该制品包含装有约420mg的帕妥珠单抗的单剂管形瓶。
在一个不同方面,本发明涉及一种用于生成制品的方法,其包括将其中有帕妥珠单抗的管形瓶和包装插页包装在一起,其中该包装插页提供图10-15中显示的安全性数据的至少部分。
本发明进一步涉及帕妥珠单抗在制备用于在具有HER2阳性局部晚期,炎性,或早期阶段乳腺癌的患者中治疗乳腺癌的药物中的用途,包括在基于蒽环类抗生素的化疗后新辅助施用有效量的帕妥珠单抗和曲妥珠单抗的组合,其中在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的组合施用相对于在基于蒽环类抗生素的化疗后曲妥珠单抗的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件。
在另一个方面,本发明涉及帕妥珠单抗,供在具有HER2阳性局部晚期,炎性,或早期阶段乳腺癌的患者中治疗乳腺癌中使用,其中该治疗包括在基于蒽环类抗生素的化疗后新辅助施用有效量的帕妥珠单抗和曲妥珠单抗的组合,其中在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的组合施用相对于在基于蒽环类抗生素的化疗后曲妥珠单抗的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件。
在还有另一个方面,本发明涉及曲妥珠单抗在制备用于在具有HER2阳性局部晚期,炎性,或早期阶段乳腺癌的患者中治疗乳腺癌的药物中的用途,包括在基于蒽环类抗生素的化疗后新辅助施用有效量的曲妥珠单抗和帕妥珠单抗的组合,其中在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的组合施用相对于在基于蒽环类抗生素的化疗后曲妥珠单抗的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件。
在又一个方面,本发明涉及曲妥珠单抗,供在具有HER2阳性局部晚期,炎性,或早期阶段乳腺癌的患者中治疗乳腺癌中使用,其中该治疗包括在基于蒽环类抗生素的化疗后新辅助施用有效量的曲妥珠单抗和帕妥珠单抗的组合,其中在基于蒽环类抗生素的化疗后曲妥珠单抗和帕妥珠单抗的组合施用相对于在基于蒽环类抗生素的化疗后曲妥珠单抗的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件。
附图简述
图1提供HER2蛋白结构的示意图,及其胞外域的域I-IV的氨基酸序列(分别为SEQID No.1-4)。
图2A和2B绘出以下的氨基酸序列的比对:鼠单克隆抗体2C4的可变轻(VL)(图2A)和可变重(VH)(图2B)域(分别为SEQ ID No.5和6);变体574/帕妥珠单抗的VL和VH域(分别为SEQ ID No.7和8),及人VL和VH共有框架(humκ1,轻卡帕亚组I;humIII,重亚组III)(分别为SEQ ID No.9和10)。星号指示帕妥珠单抗和鼠单克隆抗体2C4的可变域之间或帕妥珠单抗和人框架的可变域之间的差异。互补决定区(CDR)在括号内。
图3A和3B显示帕妥珠单抗轻链(图3A;SEQ ID NO.11)和重链(图3B;SEQ IDNo.12)的氨基酸序列。CDR粗体显示。轻链和重链的计算分子量为23,526.22Da和49,216.56Da(半胱氨酸以还原形式)。碳水化合物模块附接于重链的Asn 299。
图4A和4B分别显示曲妥珠单抗轻链(图4A;SEQ ID NO.13)和重链(图4B;SEQ IDNO.14)的氨基酸序列。可变轻和可变重域的边界由箭头指示。
图5A和5B分别绘出变体帕妥珠单抗轻链序列(图5A;SEQ ID NO.15)和变体帕妥珠单抗重链序列(图5B;SEQ ID NO.16)。
图6图示实施例1中描述的用于在具有HER2阳性,局部晚期,炎性,或早期阶段乳腺癌的患者中评估与和标准新辅助基于蒽环类抗生素的化疗组合的的新辅助施用的一项II期临床研究的研究设计。D=多西他赛;ddAC=剂量密集的多柔比星和环磷酰胺;FEC=5-氟尿嘧啶,表柔比星,环磷酰胺;T=帕利他赛。
图7图示用于为实施例1中描述的II期临床研究鉴定适格患者的筛选规程。CISH=显色原位杂交;HER2=人表皮生长因子受体2;IHC=免疫组织化学;FISH=荧光原位杂交;SISH=银原位杂交。通过中心测试的HER2阳性如下定义:在>10%的免疫反应性细胞中IHC3+或通过ISH的HER2基因扩增(HER2基因信号对着丝粒17信号之比≥2.0)。
图8图示用于HER2靶向研究药疗的继续和中止的算法。
图9图示用于心力衰竭的纽约心脏联合会(NYHA)功能分类系统。
图10图示在新辅助治疗期间不良事件(AE)的汇总,安全性群体。
图11图示选定不良事件(AE):心力衰竭(所有类别),新辅助期。
图12图示持续左心室射血分数(LVEF)下降的汇总表。
图13图示在新辅助治疗期间的最常见严重不良事件(SAE):安全性群体(所有等级)。任一队列中发生率≥2%。
图14图示在新辅助治疗期间的最常见不良事件(AE):安全性群体:3-5级。任一队列中的发生率≥5%。
图15图示在新辅助治疗期间的最常见AE:安全性群体(所有等级)。任一队列中的发生率≥25%。
图16图示总的病理学完全响应(tpCR)的汇总(当地病理学家评价)。
图17图示依肿瘤/结分期(T0N0)的德国乳房小组(GBG)病理学完全响应(pCR):意向治疗(ITT)群体。
图18图示依新辅助治疗的周期的总的病理学完全响应(tpCR)(依肿瘤和结分期):意向治疗(ITT)群体。
发明详述
I.定义
“存活”指患者保持存活,并且包括总体存活(OS)以及无进展存活(PFS)。
“总体存活”或“OS”指患者自诊断或治疗时间起保持限定时段存活,诸如1年,2年,5年,10年等。就实施例中描述的临床试验的目的而言,总体存活(OS)定义为从患者群体随机化的日期起到因任何原因而死亡的日期的时间。
“无进展存活”或“PFS”指患者保持存活且癌症没有进展或恶化。就实施例中描述的临床试验的目的而言,无进展存活(PFS)定义为从研究群体随机化到首次记载的进展性疾病或难管理的毒性或因任何原因的死亡(以先发生者为准)的时间。疾病进展可通过任何临床接受的方法记载,如例如,如通过实体瘤中的响应评估标准(RECIST)确定的射线照相进展性疾病(Therasse等,J Natl Ca Inst 2000;92(3):205-216),通过对脑脊髓液的细胞学评估诊断的癌性脑膜炎,和/或监测皮下损伤的胸壁再发的医学摄影。
“延长存活”意味着使依照本发明治疗的患者中总体或无进展存活相对于未治疗的患者和/或相对于用一种或多种已获批准的抗肿瘤药剂治疗但未接受依照本发明治疗的患者延长。在一个具体的例子中,“延长存活”意味着使接受本发明的组合疗法(例如用帕妥珠单抗,曲妥珠单抗和化疗的组合治疗)的癌症患者的无进展存活(PFS)和/或总体存活(OS)相对于仅用曲妥珠单抗和化疗治疗的患者延长。在另一个具体的例子中,“延长存活”意味着使接受本发明的组合疗法(例如用帕妥珠单抗,曲妥珠单抗和化疗的组合治疗)的癌症患者的无进展存活(PFS)和/或总体存活(OS)相对于仅用帕妥珠单抗和化疗治疗的患者延长。
“客观响应”(OR)指可测量的响应,包括完全响应(CR)或部分响应(PR)。
“完全响应”或“CR”意指癌症的所有症候响应治疗而消失。这并不总是意味着癌症得到治愈。
“部分响应”或“PR”指一处或多处肿瘤或损伤的大小或癌症在身体中的范围响应治疗而缩小。
“HER受体”是属于HER受体家族的受体蛋白质酪氨酸激酶,包括EGFR,HER2,HER3和HER4受体。HER受体通常会包含胞外域,它可结合HER配体和/或与另一个HER受体分子二聚化;亲脂性跨膜域;保守的胞内酪氨酸激酶域;和含有几个可被磷酸化的酪氨酸残基的羧基末端信号传导域。HER受体可以是“天然序列”HER受体或其“氨基酸序列变体”。优选的是,HER受体是天然序列人HER受体。
表述“ErbB2”和“HER2”在本文中可互换使用,指例如Semba等,PNAS(USA)82:6497-6501(1985)和Yamamoto等Nature 319:230-234(1986)中描述的人HER2蛋白(Genebank登录号X03363)。术语“erbB2”指编码人ErbB2的基因,而“neu”指编码大鼠p185neu的基因。优选的HER2是天然序列人HER2。
本文中“HER2胞外域”或“HER2ECD”指锚定于细胞膜或处于循环中的在细胞外部的HER2域,包括其片段。HER2的氨基酸序列显示于图1。在一个实施方案中,HER2的胞外域可以包含4个域:“域I”(约1-195的氨基酸残基;SEQ ID NO:1),“域II”(约196-319的氨基酸残基;SEQ ID NO:2),“域III”(约320-488的氨基酸残基;SEQ ID NO:3)和“域IV”(约489-630的氨基酸残基;SEQ ID NO:4)(没有信号肽的残基编号)。参见Garrett等Mol.Cell..11:495-505(2003),Cho等Nature 421:756-760(2003),Franklin等Cancer Cell 5:317-328(2004)和Plowman等Proc.Natl.Acad.Sci.90:1746-1750(1993),以及本文中图1。
“HER3”或“ErbB3”在本文中指如例如美国专利No.5,183,884和5,480,968及Kraus等,PNAS(USA)86:9193-9197(1989)中公开的受体。
“低HER3”癌症是以低于该癌症类型中HER3表达的中值水平表达HER3的癌症。在一个实施方案中,所述低HER3癌症是上皮卵巢癌,腹膜癌或输卵管癌。可评估癌症中的HER3DNA,蛋白质和/或mRNA水平来确定癌症是否是低HER3癌症。关于低HER3癌症的更多信息参见例如美国专利No.7,981,418。任选地,实施HER3mRNA表达测定法来确定癌症是低HER3癌症。在一个实施方案中,评估癌症中的HER3mRNA水平,例如使用聚合酶链式反应(PCR),如定量逆转录PCR(qRT-PCR)。任选地,所述癌症以等于或低于约2.81的浓度比表达HER3,如通过qRT-PCR,例如使用COBAS 仪评估的。
“HER二聚体”在本文中指包含至少两个HER受体的非共价联合二聚体。当表达两种或更多种HER受体的细胞暴露于HER配体时可能形成此类复合物,且可通过免疫沉淀进行分离及通过SDS-PAGE进行分析,如例如Sliwkowski等,J.Biol.Chem.269(20):14661-14665(1994)中所述。其它蛋白质,如细胞因子受体亚基(例如gp130)可与所述二聚体联合。优选地,所述HER二聚体包含HER2。
“HER异二聚体”在本文中指包含至少两个不同HER受体的非共价联合异二聚体,如EGFR-HER2,HER2-HER3或HER2-HER4异二聚体。
“HER抗体”是结合HER受体的抗体。任选地,HER抗体进一步干扰HER活化或功能。优选地,HER抗体结合HER2受体。本文中感兴趣的HER2抗体是帕妥珠单抗和曲妥珠单抗。
“HER活化”指任一种或多种HER受体的活化或磷酸化。一般而言,HER活化导致信号转导(例如由HER受体胞内激酶域引起的,磷酸化HER受体或底物多肽中的酪氨酸残基)。HER活化可由结合包含感兴趣HER受体的HER二聚体的HER配体介导。结合HER二聚体的HER配体可活化二聚体中一种或多种HER受体的激酶域,并由此导致一种或多种HER受体中酪氨酸残基的磷酸化和/或其它底物多肽如Akt或MAPK胞内激酶中酪氨酸残基的磷酸化。
“磷酸化”指一个或多个磷酸基向蛋白质如HER受体或其底物的添加。
“抑制HER二聚化”的抗体是抑制或干扰HER二聚体形成的抗体。优选地,这类抗体结合HER2于其异二聚体结合位点处。本文中最优选的二聚化抑制性抗体是帕妥珠单抗或MAb 2C4。抑制HER二聚化的抗体的其他例子包括结合EGFR并抑制其与一种或多种其他HER受体二聚化的抗体(例如EGFR单克隆抗体806,MAb 806,其结合活化或“未栓系”的EGFR;参见Johns等,J.Biol.Chem.279(29):30375-30384(2004));结合HER3并抑制其与一种或多种其他HER受体二聚化的抗体;和结合HER4并抑制其与一种或多种其他HER受体二聚化的抗体。
“HER2二聚化抑制剂”是抑制包含HER2的二聚体或异二聚体形成的药剂。
HER2上的“异二聚体结合位点”指HER2胞外域中在与EGFR,HER3或HER4形成二聚体时,接触EGFR,HER3或HER4胞外域中某区域或与EGFR,HER3或HER4胞外域中某区域形成介面的区域。已发现所述区域在HER2的域II中(SEQ ID NO:15)。Franklin等,Cancer Cell 5:317-328(2004)。
“结合HER2的异二聚体结合位点的”HER2抗体结合域II(SEQ ID NO:2)中的残基,且任选还结合HER2胞外域的其它域,如域I和III(SEQ ID NO:1和3)中的残基,而且至少在一定程度上能在空间上阻碍HER2-EGFR,HER2-HER3或HER2-HER4异二聚体的形成。Franklin等,Cancer Cell 5:317-328(2004)表征了存放在RCSB蛋白质数据库(ID Code IS78)的HER2-帕妥珠单抗晶体结构,举例说明了结合HER2的异二聚体结合位点的例示性抗体。
“结合HER2的域II”的抗体结合域II(SEQ ID NO:2)中的残基和任选HER2的其它域,如域I和III(分别为SEQ ID NO:1和3)中的残基。优选的是,结合域II的抗体结合HER2域I,II和III之间的连接处。
就本文中目的而言,可交换使用的“帕妥珠单抗”和“rhuMAb 2C4”指包含分别SEQID NO:7和8中的可变轻链和可变重链氨基酸序列的抗体。在帕妥珠单抗是完整抗体的情况下,它优选包含IgG1抗体;在一个实施方案中,包含SEQ ID NO:11或15中的轻链氨基酸序列,和SEQ ID NO:12或16中的重链氨基酸序列。任选地,所述抗体由重组中国仓鼠卵巢(CHO)细胞产生。术语“帕妥珠单抗”和“rhuMAb 2C4”在本文中覆盖具有美国采用名称(USAN)或国际非专有名称(INN):帕妥珠单抗的药物的生物类似型式。
就本文中目的而言,可交换使用的“曲妥珠单抗”和“rhuMAb4D5”指包含分别来自SEQ ID NO:13和14的可变轻链和可变重链氨基酸序列的抗体。在曲妥珠单抗是完整抗体的情况下,它优选包含IgG1抗体;在一个实施方案中,包含SEQ ID NO:13中的轻链氨基酸序列和SEQ ID NO:14中的重链氨基酸序列。任选地,所述抗体由中国仓鼠卵巢(CHO)细胞产生。术语“曲妥珠单抗”和“rhuMAb4D5”在本文中覆盖具有美国采用名称(USAN)或国际非专有名称(INN):曲妥珠单抗的药物的生物类似型式。
术语“抗体”在本文中以最广义使用,具体覆盖单克隆抗体,多克隆抗体,多特异性抗体(例如双特异性抗体),及抗体片段,只要它们展现期望的生物学活性。
非人(例如啮齿类)抗体的“人源化”形式指最低限度包含衍生自非人免疫球蛋白的序列的嵌合抗体。对于大部分而言,人源化抗体是人免疫球蛋白(受体抗体),其中来自受体高变区的残基用来自具有期望特异性,亲和力和能力的非人物种(供体抗体)如小鼠,大鼠,家兔或非人灵长类的高变区的残基替换。在有些情况中,将人免疫球蛋白的框架区(FR)残基用相应的非人残基替换。此外,人源化抗体可包含在受体抗体或供体抗体中没有发现的残基。进行这些修饰是为了进一步改进抗体的性能。通常,人源化抗体会包含至少一个,通常两个基本上整个如下的可变域,其中所有或基本上所有的高变环对应于非人免疫球蛋白的高变环,且所有或基本上所有的FR是人免疫球蛋白序列的FR。任选的是,人源化抗体还会包含至少部分的免疫球蛋白恒定区(Fc),通常是人免疫球蛋白的恒定区。更多细节参见Jones等,Nature 321:522-525(1986);Riechmann等,Nature 332:323-329(1988);及Presta,Curr.Op.Struct.Biol.2:593-596(1992)。人源化的HER2抗体具体包括曲妥珠单抗如记载于美国专利5,821,337(通过提述明确并入本文)的表3中和如本文中定义的;和人源化2C4抗体,如本文中描述和定义的帕妥珠单抗。
“完整抗体”在本文中为包含两个抗原结合区和Fc区的抗体。优选地,完整抗体具有功能性Fc区。
“抗体片段”包含完整抗体的一部分,优选包含其抗原结合区。抗体片段的例子包括Fab,Fab',F(ab')2和Fv片段;双抗体;线性抗体;单链抗体分子;及由抗体片段形成的多特异性抗体。
“天然抗体”通常是由两条相同的轻链(L)和两条相同的重链(H)构成的约150,000道尔顿的异四聚体糖蛋白。每条轻链通过一个共价二硫键与重链连接,而二硫化物连接的数目在不同免疫球蛋白同种型的重链间有所变化。每条重链和轻链还具有间隔规律的链内二硫桥。每条重链在一端具有一个可变域(VH),接着是多个恒定域。每条轻链具有在一端的一个可变域(VL)和在另一端的一个恒定域。轻链的恒定域与重链的第一恒定域排列在一起,而轻链的可变域与重链的可变域排列在一起。认为特定的氨基酸残基在轻链和重链可变域之间形成界面。
术语“高变区”在用于本文时指抗体中负责抗原结合的氨基酸残基。高变区通常包含来自“互补决定区”或“CDR”的氨基酸残基(例如轻链可变域中的残基24-34(L1),50-56(L2)和89-97(L3)及重链可变域中的31-35(H1),50-65(H2)和95-102(H3);Kabat等,Sequences of Proteins of Immunological Interest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD.(1991))和/或那些来自“高变环”的残基(例如轻链可变域中的残基26-32(L1),50-52(L2)和91-96(L3)及重链可变域中的26-32(H1),53-55(H2)和96-101(H3);Chothia和Lesk,J.Mol.Biol.196:901-917(1987))。“框架区”或“FR”残基是本文定义的高变区残基以外的那些可变域残基。
术语“Fc区”在本文中用于定义免疫球蛋白重链的C端区,包括天然序列Fc区和变体Fc区。尽管免疫球蛋白重链的Fc区的边界可以变化,但人IgG重链Fc区通常定义为自位置Cys226,或自Pro230处的氨基酸残基延伸至重链的羧基端。可以除去Fc区的C端赖氨酸(依照EU编号系统的残基447),例如在抗体的产生或纯化期间,或通过重组工程化改造编码抗体重链的核酸。因此,完整抗体的组合物可以包含已除去所有K447残基的抗体群体,未除去任何K447残基的抗体群体,和具有有和无K447残基的抗体混合物的抗体群体。
除非另有指示,本文中免疫球蛋白重链中残基的编号方式是EU索引的编号方式,如记载于Kabat等,Sequences of Proteins of Immunological Interest,5th Ed.PublicHealth Service,National Institutes of Health,Bethesda,MD(1991),其通过提述明确并入本文。“如Kabat中的EU索引”指人IgG1EU抗体的残基编号方式。
“功能性Fc区”拥有天然序列Fc区的“效应器功能”。例示性的“效应器功能”包括C1q结合;补体依赖性细胞毒性;Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬作用;细胞表面受体(例如B细胞受体;BCR)下调等。此类效应器功能一般要求Fc区与结合域(例如抗体可变域)联合,而且可使用多种测定法来评估,例如本文中所公开的。
“天然序列Fc区”包含与自然界中找到的Fc区的氨基酸序列相同的氨基酸序列。天然序列人Fc区包括天然序列人IgG1Fc区(非A和A同种异型);天然序列人IgG2Fc区;天然序列人IgG3Fc区;及天然序列人IgG4Fc区,以及其天然存在变体。
“变异/变体Fc区”包含由于至少一处氨基酸修饰,优选一处或多处氨基酸替代而与天然序列Fc区的氨基酸序列有所不同的氨基酸序列。优选的是,变异Fc区具有与天然序列Fc区或与亲本多肽的Fc区相比至少一处氨基酸替代,例如在天然序列Fc区中或在亲本多肽的Fc区中具有约1处至约10处氨基酸替代,优选约1处至约5处氨基酸替代。变异Fc区在本文中会优选与天然序列Fc区和/或亲本多肽的Fc区拥有至少约80%的同源性,最优选与其至少约90%的同源性,更优选与其至少约95%的同源性。
根据完整抗体的重链恒定域的氨基酸序列,可将其归入不同的“类”。完整抗体有五种主要的类:IgA,IgD,IgE,IgG和IgM,其中有些可进一步分为“亚类”(同种型),例如IgG1,IgG2,IgG3,IgG4,IgA1和IgA2。将与不同抗体类对应的重链恒定域分别称作α,δ,ε,γ和μ。不同类的免疫球蛋白的亚基结构和三维构造是众所周知的。
“裸抗体”指未缀合异源分子,如细胞毒性模块或放射性标记物的抗体。
“亲和力成熟的”抗体指在一个或多个其高变区中具有一处或多处改变的抗体,与不拥有此类改变的亲本抗体相比,此类改变导致该抗体对抗原的亲和力改善。优选的亲和力成熟的抗体会对靶抗原具有纳摩尔级或甚至皮摩尔级的亲和力。亲和力成熟的抗体由本领域中已知的规程产生。Marks等Bio/Technology 10:779-783(1992)描述了通过VH和VL域改组的亲和力成熟。CDR和/或框架残基的随机诱变记载于以下:Barbas等ProcNat.Acad.Sci,USA 91:3809-3813(1994);Schier等Gene 169:147-155(1995);Yelton等J.Immunol.155:1994-2004(1995);Jackson等,J.Immunol.154(7):3310-9(1995);和Hawkins et al,J.Mol.Biol.226:889-896(1992)。
“脱酰胺”的抗体是其一个或多个天冬酰胺残基已衍生化为例如天冬氨酸,琥珀酰亚胺,或异天冬氨酸的抗体。
术语“癌症”和“癌性”指向或描述哺乳动物中特征通常为不受调控的细胞生长的生理疾患。
“胃癌”具体地包括转移性或局部晚期的不可切除的胃癌,包括但不限于,组织学确认的胃或胃食管连接部腺癌,其具有不可手术(不可切除)的局部晚期或转移性疾病,不适合通过治愈性治疗处理,和术后再发的晚期胃癌,如胃或胃食管连接部腺癌,当手术意图是治愈该疾病时。
“晚期”癌症指通过局部侵入或转移而扩散到最初的部位或器官之外的癌症。因此,术语“晚期”癌症包括局部晚期的和转移性的疾病。
“顽固性/不应性(refractory)”癌症指尽管对癌症患者施用抗肿瘤剂如化疗,仍然发生进展的癌症。顽固性癌症的一个例子是铂抗性癌症。
“再发的”癌症指在对初始治疗如手术的响应之后,在初始部位或远端部位再次生长的癌症。
“局部再发的”癌症是治疗后在与先前所治疗癌症相同的位置处返回的癌症。
“不可切除的”癌症是不能通过手术除去(切除)的。
“早期乳腺癌”在本文中指尚未扩散到乳腺或腋淋巴结之外的乳腺癌。这类癌症一般用新辅助或辅助疗法治疗。
“新辅助疗法”或“新辅助治疗”或“新辅助施用”指在手术前给予的系统性疗法。
“辅助疗法”或“辅助治疗”或“辅助施用”指在手术后给予的系统性疗法。
“转移性”癌症指从身体的一个部位(例如乳腺)扩散到身体的另一个部位的癌症。
在本文中,“患者”或“受试者”是人患者。所述患者可以是“癌症患者”,即患有或有风险患上癌症(特别是乳腺癌)的一种或多种症状的患者。
“患者群体”指一组癌症患者。这类群体可用于证明药物如帕妥珠单抗和/或曲妥珠单抗的统计学显著的功效和/或安全性。
“复发的”患者是在消退后具有癌症的症候或症状的患者。任选地,患者在辅助或新辅助疗法后复发。
“展示HER表达,扩增或活化”的癌症或生物学样品是在诊断测试中表达(包括过表达)HER受体,具有扩增的HER基因,和/或以其它方式展现出HER受体活化或磷酸化的癌症或生物学样品。
“展示HER活化”的癌症或生物学样品是在诊断测试中显示HER受体活化或磷酸化的癌症或生物学样品。这类活化可直接(例如通过ELISA来测量HER磷酸化)或间接(例如通过基因表达概况分析或通过检测HER异二聚体,如本文中描述的)测定。
“HER受体过表达或扩增”的癌细胞指与同一组织类型的非癌细胞相比,具有显著更高水平的HER受体蛋白质或基因的癌细胞。此类过表达可以是由基因扩增或者转录或翻译增加引起的。可在诊断或预后测定法中通过评估细胞表面上存在的HER蛋白水平的升高(例如通过免疫组化测定法;IHC)来测定HER受体的过表达或扩增。或者/另外,可测量细胞中编码HER的核酸的水平,例如通过原位杂交(ISH),包括荧光原位杂交(FISH;参见1998年10月公布的WO 98/45479)和生色原位杂交(CISH;参见例如Tanner等,Am.J.Pathol.157(5):1467-1472(2000);Bella等,J.Clin.Oncol.26:(May 20suppl;abstr22147)(2008)),Southern印迹或聚合酶链式反应(PCR)技术,诸如定量实时PCR(qRT-PCR)。还可通过测量生物学流体诸如血清中的脱落抗原(例如HER胞外域)来研究HER受体过表达或扩增(参见例如1990年6月12日公告的美国专利No.4,933,294;1991年4月18日公布的WO 91/05264;1995年3月28日公告的美国专利No.5,401,638;和Sias等J.Immunol.Methods 132:73-80(1990))。在上述测定法之外,熟练从业人员还可利用多种体内测定法。例如,可将患者体内细胞暴露于任选用可检测标记物例如放射性同位素标记的抗体,并且可评估该抗体与患者中细胞的结合,例如通过外部扫描放射性或通过分析取自事先已暴露于所述抗体的患者的活检样品。
“HER2阳性”癌症包含具有高于正常水平的HER2的癌细胞。HER2阳性癌症的例子包括HER2阳性乳腺癌和HER2阳性胃癌。任选地,HER2阳性癌症具有2+或3+的免疫组织化学(IHC)评分和/或≥2.0的原位杂交(ISH)扩增比。
在本文中,“抗肿瘤剂”指用于治疗癌症的药物。本文中的抗肿瘤剂的非限制性例子包括化疗剂,HER二聚化抑制剂,HER抗体,针对肿瘤相关抗原的抗体,抗激素化合物,细胞因子,EGFR靶向药物,抗血管发生剂,酪氨酸激酶抑制剂,生长抑制剂和生长抑制性抗体,细胞毒剂,诱发凋亡的抗体,COX抑制剂,法尼基转移酶抑制剂,结合癌胚蛋白CA125的抗体,HER2疫苗,Raf或ras抑制剂,多柔比星脂质体,托泊替康,紫杉烷(taxene,taxane),双重酪氨酸激酶抑制剂,TLK286,EMD-7200,帕妥珠单抗,曲妥珠单抗,厄洛替尼(erlotinib)和贝伐单抗(bevacizumab)。
“表位2C4”是HER2胞外域中抗体2C4所结合的区域。为了筛选基本结合2C4表位的抗体,可进行常规的交叉阻断测定法,如Antibodies,A Laboratory Manual,Cold SpringHarbor Laboratory,Ed Harlow和David Lane(1988)中所描述的。优选地,抗体将2C4对HER2的结合阻断约50%或更多。或者,可进行表位映射以评估抗体是否基本结合HER2的2C4表位。表位2C4包含来自HER2胞外域中域II的残基(SEQ ID NO:2)。2C4和帕妥珠单抗在域I,II和III(分别为SEQ ID NO:1,2和3)的连接处结合HER2的胞外域。Franklin等Cancer Cell5:317-328(2004)。
“表位4D5”指HER2胞外域中抗体4D5(ATCC CRL 10463)和曲妥珠单抗所结合的区域。此表位接近HER2的跨膜域,且在HER2的域IV(SEQ ID NO:4)之内。为了筛选基本结合4D5表位的抗体,可进行常规的交叉阻断测定法,如Antibodies,A Laboratory Manual,ColdSpring Harbor Laboratory,Ed Harlow和David Lane(1988)中所描述的。或者,可进行表位映射以评估抗体是否基本结合HER2的4D5表位(例如约第529位残基至约第625位残基区域内的任何一个或多个残基,包含HER2ECD;残基编号包括信号肽)。
“治疗”指治疗性处理和防护性或预防性措施二者。需要治疗的那些包括已经患有癌症的以及要预防癌症的。因此,本文中待治疗的患者可能已经诊断为患有癌症或者可能有患上癌症的倾向性或易感性。
术语“有效量”指在患者中有效治疗癌症的药物量。药物的有效量可减少癌细胞的数目;缩小肿瘤的尺寸;抑制(即减缓到一定程度和优选阻止)癌细胞浸润到周围器官中;抑制(即减缓到一定程度和优选阻止)肿瘤转移;在某种程度上抑制肿瘤生长;和/或在一定程度上减轻一种或多种与癌症有关的症状。在药物可阻止生长和/或杀死现有癌细胞的程度上,它可以是抑制细胞的和/或细胞毒性的。有效量可延长无进展存活(例如如通过实体瘤的响应评估标准RECIST或CA-125变化测量的),导致客观响应(包括部分响应,PR或完全响应,CR),增加总体存活时间,和/或改善癌症的一种或多种症状(例如如FOSI评估的)。
如本文中使用的,术语“细胞毒剂”指抑制或阻止细胞的功能和/或引起细胞破坏的物质。该术语意图包括放射性同位素(例如At211,I131,I125,Y90,Re186,Re188,Sm153,Bi212,P32和Lu的放射性同位素),化疗剂,和毒素诸如小分子毒素或者细菌,真菌,植物或动物起源的酶活毒素,包括其片段和/或变体。
“化疗剂”指可用于治疗癌症的化学化合物。用于化疗的化疗剂的例子包括烷化剂类(alkylating agents),如塞替派(thiotepa)和环磷酰胺;磺酸烷基酯类(alkyl sulfonates),诸如白消安(busulfan),英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类(aziridines),诸如苯佐替派(benzodopa),卡波醌(carboquone),美妥替派(meturedopa)和乌瑞替派(uredopa);乙撑亚胺类(ethylenimines)和甲基蜜胺类(methylamelamines),包括六甲蜜胺(altretamine),三乙撑蜜胺(triethylenemelamine),三乙撑磷酰胺(triethylenephosphoramide),三乙撑硫代磷酰胺(triethiylenethiophosphoramide)和三羟甲蜜胺(trimethylolomelamine);TLK 286(TELCYTATM);番荔枝内酯类(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));δ-9-四氢大麻酚(tetrahydrocannabinol)(屈大麻酚(dronabinol),);β-拉帕醌(lapachone);拉帕醇(lapachol);秋水仙素类(colchicines);白桦脂酸(betulinic acid);喜树碱(camptothecin)(包括合成类似物托泊替康(topotecan)CPT-11(伊立替康(irinotecan),),乙酰喜树碱,东莨菪亭(scopoletin)和9-氨基喜树碱);苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin),卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);鬼臼毒素(podophyllotoxin);鬼臼酸(podophyllinic acid);替尼泊苷(teniposide);隐藻素类(cryptophycins)(特别是隐藻素1和隐藻素8);多拉司他汀(dolastatin);duocarmycin(包括合成类似物,KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;sarcodictyin;海绵抑素(spongistatin);氮芥类(nitrogen mustards),诸如苯丁酸氮芥(chlorambucil),萘氮芥(chlornaphazine),胆磷酰胺(cholophosphamide),雌莫司汀(estramustine),异环磷酰胺(ifosfamide),双氯乙基甲胺(mechlorethamine),盐酸氧氮芥(mechlorethamine oxide hydrochloride),美法仑(melphalan),新氮芥(novembichin),苯芥胆甾醇(phenesterine),泼尼莫司汀(prednimustine),曲磷胺(trofosfamide),尿嘧啶氮芥(uracil mustard);亚硝脲类(nitrosureas),诸如卡莫司汀(carmustine),氯脲菌素(chlorozotocin),福莫司汀(fotemustine),洛莫司汀(lomustine),尼莫司汀(nimustine)和雷莫司汀(ranimnustine);二膦酸盐类,如氯膦酸盐(clodronate);抗生素类,诸如烯二炔类(enediyne)抗生素(例如加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ωI1(参见例如Agnew,Chem Intl.Ed.Engl.,33:183-186(1994))和蒽环类抗生素如annamycin,AD 32,alcarubicin,柔红霉素(daunorubicin),多柔比星(doxorubicin),右雷佐生(dexrazoxane),DX-52-1,表柔比星(epirubicin),GPX-100,伊达比星(idarubicin),戊柔比星(valrubicin),KRN5500,美诺立尔(menogaril),蒽环类抗生素(dynemicin),包括dynemicin A,埃斯波霉素(esperamicin),新制癌素(neocarzinostatin)发色团和相关色蛋白烯二炔类抗生素发色团,阿克拉霉素(aclacinomysin),放线菌素(actinomycin),氨茴霉素(anthramycin),偶氮丝氨酸(azaserine),博来霉素(bleomycin),放线菌素C(cactinomycin),carabicin,洋红霉素(carminomycin),嗜癌霉素(carzinophilin),色霉素(chromomycinis),放线菌素D(dactinomycin),地托比星(detorubicin),6-二氮-5-氧-L-正亮氨酸,多柔比星(doxorubicin)(包括吗啉代多柔比星,氰基吗啉代多柔比星,2-吡咯代多柔比星,脂质体多柔比星,和脱氧多柔比星),依索比星(esorubicin),麻西罗霉素(marcellomycin),丝裂霉素类(mitomycins)诸如丝裂霉素C,霉酚酸(mycophenolic acid),诺拉霉素(nogalamycin),橄榄霉素(olivomycin),培洛霉素(peplomycin),泊非霉素(potfiromycin),嘌呤霉素(puromycin),三铁阿霉素(quelamycin),罗多比星(rodorubicin),链黑菌素(streptonigrin),链佐星(streptozocin),杀结核菌素(tubercidin),乌苯美司(ubenimex),净司他丁(zinostatin),和佐柔比星(zorubicin);叶酸类似物,诸如二甲叶酸(denopterin),蝶酰三谷氨酸(pteropterin),和三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine),6-巯基嘌呤(mercaptopurine),硫咪嘌呤(thiamiprine),和硫鸟嘌呤(thioguanine);嘧啶类似物,诸如安西他滨(ancitabine),阿扎胞苷(azacitidine),6-氮尿苷,卡莫氟(carmofur),阿糖胞苷(cytarabine),双脱氧尿苷(dideoxyuridine),去氧氟尿苷(doxifluridine),依诺他滨(enocitabine),和氟尿苷(floxuridine);雄激素类,诸如卡鲁睾酮(calusterone),丙酸屈他雄酮(dromostanolone propionate),表硫雄醇(epitiostanol),美雄烷(mepitiostane),和睾内酯(testolactone);抗肾上腺类,诸如氨鲁米特(aminoglutethimide),米托坦(mitotane),和曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸(folinic acid)(leucovorin);醋葡醛内酯(aceglatone);抗叶酸抗赘生物药剂如LY231514培美曲塞(pemetrexed),二氢叶酸还原酶抑制剂如甲氨蝶呤,抗代谢物如5-氟尿嘧啶(5-FU)及其前药如UFT,S-1和卡培他滨,和胸苷酸合酶抑制剂和甘氨酰胺核糖核苷酸甲酰基转移酶抑制剂如雷替曲塞(raltitrexed)(TOMUDEXRM,TDX);双氢嘧啶脱氢酶的抑制剂如恩尿嘧啶(eniluracil);醛磷酰胺糖苷(aldophosphamideglycoside);氨基乙酰丙酸(aminolevulinic acid);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);elfornithine;依利醋铵(elliptinium acetate);epothilone;依托格鲁(etoglucid);硝酸镓;羟脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidainine);美登木素生物碱类(maytansinoids),诸如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);二胺硝吖啶(nitraerine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙基酰肼(ethylhydrazide);丙卡巴肼(procarbazine);PSK7多糖复合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西索菲兰(sizofiran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2”-三氯三乙胺;单端孢菌素类(trichothecenes)(尤其是T-2毒素,疣孢菌素(verracurin)A,杆孢菌素(roridin)A和蛇行菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine)达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(“Ara-C”);环磷酰胺;塞替派(thiotepa);紫杉烷(taxanes);苯丁酸氮芥(chloranbucil);吉西他滨6-硫鸟嘌呤(thioguanine);巯基嘌呤(mercaptopurine);铂;铂类似物或基于铂的类似物,诸如顺铂(cisplatin),奥沙利铂(oxaliplatin)和卡铂(carboplatin);长春碱(vinblastine)依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine)长春花生物碱(vincaalkaloid);长春瑞滨(vinorelbine)能灭瘤(novantrone);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);希罗达(xeloda);伊本膦酸盐(ibandronate);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类维A酸(retinoids),诸如维A酸(retinoic acid);及任何上述各项的药学可接受盐,酸或衍生物;以及两种或更多种上述各项的组合,诸如CHOP(环磷酰胺,多柔比星,长春新碱和泼尼松龙联合疗法的缩写)和FOLFOX(奥沙利铂(ELOXATINTM)联合5-FU和亚叶酸的治疗方案的缩写)。
还包括在该定义内的是作用于调节或抑制激素对肿瘤作用的抗激素剂如抗雌激素和选择性雌激素受体调控物(SERM),包括例如,他莫昔芬(tamoxifen)(包括他莫昔芬),雷洛昔芬(raloxifene),屈洛昔芬(droloxifene),4-羟基他莫昔芬,曲沃昔芬(trioxifene),那洛昔芬(keoxifene),LY117018,奥那司酮(onapristone)和托瑞米芬(toremifene);芳香酶抑制剂类;和抗雄激素类如如氟他米特(flutamide),尼鲁米特(nilutamide),比卡米特(bicalutamide),亮丙瑞林(leuprolide),和戈舍瑞林(goserelin);以及曲沙他滨(troxacitabine)(1,3-二氧戊环核苷胞嘧啶类似物);反义寡核苷酸类,特别是那些抑制涉及异常细胞增殖的信号传导途经中的基因表达的,诸如例如PKC-alpha,Raf,H-Ras和表皮生长因子受体(EGF-R);疫苗类,如基因疗法疫苗,例如疫苗,疫苗和疫苗; rIL-2;拓扑异构酶1抑制剂;rmRH;及任何上述物质的药学可接受的盐,酸或衍生物。
“紫杉烷类”是一种抑制有丝分裂并干扰微管的化疗。紫杉烷类的例子包括帕利他赛(Bristol-Myers Squibb Oncology,Princeton,N.J.);不含克列莫佛(Cremophor),清蛋白工程化的纳米颗粒剂型帕利他赛或nab-帕利他赛(ABRAXANETM;American Pharmaceutical Partners,Schaumberg,Illinois);及多西他赛(-Poulenc Rorer,Antony,France)。
“蒽环类抗生素”是一种抗生素类型,其来自真菌Streptococcus peucetius,例子包括:柔红霉素,多柔比星,表柔比星,和任何其它蒽环类抗生素化疗剂,包括之前列出的那些。
“基于蒽环类抗生素的化疗”指组成为或包含一种或多种蒽环类抗生素的化疗方案。例子包括但不限于5-FU,表柔比星和环磷酰胺(FEC);5-FU,多柔比星和环磷酰胺(FAC);多柔比星和环磷酰胺(AC);表柔比星和环磷酰胺(EC);剂量密集的多柔比星和环磷酰胺(ddAC)等等。
就本文中目的而言,“基于卡铂的化疗”指组成为或包含一种或多种卡铂的化疗方案。例子是TCH(多西他赛/卡铂和曲妥珠单抗/)。
“芳香酶抑制剂”抑制芳香酶,其调节肾上腺中的雌激素产生。芳香酶抑制剂的例子包括:4(5)-咪唑,氨鲁米特,乙酸甲地孕酮(megestrol),依西美坦(exemestane),甲酚苯丙胺(formestanie),法倔唑(fadrozole),伏氯唑(vorozole),来曲唑(letrozole)和阿那曲唑(anastrozole)。在一个实施方案中,本文中所述芳香酶抑制剂是来曲唑或阿那曲唑。
“抗代谢物类化疗”是使用结构上与代谢物相似但不能被身体以生产性方式利用的药剂。许多抗代谢物类化疗干扰核酸,RNA和DNA的生成。抗代谢物类化疗剂的例子包括吉西他滨(gemcitabine)5-氟尿嘧啶(5-FU),卡培他滨(capecitabine)(XELODATM),6-巯基嘌呤,甲氨喋呤(methotrexate),6-硫鸟嘌呤,培美曲塞(pemetrexed),雷替曲塞(raltitrexed),阿糖胞苷(arabinosylcytosine ARA-C cytarabine)达卡巴嗪(dacarbazine)偶氮胞嘧啶(azocytosine),脱氧胞嘧啶(deoxycytosine),pyridmidene,氟达拉滨(fludarabine)克拉屈滨(cladrabine),2-脱氧-D-葡萄糖等。
“化疗抗性”癌症指癌症患者在接受化疗方案时癌症有进展(即患者是“化疗不应性”的),或者患者在完成化疗方案后12个月内(例如6个月内)有进展。
术语“铂”用于本文指基于铂的化疗,包括但不限于,顺铂,卡铂和奥沙利铂。
术语“氟嘧啶”用于本文指一种抗代谢物化疗,包括但不限于,卡培他滨,氟尿苷和氟尿嘧啶(5-FU)。
本文中,化疗剂的“固定的”(fixed)或“不变的”(flat)剂量指不考虑患者的体重(WT)和体表面积(BSA)而施用于人类患者的剂量。因此,固定的或不变的剂量不是作为mg/kg剂量或mg/m2剂量提供的,而是作为治疗剂的绝对量提供的。
“加载”(loading)剂量在本文中一般包括施用于患者的治疗剂的初始剂量,后续其一个或多个维持剂量。一般而言,施用单个加载剂量,但本文中也涵盖多个加载剂量。通常,所施用的加载剂量的量超过所施用的维持剂量的量,和/或加载剂量的施用比维持剂量更频繁,从而比使用维持剂量更早达到治疗剂的期望稳态浓度。
“维持”(maintenance)剂量在本文中指在治疗期间施用于患者的一个或多个剂量的治疗剂。通常,维持剂量以一定的治疗间隔施用,例如大约每周一次,大约每两周一次,大约每三周一次,或大约每四周一次,优选每三周一次。
“输注”指将含药物的溶液经过血管引入体内以用于治疗目的。一般地,这是经由静脉内(IV)袋实现的。
“静脉内袋”或“IV袋”是能装存可经由患者静脉施用的溶液的袋。在一个实施方案中,所述溶液是盐水溶液(例如约0.9%或约0.45%NaCl)。任选地,所述IV袋由聚烯烃或聚氯乙烯形成。
“共施用”意指在同一施用期间静脉内施用两种(或更多种)药物,而非连续输注这两种或更多种药物。一般地,这将牵涉将两种(或更多种)药物在其共施用之前组合到同一IV袋中。
“心脏毒性”指自药物或药物组合的施用产生的任何毒性副作用。心脏毒性可基于以下任一种或多种评估:症状性左心室收缩功能障碍(LVSD)或充血性心力衰竭(CHF)的发生率,或左心室射血分数(LVEF)的降低。
短语“未增加心脏毒性”对于包含帕妥珠单抗的药物组合指等于或低于在药物组合中使用帕妥珠单抗以外的药物治疗的患者中所观察到的心脏毒性发生率(例如等于或低于从施用曲妥珠单抗和化疗例如多西他赛得到的)。
“管形瓶(vial)”是一种适用于装存液体或冻干制备物的容器。在一个实施方案中,管形瓶是一次性管形瓶,例如带有塞子的20-cc一次性管形瓶。
“包装插页”是由食品和药物监督管理局或其他管理机构命令的,必须放置在每个处方药的包装内的散页印刷品。该散页印刷品一般包含药物的商标,其通用名,及其作用机制;说明其适应证,禁忌证,警告,预防,不良作用和剂量形式;而且包括用于推荐剂量,时间和施用路径的用法说明。
表述“安全性数据”涉及在受控的临床试验中获得的数据,其显示不良事件的流行性和严重度以在药物安全性方面指导使用者,包括如何监测和预防对药物的不良反应的指导。本文中表3和表4提供帕妥珠单抗的安全性数据。安全性数据包含表3和4中最常见的不良事件(AE)或不良反应(ADR)的任意一种或多种(例如两种,三种,四种或更多种)。例如,所述安全性数据包含关于嗜中性白细胞减少,发热性嗜中性白细胞减少,腹泻和/或如本文中公开的心脏毒性的信息。
“功效数据”指在受控的临床试验中获得的数据,其显示药物有效治疗疾病,如癌症。
“稳定混合物”在指代两种或更多种药物如帕妥珠单抗和曲妥珠单抗的混合物时意指混合物中的每种药物在混合物中基本保留其物理和化学稳定性,如通过一种或多种分析测定法评估的。针对此目的的例示性分析测定法包括:颜色,外观和澄清度(CAC),浓度和浊度分析,微粒分析,大小排阻层析(SEC),离子交换层析(IEC),毛细管区带电泳(CZE),成像毛细管等电聚焦(iCIEF)和效力测定法。在一个实施方案中,已显示混合物在5℃或30℃稳定达长达24小时。
与一种或多种其他药物“同时”施用的药物是在同一治疗周期期间,在与所述一种或多种其他药物治疗的同一天,且任选地,在与所述一种或多种其他药物的同一时间施用的。例如,对于每3周给予的癌症疗法,同时施用的药物各在3周周期的第1天施用。
II.抗体和化疗组合物
要用于生产抗体的HER2抗原可以是例如可溶形式的HER2受体胞外域或其部分,其含有期望的表位。或者,在其细胞表面处表达HER2的细胞(例如经转化以过表达HER2的NIH-3T3细胞;或癌细胞系如SK-BR-3细胞,参见Stancovski等,PNAS(USA)88:8691-8695(1991))可用于生成抗体。可用于生成抗体的HER2受体的其他形式对于本领域技术人员来说将是明显的。
本领域中存在多种用于制备本文中单克隆抗体的方法。例如,可使用Kohler等,Nature,256:495(1975)首次描述的杂交瘤方法,通过重组DNA方法(美国专利No.4,816,567)来制备单克隆抗体。
依照本发明使用的抗HER2抗体曲妥珠单抗和帕妥珠单抗是商品化的。
(i)人源化抗体
本领域已经记载了用于将非人抗体人源化的方法。优选的是,人源化抗体具有一个或多个从非人来源引入的氨基酸残基。这些非人氨基酸残基常常称作“输入”残基,它们典型的取自“输入”可变域。人源化可基本上遵循Winter及其同事的方法进行(Jones等,Nature 321:522-525(1986);Riechmann等,Nature 332:323-327(1988);Verhoeyen等,Science 239:1534-1536(1988)),通过用高变区序列替代人抗体的相应序列。因此,此类“人源化”抗体是嵌合抗体(美国专利No.4,816,567),其中基本上少于整个人可变域用来自非人物种的相应序列替代。在实践中,人源化抗体典型的是其中一些高变区残基和可能的一些FR残基用来自啮齿类抗体中类似位点的残基替代的人抗体。
用于构建人源化抗体的人可变域的选择,包括轻链和重链二者,对于降低抗原性非常重要。依照所谓的“最适”(best-fit)方法,用啮齿类抗体的可变域序列对已知的人可变域序列的整个文库进行筛选。然后选择与啮齿类序列最接近的人序列作为人源化抗体的人框架区(FR)(Sims等,J.Immunol.151:2296(1993);Chothia等,J.Mol.Biol.196:901(1987))。另一种方法使用由特定轻链或重链亚组的所有人抗体的共有序列衍生的特定框架区。同一框架可用于数种不同的人源化抗体(Carter等,Proc.Natl.Acad.Sci.USA 89:4285(1992);Presta等,J.Immunol.151:2623(1993))。
更为重要的是,抗体在人源化后保持对抗原的高亲和力和其它有利的生物学特性。为了实现这一目标,依照一种优选的方法,通过使用亲本和人源化序列的三维模型分析亲本序列和各种概念性人源化产物的方法来制备人源化抗体。三维免疫球蛋白模型是普遍可获的且为本领域技术人员所熟悉。可获得图解和显示所选候选免疫球蛋白序列的可能三维构象结构的计算机程序。检查这些显示图像容许分析残基在候选免疫球蛋白序列行使功能中的可能作用,即分析影响候选免疫球蛋白结合其抗原的能力的残基。这样,可以从受体和输入序列选出FR残基并进行组合,从而获得期望的抗体特征,诸如对靶抗原的亲和力提高。一般而言,高变区残基直接且最实质的涉及对抗原结合的影响。
美国专利No.6,949,245描述了例示性人源化HER2抗体的产生,该抗体结合HER2并阻断HER受体的配体活化。
人源化HER2抗体具体包括如美国专利5,821,337(通过提述明确并入本文)表3中描述的和本文中定义的曲妥珠单抗;以及如本文中描述和定义的人源化2C4抗体如帕妥珠单抗。
本文中的人源化抗体可以例如,包含掺入人可变重域的非人高变区残基,且还可以包含在选自下组的位置处的框架区(FR)取代:69H,71H和73H,其利用Kabat等,Sequencesof Proteins of Immunological Interest,5th Ed.Public Health Service,NationalInstitutes of Health,Bethesda,MD(1991)中所列的可变域编号系统。在一个实施方案中,所述人源化抗体包含在69H,71H和73H中的两个或所有位置处的FR取代。
本文中感兴趣的例示性人源化抗体包含可变重域互补决定残基GFTFTDYTMX(SEQID NO:17),其中X优选是D或S;DVNPNSGGSIYNQRFKG(SEQ ID NO:18);和/或NLGPSFYFDY(SEQID NO:19),任选包含那些CDR残基的氨基酸修饰,例如其中修饰基本上保持或改善抗体的亲和力。例如,用于本发明方法的抗体变体可在上述可变重CDR序列中具有约1个至约7个或者约5个氨基酸替代。此类抗体变体可通过亲和力成熟来制备,例如如下文所述。
例如,在前一段中的那些可变重域CDR残基之外,人源化抗体还可包含可变轻域互补决定残基KASQDVSIGVA(SEQ ID NO:20);SASYX1X2X3,其中X1优选是R或L,X2优选是Y或E,而X3优选是T或S(SEQ ID NO:21);和/或QQYYIYPYT(SEQ ID NO:22)。此类人源化抗体任选包含上述CDR残基的氨基酸修饰,例如其中修饰基本上保持或改善抗体的亲和力。例如,目的抗体变体可在上述可变轻CDR序列中具有约1个至约7个或者约5个氨基酸替代。此类抗体变体可通过亲和力成熟来制备,例如如下文所述。
本申请还涵盖结合HER2的亲和力成熟的抗体。亲本抗体可以是人抗体或人源化抗体,例如包含轻链和/或重链可变区序列分别为SEQ ID NO:7和8的抗体(即包含帕妥珠单抗的VL和/或VH)。帕妥珠单抗的亲和力成熟的变体优选以优于鼠2C4或帕妥珠单抗的亲和力结合HER2受体(例如根据使用HER2胞外域(ECD)ELISA的评估,例如亲和力提高约2倍或约4倍至约100倍或约1000倍)。例示性的用于取代的重链可变区CDR残基包括H28,H30,H34,H35,H64,H96,H99,或者两个或多个的组合(例如这些残基中的2个,3个,4个,5个,6个或7个)。用于改变的轻链可变区CDR残基的例子包括L28,L50,L53,L56,L91,L92,L93,L94,L96,L97,或者两个或多个的组合(例如这些残基中的2个至3个,4个,5个或直到约10个)。
将鼠4D5抗体人源化以生成其人源化变体,包括曲妥珠单抗,记载于美国专利No.5,821,337,6,054,297,6,407,213,6,639,055,6,719,971和6,800,738以及Carter等PNAS(USA),89:4285-4289(1992)。HuMAb4D5-8(曲妥珠单抗)对HER2抗原结合比小鼠4D5抗体紧密3倍,且具有允许人源化抗体在存在人效应器细胞情况下的定向细胞毒性活性的次级免疫功能(ADCC)。HuMAb4D5-8包含掺入VLκ亚组I共有框架的可变轻(VL)CDR残基,和掺入VH亚组III共有框架的可变重(VH)CDR残基。该抗体还包含在以下位置处的框架区(FR)取代:VH的71,73,78和93(FR残基的Kabat编号);和在VL的位置66处的FR取代(FR残基的Kabat编号)。曲妥珠单抗包含非A同种异型人γ1Fc区。
涵盖各种形式的人源化抗体或亲和力成熟的抗体。例如,人源化抗体或亲和力成熟的抗体可以是抗体片段。或者,人源化抗体或亲和力成熟的抗体可以是完整抗体,诸如完整的IgG1抗体。
(ii)帕妥珠单抗组合物
在HER2抗体组合物的一个实施方案中,该组合物包含主要种类帕妥珠单抗抗体及其一种或多种变体的混合物。本文中帕妥珠单抗主要种类抗体的优选实施方案是包含SEQID No.5和6中的轻链和重链可变域氨基酸序列,最优选包含SEQ ID No.11的轻链氨基酸序列及SEQ ID No.12的重链氨基酸序列的抗体(包括那些序列的脱酰胺和/或氧化变体)。在一个实施方案中,组合物包含主要种类帕妥珠单抗抗体及其包含氨基末端前导延伸的氨基酸序列变体的混合物。优选的是,所述氨基末端前导延伸位于抗体变体的轻链上(例如位于抗体变体的一条或两条轻链上)。所述主要种类HER2抗体或抗体变体可以是全长抗体或抗体片段(例如Fab或F(ab’)2片段),但优选二者都是全长抗体。本文中的抗体变体可以在其任何一条或多条重链或轻链上包含氨基末端前导延伸。优选的是,所述氨基末端前导延伸位于抗体的一条或两条轻链上。所述氨基末端前导延伸优选包含VHS-或由其组成。组合物中氨基末端前导延伸的存在可通过多种分析技术来检测,包括但不限于N-末端序列分析,电荷异质性的测定法(例如阳离子交换层析或毛细管区带电泳),质谱等。组合物中抗体变体的量通常在如下范围内,从构成用于检测变体的任何测定法(优选N-末端序列分析)的检出限的量至少于主要种类抗体量的量。通常,组合物中约20%或更少(例如从约1%至约15%,例如从5%至约15%)的抗体分子包含氨基末端前导延伸。这样的百分比量优选使用定量N-末端序列分析或阳离子交换分析(优选使用高分辨率,弱阳离子交换柱,诸如PROPACWCX-10TM阳离子交换柱)来测定。在氨基末端前导延伸变体之外,还涵盖主要种类抗体和/或变体的氨基酸序列改变,包括但不限于在其一条或所有两条重链上包含C-末端赖氨酸残基的抗体,脱酰胺抗体变体等。
此外,主要种类抗体或变体还可包含糖基化变异,其非限制性例子包括包含附着于其Fc区的G1或G2寡糖结构的抗体,包含附着于其轻链的碳水化合物模块的抗体(例如一种或两种碳水化合物模块,诸如葡萄糖或半乳糖附着于抗体的一条或两条轻链,例如附着于一个或多个赖氨酸残基),包含一条或两条非糖基化重链的抗体,或包含附着于其一条或两条重链的唾液酸化寡糖的抗体等。
组合物可从表达HER2抗体的基因工程细胞系回收,例如中国仓鼠卵巢(CHO)细胞系,或者可通过肽合成来制备。
关于例示性帕妥珠单抗组合物的更多信息,参见美国专利No.7,560,111和7,879,325以及US 2009/0202546A1。
(iii)曲妥珠单抗组合物
曲妥珠单抗组合物通常包含主要种类抗体(分别包含SEQ ID NO:13和14的轻链和重链序列)及其变体形式,特别是酸性变体(包括脱酰胺化变体)的混合物。优选地,组合物中的这类酸性变体的量低于约25%,或低于约20%,或低于约15%。参见美国专利No.6,339,142。亦参见Harris等,J.Chromatography,B 752:233-245(2001),其涉及可通过阳离子交换层析解析的曲妥珠单抗形式,包括峰A(Asn30在两条轻链中脱酰胺化为Asp);峰B(Asn55在一条重链中脱酰胺化为异Asp);峰1(Asn30在一条轻链中脱酰胺化为Asp);峰2(Asn30在一条轻链中脱酰胺化为Asp,且Asp102在一条重链中异构化为异Asp);峰3(主要峰形式,或主要种类抗体);峰4(Asp102在一条重链中异构化为异Asp);峰C(Asp102在一条重链中琥珀酰亚胺(Asu))。这类变体形式和组合物包含在本文的发明中。
(iv)化疗,激素疗法,和G-CSF
5-氟尿嘧啶,表柔比星,多柔比星,环磷酰胺,多西他赛,帕利他赛,G-CSF,和适合于辅助激素疗法的药物可商购获得且依照当地处方信息及如实施例中所述施用。
III.为疗法选择患者
HER2检测可用来选择用于依照本发明治疗的患者。有几种FDA批准的商业测定法用于鉴定HER2阳性癌症患者。这些方法包括(Dako)和HER2(免疫组织化学(IHC)测定法)和和HER2FISH pharmDxTM(FISH测定法)。使用者应参照特定测定试剂盒的包装插页中关于每种测定法的验证和性能的信息。
例如,HER2过表达可通过IHC分析,例如使用(Dako)。可将来自肿瘤活组织检查的石蜡包埋的组织切片进行IHC测定,并对照如下的HER2蛋白染色强度标准:
得分0:未观察到染色或者在少于10%的肿瘤细胞中观察到膜染色。
得分1+:在超过10%的肿瘤细胞中检测到微弱的/刚刚可察觉的膜染色。所述细胞只在其部分膜中有染色。
得分2+:在超过10%的肿瘤细胞中观察到微弱至中等的完全膜染色。
得分3+:在超过10%的肿瘤细胞中观察到中等至强烈的完全膜染色。
那些HER2过表达评估得分为0或1+的肿瘤可表征为HER2阴性,而那些得分为2+或3+的肿瘤可表征为HER2阳性。
HER2过表达的肿瘤可根据对应于每个细胞表达的HER2分子拷贝数的免疫组化得分进行定级,并且可通过生化方法测定:
0=0-10,000个拷贝/细胞,
1+=至少约200,000个拷贝/细胞,
2+=至少约500,000个拷贝/细胞,
3+=至少约2,000,000个拷贝/细胞。
导致酪氨酸激酶的配体独立性活化的3+水平的HER2过表达(Hudziak等,Proc.Natl.Acad.Sci.USA 84:7159-7163(1987))发生于约30%的乳腺癌中,而且在这些患者中,无复发存活和总体存活减少(Slamon等,Science244:707-712(1989);Slamon等,Science 235:177-182(1987))。
HER2蛋白过表达的存在和基因扩增高度相关,因此,或者/另外地,使用原位杂交(ISH)例如荧光原位杂交(FISH),用于检测基因扩增的测定法也可以用于选择适用于依照本发明治疗的患者。可对福尔马林固定,石蜡包埋的肿瘤组织进行FISH测定法如INFORMTM(由Ventana,Arizona销售)或(Vysis,Illinois)以测定肿瘤中HER2扩增的程度(如果有的话)。
最常见的是,使用档案性石蜡包埋的肿瘤组织,利用任一种前述方法来确认HER2阳性状态。
优选地,选择具有IHC得分为2+或3+或FISH或ISH阳性的HER2阳性患者用于依照本发明的治疗。
亦参见美国专利No.7,981,418中的筛选患者用于帕妥珠单抗治疗的其他测定法,和实施例。
IV.药物配制剂
制备依照本发明使用的HER2抗体的治疗性配制剂用于存储,其通过将具有期望纯度的抗体与任选的药学可接受的载体,赋形剂或稳定剂混合(Remington'sPharmaceutical Sciences 16th edition,Osol,A.Ed.(1980)),一般以冻干剂型或水溶液的形式。还涵盖抗体晶体(参见美国专利申请2002/0136719)。可接受的载体,赋形剂或稳定剂在所采用的剂量和浓度对接受者是无毒的,包括缓冲剂,诸如磷酸盐,柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(如十八烷基二甲基苄基氯化铵;氯化六甲双铵(hexamethonium chloride);氯化苯甲烃铵(benzalkonium chloride);氯化苄乙铵(benzethonium chloride);酚,丁醇或苯甲醇;烷基对羟基苯甲酸酯如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(低于约10个残基)多肽;蛋白质,如血清清蛋白,明胶,或免疫球蛋白;亲水性聚合物如聚乙烯吡咯烷酮;氨基酸如甘氨酸,谷氨酰胺,天冬酰胺,组氨酸,精氨酸或赖氨酸;单糖,二糖,和其它碳水化合物,包括葡萄糖,甘露糖或糊精;螯合剂如EDTA;糖如蔗糖,甘露醇,海藻糖或山梨糖醇;形成盐的反荷离子如钠;金属复合物(例如Zn-蛋白复合物);和/或非离子型表面活性剂如TWEENTM,PLURONICSTM或聚乙二醇(PEG)。冻干的抗体剂型记载于WO 97/04801,其通过提述明确并入本文。
冻干的抗体剂型记载于美国专利No.6,267,958,6,685,940和6,821,515,其通过提述明确并入本文。优选的(曲妥珠单抗)配制剂是一种针对静脉内(IV)施用的无菌,白色到浅黄色的无防腐剂冻干粉末,包含440mg曲妥珠单抗,400mgα,α-海藻糖脱水物,9.9mg L-组氨酸-HCl,6.4mg L-组氨酸和1.8mg聚山梨醇酯20,USP。用含有1.1%苯甲醇作为防腐剂的20mL抑菌性注射用水(BWFI)的重建,得到含有21mg/mL曲妥珠单抗,pH为约6.0的多剂量溶液。更多细节参见曲妥珠单抗处方信息。
用于治疗用途的优选帕妥珠单抗配制剂包含20mM组氨酸乙酸盐,120mM蔗糖,0.02%聚山梨醇酯20,pH 6.0中30mg/mL的帕妥珠单抗。备选的帕妥珠单抗配制剂包含25mg/mL帕妥珠单抗,10mM组氨酸-HCl缓冲剂,240mM蔗糖,0.02%聚山梨醇酯20,pH 6.0。
在实施例中所述临床试验中使用的安慰剂配制剂等同于无活性剂的帕妥珠单抗。
本文中配制剂还可以含有待治疗的特定适应证所必需的超过一种活性化合物,优选具有不会彼此不利影响的互补活性的那些活性成分。可与HER二聚化抑配制剂组合的多种药物在下文方法部分描述。这类分子以对意图目的有效的量适宜地组合存在。
用于体内施用的配制剂必须无菌。这可容易地通过经由无菌滤膜过滤而实现。
V.治疗方法
本发明涉及一种用于治疗乳腺癌的方法,其包括对具有HER2阳性局部晚期,炎性,或早期阶段乳腺癌的患者在基于蒽环类抗生素的化疗后新辅助施用有效量的帕妥珠单抗和曲妥珠单抗的组合,其中在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的组合施用相对于在基于蒽环类抗生素的化疗后曲妥珠单抗的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件。
依照处方信息和如贯穿本公开(包括但不限于本文中的实施例)所述施用帕妥珠单抗和曲妥珠单抗。
在一个实施方案,每2周给予剂量密集的多柔比星和环磷酰胺(ddAC),继以每周施用紫杉烷,例如帕利他赛,和每三周组合施用帕妥珠单抗和曲妥珠单抗。在一个具体的实施方案中,每两周给予ddAC达四个周期,在需要时与粒细胞集落刺激因子(G-CSF)支持一起,继以每周帕利他赛施用达12周,自帕利他赛开始起每三周给予帕妥珠单抗和曲妥珠单抗。
在另一个实施方案中,每三周给予5-氟尿嘧啶,表柔比星,和环磷酰胺(FEC)达四个周期,继以每三周给予多西他赛达四个周期,自多西他赛开始起每3周给予帕妥珠单抗和曲妥珠单抗。
在所有实施方案中,患者可接受至少四个周期的新辅助帕妥珠单抗+曲妥珠单抗,而且明确包括超过四个周期的新辅助帕妥珠单抗+曲妥珠单抗施用。如此,在各种实施方案中,可施用5个周期,或6个周期,或7个周期,或8个周期的新辅助帕妥珠单抗+曲妥珠单抗。施用至少四个周期的新辅助帕妥珠单抗+曲妥珠单抗在提高tpCR率中是有益的,尤其是在施用ddAC后。
用于治疗HER2阳性乳腺癌的化疗的剂量和进度表在下文实施例中公开,但是其它剂量和进度表依照本文中的发明是已知且涵盖的。
VI.制品
在本发明的另一个实施方案中,提供了一种制品,其装有对于治疗乳腺癌有用的材料。该制品包含有固定剂量的该HER2(帕妥珠单抗)的管形瓶,其中该固定剂量是大约420mg,大约525mg,大约840mg,或大约1050mg的该HER抗体。
该制品优选进一步包含包装插页。该包装插页可提供将该固定剂量施用于乳腺癌患者的用法说明书。
在一个实施方案,该制品包含两种管形瓶,其中第一管形瓶装有固定剂量的大约840mg的帕妥珠单抗,而第二管形瓶装有固定剂量的大约420mg的帕妥珠单抗。
在另一个实施方案中,该制品包含两种管形瓶,其中第一管形瓶装有固定剂量的大约1050mg的帕妥珠单抗,而第二管形瓶装有固定剂量的大约525mg的帕妥珠单抗。
本文中的制品的一个实施方案包含一种静脉内(IV)袋,其装有适用于对癌症患者施用的帕妥珠单抗和曲妥珠单抗的稳定混合物。任选地,所述混合物是盐水溶液;例如包含约0.9%NaCl或约0.45%NaCl。例示性IV袋是聚烯烃或聚氯乙烯输注袋,例如250mL IV袋。依照本发明的一个实施方案,所述混合物包含约420mg或约840mg的帕妥珠单抗,和约200mg至约1000mg的曲妥珠单抗(例如约400mg至约900mg的曲妥珠单抗)。
任选地,IV袋中的混合物在5℃或30℃稳定长达24小时。混合物的稳定性可通过一种或多种选自下组的测定法评估:颜色,外观和澄清度(CAC),浓度和浊度分析,微粒分析,大小排阻层析(SEC),离子交换层析(IEC),毛细管区带电泳(CZE),成像毛细管等电聚焦(iCIEF)和效力测定法。
在一个实施方案中,该制品包含有帕妥珠单抗的管形瓶和包装插页,其中该包装插页提供图10-15中显示的安全性数据的至少部分。
在另一个实施方案中,该制品包含装有约420mg的帕妥珠单抗的单剂管形瓶。
本发明还涉及一种用于生成制品的方法,包括将其中有帕妥珠单抗的管形瓶和包装插页包装在一起,其中该包装插页提供图10-15中显示的安全性数据。
VII.生物材料保藏
以下杂交瘤细胞系已保藏在美国典型培养物保藏中心,10801UniversityBoulevard,Manassas,VA 20110-2209,USA(ATCC):
抗体名 ATCC No. 保藏日期
4D5 ATCC CRL 10463 1990年5月24日
2C4 ATCC HB-12697 1999年4月8日
序列的表格
本发明的进一步的细节由以下非限制性实施例例示。说明书中所有引用的公开内容均通过提述明确并入本文。
在下面的表中提供贯穿说明书(包括实施例)使用的术语的缩写和定义的列表。
实施例1
评估与组合的的新辅助施用和标准新辅助基于蒽环类抗生素的化疗的II期临床研究
研究设计
研究的描述
研究设计的概览
这是一项非随机化,开放标签,多中心,多国,II期试验,包括两个平行组的患者。计划总共大约400名患者:每个治疗队列中大约200名患者。会分配认为适合于加基于蒽环类抗生素/紫杉烷的化疗的新辅助治疗的患者以接受两种下面的方案之一:
●队列A(ddAC→T+PH):每2周给予剂量密集的多柔比星和环磷酰胺达四个周期,依照当地指南在需要时与G-CSF支持一起,继以每周帕利他赛达12周,自帕利他赛开始起每3周和(在手术之前四个周期的和)。
或
●队列B(FEC→D+PH):每3周给予5-氟尿嘧啶,表柔比星和环磷酰胺达四个周期,继以每3周给予多西他赛达四个周期。另外,患者会自多西他赛开始起每3周接受和(在手术之前四个周期的和)。
新辅助治疗方案的选择会由调查人员在调查人员特异性基础上进行(即,在任何给定地点一次只会打开一个队列;调查人员不可以将患者同时登记入两个队列)。如果调查人员要求在研究的登记期期间改变队列的话,研究团队会在批准请求之前审查情况。
在手术后,两个治疗队列中的患者会接受进一步的每3周辅助和(13个周期),使得在研究期间给予总共17个周期的和疗法。在依照适用的指南在临床上指示时还会给予放射疗法和辅助激素疗法。
研究主要旨在评价在与新辅助和组合给予时两种常用新辅助基于蒽环类抗生素/紫杉烷的化疗方案的心脏安全性。还会评价一般安全性和功效(特别是pCR率)。
研究设计在图4中图示。注意:对于队列A,ddAC的剂量是多柔比星60mg/m2和环磷酰胺600mg/m2。每2周给予ddAC。帕利他赛的剂量是80mg/m2。对于队列B,FEC的剂量是5-氟尿嘧啶500mg/m2,表柔比星100mg/m2,和环磷酰胺600mg/m2。每3周给予FEC。多西他赛的开始剂量是周期5(第一个多西他赛周期)中的75mg/m2,然后周期6-8中的100mg/m2,如果没有发生剂量限制性毒性的话。每3周给予D。
研究的结束
研究的结束会是在研究中登记最后一名患者之后5年(或当所有患者死亡或试验被发起人终止,以最早者为准)。这个数据点会认为是最后一名患者,最后一次拜访(LPLV)。预期研究持续大约6.5年,假设募集期大约1.5年,每名患者的治疗时间大约1年(包括新辅助和辅助治疗期),和进一步跟踪心脏安全性和功效达4年。
测试产品剂量的基本原理
这项研究中使用的化疗方案基于已发表的数据和例行临床用法,以及已建立的临床实践指南(例如,NCCN指南)。化疗,和的剂量均与每种药剂的处方信息一致。依照当地处方信息施用5-氟尿嘧啶,表柔比星,多柔比星,环磷酰胺,多西他赛,帕利他赛,和G-CSF,而且这些药物不视为调查性医药产品(IMP)。和在这项研究中认为是IMP。
静脉内给予所有化疗和抗体治疗。
在两个队列中,作为840mg静脉内(IV)加载剂量,继以每3周420mg IV给予作为8mg/kg IV加载剂量,继以每3周6mg/kg IV给予手术后,患者继续接受辅助设置中的和(13个周期),直至在研究中施用总共17个周期的和
队列A(ddAC→T+PH)
在队列A(ddAC→T+PH)中,化疗的剂量和进度表基于例行实践和NCCN指南,如下:每2周给予多柔比星60mg/m2和环磷酰胺600mg/m2达四个周期,(2周后)继以每周帕利他赛80mg/m2达12周。自帕利他赛开始起每3周给予和使得在新辅助期期间给予总共四个周期的和在ddAC期间,患者应当依照当地实践指南接受G-CSF支持。
队列B(FEC→D+PH)
在队列B(FEC→D+PH)中化疗的剂量和进度表基于在TRYPHAENA研究的分支B中评估的那些(5-氟尿嘧啶500mg/m2,表柔比星100mg/m2,环磷酰胺600mg/m2,每3周给予;继以多西他赛75mg/m2,如果耐受的话提高至100mg/m2,每3周给予)。剂量与例行实践中给予的剂量一致且方案在与和组合给予时得到较好耐受。
结局度量
安全性结局度量
这项研究的安全性结局度量如下:
●心脏事件的发生率和严重度,由调查人员使用NCI CTCAE v4.0(和用于有症状的LVSD的NYHA)评价
●使用当地ECHO或MUGA扫描评价的LVEF在研究过程上的变化。在可能时,会贯穿研究由与基线时相同的评价人和用与基线时相同的技术评价患者。临床显著的LVEF下降定义为自基线≥10%点且达到<50%的数值的下降。
●其它不良事件和严重不良事件的发生率和严重度
●实验室测试异常
●针对的抗治疗剂抗体(ATA)的发生率和它们与安全性事件的相关性
所有接受至少一剂研究治疗的任何成分的患者会包括在安全性分析群体中。会在所有患者完成新辅助疗法(或退出研究或失去随访)之后进行主要心脏安全性评估。此时,感兴趣的主要心脏安全性参数如下:
●由调查人员评价的,在新辅助期期间NYHA III和IV类心力衰竭的发生率。基于在NEOSPHERE和TRYPHAENA研究(其中与化疗一起给予新辅助和多至六个周期)中观察到的≥3级LVSD(大约等同于NHYA III/IV类心力衰竭)的比率,在新辅助治疗期间NYHA III和IV类心力衰竭的发生率估计是<3%。
●在新辅助期期间临床显著的LVEF下降(自基线≥10%点且达到<50%的数值)的发生率。基于在NEOSPHERE和TRYPHAENA研究中观察到的比率,在新辅助治疗期间临床显著的LVEF下降的潜在发生率估计是<6%。
会贯穿辅助和治疗后期在所有患者中继续评价心脏安全性。会在下面的时间点在主要分析之后进行这些参数(和其它安全性和功效数据)的另外的分析:
●在所有患者完成辅助抗HER2疗法(或退出研究或失去随访)后
●在研究结束时(在登记最后一名患者之后5年)
功效结局度量
会在主要分析时和在其它关键时间点时评价功效。会在意图治疗(ITT)群体(登记的所有患者)中评价这项研究的功效结局度量且如下:
●tpCR,定义为依照当地病理学家的评价,根除乳房和腋窝(ypT0/is ypN0)中的侵袭性疾病。在手术时定义对疗法的病理学响应,而且tpCR率是ITT群体中实现tpCR的患者的比例。
●临床响应,定义为在手术之前完全响应(CR),部分响应(PR),稳定疾病(SD),或进展性疾病(PD)。临床响应率定义为在手术之前ITT群体中实现CR或PR的患者的比例。会遵照当地实践通过临床检查,乳房X射线照相术,和/或其它评估方法在每个新周期的疗法之前评价肿瘤响应。会由调查人员遵照当地实践基于实体瘤响应评估标准(RECIST)1.1版(Eisenhauer et al.,Eur J Cancer 2009;45:228-47)的原理评价响应。
●EFS,定义为自登记至由调查人员确定的第一次发生PD或复发,或任何起因的死亡的时间。同侧或对侧原位疾病和第二原发性非乳腺癌(包括原位癌和非黑素瘤皮肤癌)不会作为PD或复发计数。
●iDFS,定义为自没有疾病的第一个日期(即,初次手术日)至第一次记录进展性侵袭性疾病,复发,或任何起因的死亡的时间。同侧或对侧原位疾病和第二原发性非乳腺癌(包括原位癌和非黑素瘤皮肤癌)不会作为PD或复发计数。
●OS,定义为自登记至任何起因的死亡的时间。
探索性结局度量
这项研究的探索性结局度量如下:
●bpCR,定义为根除乳腺中的侵袭性疾病(ypT0/is)
●GBG pCR,定义为根除乳房中的侵袭性和原位疾病,和腋窝中的侵袭性疾病(ypT0ypN0)
●BCS,定义为四肢切除术或乳房肿瘤切除术。会为ITT群体中的所有女性患者(即,描述为总体BCS率),在研究进入时具有T2或T3肿瘤的女性患者,和在研究进入时计划乳房切除术的具有T2或T3肿瘤的女性患者提供BCS率。
●再切除手术,定义为在初始BCS后在分开的时机(即,要求分开的麻醉)的手术以去除残留肿瘤
●基因表达,通过在多路平台上测量的信使RNA(mRNA)表达水平测定。会评价基因小组(例如,PAM50小组)和单基因。会在多路平台上评价与乳腺癌有关的一个基因小组。会通过应用PAM50基因集来鉴定内在乳腺癌亚型,如Parker等人(2009)所述。在PAM50分类器以外,还可评估其它基因签名;例如,那些表示活化的PI3K途径或与免疫应答有关的。对内在乳腺癌亚型(特别是这项研究中包括的腔B和HER2富集亚型)和结局(由pCR定义)之间的相关性特别感兴趣。会在适宜时和在样品大小容许时评估其它分子概况或单一标志物。
调查性医药产品
和均是这项研究的调查性医药产品。
测试产品
作为840mg静脉内(IV)加载剂量,然后是420mg IV每3周给予帕妥珠单抗
剂量给药方案
在两个队列中,作为8mg/kg IV加载剂量,然后是6mg/kg IV每3周给予曲妥珠单抗
●队列A:多柔比星60mg/m2IV和环磷酰胺600mg/m2IV每2周施用(ddAC)达四个周期(周期1-4),(2周后)继以帕利他赛80mg/m2IV每周达12周(周期5-8),在周期5-8期间每3周和(自帕利他赛开始起;在新辅助期期间总共四个周期的和)。在ddAC期间,患者应当依照当地实践指南接受G-CSF支持。在手术后,患者会继续接受辅助设置中的和直至给予总共17个周期的和
●队列B:5-氟尿嘧啶500mg/m2IV,表柔比星100mg/m2IV,和环磷酰胺600mg/m2IV每3周达四个周期(周期1-4),(3周后)继以多西他赛(第一剂75mg/m2,然后后续剂100mg/m2,如果没有发生剂量限制性毒性的话)每3周达四个周期(周期5-8),在周期5-8期间每3周和(自多西他赛开始起;在新辅助期期间总共四个周期的和)。在手术后,患者应当继续接受辅助设置中的和直至给予总共17个周期的和
所有治疗剂量应当基于实际体重而非理想体重。如果患者的体重在治疗过程期间自基线增加或减少≥10%,那么应当重新计算体表面积和化疗和/或的剂量。
非调查性医药产品
依照当地处方信息施用5-氟尿嘧啶,表柔比星,多柔比星,环磷酰胺,多西他赛,帕利他赛,和G-CSF,所以这些药物并不视为调查性医药产品。
在手术后,具有激素受体阳性疾病的患者应当依照方案中包括的指南接受辅助激素疗法。还依照方案中包括的指南指示术后放射疗法。
所有患者会接受全面支持护理,包括临床上指示时的止吐药(例如,血清素拮抗剂,苯并二氮杂卓),止泻药(例如,洛哌丁胺),用于治疗或预防变应性或输注反应的短期皮质类固醇,H1和H2拮抗剂(例如,苯拉海明,西咪替丁),止痛药(例如,对乙酰酚/乙酰氨酚,哌替啶,阿片类),和抗生素。
统计方法
主要分析
会对ITT群体实施功效分析,定义为在每个治疗队列中登记的所有患者。会依照他们所登记的治疗队列分析患者。
会对安全性群体实施安全性分析。未能接受他们的计划研究药疗的任何成分的登记患者(即,根本没有接受新辅助化疗,或的患者)会排除在安全性群体以外。会依照他们所登记的治疗队列对患者分析安全性,因为治疗方案的选择是由调查人员进行的。
不会在两个治疗队列的功效和安全性结果之间进行比较。所有分析会是描述性的。
会在下面的时间点分析功效和安全性数据二者:
●在所有患者完成新辅助疗法(或退出研究或失去随访)之后;这是主要分析时间点。
●在所有患者完成辅助疗法(或退出研究或失去随访)之后
●在研究结束时(在登记最后一名患者之后5年)
然而,对头两个时间点仅仅计划有限的功效分析(主要是pCR),因为iDFS,EFS,和OS数据在研究的这个阶段会是相对不成熟的。
在主要临床研究报告(CSR)中会包括主要分析(在完成新辅助疗法之后)的结果。更新CSR中会包括后续分析的结果。
材料和方法
患者
目标群体是安排接受新辅助疗法的具有局部晚期,炎性,或早期阶段HER2阳性乳腺癌(原发性肿瘤直径>2cm或结阳性疾病)的成年男性和女性。
纳入标准
对于研究进入,患者必须达到下面的标准:
●具有局部晚期,炎性,或早期阶段,单侧,和组织学确认的侵袭性乳腺癌的男性和女性患者。具有炎性乳腺癌的患者必须能够具有芯针活检。
●原发性肿瘤直径>2cm,或直径>5mm且结阳性(临床上,成像上,或细胞学/组织病理学上)
●由中心实验室确认的HER2阳性乳腺癌(通过免疫组织化学的3+或通过原位杂交的HER2扩增,HER2基因信号对着丝粒17信号之比≥2.0)
●用于中心确认HER2,激素受体状态,和分子亚型测定的福尔马林固定,石蜡包埋(FFPE)肿瘤组织块可得
●提供知情同意书和遵守研究方案的能力和意愿
●年龄≥18岁
●基线LVEF≥55%(通过ECHO或MUGA测量)
●东部肿瘤学协作组(ECOG)性能状态≤1
●自重大无关手术起至少4周,完全恢复
●对于绝经前女性和对于在绝经开始后<12个月的女性必须阴性血清妊娠测试可得,除非她们已经经历手术绝育。
●有生育潜力的女性和伴侣有生育潜力的男性参与者必须同意由患者和/或伴侣使用“高度有效”的非激素形式的避孕或两种“有效”形式的非激素避孕。对于研究治疗的持续时间和最后一剂研究治疗之后至少7个月必须继续避孕。
●转移性疾病(阶段IV)或双侧乳腺癌
●具有原发性肿瘤的切开式活检或切除原发性肿瘤的患者
●在研究进入之前5年内的在先乳腺或非乳腺恶性,皮肤的原位癌和基细胞和鳞状细胞癌除外。如果治愈性治疗的话,具有在研究进入之前超过5年发生的恶性的患者是允许的。
●用于癌症的任何在前系统性疗法(包括化疗,免疫疗法,HER2靶向剂,和抗肿瘤疫苗),或用于癌症的放射疗法
●不容许具有原位导管癌(DCIS)或原位小叶癌(LCIS)的过去历史的患者进入研究,如果他们/她们已经接受为了它的治疗的任何系统性疗法或针对同侧乳腺的放射疗法的话(容许他们/她们进入研究,如果单独用手术治疗的话)。●不容许已经在过去接受化学预防性药物的高风险患者进入研究。
●骨髓功能不足(例如,绝对嗜中性细胞计数<1.5x109/L,血小板计数<100x109/L,和血红蛋白<9g/dL)
●肝功能受损(例如,血清[总]胆红素>1.25x正常上限[ULN][Gilbert氏综合征除外],AST和ALT>1.25xULN,清蛋白<25g/L)
●肾功能不足,血清肌酐>1.5xULN
●控制较差的高血压(例如,收缩血压>180mm Hg和/或舒张血压>100mm Hg),需要抗心绞痛药疗的心绞痛,任何NYHA分类的CHF的历史,需要治疗的严重的或不受控制的心律失常(例外:静息时的心率≤100bpm的受控制的心房纤颤,,和阵发性室上性心动过速),登记6个月内的心肌梗死的历史,或LVEF<55%
●静息时的呼吸困难或需要持续氧疗的其它疾病
●重度,不受控制的系统性疾病
●具有控制较差的糖尿病或临床显著的糖尿病血管并发症的证据的患者●妊娠或哺乳的女性
●研究开始4周内接受任何调查性治疗的患者
●具有已知的HIV,乙型肝炎病毒,或丙型肝炎病毒感染的患者
●当前长期日常皮质类固醇治疗(剂量>10mg甲泼尼龙或等同物[排除吸入式类固醇])
●已知的针对任何研究药物或赋形剂的超敏感性
●由调查人员评价为不能或不愿意遵守方案要求的患者。
研究治疗
研究治疗定义为新辅助(手术前)和辅助(手术后)治疗。贯穿研究,IMP是和
新辅助治疗方案的选择会由调查人员在调查人员特异性基础上进行(即,在任何给定地点一次只会打开一个队列;调查人员不可以将患者同时登记入两个队列)。如果调查人员要求在研究的登记期期间改变队列的话,研究团队会在批准请求之前审查情况。
在适用时,依照指南提供激素疗法的处方。在依照提供的指南在临床上指示时,还给予放射疗法。会在电子病例报告表(eCRF)上记录激素疗法和放射疗法的详情。
配制,包装,和操作
的配制
作为在20mM L-组氨酸(pH 6.0),120mM蔗糖,和0.02%聚山梨酯-20中配制的含有30mg/mL帕妥珠单抗的单次使用配制剂提供每个20cc管形瓶装有大约420mg帕妥珠单抗(14.0mL/管形瓶)。
关于进一步的详情,参见 IB或的当地处方信息。
的标示
会依照每个国家的管理要求,以及依照国际协调会议(ICH)优秀临床实践标示研究发起人会给所有研究地点提供标示仅仅用于调查性用途。
的储存
以范围为2℃-8℃(36°-46°F)的温度运输的管形瓶,而且必须在收到后立即放置在冰箱中(相同温度范围)以确保最佳保持物理和生物化学完整性,而且直至临使用前应当保持冷藏。必须在冰箱上保存温度记录(依照当地药房实践)以确保适当的储存条件。如果在运输或储存任一期间发现温度偏离容许的2℃-8℃的话,联系发起人来确定是否药物仍然适合于使用。
不可以摇晃管形瓶。所有管形瓶应当储存在外纸箱内且避光。不得超出IMP试剂盒标签上提供的截止使用日期信息使用药疗。
的制备
因为配制剂不含防腐剂,所以管形瓶密封只可以刺穿一次。应当丢弃任何剩余溶液。
应当自管形瓶取出指示体积的溶液并添加至0.9%氯化钠注射液的250cc IV袋。应当温和颠倒袋以混合溶液,但是不应剧烈摇晃。应当在施用之前对溶液目视检测颗粒和变色。应当作为连续IV输注施用袋内的整个体积。应当使用0.9%氯化钠注射液完全冲洗施用管道中含有的体积。
在装有0.9%氯化钠注射液的聚氯乙烯(PVC)或非PVC聚烯烃袋中稀释的,用于输注的溶液可以在使用之前于2℃-8℃(36°F-46°F)储存达长至24小时。已经显示稀释的于室温(2℃-25℃)稳定达长至24小时。然而,因为稀释的PERJETA不含防腐剂,所以无菌稀释的溶液应当冷藏(2℃-8℃)储存不超过24小时。
可以对所有研究药物输注使用速率调节装置。当研究药物IV袋是空的,可将50mL0.9%氯化钠注射液添加至IV袋或可以悬挂另一个袋,而且可以继续输注达与管道体积相等的体积以确保研究药物的完全投递。
如果发生研究药物输注的外渗的话,应当采取下面的步骤:
●中止输注。
●依照关于非苛性药外渗的机构指南处理外渗。
●如果保留显著体积的研究药物输注的话,在另一侧上或在相同肢体中的更近部位重新开始输注。
的配制
作为冷冻干燥制备物,发起人会供应供这项研究中使用的(冻干配制剂)。所有是供应胃肠外IV施用的;这项研究中不允许皮下在组氨酸,海藻糖,和聚山梨酯20中配制发起人会在装有用于胃肠外施用的冷冻干燥制备物的管形瓶中供应供这项研究中使用的对于IV施用,根据管形瓶大小用无菌注射用水(SWFI)重建每个管形瓶,如下:
●440mg管形瓶与20.0mL SWFI(不供应)混合
●150mg管形瓶与7.2mL SWFI(不供应)混合
不容许使用其它重建溶剂。重建的溶液含有21mg/mL曲妥珠单抗且会添加至250mL0.9%氯化钠注射液,用于施用于患者。无一配制剂含有防腐剂。并不意图在重建和稀释之后储存产品,除非这在无菌条件下发生。因此,一旦准备好输注,它仅仅供单次使用且应当迅速施用。必须在重建之后8小时内输注剂量,除非于2℃-8℃无菌制备和储存(最大冷藏储存时间是24小时)。为这项研究提供的每个管形瓶要作为仅单剂管形瓶使用。每个管形瓶不应用于超过一次施用HERCEPTIN且一次超过1名患者。不要冷冻重建的HERCEPTIN。
的标示
会依照每个国家的管理要求,以及依照ICH优秀临床实践标示研究发起人会给所有研究地点提供HERCEPTIN,标示仅仅用于调查性用途。
的储存
用冷包于范围为2℃至8℃(36°F至46°F)的温度运输管形瓶,而且必须在收到后立即放置在冰箱中(相同温度范围)以确保最佳保持物理和生物化学完整性。必须在冰箱上保存温度记录(依照当地药房实践)以确保适当的储存条件。不要超出管形瓶上盖章的截止使用日期使用。不要冷冻。
可能对剪切诱导的应力(例如,搅动或自注射器快速排出)敏感。不要摇晃。剧烈操作溶液导致蛋白质聚集且可能产生混浊的溶液。在重建期间应当小心操作在重建期间引起过量起泡或摇晃重建的可能导致能自管形瓶取出的的量的问题。
的制备
在制备研究药物时应当使用适宜的无菌技术。如上文所述用SWFI重建每个管形瓶。在重建期间应当小心操作在重建期间引起过量起泡或摇晃重建的可能导致能自管形瓶取出的的量的问题。
必须遵循下面的指令:
1.使用无菌注射器,将无菌注射用水缓慢注射入装有冻干HERCEPTIN的管形瓶,将液流引导入冻干饼。
2.温和旋转管形瓶以帮助重建。不要摇晃!
重建时产品的轻微起泡并不罕见。容许管形瓶不受扰动静置大约5分钟。重建的产生无色至淡黄色透明溶液且应当本质上没有可见颗粒。
不要冷藏或冷冻重建的
药物制备:稀释
会将重建的溶液添加至装有250mL 0.9%氯化钠注射液(美国药典)的输注袋。一旦准备好输注,它应当立即施用。如果无菌稀释的话,它可以最多自重建起储存24小时(不要在30℃以上储存)。
剂量,施用,和顺从性
两个队列,A和B
在两个队列中,作为固定的非基于重量的剂量840mg IV加载剂量,然后是420mgIV每3周给予作为8mg/kg IV加载剂量,然后是6mg/kg IV每3周给予HERCEPTIN。和的施用次序依照调查人员的偏好。应当在和之后给予化疗。
会依照安排继续治疗,或直至调查人员评价的放射学或临床疾病进展或复发或不可管理的毒性。
应当在筛选期间和在每个周期的第1天对所有患者记录重量。会在周期1第1天测量患者的基线重量。如果患者的体重自周期1第1天重量改变>10%(升高或降低)的话,必须重新计算要施用的的量。依照患者的实际体重计算施用的的量,没有上限。
依照患者的BSA计算多西他赛,帕利他赛,多柔比星,5-氟尿嘧啶,表柔比星,和环磷酰胺的量。如果患者的体重自基线改变>10%(升高或降低)的话,必须重新计算BSA和施用的药物的量。基于更小的体重或BSA改变的施用的药物的量的重新计算由调查人员斟酌。
或不容许剂量减少。如果患者错过任何周期的一剂或且各剂之间的时间≥6周的话,应当给予重新加载剂量的或(分别是840mg和8mg/kg)。然后会自3周后开始,每3周给予后续维持(420mg)和(6mg/kg)剂量。
在手术后,患者继续接受辅助设置中的和直至在研究期间施用总共17个周期的和直至手术后2周不应开始辅助和治疗。如果第一剂辅助PERJETA和HERCEPTIN和最后一剂新辅助和之间的间隔超过6周的话,需要重新加载剂量840mg的和8mg/kg的
会在60(±10)分钟里施用初始剂量的而且会进一步对患者观察60分钟。如果患者经历输注相关症状的话,应当减缓或中断输注。如果输注得到较好耐受的话,可以在30(±10)分钟里施用后续剂量,而且会进一步对患者观察30分钟的输注相关症状,诸如发热或发冷。必须在给予或化疗之前解决所有输注相关症状,或者放出该患者。可以为了后续输注用止痛药和抗组胺药对经历输注相关症状的患者预先药疗。
会在90(±10)分钟里施用初始剂量的而且会自输注结束起对患者观察至少30分钟的输注相关症状,诸如发热或发冷。中断或减缓输注可能有助于控制此类症状,而且可以在症状消退时恢复。如果输注得到较好耐受的话,可以在30(±10)分钟里施用后续输注,而且会进一步对患者观察30分钟。必须在给予或化疗之前解决所有输注相关症状,或者放出该患者。可以为了后续输注用止痛药和抗组胺药对经历输注相关症状的患者预先药疗。
队列A(ddAC→T+PH)
队列A中的患者接受多柔比星60mg/m2IV和环磷酰胺600mg/m2IV每2周,达四个周期(周期1-4),2周后继以每周帕利他赛80mg/m2IV达12周(周期5-8),自帕利他赛开始起每3周和(在新辅助期期间总共四个周期的和)。在ddAC期间,患者应当依照当地实践指南接受G-CSF支持。手术后,患者继续接受辅助设置中的和(周期9-21)直至给予总共17个周期的和
多柔比星
会在每次ddAC治疗的第1天以60mg/m2施用多柔比星。它可以作为3-5分钟里的IV推注或15-30分钟里的输注给予。允许出于毒性的剂量延迟和减少,而且患者应当依照当地实践指南接受G-CSF支持。
环磷酰胺
会在每次ddAC治疗的第1天以600mg/m2施用环磷酰胺。它应当依照当地政策作为3-5分钟里的IV推注或输注给予。BSA>2m2的患者应当将他们/她们的剂量止步于1200mg。允许出于毒性的剂量延迟和剂量减少,而且患者应当依照当地实践指南接受G-CSF支持。不允许口服环磷酰胺。
帕利他赛
会在最小1小时里作为IV输注以80mg/m2的剂量施用帕利他赛。当自同一天给予时,它应当在和之后给予。应当在依照例行实践在临床上指示时施用包括皮质类固醇的预先药疗。
队列B(FEC→D+PH)
队列B中的患者接受5-氟尿嘧啶500mg/m2IV,表柔比星100mg/m2IV,和环磷酰胺600mg/m2IV,每3周,达四个周期(周期1-4),(3周后)继以多西他赛每3周(第一剂75mg/m2,后续剂100mg/m2,如果没有发生剂量限制性毒性的话)达四个周期(周期5-8),自多西他赛开始起每3周和(周期5-8;即,在新辅助期期间总共四个周期的和)。手术后,患者继续接受辅助设置中的和(周期9-21)直至给予总共17个周期的和
5-氟尿嘧啶
会依照当地政策在FEC治疗的每个周期的第1天作为IV推注或输注施用5-氟尿嘧啶500mg/m2。BSA>2m2的患者应当将他们/她们的剂量止步于1200mg。允许出于毒性的剂量延迟和剂量减少。
表柔比星
会依照当地政策在FEC治疗的每个周期的第1天作为3-5分钟里的IV推注或1-30分钟里的输注施用表柔比星100mg/m2。允许出于毒性的剂量延迟和剂量减少。
环磷酰胺
会依照当地政策在FEC治疗的每个周期的第1天作为3-5分钟里的IV推注或输注施用环磷酰胺600mg/m2。BSA>2m2的患者应当将他们/她们的剂量止步于1200mg。允许出于毒性的剂量延迟和剂量减少。不允许口服环磷酰胺。
多西他赛
以第一个周期(周期5)的开始剂量75mg/m2,在和之后,作为60(±10)分钟里的IV输注施用多西他赛。由调查人员斟酌,后续周期(周期6至8)的剂量可以放大至100mg/m2,前提是没有发生剂量限制性毒性。
应当依照例行实践施用预先药疗,包括皮质类固醇。必须自输注开始起对患者密切观察可能在数分钟内发生的超敏感性反应。重度低血压,支气管痉挛,或全身性皮疹/红斑要求立即中止多西他赛和适宜治疗。为了轻微症状,诸如发红或局部皮肤反应,可以减缓输注。经历重度超敏感性反应的患者应当中止研究治疗但维持评价进度表,除非撤回同意。可以依照机构指南给予由皮质类固醇组成的预先药疗。类似地,可以依照当地政策使用预防性G-CSF来减轻血液学毒性的风险。依照当地政策允许用G-CSF治疗嗜中性细胞减少。在所有情况中,G-CSF不会认为是研究药物且不会由发起人提供。
并行疗法
手术
安排两个队列中的患者在八个周期的新辅助疗法之后经历手术。对于队列A中的患者,八个周期会花费约20周,而对于队列B中的患者,是约24周。患者可依照例行临床实践经历BCS或乳房切除术。会在手术之前记录选择BCS或乳房切除术的原因,而且会提供病理学报告的拷贝。
在开始新辅助治疗之前,应当使用当地标准的方法(例如,皮肤纹身或手术钳)标记原发性肿瘤部位以能够实现在新辅助疗法期间肿瘤消退的情况中的恰当手术切除。
下面关于前哨淋巴结活检(SLNB)的指南基于2013NCCN和ESMO指南(Senkus etal.2013;Theriault et al.Journal of the National Comprehensive Cancer Network,2013,Vol.11,No.7,753-761)。然而,正在进行的临床试验评估腋窝放射疗法作为腋窝清扫备选的作用,并鉴定可能能够在阳性SLNB后省略腋窝清扫的患者亚组。结果是,可能取代这些广泛的指南。一旦将它们并入机构,当地,国家,或国际指南(例如,NCCN,ESMO,StGallen,里斯本会议,或美国临床肿瘤学学会临床实践指南),调查人员就可以遵循基于正在出现的数据的更加新式的指南。下面是一些推荐;然而,调查人员可以遵循当地实践指南。
在可能时,在新辅助疗法之前具有临床结阳性疾病的患者应当在新辅助疗法开始之前经历超声指导的细针穿刺或芯针活检以确认结累及。具有确认的结阳性疾病的患者应当在确定性手术时(在新辅助疗法之后)经历I和II水平腋窝清扫。推荐的是取出至少10个淋巴结用于病理学检查。
如果有经验丰富的团队的话,SLNB对于具有临床结阴性疾病的患者是腋窝淋巴结分期的优选方法。可以依照例行实践在新辅助疗法之前或之后进行SLNB。如果SLNB不可得的话,患者应当在确定性手术时(在新辅助疗法之后)经历I和II水平腋窝清扫。推荐的是取出至少10个淋巴结用于病理学检查。
如果SLNB可得的话,应用下面的指南。
●对于在新辅助疗法之前经历SLNB的在新辅助疗法之前具有临床结阴性疾病的患者:
如果前哨淋巴结(SLN)呈组织学阴性的话,可以在确定性手术时(在新辅助疗法之后)省略腋窝清扫。
如果SLN呈组织学阳性的话,患者应当在确定性手术时(在新辅助疗法之后)经历I和II水平腋窝清扫。
●对于在新辅助疗法之前并不经历SLNB的在新辅助疗法之前具有临床结阴性疾病的患者:
可以在确定性手术时(在新辅助疗法之后)实施SLNB。如果SLN呈组织学阳性的话,应当实施I和II水平腋窝清扫。
对于累及内乳链的前哨结,参见当地,国家,或国际指南。
仅仅对具有II水平结中的严重疾病的患者应当实施III水平腋窝清扫。
放射疗法
在积极登记患者之前,每个中心必须为治疗试验中的患者确定放射疗法政策。在化疗和手术之后,在辅助抗体疗法(和激素疗法,如果指示的话)期间给予放射疗法。
激素疗法
在积极登记患者之前,每个中心必须为对试验中的患者使用他莫昔芬,卵巢消融,或二者设置政策。研究地点还必须为使用已注册的芳香酶抑制剂设置它们的当地政策。在已经注册这种适应症的国家会容许芳香酶抑制剂作为辅助激素疗法用于激素受体呈阳性的绝经后患者。它的使用必须与注册标签一致。在化疗和手术之后,在辅助抗体疗法期间给予激素疗法。
不容许用于原发性乳腺癌的其它激素疗法,包括纯抗雌激素和促孕剂,除非它在进行试验期间变成批准用于辅助疗法。
研究评价
研究评价的描述
芯活检
会遵照当地护理标准实施原发性乳腺癌的诊断。
自原发性肿瘤的(优选的)或累及淋巴结的(如果原发性肿瘤不能活检的话)芯活检提交肿瘤组织对于试验是强制性的。组织会用于确认HER2和雌激素受体(ER)/孕酮受体(PgR)状态和后续生物标志物研究(即,分子亚型测定)。样品必须福尔马林固定和石蜡包埋,而且肿瘤块是优选的。如果不可能提交肿瘤块的话,地点必须提供15个新鲜切割的载片。
推荐14号针,使用自动装置射入损害3-4次以收集足够的肿瘤组织。
鼓励提交来自具有残余疾病的患者的在手术时获得的来自切除标本的组织。这些样品必须作为FFPE组织块提交;不能接受载片。
关于适格性的HER2筛选和激素受体状态的中心评价
患者应当首先由当地实验室筛选HER2状态且应当具有3+的通过免疫组织化学(IHC)的HER2得分或通过原位杂交(FISH,SISH,或CISH)的HER2(c-erbB2)基因扩增以符合中心实验室筛选(见图7)。
对于中心确认,HER2阳性定义为>10%的免疫反应性细胞中的IHC 3+或通过ISH的c-erbB2基因扩增(c-erbB2基因信号对着丝粒17信号之比≥2.0)。
在研究中登记之前要求阳性HER2状态的中心实验室确认。这项评价的结果会通知调查人员。
另外,会依照美国临床肿瘤学学会/美国病理学家学会指南(Hammond et al.,2010)进行激素受体状态(ER和PgR)的中心评价。结果会通知调查人员。调查人员可以依照当地或中心结果用辅助激素疗法治疗患者,但是在研究的数据分析中还使用激素受体状态的中心结果。
只有通过中心测定呈HER2阳性的患者会容许进入研究;具有总体阴性和可疑得分的患者会排除在进入研究之外。
心脏功能
所有患者必须在登记之前具有至少55%的通过ECHO(优选)或MUGA扫描的LVEF测量。调查人员必须了解关于重复MUGA扫描的最大可容许频率的当地机构规定。放射性同位素的重复施用限于一些核医学实验室,而且这项研究中的患者要求1年内超过四次的监测。
患者还必须在登记之前具有心脏事件的历史,体格检查,和基线心电图(ECG)的评价以排除会使得他们/她们不适格参与这项试验的任何心脏状况。还会在完成蒽环类抗生素化疗之后(且在第一个周期的紫杉烷之前)和其后在临床上指示时实施ECG。
实验室评价
会将用于下面的标准实验室测试的样品送至研究地点的当地实验室进行分析:
●血液学:全血计数,WBC计数,RBC计数,血红蛋白,血细胞比容,血小板计数,分类计数(嗜中性细胞,嗜曙红细胞,嗜碱性细胞,单核细胞,淋巴细胞,其它细胞)。在辅助和治疗期间,遵照当地关于辅助HERCEPTIN单药疗法的医学实践安排全血计数,包括分类和血小板。
●血清化学:钠,钾,氯化物,碳酸氢盐,葡萄糖,BUN或尿素,肌酐,总蛋白质,清蛋白,磷,钙,总直接/间接胆红素(如果需要的话),碱性磷酸酶,ALT,AST,尿酸,LDH。受限的血清化学只包括碱性磷酸酶,AST,ALT,LDH,总直接/间接胆红素,和肌酐。只有在总胆红素大于ULN的情况中才需要测量胆红素分数(直接和间接)。
●凝血(INR,aPTT,PT)
●妊娠测试:所有有生育能力的女性(绝经前女性和对于绝经开始之后不到12个月的女性,除非她们经历手术绝育)会在第一次施用研究药疗之前7天内具有在当地实验室的血清妊娠测试。经历手术绝育或是绝经后的女性免于妊娠评价。
●通过试纸条(pH,比重,葡萄糖,蛋白质,酮,血)及显微镜检查(对于沉渣,RBC,WBC,管型,晶体,上皮细胞,细菌)的尿液分析,如果临床上指示的话。
临床肿瘤响应评估
临床乳房检查(CBE)包括检查乳房,腋窝,和锁骨上窝。在基线时具有≥2cm的乳腺肿瘤的患者会具有他们/她们的作为CR,PR,SD,或PD的临床响应评价,如通过乳房X线照片和CBE,和/或其它评估方法测定的。其疾病没有满足这项标准的患者(即,只有结阳性疾病和<2cm的肿瘤的患者)会具有他们/她们的作为CR,SD,或PD(而非作为PR,因为肿瘤对于精确测量这种响应而言太小)的临床响应评价,如通过乳房X线照片和/或CBE,和/或其它评估方法测定的。不管原发性肿瘤和区域淋巴结的大小和可测量性,所有患者可通过CBE和/或乳房X线照相术,和/或其它评估方法评估疾病进展且会包括在临床响应率的计算中。
在新辅助治疗期期间(在手术之前),会遵照当地医学实践依照评价进度表使用CBE和/或乳房X线照相术和/或其它评估方法评价肿瘤响应。当通过CBE评估响应时,应当在两个维度上测量损害,而且依照RECIST v1.1标准(Eisengauer et al.,2009)的原则评价响应。倘若患者的临床状态没有变化,可以直至在开始治疗之前42天实施筛选乳房X线照片。筛选时,手术前和最后一次拜访/退出时的乳房X线照片可以由调查人员斟酌用MRI替换,但是对于患者个体必须始终使用相同评价方法。
在完成新辅助疗法之后且在手术之前,要求进一步的肿瘤响应评价,包括CBE和乳房X线照片,和/或其它评估方法。
在手术之后,会依照评价进度表继续CBE以检测局部复发的迹象。
遵照例行实践,响应的评价中可包括任何另外的评价方法(诸如超声,CT,X射线,或MRI)的结果(会在eCRF中收集这些模态的结果)。应当确保对每名患者在所有评价期间连续乳房X线照片,CBE,CT扫描,X射线,或MRI的一致性,尽可能贯穿治疗期使用相同技术评估目标损害。在可行的范围内应当在研究期间对每名患者由相同调查人员或放射科医师进行肿瘤测量。在临床上可测量的浅表(诸如皮肤)损害的情况中,应当使用重复照片来记录肿瘤响应。这些照片必须包括用于记录目的的标尺。
如果损害显示明显的进展迹象的话,患者会退出研究治疗并获得当地护理标准。
在新辅助治疗期期间发现同侧或对侧DCIS或LCIS不会认为是进展性疾病。然而,侵袭性对侧乳腺癌会归类为进展性疾病。
临床响应会在当地评价且不会独立审查。
病理学响应评估
会由当地病理学家使用病理学手册中提供的指南评价病理学响应。完全病理学响应是定义为基于新辅助疗法后手术标本的显微镜检查,乳房和腋窝中没有侵袭性疾病(tpCR;即,ypT0或ypTis,ypN0)。完全病理学响应率是研究的主要功效终点。
来自患者的主要(主)手术的病理学报告的拷贝必须在手术日6周内提交给发起人。如果其它报告中存在手术时淋巴结的另外信息的话,这些也应当提交给发起人。
复发或再发的诊断
复发性疾病包括:局部,区域,和远端复发和对侧乳腺癌。诊断有原位乳腺疾病或继发性(非乳腺)恶性的患者应当尽可能维持定期随访以完全捕捉任何后续复发疾病事件。在诊断存疑(例如,照射的乳房中定义较差,可触知的块)的情况中,应当尽可能获得复发的组织学或细胞学确认。
一些患者可形成可疑的复发,快速导致死亡,没有可能确认疾病的复发。应当努力获得此类患者的尸检报告。
应当使用和记录复发性疾病的诊断的最早日期。这应当基于临床,放射学,组织学,或细胞学证据。应当作为第一次诊断损害(即,客观发现)的日期,而非第一种症状发生的日期报告疾病复发日。
在研究期间无论何时发生,要报告所有第二原发性恶性。如果调查人员认为是患者的最好利益的话,不需要系统性疗法(即,化疗,激素疗法,靶向疗法,等)且没有乳腺癌复发的证据的诊断有第二原发性恶性的患者尽可能会保持在研究中且应当依照评价方案和进度表继续研究药物治疗。
下面的事件不认为是复发性疾病,但是必须记录。
●同侧和对侧LCIS
●同侧和对侧DCIS
●宫颈的原位癌
●皮肤的基或鳞状细胞癌
复发后,应当依照评价进度表对所有患者跟踪存活。另外,应当继续实施LVEF评价,每6个月达2年,然后每年达另外2年。必须报告在研究期间的任何时间和直至在登记最后一名患者之后5年发生的心力衰竭,无论备选治疗的启动和无论任何因果关系。还应当继续妊娠测试,而且应当报告妊娠直至在最后一剂研究治疗之后7个月,无论疾病进展或复发或备选治疗的启动。还应当报告相关严重不良事件和非乳腺第二原发性恶性(作为严重不良事件可报告的)直至研究结束。
用于抗治疗剂抗体,帕妥珠单抗,和生物标志物分析的强制性血清样品
会在基线和后续时间点时收集血液样品(10mL)并分成三份血清等分试样:一份等分试样用于测量血清帕妥珠单抗ATA,一份等分试样用于测量血清帕妥珠单抗浓度,和一份等分试样用于生物标志物研究。这些是试验的强制性样品。
会使用一种经过验证的基于与经标记帕妥珠单抗分子形成桥接抗体复合物的桥接ELISA方法检测血清中针对帕妥珠单抗的ATA。这种测定法利用用生物素标记的帕妥珠单抗和用地高辛配基标记的帕妥珠单抗。会使用一种经过验证的ELISA来测量帕妥珠单抗浓度以进一步表征ATA结果。
可使用为生物标志物研究保留的等分试样来鉴定动态(非遗传的)生物标志物。这项研究可有助于更好地理解生物标志物和功效,不良事件,或疾病进展之间的联系,更好地理解疾病生物学,或改善诊断性测试。这些样品的分析可包括但不限于循环肿瘤DNA,循环蛋白质或肽(诸如HER受体家族的配体)或心脏损伤的潜在标志物。
会不晚于在相关临床数据库最终关闭日之后5年销毁样品。
特定不良事件的管理
在这项研究方案定稿时没有证据指示除了 IB和处方信息中提到的那些,特殊的警告和预防措施是适宜的。
应当仅仅在治疗癌症患者经验丰富的内科医师监督下启动
变应性反应,包括过敏反应和输注相关症状
像其它单克隆抗体一样,与输注相关症状(诸如发冷,腹泻,疲劳,头痛,恶性,和发热)和超敏感性反应有关。的施用应当在有应急设备和经过监测医学状况和应对医学紧急情况训练的人员的设置中实施。会在每次输注期间和在完成第一次输注后至少60分钟对患者监测任何不良事件。如果发生输注相关症状的话,应当监测患者直至完全解决体征和症状。由调查人员确定为临床上适宜时,可以通过减缓或中断输注和通过提供氧气和药疗(例如,β-激动剂,抗组胺药,退烧药,或皮质类固醇)的支持性护理来管理经历输注相关症状的患者。可以随后用止痛药和抗组胺药对经历输注相关症状的患者预先药疗。如果输注得到较好耐受的话,会在后续输注后对患者观察30分钟。
在发生呼吸困难或临床显著的低血压(遵照调查人员斟酌定义)的患者中应当停止的输注。经历NCI CTCAE 3或4级变应性反应或急性呼吸窘迫综合征(ARDS)的患者应当中止治疗。
心脏毒性
已经对阻断HER2活性的药物,包括和报告LVEF下降。
为了进入这项研究,所有患者必须具有≥55%的LVEF(通过ECHO或MUGA扫描)。
如果他或她的LVEF在蒽环类抗生素疗法之后<50%的话,队列A和B二者中的患者不应开始抗HER2药物。
由调查人员斟酌,在蒽环类抗生素疗法之后经历无症状LVEF下降的患者可继续接受化疗的紫杉烷成分。随后可依照图8中的算法启动(或重新开始)HER2靶向疗法;启动(重新开始)HER2靶向疗法的延迟不应超过6周。其后要求依照设定的评价进度表定期监测LVEF。
如果重度的有症状的心力衰竭发生(NYHA III或IV类)或者有显著的LVEF下降(LVEF下降≥10百分点达到<50%的LVEF值)的话,患者必须中止抗HER2疗法。应当依照标准医学实践治疗和监测心力衰竭或左心室功能障碍。应当由经过认证的心脏学家评估这些患者,而且应当在eCRF上报告这项评估的结果。
图8汇总发生无症状的LVEF下降的患者中的研究药疗的管理。启动HER2靶向疗法(对于队列B中的患者)和是否继续或停止疗法(对于两个队列中的患者)的决策应当基于两项因子:测量的LVEF和LVEF中自基线的变化。
出于心力衰竭或LVEF下降中止和的患者应当继续经历LVEF评价,无论备选系统性抗癌疗法的启动,直至解决,改善至基线状态,没有进一步改善的预期,或死亡。依照调查人员的临床判断,对这些患者可能要求另外的LVEF评价(超出评价进度表中规定的那些)。应当报告这些评价的结果。
不良事件
依照关于优秀临床实践的ICH指南,不良事件是施用医药产品的临床调查受试者中的任何不利医学事件,不管因果归因。因此,不良事件可以是任何下述的:
●时间上与医药产品的使用有关的任何不利的和非预期的迹象(包括异常实验室发现),症状,或疾病,无论是否认为与医药产品有关
●除了与潜在疾病的复发或进展的预期样式明显一致的事件以外,任何新的疾病或现有疾病恶化(已知状况的性质,频率,或严重度的恶化)不应记录为不良事件。
●在基线时不存在的间歇性医学状况(例如,头痛)的复发
●与症状有关或导致研究治疗或并行治疗改变,或中止研究药物的实验室数值或其它临床测试(例如,ECG,X射线)的任何恶化
●与方案强制干预有关的不良事件,包括在指派研究治疗之前发生的那些(例如,筛选侵入性规程,诸如活检)
严重不良事件(可立即报告发起人)
严重不良事件是满足任何下面的标准的任何不良事件:
●致命的(即,不良事件实际引起或导致死亡)
●危及生命(即,调查人员认为不良事件将患者置于立即风险死亡)
这并不包括如果以更加重度的形式发生或容许继续的话可能引起死亡的任何不良事件。
●要求或延长患者住院
●导致持续的或显著的残疾或失能(即,不良事件导致实质性破坏患者进行正常生活功能的能力)
●暴露于研究药物的母亲所生的新生儿或婴儿中的先天畸形或出生缺陷●调查人员判断的重大医学事件(例如,可能危及患者或可能要求医学或手术干扰以预防上文列出的结局之一)
术语“重度(severe)”和“严重(serious)”并不同义。严重度指不良事件的强度(例如,评定为轻度,中度,或重度,或依照NCI CTCAE标准;见下面的表1);事件本身可以具有相对轻微的医学意义(诸如没有任何进一步发现的重度头痛)。
需要为eCRF上记录的每个不良事件独立评价严重度和严重性。
要求调查人员立即(即,在了解事件之后不超过24小时)将严重不良事件报告发起人。
表1:不良事件严重度分级量表
NCI CTCAE=国家癌症研究所不良事件常用术语标准。
注:图表基于最新版的NCI CTCAE(4.0版),可以在http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm找到。
a日常生活的工具活动指准备餐食,购买杂货或衣物,使用电话,管理钱财,等。
b日常生活的自我护理活动的例子包括洗澡,穿衣和脱衣,自己进食,如厕,和服药,如由没有卧床的患者实施的。
c如果事件评价为重大医学事件的话,必须将它报告为严重不良事件,
d必须将4和5级事件报告为严重不良事件)。
有特殊兴趣的非严重不良事件(可立即报告发起人)
有特殊兴趣的非严重不良事件要求由调查人员立即(即,在了解事件之后不超过24小时)报告发起人。这项研究有特殊兴趣的不良事件包括下面的:●潜在的药物诱发肝损伤的情况,包括与升高的胆红素或临床黄疸任一组合的升高的ALT或AST,如由Hy氏法则定义的
●怀疑感染性因子通过研究药物的传播,定义为:
任何致病性的或非致病性的生物,病毒,或感染性颗粒(例如,朊病毒蛋白质传播的传染性海绵状脑病)认为是感染性因子。可以根据指示暴露于医药产品的患者中的感染的临床症状或实验室发现怀疑感染性因子的传播。只有当怀疑研究药物的污染时才应用此术语。
●无症状的LVEF下降,要求治疗或导致中止和
选定的不良事件
心力衰竭
应当将有症状的左心室收缩功能障碍(也称作心力衰竭)报告为严重不良事件。如果诊断是心力衰竭的话,应当将它这样报告,而不是作为心力衰竭的个别体征和症状。在eCRF中,应当记录体征和症状。对发生有症状的左心室收缩功能障碍(心力衰竭)的患者推荐心脏咨询。应当依照NCI CTCAE v4.0(2,3,4,或5级),以及依照NYHA分类(II,III,和IV类;见图9)对心力衰竭分级。遵照NCI CTCAE v4.0,不应使用左心室收缩功能障碍来描述有症状的功能障碍。
必须报告在研究期间和在登记最后一名患者直至之后5年发生的心力衰竭,不管因果关系,而且跟踪直至下面之一发生:解决或改善至基线状态,没有进一步改善的预期,或死亡。
无症状的左心室射血分数下降
不应将无症状的LVEF下降报告为不良事件,因为在eCRF中分开收集LVEF数据。这一规则的例外如下:
●遵照NCI CTCAE v4.0,必须将自基线≥10百分点达到LVEF<50%的无症状的LVEF下降报告为不良事件及射血分数降低项目。另外,不良事件注解栏中的注解应当确认事件是无症状的。
安全性分析
会在安全性群体中评价安全性目标。
这项研究的主要目标是评估两种治疗方案中每一种的新辅助治疗的心脏安全性。会通过评价下面的终点来评估心脏安全性:
●会为每个治疗队列计算在新辅助期(主要目标),和辅助和随访期期间的NYHAIII和IV类心力衰竭的发生率和相关95%CI。
●会为每个治疗队列计算在新辅助期(主要目标),和辅助和随访期期间的LVEF下降(自基线≥10%点且达到<50%的数值)的发生率及相关95%CI。
会使用用于二项式比例的Clopper-Pearson方法来推导95%CI。
次要安全性目标是评估两种治疗方案在新辅助,辅助,和随访期期间的安全性概况,而且会如下评价:
●会汇总和报告不良事件和严重不良事件的发生率和严重度。
●会汇总和报告实验室测试异常。
●会汇总和报告针对帕妥珠单抗的ATA的血清水平和发生率和它们与安全性事件和功效的相关性。
还会对选定时间段汇总选定亚组中的安全性(例如,队列B中在开始和之前的心脏安全性)。
主要功效终点
心脏安全性是研究的主要目标,所以所有功效分析认为是次要的或探索性的。
主要功效终点是在安排的八个周期的新辅助治疗(在队列A(ddAC→T+PH)中持续大约21周而在队列B(FEC→D+PH)中持续大约25周)后的手术之后评估的乳房和结中的pCR的比率(ypT0/is ypN0tpCR)。没有经历手术或没有有效tpCR评价的患者在分析中会认为是非响应者。
对于每个治疗队列,会计算观察比率和Clopper-Pearson 95%CI。
次要功效终点
会汇总和报告手术前的临床响应率。对于具有新辅助疗法期间但非临手术前的临床响应评价的患者和没有经历手术的患者,会在分析中考虑最后记录的临床响应评价。没有任何手术前的临床响应评价的患者在分析中会认为是非响应者。
EFS定义为自登记至第一次发生进展性疾病,复发,或任何起因的死亡的时间。同侧或对侧原位疾病和第二原发性非乳腺癌(包括原位癌和非黑素瘤皮肤癌)不会作为进展性疾病或复发计数。在没有记录进展或复发的情况下退出研究且有eCRF证据表明已经进行评估的患者会在知道患者没有进展性疾病或复发的最后一次评价之日审查。没有基线后的肿瘤评估的患者会在登记加1天之日审查。
iDFS定义为自无疾病的第一天(即,手术日)至进展性侵袭性疾病,复发,或死亡的第一次记录的时间。同侧或对侧原位疾病和第二原发性非乳腺癌(包括原位癌和非黑素瘤皮肤癌)不会作为进展性疾病或复发计数。在没有记录进展或复发的情况下退出研究且有eCRF证据表明已经进行评估的患者会在知道患者活着且无疾病的最后一次评价之日审查。没有基线后信息的患者和没有经历手术的患者会排除在分析之外。应当注意iDFS的这种定义(其排除第二原发性非乳腺癌作为事件)与APHINITY试验中使用的定义相同且与由Hudis等人(2007)定义的iDFS(其中第二原发性非乳腺癌作为事件计数)不相同。
OS定义为自登记至任何起因的死亡的时间。活着或失去随访的患者会在他们/她们在研究中的最后知道日审查。没有基线后评价的患者会在登记加1天之日审查。
会使用Kaplan-Meier办法来对EFS,iDFS,和OS绘图,以及估算每个治疗队列中在里程碑时间点时无事件的患者的比例。
探索性分析
探索性分析会包括就基线因子(例如,激素受体状态)而言分析tpCR率和计算bpCR和GBG pCR率。
会为下面三种患者群体汇总每个治疗队列的BCS率和95%CI:
●ITT群体中的所有女性患者
●在研究进入时具有T2或T3肿瘤的所有女性患者
●计划乳房切除术的在研究进入时具有T2或T3肿瘤的所有女性患者
会汇总对于BCS潜在适格且没有经历BCS的患者的百分比,以及这一决策的原因(在基线时和在手术时)。
会汇总每个治疗队列的再切除手术率,而且会在ITT群体中接受BCS的子集中计算。
所有生物标志物分析会是性质上描述性的或探索性的。会通过分子定义的乳腺癌亚型汇总pCR。在未接受对照分支缺失下,无法推导生物标志物就治疗益处而言的预测价值。
结果
研究的主要目标是要评价:
●在新辅助期期间NYHA III和IV类心力衰竭的发生率,由调查人员评价●在新辅助期期间临床上有意义的LVEF下降(自基线≥10%点且达到<50%的数值)的发生率。
次要目标:
●tpCR,定义为根除乳房和腋窝中的侵袭性疾病(即,ypT0/is ypN0),且依照当地病理学家的评价。
●其它不良事件和严重不良事件的发生率和严重度
●实验室测试异常
●针对帕妥珠单抗的抗治疗剂抗体(ATA)的发生率和它们与安全性事件的相关性。
探索性目标:
●依照备选定义评价pCR率(bpCR,德国乳房小组[GBG]pCR,和残余癌症负荷[RCB]指数)
●依照通过分子概况定义的乳腺癌亚型评价pCR率;例如,通过PAM50分类器定义的乳腺癌的内在亚型
●记录研究中的女性患者和具有T2或T3肿瘤的女性患者的BCS的比率
●记录残余疾病的再切除手术的比率
图10呈现对于队列A和B在安全性群体中在新辅助治疗期间不良事件(AE)的汇总。分开显示发生率至少5%的AE,≥3级AE和严重AE。
图11呈现在新辅助期和辅助期期间的选定AE:心力衰竭(所有类别)。
图12是在新辅助期,辅助期,和无治疗随访期间持续LVEF下降的汇总表。
图13列出在安全性群体中在新辅助治疗期间的最常见严重不良事件(SAE)(所有等级)。任一队列中的发生率≥2%。包括热性嗜中性细胞减少,腹泻,嗜中性细胞减少败血病,装置相关感染,和发热。
图14列出在新辅助治疗期间的最常见AE:安全性群体:3-5级。任一队列中的发生率≥5%。包括热性嗜中性细胞减少,嗜中性细胞减少,腹泻,口炎,嗜中性细胞计数降低。
图15列出在新辅助治疗期间的最常见AE:安全性群体(所有等级)。任一队列中的发生率≥25%。包括恶心,腹泻,便秘,呕吐,口炎,疲劳,虚弱,粘膜炎症,脱发,头痛,肌痛,和贫血。
图16是基于当地病理学家的评价的tpCR响应的汇总。在队列A中响应率(tpCR)为63.8%,而在队列B中响应率(tpCR)为61.2%。
图17显示依肿瘤/结分期(T0N0)的德国乳房小组(GBG)中的pCR响应率:意向治疗(ITT)群体。在队列A中响应率(pCR)为48.7%而在队列B中响应率(pCR)为48.8%。
图18显示依新辅助治疗的周期(依肿瘤和结分期)的tpCR响应:意向治疗(ITT)群体,包括4个周期,少于4个周期和超过4个周期的新辅助治疗。
生物标志物显示能够对大多数患者评价PAM50亚型且pCR率与HR亚组分析一致。大多数患者归类为HER2富集亚型(队列A中的39.7%[n=79]和队列B中的47.3%[n=95])。在队列A中的16.6%(n=33)和在队列B中的15.4%(n=31)中鉴定出腔A亚型,而且在队列A中的12.1%(n=24)和在队列B中的7.5%(n 15)患者鉴定出腔B亚型。
对于HER2富集和腔B亚型观察到两个队列之间各个亚型的分布的轻微不平衡。在HER2富集亚组中以76.0%(n=60)和73.7%(n=70)观察到最高tpCR率。腔A和腔B的亚组中的tpCR率相当(范围:42%-46%)。
在腔亚组中观察到的较低tpCR率类似在遵照IHC通过中心ER状态定义的ER阳性亚组中观察到的较低tpCR率。
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豪夫迈·罗氏有限公司(F. HOFFMANN-LA ROCHE AG)
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<223> /注释="人工序列的描述: 合成的多肽"
<400> 9
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 10
<211> 119
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的多肽"
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Gly Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Val Gly Tyr Ser Leu Tyr Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 11
<211> 214
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的多肽"
<400> 11
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 12
<211> 448
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的多肽"
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 13
<211> 214
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的多肽"
<400> 13
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 14
<211> 449
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的多肽"
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 15
<211> 217
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的多肽"
<400> 15
Val His Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
1 5 10 15
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val
20 25 30
Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile
85 90 95
Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 16
<211> 449
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的多肽"
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 17
<211> 10
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的 peptide"
<220>
<221> 变体
<222> (10)..(10)
<223> /替换="Ser"
<220>
<221> 混杂特征
<222> (10)..(10)
<223> /注释="序列中给出的残基相对于所述位置的注释中的残基没有偏爱"
<400> 17
Gly Phe Thr Phe Thr Asp Tyr Thr Met Asp
1 5 10
<210> 18
<211> 17
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的肽"
<400> 18
Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe Lys
1 5 10 15
Gly
<210> 19
<211> 10
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的肽"
<400> 19
Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr
1 5 10
<210> 20
<211> 11
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的肽"
<400> 20
Lys Ala Ser Gln Asp Val Ser Ile Gly Val Ala
1 5 10
<210> 21
<211> 7
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的肽"
<220>
<221> 变体
<222> (5)..(5)
<223> /替换="Leu"
<220>
<221> 变体
<222> (6)..(6)
<223> /替换="Glu"
<220>
<221> 变体
<222> (7)..(7)
<223> /替换="Ser"
<220>
<221> 混杂特征
<222> (5)..(7)
<223> /注释="序列中给出的残基相对于所述位置的注释中的残基没有偏爱"
<400> 21
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210> 22
<211> 9
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成的肽"
<400> 22
Gln Gln Tyr Tyr Ile Tyr Pro Tyr Thr
1 5
Claims (44)
1.一种用于治疗乳腺癌的方法,其包括对具有HER2阳性局部晚期,炎性,或早期阶段乳腺癌的患者在基于蒽环类抗生素的化疗后新辅助施用有效量的帕妥珠单抗和曲妥珠单抗的组合,其中在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的组合施用相对于在基于蒽环类抗生素的化疗后曲妥珠单抗的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件。
2.权利要求1任一项的方法,其中在至少4个周期的基于蒽环类抗生素的化疗之后开始帕妥珠单抗和曲妥珠单抗的组合施用。
3.权利要求1的方法,其中该基于蒽环类抗生素的化疗包含多柔比星。
4.权利要求3的方法,其中该基于蒽环类抗生素的化疗包含多柔比星加环磷酰胺。
5.权利要求4的方法,其中该基于蒽环类抗生素的化疗是多柔比星加环磷酰胺(AC)。
6.权利要求4的方法,其中该基于蒽环类抗生素的化疗是剂量密集的多柔比星和环磷酰胺(ddAC)。
7.权利要求4至6任一项的方法,其中与G-CSF支持一起施用多柔比星加环磷酰胺。
8.权利要求4至6任一项的方法,其中每两周施用该基于蒽环类抗生素的化疗。
9.权利要求4至8任一项的方法,其中在帕妥珠单抗和曲妥珠单抗的组合施用之前施用至少四个周期的该基于蒽环类抗生素的化疗。
10.权利要求1的方法,其中该基于蒽环类抗生素的化疗包含表柔比星。
11.权利要求10的方法,其中该基于蒽环类抗生素的化疗包含表柔比星,5-氟尿嘧啶和环磷酰胺。
12.权利要求11的方法,其中该基于蒽环类抗生素的化疗是5-氟尿嘧啶,表柔比星加环磷酰胺(FEC)。
13.权利要求10至12任一项的方法,其中每三周施用该基于蒽环类抗生素的化疗。
14.权利要求10至13任一项的方法,其中在帕妥珠单抗和曲妥珠单抗的组合施用之前施用至少四个周期的该基于蒽环类抗生素的化疗。
15.权利要求1至14任一项的方法,其中与紫杉烷的新辅助施用组合施用帕妥珠单抗和曲妥珠单抗。
16.权利要求15的方法,其中该紫杉烷是多西他赛。
17.权利要求15的方法,其中该紫杉烷是帕利他赛。
18.权利要求15至17任一项的方法,其中在紫杉烷施用开始时开始帕妥珠单抗和曲妥珠单抗的组合施用。
19.权利要求1至18任一项的方法,其中该pCR是乳腺病理学完全响应(bpCR)。
20.权利要求1至18任一项的方法,其中该pCR是总病理学完全响应(tpCR)。
21.权利要求1至20任一项的方法,其中该不良事件包括心脏副作用。
22.权利要求1至20任一项的方法,其中该不良事件是心脏副作用。
23.权利要求21或22的方法,其中该心脏副作用包含左心室射血分数(LVEF)下降。
24.权利要求23的方法,其中该LVEF下降是无症状的。
25.权利要求21或22的方法,其中该心脏副作用包含左心室收缩功能障碍(LVSD)。
26.权利要求25的方法,其中该LVSD是有症状的。
27.权利要求1至26任一项的方法,其中该HER2阳性乳腺癌特征在于免疫组织化学(IHC)得分3+或2+或通过荧光原位杂交测定的≥2.0的扩增比。
28.权利要求1至27任一项的方法,其中该HER2阳性乳腺癌是通过PAM50RT-qPCR测定法测定的腔A,腔B,HER2富集(HER2-E)或基样亚型的。
29.权利要求28的方法,其中该HER2阳性乳腺癌是HER2-E亚型。
30.权利要求1至27任一项的方法,其中该HER2阳性乳腺癌特征在于异常PI3K途径。
31.权利要求1至27任一项的方法,其中该HER2阳性乳腺癌呈乙酰基丹参酮IIA(ATA)阳性。
32.权利要求1至31任一项的方法,其中该新辅助施用继以确定性手术。
33.权利要求32的方法,其中在至少八个周期的新辅助疗法之后实施确定性手术。
34.权利要求32或33的方法,其中确定性手术继以帕妥珠单抗加曲妥珠单抗的辅助施用。
35.权利要求1至34任一项的方法,其中pCR与无进展存活(PFS)有关联。
36.一种通过在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的组合的新辅助施用在具有HER2-阳性,局部晚期,炎性,或早期阶段乳腺癌的患者中相对于在含有蒽环类抗生素的化疗后曲妥珠单抗的施用延长病理学完全响应(pCR),而不相对于新辅助含有蒽环类抗生素的化疗显著增加不良事件的方法。
37.一种制品,其包含其中有帕妥珠单抗的管形瓶和包装插页,其中该包装插页提供图10-15中显示的安全性数据的至少部分。
38.权利要求37的制品,其包含装有约420mg的帕妥珠单抗的单剂管形瓶。
39.一种用于生成制品的方法,其包括将其中有帕妥珠单抗的管形瓶和包装插页包装在一起,其中该包装插页提供图10-15中显示的安全性数据的至少部分。
40.一种确保帕妥珠单抗的安全和有效使用的方法,其包括将其中有帕妥珠单抗的管形瓶与包装插页包装在一起,其中该包装插页提供图10-15中显示的安全性数据的至少部分。
41.帕妥珠单抗在制备用于在具有HER2阳性局部晚期,炎性,或早期阶段乳腺癌的患者中治疗乳腺癌的药物中的用途,包括在基于蒽环类抗生素的化疗后新辅助施用有效量的所述帕妥珠单抗和曲妥珠单抗的组合,其中在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的组合施用相对于在基于蒽环类抗生素的化疗后曲妥珠单抗的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件。
42.帕妥珠单抗,供在具有HER2阳性局部晚期,炎性,或早期阶段乳腺癌的患者中治疗乳腺癌中使用,其中所述治疗包括在基于蒽环类抗生素的化疗后新辅助施用有效量的所述帕妥珠单抗和曲妥珠单抗的组合,其中在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的组合施用相对于在基于蒽环类抗生素的化疗后曲妥珠单抗的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件。
43.曲妥珠单抗在制备用于在具有HER2阳性局部晚期,炎性,或早期阶段乳腺癌的患者中治疗乳腺癌的药物中的用途,包括在基于蒽环类抗生素的化疗后新辅助施用有效量的所述曲妥珠单抗和帕妥珠单抗的组合,其中在基于蒽环类抗生素的化疗后帕妥珠单抗和曲妥珠单抗的组合施用相对于在基于蒽环类抗生素的化疗后曲妥珠单抗的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件。
44.曲妥珠单抗,供在具有HER2阳性局部晚期,炎性,或早期阶段乳腺癌的患者中治疗乳腺癌中使用,其中所述治疗包括在基于蒽环类抗生素的化疗后新辅助施用有效量的所述曲妥珠单抗和帕妥珠单抗的组合,其中在基于蒽环类抗生素的化疗后曲妥珠单抗和帕妥珠单抗的组合施用相对于在基于蒽环类抗生素的化疗后曲妥珠单抗的施用提高病理学完全响应(pCR),而不相对于新辅助基于蒽环类抗生素的化疗显著增加不良事件。
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