CN106163558A - 用曲妥珠单抗‑mcc‑dm1和帕妥珠单抗治疗早期乳腺癌的方法 - Google Patents
用曲妥珠单抗‑mcc‑dm1和帕妥珠单抗治疗早期乳腺癌的方法 Download PDFInfo
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- CN106163558A CN106163558A CN201580018961.8A CN201580018961A CN106163558A CN 106163558 A CN106163558 A CN 106163558A CN 201580018961 A CN201580018961 A CN 201580018961A CN 106163558 A CN106163558 A CN 106163558A
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Abstract
提供了用抗体‑药物缀合物曲妥珠单抗‑MCC‑DM1和帕妥珠单抗治疗具有HER2阳性、能施手术、局部晚期或炎性的乳腺癌的患者的方法。
Description
相关申请
本申请依据35 U.S.C.§119要求2014年4月25日提交的美国临时专利申请No.61/984,132的权益,在此通过援引完整收录其公开内容。
序列表
本申请含有ASCII形式的序列表,并且在此通过援引完整收录。ASCII文本文件在2015年4月23日创建,命名为GNE-0412WO_SL.txt,并且大小为30505字节。
发明领域
本发明涉及使用曲妥珠单抗-MCC-DM1和帕妥珠单抗治疗早期乳腺癌(EBC)的方法。
发明背景
乳腺癌和HER2靶向性治疗
乳腺癌是全世界的发病率和死亡率的一项高度重大的原因。每年全球诊断出超过130万例乳腺癌病例,超过450,000例死亡与该疾病相关(Jemal A,Bray F,Center M,etal.,Global cancer statistics.CA Cancer J Clin,2011;61(2):69-90)。
HER2(ErbB2)受体酪氨酸激酶是跨膜受体的表皮生长因子受体(EGFR)家族的成员。在约20%人乳腺癌中观察到HER2过表达(在下文中称为HER2阳性乳腺癌),并且其牵涉攻击性生长和与这些肿瘤有关的不良临床结果(Slamon et al(1987)Science 235:177-182)。可以使用固定肿瘤块的基于免疫组织化学的评估测定HER2蛋白过表达(Press MF,etal(1993)Cancer Res53:4960-70)。
曲妥珠单抗(Trastuzumab,CAS 180288-69-1,huMAb4D5-8,rhuMAb HER2,Genentech)是一种重组DNA衍生的、IgG1κ单克隆抗体,其是在基于细胞的测定法中以高亲和力(Kd=5nM)选择性结合HER2的胞外域的鼠抗HER2抗体(4D5)的人源化型式(US 5677171;US 5821337;US 6054297;US 6165464;US 6339142;US 6407213;US6639055;US 6719971;US 6800738;US 7074404;Coussens et al(1985)Science230:1132-9;Slamon et al(1989)Science 244:707-12;Slamon et al(2001)New Engl.J.Med.344:783-792)。在体外测定法和动物两者中,已经显示了曲妥珠单抗抑制过表达HER2的人肿瘤细胞的增殖(Hudziak et al(1989)Mol Cell Biol 9:1165-72;Lewis et al(1993)CancerImmunol Immunother;37:255-63;Baselga et al(1998)Cancer Res.58:2825-2831)。曲妥珠单抗是抗体依赖性细胞性细胞毒性ADCC的介导物(Lewis et al(1993)Cancer ImmunolImmunother37(4):255-263;Hotaling et al(1996)[摘要].Proc.Annual Meeting AmAssoc Cancer Res;37:471;Pegram MD,et al(1997)[摘要].Proc Am Assoc Cancer Res;38:602;Sliwkowski et al(1999)Seminars in Oncology 26(4),Suppl12:60-70;YardenY.and Sliwkowski,M.(2001)Nature Reviews:Molecular Cell Biology,MacmillanMagazines,Ltd.,Vol.2:127-137)。
在1998年批准用于治疗已经接受广泛在先抗癌疗法的HER2过表达性转移性乳腺癌的患者(Baselga et al(1996)J.Clin.Oncol.14:737-744),并且自此以后已经在超过300,000名患者中使用(Slamon DJ,et al.,N Engl J Med 2001;344:783-92;Vogel CL,et al.,J Clin Oncol 2002;20:719-26;Marty M,et al.,J Clin Oncol2005;23:4265-74;Romond EH,et al.,T N Engl J Med 2005;353:1673-84;Piccart-Gebhart MJ,et al.,N Engl J Med 2005;353:1659-72;Slamon D,et al.[摘要].BreastCancer Res Treat 2006,100(Suppl 1):52)。在2006年,FDA批准(曲妥珠单抗,Genentech Inc.)作为含有多柔比星(doxorubicin)、环磷酰胺(cyclophosphamide)和帕利他塞(paclitaxel)的治疗方案的一部分,用于HER2阳性结阳性乳腺癌患者的辅助治疗。
抗体靶向性疗法的一种备选方法是利用抗体将细胞毒性药物特异性投递到抗原表达癌细胞。抗体-药物缀合物,或ADC是已经与高度有力的细胞毒剂缀合的单克隆抗体。ADC代表一种对***性施用的抗肿瘤治疗剂赋予肿瘤选择性的新颖方法。利用肿瘤特异性和/或过表达的表面抗原,设计ADC以聚焦将高度有力的细胞毒剂投递至肿瘤细胞。此办法的潜力是为此类药剂创建比通过其作为游离药物施用可以实现的治疗窗更有利的治疗窗。
美登木生物碱(maytansinoids),抗有丝***药物美登素(maytansine)的衍生物,以与长春花生物碱药物相似的方式结合微管(Issell BF et al(1978)CancerTreat.Rev.5:199-207;Cabanillas F et al(1979)Cancer Treat Rep,63:507–9)。DM1是一种自天然发生酯安丝菌素P3衍生的含硫醇的美登木生物碱(Remillard S,Rebhun LI,Howie GA,et al(1975)Science189(4207):1002–1005.3;Cassady JM,Chan KK,Floss HG.(2004)Chem Pharm Bull 52(1):1–26.4)。已经在约800名患者中以化学治疗剂研究了相关的植物酯美登素,其每3周以单剂或者连续3天以2.0mg/m2的剂量施用(Issell BF,CrookeST.(1978)Maytansine.Cancer Treat Rev 5:199-207)。尽管有临床前活性,临床中的美登素活性在可以安全投递的剂量是适度的。剂量限制毒性(DLT)是胃肠的,由恶心、呕吐和腹泻(经常继之以便秘)组成。这些毒性是剂量依赖性的,但不是日程表依赖性的。报告了周围神经病(主要是感觉性),并且其在具有先前存在的神经病的患者中最明显。报告了肝转氨酶、碱性磷酸酶和总胆红素的亚临床瞬时升高。体质毒性(包括虚弱、嗜睡、病理性心境恶劣、和失眠)是常见的。不太常见的毒性包括输注部位静脉炎和轻度骨髓抑制。由于窄的治疗窗,在20世纪80年代放弃了药物的进一步开发。
曲妥珠单抗-MCC-DM1(T-DM1,曲妥珠单抗-艾美坦辛(Trastuzumab emtansine),ado-曲妥珠单抗-艾美坦辛,),一种用于治疗HER2阳性乳腺癌的新颖的抗体-药物缀合物(ADC),由经由MCC接头在赖氨酸侧链处与曲妥珠单抗缀合的细胞毒剂DM1(一种含有硫醇的美登木生物碱抗微管剂)构成,平均药物负荷(药物与抗体比率)为约3.5。在结合肿瘤细胞上表达的HER2后,T-DM1经历受体介导的内在化,从而导致含有DM1的细胞毒性分解代谢物的胞内释放及随后的细胞死亡。
在T-DM1(TDM3569g)的I期研究中,通过IV输注每3周(q3w)施用的T-DM1的最大耐受剂量(MTD)是3.6mg/kg。DLT(剂量限制毒性)由以4.8mg/kg治疗的患者中的短暂性血小板减少组成。以3.6mg/kg q3w的治疗是完全耐受的,并且与重大的临床活性有关。(Krop(2010)J.Clin.Oncol.28(16):2698-2704)。那个相同的研究还显示了以2.4mg/kg的每周给药也是完全耐受的,并且具有抗肿瘤活性。(Beeram(2012)Cancer118(23):5733-5740)。
一项II期研究(TDM4374g)证明了以3.6mg/kg q3w施用的T-DM1在具有HER2阳性转移性乳腺癌的重度预先治疗的患者群体中具有单一药剂抗肿瘤活性。(Krop(2012)30(26):3234-3241)。一项III期研究(TDM4370g)证明了在先前用曲妥珠单抗和紫杉烷治疗的HER2阳性晚期乳腺癌患者中,与用拉帕替尼(lapatinib)加卡培他滨(capecitabine)治疗相比,以3.6mg/kg q3w施用的T-DM1在更小毒性的情况下显著延长无进展存活和总体存活。(Verma(2012)New England Journal of Medicine 367:1783-1791)。
美国食品药品管理局在2013年2月22日批准在商标下销售的ado-曲妥珠单抗-艾美坦辛,用于治疗先前接受用曲妥珠单抗和紫杉烷的治疗的HER2阳性转移性乳腺癌患者。
帕妥珠单抗(Pertuzumab,又称为重组人源化单克隆抗体2C4,rhuMAb2C4,Genentech,Inc,South San Francisco)代表称为HER二聚化抑制剂(HDI)的新一类药剂中的第一种,并且发挥功能以抑制HER2与其它HER受体(诸如EGFR/HER1、HER2、HER3和HER4)形成活性异二聚体或同二聚体的能力。见例如Harari and Yarden Oncogene19:6102-14(2000);Yarden and Sliwkowski.Nat Rev Mol Cell Biol 2:127-37(2001);Sliwkowski Nat Struct Biol 10:158-9(2003);Cho et al.,Nature 421:756-60(2003);及Malik et al.,Pro Am Soc Cancer Res 44:176-7(2003)。
已经证明了帕妥珠单抗对肿瘤细胞中的HER2-HER 3异二聚体形成的阻断抑制至关重要的细胞信号传导,这导致降低的肿瘤增殖和存活(Agus et al.,Cancer Cell 2:127-37(2002))。
帕妥珠单抗已经在晚期癌症患者中的Ia期试验和卵巢癌和乳腺癌以及肺和***癌患者中的II期试验的情况中在临床中以单一药剂经历测试。在I期研究中,用每3周静脉内给予的帕妥珠单抗治疗在标准疗法期间或之后已经进展的难治性、局部晚期、复发性或转移性实体瘤患者。一般地,帕妥珠单抗是耐受良好的。在可评估响应的20名患者的3名中实现肿瘤消退。2名患者已经确认部分响应。在21名患者的6名中观察到持续超过2.5个月的稳定疾病(Agus et al.,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是线性的,并且均值清除范围为2.69至3.74mL/天/kg,并且均值终末消除半衰期范围为15.3至27.6天。没有检出针对帕妥珠单抗的抗体(Allison et al.,Pro Am Soc Clin Oncol 22:197(2003))。
US 2006/0034842描述了用于用抗ErbB2抗体组合治疗表达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,诸如乳腺癌中的用途。Baselga et al.,J Clin Oncol,2007ASCO Annual Meeting Proceedings PartI,Col.25,No.18S(6月20日增刊),2007:1004报告了用曲妥珠单抗和帕妥珠单抗的组合治疗具有预先治疗的HER2阳性乳腺癌(其在用曲妥珠单抗治疗期间已经进展)的患者。Portera et al.,J Clin Oncol,2007ASCO Annual Meeting Proceedings PartI.Vol.25,No.18S(6月20日增刊),2007:1028在HER2阳性乳腺癌患者中评估了曲妥珠单抗+帕妥珠单抗联合疗法的效力和安全性,所述HER2阳性乳腺癌患者在基于曲妥珠单抗的疗法上具有进行性疾病。作者推断需要联合治疗的效力的进一步评估以限定此治疗方案的总体风险和益处。
已经在HER2阳性转移性乳腺癌患者中与曲妥珠单抗联合在II期研究中评估了帕妥珠单抗,所述患者先前已经接受了用于转移性疾病的曲妥珠单抗。由国家癌症研究所(National cancer Institute,NCl)进行的一项研究登记11名具有先前治疗的HER2阳性转移性乳腺癌的患者。11名患者中的2名展现出部分响应(PR)(Baselga et al.,J ClinOncol 2007 ASCO Annual Meeting Proceedings;25:18S(6月20日增刊):1004。在具有早期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学疗法(多西他赛(Docetaxel))的新颖联合方案的效果的II期新辅助研究的结果(在CTRC-AACR圣安东尼奥乳腺癌研讨会(SABCS)呈现,2010年12月8-12日)显示了与曲妥珠单抗加多西他赛(29.0%的pCR)相比,在手术前的新辅助背景中给予的两种HER2抗体加多西他赛在***中显著改善完全肿瘤消失的速率(45.8%的病理学完全响应率,pCR)达超过一半,p=0.014。
在2012年批准在商品名下销售的帕妥珠单抗,用于治疗晚期或晚期阶段(转移性)HER2阳性乳腺癌患者。HER2阳性乳腺癌具有增加量的促成癌细胞生长和存活的HER2蛋白。
在2013年9月30日,美国食品药品管理局对作为手术前用于具有早期阶段乳腺癌(EBC)的患者的完全治疗方案(新辅助背景)的一部分的(帕妥珠单抗)授予加速批准。是用于乳腺癌的新辅助治疗的第一种得到FDA批准的药物。
与HER2抗体相关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;8,075,890;5,648,237;7,018,809;6,267,958;6,685,940;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;8,075,892;6,573,043;6,905,830;7,129,051;7,344,840;7,468,252;7,674,589;7,919,254;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;8,076,066;8,044,017;7,435,797;7,850,966;7,485,704;7,807,799;8,142,784;7,560,111;7,879,325;8,241,630;7,449,184;8,163,287;7,700,299;7,981,418;8,247,397;和US 2010/0016556;US 2005/0244929;US 2001/0014326;US 2003/0202972;US 2006/0099201;US 2010/0158899;US 2011/0236383;US 2011/0033460;US 2008/0286280;US2005/0063972;US 2006/0182739;US 2009/0220492;US 2003/0147884;US 2004/0037823;US 2005/0002928;US 2007/0292419;US 2008/0187533;US 2011/0250194;US 2012/0034213;US 2003/0152987;US 2005/0100944;US 2006/0183150;US 2008/0050748;US2009/0155803;US 2010/0120053;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;US2007/0269429;US 2008/0050373;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 2007/0166753;US 2008/0112958;US 2009/0239236;US2012/0034609;US 2012/0093838;US 2004/0082047;US 2012/0065381;US 2009/0187007;US 2011/0159014;US 2004/0106161;US 2011/0117096;US 2004/0258685;US 2009/0148402;US 2009/0099344;US 2006/0034840;US 2011/0064737;US 2005/0276812;US2008/0171040;US 2009/0202536;US 2006/0013819;US 2012/0107391;US 2006/0018899;US 2009/0285837;US 2011/0117097;US 2006/0088523;US 2010/0015157;US 2006/0121044;US 2008/0317753;US 2006/0165702;US 2009/0081223;US 2006/0188509;US2009/0155259;US 2011/0165157;US 2006/0204505;US 2006/0212956;US 2006/0275305;US 2012/0003217;US 2007/0009976;US 2007/0020261;US 2007/0037228;US 2010/0112603;US 2006/0067930;US 2007/0224203;US 2011/0064736;US 2008/0038271;US2008/0050385;US 2010/0285010;US 2011/0223159;US 2008/0102069;US 2010/0008975;US 2011/0245103;US 2011/0246399;US 2011/0027190;US 2010/0298156;US 2011/0151454;US 2011/0223619;US 2012/0107302;US 2009/0098135;US 2009/0148435;US2009/0202546;US 2009/0226455;US 2009/0317387;US 2011/0044977;US 2012/0121586。
HER2阳性早期阶段乳腺癌(EBC)
对于早期阶段乳腺癌(EBC),复发的预后因素包括:疾病阶段,包括扩散能力的证据,(即淋巴血管侵入或淋巴累及)和分子亚型。具有较为攻击性的生物学的肿瘤具有升高的复发风险,诸如具有下列任一项或全部的肿瘤:升高的增殖活性、较高的核级别、较低的激素受体表达水平和HER2过表达的证据(Ross J,Slodkowska E,Symmans W,et al.,TheHER-2 receptor and breast cancer:ten years of targeted anti-HER-2 therapy andpersonalized medicine.The Oncologist,2009;14(4):320-68;Mazouni C,PeintingerF,Wan-Kau S,et al.,Residual ductal carcinoma in situ in patients withcomplete eradication of invasive breast cancer after neoadjuvant chemotherapydoes not adversely affect patient outcome.J Clin Oncol,2007;125(19):2650-5)。HER2过表达增加所有EBC阶段的患者的复发风险。甚至已经将大小≤1cm的肿瘤与接近25%的复发率联系起来(Gonzalez-Angulo A,Litton J,Broglio K,et al.,High risk ofrecurrence for patients with breast cancer who have human epidermal growthfactor receptor 2 positive,node--negative tumors 1cm or smaller.J Clin Oncol,2009;27(34):5700-6)。鉴于高复发风险,用***性疗法治疗大多数早期阶段HER2阳性乳腺癌患者。最常规遵循的用于可治愈的HER2阳性乳腺癌的标准方案含有与曲妥珠单抗联合施用的两种或三种细胞毒性化学疗法药物。凭借目前的***性疗法办法,相当多数目的患者仍会具有其HER2阳性乳腺癌的致命复发,长期复发风险是20%或更高。
已经报告了评估曲妥珠单抗作为HER2阳性早期阶段乳腺癌的辅助治疗的作用的4个大的随机化研究。在辅助(HERA)研究中,将已经完成化学疗法的患者随机化至观察、或1年或2年的曲妥珠单抗(Piccart-Gebhart MJ,Procter M,Leyland-JonesB,et al.,Trastuzumab after adjuvant chemotherapy in HER2-positive breastcancer.N Engl J Med,2005;353(16):1659-1672)。关于此研究的结果,包括仅来自观察和1年持续时间的曲妥珠单抗疗法分支的数据(Smith I.Trastuzumab following adjuvantchemotherapy in HER2-positive early breast cancer(HERA trial):disease-freeand overall survival after 2 year median follow-up.Proc ASCO,2006;LateBreaking Scientific Session)显示了在23个月的中值随访时,将1年的曲妥珠单抗疗法与统计学显著的绝对无疾病存活(DFS)益处6.3%(危害比[HR]=0.64)联系起来。重要地,在曲妥珠单抗分支中治疗的患者具有其死亡风险的34%相对降低(HR=0.66;p=0.0115)。在具有***阳性和***阴性疾病两者的患者中看到此益处。在8年的中值随访后,与仅观察相比,总体存活(OS)在1年曲妥珠单抗分支中仍然显著更好(HR=0.76,p-0.0005)(Gelber R,Goldhirsch A and Piccart M.HERA Trial:2 years versus 1 year ofTrastuzumab after adjuvant chemotherapy in women with HER2-positive earlybreast cancer at 8 years of median follow up.2012 ESMO Congress;AbstractLBA6)。
进行两项辅助治疗研究,即国家手术辅助***和肠项目(National SurgicalAdjuvant Breast and Bowel Project,NSABP)B-31和北方中心癌症治疗组(NorthCentral Cancer Treatment Group,NCCTG)9831的联合分析(Romond E,Perez E,BryantJ,et al.,Trastuzumab plus adjuvant chemotherapy for operable HER2-positivebreast cancer.N Engl J Med,2005;353(16):1673-1684)。NSABP B-31研究了多柔比星+环磷酰胺(cyclophosphamide)(AC),接着是在具有或没有52周的曲妥珠单抗疗法的情况中每3周(q3w)施用的帕利他塞。NCCTG 9831比较了三种方案:AC继之以每周帕利他塞、AC继之以每周帕利他塞继之以曲妥珠单抗达52周和AC继之以每周帕利他塞+曲妥珠单抗的组合与随后的单一药剂曲妥珠单抗达总共52周的HER2定向性疗法。联合分析组合来自两项研究的对照和并行的帕利他塞+曲妥珠单抗分支的数据。作者报告了3年时的12%的3年DFS的绝对益处。III或IV类充血性心力衰竭(CHF)或来自心脏原因的死亡的积累发病率在并行的帕利他塞和曲妥珠单抗分支中是B-31研究中的4.1%和NCCTG 9831研究中的2.9%。另外,与接受序贯的帕利他塞及继之的曲妥珠单抗的患者相比,接受并行的帕利他塞和曲妥珠单抗的患者具有向DFS改善的趋势(HR:0.77;CI 0.53-1.11;p=0.02)。
评估与用于HER2阳性EBC的化学疗法联合的曲妥珠单抗的辅助用途的第四项大研究是乳腺癌国际研究组(BCIRG)006研究(Slamon D,Eiermann W,Robert N,et al.,Adjuvant Trastuzumab in HER2-positive breast cancer.N Engl J Med,2011;365(14):1273-1283)。BCIRG006设计为测定在早期阶段HER2阳性乳腺癌中引入曲妥珠单抗是否显著改善临床后果和是否可以通过使用没有蒽环类抗生素的新颖多西他赛方案避免在与蒽环类抗生素一起使用时用曲妥珠单抗观察到的增加的心脏毒性。将患者随机归入三个治疗分支之一:多柔比星和环磷酰胺继之以多西他赛(AC-T);多柔比星和环磷酰胺继之以多西他赛和曲妥珠单抗(AC-TH);或TCH。在化学疗法期间每周,并且然后此后q3w总共52周输注曲妥珠单抗。与AC-TH分支中的患者的5年DFS率84%(用于与AC-T相比的HR,0.65;P<0.001)和TCH分支中的患者的5年DFS率81%(用于与AC-T相比的HR,0.75;P=0.04)相比,AC-T分支中的患者的5年DFS率是75%。类似地,与AC-T分支相比,OS在曲妥珠单抗分支中是改善的。与对于AC-TH的92%(HR,0.63;P<0.001)和对于TCH的91%(HR,0.77;P=0.04)相比,AC-T的5年OS是87%。虽然研究没有能力检测两种基于曲妥珠单抗的方案之间的等同性,但是TCH和AC-TH之间的DFS或OS的比率没有显著差异。重要地,在与蒽环类抗生素/曲妥珠单抗分支比较时,TCH分支中有更少的3或4级CHF事件(分别为4对21,p<0.001)。此外,与TCH分支中的9.4%的患者相比,在AC-TH分支中的18.6%的患者中看到均值左心室射血分数(LVEF)>10%的亚临床损失(P<0.001)。虽然BCIRG中接受曲妥珠单抗的许多患者具有心脏功能的恢复,但是在18.6%的具有>10%的LVEF相对降低的接受AC-TH的患者中,降低在许多人中是持久的,在这些患者的33%中持续>4年。与TCH治疗组的0.2形成对比,在42个月时自基线的LVEF的均值变化对于AC-TH是-3.5(存档数据)。TCH方案在辅助背景中与基于蒽环类抗生素的方案相比携带类似的效力及更少的急性毒性效应和更低的心脏毒性和白血病的风险。
用于HER2阳性乳腺癌的新辅助治疗
多项研究已经在术前背景中评估了与不同化学治疗剂组合的曲妥珠单抗(Burstein H,Harris L,Gelman R,et al.,Preoperative therapy with Trastuzumaband paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamidefor HER2 overexpressing stage II or III breast cancer:a pilot study.J ClinOncol,2003;21(1):46-53;Buzdar A,Ibrahim N,Francis D.Significantly higherpathologic complete remission rate after neoadjuvant therapy withTrastuzumab,paclitaxel,and epirubicin chemotherapy:results of a randomizedtrial in human epidermal growth factor receptor 2-positive operable breastcancer.J Clin Oncol.2005;23(16):3676-3685;Gianni L,Eiermann W,Semiglazov V,etal.,Neoadjuvant chemotherapy with Trastuzumab followed by adjuvantTrastuzumab versus neoadjuvant chemotherapy alone,in patients with HER2-positive locally advanced breast cancer(the NOAH trial):a randomisedcontrolled superiority trial with a parallel HER2-negative cohort.Lancet,2010;375(9712):377-384;Untch M,Rezai M,Loibl S,et al.,Neoadjuvant treatmentwith Trastuzumab in HER2-positive breast cancer:results from the GeparQuattrostudy.J Clin Oncol,2010;28(12):2024-2031;Untch M,Fasching PA,Konecny GE,etal.,Pathologic complete response after neoadjuvant chemotherapy plusTrastuzumab predicts favorable survival in human epidermal growth factorreceptor-2-overexpressing breast cancer:results from the TECHNO trial of theAGO and GBG study groups.J Clin Oncol.2011;29(25):3351-7;Dent S,Oyan B,HonigA et al.,HER2-targeted therapy in breast cancer:A systematic review ofneoadjuvant trials.Cancer Treat Rev.2013 Oct;39(6):622-31)。这些试验中的第一项之一是评估与曲妥珠单抗组合的帕利他塞的安全性和效力的先导研究。此方案产生18%的pCR率和85%的临床响应率(Burstein et al.,2003,见上文)。一项随后的试验报告了与接受单独的化学疗法的患者的仅26%相比,接受新辅助的基于蒽环类抗生素的多化学疗法+曲妥珠单抗的患者实现65%的pCR率(p=0.016)(Buzdar et al.,2005见上文)。
HER2阳性群体中的最大的新辅助试验之一是一项在333名具有HER2阳性局部晚期乳腺癌的患者中在有或没有曲妥珠单抗的情况中比较序贯新辅助方案(包含多柔比星、帕利他塞、和环磷酰胺、甲氨蝶呤、和5-氟尿嘧啶(CMF))的安全性和效力的III期随机化研究(NOAH试验)。HER2阴性患者的平行观察对照组接受相同的化学疗法方案(Gianni et al.,2010,见上文)。曲妥珠单抗对新辅助化学疗法的添加和在辅助背景中继续曲妥珠单抗疗法达总共1年在先前未治疗的局部晚期HER2阳性乳腺癌患者中产生无事件存活(EFS)和OS的临床相关的且统计学显著的改善。这些数据得到次要效力参数的结果支持。
在NOAH研究中,曲妥珠单抗对完全化学疗法方案的添加与17.6%(自26.7%至44.3%)的bpCR增加有关。bpCR的增加转化为改善的EFS。基于此试验的结果,欧盟批准了用曲妥珠单抗,接着用辅助曲妥珠单抗的新辅助治疗。
已经与化学疗法及与其它HER2定向性疗法两者联合对表明HER2阳性疾病活性的乳腺癌研究了其它基于曲妥珠单抗的术前治疗方案。新辅助背景中的TCH的施用导致38.5-43.7%之间的***和***中的pCR率(Guiu S,Liegard M,Favier L et al.,Long-termfollow-up of HER2-overexpressing Stage II or III breast cancer treated byanthracycline-free neoadjuvant chemotherapy.Ann Oncol.2011;22(2):321-8;Bayraktar S,Gonzalez-Angulo A,Lei X et al.,Efficacy of neoadjuvant therapywith Trastuzumab concurrent with anthracycline-and nonanthracycline-basedregimens for HER2-positive breast cancer.Cancer.2012;118(9):2385-2393).
用于HER2阳性乳腺癌的辅助疗法
辅助疗法在最广义上是在主要疗法外给予以杀死可以已经扩散(即使通过放射学或实验室测试不能检出扩散)的任何癌细胞的治疗。
与辅助疗法相关的出版物或讨论会包括:Paik et al.,J.Natl.Cancer Inst.,92(24):1991-1998(2000);Paik et al.,J.Natl.Cancer Inst.,94:852-854(2002);Paik etal.,Successful quality assurance program for HER2 testing in the NSABP Trialfor Herceptin.San Antonio Breast Cancer Symposium,2002;Roche PC et al.,J.Natl.Cancer Inst.,94(11):855-7(2002);Albain et al.,Proceedings of theAmerican Society of Clinical Oncology Thirty-Eighth Annual Meeting,2002年5月18-21日,Orlando,FL,摘要143;The ATAC(Arimidex,Tamoxifen Alone or inCombination)Trialists'Group,Lancet,359:2131-39(2002);Geyer et al.,26th AnnualSan Antonio Breast Cancer Symposium(SABCS),2003年12月,摘要12;Perez et al.,Proc.ASCO,2005,摘要556。
美国专利公开文本No.2004/0014694(2004年1月22日公布)描述了用于治疗早期乳腺癌的辅助疗法的方法,其包括施用多西他赛、多柔比星和环磷酰胺。美国专利公开文本No.2006/0275305描述了使用曲妥珠单抗和曲妥珠单抗-药物缀合物的辅助疗法的方法。
目前利用的用于EBC的HER2定向性疗法让相当大数目的患者有复发和来自其疾病的死亡的风险。对进一步的治疗选项有较大的需要,所述治疗选项改善结果,优选包括根治***和***中的侵入性癌症的能力的显著改善。
发明概述
一般地,本发明涉及用抗体-药物缀合物,即曲妥珠单抗-MCC-DM1(T-DM1)和帕妥珠单抗治疗乳腺癌患者的方法。
在一个方面中,本发明关注用于治疗乳腺癌的方法,其包括
(i)在化学疗法缺失下用T-DM1和帕妥珠单抗的组合对具有HER2阳性、能施手术、局部晚期或炎性乳腺癌的患者进行新辅助治疗,
(ii)通过确定性手术去除所述乳腺癌,并
(iii)在化学疗法缺失下用T-DM1和帕妥珠单抗的组合对所述患者进行辅助治疗。
在一个实施方案中,在包含紫杉烷的化学疗法缺失下用T-DM1和帕妥珠单抗的组合对所述患者进行辅助治疗。
在另一个实施方案中,在确定性手术之前和/或之后在并行化学疗法缺失下用T-DM1和帕妥珠单抗的组合对所述患者进行辅助治疗。
在又一个实施方案中,所述辅助治疗包含用T-DM1和帕妥珠单抗治疗之前和/或之后的化学疗法。
在别的实施方案中,用T-DM1和帕妥珠单抗治疗之前和/或之后的化学疗法不包含紫杉烷。
在又一个实施方案中,施用的化学疗法包含基于蒽环类抗生素的化学疗法。
在另一个实施方案中,施用的化学疗法进一步包含曲妥珠单抗。
在所有实施方案中,若存在的话,基于蒽环类抗生素的疗法可以例如包含下列一种或多种:FAC(5-氟尿嘧啶、多柔比星、环磷酰胺)、FEC(5-氟尿嘧啶、表柔比星和环磷酰胺)或AC(多柔比星、环磷酰胺)。
在一个实施方案中,乳腺癌的直径为>2cm。
在另一个实施方案中,在完成新辅助治疗后至少14天实施确定性手术。
在又一个实施方案中,在完成新辅助治疗后不迟于9周实施确定性手术。
在别的实施方案中,新辅助和辅助治疗方案各自包括每3周以3.6mg/kg的剂量输注T-DM1并且以840mg的加载剂量和此后每3周以420mg的剂量输注帕妥珠单抗。
在所有实施方案中,可以并行施用,可以共施用,或者可以以任一次序序贯施用T-DM1和帕妥珠单抗。在一个具体的实施方案中,施用遵循表5中列出的日程表。
在别的实施方案中,治疗增加下列一项或多项:完全响应(CR)、EFS(无事件存活)、DFS(无疾病存活)、IDFS(无侵入性疾病存活)、和OS(总体存活)。
在又一个实施方案中,治疗增加疾病进展前时间。
在一个实施方案中,新辅助治疗基本上由T-DM1和帕妥珠单抗的施用组成。
在另一个实施方案中,新辅助治疗由T-DM1和帕妥珠单抗的施用组成。
在别的实施方案中,辅助治疗本质上由T-DM1和帕妥珠单抗的施用组成。
在又一个实施方案中,辅助治疗由T-DM1和帕妥珠单抗的施用组成。
附图简述
图1提供了HER2蛋白结构的示意图,和其胞外域的域I-IV的氨基酸序列(分别SEQID No.1-4)。
图2A和2B描绘了鼠单克隆抗体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),和人VL和VH共有框架(hum id,轻κ亚组I;humIII,重亚组III)(分别为SEQ ID No.9和10)的氨基酸序列比对。星号鉴定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的可变域和人框架之间的差异。互补性决定区(CDR)在括号中。
图3A和3B显示了帕妥珠单抗轻链(图3A;SEQ ID NO.11)和重链(图3B;SEQ IDNo.12)的氨基酸序列。以粗体显示CDR。轻链和重链的计算的分子量是23,526.22 Da和49,216.56 Da(还原形式的半胱氨酸)。碳水化合物模块附着于重链的Asn 299。
图4A和4B分别显示了曲妥珠单抗轻链(图4A;SEQ ID NO.13)和重链(图4B;SEQ IDNO.14)的氨基酸序列。通过箭标示可变轻和可变重域的边界。
图5A和5B分别描绘了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描绘了实施例1中描述的KRISTINE临床试验的方案。
发明详述
现在会详细参考本发明的某些实施方案,其例子在附随的结构和式中例示。虽然会结合例举的实施方案描述本发明,但是应当理解它们并不意图将本发明限于那些实施方案。相反,本发明意图覆盖所有备选、修改和等同方案,其可以包括在如权利要求书限定的本发明的范围内。本领域技术人员会认可与本文中描述的那些方法和材料相似或等同的许多方法和材料,它们可以在本发明的实践中使用。本发明绝不限于所描述的方法和材料。
通过援引明确将贯穿公开内容引用的所有参考文献完整收入本文。在并入的文献、专利、和类似的材料中的一个或多个与本申请(包括但不限于定义的术语、术语用法、描述的技术、等等)不同或与本申请矛盾的情况中,以本申请为准。
定义
词语“包含”和“包括”在本说明书和权利要求书中使用时意图规定叙述的特征、整数、组分、或步骤的存在,但是它们不排除一种或多种其它特征、整数、组分、步骤、或其组的存在或添加。
术语“治疗”和“处理”指治疗性处理和预防性或防范性措施二者,其中目标是预防或减缓(减轻)不想要的生理学变化或病症,诸如过度增殖性状况,诸如癌症的生长、形成或扩散。为了本发明,有利或期望的临床结果包括但不限于:缓解症状、削弱疾病的程度、疾病状态稳定(即不恶化)、延迟或减缓疾病进展、改善或减轻疾病状态、及消退(无论是部分的还是完全的),无论是可检测的还是不可检测的。“治疗/处理”还可以指与不接受治疗的预期存活相比延长存活。需要治疗的受试者包括已经患有状况或病症的受试者以及倾向于患上状况或病症的受试者或者要预防状况或病症的受试者。
术语“癌症”和“癌性”指或描述哺乳动物中通常以不受调节的细胞生长为特征的生理学状况。“肿瘤”包含一种或多种癌性细胞。癌症的例子包括但不限于癌瘤、淋巴瘤、母细胞瘤、肉瘤和白血病或淋巴样恶性。此类癌症的更具体例子包括鳞状细胞癌(例如上皮鳞状细胞癌)、肺癌(包括小细胞肺癌、非小细胞肺癌(“NSCLC”)、肺腺癌和肺鳞癌)、腹膜癌、肝细胞癌、胃癌(包括胃肠癌)、胰腺癌、成胶质细胞瘤、***、卵巢癌、肝癌(liver cancer)、膀胱癌、肝瘤(hepatoma)、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、***癌、外阴癌、甲状腺癌、肝癌(hepatic carcinoma)、***癌、***癌、及头和颈癌。
术语“早期阶段乳腺癌(EBC)”或“早期乳腺癌”在本文中用于指尚未扩散超出***或腋窝***的乳腺癌。这包括原位导管癌和I期、IIA期、IIB期、和IIIA期乳腺癌。
将肿瘤或癌症称为“0期”、“I期”、“II期”、“III期”、或“IV期”和此分类内的各个亚阶段指示使用本领域中已知的总体阶段分组(Overall Stage Grouping)或Roman数字分期(Roman Numeral Staging)方法分类肿瘤或癌症。虽然癌症的实际阶段取决于癌症的类型,但是一般地,0期癌症是原位损伤,I期癌症是小局部化肿瘤,II和III期癌症是展现出局部***累及的局部晚期肿瘤,而IV期癌症代表转移性癌症。每类肿瘤的特定阶段是熟练内科医生已知的。
术语“转移性乳腺癌”意指癌细胞通过血管或***自初始部位传播至身体中别处的一个或多个部位以在***外的一种或多种器官中形成一个或多个继发性肿瘤的乳腺癌状态。
“晚期”癌症是已经通过局部侵入或转移在起源的部位或器官外部扩散的癌症。因而,术语“晚期”癌症包括局部晚期和转移性疾病两者。
“难治性”癌症是即使对癌症患者施用抗肿瘤剂,诸如化学疗法仍进展的癌症。难治性癌症的例子是铂难治的癌症。
“复发性”癌症是在响应初始疗法,诸如手术后在初始部位处或在远端部位处已经再生长的癌症。
“局部复发性”癌症是与先前治疗的癌症在相同位置中在治疗后复发的癌症。
“能施手术的”或“可切除的”癌症是局限于原发性器官并且适合于手术(切除)的癌症。
“非可切除的”或“不能切除的”癌症不能通过手术去除(切除)。
“HER2阳性”癌症包含具有高于正常的HER2水平的癌细胞。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)得分和/或≥2.0的原位杂交(ISH)扩增比率。
在本文中,“患者”或“受试者”是人患者。患者可以是“癌症患者”,即患有或有风险患有癌症,特别是胃癌或乳腺癌的一种或多种症状的患者。
“患者群体”指癌症患者组。可以使用此类群体证明药物,诸如帕妥珠单抗的统计学显著的效力和/或安全性。
“复发”患者是在消退后具有癌症的体征或症状的患者。任选地,患者在辅助或新辅助治疗后已经复发。
“展现出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/或在其它方面表明HER受体的活化或磷酸化的。
“新辅助治疗”或“术前疗法”在本文中指在手术前给予的疗法。新辅助治疗的目的是提供即刻***性治疗,从而潜在根治微转移,所述微转移在其它情况中在遵循手术,继之以***性疗法的标准顺序时会增殖。新辅助治疗也可以帮助缩小肿瘤大小,从而容许最初不能切除的肿瘤的完全切除或者保留器官及其功能的部分。此外,新辅助治疗允许药物效力的体内评估,其可以指导随后治疗的选择。
“辅助疗法”在本文中指在确定性手术(其中不能检出残余疾病的证据)之后给予的疗法,从而来降低疾病复发的风险。辅助疗法的目标是预防癌症复发,及因此降低癌症相关死亡的机会。辅助疗法在本文中明确排除新辅助治疗。
“确定性手术”如该术语在医学界内使用的那样使用。确定性手术包括例如导致肿瘤清除或切除的规程、手术或其它,包括那些导致所有明显可见肿瘤清除或切除的。确定性手术包括例如肿瘤的完全的或治愈性的切除或完全总体切除。确定性手术包括以一个或多个阶段进行的规程,而且包括例如多阶段手术规程,其中在切除肿瘤之前实施一次或多次手术或其它规程。确定性手术包括清除或切除肿瘤,包括累及的器官、部分器官和组织,以及周围的器官,诸如***、部分器官、或组织的规程。去除可以是不完全的,使得肿瘤细胞可以保持,即使检测不到。
“存活”指患者保持存活,包括无疾病存活(DFS)、无进展存活(PFS)和总体存活(OS)。可以通过Kaplan-Meier法评估存活,并且使用分层时序检验计算存活的任何差异。
“无进展存活”(PFS)是从第一天治疗至证明的疾病进展(包括孤立性CNS进展)或来自研究的任何原因的死亡(以先发生者为准)的时间。
“无疾病存活(DFS)”指患者自治疗启动或自初始诊断起保持限定时间段活着且癌症没有复发,诸如约1年、约2年、约3年、约4年、约5年、约10年、等。在本发明的一个方面,依照治疗意图原则分析DFS,即在其指派疗法的基础上评估患者。DFS分析中使用的事件可以包括局部、区域性和远端癌症复发,继发性癌症发生,及在没有在先事件(例如乳腺癌复发或第二原发性癌症)的患者中死于任何原因。
“总体存活”指患者自治疗启动或自初始诊断起保持限定时间段活着,诸如约1年、约2年、约3年、约4年、约5年、约10年、等。在本发明基础的研究中,用于存活分析的事件是任何原因的死亡。
“延长存活”意味着相对于未治疗的患者或相对于对照治疗方案增加治疗的患者中的DFS和/或OS。在治疗启动之后或在初始诊断之后监测存活至少约6个月、或至少约1年、或至少约2年、或至少约3年、或至少约4年、或至少约5年、或至少约10年、等。
存活分析中的“危害比”是两条存活曲线之间的差异的汇总,代表随访期里与对照相比治疗的死亡风险降低。危害比是事件比率的统计定义。为了本发明的目的,危害比定义为代表任何特定时间点时实验分部中的事件概率除以对照分部中的事件概率。
“单一疗法”意指如下的治疗方案,其在治疗期的过程期间只包括单一治疗剂来治疗癌症或肿瘤。
“维持疗法”意指为了降低疾病复发或进展的可能性而给予的治疗方案。维持疗法可提供任意长度的时间,包括长至受试者终身的延长的时段。维持疗法可在初始疗法之后或与初始或别的疗法联合提供。用于维持疗法的剂量可变化,而且可包括与其它类型的疗法使用的剂量相比降低的剂量。
如本文中定义的,术语“曲妥珠单抗”、和“huMAb4D5-8”可互换使用。优选地,此类抗体包含分别在图4A(SEQ ID NO:13)和图4B(SEQ ID NO.14)中显示的轻链和重链氨基酸序列。
“表位4D5”或“4D5表位”或“4D5”指HER2的胞外域中与抗体4D5(ATCC CRL 10463)和曲妥珠单抗结合的区域。此表位接近HER2的跨膜域,且在HER2的域IV内。为了筛选结合4D5表位的抗体,可以实施常规的交叉阻断测定法,诸如Antibodies,A LaboratoryManual,Cold Spring Harbor Laboratory,Ed Harlow和David Lane,1988中所记载的。或者,可以实施表位作图以评估抗体是否结合HER2的4D5表位(例如HER2的大约第529位残基至大约第625位残基区域(含两端点)中的任何一个或多个残基)。
“表位2C4”或“2C4表位”指HER2的胞外域中与抗体2C4结合的区域。为了筛选结合2C4表位的抗体,可以实施常规的交叉阻断测定法,诸如Antibodies,A LaboratoryManual,Cold Spring Harbor Laboratory,Ed Harlow and David Lane(1988)中所记载的。或者,可以实施表位作图以评估抗体是否结合HER2的2C4表位。表位2C4包含来自HER2胞外域中的域II的残基。2C4抗体和帕妥珠单抗在域I、II和III的连接处结合HER2的胞外域(Franklin et al.,Cancer Cell 5:317-328(2004))。
为了本文中的目的,“帕妥珠单抗”、和“rhuMAb 2C4”可互换使用。优选地,此类抗体包含分别在SEQ ID NO:7和8中的轻链和重链氨基酸序列。在帕妥珠单抗是完整抗体的情况中,优选地,它包含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,通过重组中国仓鼠卵巢(CHO)细胞生成抗体。
如本文中定义的,术语“T-DM1”、“曲妥珠单抗-MCC-DM1”、“ado-曲妥珠单抗-艾美坦辛”、“曲妥珠单抗-艾美坦辛”、和可互换使用,并且指经由接头模块MCC连接至美登木素生物碱类药物模块DM1的曲妥珠单抗,包括各种负荷和附着的抗体-药物缀合物的所有混合物,其中1,2,3,4,5,6,7,和8个药物模块共价附着至抗体曲妥珠单抗(US7097840;US 2005/0276812;US 2005/0166993)。
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学治疗剂、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、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)、和贝伐珠单抗(bevacizumab)。
“化学疗法”是可用于治疗癌症的化学治疗剂的使用。
“化疗剂”指可用于治疗癌症的化学化合物,不管作用机制。化疗剂的类别包括但不限于:烷化剂类(alkyating agents),抗代谢物类(antimetabolites),纺锤体毒植物生物碱类(spindle poison plant alkaloids),细胞毒性/抗肿瘤抗生素类(cytoxic/antitumor antibiotics),拓扑异构酶抑制剂类(topoisomerase inhibitors),抗体类(antibodies),光敏剂类(photosensitizers),和激酶抑制剂类(kinase inhibitors)。化疗剂的例子包括:erlotinib(Genentech/OSI Pharm.),多西他塞(docetaxel)(Sanofi-Aventis),5-FU(氟尿嘧啶,5-氟尿嘧啶,CAS No.51-21-8),吉西他滨(gemcitabine)(Lilly),PD-0325901(CAS No.391210-10-9,Pfizer),顺铂(cisplatin)(顺式-二胺,二氯铂(II),CAS No.15663-27-1),卡铂(carboplatin)(CAS No.41575-94-4),帕利他塞(paclitaxel)(Bristol-Myers Squibb Oncology,Princeton,N.J.),替莫唑胺(temozolomide)(4-甲基-5-氧-2,3,4,6,8-五氮双环[4.3.0]九-2,7,9-三烯-9-羧酰胺,CAS No.85622-93-1,Schering Plough),他莫昔芬(tamoxifen)((Z)-2-[4-(1,2-二苯基丁-1-烯基)苯氧基]-N,N-二甲基-乙胺,),和多柔比星(doxorubicin)Akti-1/2,HPPD,和雷帕霉素(rapamycin)。
化疗剂的更多例子包括:奥沙利铂(oxaliplatin)(Sanofi),bortezomib(Millennium Pharm.),sutent(SU11248,Pfizer),来曲唑(letrozole)(Novartis),甲磺酸伊马替尼(imatinibmesylate)(Novartis),XL-518(MEK抑制剂,Exelixis,WO 2007/044515),ARRY-886(Mek抑制剂,AZD6244,Array BioPharma,Astra Zeneca),SF-1126(PI3K抑制剂,Semafore Pharmaceuticals),BEZ-235(PI3K抑制剂,Novartis),XL-147(PI3K抑制剂,Exelixis),PTK787/ZK 222584(Novartis),氟维司群(fulvestrant)(AstraZeneca),亚叶酸(leucovorin,folinic acid),雷帕霉素(rapamycin)(西罗莫司(sirolimus),Wyeth),lapatinib(GSK572016,Glaxo SmithKline),lonafarnib(SARASARTM,SCH 66336,Schering Plough),sorafenib(BAY43-9006,Bayer Labs),gefitinib(AstraZeneca),伊立替康(irinotecan)(CPT-11,Pfizer),tipifarnib(ZARNESTRATM,Johnson&Johnson),ABRAXANETM不含克列莫佛(Cremophor),清蛋白改造纳米颗粒剂型帕利他塞(paclitaxel)(American Pharmaceutical Partners,Schaumberg,Il),vandetanib(rINN,ZD6474,AstraZeneca),chloranmbucil,AG1478,AG1571(SU 5271;Sugen),temsirolimus(Wyeth),pazopanib(GlaxoSmithKline),canfosfamide(Telik),塞替派(thiotepa)和环磷酰胺(cyclophosphamide)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(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylomelamine);番荔枝内酯类(acetogenins)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(camptothecin)(包括合成类似物托泊替康(topotecan));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);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(chlorophosphamide),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(nitrosoureas),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(ranimustine);抗生素类,诸如烯二炔类抗生素(enediyne)(例如加利车霉素(calicheamicin),加利车霉素γ1I,加利车霉素ωI1(Angew Chem.Intl.Ed.Engl.,(1994)33:183-186);蒽环类抗生素(dynemicin),dynemicinA;二膦酸盐类(bisphosphonates),诸如氯膦酸盐(clodronate);埃斯波霉素(esperamicin);以及新制癌素(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(authramycin),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),柔红霉素(daunorubicin),地托比星(detorubicin),6-二氮-5-氧-L-正亮氨酸,吗啉代多柔比星,氰基吗啉代多柔比星,2-吡咯代多柔比星和脱氧多柔比星),表柔比星(epirubicin),依索比星(esorubicin),伊达比星(idarubicin),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(porfiromycin),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),佐柔比星(zorubicin);抗代谢物类,诸如甲氨蝶呤(methotrexate)和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸(denopterin),甲氨蝶呤(methotrexate),蝶罗呤(pteropterin),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),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(azauridine),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),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),睾内酯(testolactone);抗肾上腺类,诸如氨鲁米特(aminoglutethimide),米托坦(mitotane),曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamideglycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);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);埃坡霉素(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);鬼臼酸(podophyllinic acid);2-乙基酰肼(ethylhydrazide);丙卡巴肼(procarbazine);多糖复合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(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)(T-2毒素,疣孢菌素(verrucurin)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);甘露莫司汀(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(cyclophosphamide);塞替派(thiotepa);6-硫鸟嘌呤(thioguanine);巯基嘌呤(mercaptopurine);甲氨蝶呤(methotrexate);铂类似物,诸如顺铂(cisplatin)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);长春瑞滨(vinorelbine)能灭瘤(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);卡培他滨(capecitabine)(Roche);伊本膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄酸类(retinoids),诸如视黄酸(retinoicacid);及任何上述物质的制药学可接受的盐,酸和衍生物。
术语“有效量”指在患者中有效治疗癌症的药物量。有效量的药物可以减少癌细胞的数目;缩小肿瘤的尺寸;抑制(即在一定程度上减缓和优选阻止)癌细胞浸润到周围器官中;抑制(即在一定程度上减缓和优选阻止)肿瘤转移;在一定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。根据药物可阻止现有癌细胞生长和/或杀死现有癌细胞的程度,它可以是细胞抑制性的和/或细胞毒性的。有效量可延长无进展存活(例如根据实体瘤的响应评估标准(Response Evaluation Criteria for SolidTumors,RECIST)或CA-125变化的测量),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(例如根据FOSI的评估)。术语“有效量”明确包括适合于实现实施例1中描述的临床试验的任何主要或次要终点的量。
“紫杉烷”是抑制有丝***并且干扰微管的化学疗法。紫杉烷的例子包括帕利他塞(Bristol-Myers Squibb Oncology,Princeton,N.J.);帕利他塞的无克列莫佛(cremophor)的、清蛋白工程化的纳米颗粒配制剂或nab-帕利他塞(ABRAXANETM;AmericanPharmaceutical Partners,Schaumberg,Illinois);和多西他赛(Rorer,Antony,France)。
“蒽环类抗生素”是来自真菌Streptococcus peucetius的一类抗生素,例子包括:柔红霉素、多柔比星、和表柔比星、等等。
“基于蒽环类抗生素的化学疗法”指由一种或多种蒽环类抗生素组成或者包含一种或多种蒽环类抗生素的化学疗法方案。例子包括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);等等。
为了本文中的目的,“基于卡铂的化学疗法”指由一种或多种卡铂组成或包含一种或多种卡铂的化学疗法方案。一个例子是TCH(多西他赛/卡铂、和曲妥珠单抗/)。
“芳香酶抑制剂”抑制酶芳香酶,其调节肾上腺中的***生成。芳香酶抑制剂的例子包括:4(5)-咪唑、氨鲁米特(aminoglutethimide)、醋酸甲地孕酮、依西美坦、福美坦、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,芳香酶抑制剂在本文中是来曲唑或阿那曲唑。
“抗代谢物化学疗法”指在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的使用。许多抗代谢物化疗剂干扰核酸,RNA和DNA的生成。抗代谢物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。
“化学疗法抗性”癌症意指癌症患者虽然接受化学疗法方案但已经进展(即患者是“化学疗法难治的”),或者患者在完成化学疗法方案后12个月内(例如在6个月内)已经进展。
术语“铂”在本文中用于指基于铂的化学疗法,包括但不限于顺铂、卡铂和奥沙利铂。
术语“氟嘧啶”在本文中用于指抗代谢物化学疗法,包括但不限于卡培他滨、氟尿苷、和氟尿嘧啶(5-FU)。
治疗剂的“固定的”(fixed)或“平坦的”(flat)剂量在本文中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,固定的或平坦的剂量不是作为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”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,但本文中也设想了多个加载剂量。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”剂量在本文中指在治疗期里施用于患者的一剂或多剂治疗剂。通常,维持剂量以间隔的治疗间隔施用,例如大约每周,大约每2周,大约每3周,或大约每4周,优选每3周。
“输注”指出于治疗目的经由静脉将含有药物的溶液引入身体中。一般地,这经由静脉内(IV)袋实现。
“静脉内袋”或“IV袋”是可以容纳可以经由患者的静脉施用的溶液的袋。在一个实施方案中,溶液是盐水溶液(例如约0.9%或约0.45%NaCl)。任选地,IV袋由聚烯烃或聚氯乙烯形成。
“共施用”意指在同一次施用期间静脉内施用两种(或更多种)药物,而不是序贯输注两种或更多种药物。一般地,这会牵涉将两种(或更多种)药物在其共施用前组合入同一个IV袋中。
与一种或多种其它药物“并行”施用的药物在相同治疗周期期间,与一种或多种其它药物在相同治疗日,和任选地与一种或多种其它药物在相同时间施用。例如,对于每3周给予的癌症疗法,在3周周期的第-1天各自施用并行施用的药物。
“心脏毒性”指影响心脏并且源自药物或药物组合的施用的任何毒性副作用。基于下列的任一项或多项评估心脏毒性: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,或左心室射血分数(LVEF)的降低。
短语“在不增加包含帕妥珠单抗的药物组合的心脏毒性的情况中”指等于或小于用药物组合中与帕妥珠单抗不同的药物治疗的患者中观察到的心脏毒性(例如等于或小于源自施用曲妥珠单抗和化学疗法,例如多西他赛的心脏毒性)的心脏毒性的发生。
“管形瓶”是适合于容纳液体或冻干制剂的容器。在一个实施方案中,管形瓶是一次性管形瓶,例如具有塞子的20-cc一次性管形瓶。
术语“包装插页”用于指通常包括在治疗产品的商业包装中的用法说明,其含有关于涉及此类治疗产品的使用的适应征、用法、剂量、施用、禁忌症和/或警告的信息。
“不利事件”是与调查(医学)产品或其它方案强加的干预(不管属性如何)的使用短暂有关的任何不利且不想要的体征、症状或疾病;并且包括:在方案规定的AE报告期期间出现的先前在患者中没有观察到的AE,包括AE报告期前不存在的与乳腺癌有关的体征或症状;由于方案强制执行的干预(例如侵入性规程,诸如活组织检查)而发生的并发症;若适用的话,与药物清除、无治疗运转、或其它方案强制执行的干预有关的研究治疗分配前发生的AE;在方案规定的AE报告期期间由调查人员判断为在严重性或频率上已经恶化或者在特征上变化的先前存在的医学状况(除了研究的状况外)。
若不利事件满足以下标准,则它分类为“严重不利事件”(SAE):导致死亡(即,AE实际上引起或导致死亡);威胁生命的(即,按调查人员的意见,AE使患者置于立即的死亡风险,但是不包括若它以更严重的形式发生,则可以已经引起死亡的AE);需要或延长患者住院;导致持久或重大的失能/无能(即,AE导致对患者进行正常生活机能的能力的实质性破坏);导致暴露于调查产品的母亲出生的新生儿/婴儿中的先天性畸形/出生缺陷;或者基于医学判断被调查人员认为是重大的医学事件(例如可以危害患者或者可以需要医学/手术干预以防止上文列出的后果之一)。认为不满足任何严重标准的所有AE是非严重AE。术语“重度”和“严重”不是同义的。严重性(或强度)指特定AE的等级,例如轻度(1级)、中度(2级)、或重度(3级)心肌梗死(见5.2.2节)。“严重”是管理定义(见先前的定义),并且基于患者或事件后果或通常与对患者的生命或机能发挥造成威胁的事件有关的行为标准。严重度(不是严重性)充当用于限定从发起人至适用的管理当局的管理报告义务的指南。应当在eCRF上记录AE和SAE时独立评估严重性和严重度。
详细描述
曲妥珠单抗-MCC-DM1(T-DM1)
本发明包括用曲妥珠单抗-MCC-DM1(T-DM1),即抗体-药物缀合物(CASReg.No.139504-50-0)的治疗性处理,所述曲妥珠单抗-MCC-DM1(T-DM1)具有以下结构:
其中Tr是曲妥珠单抗,其经由接头模块MCC连接至美登木素生物碱类药物模块DM1(US 5208020;US 6441163)。药物对抗体比或药物载荷在曲妥珠单抗-MCC-DM1的上述结构中用p表示,并且范围为1至约8的整数值。曲妥珠单抗-MCC-DM1包括各种加载和附着的抗体-药物缀合物的所有混合物,其中1,2,3,4,5,6,7,和8个药物模块共价附着至抗体曲妥珠单抗(US 7097840;US 2005/0276812;US 2005/0166993)。
曲妥珠单抗可以由哺乳动物细胞(中国仓鼠卵巢,CHO)悬浮培养物生产。HER2(或c-erbB2)原癌基因编码一种185kDa跨膜受体蛋白,其在结构上与表皮生长因子受体相关。曲妥珠单抗是一种具有鼠4D5抗体(ATCC CRL 10463,依据布达佩斯条约于1990年5月24日保藏于美国典型培养物保藏中心,12301Parklawn Drive,Rockville,Md.20852)的或自鼠4D5抗体衍生的抗原结合残基的抗体。例示性的人源化4D5抗体包括huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8如US 5821337中的。
例如,可以依照美国申请公开文本No.20110165155的实施例1制备曲妥珠单抗-MCC-DM1。
帕妥珠单抗组合物
帕妥珠单抗组合物包含如上文定义的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SEQ ID No.7和8中的可变轻和可变重氨基酸序列,最优选包含SEQ ID No.11的轻链氨基酸序列及SEQ IDNo.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VHS--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PROPAC WCX-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。
对于关于例示性帕妥珠单抗组合物的更多信息,见美国专利No.7,560,111和7,879,325以及US 2009/0202546A1。
曲妥珠单抗-MCC-DM1(T-DM1)和帕妥珠单抗的配制剂
可以依照治疗组合中使用的标准药学实践配制曲妥珠单抗-MCC-DM1和帕妥珠单抗。药物组合物分别包含与一种或多种药学可接受载体、助流剂、稀释剂或赋形剂结合的曲妥珠单抗-MCC-DM1和帕妥珠单抗。
合适的载体,稀释剂和赋形剂是本领域熟练技术人员公知的,而且包括下述物质,诸如碳水化合物,蜡,水溶性和/或可膨胀聚合物,亲水性或疏水性物质,明胶,油,溶剂,水等等。所使用的具体载体,稀释剂或赋形剂会取决于应用本发明化合物的手段和目的。一般基于本领域技术人员公认对哺乳动物施用安全(GRAS)的溶剂来选择溶剂。一般而言,安全的溶剂是无毒的水性溶剂,诸如水和其它在水中可溶或易混合的无毒溶剂。合适的水性溶剂包括水,乙醇,丙二醇,聚乙二醇(例如PEG 400,PEG 300),等及其混合物。配制剂还可以包括一种或多种缓冲剂,稳定剂,表面活性剂,湿润剂,润滑剂,乳化剂,悬浮剂,防腐剂,抗氧化剂,不透明剂,助流剂,操作助剂,着色剂,增甜剂,芳香剂,矫味剂和其它已知添加剂以提供药物(即本发明的化合物或其药物组合物)精致的外观或帮助制造药学产品(即药物)。
可以使用常规溶解和混合规程来制备配制剂。例如,在一种或多种上文所述赋形剂存在下在合适的溶剂中溶解散装药物物质(即本发明的化合物或化合物的稳定化形式(例如与环糊精衍生物或其它已知的络合剂复合))。本发明的化合物通常配制成药学剂量形式,以提供可容易控制剂量的药物和使得患者顺从处方方案。
可以以多种方式包装供应用的药物组合物(或配制剂),这取决于用于施用药物的方法。一般而言,分发的物品包括容器,其中放置有适宜形式的药物配制剂。合适的容器是本领域技术人员公知的,而且包括诸如瓶(塑料的和玻璃的),囊,安瓿,塑料袋,金属筒,等等材料。容器还可以包括防干扰装置以防止不慎存取包装的内容物。另外,容器上放置有描述容器的内容物的标签。标签还可以包括适宜的警告。
可以以冻干配制剂,碾碎的粉末,或水溶液的形式用药学可接受稀释剂,载体,赋形剂或稳定剂(Remington's Pharmaceutical Sciences(1995)第18版,Mack Publ.Co.,Easton,PA)配制药物配制剂,供各种路径和类型的施用。可以通过于环境温度与适宜的pH,及于期望的纯度,与生理学可接受载体(即在所采用的剂量和浓度对接受者无毒的载体)混合来进行配制。配制剂的pH主要取决于具体用途和化合物的浓度,但是范围可以是约3至约8。
药物配制剂优选是无菌的。具体而言,用于体内施用的配制剂必须是无菌的。这种无菌易于通过无菌滤膜过滤来实现。
药物配制剂通常能作为固体组合物,冻干配制剂或作为水溶液来贮存。
本发明的药物配制剂会以与优良医学实践一致的方式即量,浓度,时间表,疗程,媒介和施用路径来进行剂量给药和施用。在此语境中要考虑的因素包括所治疗的具体病症,患者个体的临床状况,病症的起因,药剂的递送部位,施用方法,施用时间表,和医学从业人员知道的其它因素。
可接受的稀释剂,载体,赋形剂和稳定剂在所采用的剂量和浓度对接受者是无毒的,并且包括: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(诸如氯化十八烷基二甲基苄基铵;氯己双铵;苯扎氯铵,苄索氯铵;酚,丁醇,乙醇或苄醇;对羟基苯甲酸烃基酯,诸如对羟基苯甲酸甲酯或丙酯;邻苯二酚;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,诸如血清清蛋白,明胶或免疫球蛋白;亲水聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸,谷氨酰胺,天冬酰胺,组氨酸,精氨酸或赖氨酸;单糖类,二糖类和其它碳水化合物,包括葡萄糖,甘露糖或糊精;螯合剂,诸如EDTA;糖类,诸如蔗糖,甘露醇,海藻糖或山梨醇;成盐抗衡离子,诸如钠;金属复合物(例如Zn-蛋白质复合物);和/或非离子表面活性剂,诸如TWEENTM(包括Tween 80),PLURONICSTM或聚乙二醇(PEG)(包括PEG400)。活性药物组分还可包载于例如通过凝聚技术或通过界面聚合制备的微胶囊中(例如分别是羟甲基纤维素或明胶微胶囊和聚(甲基丙烯酸甲酯)微胶囊)、在胶状药物递送***中(例如脂质体、清蛋白微球体、微乳剂、纳米颗粒和纳米胶囊)、或在粗滴乳状液中。此类技术披露于Remington's PharmaceuticalSciences第18版,(1995)Mack Publ.Co.,Easton,PA。药物配制剂的其它例子可以参见Liberman,H.A.and Lachman,L.编,Pharmaceutical Dosage Forms,Marcel Decker,Vol3,2nd Ed.,New York,NY。
药物配制剂包括那些适合于本文详述的施用路径的。配制剂可以方便地以单位剂量形式存在,而且可以通过药学领域公知的任何方法来制备。技术和配方一般见Remington's Pharmaceutical Sciences第18版(1995)Mack Publishing Co.,Easton,PA。此类方法包括使活性组分与构成一种或多种辅助组分的载体联合的步骤。一般而言,通过均匀且紧密地使活性组分与液体载体或粉碎的固体载体或二者联合,然后在必要时使产物定形来制备配制剂。
药物组合物可以是无菌可注射制剂形式,诸如无菌可注射水性或油性悬浮液。可以依照已知技术,使用上文所述那些合适的分散剂或湿润剂和悬浮剂来配制这种悬浮液。无菌可注射制剂可以是在无毒胃肠外可接受稀释剂或溶剂中的溶液或悬浮液,诸如在1,3-丁二醇中或自冻干粉制备的溶液。在可以采用的可接受的媒介和溶剂中有水,林格氏溶液和等渗氯化钠溶液。另外,可以方便地采用无菌非挥发性油作为溶剂或悬浮介质。为了这一目的,可以采用任何温和的非挥发性油,包括合成的甘油单酯或二酯。另外,脂肪酸诸如油酸同样可以用于制备可注射制剂。
可以与载体材料联合以产生单个剂量形式的活性组分的量会根据所治疗的宿主和具体的施用模式而变化。例如,预定对人口服施用的时间-释放配制剂可以含有大约1至1000mg的活性材料,其与适当和方便量的载体材料复合,载体材料可以在总组合物的约5至约95%(重量:重量)变化。可以制备药物组合物来提供容易测量的量供施用。例如,预定用于静脉内输注的水溶液可以含有约3至500μg的活性组分每毫升溶液,以便能以约30mL/小时的速率输注合适的体积。
适合于胃肠外施用的配制剂包括水性和非水性无菌注射溶液,其可以含有抗氧化剂,缓冲剂,抑菌剂和使得配制剂与预定接受者的血液等渗的溶质;和水性和非水性无菌悬浮液,其可以包括悬浮剂和增稠剂。
可以将配制剂包装在单剂(unit-dose)或多剂(multi-dose)容器中,例如密封的安瓿和管形瓶,而且可以将其在冷冻干燥(冻干)条件下贮存,在使用前仅需要添加无菌液体载体,例如水以便即刻注射。由先前所述类型的无菌粉末,颗粒和片剂制备临时注射的溶液和悬浮液。优选的单位剂量配制剂为那些含有如上所述每日剂量或单位每日亚剂量或其合适的部分的活性组分的。
作为一般建议,每剂施用的曲妥珠单抗-MCC-DM1的初始药学有效量会在约0.3至15mg/kg/天的患者体重的范围中。
商业T-DM1配制剂(ado-曲妥珠单抗-艾美坦辛)是一次性管形瓶中的无菌的、白色至灰白色的无防腐剂的冻干粉末。每个管形瓶含有100mg或160mg ado-曲妥珠单抗-艾美坦辛。在重建后,每个一次性管形瓶含有ado-曲妥珠单抗-艾美坦辛(20mg/mL)、Polysorbate 20[0.02%(w/v)]、琥珀酸钠(10mM)、和蔗糖[6%(w/v)],具有pH 5.0和1.026g/mL的密度。通过稀释后的静脉内输注施用含有20mg/mL ado-曲妥珠单抗-艾美坦辛的所得溶液。
帕妥珠单抗的商业配制剂含有用于IV输注的无防腐剂的溶液形式的帕妥珠单抗420mg/14mL(30mg/mL)。
曲妥珠单抗-DM1(T-DM1)和帕妥珠单抗的施用
曲妥珠单抗-MCC-DM1(T-DM1)和帕妥珠单抗的药物组合物可以通过对于要治疗的状况适宜的任何路径来施用。合适的路径包括口服,胃肠外(包括皮下,肌肉内,静脉内,动脉内,吸入,皮内,鞘内,硬膜外,和输注技术),透皮,直肠,鼻,表面(包括口腔和舌下),***,腹膜内,肺内和鼻内。表面施用还可涉及使用透皮施用诸如透皮贴或离子透入装置。对于局部免疫抑制治疗,可以通过病灶内施用来施用化合物,包括灌注或以其它方式在移植前使移植物接触抑制剂。应当领会,优选的路径可以随例如接受者的状况而变化。若口服施用化合物,则它可以与药学可接受载体,助流剂,或赋形剂一起配制成丸剂,胶囊剂,片剂,等。若胃肠外施用化合物,则它可以与药学可接受胃肠外媒介或稀释剂一起,以单位剂量可注射形式配制,如下文详述的。
制品
提供了含有可用于本文中的治疗方法的曲妥珠单抗-MCC-DM1和/或曲妥珠单抗的制品,或“试剂盒”。在一个实施方案中,试剂盒包含容器,所述容器包含曲妥珠单抗-MCC-DM1。在另一个实施方案中,试剂盒包含帕妥珠单抗。在第三个实施方案中,试剂盒包含曲妥珠单抗-MCC-DM1和帕妥珠单抗。试剂盒可以进一步包含标签或包装插页,其在容器上或与容器有关。术语“包装插页”用于指通常包括在治疗用产品的商业包装中的说明书,它们包含有关涉及此类治疗用产品使用的适应征,用法,剂量,施用,禁忌症和/或警告的信息。合适的容器包括例如瓶,管形瓶,注射器,泡罩包,等,容器可以由各种材料,诸如玻璃或塑料形成。容器可以装有有效用于在本文中的治疗方法中使用的曲妥珠单抗-MCC-DM1和/或帕妥珠单抗或其配制剂,而且可以具有无菌存取口(例如容器可以是具有皮下注射针头可刺穿的塞子的静脉内溶液袋或管形瓶)。标签或包装插页指示组合物用于治疗方法,如本文中描述和要求保护的。制品还可以含有别的容器,其包含药学可接受缓冲液,诸如注射用抑菌水(BWFI),磷酸盐缓冲盐水,林格氏溶液和右旋糖溶液。它可以进一步包括从商业和用户立场看想要的其它材料,包括其它缓冲液,稀释剂,滤器,针头,和注射器。
试剂盒可以进一步包含关于施用曲妥珠单抗-MCC-DM1和/或帕妥珠单抗的指导。例如,如果试剂盒包括包含曲妥珠单抗-MCC-DM1的第一组合物和第二药物配制剂,那么试剂盒可以进一步包含关于对有所需要的患者同时,序贯或分开施用第一和第二药物组合物的指导。
在另一个实施方案中,试剂盒适合于递送固体口服形式的曲妥珠单抗-MCC-DM1和/或帕妥珠单抗,诸如片剂或胶囊剂。此类试剂盒优选包括多个单位剂量。此类试剂盒可包括卡片,其中各剂量以它们意图使用的次序定位(oriented)。此类试剂盒的一个例子是“泡罩包”。泡罩包是包装工业公知的,而且广泛用于包装制药学剂量单位形式。如果需要,可以提供记忆辅助物,例如数字,字母,其它标记的形式或者日历插页,指示治疗时间表中要施用剂量的日子。
依照一个实施方案,试剂盒可以包括(a)第一容器,其中含有曲妥珠单抗-MCC-DM1;和任选的(b)第二容器,其中含有帕妥珠单抗。或者/另外,试剂盒可以进一步包括第三容器,其装有制药学可接受缓冲液,诸如注射用抑菌水(BWFI),磷酸盐缓冲盐水,林格氏溶液和右旋糖溶液。它可以进一步包括从商业和用户立场看想要的其它材料,包括其它缓冲液,稀释剂,滤器,针头,和注射器。
若试剂盒包含曲妥珠单抗-MCC-DM1和帕妥珠单抗的组合物,则试剂盒可以包括用来装分开的组合物的容器,诸如分开的瓶或分开的箔包,然而,分开的组合物也可以装在单个,不分隔的容器内。典型地,试剂盒包括关于施用分开的成分的指导。当不同成分优选以不同剂量形式施用(例如口服和胃肠外),以不同剂量间隔施用,或者当开处方的内科医师希望调整(titration)组合的各成分时,这种试剂盒形式是特别有利的。
本文中的制品的一个实施方案包括静脉内(IV)袋,其含有适合于对癌症患者施用的帕妥珠单抗和T-DM1的稳定的混合物。任选地,混合物在盐水溶液中;例如包含约0.9%NaCl或约0.45%NaCl。一种例示性的IV袋是聚烯烃或聚氯乙烯输注袋,例如250mL IV袋。根据本发明的一个实施方案,混合物包含约420mg或约840mg帕妥珠单抗和约100mg至约160mgT-DM1。
任选地,IV袋中的混合物于5℃或30℃稳定长达24小时。可以通过选自下组的一种或多种测定法评估混合物的稳定性:颜色、外观和澄清度(CAC)、浓度和浊度分析、颗粒分析、大小排阻层析(SEC)、离子交换层析(IEC)、毛细管区带电泳(CZE)、图像毛细管等电聚焦(iCIEF)、和效力测定法。
实施例
为了例示本发明,包括下述实施例。然而,应当理解,这些实施例不限制本发明,而只是意图提示实施本发明的方法。
表1:缩写表
实施例1
III期临床研究
此研究(BO28408/TRIO021)是一项在具有能施手术、局部晚期或炎性、经中心评估的HER2阳性EBC的未治疗处理的患者中的随机化的、全球、多中心、开放标签、III期、两分支研究,所述患者的原发性肿瘤>2cm。
患者
患者群体包括具有未治疗处理的、能施手术、局部晚期或炎性、经中心确认的HER2阳性EBC的患者。如此,此研究的靶群体包括具有呈HER2阳性(如通过中心病理学实验室测定)的新诊断的原发性侵入性乳腺癌并且在确定性手术后用辅助***化学疗法治疗的患者。在随机化前在中心测试HER2状态。根据至少一次放射摄影或临床测量,原发性肿瘤的大小应当>2cm。下文包括了所有合适性标准的列表。
调查人员或辅助调查人员必须确保在研究中仅对满足纳入和排除标准的患者提供登记。在决定患者是否是适合于研究的候选者时,调查人员或辅助调查人员还应当考虑所有其它相关因素(医学和非医学),以及研究疗法的风险和益处。
纳入标准
患者必须满足以下研究进入标准:
签署的得到研究地点机构审阅委员会(IRB)/伦理委员会(EC)批准的书面知情
同意
通过至少一次放射摄影或临床测量经组织学确认的具有>2cm的原发性肿瘤大小的侵入性乳腺癌
HER2阳性乳腺癌。基于治疗前的***活组织检查材料测定HER2阳性状态,并且对于此特定研究定义为免疫组织化学(IHC)得分3+和/或根据ISH呈阳性,其在研究登记前由中心实验室前瞻性评估。ISH阳性定义为HER2基因拷贝数与染色体17拷贝的信号数目的比率≥2。中心实验室实施IHC和ISH测定法两者;然而,对于合适性仅需要一项阳性结果。必须获得经石蜡包埋的肿瘤组织块或部分块以进行HER2合适性的中心确认。仅在适用使得块提交变得不可能的合法地点管理的那些地点,并且仅在已经获得发起人批准后,可以接受与研究特定取样手册中描述的不同材料的提交。
具有多病灶肿瘤(超过一个局限于与原发性肿瘤相同的象限的肿瘤)的患者是合适的,只要中心确认所有取样的损伤为HER2阳性。
呈现时的阶段:cT2-cT4、cN0-cN3、cM0
原发性肿瘤的已知激素受体状态
患者同意在新辅助治疗后进行***切除术或***保守手术
顺从安排的访视、治疗计划、实验室测试和其它研究规程,包括完成PRO测量的自愿和能力
年龄≥18岁
0或1的ECOG表现状态
在筛选期间(在第一剂前7天内)的足够的器官功能,其定义为:
-绝对嗜中性粒细胞计数(ANC)≥1500个细胞/μL
-血小板计数≥100,000个细胞/μL
-血红蛋白≥9g/dL;患者可以接受红细胞输血以获得此水平
-血清肌酸酐≤1.5x正常上限(ULN)
-国际标准化比率(INR)和(活化的)部分促凝血酶原激酶时间(aPTT/PTT)≤1.5xULN
-天冬氨酸氨基转移酶(AST)和丙氨酸氨基转移酶(ALT)≤ULN
-血清总胆红素≤ULN,除了其直接胆红素应当在正常范围内的具有吉尔伯特(Gilbert)氏综合征的患者外。
-血清碱性磷酸酶≤ULN
通过超声心动图(ECHO)或多次门控采集(multiple gated acquisition,MUGA)测量的基线LVEF≥55%
对于不是绝经后(非疗法诱发的闭经≥12个月)或手术***(缺乏卵巢和/或子宫)的女性:同意保持禁欲或者使用单一或组合的非激素避孕方法,其导致治疗期期间每年<1%的失败率,并且在最后一剂研究药物后持续至少7个月
禁欲仅在其与患者的优选且通常的生活方式一致时是可接受的。定期禁欲(例如日历、***、症状体温、或***后方法)和撤回不是可接受的避孕方法。
每年具有<1%的失败率的非激素避孕方法的例子包括输卵管结扎、男性绝育法、和某些子宫内装置。或者,可以组合两种方法(例如两种屏障方法,诸如避孕套和宫颈帽)以实现每年<1%的失败率。屏障方法必须总是补充杀***剂的使用。
针对绝经前女性,及针对在第一剂疗法前<12个月已经经历绝经的女性的阴性血清妊娠测试
乙肝病毒(HBV),包括HB表面抗原(HBsAg)和/或总HB核心抗体(抗HBc),和丙肝病毒(HCV),包括HCV抗体测试的血清学证明。最近的血清学测试必须在启动新辅助治疗前3个月内发生。若尚未完成此类测试,则它必须在筛选期间实施。具有阳性HBV或HCV血清学且没有已知的活动性疾病的患者必须满足在28天筛选期内以至少1周分开的至少两个连续时机的ALT、AST、总胆红素、INR、aPTT/PTT、和碱性磷酸酶的合适性标准。必须在第一次施用研究药物前3天内实施这些评估的第二项。
排除标准
自研究进入排除满足任何下述标准的患者:
IV期(转移性)乳腺癌
已经接受针对乳腺癌的在先抗癌疗法的患者,除了那些具有手术管理的乳腺LCIS或仅用***切除术治疗的DCIS的历史的患者外。在LCIS/DCIS的在先历史的情况中,从手术直到诊断目前的乳腺癌必须已经经过>5年。
具有多中心(多个牵涉超过1个象限的肿瘤)乳腺癌的患者
双侧乳腺癌患者
已经进行原发性肿瘤和/或腋窝***的切割和/或切除活组织检查的患者
在启动新辅助治疗前的腋窝***解剖。若与当地实践一致,则具有临床阴性腋(通过身体检查和放射摄影成像)的患者可以在NAST前进行前哨***活组织检查规程。
新辅助治疗前的阳性前哨***
并行或先前治疗的非***恶性的历史,除了适当治疗的1)非黑素瘤皮肤癌和/或2)原位癌,包括宫颈、结肠和皮肤之外。具有先前的侵入性非乳腺癌的患者是合适的,只要他/她已经没有疾病超过5年。
在随机化前28天内用任何调查药物的治疗
目前的(NCI CTCAE)v4.03级≥2周围神经病
心肺功能障碍,如通过下列任一项限定:
-NCI CTCAE(第4.0版)≥3级症状性CHF或NYHA标准等级≥II的历史
-需要抗心绞痛药物的心绞痛,不受足够的药物控制的严重心律不齐,重度传导异常,或临床重大心瓣病
高风险的不受控制的心率不齐(即,静止时具有心率>100/min的房性心动过速,重大室性心律失常[室性心动过速],或较高等级的房室[AV]阻滞[二度AV-阻滞2型[Mobitz2]或三度AV-阻滞])
-与左心室功能障碍、心脏心律失常、或心脏缺血相关的重大症状(等级≥2)
-随机化前12个月内的心肌梗死
-不受控制的高血压(收缩血压>180mmHg和/或舒张血压>100mmHg)
-ECG上的透壁性梗塞的证据
-对氧疗的需要
目前的重度、不受控制的***性疾病,其可以干扰计划的治疗(例如,临床重大的心血管、肺、或代谢疾病;创伤愈合病症)
在随机化前28天内与乳腺癌或重大创伤性损伤无关的重大手术规程或预期在研究治疗过程期间需要重大手术
已知的活动性肝疾病,例如由于HBV、HCV、自身免疫性肝病症、或硬化性胆管炎
并行的、严重的、不受控制的感染或已知的HIV感染
当前的妊娠和/或哺乳
对研究药物、赋形剂和/或鼠蛋白质的已知的超敏感性
研究设计
将已经同意并且适合于研究的患者以1:1比率随机化至以下新辅助治疗方案之一的6个周期:
分支A:多西他赛(75mg/m2每3周[q3w])和卡铂(浓度-时间曲线下面积[AUC]6)和曲妥珠单抗(8mg/kg加载剂量,6mg/kg维持剂量q3w)和帕妥珠单抗(840mg加载剂量,然后420mg剂量q3w)(多西他赛-卡铂-曲妥珠单抗[TCH]+帕妥珠单抗)
分支B:曲妥珠单抗-艾美坦辛(3.6mg/kg q3w)和帕妥珠单抗(840mg加载剂量,然后420mg剂量q3w)(曲妥珠单抗-艾美坦辛+帕妥珠单抗)
图6中显示了研究设计的方案,其中T=多西他赛,C=卡铂,H=曲妥珠单抗。
研究在全球的约110个地点处登记总共432名患者,每个治疗分支为216名患者。
患者根据其随机化分组接受新辅助治疗的6个周期。不应进行手术,直至最后一剂新辅助治疗后至少14天。在手术前应当检查血小板计数,并且应当是≥75,000个细胞/μL。应当在最后一剂新辅助治疗后不迟于9周实施手术。另外,容许随机化至分支B(曲妥珠单抗-艾美坦辛+帕妥珠单抗)的所有患者(不考虑其在新辅助背景中的pCR结果)接受辅助背景中的标准细胞毒性疗法;施用标准细胞毒性疗法的决定和方案的选择按治疗内科医生的判断。推荐基于蒽环类抗生素的疗法(FAC、FEC或AC)的4个周期。在最终手术规程后9周内启动辅助治疗。意图按照随机化分组给予HER2定向性疗法达1年以与发表的辅助数据和全球标准一致。鉴于新辅助和辅助背景中的疗法的使用和疗法中的可能的延迟,通过给予的周期的总数限定HER2定向性疗法(曲妥珠单抗+帕妥珠单抗[分支A]和曲妥珠单抗-艾美坦辛+帕妥珠单抗[分支B])的长度。没有任何延迟的1年HER2定向性疗法涵盖18个周期;因此,研究计划施用18个周期的HER2靶向性疗法(包括新辅助和辅助疗法)。
新辅助阶段
施用新辅助治疗总共6个周期,q3w给予。在疾病进展、不能接受的毒性、同意的撤回、或由发起人进行的研究终止(以先发生者为准)的情况中,在这6个周期前中断新辅助治疗。允许患者按照随机化接受辅助研究治疗,所述患者的新辅助研究治疗在完成这6个周期前中断,并且不接受非方案新辅助治疗。
自研究治疗中断手术前接受非方案疗法的任何患者,并且按照当地实践管理。
中断曲妥珠单抗-艾美坦辛的分支B中的患者还应当中断帕妥珠单抗,并且认为从研究药物治疗中断。按照当地实践管理这些患者。
出于毒性而中断帕妥珠单抗的患者可以保留于研究治疗(分支A:[仅TCH];分支B[仅曲妥珠单抗-艾美坦辛])。
中断计划的研究治疗的所有患者保留于研究以进行次要和探索性终点的随访,除非撤回研究参与的同意。
手术
在新辅助治疗的最后一次输注后不迟于6周实施手术。
在启动新辅助治疗前,应当由具有乳腺癌手术经验的外科医生查看患者。研究评估***保留率。在新辅助治疗前,外科医生应对患者评估手术规程,所述手术规程可以基于基线访视时的检查进行(即,在新辅助治疗缺失下,需要***切除术或广泛局部切割规程,诸如区段/部分***切除术)。应当在电子病例报告表(eCRF)中记录此基线评估。在启动新辅助治疗前,必须在放射摄影引导(例如超声)下用不透射线的标志物标记肿瘤部位。
自完成新辅助治疗后,在手术前,应当基于患者对手术(***切除术或广泛局部切割规程,诸如区段/部分***切除术)的响应对他们评估他们会作为候选者接受的手术规程,并且应当在eCRF中记录此潜在的选择。还应当将选定的手术进入eCRF中。公认的是,出于多种因素(患者偏爱、风险降低等),患者及其外科医生可以选择进行与他们会作为候选者接受的不同手术。应当在eCRF中记录基于响应的潜在手术及选择的手术两者。不应进行手术,直至最后一剂新辅助治疗后至少14天。应当在手术前检查血小板计数,并且应当≥75,000个细胞/μL。
在完成新辅助治疗和手术后经由当地审阅建立主要效力终点(pCR-ypT0/is,ypN0)。
对于其肿瘤在新辅助治疗后仍然不能手术的患者,按照局部标准实践完成局部和/或***管理。这些患者从研究治疗撤回,并且保持于研究以进行次要和探索性终点的随访,除非他们已经撤回研究参与的同意。
用于腋窝***的手术管理选项在***手术时包括I和II水平***的前哨***活组织检查(SLNB)(在新辅助治疗之前或之后)和腋窝***解剖(ALND)。辅助规程的选择基于腋的临床状态、T阶段、和当地实践。
辅助阶段
已经进行手术的所有患者继续在辅助阶段中接受与研究的新辅助阶段中的施用相同的HER2定向性疗法(分支A[曲妥珠单抗+帕妥珠单抗];分支B[曲妥珠单抗-艾美坦辛+帕妥珠单抗])。给予治疗,使得施用包括新辅助和辅助背景两者中给予的疗法的HER2定向性疗法的18个总周期。由于可以归因于曲妥珠单抗组分的毒性(例如超敏感性、心脏毒性、肺炎)而中断曲妥珠单抗-艾美坦辛的患者在中断曲妥珠单抗-艾美坦辛后可以不继续接受曲妥珠单抗。
在最后一次手术规程后9周内启动辅助疗法。在侵入性疾病复发、第二主要侵入性恶性、不可接受的毒性、同意的撤回、或由发起人进行的研究终止(以先发生者为准)的情况中中断辅助疗法。仍按照次要终点的方案追踪其辅助研究治疗在完成计划的疗法前中断的患者,除非撤回参与的同意。
在手术后,应当施用放射疗法,如临床指示的。需要具有ER阳性和/或PgR阳性肿瘤的患者按照当地临床标准接受辅助内分泌疗法(例如他莫昔芬或芳香酶抑制剂)。
用于分支B的任选辅助疗法
另外,容许随机化至分支B(曲妥珠单抗-艾美坦辛+帕妥珠单抗)的所有患者(不管其在新辅助背景中的pCR结果)接受辅助背景中的标准细胞毒性疗法;施用标准细胞毒性疗法的决定和方案的选择根据治疗内科医生的判断。推荐持续最少4个周期的基于蒽环类抗生素的辅助疗法(例如,AC、FAC、FEC)。对于给予化学疗法的分支B中的患者,还应当在临床上合适时在最后一次手术规程后9周内与化学疗法一起启动辅助曲妥珠单抗。不应与辅助化学疗法组合曲妥珠单抗-艾美坦辛和帕妥珠单抗,但是一旦已经完成辅助化学疗法,便应当恢复。应当在完成任选的化学疗法后28天内恢复曲妥珠单抗-艾美坦辛和帕妥珠单抗。
对于接受标准辅助化学疗法方案的患者,应当延迟放射疗法,直至在完成辅助化学疗法后,并且在完成辅助化学疗法的28天内启动。
研究的长度
一旦所有患者已经接受手术,在已经随机化最后一名患者后约8个月,分析主要效力终点pCR。
在自随机化起的约36个月的中值随访时间时(即,对第50个百分位数患者随访约36个月时)分析EFS、IDFS、***保留率和OS的次要效力终点。当达到此中值随访时间时,联系所有患者以评估EFS、IDFS和OS的次要终点。可以在进行主要效力分析之时/之后并且在主要分析后根据HA的需要或请求进行次要效力终点EFS、IDFS和OS的描述中间分析。研究的总共持续时间是约45个月。
效力结果测量
主要效力结果测量
此研究的主要效力结果测量如下:
DFS,定义为从随机化直至下列事件之一的第一次发生的日期的时间:
1.同侧侵入性***肿瘤复发(即,与初始原发性损伤牵涉相同***实质的侵入性乳腺癌)
2.同侧局部区域性侵入性乳腺癌复发(即,同侧***的腋、区域***、胸壁、和/或皮肤中的侵入性乳腺癌)
3.对侧或同侧第二原发性侵入性乳腺癌
4.远端复发(即,已经在组织学上确认或临床/放射摄影诊断为复发性侵入性乳腺癌的任何解剖部位[与上文提及的三种部位不同]中的乳腺癌的证据)
可归因于任何原因(包括乳腺癌、非乳腺癌、或未知的原因)的死亡。
如上文描述的,主要效力变量是IDFS,其定义为随机化和IDFS事件的第一次发生的日期之间的时间。在数据分析时还没有事件的患者在最后已知他们活着并且没有事件的日期时,在相应分析的临床数据截留日期之时或之前检查。
使用通过方案限定的分层因素(排除区域)分层的时序检验比较两个治疗分组之间的IDFS。由于由一些层可以具有非常少的患者的可能性所致的能力(power)的可能丧失而排除区域。也提供未分层的时序检验结果以进行灵敏性分析。若在分析时,认为对于进行强力的分层分析必需的每个分支的最小层含有<5个事件,则使用未分层的分析作为主要分析。使用通过先前记录的分层因素(排除区域)分层的Cox比例危害模型评估两个治疗分支之间的HR及其95%CI。使用Kaplan-Meier方法对每个治疗分支评估3年IDFS率和相应的95%CI。
次要效力结果测量
此研究的次要效力结果测量如下:
IDFS加第二原发性非乳腺癌,排除非黑素瘤皮肤癌和任何部位的原发癌(CIS)
DFS,定义为随机化和上文描述的任何IDFS事件、第二原发性非乳腺癌事件(排除非黑素瘤皮肤癌和任何非***部位的CIS)、和对侧或同侧原位导管癌(DCIS)的第一次发生的日期之间的时间
DRFI,定义为随机化和远端乳腺癌复发的第一次发生之间的时间
OS,定义为从随机化至由任何原因所致的死亡的时间
安全性结果测量
依照国家癌症研究所不利事件常见术语标准(NCI CTCAE)v4.03报告临床和实验室不利事件。使用超声心动图(ECHO)或多重门控采集(MUGA)扫描评估LVEF。
此研究的安全性结果测量如下:
基于NCI CTCAE v4.03的所有不利事件的发生、类型和严重性
严重不利事件的发生、类型和严重性
≥3级不利事件的发生、类型和严重性
导致剂量中断、修改或延迟的不利事件的发生和类型
死亡原因
异常实验室数值
随时间自基线的LVEF降低
心脏安全性结果测量
1.主要心脏终点:心脏事件,其定义为来自心脏原因的死亡或重度CHF(NYHA III或IV类),伴有从基线至LVEF<50%的LVEF≥10百分点的降低
2.次要心脏终点:其它心脏相关事件(例如,与LVEF至<50%的≥10%下降有关的任何轻度症状性CHF[NYHA II类];需要剂量延迟或中断的LVEF的无症状降低)
肝安全性结果测量
3.来自肝原因的死亡
4.重度DILI(海氏规律(Hy’s law)病例)
5.NRH
肺安全性结果测量
6.来自肺原因的死亡
7.肺炎和ILD
次要终点是IDFS加第二原发性非乳腺癌、DFS、DRFI(在效力结果测量部分中定义)、和OS。
以与主要终点相似的方式分析次要终点,从而以95%CI评估每个治疗分支的3年事件率(和对于OS的5年存活率)和两个治疗分支间的HR。在数据分析时还没有事件的患者在最后知道他们活着并且没有事件的日期时或者在相应分析的临床数据截留日期前检查。
在试验结束时,使用总体方案限定群体和结阳性亚群体两者,使用Kaplan-Meier方法评估每个治疗分支的5年IDFS率和相应的95%CI。
患者报告结果(PRO)测量
用于本研究的PRO测量如下:
HRQoL,包括引起麻烦的的疗法副作用(例如周围神经病、关节/肌肉疼痛、皮肤问题),和患者机能发挥,如使用EORTC QLQ-C30和经修改的乳腺癌模块QLQ-BR23测量的
从第一次HER2靶向性治疗±紫杉烷至全局健康状态/QoL(QLQ-C30的子量表)的恶化的时间。给定患者的全局健康状态/QoL的事件恶化定义为启动HER2定向性疗法±紫杉烷后的任何时间点时均值得分增加10分或更多。均值得分增加已经定义为从患者的观点看“中等”至“非常多的”察觉的重要变化(Osoba et al.,Interpreting the significanceof changes in health-related quality-of-life scores.J Clin Oncol 1998;16(1):139-44)。
探索性生物标志物结果测量
用于本研究的探索性生物标志物结果测量是分子标志物和效力和/或安全性结果之间的关系。在适当时,对于此分析考虑的效力结果包括IDFS和OS。
生物标志物状态和效力和/或安全性之间的关联包括但不限于下列各项:
通过定量实时聚合酶链式反应(qRT-PCR)评估的HER2 mRNA表达水平与效力结果
通过PIK3CA等位基因特异性聚合酶链式反应测定法评估的PIK3CA突变的状态与效力结果
通过原位杂交(ISH)评估的HER2基因扩增的水平与效力结果
通过免疫组织化学(IHC)评估的HER2蛋白表达的水平与效力结果
生物标志物或生物标志物组随时间的表达水平变化与效力结果
剂量、施用和顺从性
SoC化学疗法主干治疗应当包括基于蒽环类抗生素的方案的3至4个周期。在分支A中,还施用3至4个周期或12周的紫杉烷。HER2靶向性疗法的施用会直至1年(直至18个周期)。在侵入性疾病复发、不能接受的毒性、同意的撤回、或由发起人进行的研究终止的情况中中断辅助研究治疗。如果调查人员认为是为了患者的最佳利益(只要有可能),那么不需要***性疗法并且没有侵入性乳腺癌复发的证据的诊断为原位乳腺癌或第二原发性癌症的患者应当继续辅助研究治疗。
蒽环类抗生素治疗阶段
可以在此研究中根据调查人员的判断选择如以下小节中描述的FEC(表2)或AC/EC(表3)方案。对于关于施用、麻醉前用药(premedications)和出于毒性的剂量延迟/降低的详细准则,请参考地方规定信息/机构准则。
表2:FEC
BSA=体表面积;IV=静脉内;q3w=每3周;x=周期。
表3:AC/EC
IV=静脉内;q2w=每2周;q3w=每3周;x=周期。
可以在G-CSF支持(例如在q2w周期的第2天的培非司亭(pegfilgrastim)6mg皮下)的情况中施用剂量密集(每2周[q2w])AC/EC方案。
可以根据内科医生的判断使用止吐方案作为麻醉前用药。
并行的紫杉烷阶段和/或仅HER2靶向性阶段
并行的紫杉烷阶段仅适用于治疗分支A(对照分支)。曲妥珠单抗加帕妥珠单抗在对照分支中必须在蒽环类抗生素疗法后与化学疗法的紫杉烷组分并行开始。在蒽环类抗生素治疗后,需要从最后一剂蒽环类抗生素至启动HER2靶向性疗法的最少3周的间隔。在开始疗法的HER2靶向性组分前,患者必须具有LVEF≥50%,并且必须尚未经历提示心脏衰竭的任何临床症状或自基线的无症状LVEF降低绝对点>15%。HER2靶向性治疗继续,直至1年的总持续时间,并且在侵入性疾病复发、不能接受的毒性、同意的撤回、或由发起人进行的研究终止的情况中中断。
对于q3w给药容许±3天窗口,并且对于qw给药容许+3天窗口。在由于毒性而指示剂量延迟时不适用此时间窗口。
曲妥珠单抗加帕妥珠单抗加紫杉烷治疗
在紫杉烷并行阶段期间,与帕妥珠单抗组合与曲妥珠单抗并行施用多西他赛q3w(以100mg/m2达3个周期,以75mg/m2达4个周期,或在第一个周期中以75mg/m2开始,并且若最少总共三个周期不发生DLT,则逐步升高至100mg/m2)或12周的帕利他塞80mg/m2qw。对于关于多西他赛或帕利他塞施用、麻醉前用药、和出于毒性的剂量延迟/降低的详细准则,请参考当地规定信息/机构准则。
在并行阶段后,继续仅施用曲妥珠单抗加帕妥珠单抗,直至总共1年的持续时间(52周;直至18个周期)。
以8mg/kg的加载剂量给予曲妥珠单抗,并且以840mg的加载剂量给予帕妥珠单抗。对于后续周期,以6mg/kg的维持剂量给予曲妥珠单抗,并且以420mg q3w给予帕妥珠单抗。不需要再计算曲妥珠单抗的剂量,除非体重已经自基线变化超过±10%。若患者缺少用于任何周期的一剂曲妥珠单抗(即,两次序贯施用时间相隔6周或更多),则应当给予再加载剂量的8mg/kg曲妥珠单抗。若患者缺少用于任何周期的一剂帕妥珠单抗并且剂量间的时间是6周或更多,则应当给予再加载剂量的帕妥珠单抗(840mg)。对于随后的输注,可以用对乙酰氨基酚(paracetamol)和抗组胺对经历曲妥珠单抗或帕妥珠单抗输注相关的症状的患者麻醉前用药。
此治疗分支的施用顺序应当遵循表4中概述的顺序(如从顶部至底部的顺序)。
表4:分支1的治疗方案
a根据调查人员对患者安全性的判断,输注期可以长于本文描述的输注期。
b曲妥珠单抗输注仅在完成帕妥珠单抗的观察期后开始。
Trastuzumab Emansine加帕妥珠单抗治疗
在治疗分支2中的患者中不施用紫杉烷。继续曲妥珠单抗-艾美坦辛加帕妥珠单抗,直至总共1年的持续时间(52周;直至18个周期)。
与初始加载剂量840mg IV,接着是维持剂量420mg IV q3w的帕妥珠单抗组合通过IV输注以3.6mg/kg的剂量给予曲妥珠单抗-艾美坦辛。不需要再计算曲妥珠单抗-艾美坦辛的剂量,除非体重已经自基线变化超过±10%。若患者缺少用于任何周期的一剂帕妥珠单抗并且剂量间的时间是6周或更多,应当给予再加载剂量的帕妥珠单抗(840mg)。
对于随后的输注,可以用对乙酰氨基酚和抗组胺对经历帕妥珠单抗输注相关的症状的患者麻醉前用药。
此治疗分支的施用顺序应当遵循下表(表5)(如从顶部至底部的顺序)。
表5:用于分支2的治疗方案
a曲妥珠单抗-艾美坦辛输注仅在完成帕妥珠单抗的观察期后开始。
认为前述描述仅例示本发明的原理。此外,由于许多修改和变化对于本领域技术人员会是容易显而易见的,不想要将本发明限于如上文描述的显示的精确的构建和方法。因而,可以认为所有合适的修改和等同方案落入如所附权利要求书限定的本发明的范围内。
Claims (22)
1.一种用于治疗乳腺癌的方法,其包括
(i)在化学疗法缺失下用T-DM1和帕妥珠单抗的组合对具有HER2阳性、能施手术、局部晚期或炎性的乳腺癌的患者进行新辅助治疗,
(ii)通过确定性手术去除所述乳腺癌,并
(iii)在化学疗法缺失下用T-DM1和帕妥珠单抗的组合对所述患者进行辅助治疗。
2.权利要求1的方法,其中在包含紫杉烷的化学疗法缺失下用T-DM1和帕妥珠单抗的组合对所述患者进行辅助治疗。
3.权利要求1的方法,其中在并行化学疗法缺失下用T-DM1和帕妥珠单抗的组合对所述患者进行辅助治疗。
4.权利要求3的方法,其中所述辅助治疗包含用T-DM1和帕妥珠单抗治疗之前和/或之后的化学疗法。
5.权利要求4的方法,其中所述用T-DM1和帕妥珠单抗治疗之前和/或之后的化学疗法不包含紫杉烷。
6.权利要求4的方法,其中施用的所述化学疗法包含基于蒽环类抗生素的化学疗法。
7.权利要求6的方法,其中施用的所述化学疗法进一步包含曲妥珠单抗。
8.权利要求6的方法,其中所述基于蒽环类抗生素的化学疗法包含下述一项或多项:FAC(5-氟尿嘧啶、多柔比星、环磷酰胺)、FEC(5-氟尿嘧啶、表柔比星和环磷酰胺)或AC(多柔比星、环磷酰胺)。
9.权利要求1-8中任一项的方法,其中所述乳腺癌的直径为>2cm。
10.权利要求1-8中任一项的方法,其中在新辅助治疗完成后至少14天实施确定性手术。
11.权利要求10的方法,其中在新辅助治疗完成后不迟于9周实施确定性手术。
12.权利要求1-8中任一项的方法,其中所述新辅助和辅助治疗方案各自包含每3周以3.6mg/kg的剂量输注T-DM1及以840mg的加载剂量和此后每3周以420mg的剂量输注帕妥珠单抗。
13.前述权利要求任一项的方法,其中并行施用T-DM1和帕妥珠单抗。
14.权利要求13的方法,其中共施用T-DM1和帕妥珠单抗。
15.权利要求13的方法,其中以任一次序序贯施用T-DM1和帕妥珠单抗。
16.权利要求13的方法,其中所述施用遵循表5中列出的日程表。
17.前述权利要求任一项的方法,其中所述治疗提高下述一项或多项:完全响应(CR)、EFS(无事件存活)、DFS(无疾病存活)、IDFS(无侵入性疾病存活)、和OS(总体存活)。
18.前述权利要求任一项的方法,其中所述治疗提高疾病进展前时间。
19.前述权利要求任一项的方法,其中新辅助治疗基本上由T-DM1和帕妥珠单抗的施用组成。
20.前述权利要求任一项的方法,其中新辅助治疗由T-DM1和帕妥珠单抗的施用组成。
21.前述权利要求任一项的方法,其中辅助治疗基本上由T-DM1和帕妥珠单抗的施用组成。
22.前述权利要求任一项的方法,其中辅助治疗由T-DM1和帕妥珠单抗的施用组成。
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CA2946860A1 (en) | 2015-10-29 |
SG11201608912VA (en) | 2016-11-29 |
RU2016146129A3 (zh) | 2018-12-18 |
RU2020120593A (ru) | 2020-09-01 |
US20170035907A1 (en) | 2017-02-09 |
RU2725093C2 (ru) | 2020-06-29 |
AU2015249633A8 (en) | 2016-12-01 |
JP2020172487A (ja) | 2020-10-22 |
KR20160141857A (ko) | 2016-12-09 |
AU2015249633B2 (en) | 2020-10-15 |
IL248487A0 (en) | 2016-12-29 |
MX2016014007A (es) | 2017-01-11 |
AU2021200109A1 (en) | 2021-03-18 |
JP2017513901A (ja) | 2017-06-01 |
EP3134440A1 (en) | 2017-03-01 |
RU2016146129A (ru) | 2018-05-25 |
EP3581586A1 (en) | 2019-12-18 |
SG10201809411PA (en) | 2018-11-29 |
AU2015249633A1 (en) | 2016-11-17 |
BR112016024789A2 (pt) | 2017-10-24 |
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