Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT1-06-01
P. Kumthekar, B. Lawrence, V. Iordanova, N. Ibrahim, R. Mazanet
Background: Annually, more than 4,000 patients are diagnosed with leptomeningeal carcinomatosis (LC) from breast cancer in the U.S. Since most therapies cannot cross the Blood-CSF-Barrier (BCB) and the Blood-Brain-Barrier (BBB), treatment options for LC are limited to local radiation and few chemotherapy agents, none of which have provided durable clinical benefit, leading to short overall survival (OS) of 3-4 months. ANG1005 is a novel peptide-drug conjugate, consisting of 3 paclitaxel molecules covalently linked to a peptide that targets the LRP-1 receptor to cross both BCB and BBB, and enter the tumor cells, where the paclitaxel is cleaved off to exert its anti-tumor activity. ANG1005 has previously shown in a phase 2 study to prolong OS in LC patients from breast cancer with brain metastases (BM) to 8 months. Trial Design: This is an open-label, multi-center phase 3 randomized study to evaluate the efficacy of ANG1005 in HER2-negative breast cancer patients with newly diagnosed LC and documented history of previously treated BM when compared to Physician Best Choice (PBC). Hundred and fifty (150) patients will be randomized 1:1 to receive either ANG1005 experimental treatment or an Investigator assigned PBC control treatment. ANG1005 will be administered by intravenous (IV) infusion at a starting dose of 600 mg/m2 every 3 weeks. Allowed PBC therapies include capecitabine, eribulin, or high-dose IV methotrexate. CNS disease (LC and BM) will be evaluated at screening and every 6 weeks by MRI, CSF cytology and neurological assessments according to LANO and RANO-BM criteria. Extracranial disease will be evaluated by CT scans according to RECIST at screening and every 6-12 weeks. All patients will be followed for survival every 6-8 weeks from the date of the last dose until death, lost to follow-up or consent withdrawal. Eligibility Criteria: Eligible patients are adults (≥ 18 years old) with HER2-negative breast cancer, newly diagnosed LC and documented history of previously treated BM. Patients must be neurologically stable and have adequate blood counts, organ and bone marrow function with an ECOG status grade ≤2. Patients previously treated with ANG1005 or with known allergy to paclitaxel or its components are excluded. Specific aims: The primary endpoint is OS. Secondary endpoints include CNS (LC and BM) progression-free survival and clinical benefit rate, 6- and 12-month OS rates, LC response rate and duration of response, OS for triple negative patients and safety. Statistical Methods: This study is sized for testing the hypothesis of improved OS for ANG1005 versus PBC in all patients (HR=0.58, two-sided test, overall type 1 error of 5%). Interim analysis for OS (using O9Brien Fleming boundaries for efficacy and a fixed HR=1 for futility) will be performed when a total of 55 death events are reached across both arms. Study Accrual: Target accrual is 150 patients. The study is currently planned to start in the fall of 2018. Citation Format:
背景:在美国，每年有超过4000名患者被诊断为乳腺癌脑薄脑膜癌(LC)，由于大多数治疗方法不能通过血csf屏障(BCB)和血脑屏障(BBB)， LC的治疗选择仅限于局部放疗和少量化疗药物，没有一种能提供持久的临床益处，导致总生存期(OS)较短，为3-4个月。ANG1005是一种新型的肽-药物偶联物，由3个紫杉醇分子共价连接到一个肽，该肽靶向LRP-1受体穿过BCB和BBB，进入肿瘤细胞，在那里紫杉醇被劈开以发挥其抗肿瘤活性。ANG1005此前在一项2期研究中显示，可将乳腺癌脑转移(BM) LC患者的生存期延长至8个月。试验设计:这是一项开放标签、多中心的3期随机研究，旨在评估ANG1005在her2阴性乳腺癌新诊断为LC和既往治疗过BM的患者中的疗效，并与医师最佳选择(PBC)进行比较。150名患者将以1:1的比例随机分配，接受ANG1005实验治疗或研究者指定的PBC对照治疗。ANG1005将通过静脉(IV)输注给药，起始剂量为每3周600 mg/m2。允许的PBC治疗包括卡培他滨、伊瑞布林或大剂量静脉注射甲氨蝶呤。中枢神经系统疾病(LC和BM)将在筛查时进行评估，每6周根据LANO和RANO-BM标准通过MRI、CSF细胞学和神经学评估。颅外疾病将在筛查时和每6-12周根据RECIST进行CT扫描评估。所有患者将从最后一次给药之日起每6-8周随访一次，直至死亡、失去随访或同意退出。资格标准:符合条件的患者为her2阴性乳腺癌的成年人(≥18岁)，新诊断的LC和既往治疗过的BM病史。患者必须神经系统稳定，血液计数、器官和骨髓功能正常，ECOG评分≤2级。先前接受ANG1005治疗或已知对紫杉醇或其成分过敏的患者被排除在外。具体目标:主要终点是操作系统。次要终点包括CNS (LC和BM)无进展生存期和临床获益率，6个月和12个月的OS率，LC反应率和反应持续时间，三阴性患者的OS和安全性。统计学方法:本研究旨在检验所有患者ANG1005与PBC的OS改善假设(HR=0.58，双侧检验，总1型误差为5%)。当两组共达到55例死亡事件时，将进行OS的中期分析(使用O9Brien Fleming边界表示疗效，固定HR=1表示无效)。研究累积:目标累积为150例患者。该研究目前计划于2018年秋季开始。Kumthekar P, Lawrence B, Iordanova V, Ibrahim N, Mazanet R. ANG1005在瘦脑膜病(angle)试验中的应用:一项随机、开放标签、3期研究:ANG1005与医师的最佳选择在her2阴性乳腺癌新诊断的瘦脑膜癌和既往脑转移患者中的比较[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志2019;79(4增刊):OT1-06-01。
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Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT2-07-04
G. Bhat, D. Potter, J. Bharadwaj, N. Khan, L. Shabazz, J. Tache, Zandong Yang
Background:Poziotinib represents a new class of irreversible quinazoline inhibitors of ErbB receptor tyrosine kinases that inhibit the proliferation of tumor cells in culture and in vivo by inhibiting HER-1 (EGFR), HER-2, HER-4. ErbB signaling plays important roles in the progression of HER2+ breast cancer. Poziotinib has promising clinical activity in breast cancer, and other solid tumors including lung, gastric, and colorectal cancers. Study SPI-POZ-101, is being conducted to evaluate the safety and efficacy of the combination of daily poziotinib and T-DM1, HER2 antibody-drug-conjugate every three weeks in patients with HER2+ advanced or metastatic breast cancer. Trial Objectives and Design: The primary objectives of the study are to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of daily poziotinib plus T-DM1 (every 3 weeks) in women with advanced or metastatic HER2 positive breast cancer; and to evaluate the Objective Response Rate (ORR) in these patients. The secondary objectives include disease control rate (DCR), progression-free-survival (PFS), safety and pharmacokinetics at the MTD/MAD dose level of poziotinib plus T-DM1. In Part 1, the dose of poziotinib plus standard dose of T-DM1 (3.6 mg/kg IV) on Day 1 of each cycle will be determined using a “3+3” design with up to 3 escalating dose levels, 8, 10 and 12 mg with no DLT or to de-escalate to 6 mg with DLT observed in Cycle 1. Patients in current dose cohort, if not discontinued, will continue treatment until discontinuation of therapy. In Part 2 of the study, approximately 10 patients will be treated at the MTD/MAD to confirm dose for safety of the combination and to evaluate preliminary efficacy. Eligibility Criteria: The study will enroll female patients between 18 and 90 years with confirmed HER2 overexpression or gene-amplified tumor via immunohistochemistry [IHC] with IHC 3+ or IHC 2+ with confirmatory fluorescence in situ hybridization [FISH]+ or [ISH]+ and must have had at least 2 lines of anti-HER2 directed therapies either in the metastatic or early-stage disease setting. Patients must have adequate hematologic, hepatic, cardiac and renal functions and have at least one measurable lesion per RECIST 1.1 criteria. Exclusion criteria includes unstable CNS metastases or seizure disorder; anticancer chemotherapy, TKIs, biologics, immunotherapy, radiotherapy, or investigational treatment within 15 days; ≥ Grade 2 adverse events; known hypersensitivity to receptor tyrosine kinase inhibitors or any of the components of poziotinib tablets or T-DM1 IV solution. Statistical Methods: Part 1 of the study will enroll 3 to 6 patients at each dose using 3+3 design. Part 2 will enroll 10 patients at the MTD/MAD. The efficacy analysis will be conducted using the Evaluable Population based on RECIST 1.1. The Clopper-Pearson 95% confidence interval will be estimated using exact method based on binomial distribution. Target Accrual:Part 1: 6-18 patients Part 2: 10 pa
背景:Poziotinib是一类新的ErbB受体酪氨酸激酶不可逆喹唑啉类抑制剂，通过抑制HER-1 (EGFR)、HER-2、HER-4，在培养和体内抑制肿瘤细胞的增殖。ErbB信号在HER2+乳腺癌的进展中起重要作用。Poziotinib在乳腺癌和其他实体肿瘤(包括肺癌、胃癌和结直肠癌)中具有良好的临床活性。SPI-POZ-101研究正在进行中，目的是评估每日poziotinib和T-DM1 (HER2抗体-药物偶联物)联合治疗HER2阳性晚期或转移性乳腺癌患者的安全性和有效性。试验目标和设计:该研究的主要目标是确定晚期或转移性HER2阳性乳腺癌妇女每日poziotinib加T-DM1(每3周)的最大耐受剂量(MTD)或最大给药剂量(MAD);评估患者的客观缓解率(ORR)。次要目标包括poziotinib + T-DM1在MTD/MAD剂量水平下的疾病控制率(DCR)、无进展生存期(PFS)、安全性和药代动力学。在第1部分中，每个周期第1天，poziotinib加标准剂量T-DM1 (3.6 mg/kg IV)的剂量将使用“3+3”设计确定，最多有3个递增剂量水平，8,10和12mg无DLT或在第1周期中观察到的DLT降至6mg。当前剂量组的患者，如果未停药，将继续治疗直至停药。在研究的第2部分中，大约10名患者将接受MTD/MAD治疗，以确认联合用药的剂量和安全性，并评估初步疗效。资格标准:该研究将招募年龄在18至90岁之间的女性患者，通过免疫组化(IHC)证实HER2过表达或基因扩增肿瘤，IHC 3+或IHC 2+，验证性荧光原位杂交(FISH) +或[ISH]+，并且必须在转移性或早期疾病环境中接受至少2种抗HER2定向治疗。患者必须具有足够的血液学、肝脏、心脏和肾脏功能，并且根据RECIST 1.1标准至少有一个可测量的病变。排除标准包括不稳定的中枢神经系统转移或癫痫发作障碍;15天内接受抗癌化疗、TKIs、生物制剂、免疫治疗、放疗或研究性治疗;≥2级不良事件;已知对受体酪氨酸激酶抑制剂或任何波齐替尼片或T-DM1 IV溶液的成分过敏。统计学方法:第1部分采用3+3设计，每个剂量入组3 - 6例患者。第2部分将在MTD/MAD招募10名患者。使用基于RECIST 1.1的可评估人群进行疗效分析。采用基于二项分布的精确方法估计Clopper-Pearson 95%置信区间。目标应计:第一部分:6-18名患者第二部分:10名患者ClinicalTrials.gov标识码:NCT03429101联系信息:Spectrum Pharmaceuticals。SPI-POZ-101@sppirx.com Poziotinib目前处于临床研究阶段，尚未被批准用于乳腺癌。引用本文:Bhat G, Potter D, Bharadwaj J, Khan N, Shabazz L, Tache J, Yang Z. poziotinib联合T-DM1治疗晚期或转移性her2阳性乳腺癌的1b期研究[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志，2019;79(4增刊):OT2-07-04。
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Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT1-03-02
V. Massard, L. Uwer, J. Salleron, M. Deblock, A. Kieffer, M. Ríos, P. Gilson, A. Lesur, A. Harlé, J. Merlin
Activating ESR1 mutations have recently been reported as a key mechanism leading to Aromatase Inhibitor (AI) resistance. ESR1 mutations occur rarely in primary breast cancers. However, in large retrospective studies, ESR1 mutations occurred in up to 39% of Estrogen-Receptor(ER)-positive metastatic breast cancer resistant to AI. Numerous hotspot mutations have been identified, most of them affecting the ligand-binding domain (LBD) and leading to ligand-independent activation of the ER and to resistance to AI. Phosphatidylinositol 3-kinase (PI3K)/AKT pathway is involved in key Cellular Mechanisms and mutations in PIK3CA and AKT1 are frequently reported in breast cancer. In this study, we propose to use a capture-based Next Generation Sequencing (NGS) assay and to use the barcoding and polishing features in our analysis pipeline. This assay will be able to detect all mutations on AKT1 , PIK3CA , ESR1 and other genes on circulating tumor DNA (ctDNA) extracted from blood samples of patients with breast cancer. We consider that this exon-screening strategy is relevant according to the recent knowledge. We plan to prospectively include women with advanced breast cancer about to begin standard-of-care first line endocrine therapy (ET). Patients will be required to have histologically confirmed ER-positive, HER2-negative breast cancer and documented loco-regionally advanced or metastatic disease, not amenable to surgery or radiation with curative intent. Patients with endocrine sensitive disease (no prior ET or relapse more than 12 months after completing adjuvant ET) as well as patients with endocrine resistant disease (relapse while on adjuvant ET or within 12 months of completing adjuvant ET) will be enrolled. ET can be prescribed alone or in combination with a targeted therapy. Nevertheless, we will recruit at least 25% of patients with exclusive ET in the endocrine sensitive group. Peripheral-blood samples, for analysis of ctDNA, will be obtained from participating patients at pre-specified time points: at start of ET to determine the baseline mutational status of ESR1 , PIK3CA , AKT1 and other genes included in a panel of genes of interest in solid tumors, and then, at evaluation of response to therapy until disease progression or end of study. Patients will be followed for 36 months or until disease progression. Determination of progression will be done per local investigator. The primary objective is to describe the prevalence of activating ESR1 mutations affecting the LBD, using NGS, from the start of ET to progression or end of study. Secondary objectives include to describe the prevalence of ESR1 mutations affecting other domains, the prevalence of ESR1 mutations in patients with and without endocrine resistance at enrolment and the prevalence of PIK3CA and AKT1 mutations, to demonstrate that ESR1 , PIK3CA and AKT1 mutations whatever their times of onset are predictors of progression free survival. As of June 2018, 8 sites were opened to recrui
最近有报道称，激活ESR1突变是导致芳香酶抑制剂(AI)耐药的关键机制。ESR1突变在原发性乳腺癌中很少发生。然而，在大型回顾性研究中，ESR1突变发生在高达39%的雌激素受体(ER)阳性转移性乳腺癌中。已经发现了许多热点突变，其中大多数影响配体结合域(LBD)，导致内质网不依赖于配体的激活和对AI的抗性。磷脂酰肌醇3-激酶(PI3K)/AKT通路参与关键的细胞机制，PIK3CA和AKT1突变在乳腺癌中经常被报道。在这项研究中，我们建议使用基于捕获的下一代测序(NGS)分析，并在我们的分析管道中使用条形码和抛光功能。该检测将能够检测从乳腺癌患者血液样本中提取的循环肿瘤DNA (ctDNA)上的AKT1、PIK3CA、ESR1和其他基因的所有突变。根据最近的知识，我们认为这种外显子筛选策略是相关的。我们计划前瞻性地纳入即将开始标准护理一线内分泌治疗(ET)的晚期乳腺癌妇女。患者需要组织学证实为er阳性，her2阴性的乳腺癌，并有局部区域晚期或转移性疾病，不适合手术或放疗治疗。内分泌敏感性疾病患者(既往无ET或完成辅助ET后12个月以上复发)以及内分泌抵抗性疾病患者(在辅助ET治疗期间或完成辅助ET治疗后12个月内复发)将被纳入研究对象。ET可以单独使用，也可以与靶向治疗联合使用。然而，我们将在内分泌敏感组中招募至少25%的排他性ET患者。用于ctDNA分析的外周血样本将在预先指定的时间点从参与研究的患者中获得:在ET开始时确定ESR1、PIK3CA、AKT1和实体瘤感兴趣基因组中其他基因的基线突变状态，然后在评估治疗反应时，直到疾病进展或研究结束。患者将被随访36个月或直到疾病进展。进展的确定将由当地调查员完成。主要目的是描述从ET开始到研究进展或研究结束，使用NGS来激活影响LBD的ESR1突变的患病率。次要目标包括描述影响其他结构域的ESR1突变的患病率，入组时有无内分泌抵抗的患者中ESR1突变的患病率以及PIK3CA和AKT1突变的患病率，以证明ESR1, PIK3CA和AKT1突变无论其发病时间如何都是无进展生存的预测因子。截至2018年6月，共有8个站点开放招聘，其中包括18名员工;目标入学人数为146人。该试验得到了阿斯利康公司的支持。引用格式:Massard V, Uwer L, Salleron J, Deblock M, Kieffer A, Rios M, Gilson P, Lesur A, Harle A, Merlin JL。CICLADES:在接受内分泌治疗的晚期乳腺癌患者的现实随访中监测ESR1、PIK3CA和AKT1 ctDNA突变[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志，2019;79(4增刊):01-03-02。
{"title":"Abstract OT1-03-02: CICLADES: Monitoring ofESR1,PIK3CAandAKT1ctDNA mutations during real-life follow-up of patients with advanced breast cancer treated with endocrine therapy","authors":"V. Massard, L. Uwer, J. Salleron, M. Deblock, A. Kieffer, M. Ríos, P. Gilson, A. Lesur, A. Harlé, J. Merlin","doi":"10.1158/1538-7445.SABCS18-OT1-03-02","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT1-03-02","url":null,"abstract":"Activating ESR1 mutations have recently been reported as a key mechanism leading to Aromatase Inhibitor (AI) resistance. ESR1 mutations occur rarely in primary breast cancers. However, in large retrospective studies, ESR1 mutations occurred in up to 39% of Estrogen-Receptor(ER)-positive metastatic breast cancer resistant to AI. Numerous hotspot mutations have been identified, most of them affecting the ligand-binding domain (LBD) and leading to ligand-independent activation of the ER and to resistance to AI. Phosphatidylinositol 3-kinase (PI3K)/AKT pathway is involved in key Cellular Mechanisms and mutations in PIK3CA and AKT1 are frequently reported in breast cancer. In this study, we propose to use a capture-based Next Generation Sequencing (NGS) assay and to use the barcoding and polishing features in our analysis pipeline. This assay will be able to detect all mutations on AKT1 , PIK3CA , ESR1 and other genes on circulating tumor DNA (ctDNA) extracted from blood samples of patients with breast cancer. We consider that this exon-screening strategy is relevant according to the recent knowledge. We plan to prospectively include women with advanced breast cancer about to begin standard-of-care first line endocrine therapy (ET). Patients will be required to have histologically confirmed ER-positive, HER2-negative breast cancer and documented loco-regionally advanced or metastatic disease, not amenable to surgery or radiation with curative intent. Patients with endocrine sensitive disease (no prior ET or relapse more than 12 months after completing adjuvant ET) as well as patients with endocrine resistant disease (relapse while on adjuvant ET or within 12 months of completing adjuvant ET) will be enrolled. ET can be prescribed alone or in combination with a targeted therapy. Nevertheless, we will recruit at least 25% of patients with exclusive ET in the endocrine sensitive group. Peripheral-blood samples, for analysis of ctDNA, will be obtained from participating patients at pre-specified time points: at start of ET to determine the baseline mutational status of ESR1 , PIK3CA , AKT1 and other genes included in a panel of genes of interest in solid tumors, and then, at evaluation of response to therapy until disease progression or end of study. Patients will be followed for 36 months or until disease progression. Determination of progression will be done per local investigator. The primary objective is to describe the prevalence of activating ESR1 mutations affecting the LBD, using NGS, from the start of ET to progression or end of study. Secondary objectives include to describe the prevalence of ESR1 mutations affecting other domains, the prevalence of ESR1 mutations in patients with and without endocrine resistance at enrolment and the prevalence of PIK3CA and AKT1 mutations, to demonstrate that ESR1 , PIK3CA and AKT1 mutations whatever their times of onset are predictors of progression free survival. As of June 2018, 8 sites were opened to recrui","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85210185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.sabcs18-ot1-12-01
K. Jerzak, D. Cescon, S. Chia, S. Bratman, M. Ennis, V. Stambolic, Martin C. Chang, R. Dowling, P. Goodwin
{"title":"Abstract OT1-12-01: Exploration of factors associated with imminent risk of late recurrence in hormone receptor positive breast cancer","authors":"K. Jerzak, D. Cescon, S. Chia, S. Bratman, M. Ennis, V. Stambolic, Martin C. Chang, R. Dowling, P. Goodwin","doi":"10.1158/1538-7445.sabcs18-ot1-12-01","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-ot1-12-01","url":null,"abstract":"","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"363 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76587747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT2-07-02
F. André, J. Shahidi, C. Lee, K. Wang, I. Krop
Background: There is no uniform standard of care for HER2-positive breast cancer (BC) after disease progression on ado-trastuzumab emtansine (T-DM1). DS-8201a is a novel HER2-targeted antibody-drug conjugate (ADC) with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a drug-to-antibody ratio of 7 to 8. It is designed with the goal of improving critical attributes of an ADC. In an ongoing phase 1 trial, DS-8201a showed promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed objective response rate [ORR] of 54.5%; April 2018 data cutoff; Iwata et al, ASCO 2018). Based on preliminary results from the phase 1 trial, DS-8201a received FDA breakthrough therapy and fast track designations for metastatic BC that progressed after prior treatment with T-DM1. The pivotal, phase 2 DESTINY-BREAST01 trial in this population with HER2-positive BC who received prior T-DM1 is ongoing (Baselga et al, ASCO 2018). Study Description: This multicenter, open-label, phase 3 trial will assess the efficacy and safety of DS-8201a in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC whose disease progressed on or after T-DM1 (NCT03523585, DESTINY-BREAST02). Approximately 600 subjects will be randomized (2:1) to DS-8201a or investigator9s choice of treatment (trastuzumab plus capecitabine or lapatinib plus capecitabine). Randomization is stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. DS-8201a (5.4 mg/kg) will be administered IV once every 3 weeks. Progression free survival (PFS) based on blinded, independent central review using RECIST v1.1 criteria is primary efficacy endpoint; overall survival (OS) is the key secondary endpoint. Other secondary efficacy endpoints are ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health-related quality of life will also be measured. The primary analysis for PFS will occur when approximately 372 PFS events have been observed; providing 90% power to detect a hazard ratio of 0.70 in PFS (a 43% improvement in median PFS from 3.3 months with investigator9s choice to 4.7 months with DS-8201a) with a 1-sided alpha of 0.025. An interim OS analysis is planned at the time of the PFS analysis. Final OS analysis will occur when approximately 428 OS events have been observed. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥1 dose of study treatment. The study will enroll subjects from approximately 160 sites including
背景:对于使用阿多曲妥珠单抗emtansine (T-DM1)治疗后病情进展的her2阳性乳腺癌(BC)，目前尚无统一的护理标准。DS-8201a是一种新型HER2靶向抗体-药物偶联物(ADC)，其人源化HER2抗体通过可切割的肽基连接物连接到拓扑异构酶I抑制剂有效载荷上，药物-抗体比为7:8。它的设计目标是提高ADC的关键属性。在一项正在进行的i期临床试验中，DS-8201a在先前接受过T-DM1治疗的her2阳性BC中显示出良好的抗肿瘤活性(证实的客观缓解率[ORR]为54.5%;2018年4月数据截止;Iwata et al, ASCO 2018)。基于i期试验的初步结果，DS-8201a获得了FDA的突破性治疗和快速通道指定，用于治疗先前使用T-DM1治疗后进展的转移性BC。在her2阳性BC患者既往接受过T-DM1治疗的关键2期试验DESTINY-BREAST01正在进行中(Baselga et al, ASCO 2018)。研究描述:这项多中心、开放标签、3期试验将评估DS-8201a在her2阳性(IHC 3+或IHC 2+/ISH+)患者中的疗效和安全性;不可切除和/或转移性BC，其疾病在T-DM1治疗或治疗后进展(NCT03523585, destiny - breast - 02)。大约600名受试者将随机(2:1)接受DS-8201a或研究者选择的治疗(曲妥珠单抗加卡培他滨或拉帕替尼加卡培他滨)。随机分组根据激素受体状态、既往帕妥珠单抗治疗和内脏疾病史分层。DS-8201a (5.4 mg/kg)将每3周静脉给药一次。采用RECIST v1.1标准的无进展生存期(PFS)是主要疗效终点;总生存期(OS)是关键的次要终点。其他次要疗效终点是ORR、反应持续时间、临床获益率和基于研究者评估的PFS。安全性评估包括严重和治疗中出现的不良事件、体格检查、生命体征和临床实验室参数。与健康有关的生活质量也将被衡量。当观察到大约372个PFS事件时，将进行PFS的初步分析;提供90%的能力检测PFS的风险比为0.70(将中位PFS从研究者选择的3.3个月提高到DS-8201a的4.7个月，提高43%)，单侧alpha为0.025。在PFS分析时，计划进行临时OS分析。最终的OS分析将在观察到大约428个OS事件时进行。初步分析后每3个月进行一次长期随访，直至死亡、撤回同意、失去随访或研究结束。疗效分析将包括所有随机受试者，安全性分析将包括所有接受≥1剂量研究治疗的随机受试者。该研究将从大约160个地点招募受试者，包括北美、南美、欧洲和亚洲。有关该试验的进一步信息，请联系法布里斯·安德烈FABRICE.ANDRE@gustaveroussy.fr或访问clinicaltrials.gov。引用本文:Andre F, Shahidi J, Lee C, Wang K, Krop IE。Trastuzumab deruxtecan (DS-8201a)与研究者对her2阳性、不可切除和/或转移性乳腺癌患者既往接受T-DM1治疗的治疗选择:一项随机的3期研究[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志，2019;79(4增刊):OT2-07-02。
{"title":"Abstract OT2-07-02: Trastuzumab deruxtecan (DS-8201a) vs investigator's choice of treatment in subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received T-DM1: A randomized, phase 3 study","authors":"F. André, J. Shahidi, C. Lee, K. Wang, I. Krop","doi":"10.1158/1538-7445.SABCS18-OT2-07-02","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT2-07-02","url":null,"abstract":"Background: There is no uniform standard of care for HER2-positive breast cancer (BC) after disease progression on ado-trastuzumab emtansine (T-DM1). DS-8201a is a novel HER2-targeted antibody-drug conjugate (ADC) with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a drug-to-antibody ratio of 7 to 8. It is designed with the goal of improving critical attributes of an ADC. In an ongoing phase 1 trial, DS-8201a showed promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed objective response rate [ORR] of 54.5%; April 2018 data cutoff; Iwata et al, ASCO 2018). Based on preliminary results from the phase 1 trial, DS-8201a received FDA breakthrough therapy and fast track designations for metastatic BC that progressed after prior treatment with T-DM1. The pivotal, phase 2 DESTINY-BREAST01 trial in this population with HER2-positive BC who received prior T-DM1 is ongoing (Baselga et al, ASCO 2018). Study Description: This multicenter, open-label, phase 3 trial will assess the efficacy and safety of DS-8201a in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC whose disease progressed on or after T-DM1 (NCT03523585, DESTINY-BREAST02). Approximately 600 subjects will be randomized (2:1) to DS-8201a or investigator9s choice of treatment (trastuzumab plus capecitabine or lapatinib plus capecitabine). Randomization is stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. DS-8201a (5.4 mg/kg) will be administered IV once every 3 weeks. Progression free survival (PFS) based on blinded, independent central review using RECIST v1.1 criteria is primary efficacy endpoint; overall survival (OS) is the key secondary endpoint. Other secondary efficacy endpoints are ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health-related quality of life will also be measured. The primary analysis for PFS will occur when approximately 372 PFS events have been observed; providing 90% power to detect a hazard ratio of 0.70 in PFS (a 43% improvement in median PFS from 3.3 months with investigator9s choice to 4.7 months with DS-8201a) with a 1-sided alpha of 0.025. An interim OS analysis is planned at the time of the PFS analysis. Final OS analysis will occur when approximately 428 OS events have been observed. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥1 dose of study treatment. The study will enroll subjects from approximately 160 sites including","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"37 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75730651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT3-05-03
S. Domchek, S. Postel-Vinay, S. Im, Y. Park, J. Delord, A. Italiano, J. Alexandre, B. You, S. Bastian, M. Krebs, S. Waqar, M. Lanasa, H. Angell, M. Tang, C. Gresty, L. Opincar, P. Herbolsheimer, B. Kaufman
Background: Olaparib (Lynparza®) is a PARP inhibitor that alters the repair of single-strand DNA breaks. Durvalumab (Imfinzi®) is a monoclonal antibody against programmed cell death ligand 1 (anti-PD-L1) that promotes antitumor immune responses. MEDIOLA (NCT02734004) is a Ph I/II open-label, multicenter study enrolling patients (pts) across several tumor types (small-cell lung cancer, gastric cancer, germline BRCA-mutated [gBRCAm] BC, or platinum sensitive relapsed gBRCAm ovarian cancer). 34 pts with gBRCAm BC received olaparib 300 mg po bid for a 4-wk run-in, followed by olaparib 300 mg po bid and durvalumab 1.5 g IV q4 wks. Encouraging preliminary results support an expansion cohort in a BRCAm popn. Evidence suggests that mutations in other homologous recombination repair (HRR) genes may confer a BRCA-like phenotype, warranting an expansion of the study population beyond BRCAm. Inhibition of vascular endothelial growth factor (VEGF) has been reported to enhance the efficacy of chemotherapy in TNBC. In addition, VEGF inhibition potentiates PARP inhibitor activity, particularly in pts who do not carry BRCAm. Combinations of immune checkpoint inhibitors and bevacizumab, an anti-VEGF-A antibody, have shown promising results in other tumor types. Thus, MEDIOLA will additionally explore the efficacy and safety of olaparib + durvalumab in combination with bevacizumab in TNBC pts. Trial design: Pts in the additional MBC cohorts will receive combination olaparib and durvalumab with no olaparib run-in. Pts in the TNBC cohort will also receive concurrent bevacizumab 10 mg/kg q 2 wks. Tumor assessments will be performed at baseline and every 8 wks thereafter. Eligibility criteria: Pts with histologically confirmed, locally advanced or metastatic HER2-neg BC, who are PARP-inhibitor and immunotherapy naive. Prior anthracycline and/or taxane therapy in early or MBC is required. Prior platinum therapy is allowed, if there was no disease progression while receiving treatment and at least 12 mths has elapsed since the last dose. Pts will undergo BRCA and HRR mutation testing and will be assigned to a cohort based on their mutation status, as illustrated in Table 1. Specific aims: Cohort-specific primary efficacy endpoint targets were calculated aiming for superiority to standard of care treatment (Table 1). Other primary outcomes are safety and tolerability. Secondary endpoints are PK, DCR at 24 wks, objective response rate, duration of response, progression-free survival and overall survival. Exploratory endpoints include the analysis of tumor-infiltrating lymphocytes and PD-L1 expression. Statistical methods: The expansion cohort will have a single-stage statistical design. Bayesian predictive probability design will be used for the analysis of the HRRm and TNBC triplet cohorts. Accrual: Accrual targets are shown in Table 1. First subject will be enrolled in Nov 2018. Citation Format: Domchek SM, Postel-Vinay S, Im S-A, Hee Park Y, Delord J-P, Italiano A, Alex
背景:Olaparib (Lynparza®)是一种PARP抑制剂，可改变单链DNA断裂的修复。Durvalumab (Imfinzi®)是一种针对程序性细胞死亡配体1(抗pd - l1)的单克隆抗体，可促进抗肿瘤免疫反应。MEDIOLA (NCT02734004)是一项Ph I/II开放标签、多中心研究，纳入了几种肿瘤类型(小细胞肺癌、胃癌、种系brca突变[gBRCAm] BC或铂敏感复发gBRCAm卵巢癌)的患者。34名患有gBRCAm BC的患者接受奥拉帕尼300 mg /次，为期4周，随后接受奥拉帕尼300 mg /次和杜伐单抗1.5 g /次，每4周IV次。令人鼓舞的初步结果支持在BRCAm研究中扩大队列。有证据表明，其他同源重组修复(HRR)基因的突变可能赋予brca样表型，这就需要将研究人群扩大到BRCAm之外。据报道，抑制血管内皮生长因子(VEGF)可提高TNBC化疗的疗效。此外，VEGF抑制增强了PARP抑制剂的活性，特别是在不携带BRCAm的患者中。免疫检查点抑制剂和贝伐单抗(一种抗vegf - a抗体)的组合在其他肿瘤类型中显示出有希望的结果。因此，MEDIOLA将进一步探索奥拉帕尼+杜伐单抗联合贝伐单抗治疗TNBC患者的有效性和安全性。试验设计:额外的MBC队列中的患者将接受奥拉帕尼和杜伐单抗的联合治疗，没有奥拉帕尼的混入。TNBC队列的患者也将同时接受贝伐单抗10mg /kg / 2周。肿瘤评估将在基线和之后每8周进行一次。入选标准:组织学证实，局部晚期或转移性her2阴性BC, parp抑制剂和免疫治疗初治的患者。早期或MBC需要既往蒽环类药物和/或紫杉烷治疗。如果在接受治疗时没有疾病进展，并且距离上次给药至少12个月，则允许先前的铂治疗。患者将接受BRCA和HRR突变检测，并根据其突变状态分配到一个队列，如表1所示。特定目的:计算队列特定的主要疗效终点目标，旨在优于标准护理治疗(表1)。其他主要结局是安全性和耐受性。次要终点是PK、24周时DCR、客观缓解率、缓解持续时间、无进展生存期和总生存期。探索性终点包括肿瘤浸润淋巴细胞和PD-L1表达的分析。统计方法:扩展队列将采用单阶段统计设计。贝叶斯预测概率设计将用于HRRm和TNBC三联体队列的分析。应计目标:应计目标如表1所示。第一名受试者将于2018年11月入学。引用格式:Domchek SM, Postel-Vinay S, Im S-A, Hee Park Y, Delord J-P, Italiano A, Alexandre J, You B, Bastian S, Krebs MG, Waqar S, Lanasa M, Angell HK, Tang M, Gresty C, Opincar L, Herbolsheimer P, Kaufman B. MEDIOLA:奥拉帕尼(PARP抑制剂)和杜valumab(抗pd - l1抗体)的开放标签，I/II期basket研究。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志，2019;79(4增刊):OT3-05-03。
{"title":"Abstract OT3-05-03: MEDIOLA: An open-label, phase I/II basket study of olaparib (PARP inhibitor) and durvalumab (anti-PD-L1 antibody)–Additional breast cancer cohorts","authors":"S. Domchek, S. Postel-Vinay, S. Im, Y. Park, J. Delord, A. Italiano, J. Alexandre, B. You, S. Bastian, M. Krebs, S. Waqar, M. Lanasa, H. Angell, M. Tang, C. Gresty, L. Opincar, P. Herbolsheimer, B. Kaufman","doi":"10.1158/1538-7445.SABCS18-OT3-05-03","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT3-05-03","url":null,"abstract":"Background: Olaparib (Lynparza®) is a PARP inhibitor that alters the repair of single-strand DNA breaks. Durvalumab (Imfinzi®) is a monoclonal antibody against programmed cell death ligand 1 (anti-PD-L1) that promotes antitumor immune responses. MEDIOLA (NCT02734004) is a Ph I/II open-label, multicenter study enrolling patients (pts) across several tumor types (small-cell lung cancer, gastric cancer, germline BRCA-mutated [gBRCAm] BC, or platinum sensitive relapsed gBRCAm ovarian cancer). 34 pts with gBRCAm BC received olaparib 300 mg po bid for a 4-wk run-in, followed by olaparib 300 mg po bid and durvalumab 1.5 g IV q4 wks. Encouraging preliminary results support an expansion cohort in a BRCAm popn. Evidence suggests that mutations in other homologous recombination repair (HRR) genes may confer a BRCA-like phenotype, warranting an expansion of the study population beyond BRCAm. Inhibition of vascular endothelial growth factor (VEGF) has been reported to enhance the efficacy of chemotherapy in TNBC. In addition, VEGF inhibition potentiates PARP inhibitor activity, particularly in pts who do not carry BRCAm. Combinations of immune checkpoint inhibitors and bevacizumab, an anti-VEGF-A antibody, have shown promising results in other tumor types. Thus, MEDIOLA will additionally explore the efficacy and safety of olaparib + durvalumab in combination with bevacizumab in TNBC pts. Trial design: Pts in the additional MBC cohorts will receive combination olaparib and durvalumab with no olaparib run-in. Pts in the TNBC cohort will also receive concurrent bevacizumab 10 mg/kg q 2 wks. Tumor assessments will be performed at baseline and every 8 wks thereafter. Eligibility criteria: Pts with histologically confirmed, locally advanced or metastatic HER2-neg BC, who are PARP-inhibitor and immunotherapy naive. Prior anthracycline and/or taxane therapy in early or MBC is required. Prior platinum therapy is allowed, if there was no disease progression while receiving treatment and at least 12 mths has elapsed since the last dose. Pts will undergo BRCA and HRR mutation testing and will be assigned to a cohort based on their mutation status, as illustrated in Table 1. Specific aims: Cohort-specific primary efficacy endpoint targets were calculated aiming for superiority to standard of care treatment (Table 1). Other primary outcomes are safety and tolerability. Secondary endpoints are PK, DCR at 24 wks, objective response rate, duration of response, progression-free survival and overall survival. Exploratory endpoints include the analysis of tumor-infiltrating lymphocytes and PD-L1 expression. Statistical methods: The expansion cohort will have a single-stage statistical design. Bayesian predictive probability design will be used for the analysis of the HRRm and TNBC triplet cohorts. Accrual: Accrual targets are shown in Table 1. First subject will be enrolled in Nov 2018. Citation Format: Domchek SM, Postel-Vinay S, Im S-A, Hee Park Y, Delord J-P, Italiano A, Alex","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"PP 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84161154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT2-04-03
B. Chua, K. Gray, M. Krishnasamy, M. Regan, N. Zdenkowski, S. Loi, B. Mann, J. Forbes, N. Wilcken, A. Spillane, A. Martín, H. Badger, S. Jafari, A. Fong, C. Mavin, S. Corachan, A. Arahmani, J-L Martinez, P. Francis
{"title":"Abstract OT2-04-03: Examining personalized radiation therapy (EXPERT): A randomised phase III trial of adjuvant radiotherapy vs observation in patients with molecularly characterized luminal A breast cancer","authors":"B. Chua, K. Gray, M. Krishnasamy, M. Regan, N. Zdenkowski, S. Loi, B. Mann, J. Forbes, N. Wilcken, A. Spillane, A. Martín, H. Badger, S. Jafari, A. Fong, C. Mavin, S. Corachan, A. Arahmani, J-L Martinez, P. Francis","doi":"10.1158/1538-7445.SABCS18-OT2-04-03","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT2-04-03","url":null,"abstract":"","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85713486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT2-06-05
H. McArthur, E. Comen, S. Solomon, M. Rodine, C. Abaya, J. Leal, S. Patil, L. Norton
Background: Triple negative breast cancer (TNBC) is a biologically distinct subtype with high risk of early relapse, particularly for patients who do not achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC), with an event free survival of Methods: Eligible pts are aged ≥18 years, with ER, PR and HER2 negative operable tumors ≥ 1.0 cm after neoadjuvant taxane-based chemotherapy. Approximately 160 patients will be randomized to one of two arms: standard-of-care breast surgery (control arm) or ipi/nivo/cryo followed by standard-of-care breast surgery (intervention arm). Subjects randomized to the intervention arm will undergo percutaneous, ultrasound- (or MRI-) guided cryoablation with concurrent research core biopsy 7-10 days prior to surgery, and will receive a pre-operative infusion with ipilimumab at the dose of 1mg/kg IV, and nivolumab 240mg flat dose IV (1 to 5 days prior to cryoablation). After surgery, patients will receive three additional doses of nivolumab 240mg flat dose IV Q2 weeks. Adjuvant capecitabine is recommended for all participants and will be administered per standard-of-care at the treating physician9s discretion. Patients will be stratified by prior platinum administration, prior anthracycline administration, and clinical nodal status (positive versus negative) at enrollment. The primary endpoint is 3-year Event Free Survival (EFS). Secondary end points include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Citation Format: McArthur HL, Comen EA, Solomon S, Rodine M, DiLauro Abaya C, Leal JHS, Patil S, Norton L. A randomized phase II study of peri-operative ipilimumab, nivolumab and cryoablation versus standard peri-operative care in women with residual triple negative early stage/resectable breast cancer after standard-of-care neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-06-05.
背景:三阴性乳腺癌(TNBC)是一种生物学上独特的亚型，具有早期复发的高风险，特别是对于新辅助化疗(NAC)后未达到病理完全缓解(pCR)的患者，其无事件生存期为:方法:符合条件的患者年龄≥18岁，ER, PR和HER2阴性可手术肿瘤≥1.0 cm新辅助紫杉烷化疗后。大约160名患者将随机分为两组:标准乳房手术组(对照组)或ipi/nivo/cryo后进行标准乳房手术组(干预组)。随机分配到干预组的受试者将在手术前7-10天接受经皮、超声(或MRI)引导下的冷冻消融，同时进行研究核心活检，并接受伊匹单抗1mg/kg IV的术前输注，纳武单抗240mg平剂量IV(冷冻消融前1 - 5天)。手术后，患者将接受三次额外剂量的nivolumab 240mg平剂量IV，每2周。辅助卡培他滨被推荐用于所有参与者，并将在治疗医师的判断下按照标准护理进行管理。在入组时，患者将根据既往铂类药物、既往蒽环类药物和临床淋巴结状态(阳性与阴性)进行分层。主要终点是3年无事件生存期(EFS)。次要终点包括侵袭性无病生存期(IDFS)、远处无病生存期(DDFS)、总生存期(OS)和安全性。将对肿瘤和血清进行探索性相关研究，以表征干预的免疫影响，并探索疗效和毒性的预测因素。引用本文:marthur HL, Comen EA, Solomon S, Rodine M, DiLauro Abaya C, Leal JHS, Patil S, Norton L. ipilimumab、nivolumab联合冷冻消融与标准新辅助化疗后残留三阴性早期/可切除乳腺癌围手术期护理的随机II期研究[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志2019;79(4增刊):OT2-06-05。
{"title":"Abstract OT2-06-05: A randomized phase II study of peri-operative ipilimumab, nivolumab and cryoablation versus standard peri-operative care in women with residual triple negative early stage/resectable breast cancer after standard-of-care neoadjuvant chemotherapy","authors":"H. McArthur, E. Comen, S. Solomon, M. Rodine, C. Abaya, J. Leal, S. Patil, L. Norton","doi":"10.1158/1538-7445.SABCS18-OT2-06-05","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT2-06-05","url":null,"abstract":"Background: Triple negative breast cancer (TNBC) is a biologically distinct subtype with high risk of early relapse, particularly for patients who do not achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC), with an event free survival of Methods: Eligible pts are aged ≥18 years, with ER, PR and HER2 negative operable tumors ≥ 1.0 cm after neoadjuvant taxane-based chemotherapy. Approximately 160 patients will be randomized to one of two arms: standard-of-care breast surgery (control arm) or ipi/nivo/cryo followed by standard-of-care breast surgery (intervention arm). Subjects randomized to the intervention arm will undergo percutaneous, ultrasound- (or MRI-) guided cryoablation with concurrent research core biopsy 7-10 days prior to surgery, and will receive a pre-operative infusion with ipilimumab at the dose of 1mg/kg IV, and nivolumab 240mg flat dose IV (1 to 5 days prior to cryoablation). After surgery, patients will receive three additional doses of nivolumab 240mg flat dose IV Q2 weeks. Adjuvant capecitabine is recommended for all participants and will be administered per standard-of-care at the treating physician9s discretion. Patients will be stratified by prior platinum administration, prior anthracycline administration, and clinical nodal status (positive versus negative) at enrollment. The primary endpoint is 3-year Event Free Survival (EFS). Secondary end points include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Citation Format: McArthur HL, Comen EA, Solomon S, Rodine M, DiLauro Abaya C, Leal JHS, Patil S, Norton L. A randomized phase II study of peri-operative ipilimumab, nivolumab and cryoablation versus standard peri-operative care in women with residual triple negative early stage/resectable breast cancer after standard-of-care neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-06-05.","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81819253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT1-08-01
W. Zhi, Mc Leeolou, L. Piulson, Phang-lang Chen, C. Patterson, T. Paul, S. Patil, J. Mao, T. Bao
Background: CIPN is a common, painful, and debilitating side effect of many standard chemotherapy regimens. Patients with CIPN typically experience paresthesia (tingling, numbness), pain, and muscle weakness, and may exhibit significant functional decline and diminished quality of life. Our prior study showed that more than half of breast cancer survivors experience persistent CIPN up to a mean duration of 5.6 years and that this symptom is associated with a doubled fall risk. There is an urgent need to identify nonpharmacological approaches to reduce CIPN symptoms and improve cancer survivors9 functional outcomes. Yoga is a mind-body modality that includes stretching, flexibility, and balance training; however, little is known about its effects on symptoms and functional outcomes among cancer survivors with CIPN. Trial Design: We are conducting a two-arm pilot randomized usual care controlled trial in breast and gynecological cancer survivors at Memorial Sloan Kettering Cancer Center (MSK), New York, NY. Eligible subjects in the intervention arm receive one-hour Hatha Yoga classes taught twice weekly for eight weeks, and practice home-based yoga for a total of 12 weeks. Subjects in the wait list control (WLC) arm continue usual care for 12 weeks, followed by eight weeks of yoga classes and home-based yoga. Eligibility Criteria: 1) Patients with a primary diagnosis of stage I-III breast, ovarian, uterine, or endometrial cancer; 2) moderate to severe CIPN, defined by four or greater on a 0–10 Numeric Rating Scale (NRS); 3) completion of neurotoxic chemotherapy at least three months prior; 4) no changes in anti-neuropathy medications within three months of enrollment; and 5) an ECOG performance status of 0–2. Specific Aims: The primary endpoint is safety, feasibility, and NRS changes at eight weeks (end of treatment). The secondary endpoints include the Neuropathic Pain Scale (NPS) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) at eight, 12, and 20 weeks. Statistical Methods: We will accrue 40 patients to get 36 patients evaluable for the primary endpoint at eight weeks. Using an ANCOVA analysis with a sample size of 36, we will be able to detect an effect size of 00.58 standard deviations (SD) of NRS (moderate effect size) between yoga and WLC assuming a NRS correlation between pre- and post-yoga of 0.5 SD. If we assume a 10% dropout rate based on our recently completed trial, we will need to recruit 20 subjects per arm (total of 40) to fall within the precision noted in the sample size calculation. We recognize that the sample size calculation was based on detecting a moderate effect between yoga and WLC and may miss small but clinically meaningful effects that can be used to design a future trial that is sufficiently powered. Present accrual and target accrual: 40 participants. We have accrued 25 participants as of June 2018 and anticipate accrual completion by October 2018. Citation Format: Z
{"title":"Abstract OT1-08-01: A pilot randomized usual care controlled study of yoga for persistent chemotherapy-induced peripheral neuropathy (CIPN) in breast and gynecological cancer survivors","authors":"W. Zhi, Mc Leeolou, L. Piulson, Phang-lang Chen, C. Patterson, T. Paul, S. Patil, J. Mao, T. Bao","doi":"10.1158/1538-7445.SABCS18-OT1-08-01","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT1-08-01","url":null,"abstract":"Background: CIPN is a common, painful, and debilitating side effect of many standard chemotherapy regimens. Patients with CIPN typically experience paresthesia (tingling, numbness), pain, and muscle weakness, and may exhibit significant functional decline and diminished quality of life. Our prior study showed that more than half of breast cancer survivors experience persistent CIPN up to a mean duration of 5.6 years and that this symptom is associated with a doubled fall risk. There is an urgent need to identify nonpharmacological approaches to reduce CIPN symptoms and improve cancer survivors9 functional outcomes. Yoga is a mind-body modality that includes stretching, flexibility, and balance training; however, little is known about its effects on symptoms and functional outcomes among cancer survivors with CIPN. Trial Design: We are conducting a two-arm pilot randomized usual care controlled trial in breast and gynecological cancer survivors at Memorial Sloan Kettering Cancer Center (MSK), New York, NY. Eligible subjects in the intervention arm receive one-hour Hatha Yoga classes taught twice weekly for eight weeks, and practice home-based yoga for a total of 12 weeks. Subjects in the wait list control (WLC) arm continue usual care for 12 weeks, followed by eight weeks of yoga classes and home-based yoga. Eligibility Criteria: 1) Patients with a primary diagnosis of stage I-III breast, ovarian, uterine, or endometrial cancer; 2) moderate to severe CIPN, defined by four or greater on a 0–10 Numeric Rating Scale (NRS); 3) completion of neurotoxic chemotherapy at least three months prior; 4) no changes in anti-neuropathy medications within three months of enrollment; and 5) an ECOG performance status of 0–2. Specific Aims: The primary endpoint is safety, feasibility, and NRS changes at eight weeks (end of treatment). The secondary endpoints include the Neuropathic Pain Scale (NPS) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) at eight, 12, and 20 weeks. Statistical Methods: We will accrue 40 patients to get 36 patients evaluable for the primary endpoint at eight weeks. Using an ANCOVA analysis with a sample size of 36, we will be able to detect an effect size of 00.58 standard deviations (SD) of NRS (moderate effect size) between yoga and WLC assuming a NRS correlation between pre- and post-yoga of 0.5 SD. If we assume a 10% dropout rate based on our recently completed trial, we will need to recruit 20 subjects per arm (total of 40) to fall within the precision noted in the sample size calculation. We recognize that the sample size calculation was based on detecting a moderate effect between yoga and WLC and may miss small but clinically meaningful effects that can be used to design a future trial that is sufficiently powered. Present accrual and target accrual: 40 participants. We have accrued 25 participants as of June 2018 and anticipate accrual completion by October 2018. Citation Format: Z","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"319 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80186187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT1-12-04
M. Laurentiis, G. Arpino, G. Bianchini, L. Malorni, D. Castelletti, R. Vecchi, D. Grasso
Background: characterizing the molecular features associated with prolonged benefit from CDK 4/6 inhibitors in HR+ HER2- BC and the acquired genomic alterations following treatment progression remains an unmet need and is crucial for leveraging the efficacy of CDK4/6 inhibitors and for elucidating resistance mechanisms. Identifying pre-treatment or pharmacodynamic predictive markers of treatment benefit, as well as predictive markers of toxicity by correlating pharmacogenomics with adverse events, could help physicians to select patients who may benefit the most from these therapies and improve the clinical management. Trial design: this is an Italian, multicenter, open-label, single-arm trial (NCT03439046) enrolling approximately 350 HR+ HER2- aBC first line patients in 48 sites. Patients are treated with ribociclib and letrozole and eligibility criteria are similar to the MONALEESA-2 trial. Patients will be followed for safety and efficacy outcomes. An extensive prospective collection of biological samples at different time points will be performed as follow: whole blood and plasma at baseline, cycle 1-D15, cycle 2-D1, at first imaging evaluation, at cycle 24-D1, as well as upon progression of disease; newly obtained tissue biopsies at baseline and at progression; a buccal swab for pharmacogenetics at baseline. Efficacy and safety data will be collected for all patients. Aims: the primary objective of this study is to identify circulating tumor DNA (ctDNA) alterations at baseline, to describe their evolution during treatment and to evaluate the association with clinical outcome. An optimized Next Generation Sequencing approach for the detection of low abundance events in ctDNA will be adopted. Single nucleotide variants and copy number alterations in a customized panel of genes relevant for BC will be analyzed. Secondary objectives include the evaluation of: serum thymidine kinase 1 activity over time as blood marker of early response; ctDNA alterations across different patient profiles and clonal evolution of ctDNA alterations under treatment; ctDNA alterations at time of tumor progression; correlation between mutational status detected in ctDNA and matched tissue samples; features of tumor microenvironment before and after treatment; association of pharmacogenomics patterns with adverse events and clinical outcomes. Clinical efficacy and safety of ribociclib + letrozole will be correlated with all biological endpoints. Statistical methods: the study is descriptive in nature and no formal statistical testing is necessary or applicable. Sample size is aligned with other biomarker studies and is based on a feasibility analysis of the trial and relative timelines. Present accrual: The first study patient was screened in Feb 2018, as in June 2018, 126 patients have been screened and 78 patients have been enrolled. Citation Format: De Laurentiis M, Arpino G, Bianchini G, Malorni L, Castelletti D, De Vecchi R, Grasso D. A phase IIIb, open-label, loc
背景:表征与CDK4/6抑制剂在HR+ HER2- BC中长期获益相关的分子特征以及治疗进展后获得的基因组改变仍然是一个未满足的需求，对于利用CDK4/6抑制剂的疗效和阐明耐药机制至关重要。通过将药物基因组学与不良事件相关联，确定治疗前或治疗获益的药效学预测标记，以及毒性预测标记，可以帮助医生选择可能从这些治疗中获益最多的患者，并改善临床管理。试验设计:这是一项意大利多中心、开放标签、单臂试验(NCT03439046)，在48个地点招募了约350名HR+ HER2- aBC一线患者。患者接受核糖环尼和来曲唑治疗，资格标准与MONALEESA-2试验相似。将对患者进行安全性和有效性随访。在不同时间点进行广泛的前瞻性生物样本采集:基线时全血和血浆，周期1-D15，周期2-D1，首次成像评估，周期24-D1以及疾病进展时;基线和进展时新获得的组织活检;基线时进行口腔拭子药物遗传学检查。将收集所有患者的疗效和安全性数据。目的:本研究的主要目的是确定基线时循环肿瘤DNA (ctDNA)的改变，描述其在治疗期间的演变，并评估与临床结果的关系。将采用优化的下一代测序方法来检测ctDNA中的低丰度事件。将分析与BC相关的定制基因面板中的单核苷酸变异和拷贝数改变。次要目标包括:血清胸苷激酶1活性随时间的变化作为早期反应的血液标志物;不同患者的ctDNA改变和治疗下ctDNA改变的克隆进化肿瘤进展时ctDNA的改变;ctDNA中检测到的突变状态与匹配组织样本的相关性;治疗前后肿瘤微环境特征;药物基因组学模式与不良事件和临床结果的关联。核波西尼+来曲唑的临床疗效和安全性将与所有生物学终点相关。统计方法:本研究是描述性的，不需要或不适用正式的统计检验。样本量与其他生物标志物研究一致，并基于试验的可行性分析和相对时间表。目前累积:2018年2月，第一个研究患者进行了筛选，截至2018年6月，126名患者进行了筛选，78名患者入组。引用本文:De Laurentiis M, Arpino G, Bianchini G, Malorni L, Castelletti D, De Vecchi R, Grasso D. A期ib，开放标签，局部，多中心研究绝经后妇女激素受体阳性(HR+) her2阴性晚期乳腺癌一线治疗核素西尼和来曲唑(BioItaLEE)的分子特征。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志，2019;79(4增刊):1-12-04。
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