Pub Date : 2020-02-15DOI: 10.1158/1538-7445.sabcs19-ot2-03-04
A. Heeke, M. Pishvaian, Hongkun Wang, A. Cohen, J. Schlom, R. Donahue, C. Jochems, M. Gatti-Mays, P. Pohlmann, A. Tan, C. Isaacs, F. Lynce
Background: Patients with advanced breast cancer (ABC) have recently gained access to promising new therapies, including PARP inhibitors (PARPi) and immunotherapy. However, not all patients benefit from these approaches, with response rates highest in patients characterized by a particular biomarker (ie BRCA1/2 mutation or PD-L1 expression). Combination strategies may be more efficacious than single agents and may induce responses in otherwise non-responders. PARPi activate the STING pathway leading to T cell recruitment and stimulate antigen presentation via increased T cell cytotoxic activity, creating a tumor microenvironment that may be more susceptible to immunotherapy. A number of trials have assessed the antitumor efficacy of this combination, though the optimal drug scheduling and the impact of BRCA1/2 status on the effect of PARP inhibition on immunomodulation are unknown. In the TALAVE study, the PARPi talazoparib is combined with the PD-L1 inhibitor avelumab. Talazoparib is an oral small molecule selective inhibitor of PARP-1/2 with potent in vitro PARP trapping capacity. Avelumab is a human IgG1 anti-PD-L1 monoclonal antibody that prevents the interaction between PD-L1 and PD-1 and allows for an engagement of Fc-γ receptors on NK cells to induce tumor-directed ADCC in vitro. Trial design: This is an open-label, multi-institutional trial (NCT03964532) for patients with ABC. During the phase I portion, 6 patients are enrolled regardless of BRCA1/2 mutation status to assess safety of the combination. A maximum of 24 patients will be enrolled. Eligibility criteria include willingness to undergo serial biopsies and no previous exposure to PARPi or prior disease progression on anti-PD1 or anti-PDL1 therapy or within 6 months of use. Patients will be enrolled to two pre-defined cohorts: cohort 1 - BRCA1/2 mutant and HER2 negative ABC (pre-identified presence of somatic or germline BRCA1/2 deleterious mutation) and cohort 2 - BRCA1/2 wild type and TNBC (patients with previous somatic or germline testing for BRCA1/2 that did not reveal a deleterious mutation). Enrolled patients will receive a 4-week induction of talazoparib (1mg orally daily, D1-D28), followed by a combination of talazoparib and avelumab (800mg IV D1 and D15). To assess the efficacy and immunomodulatory effects of PARP inhibition induction followed by anti-PD-L1 therapy, patients will undergo serial tumor biopsies (baseline, post 4 weeks of talazoparib, post 4 weeks of talazoparib and avelumab and at progression for patients who clearly benefitted from therapy) to assess tumor infiltrating lymphocytes (TILs) and PD-L1 expression. Patients will also undergo serial blood sample collection to gauge the peripheral immunoscore by flow cytometry, including an assessment of the number of immune cells and their function. Specific aims: The primary objective is to evaluate the safety and tolerability of this combination. Secondary objectives includeassessment of anti-tumor efficacy of
背景:晚期乳腺癌(ABC)患者最近获得了有希望的新疗法，包括PARP抑制剂(PARPi)和免疫疗法。然而，并非所有患者都能从这些方法中获益，在具有特定生物标志物(即BRCA1/2突变或PD-L1表达)特征的患者中，反应率最高。联合策略可能比单一药物更有效，并可能在其他无应答者中引起应答。PARPi激活STING途径，导致T细胞募集，并通过增加T细胞的细胞毒性活性刺激抗原呈递，创造一个可能对免疫治疗更敏感的肿瘤微环境。许多试验已经评估了这种组合的抗肿瘤疗效，但最佳药物计划和BRCA1/2状态对PARP抑制免疫调节作用的影响尚不清楚。在TALAVE研究中，PARPi talazoparib与PD-L1抑制剂avelumab联合使用。Talazoparib是一种口服小分子选择性PARP-1/2抑制剂，具有有效的体外PARP捕获能力。Avelumab是一种人IgG1抗PD-L1单克隆抗体，可阻止PD-L1和PD-1之间的相互作用，并允许NK细胞上的Fc-γ受体在体外诱导肿瘤导向的ADCC。试验设计:这是一项针对ABC患者的开放标签、多机构试验(NCT03964532)。在I期部分，6名患者不论BRCA1/2突变状态均入组，以评估联合用药的安全性。最多将纳入24名患者。资格标准包括愿意接受系列活检，既往无PARPi暴露或抗pd1或抗pdl1治疗或使用6个月内的疾病进展。患者将被纳入两个预先定义的队列:队列1 - BRCA1/2突变和HER2阴性ABC(预先确定存在体细胞或种系BRCA1/2有害突变)和队列2 - BRCA1/2野生型和TNBC(先前进行BRCA1/2体细胞或种系检测但未显示有害突变的患者)。入组患者将接受为期4周的talazoparib诱导治疗(每日1mg口服，D1- d28)，随后是talazoparib和avelumab联合治疗(800mg IV D1和D15)。为了评估PARP抑制诱导后抗PD-L1治疗的疗效和免疫调节作用，患者将接受一系列肿瘤活检(基线，talazoparib治疗4周后，talazoparib和avelumab治疗4周后，以及明显受益于治疗的患者的进展)，以评估肿瘤浸润淋巴细胞(til)和PD-L1表达。患者还将接受一系列血液样本采集，通过流式细胞术测量外周免疫评分，包括免疫细胞数量及其功能的评估。具体目的:主要目的是评估该联合用药的安全性和耐受性。次要目标包括通过测量ORR、OS、PFS、DOR和DCR来评估联合治疗的抗肿瘤疗效，以及评估BRCA1/2突变、talazoparib单用和talazoparib联合avelumab对免疫调节的影响。统计方法:预计样本量为24例。样本大小是基于可行性分析。统计数据将主要是描述性的，毒性将根据等级制成表格。PFS和OS将使用Kaplan Meier方法进行估计。DCR和DOR将根据RECIST v1.1计算，并与历史结果进行描述性比较。Cox回归模型将评估免疫激活措施是否与ORR、PFS或OS相关。应计收益:患者应计收益于2019年4月开始。迄今为止，24例患者中有3例已入组I期研究(队列1 2例，队列2 1例)。引文格式:Arielle L Heeke, Michael Pishvaian, Hongkun Wang, Adam Cohen, Jeffrey Schlom, Renee Donahue, Caroline Jochems, Margaret Gatti-Mays, Paula Pohlmann, Antoinette Tan, Claudine Isaacs, Filipa Lynce。Talazoparib诱导后联合Talazoparib和Avelumab治疗晚期乳腺癌的试验:TALAVE研究[摘要]。摘自:2019年圣安东尼奥乳腺癌研讨会论文集;2019年12月10日至14日;费城(PA): AACR;中国癌症杂志，2020;31(增刊):02 -03-04。
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Pub Date : 2020-02-15DOI: 10.1158/1538-7445.sabcs19-ot3-07-01
J. Maar, R. Deckers, L. Bartels, T. Dalen, J. Gorp, P. Diest, A. Witkamp, H. Vaessen, Maria NicoleGerardineJohanna Aleida Braat, C. Moonen
Background: Over the past decades, breast cancer treatment has evolved from extensive disfiguring surgery to less invasive procedures. In patients with small localized tumors breast conserving therapy (BCT) has become the standard of care. However, surgery still involves risks associated with general anesthesia and complications such as bleeding, infection and suboptimal cosmetic results. Conversely, Magnetic Resonance-guided High intensity Focused Ultrasound (MR-HIFU) ablation of breast cancer is an entirely non-invasive procedure that can be performed under procedural sedation and analgesia (PSA). With MR-HIFU, a focused ultrasound beam penetrates through soft tissues and causes localized heating (55-70°C) of a target. Magnetic resonance imaging (MRI) is used for target-identification and real-time temperature-monitoring (MR thermometry). In a previous phase I study in ten breast cancer patients, tumors were deliberately partially ablated and safety and accuracy of a dedicated MR-HIFU breast system (Profound Medical) was shown.1,2 This system’s lateral sonication approach and wide aperture reduce the risk of heating heart, lungs and skin to a minimum.3 In the current study we aim to demonstrate that complete breast tumor ablation with MR-HIFU is feasible. Trial design: Single-arm phase II study in patients with primary breast cancer. We will use a dedicated MR-HIFU breast system (Profound Medical) to ablate breast tumors before BCT or mastectomy, in a treat-and-resect protocol. We will perform MRI before MR-HIFU, during the MR HIFU session and one week after to evaluate radiologic response. Primary endpoint is efficacy, assessed by percentages of necrotic and residual viable tumor. Secondary endpoint is safety, assessed by adverse events and cosmetic changes. Descriptive statistics will be used. Eligibility criteria Non-pregnant, non-lactating women ≥18 years of age, weighing histologically proven invasive breast cancer, cT1-2 N0-2 Mx, subtypes invasive ductal carcinoma or invasive carcinoma ‘not otherwise specified’ / ‘no special type’ a tumor in reach of the HIFU beams, diameter ≤ 3.0 cm and distance ≥1.5 cm to skin, nipple and pectoral wall WHO-Performance Score ≤2 a body size fitting in the MR bore and the ability to lie in prone position no prior treatment with neoadjuvant chemotherapy in the past 3 months no prior radiotherapy, thermal therapy or surgery in the targeted breast no contraindications to PSA, MRI or MRI contrast agents no conditions that may interfere with MR-HIFU such as a pacemaker, scar tissue, breast prosthesis or surgical clips no extensive intraductal components, determined on biopsy Additionally, patients may be excluded when the risk of adjuvant over- or undertreatment (due to performing Bloom and Richardson grading on the tumor biopsy) is considered too high. Target accrual 10 patients (present: 0, IRB approval obtained) Conclusion In this phase II trial we aim to show the feasibility of complete tumor ablation of br
背景:在过去的几十年里，乳腺癌的治疗已经从广泛的毁容手术发展到微创手术。对于小的局部肿瘤患者，保乳治疗(BCT)已成为标准的治疗方法。然而，手术仍然涉及全身麻醉和并发症的风险，如出血、感染和不理想的美容效果。相反，磁共振引导的高强度聚焦超声(MR-HIFU)消融乳腺癌是一种完全无创的手术，可以在程序性镇静和镇痛(PSA)下进行。在高磁共振成像中，聚焦的超声束穿透软组织，使目标局部加热(55-70°C)。磁共振成像(MRI)用于目标识别和实时温度监测(MR测温)。在之前的一项针对10名乳腺癌患者的I期研究中，肿瘤被故意部分消融，并显示了专用MR-HIFU乳房系统(Profound Medical)的安全性和准确性。该系统的横向超声方法和大孔径将心脏、肺和皮肤受热的风险降至最低在目前的研究中，我们的目的是证明用MR-HIFU完全切除乳房肿瘤是可行的。试验设计:针对原发性乳腺癌患者的单臂II期研究。我们将在BCT或乳房切除术前使用专用的MR-HIFU乳房系统(Profound Medical)消融乳房肿瘤，采用治疗-切除方案。我们将在MR-HIFU之前，MR-HIFU期间和一周后进行MRI检查以评估放射学反应。主要终点是疗效，通过坏死和残余存活肿瘤的百分比来评估。次要终点是安全性，通过不良事件和外观变化来评估。将使用描述性统计。非怀孕、非哺乳期女性，年龄≥18岁，衡量组织学证实的浸润性乳腺癌，cT1-2 N0-2 Mx，浸润性导管癌或浸润性癌“未特别说明”/“无特殊类型”肿瘤在HIFU照射范围内，直径≤3.0 cm，距离皮肤≥1.5 cm。乳头和胸壁WHO-Performance Score≤2符合MR孔的体型和俯卧位的能力在过去3个月内没有接受过新辅助化疗，没有靶向乳房的放疗、热治疗或手术，没有PSA、MRI或MRI造影剂的禁忌症，没有可能干扰MR- hifu的情况，如起搏器、疤痕组织、乳房假体或手术夹，没有广泛的导管内组件。此外，当辅助治疗过度或治疗不足的风险(由于对肿瘤活检进行Bloom和Richardson分级)被认为过高时，患者可能被排除在外。目标累计10例患者(目前:0例，已获得IRB批准)结论在这项II期试验中，我们旨在证明使用专用MR-HIFU乳房系统完全切除乳腺癌肿瘤的可行性。这种方法可以为选定的原发性乳腺癌患者提供一种非侵入性治疗方案。1 merkel 2016, Eur Radiol;[2] deckers 2015;3Merckel 2013，心血管介入治疗;感谢转化分子医学中心和乌得勒支UMC大学的财政支持。深度医疗提供非经济支持。联系方式:Josanne de Maar, j.s.demaar@umcutrecht.nl ClinicalTrials.gov标识号:NCT02407613引文格式:Josanne Sophia de Maar, Roel Deckers, Lambertus Wilhelmus Bartels, Thijs van Dalen, Joost van Gorp, Paul J van Diest, Arjen J Witkamp, h.h.b. Vaessen, Maria NicoleGerardineJohanna Aleida Braat, Chrit Moonen。磁共振引导下高强度聚焦超声治疗乳腺癌的疗效观察[摘要]。摘自:2019年圣安东尼奥乳腺癌研讨会论文集;2019年12月10日至14日;费城(PA): AACR;中国癌症杂志，2020;31(增刊1):1 - 4 - 1。
{"title":"Abstract OT3-07-01: Efficacy of magnetic resonance-guided high intensity focused ultrasound for the ablation of breast cancer","authors":"J. Maar, R. Deckers, L. Bartels, T. Dalen, J. Gorp, P. Diest, A. Witkamp, H. Vaessen, Maria NicoleGerardineJohanna Aleida Braat, C. Moonen","doi":"10.1158/1538-7445.sabcs19-ot3-07-01","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs19-ot3-07-01","url":null,"abstract":"Background: Over the past decades, breast cancer treatment has evolved from extensive disfiguring surgery to less invasive procedures. In patients with small localized tumors breast conserving therapy (BCT) has become the standard of care. However, surgery still involves risks associated with general anesthesia and complications such as bleeding, infection and suboptimal cosmetic results. Conversely, Magnetic Resonance-guided High intensity Focused Ultrasound (MR-HIFU) ablation of breast cancer is an entirely non-invasive procedure that can be performed under procedural sedation and analgesia (PSA). With MR-HIFU, a focused ultrasound beam penetrates through soft tissues and causes localized heating (55-70°C) of a target. Magnetic resonance imaging (MRI) is used for target-identification and real-time temperature-monitoring (MR thermometry). In a previous phase I study in ten breast cancer patients, tumors were deliberately partially ablated and safety and accuracy of a dedicated MR-HIFU breast system (Profound Medical) was shown.1,2 This system’s lateral sonication approach and wide aperture reduce the risk of heating heart, lungs and skin to a minimum.3 In the current study we aim to demonstrate that complete breast tumor ablation with MR-HIFU is feasible. Trial design: Single-arm phase II study in patients with primary breast cancer. We will use a dedicated MR-HIFU breast system (Profound Medical) to ablate breast tumors before BCT or mastectomy, in a treat-and-resect protocol. We will perform MRI before MR-HIFU, during the MR HIFU session and one week after to evaluate radiologic response. Primary endpoint is efficacy, assessed by percentages of necrotic and residual viable tumor. Secondary endpoint is safety, assessed by adverse events and cosmetic changes. Descriptive statistics will be used. Eligibility criteria Non-pregnant, non-lactating women ≥18 years of age, weighing histologically proven invasive breast cancer, cT1-2 N0-2 Mx, subtypes invasive ductal carcinoma or invasive carcinoma ‘not otherwise specified’ / ‘no special type’ a tumor in reach of the HIFU beams, diameter ≤ 3.0 cm and distance ≥1.5 cm to skin, nipple and pectoral wall WHO-Performance Score ≤2 a body size fitting in the MR bore and the ability to lie in prone position no prior treatment with neoadjuvant chemotherapy in the past 3 months no prior radiotherapy, thermal therapy or surgery in the targeted breast no contraindications to PSA, MRI or MRI contrast agents no conditions that may interfere with MR-HIFU such as a pacemaker, scar tissue, breast prosthesis or surgical clips no extensive intraductal components, determined on biopsy Additionally, patients may be excluded when the risk of adjuvant over- or undertreatment (due to performing Bloom and Richardson grading on the tumor biopsy) is considered too high. Target accrual 10 patients (present: 0, IRB approval obtained) Conclusion In this phase II trial we aim to show the feasibility of complete tumor ablation of br","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80148256","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 : 2020-02-14DOI: 10.1158/1538-7445.sabcs19-ot1-04-02
O. Pagani, A. Partridge, F. Peccatori, H. Azim, C. Shimizu, C. Saura, E. Warner, A. Sætersdal, J. Kroep, M. Ruggeri, R. Gelber
{"title":"Abstract OT1-04-02: POSITIVE: A study evaluating pregnancy, disease outcome and safety of interrupting endocrine therapy for premenopausal women with endocrine responsive breast cancer who desire pregnancy (IBCSG 48-14/big 8-13)","authors":"O. Pagani, A. Partridge, F. Peccatori, H. Azim, C. Shimizu, C. Saura, E. Warner, A. Sætersdal, J. Kroep, M. Ruggeri, R. Gelber","doi":"10.1158/1538-7445.sabcs19-ot1-04-02","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs19-ot1-04-02","url":null,"abstract":"","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"281 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76795427","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 : 2020-02-14DOI: 10.1158/1538-7445.sabcs19-ot2-04-04
H. McArthur, J. Leal, D. Page, C. Abaya, R. Basho, Lindsey Ristow, H. Coleman, S. Shiao, S. Knott, M. Mita, M. Tighiouart, A. Chung, F. Dadmanesh, P. McAndrew, S. Karlan, S. Verma, A. Giuliano
{"title":"Abstract OT2-04-04: Neoadjuvant HER2-targeted therapy +/- immunotherapy with pembrolizumab (neoHIP): An open label randomized phase 2 trial","authors":"H. McArthur, J. Leal, D. Page, C. Abaya, R. Basho, Lindsey Ristow, H. Coleman, S. Shiao, S. Knott, M. Mita, M. Tighiouart, A. Chung, F. Dadmanesh, P. McAndrew, S. Karlan, S. Verma, A. Giuliano","doi":"10.1158/1538-7445.sabcs19-ot2-04-04","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs19-ot2-04-04","url":null,"abstract":"","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73082206","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-OT2-07-03
S. Verma, J. Shahidi, C. Lee, K. Wang, J. Cortés
Background: Ado-trastuzumab emtansine (T-DM1), a HER2-targeted antibody drug conjugate (ADC), is approved for patients with HER2-positive metastatic breast cancer (BC) after disease progression on a trastuzumab-based regimen. Approval of T-DM1 was based on the EMILIA trial in which T-DM1 demonstrated an objective response rate (ORR) of 43.6%, a median progression-free survival (PFS) of 9.6 months, and an overall survival (OS) of 30.9 months (Verma S, et al. NEJM . 2012). DS-8201a is a novel HER2-targeted ADC with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a high drug-to-antibody ratio of 7 to 8. In an ongoing phase 1 trial, DS-8201a showed a manageable safety profile and promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed ORR of 54.5%; April 2018 data cutoff) (Iwata et al, ASCO 2018). 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 vs T-DM1 in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC previously treated with trastuzumab and a taxane (NCT03529110, DESTINY-BREAST03). Subjects who previously received a HER2-targeted ADC are excluded. Approximately 500 eligible subjects will be randomized (1:1) to receive DS-8201a (5.4 mg/kg) or T-DM1 (3.6 mg/kg) IV once every 3 weeks. Randomization will be stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. For subjects randomized to T-DM1, the treatment will be in accordance with the approved label. The primary efficacy endpoint is PFS based on blinded, independent central review using RECIST v1.1 criteria. Secondary efficacy endpoints include OS, 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 be performed when approximately 331 PFS events have been observed. This will provide 90% power to detect a hazard ratio of 0.70 for PFS with a 1-sided alpha of 0.025, assuming a median PFS with T-DM1 of 9.6 months and that PFS follows an exponential distribution. 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 150 sites851468 including in North America, Europe, and Asia. Citation Format: Verma S, Shahidi J, L
背景:ado -曲妥珠单抗emtansine (T-DM1)是一种her2靶向抗体药物偶联物(ADC)，被批准用于以曲妥珠单抗为基础的治疗方案治疗her2阳性转移性乳腺癌(BC)患者。T-DM1的批准是基于EMILIA试验，其中T-DM1的客观缓解率(ORR)为43.6%，中位无进展生存期(PFS)为9.6个月，总生存期(OS)为30.9个月(Verma S, et al.)。NEJM。2012)。DS-8201a是一种新型HER2靶向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，具有7比8的高药抗比。在一项正在进行的i期临床试验中，DS-8201a显示出可控的安全性，并且在先前接受过T-DM1治疗的her2阳性BC中具有良好的抗肿瘤活性(确认ORR为54.5%;2018年4月数据截止)(Iwata et al, ASCO 2018)。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与T-DM1在her2阳性(IHC 3+或IHC 2+/ISH+)患者中的疗效和安全性;既往接受曲妥珠单抗和紫杉烷治疗的不可切除和/或转移性BC (NCT03529110，归宿- breast - 03)。先前接受过her2靶向ADC的受试者被排除在外。大约500名符合条件的受试者将随机(1:1)接受每3周一次的DS-8201a (5.4 mg/kg)或T-DM1 (3.6 mg/kg) IV。随机分组将根据激素受体状态、既往帕妥珠单抗治疗和内脏疾病史进行分层。对于随机分配到T-DM1的受试者，治疗将按照批准的标签进行。主要疗效终点是基于采用RECIST v1.1标准的盲法独立中心评价的PFS。次要疗效终点包括OS、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。与健康相关的生活质量也将被衡量。当观察到大约331个PFS事件时，将执行PFS的主要分析。这将提供90%的能力来检测PFS的风险比为0.70，单侧alpha为0.025，假设T-DM1的中位PFS为9.6个月，并且PFS遵循指数分布。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150个地点招募受试者，包括北美、欧洲和亚洲。引用格式:Verma S, Shahidi J, Lee C, Wang K, Cortes J.曲妥珠单抗德鲁德替康(DS-8201a)与阿多曲妥珠单抗恩坦辛(T-DM1)治疗her2阳性、不可切除和/或转移性乳腺癌患者的3期随机研究[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):OT2-07-03。
{"title":"Abstract OT2-07-03: Trastuzumab deruxtecan (DS-8201a) vs ado-trastuzumab emtansine (T-DM1) for subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received trastuzumab and a taxane: A phase 3, randomized study","authors":"S. Verma, J. Shahidi, C. Lee, K. Wang, J. Cortés","doi":"10.1158/1538-7445.SABCS18-OT2-07-03","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT2-07-03","url":null,"abstract":"Background: Ado-trastuzumab emtansine (T-DM1), a HER2-targeted antibody drug conjugate (ADC), is approved for patients with HER2-positive metastatic breast cancer (BC) after disease progression on a trastuzumab-based regimen. Approval of T-DM1 was based on the EMILIA trial in which T-DM1 demonstrated an objective response rate (ORR) of 43.6%, a median progression-free survival (PFS) of 9.6 months, and an overall survival (OS) of 30.9 months (Verma S, et al. NEJM . 2012). DS-8201a is a novel HER2-targeted ADC with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a high drug-to-antibody ratio of 7 to 8. In an ongoing phase 1 trial, DS-8201a showed a manageable safety profile and promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed ORR of 54.5%; April 2018 data cutoff) (Iwata et al, ASCO 2018). 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 vs T-DM1 in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC previously treated with trastuzumab and a taxane (NCT03529110, DESTINY-BREAST03). Subjects who previously received a HER2-targeted ADC are excluded. Approximately 500 eligible subjects will be randomized (1:1) to receive DS-8201a (5.4 mg/kg) or T-DM1 (3.6 mg/kg) IV once every 3 weeks. Randomization will be stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. For subjects randomized to T-DM1, the treatment will be in accordance with the approved label. The primary efficacy endpoint is PFS based on blinded, independent central review using RECIST v1.1 criteria. Secondary efficacy endpoints include OS, 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 be performed when approximately 331 PFS events have been observed. This will provide 90% power to detect a hazard ratio of 0.70 for PFS with a 1-sided alpha of 0.025, assuming a median PFS with T-DM1 of 9.6 months and that PFS follows an exponential distribution. 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 150 sites851468 including in North America, Europe, and Asia. Citation Format: Verma S, Shahidi J, L","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75163771","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-OT3-06-01
A. Hassan, G. Gullo, S. O'Reilly, M. Ruiz-Borrego, S. Toomey, L. Grogan, O. Breathnach, P. Morris, J. Walshe, J. Crown, D. O'mahony, A. Falcón, K. Egan, A. Hernando, A. Teiserskiene, C. Kelly, L. Coate, B. Hennessy
Background: The phosphoinositide 3 kinase (PI3K) pathway is important in the oncogenic function of HER2. Aberrant activation of PI3K is implicated in resistance to trastuzumab and other HER2-targeted therapies and is frequent, with up to 22% of HER2 positive breast cancer having a PIK3CA mutation. Copanlisib is a pan-class 1 PI3K inhibitor administered i.v. with low nanomolar activity against both PI3Kα and PI3Kβ. Copanlisib has been shown to re-sensitise trastuzumab resistant cell lines to trastuzumab with synergism seen in some cell lines between copanlisib and HER2 targeted therapy. Trial design: This is a phase Ib open label, single arm adaptive, multi-centre trial of copanlisib in combination with T-DM1. Eligible patients will receive T-DM1 at 3.6mg/kg i.v. on day 1 of a 21-day cycle plus copanlisib. Copanlisib will be administered i.v. according to the dose escalation scheme (dose level 1 is 45mg on days 1 and 8, dose level 2 is 60mg on days 1 and 8, dose level 3 is 60mg on days 1, 8, and 15). Dose level -1 will be 45 mg on day 1 in case dose de-escalation is needed. We will enrol 3 to 6 patients per dose level. All patients in each level must have completed at least the first cycle of therapy before enrolment in the next dose level. Patients not completing the first cycle for a reason other than toxicity will be replaced. Dose escalation and determination of the Maximum Tolerated Dose (MTD) will be based on the occurrence of Dose Limiting Toxicities (DLT). Eligibility criteria: Eligible patients are those with unresectable locally advanced or metastatic HER2-positive BC who previously received trastuzumab and a taxane, separately or in combination. Participants must have adequate organ function and ECOG PS ≤ 2 Objectives: The primary objective is to determine the MTD for copanlisib in combination with T-DM1 in patients with pre-treated unresectable locally advanced or metastatic HER2-positive BC. Secondary objectives include evaluating the safety, efficacy and cardiotoxicity in patients treated with this regimen. Exploratory objectives include examining for predictive biomarkers in tumour tissue and blood or plasma and to examine molecular tumour adaptation to clinical trial therapy. Statistical methods : Patients will be accrued in cohorts of 3 patients according to a standard 3+3 algorithm, with dose escalation and determination of MTD based on the occurrence of DLT, using the usual threshold probability of 33%. The final dose level will be expanded to include a total of 6 additional patients (expansion cohort). Present accrual and target accrual: The trial will start accrual in October 2018. Maximum of 24 patients will be enrolled. Citation Format: Hassan A, Gullo G, O9Reilly S, Ruiz-Borrego M, Toomey S, Grogan L, Breathnach O, Morris PG, Walshe JM, Crown J, O9Mahony D, Falcon A, Egan K, Hernando A, Teiserskiene A, Kelly CM, Coate L, Hennessy BT. Phase Ib clinical trial of coPANlisib in combination with Trastuzumab emtansine (T-DM1) in
背景:磷酸肌肽3激酶(PI3K)通路在HER2的致癌功能中起重要作用。PI3K的异常激活与曲妥珠单抗和其他HER2靶向治疗的耐药有关，并且是常见的，高达22%的HER2阳性乳腺癌具有PIK3CA突变。Copanlisib是一种静脉给药的泛1类PI3K抑制剂，对PI3Kα和PI3Kβ具有低纳摩尔活性。Copanlisib已被证明可使曲妥珠单抗耐药细胞系对曲妥珠单抗再敏感，并在一些细胞系中发现Copanlisib和HER2靶向治疗之间的协同作用。试验设计:这是一项Ib期开放标签、单臂自适应、多中心的copanlisib联合T-DM1试验。符合条件的患者将在21天周期的第1天接受3.6mg/kg静脉注射T-DM1，并联合用药。Copanlisib将按照剂量递增方案静脉注射(剂量水平1为第1天和第8天45mg，剂量水平2为第1天和第8天60mg，剂量水平3为第1、8和第15天60mg)。剂量水平-1在第1天为45毫克，以防需要降低剂量。我们将在每个剂量水平入组3 - 6名患者。每个级别的所有患者在进入下一个剂量水平之前必须至少完成第一个治疗周期。由于毒性以外的原因不能完成第一个周期的患者将被替换。剂量递增和最大耐受剂量(MTD)的确定将基于剂量限制毒性(DLT)的发生。资格标准:合格的患者是那些先前单独或联合接受曲妥珠单抗和紫杉烷治疗的不可切除的局部晚期或转移性her2阳性BC患者。参与者必须有足够的器官功能和ECOG PS≤2目的:主要目的是确定copanlisib联合T-DM1治疗预先治疗的不可切除的局部晚期或转移性her2阳性BC患者的MTD。次要目标包括评估该方案治疗患者的安全性、有效性和心脏毒性。探索目标包括检查肿瘤组织和血液或血浆中的预测性生物标志物，以及检查分子肿瘤对临床试验治疗的适应性。统计方法:根据标准的3+3算法，将患者分组为3名患者，根据DLT的发生进行剂量递增和MTD的确定，使用通常的阈值概率为33%。最终剂量水平将扩大到包括总共6名额外患者(扩大队列)。当前应计和目标应计:试验于2018年10月开始应计。最多将纳入24名患者。引用格式:Hassan A, Gullo G, O9Reilly S, Ruiz-Borrego M, Toomey S, Grogan L, Breathnach O, Morris PG, Walshe JM, Crown J, O9Mahony D, Falcon A, Egan K, Hernando A, Teiserskiene A, Kelly CM, Coate L, Hennessy BT. coPANlisib联合曲妥单抗emtansine (T-DM1)治疗不可切除的局部晚期或转移性her2阳性乳腺癌(BC)的Ib期临床试验[J]。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):OT3-06-01。
{"title":"Abstract OT3-06-01: Phase Ib clinical trial of coPANlisib in combination with Trastuzumab emtansine (T-DM1) in pre-treated unresectable locally advanced or metastatic HER2-positive breAst cancer (BC) “PANTHERA”-CTRIAL-IE 17-13","authors":"A. Hassan, G. Gullo, S. O'Reilly, M. Ruiz-Borrego, S. Toomey, L. Grogan, O. Breathnach, P. Morris, J. Walshe, J. Crown, D. O'mahony, A. Falcón, K. Egan, A. Hernando, A. Teiserskiene, C. Kelly, L. Coate, B. Hennessy","doi":"10.1158/1538-7445.SABCS18-OT3-06-01","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT3-06-01","url":null,"abstract":"Background: The phosphoinositide 3 kinase (PI3K) pathway is important in the oncogenic function of HER2. Aberrant activation of PI3K is implicated in resistance to trastuzumab and other HER2-targeted therapies and is frequent, with up to 22% of HER2 positive breast cancer having a PIK3CA mutation. Copanlisib is a pan-class 1 PI3K inhibitor administered i.v. with low nanomolar activity against both PI3Kα and PI3Kβ. Copanlisib has been shown to re-sensitise trastuzumab resistant cell lines to trastuzumab with synergism seen in some cell lines between copanlisib and HER2 targeted therapy. Trial design: This is a phase Ib open label, single arm adaptive, multi-centre trial of copanlisib in combination with T-DM1. Eligible patients will receive T-DM1 at 3.6mg/kg i.v. on day 1 of a 21-day cycle plus copanlisib. Copanlisib will be administered i.v. according to the dose escalation scheme (dose level 1 is 45mg on days 1 and 8, dose level 2 is 60mg on days 1 and 8, dose level 3 is 60mg on days 1, 8, and 15). Dose level -1 will be 45 mg on day 1 in case dose de-escalation is needed. We will enrol 3 to 6 patients per dose level. All patients in each level must have completed at least the first cycle of therapy before enrolment in the next dose level. Patients not completing the first cycle for a reason other than toxicity will be replaced. Dose escalation and determination of the Maximum Tolerated Dose (MTD) will be based on the occurrence of Dose Limiting Toxicities (DLT). Eligibility criteria: Eligible patients are those with unresectable locally advanced or metastatic HER2-positive BC who previously received trastuzumab and a taxane, separately or in combination. Participants must have adequate organ function and ECOG PS ≤ 2 Objectives: The primary objective is to determine the MTD for copanlisib in combination with T-DM1 in patients with pre-treated unresectable locally advanced or metastatic HER2-positive BC. Secondary objectives include evaluating the safety, efficacy and cardiotoxicity in patients treated with this regimen. Exploratory objectives include examining for predictive biomarkers in tumour tissue and blood or plasma and to examine molecular tumour adaptation to clinical trial therapy. Statistical methods : Patients will be accrued in cohorts of 3 patients according to a standard 3+3 algorithm, with dose escalation and determination of MTD based on the occurrence of DLT, using the usual threshold probability of 33%. The final dose level will be expanded to include a total of 6 additional patients (expansion cohort). Present accrual and target accrual: The trial will start accrual in October 2018. Maximum of 24 patients will be enrolled. Citation Format: Hassan A, Gullo G, O9Reilly S, Ruiz-Borrego M, Toomey S, Grogan L, Breathnach O, Morris PG, Walshe JM, Crown J, O9Mahony D, Falcon A, Egan K, Hernando A, Teiserskiene A, Kelly CM, Coate L, Hennessy BT. Phase Ib clinical trial of coPANlisib in combination with Trastuzumab emtansine (T-DM1) in ","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81507615","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-OT3-03-03
J. Abraham, A. Vallier, W. Qian, A. Machin, L. Grybowicz, S. Thomas, M. Weiss, C. Harvey, K. McAdam, L. Hughes-Davies, A. Roberts, R. Roylance, E. Copson, K. Pinilla, A. Armstrong, E. Provenzano, M. Tischkowitz, E. McMurty, H. Earl
Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group share some phenotypic and molecular similarities with germline BRCA (gBRCA) tumours. In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (Olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Methods:Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians9 choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A total of 527 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy. Trial Progress: PARTNER has been recruiting in UK since 27th May 2016. IDSMC recommended to continue the trial without change after reviewing the Stage 1 safety data. The recruitment of stage 2 was completed in April 2018 and results to be reviewed by the IDSMC in early 2019. The trial is open and enrolling patients to national and international sites. Citation Format: Abraham J, Vallier A-L, Qian W, Machin A, Grybowicz L, Thomas S, Weiss M, Harvey C, McAdam K, Hughes-Davies L, Roberts A, Roylance R, Copson E, Pinilla K, Armstrong A, Provenzano E, Tischkowitz M, McMurty E, Earl H. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [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 OT3-03-03.
背景:三阴性乳腺癌(TNBC)是一种侵袭性和多样化的亚群，目前尚无特异性靶向治疗方法。基础TNBC亚群与种系BRCA (gBRCA)肿瘤具有一些表型和分子相似性。在gBRCA患者和潜在的其他同源重组缺陷患者中，这些已经受损的途径可能允许称为PARP抑制剂(奥拉帕尼)的药物更有效地起作用。目的:确定在基础TNBC和/或gBRCA乳腺癌的新辅助铂基化疗中加入奥拉帕尼是否安全并提高疗效(病理完全缓解(pCR))。方法:试验设计:新辅助紫杉醇和卡铂+/-奥拉帕尼的3期开放标签随机II/III期试验，随后临床医生选择蒽环类药物方案。第一阶段和第二阶段:随机分组(1:1:1)，对照组(卡铂AUC5每周3次/紫杉醇80mg/m2每周4个周期)或两个研究组中的一个，使用相同的化疗方案，但使用两种不同的奥拉帕尼150mg BD方案，持续12天。第3阶段:患者被随机(1:1)分配到对照组或第2阶段选择的研究组。阶段1:安全性;第二阶段:使用pCR率和奥拉帕尼完成率进行计划选择，采用“选择赢家”设计。第三阶段:pCR率。采用富集设计，总体显著性水平为0.05(α)，功率为80%。总共527名患者将被纳入研究，通过在铂基化疗中加入奥拉帕尼，检测到15%(所有患者)和20% (gBRCA患者)的绝对改善。试验进展:PARTNER于2016年5月27日开始在英国招聘。IDSMC建议在审查1期安全性数据后继续进行试验，不做任何改变。第二阶段的招募于2018年4月完成，结果将于2019年初由IDSMC审查。该试验是开放的，并在国内和国际站点招募患者。引用格式:Abraham J, Vallier A-L, Qian W, Machin A, Grybowicz L, Thomas S, Weiss M, Harvey C, McAdam K, Hughes-Davies L, Roberts A, Roylance R, Copson E, Pinilla K, Armstrong A, Provenzano E, Tischkowitz M, McMurty E, Earl H. PARTNER:随机，II/III期试验评估奥拉帕尼加用新辅助化疗治疗三阴性和/或种系BRCA突变乳腺癌患者的安全性和有效性。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):OT3-03-03。
{"title":"Abstract OT3-03-03: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients","authors":"J. Abraham, A. Vallier, W. Qian, A. Machin, L. Grybowicz, S. Thomas, M. Weiss, C. Harvey, K. McAdam, L. Hughes-Davies, A. Roberts, R. Roylance, E. Copson, K. Pinilla, A. Armstrong, E. Provenzano, M. Tischkowitz, E. McMurty, H. Earl","doi":"10.1158/1538-7445.SABCS18-OT3-03-03","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT3-03-03","url":null,"abstract":"Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group share some phenotypic and molecular similarities with germline BRCA (gBRCA) tumours. In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (Olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Methods:Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians9 choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A total of 527 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy. Trial Progress: PARTNER has been recruiting in UK since 27th May 2016. IDSMC recommended to continue the trial without change after reviewing the Stage 1 safety data. The recruitment of stage 2 was completed in April 2018 and results to be reviewed by the IDSMC in early 2019. The trial is open and enrolling patients to national and international sites. Citation Format: Abraham J, Vallier A-L, Qian W, Machin A, Grybowicz L, Thomas S, Weiss M, Harvey C, McAdam K, Hughes-Davies L, Roberts A, Roylance R, Copson E, Pinilla K, Armstrong A, Provenzano E, Tischkowitz M, McMurty E, Earl H. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [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 OT3-03-03.","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":"82524645","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-OT1-05-01
T. Millard, N. Wages, G. Petroni, C. Brenin, P. Dillon
Background: HDAC inhibitors (HDACi) upregulate thymidine phosphorylase resulting in enhanced conversion of capecitabine to active 5-fluorouracil and in synergistic anti-proliferative effects. HDACi9s down regulate thymidine synthase and may prevent resistance to fluoropyrimidines. Entinostat is a well-tolerated class I HDACi in phase III trials for metastatic breast cancer. Specific Aims: The primary objective is to determine the maximum tolerated dose combination (MTDC) of entinostat and capecitabine in participants with metastatic breast cancer. It is hypothesized that entinostat and capecitabine is a synergistic, safe, and tolerable combination. An expansion phase will assess the safety of the MTDC from Part A in participants with high risk breast cancer after neoadjuvant therapy. The expansion phase will generate a preliminary estimate of disease-free survival. Exploratory objectives include estimates of the association of volume of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) with the presence of residual disease and if it decreases following treatment with the combination of entinostat and capecitabine. Trial Design: The dose escalation phase (Part A) will accrue participants with metastatic breast cancer using an adaptive design to determine the MTDC. The starting doses will be entinostat 3mg po weekly and capecitabine 800mg/m2 po bid, 14 days on and 7 days off with 21 day cycles. Patients will be monitored for toxicity and adverse events. The MTDC is defined as the dose combination with DLT rate closest to the target DLT rate of 25%. The expansion phase (Part B) will accrue breast cancer participants with residual invasive disease after neoadjuvant therapy starting at the MTDC estimated in Part A. The adaptive modeling design will be used in Part B to establish the MTDC in this patient population. Participants will be treated with the MTDC for a total of 8 cycles. Blood samples will be obtained from all enrolled patients in the expansion phase prior to the start of adjuvant treatment with entinostat and capecitabine so that ctDNA and CTCs can be measured as correlative studies. Measurements will be repeated at the end of the eighth cycle. Eligibility Criteria: Part A: Dose Escalation Phase: Stage IV breast cancer patients; Receptor Status: hormone receptor positive or negative, triple negative patients; Age: 18 year and older Part B: Expansion Phase: Stage I-III high risk breast cancer patients; Completed at least four cycles of neoadjuvant taxane or anthracycline based chemotherapy; Residual invasive disease (ypT1a or greater) or known positive lymph nodes (ypN0(itc) or greater); Receptor Status: hormone receptor positive or negative, triple negative patients; Age: 18 years and older Statistical Methods: The trial is designed to determine the MTDC, defined by acceptable toxicity of the combination, for two study populations. A Bayesian adaptive design is being used to guide accrual decisions based on the occurrence of
背景:HDAC抑制剂(HDACi)上调胸苷磷酸化酶，导致卡培他滨向活性5-氟尿嘧啶的转化增强，并具有协同抗增殖作用。hdac9s下调胸腺嘧啶合成酶，可能防止对氟嘧啶的耐药性。在转移性乳腺癌的III期临床试验中，恩替诺他是一种耐受性良好的I类HDACi。具体目的:主要目的是确定转移性乳腺癌患者使用恩替司他和卡培他滨的最大耐受剂量组合(MTDC)。假设恩替司他和卡培他滨是一种协同、安全、耐受的组合。扩展阶段将评估来自A部分的MTDC在新辅助治疗后高风险乳腺癌患者中的安全性。扩展阶段将产生无病生存期的初步估计。探索性目标包括估计循环肿瘤DNA (ctDNA)和循环肿瘤细胞(CTCs)的体积与残留疾病的存在之间的关系，以及在恩替司他和卡培他滨联合治疗后是否会减少。试验设计:剂量递增阶段(A部分)将纳入转移性乳腺癌患者，采用适应性设计确定MTDC。起始剂量为依替他汀3mg /周，卡培他滨800mg/周，开药14天，停药7天，21天为一个周期。将监测患者的毒性和不良事件。MTDC定义为与DLT率最接近目标DLT率25%的剂量组合。扩展阶段(B部分)将积累在新辅助治疗后残留侵袭性疾病的乳腺癌参与者，从a部分估计的MTDC开始。自适应建模设计将在B部分使用，以建立该患者群体的MTDC。参与者将接受MTDC治疗，共8个周期。在开始用恩替司他和卡培他滨辅助治疗之前，将从所有入组患者的扩展期获得血液样本，以便ctDNA和ctc可以作为相关研究进行测量。测量将在第八周期结束时重复。入选标准:A部分:剂量递增阶段:IV期乳腺癌患者;受体状况:激素受体阳性或阴性，三阴性患者;年龄:18岁及以上B部分:扩展期:I-III期高危乳腺癌患者;完成至少四个周期的新辅助紫杉烷或蒽环类化疗;残留侵袭性疾病(ypT1a或更大)或已知阳性淋巴结(ypN0(itc)或更大);受体状况:激素受体阳性或阴性，三阴性患者;年龄:18岁及以上统计方法:该试验旨在确定两个研究人群的MTDC，由联合用药的可接受毒性定义。贝叶斯自适应设计用于指导基于dlt发生的应计决策，确定升级的最小随访期为3周。累计人数:最大目标累计人数为55人。预计每月1-2名参与者。联系方式:Trish Millard, MD tas9g@virginia.edu引文格式:Millard TA, Wages NA, Petroni GR, Brenin CM, Dillon PM。恩替司他联合卡培他滨治疗转移性及高危乳腺癌新辅助治疗的初步研究[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):01 -05-01。
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Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT2-06-04
D. Yardley, M. Abu-Khalaf, V. Boni, A. Brufsky, L. Emens, M. Gutierrez, S. Hurvitz, S. Im, S. Loi, McCune Sl, P. Schmid, C. O'Hear, X. Zhang, G. Vidal
Background: Cancer immunotherapy (CIT) has significantly improved overall survival across multiple tumor types, but only subsets of patients experience durable response with single-agent CIT. Combinations of CIT with targeted therapy or chemotherapy may be needed in order to target multiple cancer immune escape mechanisms simultaneously, thus providing personalized treatment options that extend clinical benefit to more patients. The MORPHEUS platform includes multiple phase Ib/II trials designed to identify early signals of safety and activity of CIT combinations. Using a randomized trial design, multiple CIT combination arms are compared with a single standard-of-care control arm. These trials have the flexibility to open new treatment arms with novel CIT combinations as they become available and to close arms that show minimal activity or unacceptable toxicity. Here we describe MORPHEUS trials in patients with metastatic or unresectable locally advanced hormone receptor–positive (HR+BC) or triple-negative breast cancer (TNBC), 2 patient populations in need of more treatment options. Trial design: MORPHEUS-HR+BC (NCT03280563) will enroll patients with metastatic or unresectable locally advanced HR+BC who have progressed during or after first-line treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor and whose tumors do not express human epidermal growth factor 2 (HER2). MORPHEUS-TNBC (NCT03424005) will enroll patients with metastatic or unresectable locally advanced TNBC who have progressed during or after first-line treatment with chemotherapy. For both studies, key inclusion criteria include Eastern Cooperative Oncology Group performance status of 0-1 (stage 1) or 0-2 (stage 2) and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Key exclusion criteria include prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, and symptomatic, untreated, or actively progressing central nervous system metastases. Patients in both trials will be randomized to one of the CIT atezolizumab combination arms or a control arm (up to 5 arms in HR+BC and up to 6 arms in TNBC). Patients experiencing loss of clinical benefit or unacceptable toxicity in stage 1 may be eligible to switch to a different CIT atezolizumab combination arm in stage 2. Primary endpoints are safety measures and investigator-assessed objective response rate per RECIST v1.1. Progression-free survival, overall survival, duration of response, clinical benefit rate (HR+BC) or disease control rate (TNBC) are among the secondary endpoints. Exploratory biomarkers will also be examined. Citation Format: Yardley DA, Abu-Khalaf M, Boni V, Brufsky A, Emens LA, Gutierrez M, Hurvitz S, Im S-A, Loi S, McCune SL, Schmid P, O9Hear C, Zhang X, Vidal GA. MORPHEUS: A phase Ib/II trial platform evaluating the safety and efficacy of multiple cancer immunotherapy combinations in patients with hormone receptor–positive and triple-negative breast ca
背景:癌症免疫治疗(Cancer immunotherapy, CIT)可以显著提高多种肿瘤类型的总生存率，但只有一小部分患者在单药CIT治疗下能获得持久的应答。为了同时靶向多种癌症免疫逃逸机制，可能需要将CIT与靶向治疗或化疗联合使用，从而提供个性化的治疗选择，使更多患者获得临床受益。MORPHEUS平台包括多个Ib/II期试验，旨在识别CIT组合的安全性和活性的早期信号。采用随机试验设计，将多个CIT组合组与单个标准护理对照组进行比较。这些试验具有灵活性，可以在新的CIT组合出现时开放新的治疗组，也可以关闭活性最小或毒性不可接受的治疗组。在这里，我们描述了MORPHEUS在转移性或不可切除的局部晚期激素受体阳性(HR+BC)或三阴性乳腺癌(TNBC)患者中的试验，2例患者需要更多的治疗选择。试验设计:MORPHEUS-HR+BC (NCT03280563)将招募转移性或不可切除的局部晚期HR+BC患者，这些患者在使用周期蛋白依赖性激酶(CDK) 4/6抑制剂的一线治疗期间或之后出现进展，并且肿瘤不表达人表皮生长因子2 (HER2)。MORPHEUS-TNBC (NCT03424005)将招募在一线化疗治疗期间或之后发生转移性或不可切除的局部晚期TNBC患者。在这两项研究中，主要的纳入标准包括东方肿瘤合作组织(Eastern Cooperative Oncology Group) 0-1(1期)或0-2(2期)的绩效状态，以及根据实体肿瘤反应评估标准(RECIST) v1.1可测量的疾病。关键的排除标准包括先前接受过t细胞共刺激或免疫检查点阻断治疗，有症状的、未经治疗的或进展积极的中枢神经系统转移。两项试验的患者将被随机分配到CIT atezolizumab联合组或对照组(HR+BC组最多5组，TNBC组最多6组)。在1期经历临床获益丧失或不可接受毒性的患者可能有资格在2期切换到不同的CIT atezolizumab联合治疗组。主要终点是安全措施和研究者根据RECIST v1.1评估的客观缓解率。次要终点包括无进展生存期、总生存期、反应持续时间、临床获益率(HR+BC)或疾病控制率(TNBC)。探索性生物标志物也将被检查。引文格式:Yardley DA, Abu-Khalaf M, Boni V, Brufsky A, Emens LA, Gutierrez M, Hurvitz S, Im S-A, Loi S, McCune SL, Schmid P, O9Hear C, Zhang X, Vidal GA。MORPHEUS:一个评估多种癌症免疫治疗联合治疗激素受体阳性和三阴性乳腺癌患者安全性和有效性的Ib/II期试验平台[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):OT2-06-04。
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Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT2-01-05
T. Hojo, N. Masuda, T. Shibata, T. Mizutani, T. Shien, T. Kinoshita, T. Iwatani, C. Kanbayashi, D. Kitagawa, M. Tsuneizumi, H. Iwata
Background: The standard follow-up after surgery for breast cancer includes periodic interviews, clinical examinations, and mammography, but many institutions are conducting intensive follow-up including periodic computed tomography(CT), magnetic resonance imaging(MRI), and bone scintigraphy in the world, despite the lack of evidence to support this approach. While intensive follow-up may contribute to prolonged survival through earlier diagnosis and treatment of relapse, it has the disadvantages of high effort and costs placed on patients(pts) and healthcare workers, radiation exposure for imaging examinations, and overtreatment owing to false-positive results. Although past two randomized trials could not show significant difference in overall survival (OS), as imaging methods have remarkably improved, leading to the earlier detection of relapse, and medical therapies have remarkably improved in recent years, randomized controlled trials are needed to confirm whether intensive follow-up can really prolong survival sufficiently to offset these disadvantages in high-risk breast cancer pts. Trial design: This study is a multi-institutional two-arm open label randomized controlled phase III trial being conducted with the participation of 42 hospitals belonging to the Breast Cancer Study Group of Japan Clinical Oncology Group. Eligible pts are randomized either to the intensive follow-up group or to the standard follow-up group; the former will undergo physical examination, bone scintigraphy, chest and abdominal CT, brain MRI/CT and frequent tumor markers, whereas the latter will undergo physical examination at the same frequency and tumor markers will be evaluated once a year. Mammography once a year is planned for both groups. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000012429. Eligibility criteria: High-risk breast cancer pts, who are expected to have recurrence rates of over 30% within 5 years after surgery. The main inclusion criteria are as follows: four or more axillary nodal metastases in the estrogen receptor (ER) positive pts without neoadjuvant chemotherapy(NC)., axillary node metastases in ER-negative pts without NC, axillary nodal metastases in ER-positive pts with NC, histologically proven residual invasive cancer in the breast or axilla in ER-negative with NC. Specific Aims: The primary endpoint is OS, and secondary endpoints are disease-free survival, relapse-free survival, distant metastasis–free survival, OS in intrinsic subtypes, actual number of implemented examinations, compliance with pre-specified examinations, and adverse events. Statistical methods: The primary endpoint will require a total of 538 events to be assessed in order to obtain a statistical power of 80% with a one-sided significance level of 0.05. Thus, the planned sample size to compare the two survival curves is set at 1500 pts, assuming an accrual time of 6 years and a follow-up time of 7 years according to the Schoenfeld and R
{"title":"Abstract OT2-01-05: A randomized controlled trial comparing post-operative intensive follow-up with standard follow-up in high-risk breast cancer patients (JCOG1204: INSPIRE)","authors":"T. Hojo, N. Masuda, T. Shibata, T. Mizutani, T. Shien, T. Kinoshita, T. Iwatani, C. Kanbayashi, D. Kitagawa, M. Tsuneizumi, H. Iwata","doi":"10.1158/1538-7445.SABCS18-OT2-01-05","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT2-01-05","url":null,"abstract":"Background: The standard follow-up after surgery for breast cancer includes periodic interviews, clinical examinations, and mammography, but many institutions are conducting intensive follow-up including periodic computed tomography(CT), magnetic resonance imaging(MRI), and bone scintigraphy in the world, despite the lack of evidence to support this approach. While intensive follow-up may contribute to prolonged survival through earlier diagnosis and treatment of relapse, it has the disadvantages of high effort and costs placed on patients(pts) and healthcare workers, radiation exposure for imaging examinations, and overtreatment owing to false-positive results. Although past two randomized trials could not show significant difference in overall survival (OS), as imaging methods have remarkably improved, leading to the earlier detection of relapse, and medical therapies have remarkably improved in recent years, randomized controlled trials are needed to confirm whether intensive follow-up can really prolong survival sufficiently to offset these disadvantages in high-risk breast cancer pts. Trial design: This study is a multi-institutional two-arm open label randomized controlled phase III trial being conducted with the participation of 42 hospitals belonging to the Breast Cancer Study Group of Japan Clinical Oncology Group. Eligible pts are randomized either to the intensive follow-up group or to the standard follow-up group; the former will undergo physical examination, bone scintigraphy, chest and abdominal CT, brain MRI/CT and frequent tumor markers, whereas the latter will undergo physical examination at the same frequency and tumor markers will be evaluated once a year. Mammography once a year is planned for both groups. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000012429. Eligibility criteria: High-risk breast cancer pts, who are expected to have recurrence rates of over 30% within 5 years after surgery. The main inclusion criteria are as follows: four or more axillary nodal metastases in the estrogen receptor (ER) positive pts without neoadjuvant chemotherapy(NC)., axillary node metastases in ER-negative pts without NC, axillary nodal metastases in ER-positive pts with NC, histologically proven residual invasive cancer in the breast or axilla in ER-negative with NC. Specific Aims: The primary endpoint is OS, and secondary endpoints are disease-free survival, relapse-free survival, distant metastasis–free survival, OS in intrinsic subtypes, actual number of implemented examinations, compliance with pre-specified examinations, and adverse events. Statistical methods: The primary endpoint will require a total of 538 events to be assessed in order to obtain a statistical power of 80% with a one-sided significance level of 0.05. Thus, the planned sample size to compare the two survival curves is set at 1500 pts, assuming an accrual time of 6 years and a follow-up time of 7 years according to the Schoenfeld and R","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83087722","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}
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