ADMINISTRATION OF MOST CLOSELY MATCHED THIRD PARTY RAPIDLY GENERATED LMP, BARF1 and EBNA1 SPECIFIC CYTOTOXIC T-LYMPHOCYTES TO PATIENTS WITH EBV-POSITIVE LYMPHOMA AND OTHER EBV-POSITIVE MALIGNANCIES

The subject has a type of cancer or lymph gland disease associated with a virus called Epstein Barr Virus (EBV), which has come back, is at risk of coming back, or has not gone away after standard treatments. This research study uses special immune system cells called LMP, BARF-1 and EBNA1- specific cytotoxic T lymphocytes (MABEL CTLs).
Some patients with Lymphoma (such as Hodgkin (HD) or non-Hodgkin Lymphoma (NHL)), T/NK-lymphoproliferative disease, or CAEBV, or solid tumors such as nasopharyngeal carcinoma (NPC), smooth muscle tumors, and leiomyosarcomas show signs of a virus called EBV before or at the time of their diagnosis. EBV causes mononucleosis or glandular fever ("mono" or the "kissing disease"). EBV is found in the cancer cells of up to half the patients with HD and NHL, suggesting that it may play a role in causing Lymphoma. The cancer cells (in lymphoma) and some immune system cells (in CAEBV) infected by EBV are able to hide from the body's immune system and escape destruction. EBV is also found in the majority of NPC and smooth muscle tumors, and some leiomyosarcomas. We want to see if special white blood cells (MABEL CTLs) that have been trained to kill EBV infected cells can survive in your blood and affect the tumor.
In previous studies, EBV CTLs were generated from the blood of the patient, which was often difficult if the patient had recently received chemotherapy. Also, it took up to 1-2 months to make the cells, which is not practical when a patient needs more urgent treatment. To address these issues, the MABEL CTLs were made in the lab in a simpler, faster, and safer way. The MABEL CTLs will still see LMP proteins but also two other EBV proteins called EBNA-1 and BARF. To ensure these cells are available for use in patients in urgent clinical need, we have generated MABEL CTLs from the blood of healthy donors and created a bank of these cells, which are frozen until ready for use. We have previously successfully used frozen T cells from healthy donors to treat EBV lymphoma and virus infections and we now have improved our production method to make it faster.
In this study, we want to find out if we can use banked MABEL CTLs to treat HD, NHL, T/NK-lymphoproliferative disease, CAEBV, NPC, smooth muscle tumors or leiomyosarcoma. We will search the bank to find a MABEL CTL line that is a partial match with the subject.
MABEL CTLs are investigational and not approved by the Food and Drug Administration.

开始日期2015-02-01

申办/合作机构

Baylor College of Medicine

[+2]

NCT02578641 / Completed临床3期

A Multicentre, Randomized, Open-Label, Phase III Clinical Trial Of Gemcitabine And Carboplatin Followed By Epstein-Barr Virus-Specific Autologous Cytotoxic T Lymphocytes Versus Gemcitabine And Carboplatin As First Line Treatment For Advanced Nasopharyngeal Carcinoma(NPC) Patients

This study is a multi-center, randomized, open label, Phase III clinical trial for advanced Nasopharyngeal Carcinoma(NPC) Patients.
Drugs used in chemotherapy, such as gemcitabine and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving an infusion of a person's cytotoxic T cells (CTL) that have been treated in the laboratory may help the body build an effective immune response to kill tumor cells. Giving combination chemotherapy together with laboratory-treated T cells may kill more tumor cells. This Phase III trial is to assess if combined gemcitabine-carboplatin (GC) followed by adoptive T-cell therapy would improve clinical outcome for patients with advanced nasopharyngeal carcinoma (NPC). It is also the world's first, and largest, Phase 3 T-cell therapy cancer trial ever conducted, and enrollment is ongoing for 330 patients from 30 hospital centers across Asia and the United States.
This clinical trial is conducted on the back of a successful Phase 2 NPC trial involving 38 patients at the National Cancer Centre, Singapore. This trial produced the best published 2-year (62.9%), and median overall survival (OS) data (29.9 months) in 35 patients with advanced NPC who received autologous EBV-specific CTL. Kindly see https://www-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/pmc/articles/PMC3978790/ for the Phase 2 publication titled "Adoptive T-cell Transfer and Chemotherapy in the First line treatment of Metastatic and/or Locally Recurrent Nasopharyngeal Carcinoma".

开始日期2014-07-01

申办/合作机构

Tessa Therapeutics Ltd

NCT00058773 / Terminated临床1期IIT

Administration of Autologous Neomycin Resistant Gene Marked EBV Specific Cytotoxic T-Lymphocytes as Therapy for Patients Receiving Autologous Bone Marrow Transplant for Relapsed EBV-Positive Lymphoma.

Subjects have a type of lymph gland cancer called Hodgkin or non-Hodgkin Lymphoma, which has come back or not gone away after treatment, including the best treatment we know for relapsed Lymphoma. We are asking subjects to volunteer to be in a research study using Epstein Barr virus (EBV) specific cytotoxic T lymphocytes, a new experimental therapy. This therapy has never been used in patients with Hodgkin disease or this type of non-Hodgkin Lymphoma but it has been used successfully in children with other types of blood cancer caused by EBV after bone marrow transplantation.
Some patients with Hodgkin disease or non-Hodgkin Lymphoma show evidence of infection with the virus that causes infectious mononucleosis Epstein Barr virus (EBV) before or at the time of their diagnosis of Lymphoma. EBV is often found in the cancer cells suggesting that it may play a role in causing Lymphoma. The cancer cells infected by EBV are very clever because they are able to hide from the body's immune system and escape destruction. We want to see if we can grow special white blood cells, called T cells, that have been trained to kill EBV infected cells and give them back to subjects.

开始日期1996-01-01

申办/合作机构

Baylor College of Medicine

[+2]

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项与 TT-10x 相关的文献（医药）

2021-03-01·European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences2区 · 医学

Mechanistic prediction of first-in-human dose for bispecific CD3/EpCAM T-cell engager antibody M701, using an integrated PK/PD modeling method

2区 · 医学

Review

作者: Zhou, Tianyan ; Xue, Junsheng ; Zhang, Jing ; Song, Ling ; Liu, Dongyang ; Li, Si

AIM:

M701 is a bispecific CD3/EpCAM T-cell engager antibody to treat malignant ascites. This study aimed to predict in vivo exposure-cytotoxicity relationship and human pharmacokinetics (PK) characteristics of M701, as well as to design optimal starting dose and effective dose for M701 first-in-human (FIH) study.

METHOD:

Mechanistic in vitro PK/PD model was firstly developed based on in vitro data of M701's cytotoxicity and binding affinities with targeting receptors. The cell killing effect of M701 in vitro was driven by tri-molecular synapse, which formed by binding drug to both CD3 receptor on T cells and EpCAM receptor on tumor cells. Human exposure-response (E-R) curve in ascites was estimated using the same model structure with clinical systemic model parameters. Human PK was predicted by allometrically scaling monkey PK data, which was characterized using a two compartment model. Human PK model was integrated into in vivo synapse-based cell killing model to provide human PK/PD characteristics. Integrated human PK/PD model was applied in FIH dose design. Clinical starting dose and effective dose were suggested as the simulated drug concentration in human ascites that achieved the estimated in vivo minimally anticipated biological effect level (MABEL) and pharmacologically active level. Other approaches including PK-driven and receptor occupancy calculation were also employed in this study to verify the starting dose prediction.

RESULTS:

In vitro M701 cytotoxicity curves under 24, 48, 72 h incubations were well captured by mechanistic synapse-based cell killing model. Human E-R curve in ascites was obtained based on in vitro model structure and clinical systematic parameters. We defined 10~20% and 80% of maximum cytotoxicity effect as in vivo MABEL and pharmacologically active level. Human E-R curve indicated in vivo EC₁₀, EC₂₀ and EC₈₀ were 0.56, 1.26 and 31.6 ng/mL. For human PK model, clearance (CL, CL_d), distribution volumes (V_c, V_p) and absorption rate were allometrically scaled using exponent of 0.9, 1 and -0.25. Predicted clearance and volume were 0.53- and 1.19-fold of observed data. Simulated average ascites M701 concentrations (calculated as C_{ave_ ascites} = AUC_τ/τ) were 0.81 and 32.5 ng/mL under dose of 5 and 200 μg within 2-hour i.p. infusion. By integrating human E-R curve and the simulated PK profile in ascites, we suggested 5 and 200 μg within 2-hour i.p. infusion as MABEL dose and pharmacologically active dose (PAD) for M701 FIH study. PK-driven approach predicted a starting dose of 5 μg, which was comparable to that predicted via PK/PD-driven approach.

CONCLUSIONS:

This study predicted human ascites PK and E-R curve by integrating human PK model into in vivo synapse-based cell killing model. Optimal clinical MABEL dose and PAD of bispecific T cell engager antibody M701 were suggested based on current integrated PK/PD approach.

2019-05-01·Journal of clinical pharmacology3区 · 医学

Pharmacokinetics, Pharmacodynamics, and Safety of E6011, a Novel Humanized Antifractalkine (CX3CL1) Monoclonal Antibody: A Randomized, Double‐Blind, Placebo‐Controlled Single‐Ascending‐Dose Study

3区 · 医学

Article

作者: Obara, Takashi ; Tabuchi, Hiroko ; Aoyama, Muneo ; Ieiri, Ichiro ; Imai, Toshio ; Kawano, Tetsu ; Kumagai, Yuji ; Katsurabara, Toshinori ; Mori, Masahiko ; Yasuda, Nobuyuki

Abstract:

E6011 is a novel humanized antifractalkine (FKN) monoclonal antibody being developed as a therapeutic target for Crohn's disease, rheumatoid arthritis, and primary biliary cholangitis. This study was a randomized, double‐blind, placebo‐controlled single‐ascending‐dose study of intravenous administration of E6011 (0.0006‐10 mg/kg) in healthy Japanese adult men (n = 64). The starting dose was the minimum anticipated biological effect level (MABEL). MABEL was estimated by extrapolating results of a pharmacokinetic/pharmacodynamic (PK/PD) model relating E6011 exposure and suppression of free soluble FKN using data obtained from cynomolgus monkeys. Safety assessments consisted of monitoring and recording adverse events, laboratory tests, vital signs, intensive electrocardiograms, and chest x‐rays. Blood samples to determine PK, PD (serum total FKN concentration), and serum anti‐E6011 antibody were collected. Noncompartmental analysis was used to derive PK parameters. Single intravenous infusions of E6011 were safe and well tolerated in healthy subjects. Serum E6011 concentrations showed triphasic elimination. An increase in serum total FKN concentration was observed, confirming target engagement. The dose strategy for patient studies is to select regimens that will attain a minimum serum E6011 exposure of 10 μg/mL, identified as the minimum concentration needed to saturate the target‐mediated elimination pathway. Model‐based drug development from preclinical stage was successful in identifying dose regimens for clinical testing.

2015-12-01·The Journal of pharmacology and experimental therapeutics3区 · 医学

Integrated Pharmacokinetic/Pharmacodynamic Analysis for Determining the Minimal Anticipated Biological Effect Level of a Novel Anti-CD28 Receptor Antagonist BMS-931699

3区 · 医学

Article

作者: Marathe, Punit H ; Fleener, Catherine A ; Xie, Jenny H ; Schneeweis, Lumelle A ; Shi, Rong ; Suchard, Suzanne J ; Yang, Zheng ; Nadler, Steven G ; Calore, James D ; Rodrigues, A David ; Car, Bruce D ; Wang, Haiqing ; Salcedo, Theodora W ; Zhang, Sean X Y

BMS-931699 (lulizumab pegol), a domain antibody (dAb) conjugated with 40-kDa branched polyethylene glycol, is a human anti-CD28 receptor antagonist under development for the treatment of inflammatory and autoimmune diseases. In the present work, the minimal anticipated biologic effect level (MABEL) was determined for BMS-931699 by integrating all the available preclinical data. The relevance of the in vitro mixed lymphocyte reaction (MLR) assay to a whole blood CD28 receptor occupancy (RO) assessment, as well as the relationship between the CD28 RO and the inhibition of T-cell-dependent antibody response to keyhole limpet hemocyanin in vivo, was demonstrated through an integrated pharmacokinetic/pharmacodynamic analysis using anti-hCD28 dAb-001 (differing from BMS-931699 by two additional amino acids at the N-terminus) and a mouse surrogate. Based on this analysis, the EC10 value (0.32 nM) from the human MLR assay and the human plasma volume (0.04 l/kg) were employed to calculate the MABEL (0.01 mg) of BMS-931699 in humans, with a CD28 RO predicted to be ≤10%. The estimated MABEL dose was threefold higher than the value derived from the binding constant and twofold less than the MABEL converted from animal efficacy studies based on the body surface area. Furthermore, it was 2900-fold lower than the human equivalent dose derived from the no observed adverse effect level in monkeys (15 mg/kg/week for 5 doses, intravenous dosing) with a 10-fold safety factor applied. Therefore, the MABEL dose represented a sound approach to mitigate any potential risk in targeting CD28 and was successfully used as the first-in-human starting dose for BMS-931699.

项与 TT-10x 相关的新闻（医药）

2023-10-22

·行舟Drug

临床起始剂量计算那点事

新药开发涉及的核心内容主要是3部分，药学研究、非临床研究和临床研究。非临床研究和临床研究相互关联，密不可分，非临床研究的主要目的也是为了支持临床研究的正常开展。其中一个重要作用就是临床起始剂量的计算。之前微信群有朋友提议能不能总结下临床起始剂量相关的主题，本来随意挥洒的主题一不小心变成命题作文了。临床起始剂量这个话题很大，主要因为药物治疗种类太多，肿瘤药和非肿瘤药有区别，免疫调节类药物与非免疫调节类药物也有区别，临床采用健康人还是患者也会不同，计算方式也是五花八门，有基于毒理学终点的、有药理学终点的，也有基于模型计算的。很难完全讲透，先稍作展开，欢迎讨论。关于临床起始剂量计算已经有很多指导原则出台，比如2005年，FDA出台的基于未见不良反应剂量水平（NOAEL）和药理活性剂量水平（PAD）计算人体最大推荐起始剂量（MRSD）。当然，EMA和ICH也有多项指南发布。罗列如下：FDA, 2005. Food and Drug Administration Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.FDA,2018. Physiologically Based Pharmacokinetic Analyses-Format and Content Guidance for Industry.EMA, 2017. European Medicines Agency: Guideline on Strategies to Identify and Mitigate Risks for First-In-Human and Early Clinical Trials with Investigational Medicinal Products.EMA,2018. Guideline on the Reporting of Physiologically Based Pharmacokinetic (PBPK) Modelling and Simulation.ICH M3(R2), 2009. International Conference on Harmonization: Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorisation for Pharmaceuticals.NMPA, 健康成年志愿者首次临床试验药物最大推荐起始剂量的估算指导原则.起始剂量计算的线索比较多，而且比较杂，本文就以问题驱动的方式展开吧。尝试回答一些常见的问题，有些是群友私信讨论的，有些则是平时比较常见的。1、非肿瘤适应症的新药临床起始剂量如何计算？先看一篇回顾性分析的文章。2021年，科文斯发表了一篇从临床前数据外推临床剂量的文章，统计了58个非肿瘤新药的临床前-临床数据外推情况，其中包括41个小分子化药，17个大分子生物药。非临床数据主要来自研究者手册（IB），临床数据则来自在科文斯开展的临床研究报告（CSR），所涉及的临床研究主要在2001-2019年期间开展。58个纳入统计的药物，在GLP毒理研究中均成功获得NOAEL剂量。这在非肿瘤药毒理研究中非常关键，也是与肿瘤药物相比很大的不同。41个小分子化药中，37个啮齿类动物种属选择大鼠，4个选择小鼠。很明显，大鼠是啮齿类研究的主流种属。相反，非啮齿类种属就不太一样，27/41选择比格犬、13/41选择食蟹猴、1/41选择迷你猪，犬比猴多，但不像啮齿类动物种属集中。17个大分子生物药中，5个采用大鼠和食蟹猴作为毒理研究种属，12个仅采用食蟹猴进行了研究。这点也容易理解，啮齿类动物对于很多生物药来讲，并不是相关种属。先看下化药的最大推荐起始剂量（Maximum Recommended Starting Dose, MRSD）计算，25/41药物采用来自最相关种属的NOAEL进行临床起始剂量计算。基于体重进行种属间剂量换算，并在此基础上设置一定的安全窗口。21/25的药物设置的安全窗口小于100倍，大部分在2-30倍之间。当然NOAEL并不是唯一路径，20/41的药物采用来自体内药理学研究的药理学活性剂量（Pharmacological Active Dose, PAD）作为临床起始剂量计算的依据。与NOAEL不同的是，PAD剂量换算成人体等效剂量（Human Equivalent Dose, HED）后，安全窗口一般只有几倍（few-fold less），不会达到几十上百倍那么高。41个化药中，有6个是基于异速放大模型或PK/PD方法计算的临床起始剂量。与化药不同，17个生物药案例中，大部分是基于药理学试验结果及建模方法计算的临床起始剂量，仅3个案例是采用最低预期生物效应剂量（Minimal Anticipated Biological Effect Level, MABEL）法进行的计算。2、肿瘤适应症新药如何计算起始剂量？ICH S9作为抗肿瘤药物非临床研究的指导原则，对临床起始剂量设计也有提及。对于小分子药物，可以考虑采用啮齿类动物STD剂量的十分之一，或者非啮齿类动物HNSTD的六分之一，最终选择基于种属相关程度确定。Hansen等人（Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials）对23种生物制品进行回顾分析，发现HNSTD的六分之一也可以作为生物制品的安全起始剂量。CDE张凤琴等老师在《新药人体首次剂量设计的技术考虑》一文中，还介绍几种其它方法，如类似药物比较法等。也可以参考CDE叶旋老师的《抗肿瘤药物首次临床试验起始剂量的一般考虑》、闫莉萍老师的《生物制品首次临床试验起始剂量拟定的一般考虑》，感兴趣的可以自行翻阅，不再赘述。3、MABEL法计算起始剂量的应用场景有哪些？2006年，针对T淋巴细胞的单克隆抗体TGN1412的FIH临床试验中，6名健康志愿者产生多器官衰竭，虽然其选择MRSD（0.1mg/kg）时，在食蟹猴NOAEL缩放的HED（16m/kg）中使用了非常保守的安全系数160。而且，临床最相关种属为食蟹猴，因为食蟹猴CD28胞外区序列与人100%一致，且与人和猴CD28的亲和力相近，具备相似的组织交叉反应。这就提示，基于NOAEL的临床起始剂量计算，对于某些高风险产品，还是不能保障受试者的安全。2007年，欧洲EMA针对高风险药品的首次临床试验颁布了相应指南（GUIDELINE ON REQUIREMENTS FOR FIRST-IN-MAN CLINICAL TRIALS FOR POTENTIAL HIGH-RISK MEDICINAL PRODUCTS），推荐高风险产品采用MABEL进行起始剂量计算。对FDA数据库中以MABEL作为起始剂量的32个生物制品进行分析，发现靶点涵盖PD-1、PD-L1、CD40、GITR、OX40、OX40L、CD33、CD38、CD19、CD137、c-fms、B7家族抗原以及CTLA-4。所以，免疫调节类产品尤其免疫激动剂，MABEL法的使用渐成主流。事后分析，TGN1412临床起始剂量0.1mg/kg，受体占有率已超过90%，而受体占有率10%对应的剂量约为1.5μg/kg，较前者低60倍以上。所以，对于这类高风险产品，MABEL法应引起足够重视。4、种属间剂量换算用mg/m2还是mg/kg？通常来讲，将剂量归一化为体表面积剂量（mg/m2），通常在不同种属间可呈现良好的比例关系。但是在某些情况下，比如不同种属间NOAEL的mg/kg比较相似时，或者当有两个NOAEL剂量时，药物为口服给药且剂量受局部毒性限制，或药物在人体毒性反应受某一药代参数影响，且这一参数与mg/kg更相关，或不同种属间的药理学终点和毒理学终点具有可比性，或血浆药物浓度与mg/kg剂量之间有显著的相关性，或分子量大于100000道尔顿的血管内给药的蛋白等情况吧，采用mg/kg计算更为合适。5、安全系数如何选择？科文斯这篇文章介绍的，大部分基于NOAEL计算的MRSD，选择的安全系数是2-30。这点与指导原则推荐的10倍是大体匹配的。但很明显，安全系数肯定不是固定的，某些情况下需要增加安全系数，某些情况也可以减小安全系数。增加安全系数的情况包括：1）人的药理学活性高于试验动物，即人比动物敏感。这样通过动物数据外推获得的人体剂量，就有很大的不确定性；2）受体密度或亲和力差异。这点也比较容易理解，比如单抗与猴子或大鼠的亲和力显著低于人体，那么换算成人体剂量时，自然增大安全系数更为保险；3）剂量反应曲线斜率很陡时。这类药物毒性对剂量比较敏感，也要注意；4）动物试验出现严重毒性反应时，提示对人的风险增加；5）不可监测的毒性反应。比如有些毒性病理显示异常，但临床病理无法监测，且有些反应动物无法给出反馈如头痛、精神异常；6）动物试验出现不可逆毒性反应或者动物不明原因的死亡；7）PK方面的原因如种属间生物利用度差异过大、药物呈现非线性药代动力学等；8）新靶点。对于全新靶点，首次进入临床，人体反应完全未知，保险起见，也是建议增加安全系数。其它情况应该还有很多，指导原则或者一些电子刊物肯定无法覆盖所有情况，安全系数的确定核心还是基于风险的证据分析，需要结合产品作用机制、非临床数据、充分的文献调研及相关法规等综合判定。那有没有可以缩小安全系数的情况呢？答案也是肯定的。对于很多me-too，fast-follow产品，如果临床前毒性表现，剂量-反应关系跟同类临床在研或已上市产品差不多，是不是可以考虑缩小安全系数？当然，指导原则还有句原话“药物的毒理学实验的实施和设计均十分完善时，安全系数小于10是合适的”。6、NOAEL和PAD的应用场景有什么区别？NOAEL和PAD，一个来自于毒理学研究，一个属于药理学终点，又该如何选择呢。对于小分子化药，其实科文斯这篇文章中的数据有一定参考价值，25/41药物是采用NOAEL进行FIH剂量计算的。但对于生物药，科文斯这篇文章提示17个产品，大都采用药理学剂量进行的推算。不过，Sun等人在Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013文章中显示，79个单抗大都采用NOAEL进行的计算。差异可能跟样本来源、样本数量（17vs79）、适应症（科文斯仅统计的非肿瘤适应症）、时间（科文斯统计的2010-2019年间）等有关。另外，从健康成年志愿者首次临床试验药物最大推荐起始剂量的估算指导原则看，也是首选NOAEL，如果采用PAD，需要特别说明和解释。所以，对于非肿瘤产品，可以考虑优先用NOAEL进行外推。也有些情况，比如临床前毒性预测数据价值有限，或者无合适毒理研究种属等情况时，PAD的价值会更大一些。7、NOAEL暴露量、PK/PD、PBPK等基于模型计算起始剂量临床应用如何？基于模型的临床起始剂量推算应用也比较多。尤其生物制品，PK预测较小分子化药简单很多。简单讲就是先找到NOAEL剂量下或PAD剂量对应的暴露量。根据动物药代动力学参数，采用不同方式计算人体药代参数，比如抗体常用的经验的异速缩放法。当然，动物药代参数预测人体参数比较复杂，要考虑很多因素如药物与靶点的亲和力、药物是肾小球滤过为主要代谢机制还是肝脏代谢为主、缩放指数如何选择等。有了暴露量和人体清除率等参数，自然可以推算出剂量。如果药物的药动学机制相对复杂时，则需要运用更复杂的药代动力学手段来推算。目前最受关注的是基于不同动物生理药动学模型（Physiologically Based Pharmacokinetic Model，PBPK）。但PBPK目前在起始剂量计算中的应用还不多。EMA和FDA在指南中均有提及，需要对PBPK模型的可靠性进行充分验证。2020年，AstraZeneca公布了一项研究结果，116个候选化合物采用PBPK模型，基于临床前体外和体内数据，预测FIH试验暴露量，效果并不是特别理想，约58-64%的AUC预测在实测值的2倍以内。关于起始剂量计算的话题先抛砖引玉，简单讨论至此。无论CDE，还是医院的主要研究者，起始剂量计算的方式、科学性、合理性一直都是重点关注对象，也是审查的核心。基于各自产品的特点，肿瘤药还是非肿瘤药、高风险还是低风险、生物药还是化药、入组健康人还是患者等，按照监管机构出具的指南或权威资料，提供充分的依据，选择最佳路径获得临床起始剂量。既不能太冒进，增加受试者安全性风险，也不能太保守，使患者不能充分获益。具体问题，具体分析，多查资料，多思、多想、多讨论。注：未经同意，禁止转载！药理毒理开发的1群和2群已满，进3群请加微信，备注：姓名-企业名称-专长领域，邀请入群，谢谢！

临床研究诊断试剂

100 项与 TT-10x 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
晚期鼻咽癌	临床3期	美国	Tessa Therapeutics Ltd	2014-07-01
晚期鼻咽癌	临床3期	马来西亚	Tessa Therapeutics Ltd	2014-07-01
晚期鼻咽癌	临床3期	新加坡	Tessa Therapeutics Ltd	2014-07-01
晚期鼻咽癌	临床3期	中国台湾	Tessa Therapeutics Ltd	2014-07-01
晚期鼻咽癌	临床3期	泰国	Tessa Therapeutics Ltd	2014-07-01
鼻咽癌	临床3期	美国	Tessa Therapeutics Ltd	2014-07-01
鼻咽癌	临床3期	马来西亚	Tessa Therapeutics Ltd	2014-07-01
鼻咽癌	临床3期	新加坡	Tessa Therapeutics Ltd	2014-07-01
鼻咽癌	临床3期	中国台湾	Tessa Therapeutics Ltd	2014-07-01
鼻咽癌	临床3期	泰国	Tessa Therapeutics Ltd	2014-07-01

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临床结果

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02578641 (VANCE, Pubmed \| Ann Oncol) 人工标引	临床3期	鼻咽癌一线	330	Gemcitabine + carboplatin + EBV-CTL	網廠築壓鬱襯艱觸網鹹(夢鏇廠顧窪築醖網觸醖) = 獵齋夢夢艱築壓衊遞鏇淵選遞範鹽廠遞艱夢鹹 (繭憲夢襯夢醖簾醖鑰選 )	不佳	2024-09-01
				Gemcitabine+carboplatin	網廠築壓鬱襯艱觸網鹹(夢鏇廠顧窪築醖網觸醖) = 廠憲願鏇鹹鑰襯築鏇構淵選遞範鹽廠遞艱夢鹹 (繭憲夢襯夢醖簾醖鑰選 )
NCT02578641 (VANCE, CTgov)	临床3期	鼻咽癌 \| 晚期鼻咽癌	330	carboplatin+gemcitabine (Chemo + EBV-CTL)	遞艱顧廠積襯餘觸範鬱(壓糧願艱鏇襯鹽簾廠鏇) = 鹹積壓獵齋積壓憲積醖築選膚憲鹹淵顧衊壓襯 (選顧簾簾鏇蓋遞網齋襯, 窪願鑰廠衊醖製網蓋淵 ~ 蓋衊廠繭餘壓鏇鏇築鑰) 更多	-	2023-06-28
				carboplatin+gemcitabine (Chemo Only)	遞艱顧廠積襯餘觸範鬱(壓糧願艱鏇襯鹽簾廠鏇) = 餘範繭淵範築醖簾糧積築選膚憲鹹淵顧衊壓襯 (選顧簾簾鏇蓋遞網齋襯, 廠餘觸夢鹹淵齋鬱憲遞 ~ 衊醖遞顧簾窪願膚選積) 更多