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/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）

2022-09-01·CTS-Clinical and Translational Science

Model-informed drug development for immuno-oncology agonistic anti-GITR antibody GWN323: Dose selection based on MABEL and biologically active dose.

Article

作者: Wolf, Babette ; Sy, Sherwin K B ; Dang, Anhthu ; Knee, Deborah ; Ji, Yan ; Chen, Xinhui ; Mataraza, Jennifer

GWN323, an agonistic human anti-GITR (glucocorticoid-induced TNFR-related protein) IgG1 antibody, was studied clinically as an immuno-oncology therapeutic agent. A model-based minimum anticipated biological effect level (MABEL) approach integrating in vitro and in vivo data informed dose selection for the first-in-human (FIH) study. Data evaluated included pharmacokinetics (PK) of DTA-1.mIgG2a (mouse surrogate GITR antibody for GWN323), target-engagement pharmacodynamic (PD) marker soluble GITR (sGITR), tumor shrinkage in Colon26 syngeneic mice administered with DTA-1.mIgG2a, cytokine release of GWN323 in human peripheral blood mononuclear cells, and GITR binding affinity. A PK model was developed to describe DTA-1.mIgG2a PK, and its relationship with sGITR was also modeled. Human GWN323 PK was predicted by allometric scaling of mouse PK. Based on the totality of PK/PD modeling and in vitro and in vivo pharmacology and toxicology data, MABEL was estimated to be 3-10 mg once every 3 weeks (Q3W), which informed the starting dose selection of the FIH study. Based on tumor kinetic PK/PD modeling of tumor inhibition by DTA-1.mIgG2a in Colon26 mice and the predicted human PK of GWN323, the biologically active dose of GWN323 was predicted to be 350 mg Q3W, which informed the dose escalation of the FIH study. GWN323 PK from the FIH study was described by a population PK model; the relationship with ex vivo interleukin-2 release, a target-engagement marker, was also modeled. The clinical PK/PD modeling data supported the biological active dose projected from the translational PK/PD modeling in a "learn and confirm" paradigm of model-informed drug development of GWN323.

2021-06-01·CLINICAL PHARMACOLOGY & THERAPEUTICS

Strategies and Recommendations for Using a Data-Driven and Risk-Based Approach in the Selection of First-in-Human Starting Dose: An International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Assessment.

Review

作者: Bailey, Wendy J ; Chen, Yingxue ; Yang, Zheng ; Brennan, Frank R ; Mayawala, Kapil ; Rogge, Mark C ; Li, Chunze ; Clarke, David O ; Deslandes, Antoine ; Chemuturi, Nagendra V ; Dudal, Sherri ; Todd, Marque ; Leach, Michael W ; Han, Chao ; Loberg, Lise I

Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development convened a working group to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry-wide survey suggested the achieved or estimated maximum tolerated dose, efficacious dose, or recommended phase II dose was > 100-fold higher than the MABEL-based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven-based, and risk-based approach for selecting FIH starting doses.

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.

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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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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 ancarboplatinin EBV-CTLEBV-CTL	鬱製憲蓋積壓壓淵廠獵(鬱積鹹窪獵餘繭顧製網) = 鏇繭鹽鹹繭餘壓淵襯糧廠鏇積範鑰壓網壓鹽鹹 (夢壓遞簾淵艱廠衊夢顧 )	不佳	2024-09-01
				Gemcitabine carboplatinatin (GC)	鬱製憲蓋積壓壓淵廠獵(鬱積鹹窪獵餘繭顧製網) = 衊繭廠獵廠膚淵築構獵廠鏇積範鑰壓網壓鹽鹹 (夢壓遞簾淵艱廠衊夢顧 )
NCT02578641 (VANCE, CTgov)	临床3期	鼻咽癌 \| 晚期鼻咽癌	330	carboplatin+gemcitabine (Chemo + EBV-CTL)	艱顧築遞鑰構襯鹹糧蓋(淵淵築廠製築網觸壓簾) = 膚積夢壓遞鏇遞壓構鹹襯簾襯艱範繭窪壓網襯 (簾憲積鑰鏇網選餘遞網, 膚鬱遞鏇糧憲餘齋廠選 ~ 遞壓積遞構積鏇窪淵糧) 更多	-	2023-06-28
				carboplatin+gemcitabine (Chemo Only)	艱顧築遞鑰構襯鹹糧蓋(淵淵築廠製築網觸壓簾) = 鏇築窪衊構鏇壓獵鏇製襯簾襯艱範繭窪壓網襯 (簾憲積鑰鏇網選餘遞網, 餘夢製積積選簾願廠鹹 ~ 膚餘醖繭襯餘構齋夢餘) 更多