LIVIVO - Search results -

Search results

Result 1 - 10 of total 10

Search options

Article ; Online: The tumor microenvironment in colorectal carcinogenesis.

Peddareddigari, Vijay G / Wang, Dingzhi / Dubois, Raymond N

Cancer microenvironment : official journal of the International Cancer Microenvironment Society

2010 Volume 3, Issue 1, Page(s) 149–166

Abstract: Colorectal cancer is the second leading cause of cancer-related mortality in the United States. Therapeutic developments in the past decade have extended life expectancy in patients with metastatic disease. However, metastatic colorectal cancers remain ... ...

Abstract	Colorectal cancer is the second leading cause of cancer-related mortality in the United States. Therapeutic developments in the past decade have extended life expectancy in patients with metastatic disease. However, metastatic colorectal cancers remain incurable. Numerous agents that were demonstrated to have significant antitumor activity in experimental models translated into disappointing results in extending patient survival. This has resulted in more attention being focused on the contribution of tumor microenvironment to the progression of a number of solid tumors including colorectal cancer. A more complete understanding of interactions between tumor epithelial cells and their stromal elements will enhance therapeutic options and improve clinical outcome. Here we will review the role of various stromal components in colorectal carcinogenesis and discuss the potential of targeting these components for the development of future therapeutic agents.
Language	English
Publishing date	2010-03-05
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2422345-1
ISSN	1875-2284 ; 1875-2292
ISSN (online)	1875-2284
ISSN	1875-2292
DOI	10.1007/s12307-010-0038-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Details ▾
- Full text online
- Order with fees

Article ; Online: Dual targeting of CD19 and CD22 with bicistronic CAR-T cells in patients with relapsed/refractory large B-cell lymphoma.

Roddie, Claire / Lekakis, Lazaros J / Marzolini, Maria A V / Ramakrishnan, Aravind / Zhang, Yiyun / Hu, Yanqing / Peddareddigari, Vijay G R / Khokhar, Nushmia / Chen, Robert / Basilico, Silvia / Raymond, Meera / Vargas, Frederick Arce / Duffy, Kevin / Brugger, Wolfram / O'Reilly, Maeve A / Wood, Leigh / Linch, David C / Peggs, Karl S / Bachier, Carlos /

Budde, Elizabeth Lihua / Lee Batlevi, Connie / Bartlett, Nancy / Irvine, David / Tholouli, Eleni / Osborne, Wendy / Ardeshna, Kirit M / Pule, Martin A

Blood

2022 Volume 141, Issue 20, Page(s) 2470–2482

Abstract: Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational ... ...

Abstract	Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in relapsed/refractory LBCL (NCT03289455). End points include toxicity (primary) and response rates (secondary). Fifty-two patients received AUTO3 and 48/52 received pembrolizumab. Median age was 59 years (range, 27-83), 46/52 had stage III/ IV disease and median follow-up was 21.6 months. AUTO3 was safe; grade 1-2 and grade 3 cytokine release syndrome affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), and hemophagocytic lymphohistiocytosis affected 2 patients. Outpatient administration was tested in 20 patients, saving a median of 14 hospital days per patient. Overall response rates were 66% (48.9%, complete response [CR]; 17%, partial response). Median duration of remission (DOR) for CR patients was not reached and for all responding patients was 8.3 months (95% confidence interval [CI]: 3.0-not evaluable). 54.4% (CI: 32.8-71.7) of CR patients and 42.6% of all responding patients were projected to remain progression-free at ≥12 months. AUTO3 ± pembrolizumab for relapsed/refractory LBCL was safe and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion in vivo, and selection of CAR binders active at low antigen densities.
MeSH term(s)	Humans ; Middle Aged ; Receptors, Chimeric Antigen ; Neoplasm Recurrence, Local ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Immunotherapy, Adoptive ; T-Lymphocytes ; Antigens, CD19 ; Sialic Acid Binding Ig-like Lectin 2
Chemical Substances	Receptors, Chimeric Antigen ; Antigens, CD19 ; CD22 protein, human ; Sialic Acid Binding Ig-like Lectin 2
Language	English
Publishing date	2022-11-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022018598
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 364: Show issues

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial.

Cordoba, Shaun / Onuoha, Shimobi / Thomas, Simon / Pignataro, Daniela Soriano / Hough, Rachael / Ghorashian, Sara / Vora, Ajay / Bonney, Denise / Veys, Paul / Rao, Kanchan / Lucchini, Giovanna / Chiesa, Robert / Chu, Jan / Clark, Liz / Fung, Mei Mei / Smith, Koval / Peticone, Carlotta / Al-Hajj, Muhammad / Baldan, Vania /

Ferrari, Mathieu / Srivastava, Saket / Jha, Ram / Arce Vargas, Frederick / Duffy, Kevin / Day, William / Virgo, Paul / Wheeler, Lucy / Hancock, Jeremy / Farzaneh, Farzin / Domning, Sabine / Zhang, Yiyun / Khokhar, Nushmia Z / Peddareddigari, Vijay G R / Wynn, Robert / Pule, Martin / Amrolia, Persis J

Nature medicine

2021 Volume 27, Issue 10, Page(s) 1797–1805

Abstract: Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially ...

Abstract	Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3-5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.
MeSH term(s)	Adolescent ; Adult ; Antigens, CD19/genetics ; Antigens, CD19/immunology ; Child ; Child, Preschool ; Female ; Humans ; Immunotherapy/adverse effects ; Immunotherapy/trends ; Immunotherapy, Adoptive/adverse effects ; Immunotherapy, Adoptive/trends ; Infant ; Male ; Pediatrics ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy ; Progression-Free Survival ; Receptors, Chimeric Antigen/administration & dosage ; Receptors, Chimeric Antigen/immunology ; Sialic Acid Binding Ig-like Lectin 2/genetics ; Sialic Acid Binding Ig-like Lectin 2/immunology ; Young Adult
Chemical Substances	Antigens, CD19 ; Receptors, Chimeric Antigen ; Sialic Acid Binding Ig-like Lectin 2
Language	English
Publishing date	2021-10-12
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-021-01497-1
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 39: Show issues

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Differential expression of the G-protein-coupled formyl Peptide receptor in melanoma associates with aggressive phenotype.

Chakravarti, Nitin / Peddareddigari, Vijay G R / Warneke, Carla L / Johnson, Marcella M / Overwijk, Willem W / Hwu, Patrick / Prieto, Victor G

The American Journal of dermatopathology

2012 Volume 35, Issue 2, Page(s) 184–190

Abstract: Melanoma, due to its metastatic rate, is among the most aggressive forms of skin cancer. Human formyl peptide receptor (FPR) and its variant FPR-like 1 (FPRL1) have been associated with cell migration and invasiveness in neoplasms. We have studied the in ...

Abstract	Melanoma, due to its metastatic rate, is among the most aggressive forms of skin cancer. Human formyl peptide receptor (FPR) and its variant FPR-like 1 (FPRL1) have been associated with cell migration and invasiveness in neoplasms. We have studied the in situ expression of these receptors in a large series of melanocytic lesions and correlated the expression with clinicopathological features and prognosis. Tissue microarray blocks of 141 cases including nevi (31 cases), primary (84 cases), and metastatic melanomas (26 cases) were semiquantitatively evaluated by immunohistochemistry for the expression of FPR and FPRL1 proteins. A significant association was observed regarding diagnosis and percentage of cells showing expression of FPR (P = 0.0311) and FPRL1 (P = 0.0053). A gain of FPR immunoreactivity was observed in the lesions having ulceration (P = 0.0194) and Breslow thickness (P = 0.044). Also, high FPRL1 cytoplasmic immunoreactivity was seen in lesions without tumor regression (P = 0.04). In addition, in patients with increased cytoplasmic staining for FPR, the probability of disease-specific survival was significantly lower (log rank test, P = 0.0089). Our findings reveal that FPR and FPRL1 are overexpressed in primary melanoma and correlate with aggressive tumor characteristics, underscoring them as potential therapeutic targets.
MeSH term(s)	Biomarkers, Tumor/analysis ; Disease-Free Survival ; Female ; Humans ; Immunohistochemistry ; Male ; Melanoma/metabolism ; Melanoma/mortality ; Melanoma/pathology ; Middle Aged ; Phenotype ; Receptors, Formyl Peptide/analysis ; Receptors, Formyl Peptide/biosynthesis ; Receptors, Lipoxin/analysis ; Receptors, Lipoxin/biosynthesis ; Skin Neoplasms/metabolism ; Skin Neoplasms/mortality ; Skin Neoplasms/pathology ; Tissue Array Analysis
Chemical Substances	Biomarkers, Tumor ; FPR2 protein, human ; Receptors, Formyl Peptide ; Receptors, Lipoxin
Language	English
Publishing date	2012-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	448469-1
ISSN	1533-0311 ; 0193-1091
ISSN (online)	1533-0311
ISSN	0193-1091
DOI	10.1097/DAD.0b013e31825b2506
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 1518: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: NUT midline carcinoma: an aggressive intrathoracic neoplasm.

Parikh, Sameer A / French, Christopher A / Costello, Brian A / Marks, Randolph S / Dronca, Roxana S / Nerby, Craig L / Roden, Anja C / Peddareddigari, Vijay G / Hilton, John / Shapiro, Geoffrey I / Molina, Julian R

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

2013 Volume 8, Issue 10, Page(s) 1335–1338

Abstract: Nuclear protein in testis (NUT) midline carcinoma (NMC) is a poorly differentiated squamous cell carcinoma that is characterized by a balanced translocation between chromosomes 15 and 19 [t(15;19)(q14;p13.1)]. This genetic aberration results in the ... ...

Abstract	Nuclear protein in testis (NUT) midline carcinoma (NMC) is a poorly differentiated squamous cell carcinoma that is characterized by a balanced translocation between chromosomes 15 and 19 [t(15;19)(q14;p13.1)]. This genetic aberration results in the fusion of the NUT gene on chromosome 15 to the bromodomain containing 4 (BRD4) gene on chromosome 19. The resultant BRD4-NUT fusion oncogene leads to global hypoacetylation and transcriptional repression of genes required for differentiation." Although it was first reported in 1991 by Kubonishi et al., awareness of this condition remains low and the diagnosis is overlooked initially in a number of patients. A 36-year-old man complained of cough and right-sided chest pain for 3 weeks before presentation. Imaging studies revealed a right hilar mass, and a bronchoscopic biopsy was consistent with an aggressive poorly differentiated neoplasm. A combination of cisplatin, ifosfamide, and etoposide was administered for two cycles without any improvement. A repeat core biopsy showed focal squamous differentiation; and given the clinical presentation along with the histologic features, NMC was considered in the differential diagnosis. Immunohistochemical staining for NUT was positive, and dual-color break-apart fluorescence in situ hybridization demonstrated BRD4-NUT rearrangement, thereby confirming a diagnosis of NMC. Our patient was subsequently enrolled on a phase 1 clinical trial of a novel, orally bioavailable bromodomain and extra terminal inhibitor, GSK525762 (NCT01587703). This report illustrates the challenges in diagnosing this rare malignancy, and highlights new treatment options for these patients.
MeSH term(s)	Adult ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/pathology ; Cisplatin/administration & dosage ; Etoposide/administration & dosage ; Gene Rearrangement ; Humans ; Ifosfamide/administration & dosage ; In Situ Hybridization, Fluorescence ; Male ; Nuclear Proteins/genetics ; Oncogene Proteins, Fusion/genetics ; Prognosis ; Thoracic Neoplasms/drug therapy ; Thoracic Neoplasms/genetics ; Thoracic Neoplasms/pathology ; Translocation, Genetic
Chemical Substances	BRD4-NUT fusion oncogene protein, human ; Nuclear Proteins ; Oncogene Proteins, Fusion ; Etoposide (6PLQ3CP4P3) ; Cisplatin (Q20Q21Q62J) ; Ifosfamide (UM20QQM95Y)
Language	English
Publishing date	2013-10
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	2432037-7
ISSN	1556-1380 ; 1556-0864
ISSN (online)	1556-1380
ISSN	1556-0864
DOI	10.1097/JTO.0b013e3182a00f41
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 6664: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 652: Show issues

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: ACCELERATE and European Medicines Agency Paediatric Strategy Forum for medicinal product development of checkpoint inhibitors for use in combination therapy in paediatric patients.

Pearson, Andrew D J / Rossig, Claudia / Lesa, Giovanni / Diede, Scott J / Weiner, Susan / Anderson, John / Gray, Juliet / Geoerger, Birgit / Minard-Colin, Veronique / Marshall, Lynley V / Smith, Malcolm / Sondel, Paul / Bajars, Marcis / Baldazzi, Claudia / Barry, Elly / Blackman, Sam / Blanc, Patricia / Capdeville, Renaud / Caron, Hubert /

Cole, Peter D / Jiménez, Jorge Camarero / Demolis, Pierre / Donoghue, Martha / Elgadi, Mabrouck / Gajewski, Thomas / Galluzzo, Sara / Ilaria, Robert / Jenkner, Alessandro / Karres, Dominik / Kieran, Mark / Ligas, Franca / Lowy, Israel / Meyers, Michael / Oprea, Corina / Peddareddigari, Vijay G R / Sterba, Jaroslav / Stockman, Paul K / Suenaert, Peter / Tabori, Uri / van Tilburg, Cornelis / Yancey, Todd / Weigel, Brenda / Norga, Koenraad / Reaman, Gregory / Vassal, Gilles

European journal of cancer (Oxford, England : 1990)

2020 Volume 127, Page(s) 52–66

Abstract: ... mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional ... are being evaluated in adults. Immunotherapy in the form of engineered proteins (e.g ... monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic ...

Abstract	The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination. Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours. Activity has been very limited, however, in more common malignancies of childhood and adolescence. Furthermore, apart from tumour mutational burden, no other predictive biomarker for monotherapy activity in paediatric tumours has been identified. Based on these observations, there is collective agreement that there is no scientific rationale for children to be enrolled in new monotherapy trials of additional checkpoint inhibitors with the same mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional scientific knowledge supporting a different approach becomes available. This shared perspective, based on scientific evidence and supported by paediatric oncology cooperative groups, should inform companies on whether a paediatric development plan is justified. This could then be proposed to regulators through the available regulatory tools. Generally, an academic-industry consensus on the scientific merits of a proposal before submission of a paediatric investigational plan would be of great benefit to determine which studies have the highest probability of generating new insights. There is already a rationale for the evaluation of combinations of checkpoint inhibitors with other agents in paediatric Hodgkin lymphoma and hypermutated tumours in view of the activity shown as single agents. In paediatric tumours where no single agent activity has been observed in multiple clinical trials of anti-PD1, anti-PDL1 and anti-CTLA-4 agents as monotherapy, combinations of checkpoint inhibitors with other treatment modalities should be explored when a scientific rationale indicates that they could be efficacious in paediatric cancers and not because these combinations are being evaluated in adults. Immunotherapy in the form of engineered proteins (e.g. monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic potential for benefit in paediatric cancer. The major challenge for developing checkpoint inhibitors for paediatric cancers is the lack of neoantigens (based on mutations) and corresponding antigen-specific T cells. Progress critically depends on understanding the immune macroenvironment and microenvironment and the ability of the adaptive immune system to recognise paediatric cancers in the absence of high neoantigen burden. Future clinical studies of checkpoint inhibitors in children need to build upon strong biological hypotheses that take into account the distinctive immunobiology of childhood cancers in comparison to that of checkpoint inhibitor responsive adult cancers.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; B7-H1 Antigen/antagonists & inhibitors ; CTLA-4 Antigen/antagonists & inhibitors ; Child ; Drug Development ; Drug Therapy, Combination ; Government Agencies/organization & administration ; Humans ; Immunotherapy/methods ; Needs Assessment ; Neoplasms/drug therapy ; Neoplasms/pathology ; Patient Care Planning/organization & administration ; Prognosis
Chemical Substances	Antineoplastic Agents ; B7-H1 Antigen ; CTLA-4 Antigen ; CTLA4 protein, human
Language	English
Publishing date	2020-01-24
Publishing country	England
Document type	Journal Article
ZDB-ID	82061-1
ISSN	1879-0852 ; 0277-5379 ; 0959-8049 ; 0964-1947
ISSN (online)	1879-0852
ISSN	0277-5379 ; 0959-8049 ; 0964-1947
DOI	10.1016/j.ejca.2019.12.029
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 456: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 583: Show issues

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non-Small Cell Lung Cancer.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

2016 Volume 12, Issue 3, Page(s) 556–566

Abstract: Objectives: This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 ...

Abstract	Objectives: This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations. Methods: Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m Results: The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events-most commonly diarrhea, nausea, and fatigue-were manageable. Conclusions: Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.
MeSH term(s)	Adenocarcinoma/drug therapy ; Adenocarcinoma/secondary ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Large Cell/drug therapy ; Carcinoma, Large Cell/secondary ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/pathology ; Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/secondary ; Docetaxel ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Pemetrexed/administration & dosage ; Prognosis ; Pyridones/administration & dosage ; Pyrimidinones/administration & dosage ; Survival Rate ; Taxoids/administration & dosage
Chemical Substances	Pyridones ; Pyrimidinones ; Taxoids ; Pemetrexed (04Q9AIZ7NO) ; Docetaxel (15H5577CQD) ; trametinib (33E86K87QN)
Language	English
Publishing date	2016-11-19
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Multicenter Study
ZDB-ID	2432037-7
ISSN	1556-1380 ; 1556-0864
ISSN (online)	1556-1380
ISSN	1556-0864
DOI	10.1016/j.jtho.2016.11.2218
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 6664: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 652: Show issues

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial.

Infante, Jeffrey R / Fecher, Leslie A / Falchook, Gerald S / Nallapareddy, Sujatha / Gordon, Michael S / Becerra, Carlos / DeMarini, Douglas J / Cox, Donna S / Xu, Yanmei / Morris, Shannon R / Peddareddigari, Vijay G R / Le, Ngocdiep T / Hart, Lowell / Bendell, Johanna C / Eckhardt, Gail / Kurzrock, Razelle / Flaherty, Keith / Burris, Howard A / Messersmith, Wells A

The Lancet. Oncology

2012 Volume 13, Issue 8, Page(s) 773–781

Abstract: Background: Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and ... ...

Abstract	Background: Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours. Methods: We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622. Findings: We enrolled 206 patients (median age 58·5 years, range 19-92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. Interpretation: The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. Funding: GlaxoSmithKline.
MeSH term(s)	Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/pharmacokinetics ; Area Under Curve ; Biopsy ; Drug Administration Schedule ; Drug Monitoring ; Female ; Half-Life ; Humans ; MAP Kinase Kinase 1/antagonists & inhibitors ; MAP Kinase Kinase 1/metabolism ; MAP Kinase Kinase 2/antagonists & inhibitors ; MAP Kinase Kinase 2/metabolism ; Male ; Maximum Tolerated Dose ; Metabolic Clearance Rate ; Middle Aged ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Neoplasms/pathology ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/adverse effects ; Protein Kinase Inhibitors/pharmacokinetics ; Pyridones/administration & dosage ; Pyridones/adverse effects ; Pyridones/pharmacokinetics ; Pyrimidinones/administration & dosage ; Pyrimidinones/adverse effects ; Pyrimidinones/pharmacokinetics ; Treatment Outcome ; United States ; Young Adult
Chemical Substances	Antineoplastic Agents ; Protein Kinase Inhibitors ; Pyridones ; Pyrimidinones ; trametinib (33E86K87QN) ; MAP2K2 protein, human (EC 2.7.1.-) ; MAP Kinase Kinase 1 (EC 2.7.12.2) ; MAP Kinase Kinase 2 (EC 2.7.12.2) ; MAP2K1 protein, human (EC 2.7.12.2)
Language	English
Publishing date	2012-08
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't ; Webcasts
ZDB-ID	2049730-1
ISSN	1474-5488 ; 1470-2045
ISSN (online)	1474-5488
ISSN	1470-2045
DOI	10.1016/S1470-2045(12)70270-X
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 5696: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 460: Show issues

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial.

The Lancet. Oncology

2012 Volume 13, Issue 8, Page(s) 782–789

Abstract: Background: MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small- ... ...

Abstract	Background: MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma. Methods: We undertook a multicentre, phase 1 three-part study (dose escalation, cohort expansion, and pharmacodynamic assessment). The main results of this study are reported elsewhere; here we present data relating to patients with melanoma. We obtained tumour samples to assess BRAF mutational status, and available tissues underwent exploratory genotyping analysis. Disease response was measured by Response Evaluation Criteria in Solid Tumors, and adverse events were defined by common toxicity criteria. This study is registered with ClinicalTrials.gov, number NCT00687622. Findings: 97 patients with melanoma were enrolled, including 81 with cutaneous or unknown primary melanoma (36 BRAF mutant, 39 BRAF wild-type, six BRAF status unknown), and 16 with uveal melanoma. The most common treatment-related adverse events were rash or dermatitis acneiform (n=80; 82%) and diarrhoea (44; 45%), most of which were grade 2 or lower. No cutaneous squamous-cell carcinomas were recorded. Of 36 patients with BRAF mutations, 30 had not received a BRAF inhibitor before; two complete responses (both confirmed) and ten partial responses (eight confirmed) were noted in this subgroup (confirmed response rate, 33%). Median progression-free survival of this subgroup was 5·7 months (95% CI 4·0-7·4). Of the six patients who had received previous BRAF inhibition, one unconfirmed partial response was recorded. Of 39 patients with BRAF wild-type melanoma, four partial responses were confirmed (confirmed response rate, 10%). Interpretation: Our data show substantial clinical activity of trametinib in melanoma and suggest that MEK is a valid therapeutic target. Differences in response rates according to mutations indicate the importance of mutational analyses in the future. Funding: GlaxoSmithKline.
MeSH term(s)	Administration, Oral ; Adult ; Aged ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; DNA Mutational Analysis ; Disease-Free Survival ; Drug Administration Schedule ; Female ; Humans ; Kaplan-Meier Estimate ; MAP Kinase Kinase 1/antagonists & inhibitors ; MAP Kinase Kinase 1/metabolism ; MAP Kinase Kinase 2/antagonists & inhibitors ; MAP Kinase Kinase 2/metabolism ; Male ; Melanoma/drug therapy ; Melanoma/enzymology ; Melanoma/genetics ; Melanoma/mortality ; Melanoma/pathology ; Middle Aged ; Molecular Targeted Therapy ; Mutation ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/adverse effects ; Proto-Oncogene Proteins B-raf/genetics ; Pyridones/administration & dosage ; Pyridones/adverse effects ; Pyrimidinones/administration & dosage ; Pyrimidinones/adverse effects ; Skin Neoplasms/drug therapy ; Skin Neoplasms/enzymology ; Skin Neoplasms/genetics ; Skin Neoplasms/mortality ; Skin Neoplasms/pathology ; Time Factors ; Treatment Outcome ; United States ; Uveal Neoplasms/drug therapy ; Uveal Neoplasms/enzymology ; Uveal Neoplasms/genetics ; Uveal Neoplasms/mortality ; Uveal Neoplasms/pathology ; Young Adult
Chemical Substances	Antineoplastic Agents ; Protein Kinase Inhibitors ; Pyridones ; Pyrimidinones ; trametinib (33E86K87QN) ; MAP2K2 protein, human (EC 2.7.1.-) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; MAP Kinase Kinase 1 (EC 2.7.12.2) ; MAP Kinase Kinase 2 (EC 2.7.12.2) ; MAP2K1 protein, human (EC 2.7.12.2)
Language	English
Publishing date	2012-07-16
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't ; Webcast
ZDB-ID	2049730-1
ISSN	1474-5488 ; 1470-2045
ISSN (online)	1474-5488
ISSN	1470-2045
DOI	10.1016/S1470-2045(12)70269-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 5696: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 460: Show issues

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: Impact of clinical and pathologic features on tumor-infiltrating lymphocyte expansion from surgically excised melanoma metastases for adoptive T-cell therapy.

Joseph, Richard W / Peddareddigari, Vijay R / Liu, Ping / Miller, Priscilla W / Overwijk, Willem W / Bekele, Nebiyou B / Ross, Merrick I / Lee, Jeffrey E / Gershenwald, Jeffrey E / Lucci, Anthony / Prieto, Victor G / McMannis, John D / Papadopoulos, Nicholas / Kim, Kevin / Homsi, Jade / Bedikian, Agop / Hwu, Wen-Jen / Hwu, Patrick / Radvanyi, Laszlo G

Clinical cancer research : an official journal of the American Association for Cancer Research

2011 Volume 17, Issue 14, Page(s) 4882–4891

Abstract: Purpose: Clinical trials on adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) have shown response rates of over 50% in refractory melanoma. However, little is known how clinical and pathologic features impact TIL ... ...

Abstract	Purpose: Clinical trials on adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) have shown response rates of over 50% in refractory melanoma. However, little is known how clinical and pathologic features impact TIL outgrowth isolated from metastatic melanoma tumors. Experimental design: We analyzed the impact of clinical and pathologic features on initial TIL outgrowth in 226 consecutive patients undergoing tumor resection. Successful initial TIL outgrowth was defined as ≥40 million viable lymphocytes harvested from all tumor fragments in a 5-week culture. To normalize for the different size of resected tumors and thus available tumor fragments, we divided the number of expanded TIL by the starting number of tumor fragments (TIL/fragment). Results: Overall, initial TIL outgrowth was successful in 62% of patients, with patients ≤30 years of age (94%; P = 0.01) and female patients (71% vs. 57% for males; P = 0.04) having the highest rate of success. Systemic therapy 30 days before tumor harvest negatively impacted initial TIL outgrowth compared to patients who never received systemic therapy (47% vs. 71%, P = 0.02). Biochemotherapy within 0 to 60 days of tumor harvest negatively impacted the initial TIL outgrowth with a success rate of only 16% (P < 0.0001). Conclusion: Parameters such as age, sex, and the type and timing of prior systemic therapy significantly affect the success rate of the initial TIL outgrowth from tumor fragments for ACT; these parameters may be helpful in selecting patients for melanoma ACT.
MeSH term(s)	Adolescent ; Adult ; Aged ; Antineoplastic Agents/therapeutic use ; Female ; Humans ; Immunotherapy, Adoptive ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/pathology ; Lymphocytes, Tumor-Infiltrating/transplantation ; Male ; Melanoma/immunology ; Melanoma/pathology ; Melanoma/surgery ; Melanoma/therapy ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Staging ; Risk Factors ; Time Factors ; Treatment Outcome ; Young Adult
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2011-06-01
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-10-2769
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 4223: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾
- See ZB MED holdings
- Order with fees

To top

Full text online

More links

Kategorien

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito