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Lorusso D.,Catholic University of Rome | Scambia G.,Catholic University of Rome | Amadio G.,Catholic University of Rome | Di Legge A.,Catholic University of Rome | And 10 more authors.
British Journal of Cancer | Year: 2012

Background: The NGR-hTNF (asparagine-glycine-arginine-human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels. Methods: Patients progressing after ≥ 1 platinum/taxane-based regimen received NGR-hTNF 0.8 g m -2 and doxorubicin 60 mg m -2 every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients. Results: A total of 37 patients with platinum-free interval lower than 6 months (PFI=6; n=25), or between 6 and 12 months (PFI=6-12; n=12) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6 per ml (interquartile range, 1.2-2.1). In all, 18 patients (49%) received more than 6 cycles. Febrile neutropaenia was registered in one patient (3%). Among 35 assessable patients, 8 (23%; 95% CI 12-39%) had partial response (2 with PFI6; 6 with PFI=6-12) and 15 (43%) had stable disease (10 with PFI=6; 5 with PFI=6-12). Median progression-free survival (PFS) was 5.0 months for all patients, 3.8 months for patients with PFI6, and 7.8 months for patients with PFI=6-12. Median overall survival (OS) was 17.0 months. Patients with baseline PBLC higher than the first quartile had improved PFS (P=0.01) and OS (P=0.001). Conclusion: Tolerability and activity of this combination warrant further randomised testing in patients with PFI=6. The role of PBLC as a blood-based biomarker deserves further investigation. © 2012 Cancer Research UK All rights reserved.


Corti A.,Tumor Biology and Vascular Targeting Unit | Caligaris-Cappio F.,Vita-Salute San Raffaele University | Maschio A.D.,Vita-Salute San Raffaele University | Troysi A.,MolMed | And 3 more authors.
European Journal of Cancer | Year: 2010

Background: NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-α) fused to the tumour-homing peptide NGR, a ligand of an aminopeptidase N/CD13 isoform, which is overexpressed on endothelial cells of newly formed tumour blood vessels. NGR-TNF showed a biphasic dose-response curve in preclinical models. This study exploring the low-dose range aimed to define safety and optimal biological dose of NGR-hTNF. Patients and methods: Pharmacokinetics, plasma biomarkers and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated at baseline and after each cycle in 16 patients enrolled at four doubling-dose levels (0.2-0.4-0.8-1.6 μg/m2). NGR-hTNF was given intravenously as 1-h infusion every 3 weeks (q3w). Tumour response was assessed q6w. Results: Eighty-three cycles (median, 2; range, 1-29) were administered. Most frequent treatment-related toxicity was grade 1-2 chills (69%), occurring during the first infusions. Only one patient treated at 1.6 μg/m2 had a grade 3 drug-related toxicity (chills and dyspnoea). Both Cmax and AUC increased proportionally with dose. No shedding of soluble TNF-α receptors was observed up to 0.8 μg/m2. Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of Ktrans, which was more pronounced at 0.8 μg/m2. Seven patients (44%) had stable disease for a median time of 5.9 months, including a colon cancer patient who experienced an 18-month progression-free time. Conclusion: Based on tolerability, soluble TNF-receptors kinetics, anti-vascular effect and disease control, NGR-hTNF 0.8 μg/m2 will be further developed either as single-agent or with standard chemotherapy. © 2009 Elsevier Ltd. All rights reserved.


De Braud F.G.,Instituto Europeo Of Oncologia | De Pas T.M.,Instituto Europeo Of Oncologia | Scalamogna R.,Instituto Europeo Of Oncologia | Milani A.,Instituto Europeo Of Oncologia | And 10 more authors.
Clinical Cancer Research | Year: 2011

Purpose: NGR-hTNF exploits the tumor-homing peptide asparagine-glycine- arginine (NGR) for selectively targeting TNF-α to an aminopeptidase N overexpressed on cancer endothelial cells. Preclinical synergism with cisplatin was displayed even at low doses. This study primarily aimed to explore the safety of low-dose NGR-hTNF combined with cisplatin in resistant/refractory malignancies. Secondary aims included pharmacokinetics (PKs), pharmacodynamics, and activity. Experimental Design: NGR-hTNF was escalated using a doubling-dose scheme (0.2-0.4-0.8-1.6 μg/m 2) in combination with fixed-dose of cisplatin (80 mg/m 2), both given intravenously once every three weeks. PKs and circulating TNF-receptors (sTNF-Rs) were assessed over the first three cycles. Results: Globally, 22 patients (12 pretreated with platinum) received a range of one to ten cycles. Consistently with the low-dose range tested, maximum-tolerated dose was not reached. No dose-limiting toxicities (DLTs) were observed at 0.2 (n = 4) and 0.4 μg/m 2 (n = 3). One DLT (grade 3 infusion-related reaction) was observed at 0.8 μg/m 2. This dose cohort was expanded to six patients without further DLTs. No DLTs were noted also at 1.6 μg/m 2 (n=3). NGR-hTNF exposure increased dose-proportionally without apparent PK interactions with cisplatin. No shedding of sTNF-Rs was detected up to 0.8 μg/m 2. At the dose level of 0.8 μg/m 2, expanded to 12 patients for activity assessment, a platinum-pretreated lung cancer patient achieved a partial response lasting more than six months and five patients maintained stable disease for a median time of 5.9 months. Conclusions: The combination of NGR-hTNF 0.8 μg/m 2 with cisplatin 80 mg/m 2 showed favorable toxicity profile and promising antitumor activity. ©2011 AACR.


Santoro A.,Instituto Clinico Humanitas | Pressiani T.,Instituto Clinico Humanitas | Citterio G.,Instituto Scientif Ico San Raffaele | Rossoni G.,Instituto Scientif Ico San Raffaele | And 13 more authors.
British Journal of Cancer | Year: 2010

Background:Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels.Methods:Twenty-seven patients with advanced-stage disease resistant to either locoregional (59%; range, 1-3), systemic treatments (52%; range, 1-3) or both (33%) received NGR-hTNF 0.8 gm-2 once every 3 weeks. The primary aim of the study was progression-free survival (PFS).Results:No grade 3-4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7-2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5-10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months.Conclusion:NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest. © 2010 Cancer Research UK All rights reserved.


News Article | December 19, 2016
Site: marketersmedia.com

— Neuroendocrine Tumors - Companies Involved in Therapeutics Development are AbbVie Inc, Advanced Accelerator Applications SA, Aegis Therapeutics LLC, Amgen Inc, Amryt Pharma plc, AVEO Pharmaceuticals Inc, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Celgene Corp, Chiasma Inc, Crinetics Pharmaceuticals Inc, Daiichi Sankyo Company Ltd, DexTech Medical AB, Eisai Co Ltd, Eli Lilly and Company, Esperance Pharmaceuticals Inc, Exelixis Inc, Foresee Pharmaceuticals LLC, Hutchison MediPharma Ltd, INVENT Pharmaceuticals Inc, Ipsen SA, Jiangsu Hengrui Medicine Co Ltd, Karyopharm Therapeutics Inc, Lexicon Pharmaceuticals Inc, Mateon Therapeutics Inc, Merck & Co Inc, Midatech Pharma Plc, Millennium Pharmaceuticals Inc, MolMed SpA, Northwest Biotherapeutics Inc, Novartis AG, Peptron Inc, Pfizer Inc, Pharma Mar SA, Progenics Pharmaceuticals Inc, Provectus Biopharmaceuticals Inc, Strongbridge Biopharma plc, Taiwan Liposome Company Ltd, Threshold Pharmaceuticals Inc, Vascular Biogenics Ltd and Xencor Inc. Neuroendocrine tumor begins in the hormone-producing cells of the body’s neuroendocrine system, which is made up of cells that are a cross between traditional endocrine cells (or hormone-producing cells) and nerve cells. Symptom includes hyperglycemia, diarrhea, loss of appetite/weight loss, thickening or lump in any part of the body, jaundice, headache, anxiety and gastric ulcer disease. Treatments include surgery, radiation therapy and chemotherapy. The Neuroendocrine Tumors (Oncology) pipeline guide also reviews of key players involved in therapeutic development for Neuroendocrine Tumors and features dormant and discontinued projects. The guide covers therapeutics under Development by Companies /Universities /Institutes, the molecules developed by Companies in Pre-Registration, Phase III, Phase II, Phase I and Preclinical stages are 2, 1, 26, 18 and 12 respectively. Similarly, the Universities portfolio in Phase II and Preclinical stages comprises 2 and 1 molecules, respectively. Neuroendocrine Tumors (Oncology) pipeline guide helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. The guide is built using data and information sourced from Global Markets Directs proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, investor presentations and featured press releases from company/university sites and industry-specific third party sources. Additionally, various dynamic tracking processes ensure that the most recent developments are captured on a real time basis. Inquire more about this report at http://www.reportsnreports.com/contacts/inquirybeforebuy.aspx?name=786902 Note:Certain content / sections in the pipeline guide may be removed or altered based on the availability and relevance of data. • The pipeline guide provides a snapshot of the global therapeutic landscape of Neuroendocrine Tumors (Oncology). • The pipeline guide reviews pipeline therapeutics for Neuroendocrine Tumors (Oncology) by companies and universities/research institutes based on information derived from company and industry-specific sources. • The pipeline guide covers pipeline products based on several stages of development ranging from pre-registration till discovery and undisclosed stages. • The pipeline guide features descriptive drug profiles for the pipeline products which comprise, product description, descriptive licensing and collaboration details, R&D brief, MoA & other developmental activities. • The pipeline guide reviews key companies involved in Neuroendocrine Tumors (Oncology) therapeutics and enlists all their major and minor projects. • The pipeline guide evaluates Neuroendocrine Tumors (Oncology) therapeutics based on mechanism of action (MoA), drug target, route of administration (RoA) and molecule type. • The pipeline guide encapsulates all the dormant and discontinued pipeline projects. • The pipeline guide reviews latest news related to pipeline therapeutics for Neuroendocrine Tumors (Oncology) • Procure strategically important competitor information, analysis, and insights to formulate effective R&D strategies. • Recognize emerging players with potentially strong product portfolio and create effective counter-strategies to gain competitive advantage. • Find and recognize significant and varied types of therapeutics under development for Neuroendocrine Tumors (Oncology). • Classify potential new clients or partners in the target demographic. • Develop tactical initiatives by understanding the focus areas of leading companies. • Plan mergers and acquisitions meritoriously by identifying key players and it’s most promising pipeline therapeutics. • Formulate corrective measures for pipeline projects by understanding Neuroendocrine Tumors (Oncology) pipeline depth and focus of Indication therapeutics. • Develop and design in-licensing and out-licensing strategies by identifying prospective partners with the most attractive projects to enhance and expand business potential and scope. • Adjust the therapeutic portfolio by recognizing discontinued projects and understand from the know-how what drove them from pipeline. For more information, please visit http://www.reportsnreports.com/reports/786902-neuroendocrine-tumors-pipeline-review-h2-2016.html


Biffi A.,San Raffaele Scientific Institute | Montini E.,San Raffaele Scientific Institute | Lorioli L.,San Raffaele Scientific Institute | Lorioli L.,Vita-Salute San Raffaele University | And 38 more authors.
Science | Year: 2013

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.


Zucali P.A.,Humanitas Cancer Center | Simonelli M.,Humanitas Cancer Center | De Vincenzo F.,Humanitas Cancer Center | Lorenzi E.,Humanitas Cancer Center | And 13 more authors.
British Journal of Cancer | Year: 2013

Background:NGR-hTNF exploits the peptide asparagine-glycine-arginine (NGR) for selectively targeting tumour necrosis factor (TNF) to CD13-overexpressing tumour vessels. Maximum-tolerated dose (MTD) of NGR-hTNF was previously established at 45 μg m-2 as 1-h infusion, with dose-limiting toxicity being grade 3 infusion-related reactions. We explored further dose escalation by slowing infusion rate (2-h) and using premedication (paracetamol).Methods:Four patients entered each of 12 dose levels (n=48; 60-325 μg m-2). Pharmacokinetics, soluble TNF receptors (sTNF-R1/sTNF-R2), and volume transfer constant (K trans) by dynamic imaging (dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)) were assessed pre-and post-treatment.Results:Common related toxicity included grade 1/2 chills (58%). Maximum-tolerated dose was not reached. Both C max (P<0.0001) and area under the plasma concentration-time curve (P=0.0001) increased proportionally with dose. Post-treatment levels of sTNF-R2 peaked significantly higher than sTNF-R1 (P<0.0001). Changes in sTNF-Rs, however, did not differ across dose levels, suggesting a plateau effect in shedding kinetics. As best response, 12/41 evaluable patients (29%) had stable disease. By DCE-MRI, 28/37 assessed patients (76%) had reduced post-treatment K trans values (P<0.0001), which inversely correlated with NGR-hTNF C max (P=0.03) and baseline K trans values (P<0.0001). Lower sTNF-R2 levels and greater K trans decreases after first cycle were associated with improved survival.Conclusion:asparagine-glycine- arginine-hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects. © 2013 Cancer Research UK. All rights reserved.


Van Laarhoven H.W.M.,Radboud University Nijmegen | Fiedler W.,Universitats Krankenhaus Hamburg Eppendorf | Desar I.M.E.,Radboud University Nijmegen | Van Asten J.J.A.,Radboud University Nijmegen | And 11 more authors.
Clinical Cancer Research | Year: 2010

Purpose: This phase I trial investigating the vascular targeting agent NGR-hTNF aimed to determine the (a) dose-limiting toxicities, (b) maximum tolerated dose (MTD), (c) pharmacokinetics and pharmacodynamics, (d) vascular response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and (e) preliminary clinical activity in solid tumors. Experimental Design: NGR-hTNF was administered once every 3 weeks by a 20- to 60-minute i.v. infusion to cohorts of three to six patients with solid tumors in escalating doses. Pharmacokinetic and pharmacodynamic analyses in blood were done during the first four cycles. DCE-MRI was done in cycle 1 at baseline and 2 hours after the start of the infusion. Results: Sixty-nine patients received a total of 201 cycles of NGR-hTNF (0.2-60 μg/m2). Rigors and fever were the most frequently observed toxicities. Four dose-limiting toxicities were observed (at doses of 1.3, 8.1, and 60 μg/m2), of which three were infusion related. The MTD was 45 μg/m2. The mean apparent terminal half-life ranged from 0.963 to 2.08 hours. DCE-MRI results of tumors showed a vascular response to NGR-hTNF. No objective responses were observed, but 27 patients showed stable disease with a median duration of 12 weeks. Conclusions: NGR-hTNF was well tolerated. The MTD was 45 μg/m2 administered in 1 hour once every 3 weeks. DCE-MRI results showed the antivascular effect of NGR-hTNF. These findings call for further research for defining the optimal biological dose and clinical activity of NGR-hTNF as a single agent or in combination with cytotoxic drugs. ©2010 AACR.


Borchers S.,Hannover Medical School | Provasi E.,San Raffaele Hospital | Silvani A.,MolMed | Radrizzani M.,MolMed | And 13 more authors.
Human Gene Therapy | Year: 2011

Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with CD34 + cell-enriched stem cells (HSCTs) without further immunosuppression. The myeloablative standard transplantation protocol was adapted to include transfusion of gene-modified donor T cells after HSCT. Donor T cells were transduced with the replication-deficient retrovirus SFCMM-3, which expresses herpes simplex thymidine kinase (HSV-Tk) and a truncated version of low-affinity nerve growth factor receptor (ΔLNGFR) for selection and characterization of transduced cells. Transduced T cells were detectable in all patients during follow-up for up to 5 years after transfusion. Proteomic screening for development of acute graft-versus-host disease (aGvHD) was applied to five of the seven patients with AML. No positivity for the aGvHD grade II-specific proteomic pattern was observed. Only one patient developed aGvHD grade I. To date, three of the patients with AML relapsed; one responded to three escalating transfusions of lymphocytes from the original donor and is in complete remission. Two were retransplanted with non-T cell-depleted peripheral blood stem cells from their original donors and died after retransplantation of septic complications or relapse, respectively. In one patient with CML, loss of bcr-abl gene expression was observed after an expansion of transduced cells. Seven of nine patients are alive and in complete remission. © 2011, Mary Ann Liebert, Inc.


Weissinger E.M.,Hannover Medical School | Borchers S.,Hannover Medical School | Silvani A.,MolMed | Provasi E.,Cancer Immunotherapy and Gene Therapy Program | And 14 more authors.
Frontiers in Pharmacology | Year: 2015

Allogeneic stem cell transplantation (allo-HSCT) is one of the curative treatments for hematologic malignancies, but is hampered by severe complications, such as acute or chronic graft-versus-host-disease (aGvHD; cGvHD) and infections. CD34-selcetion of stem cells reduces the risk of aGvHD, but also leads to increased infectious complications and relapse. Thus, we studied the efficacy, safety and feasibility of transfer of gene modified donor T-cells shortly after allo-HSCT in two clinical trials between 2002 and 2007 and here we compare the results to unmodified donor leukocyte transfusion (DLI). The aim of these trials was to provide patients with the protection of T-cells after T-cell-depleted allo-HSCT in the matched or mismatched donor setting with an option to delete transduced T-cells, if severe aGvHD occurred within the trial period. Donor-T-cells were transduced with the replication-deficient retrovirus SFCMM-3, expressing HSV-Tk and the truncated LNGFR for selection of transduced cells. Transduced cells were transfused either after day +60 (matched donors) or on day +42 (haploidentical donors).Nine patients were included in the first trial (MHH; 2002 until 2007) 2 were included in TK007 (2005-2009) and 6 serve as a control group for outcome after haploidentical transplantation without HSV-TKtransduced DLI. Three patients developed acute GvHD, two had grade I of the skin, one had aGvHD on day +131 (post-HSCT; +89 post-HSV-Tk DLI) grade II, which was successfully controlled by ganciclovir (GCV). Donor chimerism was stabilized after transfusion of the transduced cells in all patients treated. Functionality of HSVTk gene expressing T-cells was shown by loss of bcr-abl gene expression as well as by control of cytomegalovirus-reactivation. To date, 6patients have relapsed and died, 2 after a second HSCT without T-cell depletion or administration of unmodified T-cells. Eleven patients (7 post-HSV-Tk DLI) are alive and well to date. © 2015 Weissinger, Borchers, Silvani, Provasi, Radrizzani, Beckmann, Benati, Schmidtke, Kuehnau, Schweier, Luther, Fernadez-munoz, Beutel, Ciceri, Bonini, Ganser, Hertenstein and Stadler.

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