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Phase I Dose-Escalation Study of Seneca Valley Virus (SVV-001), a Replication-Competent Picornavirus, in Patients With Advanced Solid Tumors With Neuroendocrine Features

The primary purpose of the study is to determine if Seneca Valley Virus may be administered safely to patients with certain types of advanced cancer.

开始日期2006-04-01

申办/合作机构

Neotropix, Inc.

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0 项与 Neotropix, Inc. 相关的专利（医药）

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7

项与 Neotropix, Inc. 相关的文献（医药）

2013-05-20·Journal of Clinical Oncology

A randomized double-blind phase II study of the Seneca Valley virus (NTX-010) versus placebo for patients with extensive stage SCLC (ES-SCLC) who were stable or responding after at least four cycles of platinum-based chemotherapy: Alliance (NCCTG) N0923 study.

作者: Mandrekar, Sumithra J. ; Dakhil, Shaker R. ; Dy, Grace K. ; Allen Ziegler, Katie L ; Nieva, Jorge J. ; Molina, Julian R. ; Rudin, Charles M. ; Aubry, Marie-Christine ; Adjei, Alex A. ; Williams, Anthony ; Sachs, Bradley A. ; Schild, Steven E. ; Burroughs, Kevin

7509 Background: NTX-010 is a naturally occurring replication-competent picornavirus with potent and selective tropism for SCLC tumor cells expressing neuroendocrine markers. A phase I study of NTX-010 showed evidence of antitumor activity in patients with SCLC. Methods: ES-SCLC patients (pts) with SD, PR or CR after at least 4 cycles of platinum-based chemotherapy were pre-registered to confirm diagnosis of SCLC with > 1 neuroendocrine marker by a central pathology review. Eligible pts were.randomized 1:1 to placebo (B) or NTX-010 (A). NTX-010 or placebo was administered intravenously as a 1-hour infusion in 100 mL normal saline as a single dose of 1 x1011vp/kg. Viral studies to determine distribution, clearance of the virus and the presence of neutralizing antibodies were done. The primary goal of this trial was to compare the progression-free survival (PFS) of arm A to B based on a sample size of 45 patients per arm to detect an improvement in median PFS from 3 to 5 months (m). A pre-planned interim futility analysis was done after 40 PFS events, and reported here. Results: The trial is permanently closed to accrual. One-hundred and twenty pts were pre-registered, of whom 58 were randomized. Baseline age, gender, ECOG performance status, and histology were balanced between arms. Median age was 63 (range: 44 - 82). 31% of pts had a PS of 0 and 69% of 1. Grade 4 adverse events were seen in 3 (12.5%) patients in arm A and none in arm B. Based on the interim futility analysis, PFS was 1.7 m (95% CI: 1.3-3.1) for arm A and 1.7 m (95% CI: 1.4-4.3) for arm B. Pts with viral RNA at 7 (7 pts) and 14 (6 pts) days had worse PFS compared to those with no detectable levels within arm A (1.0 vs 1.6 m, p=0.02; 0.9 vs. 1.2 m, p=0.06). Median follow-up in pts is 6.1 m. The 3-month OS estimates are 83% (95% CI: 69%-100%) and 85% (70%-100%) for arms A and B respectively. Conclusions: This phase II study showed no benefit in PFS for ES-SCLC patients receiving NTX-010. Pts with detectable virus at 7 and 14 days had worse PFS. Clinical trial information: NCT01017601.

2012-12-01·Journal of General Virology3区 · 医学

Characterization of a full-length infectious cDNA clone and a GFP reporter derivative of the oncolytic picornavirus SVV-001

3区 · 医学

Article

作者: Stump, Kristine L. ; Poirier, John T. ; Hallenbeck, Paul L. ; Rudin, Charles M. ; Li, Shawn S. ; Idamakanti, Neeraja ; Reddy, P. Seshidhar ; Burroughs, Kevin D.

Seneca Valley virus (SVV-001) is an oncolytic picornavirus with selective tropism for a subset of human cancers with neuroendocrine differentiation. To characterize further the specificity of SVV-001 and its patterns and kinetics of intratumoral spread, bacterial plasmids encoding a cDNA clone of the full-length wild-type virus and a derivative virus expressing GFP were generated. The full-length cDNA of the SVV-001 RNA genome was cloned into a bacterial plasmid under the control of the T7 core promoter sequence to create an infectious cDNA clone, pNTX-09. A GFP reporter virus cDNA clone, pNTX-11, was then generated by cloning a fusion protein of GFP and the 2A protein from foot-and-mouth disease virus immediately following the native SVV-001 2A sequence. Recombinant GFP-expressing reporter virus, SVV–GFP, was rescued from cells transfected with in vitro RNA transcripts from pNTX-11 and propagated in cell culture. The proliferation kinetics of SVV-001 and SVV–GFP were indistinguishable. The SVV–GFP reporter virus was used to determine that a subpopulation of permissive cells is present in small-cell lung cancer cell lines previously thought to lack permissivity to SVV-001. Finally, it was shown that SVV–GFP administered to tumour-bearing animals homes in to and infects tumours whilst having no detectable tropism for normal mouse tissues at 1×1011 viral particles kg−1, a dose equivalent to that administered in ongoing clinical trials. These infectious clones will be of substantial value in further characterizing the biology of this virus and as a backbone for the generation of additional oncolytic derivatives.

2008-10-01·Structure2区 · 生物学

Structure of Seneca Valley Virus-001: An Oncolytic Picornavirus Representing a New Genus

2区 · 生物学

Article

作者: Sangita Venkataraman ; Neeraja Idamakanti ; Vijay S. Reddy ; Seshidhar P. Reddy ; Paul L. Hallenbeck ; Jackie Loo

The crystal structure of Seneca Valley Virus-001 (SVV-001), the representative member of a new genus, Senecavirus, is reported at 2.3A resolution. SVV-001 is the first naturally occurring nonpathogenic picornavirus shown to mediate selective cytotoxicity towards tumor cells with neuroendocrine cancer features. The nonsegmented (+) ssRNA genome of SVV-001 shares closest sequence similarity with the genomes of the members of Cardiovirus. The overall tertiary structure of VP1-VP4 subunits is conserved with the exception of loops, especially those of VP1 that show large deviations relative to the members of the cardioviruses. The surface loops of VP1 and VP2 are predicted to mediate cell tropism of SVV-001. In addition, the organization of the packaged nucleic acid density indicates that certain regions of VP2 and VP4 interact closely with the packaged nucleic acid.

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