This is a clinical trial examining the vascular disrupting agent NPI-2358 combined with docetaxel in patients with advanced non-small cell lung cancer (NSCLC). The formation of new blood vessels (angiogenesis) is an important component of tumor growth, vascular disrupting agents are intended to target the differences between these tumor blood vessels and the blood vessels in normal tissues.

Start Date01 Feb 2008

Sponsor / Collaborator

Nereus Pharmaceuticals, Inc.

NCT00322608 / CompletedPhase 1

Phase I Study of the Vascular Disrupting Agent NPI-2358 Administered Via Intravenous Infusion in Patients With Advanced Solid Tumor Malignancies or Lymphoma

This is a Phase 1 clinical trial examining the safety, pharmacokinetics and pharmacodynamics of escalating doses of the vascular disrupting agent NPI-2358 in patients with refractory solid tumors or lymphoma. The formation of new blood vessels (angiogenesis) is an important component of tumor growth and vascular disrupting agents are intended to target the differences between these tumor blood vessels and the blood vessels in normal tissues. NPI-2358 has also been seen to directly affect tumor cells.

Start Date01 Apr 2006

Sponsor / Collaborator

Nereus Pharmaceuticals, Inc.

100 Clinical Results associated with Nereus Pharmaceuticals, Inc.

0 Patents (Medical) associated with Nereus Pharmaceuticals, Inc.

110

Literatures (Medical) associated with Nereus Pharmaceuticals, Inc.

01 Oct 2014·Cancer Research

Abstract 1809: Marizomib (NPI-0052) activity as a single agent in malignant glioma

Author: Bota, Daniela A. ; Gong, Xing ; Palladino, Michael A. ; Curticiu, Dana M. ; Di, Kaijun

AbstractBackground: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor, which displays innate resistance to multiple treatment modalities. Previous studies have shown that the proteasome plays a vital role in the physiology of GBM, and that proteasome inhibition can be used as a strategy for treating malignant gliomas. Marizomib (NPI-0052) is a second generation irreversible proteasome inhibitor, which has a more lipophilic structure and has a broader and more prolonged inhibition profile for 20S proteasome activities compared to bortezomib and carfilzomib, two proteasome inhibitors approved by FDA for treatment of multiple myeloma. While bortezomib and carfilzomib have only modest activity as a treatment of malignant gliomas, marizomib might potentially be a novel therapeutic strategy for primary brain tumors. Unfortunately, to date, the number of studies that have analyzed the effect of marizomib on glioma is limited.Methods: In these studies, we investigated the in vitro activities of marizomib in primary cell cultures derived from a multitude of human brain tumors (high-grade and low-grade gliomas and meningiomas), normal neural stem/progenitor cells (NSC) and as well as in the established human malignant glioma lines U251-MG and D54-MG. The effect of marizomib on cell proliferation, proteasome activity, motility, apoptosis and Reactive Oxygen Species (ROS) were evaluated in glioma cell lines. The inhibition of marizomib by the ROS quenching agent, N-acetyl cysteine (NAC) was also tested.Results: The sensitivities varied in function of the pathology of the tumor, with the malignant glioma stem-like cells being the most severely affected, in contrast with the low-grade glioma, meningioma and NSC-derived cultures. Marizomib inhibited the proliferation of U251-MG and D54-MG cell lines with a half maximal effective concentration (EC50) of 52nM and 20nM respectively, along with a significant decrease in cell migration and invasion. Treatment with marizomib at a concentration of 60nM for 4 hours inhibited proteasome chymotrypsin-like (CT-L, β5) activity by 85% in U251-MG and D54-MG cells. Marizomib treatment of human glioma cells was associated with increased free radical production and apoptosis, along with activation of caspase-3 and cleavage of PARP. Those effects of marizomib can be suppressed by exposure to the ROS quenching agent N-acetyl cysteine (NAC).Conclusion: These preclinical studies demonstrate a significant anti-tumor effect of marizomib in malignant glioma cells. Marizomib has relatively little effect on neural stem/progenitor cells suggesting minimal neurotoxicity, while severely affecting both malignant glioma stem cells and glioma cell lines. But importantly, unlike bortezomib and carfilzomib, marizomib can cross the blood brain barrier. Additional research into the use of marizomib as a potential treatment for malignant gliomas as a single agent or in combination with SOC therapies for glioma is warranted.Citation Format: Kaijun Di, Xing Gong, Dana M. Curticiu, Michael A. Palladino, Daniela A. Bota. Marizomib (NPI-0052) activity as a single agent in malignant glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1809. doi:10.1158/1538-7445.AM2014-1809

20 May 2014·Journal of Clinical Oncology

Randomized phase 2 trial of plinabulin (NPI-2358) plus docetaxel in patients with advanced non-small cell lung cancer (NSCLC).

Author: Heist, Rebecca Suk ; Aren, Osvaldo Rudy ; Lloyd, G Kenneth ; Mikrut, William ; Spear, Matthew A. ; Mita, Alain C. ; Huang, Lan ; Polikoff, Jonathan ; Bazhenova, Lyudmila ; Reich, Steven D.

8054 Background: Plinabulin (N) inhibits tumor growth by targeting both angiogenesis and tumor vasculature as well as directly by inducing apoptosis via the Ras-JNK pathway. This trial compared the...

01 Dec 2012·Investigational New DrugsQ3 · MEDICINE

Phase I clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma

Q3 · MEDICINE

Article

Author: Jakob Dupont ; Martee L. Hensley ; Alison L. Hannah ; Jae Park ; Rachel N. Grisham ; Owen A. O’Connor ; Carol Aghajanian ; Samuel Danishefsky ; David R. Spriggs ; Svetlana Mironov ; Paul Sabbatini ; Jason Konner ; Robert Johnson ; David Hyman ; Gillian Cropp

PURPOSETo determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma.PATIENTS AND METHODSPatients were treated weekly for 3 out of 4 weeks (Schedule A) or 2 out of 3 weeks (Schedule B) with KOS-862 (16-120 mg/m(2)). Pharmacokinetic (PK) sampling was performed during cycles 1 and 2; pharmacodynamic (PD) assessment for microtubule bundle formation (MTBF) was performed after the 1st dose, only at or above 100 mg/m(2).RESULTSThirty-two patients were enrolled, and twenty-nine completed ≥1 cycle of therapy. Dose limiting toxicity [DLT] was observed at 120 mg/m(2). PK data were linear from 16 to 100 mg/m(2), with proportional increases in mean C(max) and AUC(tot) as a function of dose. Full PK analysis (mean ± SD) at 100 mg/m(2) revealed the following: half-life (t (½)) = 9.1 ± 2.2 h; volume of distribution (V(z)) = 119 ± 41 L/m(2); clearance (CL) = 9.3 ± 3.2 L/h/m(2). MTBF (n = 9) was seen in 40% of PBMCs within 1 h and in 15% of PBMC at 24-hours post infusion at 100 mg/m(2). Tumor shrinkage (n = 2, lymphoma), stable disease >3 months (n = 5, renal, prostate, oropharynx, cholangiocarcinoma, and Hodgkin lymphoma), and tumor marker reductions (n = 1, colorectal cancer/CEA) were observed.CONCLUSIONKOS-862 was well tolerated with manageable toxicity, favorable PK profile, and the suggestion of clinical activity. The maximum tolerated dose was determined to be 100 mg/m(2) weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862.

100 Deals associated with Nereus Pharmaceuticals, Inc.

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

NPI-1302a-3 ( TNF )	Rheumatoid Arthritis More	Discontinued
NPI-3114	Gram-Positive Bacterial Infections More	Discontinued
NPI-3304	Gram-Positive Bacterial Infections More	Discontinued
NPI-1432a	Osteoarthritis More	Pending
Plinabulin ( GEF-H1 x KRAS )	Advanced Malignant Solid Neoplasm More	Pending

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