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For most advanced solid tumors, current therapy is inadequate at improving quality of life, slowing progression of disease, prolonging survival, and providing a cure. Hence, there is a continuous need for innovative, safer and more effective anti-cancer therapies. Our study is based on the dependence receptor paradigm and the associated therapeutic strategy. In preclinical models, preventing Netrin-1 interaction with its receptors is sufficient to trigger Netrin-1-expressing tumor cell death in vitro as well as tumor growth and metastasis inhibition in vivo. This indicates that a therapeutic approach based on Netrin-1/Netrin-1 receptors interaction inhibition is both feasible and promising. NP137 is a "first-in-class" humanized monoclonal antibody targeting the Netrin-1 ligand, a secreted protein recently described as a driver of tumor initiation and progression. NP137 demonstrated anti-tumor activity as a single agent in several pre-clinical models of cancer, including breast and lung cancer. Taken together, several studies strongly support the rational for preclinical development and clinical evaluation of a highly potent and selective anti-Netrin-1 antibody in cancer patients. The proposed study is an open label, multicenter, Phase I dose escalation study to assess the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and preliminary anti-tumor activity of NP137 administered every 2 weeks (Q2W) as single agent in patients with locally advanced or metastatic solid tumors. This trial will be the First in Human (FIH) study for NP137; there is no clinical experience with this antibody in the clinic. Dose escalation part will define the Maximum tolerated dose and the Recommended Phase II dose (MTD /RP2D) of NP137 and Expansion part will assess the PD and anti-tumor activity of NP137.
The dose escalation part (NP137 administered as a single agent by intravenous injection with up to 7 ascending dose levels) will be initiated with an accelerated dose titration with 1 patient per DL until the occurrence of a ≥ Grade 2 drug-related AE. Following the occurrence of such moderate toxicity, patients will be enrolled in a slower dose escalation design with at least 3 patients per DL using a Modified Continual Reassessment Method. Of note, in case no toxicity occurs up to the DL4, the classical 3+3 design will be initiated. In both parts, NP137 will continue to be administered as long as patient experience clinical benefit in the opinion of the investigator or until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent or patient willingness to stop the treatment. In the expansion part, patients will be treated at the RP2D defined in Part 1.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Advanced Solid Tumor
Centre Léon Bérard
Not yet recruiting
Centre Leon Berard
Published on BioPortfolio: 2016-12-01T16:08:22-0500
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