First in Human Evaluation of Safety, Pharmacokinetics, and Clinical Activity of a Monoclonal Antibody Targeting Netrin 1 in Patients With Advanced/Metastatic Solid Tumors

Summary

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. The study consists of 3 parts: Part 1) a dose escalation part to define the Maximum tolerated dose and the Recommended Phase II dose (MTD /RP2D) of NP137 as well as to research some PD biomarkers (Biological collection cohorts) - This part is now completed with Last Patient In on December 20th 2018 - Part 2) an expansion part#1 to investigate NP137 clinical activity as a single agent by collecting the 3-month objective response rate (ORR3m). Part 3) an expansion part#2 to investigate NP137 clinical activity as a single agent by collecting the 3-month objective response rate (ORR3m) in RH+ patients with endometrial carcinoma.

Timeline

Start

2017-01-09

Primary completion

2021-12

Completion

2022-06

Publications

• Lengrand J, Pastushenko I, Vanuytven S, Song Y, Venet D, Sarate RM, Bellina M, Moers V, Boinet A, Sifrim A, Rama N, Ducarouge B, Van Herck J, Dubois C, Scozzaro S, Lemaire S, Gieskes S, Bonni S, Collin A, Braissand N, Allard J, Zindy E, Decaestecker C, Sotiriou C, Salmon I, Mehlen P, Voet T, Bernet A, Blanpain C. Pharmacological targeting of netrin-1 inhibits EMT in cancer. Nature. 2023 Aug;620(7973):402-408. doi: 10.1038/s41586-023-06372-2. Epub 2023 Aug 2.
• Sun Y, Manceau A, Frydman L, Cappuccio L, Neves D, Basso V, Wang H, Fombonne J, Maisse C, Mehlen P, Paradisi A. Delta40p53 isoform up-regulates netrin-1/UNC5B expression and potentiates netrin-1 pro-oncogenic activity. Proc Natl Acad Sci U S A. 2021 Sep 7;118(36):e2103319118. doi: 10.1073/pnas.2103319118.

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