A first in human, phase 1 trial of NP137, a first-in-class antibody targeting netrin-1, in patients with advanced refractory solid tumors.

Date 29 September 2019
Event ESMO 2019 Congress
Session Proffered Paper – Developmental therapeutics
Topics Biological Therapy
Presenter Philippe Cassier
Citation Annals of Oncology (2019) 30 (suppl_5): v159-v193. 10.1093/annonc/mdz244
Authors P. Cassier1, L. Eberst1, G. Garin2, Y. Courbebaisse3, C. Terret1, M. Robert4, J. Frenel5, S. Depil1, J. Delord6, D. Perol7, I.L. Ray-Coquard1, A. Bidaux8, S. Tabone-Eglinger9, L. Gilles-Afchain1, I. TREILLEUX10, Q. Wang11, B. Ducarouge12, P. Mehlen13, J. Blay14, C.A. Gomez-Roca15
  • 1Medical Oncology, Centre Léon Bérard, 69008 - Lyon/FR
  • 2Direction De La Recherche Clinique Et De L'innovation, Centre Léon Bérard, 69008 - Lyon/FR
  • 3/, Société COURBEBAISSE YANN, 69008 - Lyon/FR
  • 4Medical Oncology, Centre Rene Gauducheau, 44800 - Nantes/FR
  • 5Medical Oncology, ICO Institut de Cancerologie de l'Ouest René Gauducheau, 44805 - Saint-Herblain/FR
  • 6Medical Oncology, Institut Universitaire du Cancer -Toulouse- Oncopole, 31059 - Toulouse/FR
  • 7Clinical Research, Centre Léon Bérard, 69008 - Lyon/FR
  • 8Drci Promotion, Centre Léon Bérard, 69008 - Lyon/FR
  • 9Cancérologie, Centre Léon-Bérard, 69008 - Lyon/FR
  • 10Pathology, Centre Léon Bérard, 69008 - Lyon/FR
  • 11Recherche Translationnelle, Centre Léon Bérard, 69008 - Lyon/FR
  • 12Preclinical Science, Netris Pharma, 69008 - Lyon/FR
  • 13/, Netris Pharma, 69008 - Lyon/FR
  • 14Medicine, Centre Léon Bérard, 69008 - Lyon/FR
  • 15Medical Oncology & Clinical Research, Institut Universitaire du Cancer -Toulouse- Oncopole, 31059 - Toulouse/FR

Abstract

Background

Netrin-1, a dependence receptor ligand, is overexpressed in many cancers and leads to resistance to cell death. In preclinical studies, targeting netrin-1 with the humanized anti-netrin-1 antibody NP137 inhibits tumor growth and metastasis.

Methods

Adults with advanced, refractory solid tumors received NP137 IV Q2W, starting at 1 mg/kg. Dose was escalated using a rapid titration design followed by a model-based design with 3-6 pts per cohort; Additional patients (pts) were enrolled in 4 biomarker cohorts, at dose levels that had been declared safe, starting at 6 mg/kg, and underwent paired biopsies for pharmacodynamics (PD) purposes.

Results

Nineteen pts were enrolled in 7 dose levels (1 to 20 mg/kg). No DLTs were observed but 11 (58%) had infusion related reactions (IRR) of grade 1-2 severity, all at doses of 4 mg/kg and above. Twenty-three pts were enrolled in the biomarker cohorts (up to 6 pts per cohort), and 18 (78%) experienced IRR. To date, 9 of 42 pts (21%) experienced at least one grade ≥ 3 drug related AE and 9 pts had at least one related SAEs (total of 14 SAEs including 10 IRRs and ischemic stroke, back pain, hyponatremia, pneumonia, n = 1 each). Among 36 pts with at least one follow-up RECIST 1.1 assessment, 1 pt with endometrial carcinoma had a confirmed PR (> 6 months to date, >50%, 14mg/kg) and 6 pts had SD at 3 months including one long-lasting SD over 1 year (cervical carcinoma, 6mg/kg) with a shrinkage > 30% in an irradiated lesion. To date, 3 pts are still on treatment (median duration: 43.0 days [7.0; 476.0]). Serum NP137 concentrations had biphasic disposition characteristic of both target and non-target-mediated clearances. PK data up to 5 consecutive cycles showed no evidence of NP137 accumulation. No ADAs were noted. RNAseq data on paired biopsies suggests that NP137 triggers a shift toward a more epithelial phenotype. Based on available data, 14mg/kg Q2W was selected as the RP2D. Recruitment in the extension phase is ongoing in gynecological tumors.

Conclusions

NP137 was well-tolerated, with mild to moderate IRR as the most frequent treatment-related AEs and showed encouraging signs of clinical activity. Updated data will be presented at the meeting.

Clinical trial identification

NCT02977195.

Editorial acknowledgement

Legal entity responsible for the study

Centre Léon Bérard.

Funding

Netris Pharma.

Disclosure

P. Cassier: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Abbvie; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. Y. Courbebaisse: Full / Part-time employment: Netris Pharma. S. Depil: Advisory / Consultancy: Cellectis; Advisory / Consultancy: Netris Pharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: PDCLine Pharma; Advisory / Consultancy: Erytech; Advisory / Consultancy: Servier. J. Delord: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Roche/Genentech; Advisory / Consultancy: EMD Serono; Research grant / Funding (self): AstraZeneca. I.L. Ray-Coquard: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astr-Zeneca; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: PharmaMar; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GenMab. B. Ducarouge: Full / Part-time employment: Netris Pharma. P. Mehlen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netris Pharma. J. Blay: Non-remunerated activity/ies, uncompensated scientific advice: Netris Pharma. All other authors have declared no conflicts of interest.