First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma

Christophe Le Tourneau (1, 2) , Brigitte R.I. Dreno (3) , Youlia M. Kirova (2) , Jean Jacques Grob (4) , Thomas Jouary (5) , Caroline Dutriaux (5) , Luc Thomas (6) , Célèste Lebbé (7) , Laurent Mortier (8) , Phillippe Saiag (9) , Marie Fraņcoise Avril (10) , Eve Maubec (11) , Pascal Joly (12) , Pierre Bey (2) , Jean Marc Cosset (2) , Jiansheng Sun (13) , B. Asselain (2) , Flavien Devun (13, 2) , Michael E. Marty (7) , Marie Dutreix (14, 2)

1 RISCQ - Risques cliniques et sécurité en santé des femmes et en santé périnatale
2 Institut Curie [Paris]
3 CHU Nantes - Centre Hospitalier Universitaire de Nantes
4 TIMONE - Hôpital de la Timone [CHU - APHM]
5 Service de dermatologie Hôpital Saint-André Bordeaux
6 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
7 AP-HP - Hopital Saint-Louis [AP-HP]
8 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
9 Hôpital Ambroise Paré [AP-HP]
10 Hôpital Cochin [AP-HP]
11 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
12 CHU Rouen
13 DNA-therapeutics
14 UP11 - Université Paris-Sud - Paris 11

Background: DT01 is a DNA-repair inhibitor preventing recruitment of DNA-repair enzymes at damage sites. Safety, pharmacokinetics and preliminary efficacy through intratumoural and peritumoural injections of DT01 were evaluated in combination with radiotherapy in a first-in-human phase I trial in patients with unresectable skin metastases from melanoma.Methods:Twenty-three patients were included and received radiotherapy (30 Gy in 10 sessions) on all selected tumour lesions, comprising of two lesions injected with DT01 three times a week during the 2 weeks of radiotherapy. DT01 dose levels of 16, 32, 48, 64 and 96 mg were used, in a 3+3 dose escalation design, with an expansion cohort at 96 mg.Results:The median follow-up was 180 days. All patients were evaluable for safety and pharmacokinetics. No dose-limiting toxicity was observed and the maximum-tolerated dose was not reached. Most frequent adverse events were reversible grades 1 and 2 injection site reactions. Pharmacokinetic analyses demonstrated a systemic passage of DT01. Twenty-one patients were evaluable for efficacy on 76 lesions. Objective response was observed in 45 lesions (59%), including 23 complete responses (30%).Conclusions:Intratumoural and peritumoural DT01 in combination with radiotherapy is safe and pharmacokinetic analyses suggest a systemic passage of DT01.

Mots clés: DNA repair; DT01; melanoma; phase I trial; radiotherapy; skin metastases

Domaines: Sciences du Vivant [q-bio]

Christophe Le Tourneau, Brigitte R.I. Dreno, Youlia M. Kirova, Jean Jacques Grob, Thomas Jouary, et al.. First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma. British Journal of Cancer, 2016, 114 (11), pp.1199-1205. ⟨10.1038/bjc.2016.120⟩. ⟨hal-02559115⟩