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Br J Cancer. 2016 May 24;114(11):1199-205. doi: 10.1038/bjc.2016.120. Epub 2016 May 3.

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

Author information

1
Department of Medical Oncology, Institut Curie, Paris & Saint-Cloud 75005, France.
2
EA7285, Versailles-Saint-Quentin-en-Yvelines University, Versailles 78000, France.
3
CHU de Nantes-Hôtel Dieu, Nantes 44093, France.
4
Radiotherapy Department, Institut Curie, Paris 75005, France.
5
La Timone Hospital-APHM, Aix-Marseille University, Marseille 13385, France.
6
Dermatology department, Saint-André Hospital, CHU de Bordeaux, Bordeaux 33000, France.
7
Lyon Sud Hospital Center, Lyon 1 University, Pierre Benite 69495, France.
8
Saint-Louis Hospital, APHP, Paris 75010, France.
9
Dermatology department, CHRU of Lille, Lille 59037, France.
10
Ambroise Paré Hospital, Boulogne Billancourt 92104, France.
11
Cochin hospital, APHP, Paris 75014, France.
12
Bichat Hospital, Paris 75877, France.
13
CHU Rouen, Charles-Nicolle, Rouen 76000, France.
14
Institut Curie, Paris 75005, France.
15
DNA Therapeutics, Evry 91058, France.
16
Department of Biostatistics, Institut Curie, Paris 75005, France.
17
Institut Curie, Orsay 91405, France.
18
CNRS-UMR3347, INSERM-U1021, Paris-Sud University, Orsay 91405, France.

Abstract

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.

PMID:
27140316
PMCID:
PMC4891504
DOI:
10.1038/bjc.2016.120
[Indexed for MEDLINE]
Free PMC Article

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