First-in-human phase I study of the DNA repair inhibitor DT01 in combination with radiotherapy in patients with in transit melanoma.
Authors: Christophe Le Tourneau, Brigitte Dreno, Youlia Kirova, Jean Jacques Grob, Thomas Jouary, Caroline Dutriaux, Luc Thomas, Celeste Lebbe, Laurent Mortier, Philippe Saiag, Marie-Françoise Avril, Eve Maubec, Pierre Bey, Jean-Marc Cosset, Jian-sheng Sun, Bernard Asselain, Flavien Devun, Michel E. Marty, Marie Dutreix
Journal: Journal of Clinical Oncology (2015)

Article Tools Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/jco.2015.33.15_suppl.2555 Journal of Clinical Oncology - published online before print May 20, 2015 First-in-human phase I study of the DNA repair inhibitor DT01 in combination with radiotherapy in patients with in transit melanoma. Christophe Le TourneauxChristophe Le TourneauSearch for articles by this author , Brigitte DrenoxBrigitte DrenoSearch for articles by this author , Youlia KirovaxYoulia KirovaSearch for articles by this author , Jean Jacques GrobxJean Jacques GrobSearch for articles by this author , Thomas JouaryxThomas JouarySearch for articles by this author , Caroline DutriauxxCaroline DutriauxSearch for articles by this author , Luc ThomasxLuc ThomasSearch for articles by this author , Celeste LebbexCeleste LebbeSearch for articles by this author , Laurent MortierxLaurent MortierSearch for articles by this author , Philippe SaiagxPhilippe SaiagSearch for articles by this author , Marie-Françoise AvrilxMarie-Françoise AvrilSearch for articles by this author , Eve MaubecxEve MaubecSearch for articles by this author , Pierre BeyxPierre BeySearch for articles by this author , Jean-Marc CossetxJean-Marc CossetSearch for articles by this author , Jian-sheng SunxJian-sheng SunSearch for articles by this author , Bernard AsselainxBernard AsselainSearch for articles by this author , Flavien DevunxFlavien DevunSearch for articles by this author , Michel E. MartyxMichel E. MartySearch for articles by this author , Marie DutreixxMarie DutreixSearch for articles by this author Show More Institut Curie, Department of Medical Oncology, Paris, France; CHU de Nantes - Hôtel Dieu, Nantes, France; Institut Curie, Radiotherapy Department, Paris, France; CHU Timone APHM, Aix-Marseille University, Marseille, France; Saint André Hospital CHU de Bordeaux, Dermatology, Bordeaux, France; Hôpital Saint-André,CHU Bordeaux, Bordeaux, France; Lyon 1 University Centre Hospitalier Lyon Sud, Pierre Benite, France; Dermatology Department, Hôpital Saint-Louis, Assistance-Publique-Hôpitaux de Paris, Paris, France; CHRU de Lille, Lille, France; Hospital Ambroise Pare, Boulogne-Billancourt, France; Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Paris, France; Hopital Bichat, Paris, France; CUrie Institute, Paris, France; Institut Curie, Paris, France; DNA Therapeutics, Evry, France; Institut Curie, Orsay, France; Hopital Saint Louis, Paris Cedex, France; Institut Curie, Université Paris-Sud, Orsay, France Abstract Disclosures https://doi.org/10.1200/jco.2015.33.15_suppl.2555 Abstract Abstract 2555 Background: DT01 is a double stranded DNA oligonucleotide conjugated to cholesterol, which mimics "false" double strand breaks (DSB). DT01 triggers DNA repair proteins trapping, thereby inhibiting their repair activity. In non-clinical studies, DT01 showed antitumor activity as a single agent and in combination with radiotherapy (RT) in several tumor types including melanoma. No NOAEL could be defined. Methods: Subcutaneous peritumoral and intratumoral injections of DT01 were evaluated in combination with RT in a first-in-human phase I trial in patients (pts) with unresectable in-transit metastases of melanoma. Each pt received RT at a standard dose (3Gy/d 5 days/week for 2 weeks) on all selected tumor lesions, while only one or two tumor lesions were treated with DT01 3 times a week during both weeks of RT. A 3+3 dose escalation design was used. DT01 dose levels explored were 16, 32, 48, 64, and 96 mg. RT was given using a rectangular field by a linear accelerator. Tolerance was assessed using NCI CTCAE v4.3 and efficacy using modified RECIST criteria 1.1. Results: Seventeen pts (16 eligible) were included in the trial, of whom received RT alone in 31 and RT + DT01 in 31 tumor target lesions. As no dose-limiting toxicity was observed, the maximum tolerated dose was not reached. Most frequent adverse events were reversible grade 1 and 2 injection site reactions. PK analyses suggested a systemic passage of DT01 in a non-linear fashion. Overall response rates (ORR) were 68% and 48% in tumor lesions treated with RT + DT01 and RT alone, respectively. Notably, ORR correlated with blood AUC (p = 0.01), suggesting 1) an anti-tumor activity of DT01, and 2) a systemic effect of DT01. Conclusions: DT01 in combination with RT is safe in patients with metastatic in-transit melanoma, and provides antitumor activity in DT01-treated and non-treated lesions possibly explained by a systemic distribution of the drug. Clinical trial information: NCT01469455. © 2015 by American Society of Clinical Oncology