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.

To report the results of the first in-human phase 1 study of the association of DT01 (a double stranded DNA oligonucleotide conjugated to cholesterol, which mimics “false” double strand breaks [DSB]) as radiosensitizer in association with radiation therapy (RT) in melanoma patients. Subcutaneous peritumoral and intratumoral injections of DT01 were evaluated in combination with RT in a first in-human phase 1 trial in patients (pts) with unresectable cutaneous metastases of melanoma. Each pt received RT of 30 Gy/10 fractions/15 days to 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. Radiation therapy was given using a rectangular field by a linear accelerator using electrons or photons. Tolerance was assessed using NCI CTCAE v4.3 and efficacy using modified RECIST criteria 1.1. Injected, as well as non-injected lesions into the irradiated volume were evaluated. Twenty-three pts with 45 injected lesions were included in the trial at median age of 72 years (range, 40–85). All of them (100%) underwent previous surgical procedure and experienced recurrence. There were 11 male and 12 female patients. The studied lesions were situated mostly at the legs (in 17 pts, 74%); PK analyses suggested a systemic passage of DT01 in a non-linear fashion. Overall response rates (ORR) were 68% and 48% in tumor lesions injected with DT01 and not injected, respectively. Notably, ORR correlated with blood exposure (P = .03 for all included lesions), suggesting, 1) an antitumor activity of DT01, and 2) a systemic effect of DT01. No dose-limiting toxicity was observed, the maximum tolerated dose was not reached. The detailed results of the tolerance are given in Table 1. DT01 in combination with RT is safe in patients with metastatic in-transit melanoma, and provides antitumor activity in DT01, directly injected and non-directly injected lesions possibly explained by a systemic distribution of the drug.Oral Scientific Abstracts 62; Table 1GradeDT01 dosePossibly related toResolved / RecoveredCTCAE v4 criteria16 mg32 mg48 mg64 mg96 mgno.%no.%no.%no.%no.DT01RTCQAny AEs related to treatmentN/A3100%3100%266%3100%583%N/AN/AN/ALocal AEsPain, irritation, erythema, induration, ulceration, pruritus, serous bullous, hyperpigmentation13100%3100%266%266%466%xxyesIrritation, erythema, burning sensation2133%133%266%350%xxyesSystemic AEsRedness/Tickling of the face1133%xxyesBullous pemphigoid2133%?yesLymphocyte count decrease1117%xxStatus not available Open table in a new tab

Trans-arterial chemo-embolization (TACE) using doxorubicin is the treatment of choice for intermediate stage HCC despite a limited efficacy and effect on survival. Increasing efficacy of this treatment is the challenge of the next years. Recently a new DNA repair inhibitor has been introduced that may potentialize the biological action of doxorubicin on DNA. The purpose of this study is to explore the antitumor effect of a new DNA repair inhibitor, DT01, combined with TACE on VX2 rabbit liver tumors.

La poly-ADP-ribosylation, assurée par les protéines de la famille des poly(ADP-ribose)polymérases (PARP), correspond à une modification post-traductionnelle de protéines impliquées dans la régulation de plusieurs processus cellulaires. Parmi les protéines de cette famille, seules PARP-1, PARP-2 et PARP-3 semblent pouvoir être activées en réponse aux dommages de l’ADN. Une fois activées, les PARPs synthétisent de longs polymères d’ADP-ribose à partir du nicotinamide adénine dinucléotide (NAD+). L’absence de PARP-1 ou de PARP-2 a pour conséquence une hypersensibilité aux radiations ionisantes et aux agents alkylants. De nombreux inhibiteurs de PARP (PARPi) synthétisés à visée thérapeutique sont des compétiteurs du NAD+. Ils peuvent être utilisés en monothérapie dans les cellules déficientes pour la réparation des cassures double-brin de l’ADN par recombinaison homologue (cas des cellules déficientes pour BRCA1/BRCA2), à travers le principe de létalité synthétique. Des données précliniques montrant une amélioration de la réponse tumorale à l’irradiation ont été documentées pour plusieurs inhibiteurs de PARP. Néanmoins, il reste à déterminer si la radio-sensibilisation tumorale induite par ces PARPi est liée exclusivement aux anomalies de réparation des lésions de l’ADN ou aux effets vasoactifs contribuant à une ré-oxygénation tumorale. Ces résultats prometteurs ont ouvert la voie à l’évaluation des inhibiteurs de PARP associés à la radiothérapie dans des études de phase I et de phase II pour les gliomes malins, les cancers de la tête et du cou et les cancers du sein. De nombreux défis qui sont également discutés dans cet article, restent encore à être relevés comme l’optimisation des schémas de traitement d’association et la validation de biomarqueurs identifiant les patients pouvant bénéficier des inhibiteurs de PARP en association à la radiothérapie.Poly(ADP-ribosyl)ation is a ubiquitous protein modification involved in the regulation of many cellular processes that is carried out by the poly(ADP-ribose) polymerase (PARP) family. The PARP-1, PARP-2 and PARP-3 are the only PARPs known to be activated by DNA damage. The absence of PARP-1 and PARP-2, that are both activated by DNA damage and participate in DNA damage repair processes, results in hypersensitivity to ionizing radiation and alkylating agents. PARP inhibitors that compete with NAD+ at the enzyme's activity site can be used in BRCA-deficient cells as single agent therapies acting through the principle of synthetic lethality exploiting these cells deficient DNA double-strand break repair. Preclinical data showing an enhancement of the response of tumors to radiation has been documented for several PARP inhibitors. However, whether this is due exclusively to impaired DNA damage responses or whether tumor re-oxygenation contributes to this radio-sensitization via the vasoactive effects of the PARP inhibitors remains to be fully determined. These promising results have paved the way for the evaluation of PARP inhibitors in combination with radiotherapy in phase I and phase II clinical trials for malignant glioma, head and neck, and breast cancers. A number of challenges remain that are also reviewed in this article, including the optimization of treatment schedules for combined therapies and the validation of biomarkers that will identify which patients will most benefit from either PARP inhibitors in combination with radiotherapy.