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

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.

The DNA Repair Inhibitor Dbait Is Specific for Malignant Hematologic Cells in Blood

“…However, no tests have yet been performed in blood cells. Here, we tested the effects of AsiDNA, the form of Dbait molecules used in the clinic (19), on the treatment of malignant blood cells and the toxicity of combined treatment to human blood cells. All tests were performed on human cells, as mouse blood cells have been shown to contain 50-fold less DNA-PK, one of the main targets of Dbait, than human blood cells (34).…”

“…Radiotherapy is often used for the treatment of cancer, such as non-Hodgkin lymphoma, Hodgkin lymphoma, and all types of leukemia and the addition of AsiDNA could increase the efficacy of such treatment. We previously demonstrated in a first-in-man clinical trial that AsiDNA does not increase local toxicity of the irradiation (19). Treating lymphomas by combining treatment with AsiDNA and radiotherapy is a potentially promising method.…”

“…It is composed of the active part of Dbait, a stable 32-bp long double-stranded DNA with a blunt end, covalently bound to a cholesterol, to allow molecules to enter the cells without the help of transfection vectors. AsiDNA (called DT01 for the first-in-man trial) was recently tested in a phase I clinical trial on melanoma skin metastases in association with radiotherapy (19). The results demonstrated the lack of toxicity of locally administered molecules and suggested an increase in radiotherapy efficacy.…”

Targeting the DNA-PK complex: Its rationale use in cancer and HIV-1 infection

“…This pharmacological form called AsiDNA (or DT01), has been tested in phase I clinical trial on melanoma in association with radiotherapy. Two studies show the selective increase of cancerous cells sensitization [39,40]. Preclinical studies showed a chemo-sensitization of metastatic colorectal and liver cancers with AsiDNA [41].…”

Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors

“…This strategy sensitizes tumors to DNA damaging therapies such as radiotherapy and chemotherapy (15)(16)(17)(18). The first-in-human phase I trial, combining AsiDNA to radiotherapy to treat patients with skin metastases from melanoma showed encouraging results, with 30% of complete responses (19). We anticipated that AsiDNA could potentiate PARPi activity in BRCA proficient cells by inhibiting HR and establishing a transient state of BRCAness.…”