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

ABSTRACT: 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.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.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%).Intratumoural and peritumoural DT01 in combination with radiotherapy is safe and pharmacokinetic analyses suggest a systemic passage of DT01.

SUBMITTER: Le Tourneau C

PROVIDER: S-EPMC4891504 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Le Tourneau C C Dreno B B Kirova Y Y Grob J J JJ Jouary T T Dutriaux C C Thomas L L Lebbé C C Mortier L L Saiag P P Avril M F MF Maubec E E Joly P P Bey P P Cosset J M JM Sun J S JS Asselain B B Devun F F Marty M E ME Dutreix M M

British journal of cancer 20160503 11

<h4>Background</h4>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.<h4>Methods</h4>Twenty-three patients were included and received radiotherapy (30 Gy in 10 sessions) on all selected tumour lesions, compr ...[more]

PMID: 27140316

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Project description:ObjectiveImmune checkpoint inhibitor (ICI) therapy has shown activity against melanoma brain metastases. Recently, promising results have also been reported for ICI combination therapy and ICI combined with radiotherapy. We aimed to evaluate radiologic response and adverse event rates of these therapeutic options by a systematic review and meta-analysis.Materials and methodsA systematic literature search of Ovid-MEDLINE and EMBASE was performed up to October 12, 2019 and included studies evaluating the intracranial objective response rates (ORRs) and/or disease control rates (DCRs) of ICI with or without radiotherapy for treating melanoma brain metastases. We also evaluated safety-associated outcomes.ResultsEleven studies with 14 cohorts (3 with ICI combination therapy; 5 with ICI combined with radiotherapy; 6 with ICI monotherapy) were included. ICI combination therapy {pooled ORR, 53% (95% confidence interval [CI], 44-61%); DCR, 57% (95% CI, 49-66%)} and ICI combined with radiotherapy (pooled ORR, 42% [95% CI, 31-54%]; DCR, 85% [95% CI, 63-95%]) showed higher local efficacy compared to ICI monotherapy (pooled ORR, 15% [95% CI, 11-20%]; DCR, 26% [95% CI, 21-32%]). The grade 3 or 4 adverse event rate was significantly higher with ICI combination therapy (60%; 95% CI, 52-67%) compared to ICI monotherapy (11%; 95% CI, 8-17%) and ICI combined with radiotherapy (4%; 95% CI, 1-19%). Grade 3 or 4 central nervous system (CNS)-related adverse event rates were not different (9% in ICI combination therapy; 8% in ICI combined with radiotherapy; 5% in ICI monotherapy).ConclusionICI combination therapy or ICI combined with radiotherapy showed better local efficacy than ICI monotherapy for treating melanoma brain metastasis. The grade 3 or 4 adverse event rate was highest with ICI combination therapy, and the CNS-related grade 3 or 4 event rate was similar. Prospective trials will be necessary to compare the efficacy of ICI combination therapy and ICI combined with radiotherapy.

Project description:IMPORTANCE:Few data are available on patients with leptomeningeal disease (LM) from melanoma treated with new systemic therapies. OBJECTIVE:To gain a better understanding of patients, disease characteristics, and therapeutic interventions in melanoma patients with LM in the era of new systemic treatment. DESIGN:Clinical characteristics, treatments, and survival of melanoma patients diagnosed with LM, isolated or associated with brain metastases, were collected. The Cox regression model assessed the influence of patient and melanoma characteristics on survival. SETTING:Monocentric, retrospective, real-life cohort of patients with LM from melanoma. PARTICIPANTS:All patients followed up at Saint-Louis University Hospital and diagnosed with LM between December 2013 and February 2020 were included. For each patient identified, a central review by dermato-oncologist and neuro-oncologist experts was performed to confirm the diagnosis of LM. EXPOSURE:Impact of new systemic therapies and radiotherapy. RESULTS:Among the 452 advanced melanoma patients followed at St Louis Hospital between 2013 and 2020, 41 patients with LM from melanoma were identified. Among them, 29 patients with a diagnosis of LM "confirmed" or "probable" after central neuro-oncologists reviewing were included. Nineteen patients had known melanoma brain metastases at LM diagnosis. Among the 27 patients treated with systemic therapy, 17 patients were treated with immunotherapy, 5 patients received targeted therapy, 1 was treated with chemotherapy, and 4 patients were treated with anti-PD-1 in combination with BRAF inhibitor. The median overall survival (OS) from LM diagnosis was 5.1 months. Median OS was 7.1 months for the 9 patients receiving systemic therapy combined with radiotherapy, and 3.2 months for the 20 patients not receiving combined radiotherapy. Elevated serum lactate dehydrogenase (LDH) (HR 1.44, 95% CI 1.09-1.90, p < 0.01) and presence of neurological symptoms at LM diagnosis (HR 2.96, 95% CI 1.25-6.99, p = 0.01) were associated with poor survival. At the time of data analysis, five patients were still alive with a median follow-up of 47.4 months and had persistent complete response. CONCLUSION:Targeted therapy and immunotherapy are promising new treatment options in LM from melanoma that can increase overall survival, and may induce long lasting remission in some patients.

Dataset Information

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

Publications

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

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