Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients

Abstract

Gemcitabine and treosulfan are DNA-damaging agents. Preclinical studies suggest that synergism exists when melanoma cells are exposed to both drugs concurrently. We conducted a phase I trial in advanced melanoma patients to determine the optimal dose of gemcitabine to be combined with treosulfan. Cohorts of three patients received increasing doses of gemcitabine, commencing at 0.5 g m À2 , followed by a fixed dose of 5.0 g m À2 treosulfan on day one of a 21-day cycle. Patients alternately received a first cycle of single-agent gemcitabine or treosulfan before subsequent cycles of both drugs. Peripheral blood lymphocytes were collected in cycles 1 and 2 at various time points until 48 h post-treatment. The single-cell gel electrophoresis (Comet) assay was used to measure chemotherapy-induced DNA damage. A total of 27 patients were enrolled, no objective responses were observed, but two uveal melanoma patients had minor responses. Dose-limiting myelosuppression was reached at 3.0 g m À2 gemcitabine. DNA single-strand breaks were detected 4 h post-gemcitabine, repaired by 24 h. DNA interstrand crosslinks were detected 4 h post-treosulfan, fully removed by 48 h. Following combination chemotherapy, treosulfan-induced DNA crosslinks persisted, still being detectable 48 h post-treatment, supporting the hypothesis that gemcitabine potentiates treosulfan-induced cytotoxicity. The recommended regimen for further study is 2.5 g m À2 gemcitabine combined with 5.0 g m À2 treosulfan.

Enhanced repair of DNA interstrand crosslinking in ovarian cancer cells from patients following treatment with platinum-based chemotherapy

“…This can be used to measure crosslinking in lymphocytes or solid tumour material where samples are taken following treatment of patients with drugs such as ifosfamide , treosulfan (Corrie et al, 2005) or antibody directed enzyme pro-drug therapy (Webley et al, 2001). Alternatively, it can be used to measure crosslink formation and repair in cells isolated from patients and treated ex vivo with drug as in the present study, or as previously demonstrated in myeloma plasma cells treated with melphalan (Spanswick et al, 2002).…”

“…We have previously demonstrated that a modification of the single cell gel electrophoresis (comet) assay can be used successfully in the clinical setting to detect and quantify the levels of ICLs in patient lymphocytes and tumour cells at pharmacologically relevant doses of bifunctional alkylating agents Webley et al, 2001;Spanswick et al, 2002;Corrie et al, 2005). The method has also been used to measure cisplatin-induced ICLs in vitro (De Silva et al, 2002).…”

Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents

“…It is now increasingly used to monitor ICL formation and unhooking in clinical samples (30,40) as a pharmacodynamic end point in clinical trials (41,42), and following ex vivo treatment (39,43).…”

The use of treosulfan and gemcitabine in the treatment of platinum-resistant ovarian cancer

“…A phase I trial in this disease suggested a synergistic effect between the two agents, with gemcitabine causing the persistence of treosulfaninduced DnA interstrand crosslinks (4).…”