First-into-man phase I and pharmacokinetic study of XR5944.14, a novel agent with a unique mechanism of action

• Published in: British journal of cancer Vol. 97; no. 7; pp. 844 - 850
• Main Authors: VERBORG, W, THOMAS, H, BISSETT, D, WATERFALL, J, STEINER, J, COOPER, M, RANKIN, E. M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 08.10.2007
• Subjects: Adult; Aged; Area Under Curve; Biological and medical sciences; Clinical Study; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Phenazines - pharmacokinetics; Phenazines - toxicity; Tumors; Human; Solid tumor; Male; Malignant tumor; solid tumours; Cancerology; Treatment; Phase I trial; Adult; XR5944.14; phase I; Mechanism of action; Pharmacokinetics
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6603953

The bis-phenazine XR5944.14 is a novel cytotoxic agent which intercalates into DNA and inhibits transcription. The objectives of this study were to determine the dose-limiting toxicity (DLT), the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR5944.14 when given at doses ranging from 3.6 to 36 mg m(-2) every 3 weeks to patients with advanced tumours. Twenty-seven patients were treated with a total of 77 cycles. Dose-limiting toxicities occurred at doses > or =24 mg m(-2). Oral mucositis was the most common DLT. Two patients developed acute renal failure possibly related to the study drug. Other less-severe toxicities were diarrhoea, nausea, vomiting and fatigue. Haematological toxicity was mild. One patient showed an objective partial response. Pharmacokinetic analysis was performed during the first cycle of treatment and plasma was assayed for XR5944.14 using a validated liquid chromatography tandem mass spectrometry. The systemic exposure of XR5944.14 increased more than proportionally with increasing dose, with inter-patient variability increasing from dose level 24 mg m(-2) onwards. The lack of correlation between toxicity and PK values makes it difficult to recommend a dose for further study in phase 2 trials. More work is needed to explain the inter- and intra-individual variation in PKs and pharmacodynamics.