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 À2 every 3 weeks to patients with advanced tumours. Twentyseven patients were treated with a total of 77 cycles. Dose-limiting toxicities occurred at doses X24 mg m À2 . 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 À2 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.
The optimal treatment of progressive ovarian cancer after first-line platinum-based therapy remains a challenge. We collected prospectively data on patients with relapsed or progressive ovarian cancer treated with weekly cisplatin and oral etoposide in our institution to evaluate the feasibility, efficacy, and toxicity of this regimen. Patients (n = 34) had stage IIIC/IV ovarian cancer, which was recurrent or progressive following previous treatment with carboplatin and a taxane. Cisplatin (50 mg/m(2)) was given days 1, 8, 15, 29, 36, and 43, with oral etoposide (50 mg daily) on days 1-15 and 29-43. Responders and those with stable disease then received oral etoposide (50 mg daily for 21 days of a 28-day cycle) until disease progression. The overall CA125 response rate was 88%. The overall radiological response rate was 57%: 78% in the platinum-sensitive group, 50% in the intermediate-sensitive group, and 46% in the platinum-resistant group. Treatment was well tolerated. Median survival in the overall group was 14 months: in the platinum-sensitive group 16.5 months, in the intermediate-sensitive group 11 months, and 10.5 months in the platinum-resistant group. We conclude that weekly cisplatin/etoposide, followed by maintenance oral etoposide, is an active and well-tolerated regimen in relapsed or progressive ovarian cancer, even in platinum-resistant patients.
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