Phase II and pharmacokinetic study of lobaplatin in patients with relapsed ovarian cancer

Abstract

Summary In phase I studies. lobaplatin showed activity in ovarian cancer patients pretreated with platinum. A phase II trial with lobaplatin was performed in patients with refractory or relapsed ovarian cancer to define activity and pharmacokinetics. Twenty-two patients were treated with lobaplatin administered as an intravenous bolus every 4 weeks. Dependent on creatinine clearance (CRCL) patients received 30 or 50 mgm-2 lobaplatin as the starting dose. Twenty-two patients received 78 courses (median 3, range 1-6). In eight patients total platinum (TPt) in plasma and urine, free platinum (FPt) in plasma ultrafiltrate (both measured by atomic absorption spectrometry) and lobaplatin in plasma ultrafiltrate measured (by high-performance liquid chromatography) were measured. Toxicity was confined to mild nausea and vomiting, mild leucocytopenia (WHO grade 3 in 18% of the courses), and renal function-related thrombocytopenia (WHO grade 3 4 in 53% of the courses). A correlation was found between CRCL and reduction in platelet count (r = -0.77; P<0.0l). No renal toxicity was encountered. Five of 21 evaluable patients (24%) achieved a response (four complete remissions and one partial remission). Remissions occurred mainly in patients who relapsed more than 6 months after primary treatment. The median survival from start of lobaplatin treatment was 8 months. The mean areas under the curve (AUCs) were 4.2 ± 0.5, 3.0 ± 0.6. and 3.2 ± 1.1 h mgl-' for TPt, FPt and lobaplatin respectively. The free platinum fraction (FPt TPt) was initially very high, indicating low protein binding. FPt was essentially present as intact lobaplatin. Four hours after infusion 54 ± 5% and 24 h after infusion 74 ± 3% of the lobaplatin dose was excreted in the urine. In conclusion. lobaplatin is a platinum compound with anti-tumour activity in patients with relapsed ovarian cancer, especially in those who have platinum-sensitive tumours. The main toxicity of lobaplatin is thrombocytopenia and its dose should be corrected according to renal function.Keyword: ovarian cancer; phase II; lobaplatin Over the last decade, treatment of patients with ovarian cancer has been dominated by cisplatin-containing regimens (Neijt et al., 1984;Williams et al., 1985; Omura et al., 1986). Combinations of cisplatin with one single alkylating agent give equivalent results to three-or four-drug schedules, but appear to be less toxic (Neijt et al., 1987). In recent years, the development of new drugs has been directed towards the development of platinum analogues that are equipotent but less toxic than the parent compound. Carboplatin has emerged as leading analogue in this respe-t with reduced nephrotoxicity, gastointestinal toxicity and neurotoxicity (Calvert et al., 1982;Evans et al., 1983). Myelotoxicity, especially thrombocytopenia. has been found to be the doselimiting toxicity of carboplatin. Especially in ovarian cancer, carboplatin appears to have equivalent activity to cisplatin (Alberts et al., 1992;Swenerton et al., 1992).An important direction in current r...

Preclinical Activity of Lobaplatin as a Single Agent and in Combination with Taxanes for Ovarian Carcinoma Cells

“…Besides, cisplatin and carboplatin are cross-resistant. Lobaplatin, as a thirdgeneration platinum complex with reduced nephrotoxicity and incomplete cross-resistance with cisplatin, has potential clinical advantages for certain patients (Oguri et al, 1988;Harstrick et al, 1989;Gietema et al, 1995). In the present study, we assessed the in-vitro and in-vitro activities of lobaplatin alone or in combination with taxanes against human ovarian cancer.…”

Estimation of glomerular filtration rate in cancer patients

“…Assessing renal function in such studies is additionally important because impaired renal clearance of a drug can lead to toxicities in organs other than the kidney that are related to pre-treatment renal function (Gietema et al, 1995).…”

Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation of lobaplatin and oxaliplatin in cultured SW 1573 cells

“…Lobaplatin showed activity in patients with refractory or relapsed ovarian cancer (Gietema et al 1995) and also had potential activity in patients with nonsmall-cell lung cancer and oesophageal cancer (Fiebig et al 1992;Kelland 1993). The dose-limiting toxicity of lobaplatin was a renal-function-related thrombocytopenia; if this toxicity is influenced by hyperthermia remains to be established.…”