relapsed ovarian cancer - BioMedSearch

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JA Gietema', G-J Veldhuis', H-J Guchelaar', PHB Willemsel, DRA Uges', A Cats', H ... Summary In phase I studies. lobaplatin showed activity in ovarian cancer ...
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British Joumal Cancw (1995) 71, 1302-1307 ©(9) 1995 Stockton Press AlJ rights reserved 0007-920/95 $12.00

Phase H and pharmacokinetic study of lobaplatin in patients with relapsed ovarian cancer JA Gietema', G-J Veldhuis', H-J Guchelaar', PHB Willemsel, DRA Uges', A Cats', H Boonstra3, WTA van der Graaf', D Th Sleijferl, EGE de Vnres' and NH Mulderl Departments of 'Medical Oncology, 2Hospital Pharmacy and 3Oncologic Gynaecologv, L'niversity Hospital Groningen, The Netherlands. 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 3 months; (c) a WHO performance status of < 2; (d) complete recovery from all toxic effects from prior treatments with a treatment-free interval of at least 4 weeks; (e) adequate bone marrow function (leucocyte count > 3 x 109 1- ' and platelet count > I00 x 109 -1; (f) serum creatinine level < 135 jmol 1-' and a creatinine clearance (CRCL) > 40 ml min '; (g) serum bilirubin < 30 izmol 1'. This protocol was approved by the Medical Ethical Committee of the University Hospital Groningen, The Netherlands. Informed consent was obtaied from all patients after they were informed of the investigational nature of this treatment. Lobaplatin was supplied by ASTA Medica (Frankfurt, Germany). The dose of lobaplatin was dissolved in sterile water and reconstituted in 100 ml of 0.9% sodium chloride. Lobaplatin was administered as an i.v. bolus once every 4 weeks. The starting dose of lobaplatin depended on renal function expressed as creatinine clearance (CRCL). Patients with a CRCL > 80 ml min-' started with 50 mg m2 lobaplatin. Patients with a CRCL < 80 ml min ' start with 30 mg m2. Dose escalation with 10 mg m2 was performed in case of haematological toxicity < WHO grade 2. In the case of WHO grade 4 haematological toxicity the dose of the next cycle was de-escalated with 10 mg m-2. For WHO grade 3 myelotoxicity no changes were made. This dose modification scheme would allow every patient to be treated on the maximum tolerated dose level of lobaplatin. Toxicity was evaluated according to WHO criteria Prophylactic antiemetics, i.e. 5-HT3 antagonists, were administered to all patients. To be evaluable for response, patients had to receive at least two of lobaplatin. Tumour evaluations were performed at entry and after every two treatment cycles. A complete response (CR) was defined as a disappearance of all evidence of the tumour and no development of new lesions for at least 4 weeks. A partial response (PR) was defined as a decrease of at least 50% in the sum of the products of the largest perpendicular diameters of all measurable lesion. Stable disease meant a decrease within 50% or an increase of less than 25% in any measurable lesions. Progressive disease was defined as an increase of more than 25% of the lesions or the occurrence of any new lesions. Measurements of CA125 were only used to support these response data. Patients were removed from the study in case of progressive disease and for severe non-haematological toxicity (WHO grade 3-4). A maximum of six cycles were given. At entry and during each 28 days course, complete blood cell count, electrolytes, liver and renal function and glucose were measured on the treatment day and on days 14, 21, and 28. Twenty-four hour urinary creatinine clearances were performed twice before study entry, before each course and after the last course of lobaplatin. Pharmacokinetic analysis was performed in eight consecutive patients during the first course of lobaplatin 50 mg m-2. Blood samples were drawn on ice from the noninfused arm in heparinised glass tubes (Venoject, Omnilabo, cancer and after pnor

courses

Breda, The Netherlands) before infusion and at t =0 (just after end of infusion) and 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 300, 720 and 1440 min after end of lobaplatin infusion. Samples were immediately centrifuged. Ultrafiltrate samples

were prepared by centrifugation over an Amicon Centifree microparitition system provided with a YMT cut-off filter (MW>30 000 Da) (Product No. 4104, Amicon, Oosterhout, The Netherlands). The plasma and ultrafiltrate samples were

stored at - 20'C until analysis. Portions of urine were collected at six appropriate intervals during 24 h following the infusion and stored at - 20'C until analysis. Platinum concentration in the samples was determined by flameless atomic absorption spectrometry (AAS) (Leroy et al., 1977). The amount of platinum was determined using a model AA1275 atomic absorption spectrophotometer with a GTA9S graphite furnace and autosampler unit (Varian Techtron, Mulgrave, Victoria, Australia). Absorption was measured at 265.9 nm with a spectral bandwidth of 0.5 nm and deuterium background correction. This method has a limit of detection for platinum of 0.1 mg l-'. Lobaplatin was determined by a high-performance liquid chromatographic (HPLC) method which has been described previously (Guchelaar et al., 1992). This method has a limit of detection of lobaplatin of 0.2 mg 1-'. The plasma concentration-time data for the individual patients were subjected to analysis using a computer program for pharmacokinetic linear curve fitting (MWPharm, Mediware, Groningen, The Netherlands). The area under the plasma concentration-time curve (AUC) was calculated using the model-independent trapezoidal rule. Regression analysis in this study was calculated by the method of least squares. Statistical analysis was performed with the Student's t-test. Only two-tailed P-values 6 months Mean creatinine clearance at study entry CRCL > 80 ml min- ' CRCL < 80 ml min- ' Starting dose of lobaplatin 50 mg m-2

30mgm-'

1 week. All patients recovered from haematological toxicity within 28 days after lobaplatin admiimstration. Seven patients required prophylactic platelet transfusions during grade 4 thrombocytopenia. There were no signs of clinical bleeding during thrombocytopenia. As anticipated from phase I studies with lobaplatin, we suspected a relation between thrombocytopenia and renal function. For 15 patients treated with 50 mg m-2 lobaplatin as first course, we observed (see Figure 3) a significant correlation between CRCL and percentage reduction in platelet count (r = -0.77; P