Phase II and pharmacokinetic study of lobaplatin in patients with relapsed ovarian cancer.
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 mg m-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 < 0.01). 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-1 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.
Gietema
J A
JA
Department of Medical Oncology, University Hospital Groningen, The Netherlands.
Veldhuis
G J
GJ
Guchelaar
H J
HJ
Willemse
P H
PH
Uges
D R
DR
Cats
A
A
Boonstra
H
H
van der Graaf
W T
WT
Sleijfer
D T
DT
de Vries
E G
EG
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D003404:Creatinine / Q000378:metabolism; D003503:Cyclobutanes / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D006801:Humans; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010386:Pelvic Neoplasms / Q000188:drug therapy / Q000556:secondary; D012008:Recurrence; D014625:Vaginal Neoplasms / Q000188:drug therapy / Q000556:secondary
D000970:Antineoplastic Agents; D003503:Cyclobutanes; D009944:Organoplatinum Compounds; D003404:Creatinine; C066228:lobaplatin