A phase I study of paclitaxel and altretamine as second-line therapy to cisplatin regimens for ovarian cancer

• Published in: Cancer chemotherapy and pharmacology Vol. 48; no. 2; pp. 109 - 114
• Main Authors: OLVER, Ian, DAVY, Margaret, LÜFTNER, Diana, PARK, So-Hyang, EGORIN, Merrill, ELLIS, Andrew, WEBSTER, Lorraine
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-08-2001
• Subjects: Administration, Oral; Adult; Aged; Altretamine - administration & dosage; Altretamine - adverse effects; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Chemotherapy; Cisplatin - therapeutic use; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Infusions, Intravenous; Medical sciences; Middle Aged; Ovarian Neoplasms - drug therapy; Paclitaxel - administration & dosage; Paclitaxel - adverse effects; Paclitaxel - pharmacokinetics; Pharmacology. Drug treatments; Antineoplastic agent; Human; Drug combination; Relapse; Intravenous administration; Toxicity; Malignant tumor; Cisplatin; Female genital diseases; Ovarian diseases; Increasing dose; Ovary; Chemotherapy; Treatment; Taxane derivatives; Paclitaxel; Triazine derivatives; Phase I trial; Female; Altretamine; Drug interaction; Pharmacokinetics; Platinum II Complexes
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s002800000263

The efficacy and pharmacokinetics of paclitaxel when combined with altretamine for ovarian cancer were studied.
A group of 30 patients, whose only chemotherapy was one or more cisplatin-based non-paclitaxel-containing regimens and whose ovarian cancer failed to respond or had relapsed within 6 months of their last platinum regimen, received paclitaxel as a 3-h intravenous infusion and altretamine given orally in four divided doses daily for 14 days repeated every 28 days. Doses were escalated from paclitaxel/altretamine 135/150 mg/m2 to 250/300 mg/m2 in cohorts of three patients.
The dose-limiting toxicities at 250/300 mg/m2 were WHO grade 3 myalgias and arthralgias in two patients and grade 3 lethargy, stomach cramps, peripheral neuropathy and vomiting in single patients. Considering all dose levels in cycle 1, 16 patients had grade 3 or 4 neutropenia but there was only one episode of febrile neutropenia. Other grade 3 toxicities were vomiting in four patients, myalgias in three, peripheral neuropathy in two and lethargy in two. Grade 3 alopecia occurred in 23 patients. Three patients achieved a complete response and 12 achieved a partial response for an overall objective response rate of 50%. Responses occurred at all dose levels of 175/150 mg/m2 and higher. The median freedom from progression was 35 weeks, with a median survival of 55 weeks. Altretamine did not alter the pharmacokinetics of paclitaxel and there were no consistent differences in paclitaxel pharmacokinetic parameters or toxicities between course 1 and 2. No dose-response relationships were evident above paclitaxel/altretamine 175/150 mg/m2.
Paclitaxel and altretamine can be safely combined and with a high response rate in relapsed ovarian cancer, justifying further studies with this combination.