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| |  AACR-NCI-EORTC: Irofulven/Cisplatin Combination Well Tolerated, Promising in Advanced Solid Tumours By Paula Moyer BOSTON, MA -- November 21, 2003 -- The investigative compound irofulven may be a useful adjunct to cisplatin in the treatment of advanced solid tumours, according to Gary Weems, PharmD. "Although the focus of our study was the assessment of toxicity, we did see anti-tumour activity in certain tumour types," said Dr. Weems, the senior manager of clinical research for MGI Pharma, the manufacturer of the compound and the study's sponsor. "On the basis of these findings, a phase 2 study is now under discussion." Irofulven is a derivative of illudin S, a natural compound of the mushroom Omphalotus illudens, and inhibits DNA synthesis and causes apoptosis in certain tumour types. Dr. Weems presented the study findings here November 18th at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. The investigators recruited 33 patients with solid tumours for whom conventional therapy had failed. The patients received cisplatin followed by irofulven on Days 1 and 15. Irofulven was administered as a 30-minute intravenous infusion along with a 5HT3 antagonist, typically given as a prophylactic antidote for nausea, as well as steroids and hydration. The investigators defined dose-limiting toxicity as causing a dosing omission or delay of more than one week due to toxicity or visual disturbance of at least grade 2. The maximum tolerated dose was the level at which two patients experienced a dose-limiting toxicity during the first two treatment cycles. Among the patients, 20 were men and 13 were women. They were a median of 56 years old, and all had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. The tumour types consisted of sarcoma in 11 patients, prostate cancer in nine patients, and renal carcinoma in four patients, as well as two patients each with endometrial, ovarian, and head and neck malignancies, and three patients with other solid tumours. The patients received a total of 104 cycles at four dosage levels. Six patients received the first dose level, irofulven 0.3 mg/m2 and cisplatin 30 mg/m2. The second dose level, consisting of irofulven 0.4 mg/m2 and cisplatin 40 mg/m2, was received by 18 patients. Six patients received the third dose level of irofulven 0.4 mg/m2 and cisplatin 40 mg/m2. Three patients received the fourth dose level of irofulven 0.50 mg/m2 and cisplatin 40 mg/m2. At the first dose level, one patient had grade 3 diarrhoea. One patient at the second dose had a treatment delay for prolonged thrombocytopaenia. One incident of grade 4 febrile neutropaenia occurred at the third dose level. The fourth dose level was associated with one incident of transient grade 2 visual disturbances and one incident of delay for prolonged thrombocytopaenia. Other adverse events included nausea and vomiting, asthenia, and diarrhoea at grades 1 and 2. The investigators concluded that the maximum tolerated dose was the third dose level and that the second dose level was the recommended dose. Among the 32 evaluable patients, the investigators observed one partial response in the first dose level that consisted of a 98% reduction in a bulky lung metastasis in a patient with heavily pretreated synovial sarcoma; this effect persisted for at least 10 months. They also saw one complete prostate specific antigen (PSA) response in a patient with hormone-refractory metastatic cancer; this effect persisted for 5.8 months. The investigators also observed a major clinical response in a patient with endometrial cancer who had peritoneal carcinomatosis. The response consisted of a normalisation of the antibody Ca15-3, a 95% decrease of the antibody Ca125, and the near disappearance of bulky recurrent malignant ascites. Unconfirmed partial responses in measurable lesions were observed in two patients -- one ovarian cancer patient at the second dose level, whose response lasted 3.2 months, and a patient with renal cancer at the fourth dose level, whose response lasted for 6.5 months. Twelve patients had stable disease as their best response, eight of whom were stable for at least three months, and 15 patients progressed.
[Study title: Phase I and Pharmacokinetic Study of Irofulven (IROF) in Combination With Cisplatin (CDDP), Given Every 2 Weeks, in Patients (pts) With Advanced Solid Tumors. Abstract A46]
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