NEW YORK-A phase II trial of ecteinascidin-743 (ET-743) is underway in Europe in ovarian cancer patients who have failed platinum/taxane regimens, Nicoletta Colombo, MD, of the European Institute of Oncology, Milan, reported at the Chemotherapy Foundation Symposium XX.
NEW YORKA phase II trial of ecteinascidin-743 (ET-743) is underway in Europe in ovarian cancer patients who have failed platinum/taxane regimens, Nicoletta Colombo, MD, of the European Institute of Oncology, Milan, reported at the Chemotherapy Foundation Symposium XX.
Derived from a marine organism, ET-743 (named Yondelis by developer PharmaMar, Madrid, Spain) has a novel mechanism of action and interaction with DNA, Dr. Colombo said. The drug binds several transcription factors to DNA. In vitro studies, demonstrated the drug’s activity against ovarian cancer xenografts.
The phase II study, coordinated by the Southern Europe New Drug Organization, enrolled 38 patients from June 2000 to October 2002 in four centers in Italy and Switzerland. Eligible patients had failed one prior platinum-taxane treatment plus or minus other drugs, Dr. Colombo said. Other eligibility criteria included performance status of 0 or 1, complete recovery from prior toxicities, and measurable disease. The median age was 57 years (range, 28 to 81 years). ECOG performance status was 0 in 82% of the patients.
Patients were stratified as refractory or relapsed. The refractory cohort was made up of patients whose disease progressed during platinum/taxane treatment or within 6 months afterward. Patients whose disease progressed more than 6 months after the last treatment were categorized as relapsed. The median time to relapse was 13 months (range, 7 to 43 months).
Of the 38 patients, Dr. Colombo said, 34 were evaluable for toxicity at the time of the latest analysis and 27 for response by a peer review panel.
Doses of ET 743 were adjusted in the phase II trial, Dr. Colombo pointed out. Based on phase I data, the starting dose was 1,650 µg/m2 given in a 3-hour infusion to be repeated every 21 days. This dose was given to only six of the evaluable patients, Dr. Colombo reported.
"Subsequent doses had to be reduced because of the occurrence of excessive grade 4 toxicity. So 12 patients were treated at 1,500 µg/m2," she said. "Finally, the dose had to be further decreased to the current 1,300 µg/m2, which was given in 16 patients." All patients received prophylactic steroids. Grade 3-4 liver enzyme elevations and asthenia were recognized as dose-limiting toxicities at the higher dose levels, Dr. Colombo said. "Neutropenia is another common side effect," she said, "and it is grade 3-4 in 50% of patients even at the lower level. However, this neutropenia is rapidly reversible and was never associated with febrile neutropenia."
Grade 1 bilirubin elevation has occurred in 33% of patients at the 1,300 µg/m2 dose, she noted, but was rapidly reversible. Thrombocytopenia, she added, has not been a problem with ET-743.
Of the patients evaluable for response, 7 of the 13 in the relapsing group had an objective response, including one complete response. There were no responses among the 14 patients with refractory disease. "We are currently discussing with the peer review a possible partial response in one of these patients," Dr. Colombo said. The overall response rate for the 27 evaluable patients was 26%, but for the relapsing group, it was 54%. The median duration of response was 6 months (range, 2+ to 11 months). An overall response rate of 28% was attained with the 1,300 µg/m2 dose.
Future research efforts, Dr. Colombo said, will be directed at confirming the drug’s activity by treating more patients at the 1,300 µg/m2 dose level. Plans are also being made, she said, to test combination regimens in which ET-743 would be given with other drugs such as cisplatin (Platinol) or doxorubicin.