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
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 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
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."