ADRIA’s ZINECARD CHEMOTHERAPY CARDIOPROTECTANT VOTED "NOT APPROVABLE" BY FDA ADVISORY CMTE.; POSSIBLE DECREASE IN DOXORUBICIN TUMOR-KILLING EFFICACY CITED

Adria Labs' Zinecard (dexrazoxane) for the prevention or reduction of the incidence and severity of cardiomyopathy associated with doxorubicin (Adria's Adriamycin and generics) therapy should not be approved by FDA, the agency's Oncologic Drugs Advisory Committee unanimously recommended June 19. The committee's main reason for recommending against Zinecard approval was its concern that dexrazoxane may reduce the tumor- killing effectiveness of the chemotherapeutic agent doxorubicin in addition to reducing heart damage. In a clinical trial of approximately 120 patients with advanced breast cancer, Zinecard combined with a chemotherapy regimen of doxorubicin, 5-fluorouracil and cyclophosphamide showed a chemotherapy response rate of 48%, while patients randomized to chemotherapy and placebo had a 63% response rate. Committee member David Ahmann, MD, Mayo Medical School, called the study "rather substantial evidence to suggest the compound may interfere with anti-tumor effect." Richard Gams, MD, Ohio State University, who presented the 1,000-patient database on Zinecard for Adria, conceded the "possibility of, in truth, some degree of modest interference." He noted, however, that three other studies "did not show statistically significant differences" in response rates between placebo and Zinecard-treated arms. * Gams said that in children "at grave risk for developing serious life-threatening cardiomyopathy" and other "patients not receiving anthrocyclines because of their pre-existing heart disease...one might be willing to sacrifice a small amount of [doxorubicin's tumor-killing] responsiveness to guarantee that those patients who are cured are cured with sound hearts." Gams said pediatric studies of Zinecard "are planned." Committee consultant Judith Ochs, MD, St. Jude Children's Research Hospital, commented that "we can limit the doses of Adriamycin and still maintain high cure rates with multi-agent chemotherapy" in children. She also questioned whether short-term reduction of doxorubicin-induced cardiomyopathy "will correlate with future problems" in children, adding: "No one knows how to predict long-term cardiotoxicity of doxorubicin" in pediatric populations. The committee voted nine to one that Zinecard is effective in preventing or reducing cardiomyopathy associated with doxorubicin therapy. However, because patients receiving Zinecard showed no survival benefit over those who were treated with placebo, the panel questioned its clinical significance. Adria consultant Gams presented clinical trial results that he said demonstrated "a less than 3% drop in left ventricular ejection fraction" in patients receiving Zinecard-augmented chemotherapy compared to 12% to 15% drops for placebo-treated patients. Committee member Ahmann commented: "There is little doubt that it has a cardioprotective effect." However, because the frequency of cardiac events from doxorubicin "is not real high," Ahmann said, "the number of people who you are able to impact positively is really rather insignificant. That is pretty much borne out by the lack of effect in terms of survival." * The committee and its consultants had a wide range of opinions on how much further testing would be required to demonstrate that zinecard does not reduce doxorubicin's effectiveness. After discussing several statistical issues, the committee voted eight to two that it "would be reassured that Zinecard does not significantly lower the response rate or time to progression in metastatic breast cancer if another study had sufficient power to show that the lower limit of the confidence interval was not lower than minus 15%." Adria is currently enrolling patients in a clinical trial that will eventually involve 200 late-stage breast cancer patients, Gams said. In preliminary results obtained from 113 patients, Gams said, Zinecard-treated patients have shown a 50% response rate, versus 54% for placebo-treated patients.