FDA Advisory Panel Recommends Vesanoid, Zinecard

ROCKVILLE, Md--The FDA Oncologic Drugs Advisory Committee hasrecommended approval of two agents: Hoffmann-La Roche's Vesanoid(tretinoin, all-trans-retinoic acid) and Pharmacia Inc.'s Zinecard(dexrazoxane forinjection).

Vesanoid is indicated for use in acute promyelocytic leukemia(APL) in patients who relapse after an anthracycline regimen orin those for whom standard regimens are contraindicated.

Although only a few patients in the Vesanoid studies were clearlyrefractory to anthracycline-based induction regimens or showedreasons why such therapy was contraindicated, these patients appearedto respond at least as well as relapsed patients to Vesanoid therapy.Therefore, the agent was also recommended for the treatment ofrefractory patients, or those for whom anthracycline regimensare not appropriate because of cardiomyopathy.

APL has a high early mortality rate. Ed Schnipper, MD, of Hoffmann-LaRoche, presented data from nonrandomized, uncontrolled studiesshowing that Vesanoid has no appreciable effect on early deathfrom APL, but does improve long-term survival and strikingly decreasesearly morbidity.

At a Vesanoid dosage of 45 mg/m² for 90 days, the completeresponse rate was 62% to 93%. Median survival was 11 months forpatients who had been in relapse. The time to complete remissionranged from 40 to 90 days. The company recommends that patientsbe placed on consolidation chemotherapy after 90 days of Vesanoidtreatment or when complete remission is achieved.

In APL patients who had been refractory to all types of chemotherapyand in those for whom anthracyclines were contraindicated, treatmentwith Vesanoid led to 1-year survival rates of 88% and 41%, respectively,the company said.

Mortality from retinoic acid-APL syndrome (characterized by dyspnea,fever, leukocytosis, pulmonary infiltrates, shivering, and renalfailure) had been high until the investigators discovered an effectivetreatment--high doses of dexamethasone administered intravenouslyfor at least 3 days.

Zinecard Reduces Cardiac Events

The FDA Committee also recommended approval of Zinecard to preventand/or reduce the incidence and severity of cardiomyopathy inwomen with metastatic breast cancer who have received a cumulativedoxorubicin dose of at least 300 mg/m² and who would benefitfrom continuing chemotherapy

In multicenter, prospectively randomized trials, Zinecard wasshown to be clearly cardioprotective when administered beginningwith the seventh course of doxorubicin. According to FrederickS. Whaley, PhD, a Pharmacia statistician, the risk of an adversecardiac event was 3.5 times higher in controls than in patientsgiven Zinecard, even during follow-up at the end of the trials.Moreover, the higher the doxorubicin dose, the greater the cardioprotectiveeffects, as long as the patient receives the drug beginning withthe seventh course of chemotherapy.

When measured from the seventh doxbicin course, the time to diseaseprogression was no different between controls and patients receivingthe drug. But, significantly, the survival rate for Zinecard patientswas double that of controls.

Adverse effects of Zinecard were limited to mild pain on injectionand myelosuppression, which Pharmacia described as transient andnot life threatening. Of more serious concern were cardiac deaths.Of 1,008 patients participating in the clinical trials, six controlsand one patient receiving Zinecard died of an adverse cardiacevent.

The recommendation for approval comes under the FDA's AcceleratedApproval Regulations, which require postmarketing studies.

Some members of the panel expressed concern that the success ofZinecard will rise or fall based only on its efficacy in breastcancer, because the company plans to limit its postmarketing studiesto breast cancer patients. They urged Phar-macia to test the agentin other cancers, such as lymphomas.