ODAC Recommends Accelerated FDA Approval of Ethyol for Cytoprotection

July 1, 1995

ROCKVILLE, Md--The Food and Drug Administration's Oncologic Drugs Advisory Committee (ODAC) has voted unanimously to recommend accelerated approval of Ethyol (amifostine injection) as a cytoprotective agent against cumulative renal toxicities associated with cyclophosphamide (Cytoxan, Neosar) and cisplatin (Pla-tinol) in patients with advanced solid tumors of non-germ-cell origin.

ROCKVILLE, Md--The Food and Drug Administration's Oncologic DrugsAdvisory Committee (ODAC) has voted unanimously to recommend acceleratedapproval of Ethyol (amifostine injection) as a cytoprotectiveagent against cumulative renal toxicities associated with cyclophosphamide(Cytoxan, Neosar) and cisplatin (Pla-tinol) in patients with advancedsolid tumors of non-germ-cell origin.

Accelerated approval, as opposed to unconditional approval, meansthat a new drug may be marketed, but FDA will require additionalstudies to determine if the observed effect will lead to clinicallymeaningful benefits. If such studies are inconclusive, or if thecompany, in this case, U.S. Bioscience, does not perform them,FDA reserves the right to withdraw the accelerated approval.

Efficacy and Safety

In a randomized, double-blind study, women with ovarian cancerwere divided into two arms: one group received cis-platin andcyclophosphamide alone and the other group received the two chemotherapeuticagents with Ethyol. The objective was to determine whether amifostinereduced cumulative renal toxicity associated with cisplatin, asmeasured by creatinine clearance levels.

The toxic effects of cisplatin therapy (neurotoxicity, ototoxicity,myelosuppression, and neutropenia, as well as nephrotoxicity)can be permanent and severe. Patients may be left with significantreduction in renal function, which can preclude their abilityto receive further cisplatin therapy, thus shortening their lives.

Moreover, renal failure, myelosuppression, and neutropenia cannegatively affect the action of other chemotherapeutic agentssuch as carboplatin (Paraplatin), methotrexate, and bleomycin.

According to U.S. Bioscience, Ethyol, when given with cisplatin,reduced nephrotoxicity, ototoxicity, and peripheral neuropathy.In addition, possible confounding factors, such as preexistingdiabetes, preexisting hypertension, and the existence of othertumors, had no significant negative effect on the efficacy ofamifostine.

Amifostine also preserves antitumor activity in ovarian cancer,non-small-cell lung cancer, head and neck cancer, rectal cancer,and melanoma, the company said. It is most effective in the latercycles of chemotherapy after patients have received a cumulativedose of at least 400 mg/m² of cisplatin over six cycles.

Adverse effects of amifostine include mild and transient hypotensionon the day of treatment; nausea and vomiting that occurs duringtreatment and is alleviated by premedication with dexamethasoneand ondansetron (Zo-fran); and flushing and sneezing during treatment.

There have been no deaths or adverse clinical sequelae associatedwith amifos-tine. No cumulative toxicity was reported during clinicaltrials of amifostine and radiation therapy in which amifostinewas administered daily for 5 weeks.

The FDA's review of the data submitted by U.S. Bioscience showedthat the survival rates for patients on Ethyol with cisplatinand cyclophosphamide were the same as for patients on cisplatinand cyclophosphamide alone.

FDA reviewers concluded that amifostine is effective in reducingcumulative renal toxicity. In terms of hematologic toxicity, theevidence is not as strong, and more data need to be gathered.Adverse effects of amifostine, the FDA said, were unpleasant buttransient.

Members of ODAC were unanimous in their conclusion that Ethyolreduces cumulative renal injury, as manifested by decreases increatinine clearance, in cancer patients treated with cisplatinat a dosage regimen of 100 mg/m² for six cycles. However,when the votes for unconditional approval were counted, the memberswere equally divided.

U.S. Bioscience said it was willing to negotiate with FDA aboutadditional studies that would be most appropriate to evaluatethe continuing clinical efficacy of Ethyol and to meet the requirementsof accelerated approval.

Studies might include those to assess decreased risk of subsequentrenal failure; ability to complete a planned course of cisplatinfor a cisplatin-responsive cancer; ability to give additionalcisplatin cycles at a later date, for example, to patients withrelapsed ovarian cancer; or ability to safely administer largercisplatin doses and thus obtain a better response.