SILVER SPRING, Md-The FDA's Oncologic Drugs Advisory Committee (ODAC) has voted 6 to 0 with one abstention to recommend that Rhône-Poulenc Rorer's Taxotere (docetaxel) be approved for the treatment of patients with anthracycline-resistant locally advanced or metastatic breast carcinoma.
SILVER SPRING, Md-The FDA's Oncologic Drugs Advisory Committee(ODAC) has voted 6 to 0 with one abstention to recommend thatRhône-Poulenc Rorer's Taxotere (docetaxel) be approved forthe treatment of patients with anthracycline-resistant locallyadvanced or metastatic breast carcinoma.
The panel also recommended that, due to increased toxicity, theagent should not be used in patients who have poor liver function.
Problems of fluid retention with Taxotere in earlier studies,a principal stumbling block to approval, were reduced in currentstudies to an acceptable level by premedication with corticosteroids,the panel found.
Taxotere, which has already been approved for use in Australia,Canada, South Africa, Mexico, Uruguay, and Brazil, is a semisynthetictaxoid that promotes tubulin assembly in microtubules and blocksthe disassembly of microtubules, thereby preventing cancer cellsfrom dividing and leading to cancer cell death. Hepatic clearanceis the main route of elimination.
At the ODAC meeting, Dr. Lewis Sheiner, of the University of California,San Francisco, said that an important problem to deal with whenprescribing Taxotere is altered pharmacokinetics. He warned thatit is crucial to identify patients who are potentially at riskof overdose due to slow drug elimination.
Of 15 factors tracked for their impact on Taxo-tere's pharmaco-kinetics,only three were found to be important, Dr. Sheiner said. Thosewere body size, protein binding, and, most important, hepaticfunction.
Daniel D. Von Hoff, MD, of the Cancer Therapy and Research Center,University of Texas Health Science Center, San Antonio, said thatof 1,070 patients who received Taxotere at 100 mg/m2 once every3 weeks, the 42 with reduced drug clearance had more drug-inducedtoxicity, with 5 toxic deaths.
Gabriel N. Hortobagyi, MD, of M.D. Anderson Cancer Center, notedthat in three phase II studies of patients with anthracycline-resistantcancer, the overall response rate for Taxotere was 41%.
The 0.8% rate of toxic death and the 22% rate of febrile neutropeniaseen in these studies are acceptable, he said. However, patientswith low drug clearance had an unacceptable 29% toxic death rate.
Dr. Julie Beitz, representing the FDA, stated that Taxotere isactive as second-line therapy of anthracycline-resistant breastcancer. She added that the rate of toxic deaths in all subjectson Taxotere was 1.5% to 2%, and the rate of fluid retention was49%. Thus, she recommended the use of dexamethasone for fluidretention. Also, she said that those patients at risk for toxicitydue to poor liver function should be excluded from treatment.
Dr. Beitz added that the 100 mg/m² dose may be too high,and that studies show that a 60 mg/m² dose eliminates themost severe reactions to the drug. She recommended continued studyof Taxo-tere in well-controlled trials.
The ODAC panel agreed unanimously that the phase II trials evaluatingTax-otere were well controlled, and voted 6 to 1 that hematologictoxicities were acceptable as long as patients have normal liverfunction. They voted unanimously that the fluid retention problemswere ameliorated with premedication, and voted 6 to 1 to recommenda starting dose of 100 mg/m² every 3 weeks in patients withnormal liver function tests.
The panel agreed 6 to 0 with one abstention that there is no safelevel of the drug for patients with poor liver function. Theyalso recommended that clinical research continue after the drugis approved for marketing.
In a teleconference held after the FDA vote, Howard A. BurrisIII, MD, of the Cancer Therapy and Research Center, San Antonio,said, "I am enthusiastic about ODAC's recommendation thatTaxotere be approved. We've been administering Taxotere in SanAntonio now for more than 5 years and have been very impressedwith its activity in breast cancer as well as in a variety ofother tumors."
Taxotere's main advantage is that it can achieve responses inpatients who have failed standard therapy, he said. "Thesepatients now have an option. We've seen patients with metastasesto the liver, lungs, and bone respond with dramatic reductionsin tumor."