ROCKVILLE, MarylandThe United States Food and Drug Administration has approved Eloxatin (oxaliplatin for injection, Sanofi-Synthelabo) in combination with infusional fluorouracil(Drug information on fluorouracil) (5-FU) and leucovorin (LV) for the treatment of colorectal cancer that has recurred or become worse following initial therapy with irinotecan(Drug information on irinotecan) (Camptosar) plus bolus 5-FU and LV. The agency granted approval in 7 weeks, the fastest review ever for a cancer drug.
The FDA granted accelerated approval to Eloxatin based on results from a multicenter, randomized, controlled phase III study that compared the effectiveness and safety of Eloxatin alone, infusional 5-FU/LV alone (the standard treatment for colorectal cancer at the time of the study), and the two treatments in combination.
The review was carried out using the agency’s rolling review procedures, which are available to new drug applications designated for fast-track processing. These procedures allow submission of some components of the application before others are completed and submitted to the FDA.
"Eloxatin in combination with infu-sional 5-FU/LV adds a new weapon to what has been a very small arsenal of effective treatments for advanced colo-rectal cancer," said Eloxatin investigator Daniel Haller, MD, professor of medicine, University of Pennsylvania Cancer Center. "In patients whose advanced colorectal cancer has recurred or progressed, meaningful options have been few. The approval of Eloxatin may change the way we treat our patients."
Eloxatin is now marketed in 55 countries. Data from the pivotal trial submitted to the FDA showed that the combination of Eloxatin and 5-FU/LV shrank tumors and delayed progression of tumor growth in some patients. No data were available on the survival effects of the combination therapy.
The approval came with a statement that Eloxatin should be used only by physicians experienced in administering cancer agents and a "black box" warning in the drug’s labeling that highlights anaphylactic-like reactions associated with Eloxatin. "Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available," Sanofi-Synthelabo said in its announcement of Eloxatin’s approval.
The three-arm pivotal clinical trial, carried out in the United States and Canada, involved 463 patients with metastatic colorectal cancer. These patients had re-lapsed or progressed while on therapy or within 6 months of completing therapy with bolus 5-FU/LV plus irinotecan.
Objective tumor response was defined as a 30% or greater reduction in overall tumor size maintained for 4 months. The study found tumor response in 9% of the patients treated with Eloxatin/5-FU/LV, in none of the patients receiving infusional 5-FU/LV, and in 1% of the Eloxatin-only patients. Time to tumor progression was 4.6 months in the Eloxatin/5-FU/LV arm, and 2.7 months and 1.6 months in the 5-FU/LV and Eloxatin-only groups, respectively.
Medical trials and clinical use have shown an association between Eloxatin and pulmonary toxicity, which can be fatal. An acute syndrome of pharyngo-laryngeal dysesthesia may occur in 1% to 2% of patients and is characterized by subjective sensations of dysphagia and dyspnea without laryngospasm or bronchospasm.
Both Eloxatin and 5-FU are associated with adverse hematologic and gastrointestinal events. "When Eloxatin is administered in combination with 5-FU, the incidence of these events is increased," the company said.
The most common adverse events found in the trial for patients receiving the Eloxatin/5-FU/LV combination were peripheral neurosensory events (74% overall; 56% acute and 48% persistent), fatigue (68%), diarrhea (67%), nausea (65%), and vomiting (40%). Hematologic events included anemia (81%), leukopenia (76%), neutropenia (73%), and thrombocytopenia (64%).
In accepting accelerated approval for Eloxatin, Sanofi-Synthelabo obligated itself to carry out postmarketing studies to verify the clinical benefits seen in the pivotal study. In addition, according to the FDA, the company has agreed to a series of other commitments unrelated to accelerated approval. These include conducting a study to examine the safety of repeated doses of Eloxatin 85 mg/m2 in combination with infusional 5-FU/LV, at the doses and schedule recommended in the product label, in patients with varying degrees of renal impairment.
The company also will submit reports on potential and actual medication errors with Eloxatin that occur in the United States during the first 2 years after the drug’s approval date, and will complete two phase II studies of the agent as third-line therapy of metastatic colorectal cancer.