MarylandThe United States Food and Drug Administration has approved Eloxatin
(oxaliplatin for injection, Sanofi-Synthelabo) in combination with infusional
fluorouracil (5-FU) and leucovorin (LV) for the treatment of colorectal cancer
that has recurred or become worse following initial therapy with 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
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.