ODAC Recommends Full FDA Approval for Camptosar

BETHESDA, Md--The Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended that the Food and Drug Administration (FDA) grant full approval to Camptosar (irinotecan hydrochloride injection, Pharmacia & Upjohn) for the treatment of metastatic colon or rectal cancer that recurs or progresses after fluorouracil (5-FU) therapy.

The FDA gave accelerated approval to Camptosar in 1996 on the basis of studies indicating it reduced tumor size. Accelerated approval requires the sponsoring company to conduct further studies on a drug, and failure to do so can lead to withdrawal of FDA approval. Backed by two new studies documenting that the drug prolongs survival in colorectal cancer, Pharmacia & Upjohn returned for a new hearing before the committee.

Camptosar is a collaborative development and marketing effort by four companies. The two randomized, prospective, multicenter phase III studies presented to the panel by Langdon Miller, MD, Phar-macia & Upjohn’s vice president and clinical director for oncology in the Americas, were sponsored by Rhône-Poulenc Rorer, which is also one of the four Camptosar partners.

Study V301 involved 279 patients; 189 received Camptosar and 90 received only best supportive care (BSC), which included antibiotics, analgesics, transfusions, corticosteroids, or anticancer agents other than the trial drug or another topo-isomerase I inhibitor. V302 included 256 patients, 127 randomized to Camptosar and 129 to one of three 5-FU regimens.

In both studies, the standard Camptosar dose was 350 mg/m² every 3 weeks, up from the 125 mg/m² weekly for 4 weeks with a 2-week rest currently used in the United States. Survival served as the primary endpoint in each study.

Median Survival

The median survival for the Camptosar group in V301 with 13 month follow-up was 9.2 months vs 6.5 months in the BSC arm. Camptosar patients had a 1-year survival of 36%, compared with 14% in the BSC arm. In V302, with 15 months of follow-up, median survival was 10.8 months for Camptosar patients and 8.5 months for the 5-FU group. One-year survival was 45% for the Camptosar group vs 32% for the 5-FU arm, Dr. Miller told the panel.

The FDA’s survival analysis generally agreed with that of the company. The agency put the median survival in V301 at 9.2 months for the Camptosar recipients vs 6.2 months for the BSC patients, and at 10.2 months in V302 for the Camptosar arm vs 8.4 for the 5-FU group. Camptosar "showed a consistent advantage for survival," said FDA reviewer Isagani Chico, MD.

In V301, 22% of the Camptosar patients experienced grade 3 and 4 neutro-penia and another 3% had neutropenia plus fever or infection. Other grade 3 and 4 adverse events that occurred more commonly in the Camptosar group included diarrhea (22% vs 6%), vomiting (14% vs 8%), cholinergic symptoms (12% vs 0%), and infection (9% vs 3%). Asthenia, at 19%, was slightly increased in the BSC arm over the 15% in the treatment group. Grade 3 and 4 abdominal pain and muco-sitis were similar in the two arms.

Grade 3 and 4 adverse events in V302 that were seen more commonly in the Camptosar group included diarrhea (22% vs 11% in 5-FU patients), neutropenia (14% vs 2%), neutropenia plus fever or infection (6% vs 2%), and vomiting (14% vs 5%). Asthenia, abdominal pain, mucositis, and cholinergic symptoms were similar in the two groups. Cutaneous signs, including hand-foot syndrome, and infections, were below 4% but more common among patients getting 5-FU.

Camptosar "has consistent activity in therapy of patients with previously treated colorectal cancer . . . can safely provide survival and quality of life benefits to these patients . . . and represents a new standard of care" in these patients, Dr. Miller told the committee.

"Two excellently designed and analyzed trials," Richard M. Simon, DSc, chief of NCI’s Biometric Research Branch, said after Dr. Miller’s presentation.

Dr. Chico said his analysis of the two studies showed "toxicity was expected, well accepted, and manageable." One committee member did express concern about an increased level of hospitalization among patients receiving Camptosar (60% were hospitalized at least once due to adverse events vs 63% of BSC patients and 39% of 5-FU patients).

However, the panel found the two trials demonstrated the drug’s efficacy and safety, and voted 7 to 0 to recommend full approval "for the treatment of metastatic carcinoma of the colon or rectum that has progress or recurred following 5-FU-based chemotherapy."

ODAC also recommended, by a 6 to 1 vote, that the FDA approve both the current 125 mg/m2 regimen and the 350 mg/m² regimen used in the studies.