Irinotecan Added to SU-5416, 5-FU, and Leucovorin in Phase I/II Trial

NASHVILLE, Tennessee—Irinotecan (Camptosar) has been added to the combination of SU-5416/5-fluorouracil (5-FU)/leucovorin, and is being tested in a phase I/II study in metastatic colorectal cancer. That study is being conducted at Vanderbilt Medical Center in Nashville, Tennessee. Due to dose-limiting toxicity, the schedule and/or dose will be altered to make it more tolerable, according to Jordan D. Berlin, MD, assistant professor of medicine and oncology at Vanderbilt Medical Center.

The trial builds on studies in models, preclinical studies, and previous phase I/II trials. Used as a single agent in models of colon cancer, SU-5416, a small molecule angiogenesis inhibitor decreased colon metastases and microvessel formation and increased the rate of apoptosis. Preclinical studies suggested that SU-5416 plus 5-FU would produce more tumor inhibition than either agent used alone. Conducted by Lee Rosen, MD, and colleagues at the University of California, Los Angeles, a previous phase I/II trial in advanced colorectal cancer compared single-agent SU-5416 to two regimens: the Mayo Clinic regimen of leucovorin plus 5-FU daily × 5, and the Roswell Park regimen of leucovorin plus 5-FU weekly × 6 out of every 8 weeks. This trial identified CYP3A4 and CYP1A2 as the significant metabolic pathways and found that induction of clearance with the combination of SU-5416/5-FU/leucovorin was only slightly less than had been observed with single-agent SU-5416.

"This seems to be a very effective combination, particularly SU-5416 combined with the Roswell Park Regimen. Survival was fairly long, but this was in a highly selected group of patients," Dr. Berlin said.

Additive Antitumor Activity

Irinotecan was added to the regimen because in combination with SU-5416 it has additive antitumor activity. The phase I/II open label study against metastatic colorectal cancer is a two-stage study. Up to 30 patients will be enrolled. "We started at the maximum tolerated dose (MTD) for irinotecan, 5-FU, leucovorin (IFL) and added SU-5416 at two different dose levels, 85 mg/m² (5 patients) and 145 mg/m² (7 patients)," Dr. Berlin explained.

Some Serious Toxicities

The researchers have now given a total of 27 6-week cycles. "At the time of this report we stopped accrual to this trial due to the toxicities of the IFL regimen that were reported in two National Cancer Institute-sponsored cooperative group studies," Dr. Berlin said. "The most common toxicities were those generally expected for IFL: diarrhea, abdominal pain, nausea, and vomiting." The investigators are still evaluating toxicities in two patients with bowel obstruction.

Serious toxicities possibly related to SU-5416 included one idiopathic reaction to coumadin, one catheter-related thrombosis with subsequent fever and infection, and two patients with severe nausea, vomiting, and diarrhea requiring intravenous hydration. One of these patients was found to have Clostridium difficile.

"The most bothersome toxicities are diarrhea and vomiting. This has not been a particularly well tolerated regimen for long-term dosing. The last patient to go off study had a partial response but couldn’t tolerate the quality of life impact," Dr. Berlin said. "We are going to alter the schedule and/or doses on this trial to make it more tolerable."