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

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.

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