LOS ANGELESA new angiogenesis signaling inhibitor called SU5416
can be safely used with 5-fluorouracil (5-FU) and leucovorin to treat
metastatic colorectal cancer, according to results presented at the
36th annual meeting of the American Society of Clinical Oncology (ASCO).
SU5416 blocks the vascular endothelial growth factor receptor
(VEGF-R). Without VEGF-R, tumors may lose the ability to form
nourishing blood vessels. It is thought that as a result, SU5416 may
starve tumors and keep them from growing.
Combination Phase I-II Trial
The research, presented by scientists from the University of
California at Los Angeles (UCLA) School of Medicine and from SUGEN,
Inc., South San Francisco, California, was a combination phase I and
phase II trial of two dose levels of SU5416 (85 mg/m² and 145
mg/m²) administered twice a week combined with 5-FU and
The 28 patients had untreated metastatic colorectal cancer. Of these,
13 received 5-FU/leucovorin according to the Mayo Clinic regimen (425
mg/m² intravenous push of 5-FU and 20 mg/m² intravenous
push of leucovorin), and 15 according to the Roswell Park regimen
(500 mg/m² of leucovorin as a 2-hour infusion with a 600
mg/m² intravenous push of 5-FU halfway through).
The goal of the study was to determine whether SU5416 could be
administered safely with 5-FU and leucovorin.
The results showed that SU5416 could indeed be safely combined with
the other two agents. No dose-limiting toxicities were attributed to
SU5416. In an interview with ONI, Lee Rosen, MD, assistant
professor, Division of Hematology and Oncology, and director, Cancer
Therapy Development Program, UCLAs Jonsson Cancer Center, said
that SU5416 caused mild headaches in some patients. Otherwise, no
clearcut toxicities were attributable to SU5416.
We did see about a 15% to 20% incidence of catheter-related
deep vein thrombosis, but it was never really clear whether it was
due to the catheter, the cancer, or the drug, Dr. Rosen said.
After we started prophylactic low doses of anticoagulation, we
saw almost no new clots.
Some patients did experience the typical grade 3 and 4 toxicities
expected with 5-FU and leucovorin, including severe nausea, vomiting,
diarrhea, mucositis, and neutropenia. The rates of these were lower
with the Roswell Park regimen.
Of the 28 patients who started therapy, 41% had a complete or partial
response, with their tumors shrinking at least 50%. Twenty-six of the
28 patients are still alive, and three patients have remained on
therapy for more than a year. The median time to progression in this
trial was 9.3 months. This compares favorably with 5-FU alone, which
typically has a median time to progression of 6 months, Dr. Rosen
SU5416 is now being evaluated in a phase III trial for advanced
colorectal cancer. The trial pits 5-FU plus leucovorin alone against
the two agents plus SU5416.
SU5416 Well Tolerated
The researchers concluded that patients tolerated SU5416 combined
with 5-FU and leucovorin well, with most side effects due to the
latter two agents. The Roswell Park regimen did result in fewer
toxicities and is preferable for that reason.
Dr. Rosen told ONI that the study showed two important points.
One is that very clearly you can give full doses of
chemotherapy with the angiogenesis inhibitor. Its safe;
its well tolerated for long periods of time, he said.
Second, this and other studies of SU5416, combined with the results
of a Genentech study with anti-VEGF, also reported at ASCO, seem to
provide proof of principle that interfering with angiogenesis by
blocking VEGF or VEGF-R is an appropriate approach to some cancers.
Hopefully, within the next year and a half or so, well
have the answer to whether this particular angiogenesis inhibitor, by
manipulating VEGF, will prolong patient survival, which is what
its all about, he said.