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Angiogenesis Inhibitor SU5416 a Safe Addition to Therapy for Colorectal Cancer

Angiogenesis Inhibitor SU5416 a Safe Addition to Therapy for Colorectal Cancer

LOS ANGELES—A 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 leucovorin.

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, UCLA’s 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 told ONI.

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. It’s safe; it’s 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, we’ll have the answer to whether this particular angiogenesis inhibitor, by manipulating VEGF, will prolong patient survival, which is what it’s all about,” he said.

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