Anti-VEGF MoAb Promising in Phase II Renal Cancer Study

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Oncology NEWS InternationalOncology NEWS International Vol 8 No 11
Volume 8
Issue 11

BETHESDA, Md-Some kidney cancer patients in an ongoing phase II trial of an experimental antiangiogenesis monoclonal antibody have shown improvement. The randomized, three-arm study by National Cancer Institute researchers compares two different doses of the drug against a placebo.

BETHESDA, Md—Some kidney cancer patients in an ongoing phase II trial of an experimental antiangiogenesis monoclonal antibody have shown improvement. The randomized, three-arm study by National Cancer Institute researchers compares two different doses of the drug against a placebo.

“We have some evidence of objective regression,” James C. Yang, MD, a senior investigator in NCI’s Division of Clinical Sciences, told the National Cancer Advisory Board. However, because the trial remains double-blinded, “I can’t say these patients are on the agent. But there is a two out of three chance they are.”

The Genentech drug—recombinant humanized monoclonal anti-VEGF antibody (rhMAb-VEGF)—is a chimera made from a murine antibody and the IgG1 cassette used for Herceptin (tras-tuzumab). It is 93% human and 7% mouse in its amino acid sequence.

The drug binds and neutralizes all isoforms of vascular endothelial growth factor (VEGF), a protein that induces endothelial growth, angiogenesis, and vascular permeability. “These activities promote both tumor growth through the generation of new blood vessels and the elaboration of metastasis through the leakage of proteins into the extracellular space,” Dr. Yang said. The rationale behind rhMAb-VEGF is that blocking VEGF will prevent the growth of blood vessels into renal tumors.

Kidney cancers are among the most vascular of tumors. Studies indicate that in these cancers, mutations in the VHL tumor-suppressor gene are tightly linked to an overproduction of VEGF. “These molecular observations led us to feel that renal cell carcinoma would be a particularly good histology in which to test the new drug,” Dr. Yang said.

The NCI launched its study after a Genentech phase I trial of rhMAb-VEGF found the drug safe in patients with a variety of advanced solid tumors. Patients in the study were treated by IV infusions four times over a 42-day period. One of the patients had a minor response, and 13 had stable disease for the 72-day follow-up. However, 6 of the patients had isolated episodes of tumor bleeding, two of which were serious and considered possibly treatment related.

NCI opened its study to patients with progressive, measurable metastatic clear-cell renal cell carcinoma in October 1998. By August 1999, the researchers had enrolled 52 of an anticipated 150 participants. The study protocol calls for 50 patients in each of three arms—placebo vs rhMAb-VEGF in doses of 3 or 10 mg/kg. Patients receive infusions every 2 weeks and will continue to do so, unless they progress, throughout the 2-year trial.

Patients entering the study must already have had interleukin-2 therapy or be ineligible for IL-2 therapy. Those with CNS involvement, tumor bleeding, or any ischemic disease are excluded. Endpoints are response rate, time to progression, and survival.

“We are measuring antibody levels and bioactive VEGF levels,” Dr. Yang said. “The toxicity has been minimal, with only about 10% of patients developing a mild-to-moderate limited proteinuria. There have been no other significant toxicities.”

In addition to testing rhMAb-VEGF, the NCI research team is evaluating imaging technologies to see if they can correlate blood flow to the tumors with disease regression and progression. The goal is to identify noninvasive methods to quantify changes in tumor vasculature, validate these methods as a means of quantifying the effects of antivascular agents, and evaluate the variability of repeated measurements. The hope is to find surrogate endpoints for use in future antiangiogenesis studies.

“A whole wave of antiangiogenesis trials is coming along that will be looking at stable disease and time to progression,” Dr. Yang said. “If every one of these new agents requires a large, randomized phase II study, that will be laborious.”

The imaging modalities being evaluated are dynamic MRI and PET using three separate radioisotopes.

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