BETHESDA, MdSome 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 NCIs Division of Clinical
Sciences, told the National Cancer Advisory Board. However, because
the trial remains double-blinded, I cant say these
patients are on the agent. But there is a two out of three chance
The Genentech drugrecombinant 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 armsplacebo 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.