LOS ANGELES--While the flurry of media attention on antiangiogenesis
drugs has focused on angiostatin and endostatin, other such agents
are further along in development. One of them, BAY 12-9566, has
stopped tumor growth in patients for up to 11 months in an ongoing
trial, Louise Grochow, MD, said at an ASCO session on novel
approaches in drug development.
BAY 12-9566 is a novel matrix metalloproteinase inhibitor (MMPI) that
directly inhibits MMP-2 and MMP-9 at achievable nanomolar
concentrations. In preclinical trials, BAY 12-9566 has demonstrated
antiangiogenesis and antiprolif-erative effects, including reduction
in tumor growth and decreased metastatic potential, said Dr. Grochow,
associate professor of oncology, Johns Hopkins Oncology Center.
This phase I trial has enrolled 27 solid tumor patients whose cancers
had not responded to standard therapy. Each was treated with oral
doses of BAY 12-9566--100 mg/d escalating up to 1,600 mg/d (400 mg
four times daily or 800 mg twice daily). The first 6 patients were
treated for 4 weeks followed by a 2-week rest; subsequent patients
received continuous daily doses unless disease progressed or toxicity intervened.
Dr. Grochow reported that treatment has been well tolerated. Changes
in liver enzymes and mild thrombocytopenia at the highest doses were
reversible after dose reduction. No patients have developed the
diffuse arthralgia that has been seen in trials of some other MMPIs,
she said. One patient developed back pain due to vertebral bone loss
that is potentially treatment related. It may be that the MMPI
prevented the absorption of cortical and trabecular bone, she said.
Tumor measurements obtained every 8 weeks have shown 14 patients to
have no tumor growth for at least 4 months, and 5 patients to have
stable disease for 7 to 11 months, she said. The cohort included
primarily colorectal cancer patients but also patients with breast,
cervical, ovarian, and a variety of other solid tumors. All had
received prior chemotherapy, and some had also received radiotherapy.
Dr. Grochow pointed out that the trials endpoint (ability to
achieve an acceptable drug exposure) was "nonstandard" for
a phase I trial; toxicity was not an endpoint because none was
expected. "Our target exposure was 100 mg/L, and we got 50%
greater than that," she said.
Dr. Grochow concluded that chronic oral doses of BAY 12-9566 are well
tolerated with minimal reversible toxicities at doses up to 800 mg
twice a day. Steady-state plasma levels can be sustained at levels
shown to be active in preclinical models, she said.
"There is legitimate reason for excitement about these new
agents," Dr. Grochow told Oncology News International. She
emphasized that while endostatin and angiostatin, because they are
complex proteins (peptides), have to be administered parenterally,
some of the MMPIs, like BAY 12-9566, AG3340, and marimastat are
"What is interesting about the experience with BAY 12-9566,"
she said, "is that you get growth inhibition and some cytotoxic
effects as well." She said that in animal models, stopping
administration resulted in renewed tumor growth, and resuming dosing
once again stopped growth.
Karen Kumor, MD, Bayers international clinical project manager
for BAY 12-9566, noted that the MMPIs are further along in testing
than endostatin and angiostatin. "The MMPIs are smaller
molecules and are easier to synthesize and administer," she said.
Development of the MMPIs represents a novel approach to inhibiting
oncogenesis. "The metalloproteases were discovered within the
last 7 to 8 years in arthritis research. They are involved in
remodeling of the extracellular matrix. In order for a cell mass to
grow, it has to get through this tough matrix," Dr. Kumor explained.
The metalloproteases, in their normal function, break down matrix to
allow embryogenesis, vessel formation, and wound healing. An
extraordinary number of diseases, she observed, have been discovered
to be associated with excesses of matrix metalloproteases.
Invading tumor cells, through a signaling process, engage the normal
surrounding matrix cells and induce them to produce the digestive
proteases that break down structures and create room for the tumor
mass to expand. The MMPIs interdict this process, inhibiting
angiogen-esis, cell proliferation, metastasis, and angio-genesis,
thus preventing endothelial cell invasion without affecting normal
endothelial cell proliferation.
While BAY 12-9566 is very selective for MMP-2 and MMP-9, other MMPIs
target MMP-1 and MMP-13 as well. These are collegenase proteins that
may be important for joint structural integrity, Dr. Grochow said,
adding that "inhibiting them may lead to joint structure
problems," as have been seen with some other MMPIs.
Another possible explanation for the joint problems experienced in
patients in clinical trials of agents targeting the collagenase MMPs
is that they may induce inflammatory cytokines.
Clinical experience in humans has suggested that the MMPIs are best
given after cytoreduction. "You reduce the tumor with radiation
or chemotherapy, and then this drug is given to prevent further
spread and metastasis--to keep any remaining cancer cells so small
that they do not develop," Dr. Kumor said.
BAY 12-9566 is now in phase II-III trials for lung cancer, pancreatic
cancer, and ovarian cancer in Europe, the United States, and Canada.
In addition, a trial of the agent in combination with a cytotoxic
agent is planned, Dr. Kumor said.