A Phase I/Biomarker Study of Bevacizumab in Combination With CNTO 95 in Patients With Refractory Solid Tumors
Targeting molecular pathways of tumor growth has recently become a major focus of
anti-cancer treatments. The VEGF pathway has demonstrated significant mitogenic activity for
arterial, venous, and lymphatic endothelial cells, induction of vascular permeability for
extracellular remodeling, and activity as an endothelial cell growth factor. The proof of
principle that targeting the VEGF pathway as an anti-cancer therapy was demonstrated by the
phase III trial of the anti-VEGF monoclonal antibody bevacizumab versus placebo in
combination with chemotherapy for metastatic colorectal cancer. In this trial the addition
of bevacizumab to chemotherapy showed a statistically significant improvement in overall
survival for these subjects (11). Since this trial, the addition of bevacizumab to
chemotherapy has been shown to be beneficial in non-small cell lung cancer subjects and
metastatic breast cancer subjects (9, 12).
Integrins have been shown to be essential components of angiogenesis. One of the
best-characterized integrins in tumor-induced angiogenesis is αvβ3. Angiogenesis
dramatically up-regulates integrin αvβ3 expression by endothelial cells (13). Integrin αvβ3
has been linked to cell migration and invasion (14), and cell survival (15). Inhibition of
αvβ3 results in apoptosis of endothelial cells (16) and inhibition of microvascular network
formation (17). The signaling pathways activated by αvβ3 and VEGF act synergistically in the
formation of microvascular networks (17). Both αvβ3 and VEGF activate Src, Ras, PI3K, and
Erk cascades (18). CNTO 95 is a fully humanized monoclonal antibody that blocks integrin
αvβ3 with high affinity.
The combination of different targeted therapies has the potential of providing a more
complete inhibition of angiogenesis. It is our hypothesis that the combination of CNTO 95
and bevacizumab will be a safe and potentially efficacious anti-angiogenesis strategy for
the treatment of adult solid tumors. This combination may have utility directly or may prove
useful when subsequently combined with other anti-angiogenic agents or standard chemotherapy
regimens. We also hypothesize that our clinical dermal wound angiogenesis assay will help
quantify and characterize the anti-angiogenic contribution of each agent in this
combination.
Bevicizumab (Avastin) is a humanized monoclonal antibody to VEGF. VEGF is known to play a
pivotal role in tumor angiogenesis and is a significant mitogenic stimulus for arterial,
venous and lymphatic endothelial cells. The addition of bevacizumab to chemotherapy has been
shown to increase overall response rate, duration of response and survival for patients with
metastatic colon cancer (4) and is beneficial in first line non-small cell lung cancer and
metastatic breast cancer [1, 2], and second line metastatic colorectal cancer (7). VEGF
signals through phosphoatidylinositol 3-kinase (PI3K) and Akt as well as through the
extracellular regulated kinase (ERK 1/2), a mitogen activated protein kinase (MAPK). VEGF's
multiple biologic actions may be mediated by different pathways. Erikkson demonstrated that
VEGF induced hyperpermeability was highly dependent on activation of the AKT pathway, while
the angiogenic effect was largely unaffected by blocking this pathway and likely depended on
ERK activation [3].
CNTO 95 is a fully human mAb immunoglobulin G (IgG) of the gamma isotype and kappa light
chain that has been shown to have antiangiogenic and antitumor properties. Results of in
vitro studies demonstrate that CNTO 95 is an anti-αv integrin antibody that binds and blocks
integrin ανβ3 with high affinity. CNTO 95 has also been shown to bind to integrins ανβ1,
ανβ5, and ανβ6. No cross-reactivity of CNTO 95 to glycoprotein IIb/IIIa, ανβ1 or platelets
has been observed. By binding and blocking the ανβ3 and ανβ5 integrins, CNTO 95 can inhibit
cell adhesion, migration, proliferation, and invasion of both tumor and endothelial cells in
vitro. It is known that CNTO 95 binds to other αν integrins. However, the clinical
implications of binding to these integrins are unknown.
Interventional
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label
To define a recommended phase II dose for the combination of CNTO 95 plus bevacizumab in subjects with advanced solid tumors.
Every cycle (21 days)
Yes
Herbert I Hurwitz, MD
Principal Investigator
Duke University
United States: Food and Drug Administration
Pro00004929
NCT00888043
March 2009
March 2014
Name | Location |
---|---|
Duke University Medical Center | Durham, North Carolina 27710 |