Phase I/II Trial of Motesanib in Combination With Ixabepilone and Capecitabine in Women With Locally Recurrent or Metastatic Breast Cancer
Endocrine therapy and chemotherapy (using either sequential single agents or combination
regimens) remain the principal treatments for women with metastatic breast cancer. A wide
variety of classes of chemotherapeutic agents have demonstrated anti-tumor activity as
single agents or in combination regimens. Cytotoxic chemotherapeutic agents have been the
mainstay of cancer therapies for many years and have improved survival in many disease
settings. Median survivals remain approximately two years for women with metastatic breast
cancer, and less than 3% of patients experience long-term survival after initiation of
treatment. The development of new treatment strategies is therefore essential to improve
outcome for patients with metastatic breast cancer.
One of the most promising pathways for the development of new anti-neoplastic agents is
targeting tumor vascular endothelium. There is significant preclinical and clinical evidence
indicating that tumor neoangiogenesis is critical in pathogenesis and progression of solid
tumors, including breast cancer. Of the numerous known growth factors that have been
implicated in tumor angiogenesis, vascular endothelial growth factor (VEGF) is one of the
important molecules regulating new blood vessel formations and subsequent invasion and
metastases. As a result, agents that inhibit VEGF are of substantial interest for the
treatment of advanced diseases. More thorough elucidation of mechanisms behind intrinsic and
acquired resistance therefore is imperative disease and to identify patients most likely to
benefit from treatment options.
Motesanib has been shown in preclinical pharmacology and PK studies to be a potent, orally
bioavailable multi-kinase inhibitor with anti-angiogenic and anti-tumor activity achieved by
selectively targeting all known VEGF, PDGF and Kit receptors. It has an acceptable safety
profile in both non-clinical and clinical studies, and a PK profile that appears suitable
for daily oral dosing in humans.
The investigational product motesanib (Amgen) is a small molecule tyrosine kinase inhibitor
with high efficacy against VEGFR and c-Kit kinases. C-kit has been detected in 12% of breast
cancers, correlating with basal or triple-negative breast cancer. In addition, efficacy of
the drug has been noted to PDGFRα, which is expressed in approximately 40% of breast cancers
and is associated with aggressive disease, metastatic invasion and poor prognosis.
Importantly, in more than half (56%) of these cases, the carcinoma cells bearing the
receptors expressed the PDGF-A ligand, suggesting an autocrine loop and a cancer
cell-autonomous process. Cancer cell-autonomous pathways are especially attractive as drug
targets against metastatic breast cancer because they are expected to continue to be
functional at metastatic sites, since they do not depend on stromal factors.
The primary molecular target of motesanib, VEGFR, is intriguing because neovascularization
is expected to be required also at metastatic sites. A preliminary analysis revealed that
VEGF expression correlated with the triple-negative, basal breast cancer subtype and poor
outcome. Importantly, PDGF receptors are also present on vascular pericytes, cells required
for adequate vascularization. Thus, motesanib is a unique multikinase inhibitor that targets
both growth factor receptors on the carcinoma cells and growth factor receptors related to
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Progression-free survival (PFS) is defined as the time from the date of enrollment to the first occurrence of having documented disease progression or death due to any cause. Evaluation of target lesions and non-target lesions will be in accordance with the RECIST criteria. During the study, assessments of tumor response will take place every 6 weeks. Confirmation of objective response, when applicable, must be performed at a minimum of 4 weeks after the first response has been recorded.
Up to 3 years or disease progression
Edith Mitchell, MD
Thomas Jefferson University
United States: Food and Drug Administration
|Thomas Jefferson University||Philadelphia, Pennsylvania 19107-6541|