Investigational Drug in Combination With Two Chemotherapy Drugs in Women With Locally Recurrent or Metastatic Breast Cancer
In 2008 there were more than 40,000 deaths caused by metastatic breast cancer in the United States. The development of new treatment strategies is essential to improve outcome for patients with metastatic breast cancer
There is significant preclinical and clinical evidence indicating that creating new blood vessels (neoangiogenesis) to provide nutrients to solid tumors, including breast cancer, provides the necessary conditions to allow tumor growth. 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.
This study will further the body of research of motesanib which has been shown in preclinical pharmacology and clinical pharmacology studies to be a potent, orally bioavailable multi-kinase inhibitor with anti-angiogenic and anti-tumor activity achieved by selectively targeting all known VEGF, platelet-derived growth factor (PDGF), and Kit receptors.
Metastatic Breast Cancer
Stage IV Breast Cancer
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Trial of Motesanib in Combination With Ixabepilone and Capecitabine in Women With Locally Recurrent or Metastatic Breast Cancer|
- Progression-Free Survival [ Time Frame: Up to 3 years or disease progression ] [ Designated as safety issue: No ]
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.
- Maximum Tolerated Dose of Motesanib [ Time Frame: 120 days ] [ Designated as safety issue: Yes ]Maximum tolerated dose (MTD) of Motesanib to be determined in the first 3-6 patients enrolled to study (Phase I portion).
- Overall Response Rate [ Time Frame: Through 28 days post-treatment ] [ Designated as safety issue: No ]
The best overall response in an individual patient according to the RECIST criteria is the best response recorded from the time of study entry till disease progression/recurrence. The patient's overall best response can be complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).
Patients with CR or PR are deemed as responders. Patients with no tumor assessment after the study entry are to be considered as non-responders.
- Toxicity [ Time Frame: Through 28 days post-treatment ] [ Designated as safety issue: No ]To determine the toxicity of motesanib, ixabepilone, and capecitabine, using a single arm design trial.
- Correlation of Tumor Levels [ Time Frame: Up to 3 years or disease progression ] [ Designated as safety issue: No ]To correlate quantitative tumor levels of motesanib-relevant markers PDGFR, VEGFR, C-Kit, and their ligands with response, survival, and time to disease progression in patients treated on this regimen.
- Pharmacokinetics of Study Regimen [ Time Frame: Through 28 days post-treatment ] [ Designated as safety issue: No ]To investigate the pharmacokinetics of motesanib (Cmin), ixabepilone (concentration at the end of infusion), and capecitabine in the combination therapy.
|Study Start Date:||December 2013|
|Estimated Study Completion Date:||September 2018|
|Estimated Primary Completion Date:||September 2015 (Final data collection date for primary outcome measure)|
Eligible patients will be enrolled to receive ixabepilone, capecitabine, plus motesanib.
Patients will receive ixabepilone at 40 mg/m2.
Other Names:Drug: Capecitabine
Patients will receive capecitabine at 2000 mg/m2.
Other Name: XelodaDrug: Motesanib
Patient will receive motesanib at 100mg or 125mg once daily dependent on outcome of Phase I, which will involve the first 3-6 patients.
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 neovascularization.
|Contact: Edith Mitchell, MD||215-955-8874||Edith.Mitchell@jefferson.edu|
|Contact: Clinical Research Management Office||215-955-1661|
|United States, Pennsylvania|
|Thomas Jefferson University||Not yet recruiting|
|Philadelphia, Pennsylvania, United States, 19107|
|Contact: Edith Mitchell, MD 215-955-8874|
|Contact: Clinical Research Management Office 215-955-1661|
|Principal Investigator: Edith Mitchell, MD|
|Sub-Investigator: Rebecca Jaslow, MD|
|Sub-Investigator: Susan Littman, MD|
|Sub-Investigator: Hallgeir Rui, MD, PhD|
|Sub-Investigator: Agnieszka Witkiewicz, MD|
|Sub-Investigator: Terry Hyslop, PhD|
|Principal Investigator:||Edith Mitchell, MD||Thomas Jefferson University|