This is a single center, open label, phase I study involving grade I-III gastroenteropancreatic neuroendocrine tumors, consisting of a dose escalation Part A followed by an expansion cohort Part B. On Part A Patients will be treated with daily oral everolimus. Fosbretabulin will be administered IV either q3 weekly or q weekly based on PO CRM cohort. Part B: Once the investigators have established an MTD in Part A, the investigators will be treating 15 more patients at that dose combination. The primary and secondary objectives of the expansion cohort will be similar to Part A of the study, i.e., to establish a safety profile of the experimental drug combination and to collect and assess efficacy data. Patients will be treated with concurrent everolimus and fosbretabulin for 12 weeks.
A variety of treatment options are available for NETs with carcinoid syndrome including surgical and medical therapies. Most subjects require somatostatin analogs to control the symptoms of carcinoid syndrome. Subjects who no longer respond to somatostatin and other liver-directed therapies, who experience progression of disease and increasing symptoms have limited options, including participation in a clinical trial. Recently everolimus and sunitinib have been approved for the treatment of subjects with progressive locally advanced or metastatic neuroendocrine tumors. Based on the preclinical data in models of NETs and the clinical activity seen in NETS and other tumor types that have existing tumor vascculature, this study will examine the effectiveness of fosbretabulin given in combination with everolimus in subjects with GI-NETs and PNETs.The vasoconstrictive effect of fosbretabulin is potent, though short-lived (4-8 hours), with no cumulative adverse effect. Everolimus inhibits angiogenesis, slows tumor growth and has a prolonged half-life (30 hours). Combining these two agents with distinctly different mechanisms of action may improve tumor control without additional toxicities, and has the potential of reducing drug resistance.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
17
everolimus
fosbretabulin
University of Kentucky Markey Cancer Center
Lexington, Kentucky, United States
Maximum Tolerated Dose (MTD)
To establish the maximum tolerated dose of the combination of everolimus plus fosbretabulin in neuroendocrine tumors (Grades 1-3) who have progressed after at least one prior regimen for metastatic disease.
Time frame: 12 weeks
Incidence of Toxicities
Incidence of patients reporting at least one adverse event per NCI CTCAE v4.0
Time frame: 12 weeks
Anti-tumor activity
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes.
Time frame: 12 weeks
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