Pazopanib as Single Agent in Advanced NETs
The incidence of new diagnosed patients with NET of the digestive tract including carcinoid and pancreatic islet cells tumors ranges from 2 to 10 per 100,000 in the western Countries (Kulke M, Mayer R. N Engl J Med 340:858-868, 1999). Despite of the low incidence, the prevalence of these tumors is high because of their relatively long survival estimated in 35% at 5 years for those patients with well or moderate differentiated tumors (Yao JC, et al. J Clin Oncol. 2008;26:3063-3072). In fact, digestive NETs are the second most prevalent tumors derived from the digestive tract after colorectal carcinoma.
NETs are characterized by abundant vasculature, moreover VEGFR and VEGFR are overexpressed in 60-84% of the carcinoids and pancreatic islet cells NETs (Zhang et al. Cancer 2007;109:1478-1486). Other pro-angiogenic factors like the platelet derived growth factor (PDGFR) have been also involved in NET progression and development (Chaudhry A, et al.Cancer Res 1992;52:1006-12).
Pazopanib is an oral tyrosine kinase inhibitor of the VEGFR, PDGFR and KIT with a dual activity both as an antiangiogenic and also and anti-tumoral agent (Kumar et al. Mol Cancer Ther2007;6:2012-2021, Hurwitz et al. Clin Cancer Res 2009;15:4220-4227). Pazopanib seems to have a better toxicity profile versus the other antiangiogenic tyrosine kinase inhibitors and has already shown activity in several tumor types like renal cell carcinoma (Sternberg et al. J Clin Oncol 2009;27:abst. 5021), soft tissue sarcomas (Sleijfer et al. J Clin Oncol 2009;27:3126-32), hepatocellular carcinoma (Yau et al. J Clin Oncol 2009;27:abst. 3561), colorectal cancer (Brady et al. J Clin Oncol 2009;27:abst.4133), and thyroid cancers (Bible et al. J Clin Oncol 2009;27:abst. 3521).
The Spanish Group for Research in Neuroendocrine Tumors (GETNE) group is an active Member inside of the GENET group and has a large tradition in clinical trials in NETs. The investigators hypothesize that pazopanib may have at least as good activity and better safety profile than other VEGFR inhibitors in progressive advanced or metastatic NET tumors derived from the digestive tract.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II, Open Label, Uncontrolled and Multicenter Trial of Pazopanib Given as a Single Agent in Patients With Progressive Advanced/Metastatic Neuroendocrine Tumors (NET): a Search for Activity, Safety, and Predictive Biomarkers|
- Clinical Benefit Rate at six months [ Time Frame: anticipated 3 years ] [ Designated as safety issue: No ]Defined as the percentage of patients with a confirmed CR or PR and SD as per RECIST 1.0 criteria at six months.
- Progression-Free Survival [ Time Frame: anticipated 3 years ] [ Designated as safety issue: No ]
Defined as the time between the starting date of treatment and the earliest date of disease progression or death due to any cause.
If the patient does not have a documented date of progression or death, then PFS will be censored at the date of last adequate assessment.
- Radiological Objective Response Rate [ Time Frame: anticipated 3 years ] [ Designated as safety issue: No ]Defined as the sum of complete responses plus partial responses of the disease.
- Duration of Response (DR) [ Time Frame: anticipated 3 years ] [ Designated as safety issue: No ]Defined, for the subset of patients with a confirmed CR o PR, as the time from first documented evidence of CR or PR until first documented disease progression or death due to any cause. The DR data will be censored the day after the last evaluation in those patients who did not present an objective tumoral progression and did not died during their participation in the trial. The DR will be assessed only in the subset of patients presenting objective response.
- Time to Tumor Response (TTR) [ Time Frame: anticipated 3 years ] [ Designated as safety issue: No ]Defined as the time between the inclusion date until the first documentation of confirmed objective response.
- Safety assessment criteria [ Time Frame: anticipated 3 years ] [ Designated as safety issue: Yes ]Security and tolerance to the study medication will be determined evaluating the type, incidence, severity, timing, seriousness and connections with the treatment of the reported adverse events, physical examinations and laboratory tests. Toxicity will be classified according to NCI-CTCAE v 4.0.
- Biomarkers assessment [ Time Frame: anticipated 3 years ] [ Designated as safety issue: No ]
To assess different related biomarkers and to correlate their variations with the clinical outcomes of the patients.
Identify polymorphisms that could predict response of patients to pazopanib
|Study Start Date:||December 2010|
|Estimated Study Completion Date:||December 2013|
|Estimated Primary Completion Date:||September 2013 (Final data collection date for primary outcome measure)|
Single arm of pazopanib 800 mg (2x400mg) given once daily as a single agent.
|Institut Català d'Oncologia L'Hospitalet|
|L'Hospitalet de Llobregat, Barcelona, Spain|
|Hospital Universitari Vall d'Hebron|
|Hospital Universitario Ramón y Cajal|
|Hospital Universitario 12 de Octubre|
|Hospital Clínico San Carlos|
|Centro Integral Oncológico Clara Campal|
|Hospital Universitario Virgen de la Victoria|
|Hospital Universitari Son Espases|
|Palma de Mallorca, Spain|
|Hospital Universitario Virgen del Rocío|
|Hospital Clínico Universitario Lozano Blesa|
|Study Chair:||Enrique Grande Pulido, MD||Grupo Espanol de Tumores Neuroendocrinos|