89Zr-bevacizumab PET Imaging in Patients With Neuroendocrine Tumors

Neuroendocrine Tumors Clinical Trial

— NETPET  

Official title:

89Zr-bevacizumab PET Imaging as Predictive Biomarker for Everolimus Efficacy in Patients With Neuroendocrine Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01338090
• Other study ID #: 20091104
• Secondary ID: 2009-017195-24
• Status: Completed
• Phase: N/A
• First received: April 12, 2011
• Last updated: April 2, 2012
• Start date: April 2010
• Est. completion date: March 2012

Study information

• Verified date: August 2011
• Source: University Medical Center Groningen
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)Netherlands: Medical Ethics Review Committee (METC)
• Study type: Observational

Clinical Trial Summary

This is a pilot study for evaluation of 89Zr-bevacizumab PET imaging as predictive biomarker during treatment with everolimus in patients with neuroendocrine tumors.

Patients with progressive disease during the last year will receive treatment with everolimus 10 mg/day orally and 89Zr-bevacizumab PET imaging will be performed before start of treatment and after 2 and 12 weeks of treatment in the first three patients. If the scan after 2 weeks of treatment is already informative further patients will not undergo a scan at 12 weeks. A scan is considered already informative if both scans show at least 30% decrease in uptake in case of response, or at least 30% increase in uptake in case of disease progression.

Four days before the scan patients will be injected intravenously 37 MBq, protein dose 5 mg 89Zr-bevacizumab. At day 1, day 15 and day 99, PET images will be made for visualization and quantification of VEGF in the tumor lesions and blood will be drawn for determination of angiogenesis and mTOR pathway related biomarkers.

Description:

1. Rationale:

Profound angiogenesis is an important characteristic of neuroendocrine tumors. Antiangiogenic drugs including sunitinib, bevacizumab and everolimus have shown antitumor activity in neuroendocrine tumors. The investigators participated in the RAD001 studies for neuroendocrine tumors. From preclinical studies including studies performed in our own lab the investigators know that everolimus downregulates VEGF.

Currently it is not possible to predict which individual patient will benefit from treatment with an mTOR inhibitor. A predictive biomarker for efficacy of mTOR inhibitors is urgently needed and would be helpful, as a predictive biomarker may facilitate the development of combination therapies, of individual titration of the dose, and it may facilitate early clinical studies. Furthermore, it may spare the patients unnecessary side effects. mTOR inhibitors may fail in individual patients because angiogenesis is not sufficiently inhibited. Non-invasive imaging of VEGF before and early after start of treatment may have predictive value for treatment efficacy.

Within the UMCG the investigators have an active ongoing research line on molecular imaging. The investigators have developed as part of this the 89Zr-bevacizumab PET label for non-invasive measurement of VEGF levels in the tumor and its surrounding microenvironment. This tracer can give insight in the tumors' dependency on angiogenesis as the investigators have already proven for a VEGF-receptor tyrosine kinase inhibitor. Currently this tracer is used in clinical trials. The investigators would like to examine whether all neuroendocrine tumors produce VEGF and whether they differ in their response to inhibition of VEGF by mTOR.

2. Objectives:

The primary objective is to evaluate the feasibility of 89Zr-bevacizumab-PET imaging as predictive biomarker before and during treatment with everolimus in patients with neuroendocrine tumors.

The secondary Objectives are the following:

• To explore if 89Zr-bevacizumab PET imaging can differentiate patients with progressive neuroendocrine tumors from patients with non-progressive disease early during treatment with everolimus.

• To explore relationships between VEGF pathway related blood biomarkers and changes in 89Zr-bevacizumab tumor uptake.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: March 2012
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• adult patients with metastatic neuroendocrine tumors

• radiological documentation of progressive disease over the past year

• measurable disease according to RECIST criteria

• Adequate bone marrow function as shown by: ANC = 1.5 x 109/L, Platelets = 100 x 109/L, Hb > 9 g/dL.

• Adequate liver function: serum bilirubin: = 1.5 x ULN, ALT and AST = 2.5x ULN. Patients with known liver metastases: AST and ALT = 5x ULN.

• Adequate renal function: serum creatinine = 1.5 x ULN.

• Fasting serum cholesterol =300 mg/dL OR 7.75 mmol/L AND fasting triglycerides = 2.5 x ULN. NOTE: In cases where one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication

Exclusion Criteria:

• uncontrolled medical conditions (eg, unstable angina, symptomatic heart failure, serious intercurrent infections)

• any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule of the study

• Patients with uncontrolled diabetes mellitus as defined by fast blood sugar > 1.5 x ULN.

• Prior therapy with RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus).

• Concomitant medications known to inhibit, induce or be a substrate to isoenzyme CYP3A are excluded unless the drugs are medically necessary and no substitutes are available. If there are no acceptable substitutes, special precautions should be taken in these patients

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Carcinoid Tumor
• Neuroendocrine Tumors

Intervention

Drug:
• 89Zr-bevacizumab
Intravenous injection 120 MBq
• Everolimus
Oral use, 10 mg per day

Locations

Country	Name	City	State
Netherlands	University Medical Center Groningen	Groningen

Sponsors (2)

Lead Sponsor	Collaborator
University Medical Center Groningen	Novartis Pharmaceuticals

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	change in 89Zr-bevacizumab uptake	The change in 89Zr-bevacizumab uptake in tumor lesions between the baseline PET scan and the scans performed after 2 and 12 weeks of everolimus treatment in patients with neuroendocrine tumors. In addition, effect sizes and confidence intervals will be determined.	12 weeks	No
Secondary	Progressive disease	Progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST)22 criteria on CT after 12 weeks of treatment.; Progression is defined as the appearance of new disease or an increase of 20% in the sum of the longest diameters of the target lesions.	12 weeks	No