Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Renal Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Kidney Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Bevacizumab

Everolimus

Endothelial Growth Factors

Mitogens

89Zr-bevacizumab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Radiopharmaceuticals

Renal Cancer patients treated with everolimus

A tracer dose of 89Zr-bevacizumab (37 MBq, 5 mg protein dose) is given intravenously at day -3, day 11 and day 39.

PET scans are made on day 1, day 15 and day 43.

89Zr-bevacizumab PET scan

Sjoukje Oosting, MD

Everolimus indirectly inhibits angiogenesis by reducing VEGF production. VEGF can be non-invasively visualized and quantified with serial 89Zr-bevacizumab PET imaging in patients.

The investigators hypothesize that a decline in VEGF early during everolimus treatment in patients with metastatic renal cell carcinoma predicts treatment efficacy.

89Zr-bevacizumab PET scans will be performed at baseline, after 2 and 6 weeks of everolimus treatment in 14 adult patients with metastatic renal cell carcinoma.

Background of the study

The majority of renal cell carcinomas (RCC) is characterized by profound angiogenesis because of inactivation of the Von Hippel Lindau gene. Angiogenesis inhibitors are established first line treatment options in the metastatic setting. Patients with progressive disease during or after treatment with angiogenesis inhibitors can benefit from treatment with everolimus, an oral mTOR inhibitor that resulted in doubling of progression free survival in a phase III study. Currently it is not possible to predict which patient will benefit from treatment with mTOR inhibitors. A predictive biomarker for efficacy of mTOR inhibitors is urgently needed as it may spare the patients unnecessary side effects, safes costs for the society as mTOR inhibitors are very expensive agents, and may speed up research on new drugs, drug combinations and drug dosing. One of the actions of mTOR inhibitors is blockage of production of vascular endothelial growth factor (VEGF), and this is thought to be the primary mechanism that is responsible for antitumor activity in RCC. The investigators hypothesize that non-invasive measurement of VEGF in the tumour and its surroundings by 89Zr-bevacizumab PET imaging before and shortly after start of everolimus is a good readout of efficacy of everolimus in patients with RCC.

Objective of the study

The primary objective of the study is to evaluate the feasibility of 89Zr-bevacizumab PET imaging as a biomarker before and during treatment with everolimus in patients with metastatic RCC. 89Zr-bevacizumab PET imaging will be regarded a promising biomarker if uptake changes after institution of treatment.

Study design

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

89Zr-bevacizumab PET imaging will be performed before start of treatment and after 2 and 6 weeks of treatment.

Study population

14 patients who will start treatment with everolimus for metastatic RCC will be included in this study.

Primary study parameters

The primary endpoint is change in 89Zr-bevacizumab uptake in tumor lesions between the baseline scan and the scan during treatment.

Secondary study parameters The secondary endpoint is progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, after 3 months 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.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness

Patients will be intravenously injected at 3 time points with 37MBq resulting in a cumulative radiation dose of 54 mSv. According to ICRP 62 this radiation dose falls in category III (moderate risk).

Life expectancy of the patients is limited because of their incurable renal cell carcinoma, making the risk of development of a secondary malignancy clinically likely not relevant.

Patients have to pay 3 extra visits to the hospital for tracer injection. PET scans will be performed on regular visit days. Blood samples for biomarkers will be drawn during routine blood investigations.

There is no direct benefit for the patients in this study. If 89Zr-bevacizumab PET imaging however is a predictive biomarker for angiogenesis inhibitors, many patients can be spared unnecessary side effects and society can be spared costs of futile treatment in the future.

whole blood, white blood cells, plasma, serum, urine

Vascular Endothelial Growth Factor (VEGF) Imaging Before and During Everolimus Treatment for Renal Cell Carcinoma

89Zr-bevacizumab PET Imaging in Patients With Renal Cell Carcinoma Treated With Everolimus; a Pilot Study

Novartis

University Medical Center Groningen

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Neuroepithelioma

Anti-Infective Agents

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Elisabeth GE de Vries, MD, PHD

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.

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.

89Zr-bevacizumab PET Imaging in Patients With Neuroendocrine Tumors

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

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.

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.

Novartis Pharmaceuticals

Prof.dr. E.G.E. de Vries

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Vascular Endothelial Growth Factor (VEGF) Imaging Before and During Everolimus Treatment for Renal Cell Carcinoma	NCT01028638	Metastatic Rena...	89Zr-bevacizuma...	18 Years -	University Medical Center Groningen
89Zr-bevacizumab PET Imaging in Patients With Neuroendocrine Tumors	NCT01338090	Neuroendocrine ...	89Zr-bevacizuma... Everolimus	18 Years - 80 Years	University Medical Center Groningen
89Zr-bevacizumab PET Imaging in Patients With Neuroendocrine Tumors	NCT01338090	Neuroendocrine ...	89Zr-bevacizuma... Everolimus	18 Years - 80 Years	University Medical Center Groningen
Vascular Endothelial Growth Factor (VEGF) Imaging Before and During Everolimus Treatment for Renal Cell Carcinoma	NCT01028638	Metastatic Rena...	89Zr-bevacizuma...	18 Years -	University Medical Center Groningen

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