Image Guided Treatment Optimization With Cetuximab for Patients With Metastatic Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Uitgezaaide Dikke Darmkanker,Colorectal Neoplasms
PROVIDER: 2164992 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Primary objectives: The main objective of the first part of the study is the demonstration of 89Zr-cetuximab uptake in non-hepatic tumour lesions. The main objective of the second part is the association between 89Zr-cetuximab uptake in non-hepatic tumour lesions and treatment outcome.
Primary endpoints: Part one - Primary endpointThe detection of 89Zr-cetuximab uptake in non-hepatic tumour lesions (present/absent; present being defined as levels measured in ROI’s > standard deviation of background +1).
Part two – primary endpointThe % uptake (of total injected) 89Zr-cetuximab in non-hepatic tumour lesions as measured in ROI’s corrected for background levels.
Part two - secondary endpoints1) The % uptake (of total injected) 89Zr-cetuximab in liver lesions as measured in ROI’s corrected for background levels.2) [18F-]FDG PET measurements (SUVmax) before and after 4 weeks of treatment with cetuximab.3) Grade of skin toxicity as measured by predefined criteria (see below).
Other study parameters4) Serum magnesium levels before and during treatment. 5) EGFR saturation with cetuximab in skin samples.6) Kinase activity in skin samples before and after treatment
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Project description:Interventions: 89Zr-cetuximab PET scan: After a therapeutic dose of cetuximab, 10mg of 89Zr-cetuximab is injected. Six days after injection a PET-scan will be made. If this scan is considerd positive, meaning uptake in extra-hepatic metastases is present, the normal dose of cetuximab will be continued.
If the first PET-scan is negative, we will increase the dose of cetuximab (3 by 3 cohort design) and repeat the PET-scan. The patient will continue the higher dose biweekly.
Furthermore we will preform a 18F-FDG PET scan and 15O-H2O PET scan, on baseline and after 2 weeks of treatment, to evaluate early changes in respectively metabolic changes and changes in tumor perfusion.
At baseline and after 3-4 week of treatment a skin biopsy and tumor biopsy will be done. We will preform oncogenic mutation analysis, we will determine EGFR expression and saturation.
Primary outcome(s): 89Zr-cetuximab uptake in non-hepatic metastases (corrected VOIs) and the correlation with clinical benefit rate.
89Zr-cetuximab uptake in non-hepatic metastases with increased dosing of cetuximab (corrected VOIs).
The clinical benefit rate (CR, PR and SD) based upon 89Zr-cetuximab image adjusted dosing
Study Design: Non-randomized controlled trial, Open (masking not used), N/A , unknown, Parallel
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Project description:Programmed death-ligand 1 (PD-L1) expression has been associated with response to PD-1/PD-L1 inhibition, but responses are also seen in patients with PD-L1 negative tumors when assessed immunohistochemically (IHC) with various antibodies. To help elucidate these findings, we performed a positron emission tomography (PET) imaging study in human with the anti-PD-L1 antibody atezolizumab labeled with Zirconium-89 (89Zr) prior to treatment with atezolizumab to assess normal tissue distribution and evaluate tumor tracer uptake. Additionally, to help explain why some patients respond to checkpoint inhibitors despite low or absent PD-L1 expression, we compared PD-L1 expression and immune phenotypes based on both CD8 IHC and RNA sequencing of post-tracer biopsies to tumor tracer uptake (SUVmax).
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Project description:Interventions: Patients will be treated with cetuximab. For pharmacodynamic purposes PET-imaging with 89Zr-labelled cetuximab will be performed. In addition, two [18F-]-FDG PET-CT will be performed to explore early response. Patients will undergo blood sampling and two skin biopsies for pharmacodynamic purposes of 89Zr-labelled cetuximab and kinase activity profiles, respectively.
Primary outcome(s): To demonstrate uptake of 89Zr-cetuximab in non-hepatic tumor lesions using immuno-PET when administered during the loading dose of cetuximab.
Part two - Primary objective:
To investigate whether there is an association between uptake of cetuximab in non-hepatic tumor lesions and response according to RECIST 1.1 criteria.
Study Design: N/A: single arm study, Open (masking not used), N/A , unknown, Parallel
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The investigators hypothesize that the differences in response to treatment with cetuximab are due to variability in the pharmacokinetics and -dynamics of the antibody. Thus, the investigators hypothesize that patients who do not respond to anti-EGFR treatment, have insufficient drug levels in tumor tissue. The investigators hypothesize that this is due to pharmacodynamic processes such as sequestration of cetuximab in the liver which expresses high levels of EGF receptor.
The phase I part of the study was fulfilled after inclusion of 36 patients to evaluate the potential applicability of the 89Zr-cetuximab PET as predictive marker for (absence of) response to cetuximab. Along with this analysis, FDG-PET evaluation before and after 1 administration of cetuximab was being performed. While we observed no correlation of 89Zr-cetuximab tumor uptake with clinical benefit in these 36 patients, we did find a clinical significant predictive value for the absence of response with early 18F-FDG-PET with the lack of clinical benefit at 2 months of treatment in this group of patients. Early 18F-FDG PET response evaluation shows great potential to be a clinically applicable tool to stop an ineffective treatment in a very early phase after one administration of treatment. Such an early predictor is unprecedented in clinical daily practice and will 1) avoid unnecessary toxicity of inactive treatment, 2) will lead to faster prescription of a potentially active alternative treatment and 3) will reduce costs by preventing administration of inactive treatment. In order to provide solid evidence for this new approach, we aim to validate early 18F-FDG-PET as a predictive imaging strategy to identify non-responders in part 2 of the study.
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