89Zr-girentuximab for PET Imaging of CAIX Positive Solid Tumors
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ABSTRACT:
DISEASE(S): Nasopharyngeal Carcinoma,Glioblastoma Multiforme,Carcinoma,Sarcoma,Cervical Cancer,Small Cell Lung Cancer,Glioblastoma,Colorectal Cancer,Small Cell Lung Carcinoma,Non Small Cell Lung Cancer,Soft Tissue Sarcoma,Lung Neoplasms,Pancreatic Ductal Adenocarcinoma,Squamous Cell Carcinoma Of Head And Neck,Gastric Cancer,Carcinoma, Ovarian Epithelial,Epithelial Ovarian Cancer,Esophageal Cancer,Head And Neck Squamous Cell Carcinoma,Cholangiocarcinoma,Hepatocellular Carcinoma
PROVIDER: 2750119 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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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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Project description:Over-expression of Epidermal Growth Factor Receptor (EGFR) on cells occurs in all aggressive cancers of epithelial origin. Existing tests for monitoring EGFR expression are invasive and not reliable. There needs to be a better way to measure EGFR expression in cancerous tumors to better tailor cancer treatments.
This clinical trial aims to demonstrate the feasibility of imaging cancers that express EGFR using 89Zr-DFO-nimotuzumab and Positron Emission Tomography (PET)/Computerized Tomography (CT). By non-invasively imaging the status of EGFR, 89Zr-DFO-nimotuzumab could be used to assist in the identification of patients who are likely to respond to anti-EGFR treatments, including nimotuzumab. The hypothesis is that 89Zr-DFO-nimotuzumab will accumulate to tumors over-expressing EGFR making them visible when imaged with PET/CT. This hypothesis will be tested in this study, along with the optimal imaging time and diagnostic ability.
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Project description:This clinical study will investigate the utility of PET imaging with [89Zr]Panitumumab for imaging of EGFR expression in newly diagnosed colon cancer patients to assess lymph node involvement. If promising, this data will be used to design larger trials.
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Project description:BACKGROUND. Improving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor β (TGF-β) inhibitor that targets cancer associated fibroblasts (CAFs) is promising to enhance efficacy of cancer immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy. METHODS. We measure CAFs in vivo using gallium 68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) for PET/CT imaging to guide TGF-β inhibition and sensitize metastatic colorectal cancer (CRC) to immunotherapy. A total of 131 patients with metastatic CRC underwent 68Ga-FAPI and 18F-fludeoxyglucose (18F-FDG) PET/CT imaging. Fourteen patients underwent surgery after the imaging. Relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed. Mouse cohorts of metastatic CRC were treated with TGF-β receptor (TGF-βR) inhibitor combined with KN046 which blocks PD-L1 and CTLA4, followed with 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses. RESULTS. Patients with metastatic CRC demonstrated high uptakes of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. TGF-βR inhibitor enhanced tumor infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamical changes of CAFs and tumor response to combined TGF-βR inhibitor with immunotherapy. CONCLUSION. 68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to stratify and guide patients with CRC for precise TGF-β inhibition plus immunotherapy, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management.
2023-12-19 | GSE247303 | GEO
Project description:The objective of this study is to construct a noninvasive approach using 68Ga- Mirc415 PET/CT to detect the PD-L2 expression of tumor lesion in patients with colorectal cancer, lung cancer and other solid tumor to identify patients benefiting from anti-PD-(L)1 treatment.
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Project description:Monoclonal antibodies (mAbs) against the epidermal growth factor receptor (EGFR) are used in the treatment of advanced colorectal cancer (mCRC). Approximately 50% of patients benefit despite patient selection for RAS wild type (wt) tumors. Based on the hypothesis that tumor targeting is required for clinical benefit of anti-EGFR treatment, biodistribution and tumor uptake of (89)Zr-cetuximab by Positron Emission Tomography (PET), combining the sensitivity of PET with the specificity of cetuximab for EGFR was evaluated. Ten patients with wt K-RAS mCRC received 37 ± 1 MBq (89)Zr-cetuximab directly (<2 h) after the first therapeutic dose of cetuximab. PET-scans were performed from 1 hour to 10 days post injection (p.i.). Biodistribution was determined for blood and organs. Uptake in tumor lesions was quantified by Standardized Uptake Value (SUV) and related to response. In 6 of 10 patients (89)Zr-cetuximab uptake in tumor lesions was detected. Four of 6 patients with (89)Zr-cetuximab uptake had clinical benefit, while progressive disease was observed in 3 of 4 patients without (89)Zr-cetuximab uptake. Taken together, tumor uptake of 89Zr-cetuximab can be visualized by PET imaging. The strong relation between uptake and response warrants further clinical validation as an innovative selection method for cetuximab treatment in patients with wt RAS mCRC.
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Project description:PURPOSE:c-MET and its ligand hepatocyte growth factor are often dysregulated in human cancers. Dynamic changes in c-MET expression occur and might predict drug efficacy or emergence of resistance. Noninvasive visualization of c-MET dynamics could therefore potentially guide c-MET-directed therapies. We investigated the feasibility of 89Zr-labelled one-armed c-MET antibody onartuzumab PET for detecting relevant changes in c-MET levels induced by c-MET-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib resistance or heat shock protein-90 (HSP90) inhibitor NVP-AUY-922 treatment in human non-small-cell lung cancer (NSCLC) xenografts. METHODS:In vitro membrane c-MET levels were determined by flow cytometry. HCC827ErlRes, an erlotinib-resistant clone with c-MET upregulation, was generated from the exon-19 EGFR-mutant human NSCLC cell line HCC827. Mice bearing HCC827 and HCC827ErlRes tumours in opposite flanks underwent 89Zr-onartuzumab PET scans. The HCC827-xenografted mice underwent 89Zr-onartuzumab PET scans before treatment and while receiving biweekly intraperitoneal injections of 100 mg/kg NVP-AUY-922 or vehicle. Ex vivo, tumour c-MET immunohistochemistry was correlated with the imaging results. RESULTS:In vitro, membrane c-MET was upregulated in HCC827ErlRes tumours by 213?±?44% in relation to the level in HCC827 tumours, while c-MET was downregulated by 69?±?9% in HCC827 tumours following treatment with NVP-AUY-922. In vivo, 89Zr-onartuzumab uptake was 26% higher (P?<?0.05) in erlotinib-resistant HCC827ErlRes than in HCC827 xenografts, while HCC827 tumour uptake was 33% lower (P?<?0.001) following NVP-AUY-922 treatment. CONCLUSION:The results show that 89Zr-onartuzumab PET effectively discriminates relevant changes in c-MET levels and could potentially be used clinically to monitor c-MET status.
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Project description:UnlabelledHepatocellular carcinoma (HCC) is a devastating malignancy in which imperfect imaging plays a primary role in diagnosis. Glypican-3 (GPC3) is an HCC-specific cell surface proteoglycan overexpressed in most HCCs. This paper presents the use of (89)Zr-conjugated monoclonal antibody against GPC3 ((89)Zr-αGPC3) for intrahepatic tumor localization using PET.MethodsPolymerase chain reaction confirmed relative GPC3 expression in cell lines. In vitro binding, in vivo biodistribution, and small-animal PET studies were performed on GPC3-expressing HepG2 and non-GPC3-expressing HLF and RH7777 cells and orthotopic xenografts.Results(89)Zr-αGPC3 demonstrated antibody-dependent, antigen-specific tumor binding. HepG2 liver tumors exhibited high peak uptake (836.6 ± 86.6 percentage injected dose [%ID]/g) compared with background liver (27.5 ± 1.6 %ID/g). Tumor-to-liver contrast ratio was high and peaked at 32.5. The smallest HepG2 tumor (<1 mm) showed lower peak uptake (42.5 ± 6.4 %ID/g) and tumor-to-liver contrast (1.57) but was still clearly visible on PET. Day 7 tissue activity was still substantial in HepG2 tumors (466.4 ± 87.6 %ID/g) compared with control RH7777 tumors (3.9 ± 1.3 %ID/g, P < 0.01), indicating antigen specificity by (89)Zr-αGPC3. HepG2 tumor treated with unlabeled αGPC3 or heat-denatured (89)Zr-αGPC3 demonstrated tumor activity (2.1 %ID/g) comparable to that of control xenografts, confirming antibody dependency.ConclusionThis study demonstrated the feasibility of using (89)Zr-αGPC3 to image HCC in the liver, as well as the qualitative determination of GPC3 expression via small-animal PET. The ability to clarify the identity of small liver lesions with an HCC-specific PET probe would provide clinicians with vital information that could significantly alter patient management, warranting further investigation for clinical translation.
| S-EPMC4116087 | biostudies-literature
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
| 2528499 | ecrin-mdr-crc
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
| 18849 | ecrin-mdr-crc