Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Neoplasm Metastasis

Breast Neoplasms

Breast Diseases

Skin Diseases

All Drugs and Chemicals

Aromatase Inhibitors

Dr Sacha Howell, MD, PhD

Maria Ekholm, MD, PhD

Patients with metastatic breast cancer may respond well to treatment and metastases can remain stable for several years. Despite personalised medicine being increasingly used for diagnosis and treatment, follow-up still include radiological response evaluation every 3-4 months, which renders a significant number of 'unnecessary' exams for patients with long-term stable disease. Increasing evidence indicates that tumour markers such as circulating tumour DNA (ctDNA), thymidine kinase 1 (TK1) and cancer antigen 15-3 (CA15-3) may be useful for disease monitoring in the metastatic setting. However, algorithms that accurately define the time-points at which imaging can be foregone or reinstituted when progression is forecast, have not been developed. This study will measure ctDNA, TK1 and CA15-3 at all imaging time-points. The primary aim is to develop an algorithm based on these biomarkers, alone or in combination, that with sufficient specificity and sensitivity can advise whether a scan can be safely admitted at a specific time-point, for patients with MBC receiving first line therapy with AI plus cyclin dependent kinase 4/6 inhibitor (CDK4/6i). Additional samples will be stored such that novel biomarkers can also be tested in future. The cost-effectiveness of using the devised biomarker protocol will be evaluated.

One hundred patients with estrogen receptor positive (ER+)/ Human epidermal growth factor receptor negative (HER2-) metastatic or locally advanced breast cancer, eligible for 1st line endocrine therapy with AI + CDK4/6i will be included. Patients will receive standard therapy (AI + CDK4/6i) and follow-up will proceed according to local guidelines, namely cross sectional imaging with CT thorax/abdomen/pelvis +/- MRI as required and analysis of CA 15-3, every 3 cycles for the first year and every 3-4 cycles thereafter. Participation in the study will include serial blood sampling for the bespoke study biomarkers. Decisions on progression will be made according to the routine imaging tests and the biomarkers will be subsequently analysed.

The investigators hypothesise that the biomarkers ctDNA, TK1 and CA15-3, alone or in combination, will accurately correlate with disease status in patients receiving AI + CDK4/6i for metastatic breast cancer such that routine imaging can be delayed until predefined levels of biomarker progression.

Primary aim: To develop a biomarker-based prediction model to be used in patients with metastatic breast cancer, receiving first line therapy with AI and CDK4/6i, that provides the physician with a recommendation whether or not a radiological examination is required, based on the likelihood that the scan will actually show progressive disease.

Secondary aims

* To define the lead time between rising biomarker and subsequent progression on imaging
* To define the clinical utility of the bespoke biomarkers for disease monitoring
* The relative value of analysing TK1 "on CDK4/6i treatment" versus "off CDK4/6i treatment" for disease monitoring
* To define the economic impact of implementation of the chosen prediction model

Archived tumour tissue will be analysed using mutation panels to make personalised assays for circulating tumour DNA (dtDNA). ctDNA will be serially collected for subsequent analysis.

Personalised Disease Monitoring in Metastatic Breast Cancer

Personalised Disease Monitoring During Treatment With an Aromatase Inhibitor + Cyclin Dependent Kinase (CDK) 4/6 Inhibitor as 1st Line Endocrine Therapy in Patients With ER-positive/HER2-negative Metastatic Breast Cancer

ctDNA, CA15-3 and TK-1 assays will be performed at baseline, 2 weeks and at every imaging timepoint to develop a statistical algorithm to predict disease progression taht can be tested prospectively in future studies.

The relative value of analysing TK1 "on CDK4/6i treatment" versus "off CDK4/6i treatment" for disease monitoring

Cost effectiveness analysis of the using the prediction model

Sahlgrenska University Hospital, Sweden

The Christie NHS Foundation Trust

Pharmaceutical Solutions

Dimercaprol

Chelating Agents

Blood will be removed from the circulatory system through a cut (incision) or puncture for the purpose of analysis by qualified staff. Serum or plasma will be separated from the cellular fraction and stored for analyses.

Venesection

Urine will be collected in appropriate sterile holders provided.

Urine collection

Saliva will be collected in appropriate sterile holders provided.

Sputum collection

Bronchoscopy will be performed. Briefly, clinical care team will collect liquid after an instrument (bronchoscope) is passed through the nose or mouth into the lungs, and saline solution is squirted into a small part of the lung, then collected for analyses.

Bronchoalveolar lavage

James Spicer, FRCP, PhD

Claudia Prevosto, PhD

Keith Brennan

Jennifer Boston

James F Spicer, PhD

James F Spicer, FRCP, PhD

Tumour biomarkers are substances produced by cancer or by other cells of the body in response to cancer conditions. They are used to help detect, diagnose, manage and predict outcome or recurrence of some types of cancer. Tumour biomarkers can also help doctors choose the most appropriate therapy or judge if treatment is successful. Several tumour biomarkers are already used in the clinic; however, many others do not meet rigorous scientific standards to enter into clinical practice and some solid cancers can be only detected using tissue biopsy, a rather invasive procedure. Likewise, evaluating efficacy of novel therapies during clinical trials relies on adequate and specific laboratory tests. Therefore novel biomarkers and novel methods, to measure them, still represent an un-met clinical need.

This study aims to develop innovative, more sensitive and reliable tests for better targets, in order to assess and monitor circulating cancer biomarkers. Easily accessible samples, like blood, will be tested such that invasive tissue biopsies can be avoided. Both healthy individuals and cancer patients will be recruited in this study to establish if a laboratory test is powerful enough to distinguish between individuals that may have cancer or not. Participants' involvement will also support development of novel tests to decide if a novel therapy is efficiently counteracting cancer growth or not.

Participants in the study will be asked to donate blood, sputum, urine or other body fluids, depending on the cancer and the assay being developed. After participants give their informed consent, the researchers will isolate cells, soluble factors or nucleic acids from body fluids. Researchers will then use various laboratory techniques to screen cells, soluble factors or nucleic acids for specific markers. This study looks at the effectiveness of using laboratory tests to quantify tumour markers in body fluids and, subsequently, to monitor patients' response to treatments.

Potential participants will be approached by clinical or research team members and asked whether they would be interested in joining this study. Participant Information Sheet will be handled and discusses with individuals, highlighting their involvement, risk and benefit of this research. In particular, participation in the study will not alter any current therapies of the volunteers. Having left sufficient time to decide, potential participants will be asked to sign a Consent Form.

After obtaining informed consent, volunteers will be asked to donate blood, urine, sputum (saliva) or other body fluids, like bronchoalveolar lavage, for our study, at the same time other analyses are carried out as part of individuals' usual medical care. If some participants are already scheduled to receive a novel drug therapy in an existing trial, we may ask them to contribute with small amount of blood, saliva, urine or other body fluids, twice, before and after the programmed treatment. Samples will be collected at the same time as participants' routine medical examinations are carried out.

Biological specimens will be collected and stored according to sample type and test specifications; then separation of cellular components and soluble factors from liquid part will be performed by research team members. Isolation techniques will vary based on the sample source.

Depending on the specific assay to be developed, protein content will be analysed by flow cytometry, enzyme-linked immunoassay (ELISA) or other immunoassays, including the beads-based Luminex® technology. In all these laboratory techniques, the unique interaction between a specific antibody and antigen enables identification of single or multiple target proteins inside a complex protein mixture.

Flow cytometry uses fluorescence properties of some dyes to evaluate the presence of specific markers on the surface or inside healthy or cancerous cells. This will help establish frequency of specific cell populations or intensity of specific markers on the cells. Likewise, ELISA allows qualitative and quantitative characterisation of soluble substances; multiple target proteins in suspension can be evaluated with Luminex® procedure within the same sample. Other biochemical techniques, such as immunoblotting can be used to determine presence/ absence of proteins located either on the cell surface of or intracellularly.

In addition to proteins, nucleic acid content can be assessed, including DNA, RNA or microRNA by biomolecular techniques.

Research data will be generated by these laboratory methods as software-specific files, such as flow cytometry standard (FCS) files for results by flow cytometry, images and data tables. Parameters like sensitivity, limit of detection and assay variability will also be evaluated and reported in numeric tables. During assay development, data from both healthy donors and cancer patients will be compared with standard statistical packages, in order to establish robust tests that can discriminate between the two groups.

Assay Development for Cancer Biomarkers

Development of Novel Assays to Evaluate and Measure Circulating Cancer Biomarkers

Guy's and St Thomas' NHS Foundation Trust

Cancer Research UK

King's College London

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lymphoma

Lymphosarcoma

Immunomodulating Agents

All participants will receive a mass dose of 40 μg or less of \[68Ga\]-NOTA-hGZP (radioactivity dose of 3 mCi to 8 mCi) and have a PET and CT scan.

\[68Ga\]-NOTA-hGZP is a PET imaging agent.

Single Arm

Colin G Miller, PhD

Lieselotte Bloss, DVM

Chihhsi Kuo, MD

Little Ho, MD

First in Human Safety of \[68Ga\]-NOTA-hGZP PET Imaging in subjects with cancer undergoing treatment with a checkpoint inhibitor either as a monotherapy of in combination I-O therapy

This is a first in human research study (Phase I clinical trial) to test the safety and effectiveness of a new radioactive PET imaging drug and biomarker \[68Ga\]-NOTA-hGZP. It is a multi-center, open label, non-randomized, two dose study to evaluate the safety of \[68Ga\]-NOTA-hGZP and the ability to predict the clinical response to checkpoint inhibitor therapy within 2 cycles of treatment.

Multiple center, open label, non-randomized, single dose study, in subjects with cancer undergoing or treatment with a checkpoint inhibitor either as a monotherapy or in combination. subjects. Eligible subjects will receive an injection of \[68Ga\]-NOTA-hGZP pre checkpoint inhibitor administration and a second dose between 5 and 42 days post initial checkpoint inhibitor administration. Upon dosing each subject will undergo PET scans at 40, 60 and 90 minutes post dosing. The images will be analyzed for the distribution of radioactivity. Subjects will be followed for adverse events for approximately 4-6 hours post injection or until pembrolizumab injection plus a follow up phone call to assess adverse events 1-3 days after injection.

Granzyme B PET Imaging Drug as a Predictor of Immunotherapy Response to Checkpoint Inhibitors

First in Human Safety of [68Ga]-NOTA-hGZP- PET Imaging in Subjects Receiving Checkpoint Inhibitor Immunotherapy

Clinically significant changes from baseline in physical examination findings

Clinically significant changes from baseline to follow-up analysis in systolic and diastolic blood pressure (mmHg)

Clinically significant changes from baseline to follow-up analysis in heart rate (beats per minute)

Clinically significant changes in respiration rate.

Clinically significant changes from baseline to follow-up analysis in blood chemistry for:

1. Leukocytes (/mcL),
2. Absolute neutrophil count (mcL)
3. Platelets (/mcL)
4. Total bilirubin (mg/d)
5. AST/ALT (unitless)
6. Albumin (g/dL)
7. Alkaline phosphatase (IU/L)
8. eGRF (mL/min/1.73 m2)

Clinically significant changes from baseline to follow-up analysis in ECG change in QT (ms) Quantification of \[68Ga\]-NOTA-hGZP PET accumulation at tumor site in subjects after treatment with checkpoint inhibitor therapy as determined by region of interest analysis (SUVmean).

The absolute number of participants with AEs according to CTCAE 5.0

Identification by the central reader of the number of avid lesions observed in each subject and the number of subjects with avid lesions seen on the PET images

To be determined by region of interest analysis the mean standardized uptake value (SUVmean) (SUV does not have any units)

Compare quantified \[68Ga\]-NOTA-hGZP uptake to participant treatment response in individual lesions as assessed at 6-month clinical follow-up and/or CT assessments.

The number of lesions that were avid and the lesions that showed a decrease in size compared to those which increased in size.

Compare granzyme B protein quantification from biopsied tissue to the \[68Ga\]-NOTA-hGZP PET uptake acquired at the same location.

Massachusetts General Hospital

University of Alabama at Birmingham

Chang Gung Memorial Hospital

Cytosite Biopharma Inc.

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Neuroepithelioma

Franck G Billmann, MD, PhD

Ulrich Wellner, MD

Oliver Thomusch, MD

Franck Billmann, MD, PhD

Karl Khatib-Chahidi, MD

Tobias Keck, MD, PhD

Although gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) were considered for years as rare tumors, their incidences are increasing. Due to their potential of early metastases and their heterogenous response to therapy, these tumors are important clinical entities. A major problem remains the impossibility to adequately predict tumors' response to treatment, precluding an individualized therapy. Further, there is no method to efficiently screen these tumors. Protein based analyses (proteomic analyses) gain in interest as methods to address this problematic.

The present study was designed to investigate epidemiologic data of patients with GEP-NEN and to answer following questions using proteomic analysis applied to existing pathology specimens (paraffin-embedded specimens, FFPE): is it possible to explore protein signatures in this type of tumors? Is the response to therapy predictable using specific protein signatures? Is the tumor's tendency to metastasize related to specific protein signatures?

Gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) were considered for years as rare tumors. In last years however, their incidences are increasing (3,65 / 100.000 / year) \[Lawrence et al., 2011; Friling et al, 2014\]. These tumors are important clinical entities: 1) 40-95% of tumors have metastasized at diagnosis, 2) evidence-based data dealing with the therapeutic strategy and screening are still scarce.

A central problem remains the impossibility to adequately predict the response to surgery, chemotherapy, radiochemotherapy, peptid-receptor-based Radiotherapy or biotherapy, precluding an individualized therapy (precision medicine) \[Rinke et al., 2014\]. An actual research topic in these patients is the identification of patient markers allowing an response prediction. Moreover, researchers try to identify tumor markers in patients with unknown primary in order to locate the origin of metastases. Further, identification of tumor specific markers would allow the development of screening strategies in GEP-NEN. Due to the ability of these techniques to describe the biological heterogenity of a tumor, proteomics (protein based analysis methods) are promising in the present problematic \[Bezabeh et al., 2014; Löhr et al., 2006; Pan et al., 2013\].

The present study was designed to investigate epidemiologic data of patients with GEP-NEN and to answer following questions using proteomic analysis (MALDI-MS) applied to existing pathology specimens (paraffin-embedded specimens, FFPE): is it possible to explore protein signatures in this type of tumors? Is the response to therapy predictable using specific protein signatures? Is the tumor's tendency to metastasize related to specific protein signatures? The present investigation explores the GEP-NEN database/register of following institutions: University Hospital Schleswig Holstein, University hospital of Freiburg, Agaplesion Hospital Rotenburg. The pathology specimens of the studied register-population, were identified in the biobank and pathology-institutes of the participating hospitals and investigated using MALDI-MS technique.

proteomic analysis (MALDI-MS) applied to existing pathology specimens of Neuroendocrine tumors (paraffin-embedded specimens, FFPE).

Identification of Biomarker Profiles GEP-NEN Patients

Identification of Biomarker Profiles for Individualized Prognostic Stratification and Therapy in Patients With Gastroenteropancreatic Neuroendocrine Neoplasia (GEP-NEN)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Personalised Disease Monitoring in Metastatic Breast Cancer	NCT04597580	Breast Cancer M... Estrogen Recept...		18 Years -	The Christie NHS Foundation Trust
Assay Development for Cancer Biomarkers	NCT02874729	Tumors	Venesection Urine collectio... Sputum collecti... Bronchoalveolar...	18 Years -	King's College London
Assay Development for Cancer Biomarkers	NCT02874729	Tumors	Venesection Urine collectio... Sputum collecti... Bronchoalveolar...	18 Years -	King's College London
Personalised Disease Monitoring in Metastatic Breast Cancer	NCT04597580	Breast Cancer M... Estrogen Recept...		18 Years -	The Christie NHS Foundation Trust
Granzyme B PET Imaging Drug as a Predictor of Immunotherapy Response to Checkpoint Inhibitors	NCT04169321	Solid Tumor, Un... Lymphoma	Single Arm	18 Years -	Cytosite Biopharma Inc.
Identification of Biomarker Profiles GEP-NEN Patients	NCT02838862	Neuroendocrine ...		12 Years - 95 Years	University Hospital Schleswig-Holstein

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