Neoplasms

Symptoms and General Pathology

All Conditions

Neoplastic Cells, Circulating

Neoplasm Metastasis

Neoplastic Processes

For the first stage, 60 healthy volunteers, 10 patients with stage 4 breast cancer and 10 patients with other types of cancer will be recruited.

For the second stage, approximately 65 breast cancer patients will be recruited.

To address the challenges of isolating and analyzing rare cells, this study aims to validate technical diagnostic instrumentation, tests, protocols and analysis to correlate the number of circulating tumor cells present in whole blood for predicting cancer prognosis and treatment efficacy. Investigators propose to enroll and follow cohorts of cancer patients. Blood samples will be collected from these patients at regular intervals as determined by their doctors. The patient's disease progression will be monitored over the lifetime of this study. The specific aims are to isolate, enumerate and analyze the number of circulating tumor cells (CTCs) in patient blood using chip-based sorting, filtration and imaging techniques. Investigators will also use this study to optimize diagnostic instrumentation, test protocols and downstream CTC analysis. Investigators may also correlate the results of these tests with the prognosis of the patients as well as any clinical evidence (e.g. from radiological imaging scans). While investigators focus on prognosis in this study, these correlated tests potentially may also be valuable in future studies for early diagnosis and monitoring of cancer.

Detection of Circulating Tumor Cells in Peripheral Blood From Healthy Volunteers and Patients With Cancer

MiCareo Taiwan Co., Ltd.

Disease Progression

Anticoagulants

All Drugs and Chemicals

Edetic Acid

Pentetic Acid

Blood samples (3 ethylenediaminetetraacetic acid (EDTA) tubes with a volume of 7.5 ml blood each) will be processed for CTC isolation and characterization, ranging from molecular analysis to culture and drug screen.

Blood samples

In case of tumor resection, 3 EDTA tubes (5 ml) will be withdrawn from the tumor draining vessels for CTC isolation and characterization, ranging from molecular analysis to culture and drug screen.

Samples from tumor draining vessels

Marcus Vetter, PD Dr. med.

Nicola Aceto, Prof. Dr. med.

Christian Kurzeder, PD Dr. med.

Fabienne Schwab, Dr. med

Viola Heinzelmann-Schwarz, Prof. Dr. med

Christoph Rochlitz, Prof. Dr. med.

Julia Landin, Dr. med.

Alfred Zippelius, Prof. Dr. med.

Heinz Läubli, PD Dr. med.

Walter Weber, Prof. Dr. med.

Dörthe Schaefer-Rohr, Dr. med.

Homen Begovic, Dr. med.

Christine Wenk, Dr. med.

Daniel Steffens, Dr. med.

Anna Schollbach, Dr. med.

Ilker Acemoglu, Dr. med.

Simone Münst, PD Dr. med.

Tatjana Vlajnic, Dr. med.

Robert Rosenberg, Prof. Dr. med.

Emanuel Burri, PD Dr. med.

This observational study with circulating tumor cells (CTC) count, isolation and analysis at several time points during disease progression is to investigate the role and biology of CTCs and clusters of CTCs in different cancer types. It also evaluates the role of CTCs as biomarkers, and aims at the identification of key signaling networks that are active in CTCs.

CTC cultures stored in the refrigerator. A "Biobank Reglement" is enclosed to this protocol.

Circulating Tumor Cells (CTC) in Cancer

Change in circulating tumor DNA (ctDNA) from blood samples

overall survival (OS) in heterogeneous cancer population

progression free survival (PFS) in the different cancer cohorts with different treatment regimes

University Hospital, Basel, Switzerland

Death

Carcinoma

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Head and Neck Neoplasms

Antineoplastic Agents

Nivolumab

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Retrospectively analyze WGS information from cancer tissues from HNSCC patients have used Nivolumab

Using Whole-Genome Analysis on Cancer Tissue of Patients with Platinum-refractory Head and Neck Squamous cell carcinoma Who Underwent Nivolumab to Precisely Predict Responders: An Observational Biomarker Study

HNSCC patients have used Nivolumab

Jason Chia-Hsun Hsieh, M.D. Ph.D.

CHIA-HSUN HSIEH, MD,PhD

Tsang-Tang Hsieh, M.D

Chia-Hsun Hsieh, M.D,M.S.

Chia-Hsun Hsieh, M.D., M.S

Min-Hsien Wu, PhD.

Hung-Ming Wang, M.D.

Siang-Fu Huang, M.D.,PhD.

Yonɡ-Chanɡ Lin, M.D.

Tsang-Tang Hsieh, M.D.

To choose a subgroup who could clearly benefit from Nivolumab, we are proposing a prospective observational study. Whole-genome study (WGS) analysis will be performed on archived cancer tissues from patients who were (1) cisplatin-refractory and subsequently (2) received Nivolumab (at least 4 doses) and (3) had completed imaging response evaluation at 3-4 month after Nivolumab. The estimated sample size was designed to be 80, including 20 responders and 60 non-responders (1:3 design) after Nivolumab alone at a dosage of 2-3mg/kg every 2 weeks (+/- 7 days could be allowed), given the minimal requirement of statistical significance. The specific bio-signature(s) found in this prospective observational study could possibly greatly contribute to precision immuno-oncology medicine, especially Nivolumab.

1-1 PD-1 pathway as a novel and effective pathway in cancer treatment The programmed death 1 (PD-1) receptor, which is expressed on activated T cells, is engaged by ligands PD-L1 and PD-L2, which are expressed by tumor cells and infiltrating immune cells 1. Tumor PD-L1 expression is commonly seen in a broad spectrum of cancers, and the interaction between PD-1 and PD-L1, PD-L2 ligands inhibits T-cell activation and promotes tumor immune escape (i.e., the mechanism by which tumor cells escape recognition and elimination by the immune system) 2, 3. Immune checkpoint inhibitors (ICI) developed on the basis of the above mechanism have shown their success with good treatment efficacy in patients with melanoma4-8, lung cancer3, 7, 9-21, and renal cell carcinoma12, 22-24 to date. Owing to the mechanism of targeting probably very common pathways of cancer (PD-1 pathway), ICIs seems to be equally effective in a wide range of cancers with a similar response rate of 20-30% 25, which indicates a common immune defect on PD-1 pathway exists amongst the various type of cancer.

1-2 Subpopulation selection could possibly contribute better efficacy Recently, two PD1 inhibitors, Nivolumab and Pembrolizumab, showed their different results in large-scale clinical trials 11, 14. Subpopulation selection strategies in these 2 trials have been widely considered as one of the major reasons. A precise selection of patients with the best response is critically warranted and a truly unmet need, given PD-L1 cannot clearly stratify patients who will benefit most from Nivolumab.

1-3 No available biomarkers to predict severe irAEs is an unmet need Another problem is that all ICIs have occasionally severe and sometimes life-threatening immune-related adverse events (irAEs). At present, no good biomarker is available to predict such irAEs. It is imperative to identify the biomarkers that can predict the risk of severe irAEs 25.

1-4 NGS technology could probably provide solutions to the above 2 problems Next-generation sequencing (NGS) technology has been introduced in recent years (Fig. 1), and allows the analysis of genomes, including those representing disease states 26, 27. Generally speaking, there are three NGS approaches to improve diagnostics for cancer gene mutations: (1) targeted enrichment of a set of genes (gene panel), (2) whole-exome sequencing (WES), and (3) whole-genome sequencing (WGS) 28. When comparing the three options, it is clear that-theoretically-WGS is the superior approach as it will produce the most complete data set on an individual's genome (Table 1)28. A recent study 29 concluded that WGS offers signiﬁcant advantages of (a) more coverage of the exome, (b) detection of intronic variants, and (c) calling of all structural variants, including single exon deletions; however, the costs and testing time limited the routine use of WGS. In brief, WGS for cancer patients before treatment could most possibly help to select patients with specific signature(s) to receive specific treatment in a manner of precision medicine 30-37.

1-5 Host immunity (inherent, host) and Cancer (somatic, acquired) interaction could only be seen in whole genome analysis By means of WGS, we could approach the question of how to identify the responders from Nivolumab in the direction of "cancer part (somatic)" conventionally. In another way, we could also approach this question by "host part", which is also the advantages of WGS testing.

In WGS analysis, we could use genome-wide association studies (GWAS) analysis to compare common genetic variants in large numbers of affected cases to those in unaffected controls to determine whether an association with disease exists 38, 39. GWAS have been made possible by the identification of millions of single nucleotide polymorphisms (SNPs) across the human genome and the realization that a subset of these SNPs can capture ("tag") common genetic variation via linkage disequilibrium 40. By SNP analysis in WGS, we proposed to find genotypic characteristics to predict which patients could more possibly respond to Nivolumab.

In further hypothesis, we could analyze the upstream and downstream of the B cell signaling pathway in addition to T cell pathway. Currently, almost all studies addressed the T functional analysis when investigating PD-1-PD-L1 inhibitors. We hypothesize that B cell or even Natural killer's pathway could play some roles to T cell activation to help us to predict the response of immunotherapy.

1-6 Current evidence of NGS for stratification before ICIs Currently, there are only very few data available carrying out a design using the WGS method. In 2016, Kimura et al. 25 from the U.S.A used targeted panel NGS to prove a strong T cell response and further suggested to exclude of patients with subclinical autoimmune disease is very important for treatment with immune checkpoint inhibitors 25. Yaghmour et al. (2016) also used a panel NGS (Foundation One panel) and found that the use of immune checkpoint blockade in tumors with higher mutational load was associated with improved OS. They further suggested that the evaluation of tumor genomes may be predictive of immunotherapy benefit 41. Voss et al. (2016) presented their preliminary data using WES and RNA-Seq in patients with RCC in ASCO. They found that somatic mutations, particularly those causing tumor neoantigens, and the counterbalance between molecular immune compartments may be determinants of treatment benefit from Nivolumab and warrant future study 42. Another team (de Velasco et al.) also found that both DNA- and RNA-level data may be relevant for explaining clinical benefit from nivolumab in mRCC. In contrast with results from other tumor types, responders to nivolumab did not have more mutated tumors, though immune-related gene expression may be related to response 43. However, their sample sizes of study, retrospective in nature, study scale, and NGS methods are all relatively small.

Fig. 1. Recent advances of genetic analysis.44

Fig 2. The differences between several methods of NGS analysis. 45

1-7 The purpose of the study and brief design To choose a subgroup who could clearly benefit from Nivolumab, we are proposing a prospective observational study. Whole-genome study (WGS) analysis will be performed on archived cancer tissues from patients who were (1) cisplatin-refractory and subsequently (2) received Nivolumab (at least 4 doses) and (3) had completed imaging response evaluation at 3-4 month after Nivolumab. The estimated sample size was designed to be 80, including 20 responders and 60 non-responders (1:3 design) after Nivolumab alone at a dosage of 2-3mg/kg every 2 weeks (+/- 7 days could be allowed), given the minimal requirement of statistical significance. The specific bio-signature(s) found in this prospective observational study could possibly greatly contribute to precision immuno-oncology medicine, especially Nivolumab.

1. The study will retrieve cancer tissues from HNSCC patients received threshold Nivolumab. WGS by Illumina HighSeq X Ten Platform will be used for exploring biomarkers of Nivolumab.
2. All Samples will be collected from pathologic departments from participating hospitals, including 10μm x 5-10 slices non-coating, 3μm x 3 slices for PD-L1 staining.
3. Also, Pathologist will involve PD-L1 IHC staining (Ventana SP 263) and grading.
4. Cancer Tissues will be sent for WGS analysis (Application for sampling tests will be sent and obtained.)
5. Data will be sent to biostatistics analysis company or experts for analysis with charges.

WGA in Platinum-refractory HNSCC Underwent Nivolumab

Using Whole-Genome Analysis on Cancer Tissue of Patients With Platinum-refractory Head and Neck Squamous Cell Carcinoma Who Underwent Nivolumab to Precisely Predict Responders: An Observational Biomarker Study

Adverse effects (types and grading) of Nivolumab

Chang Gung Memorial Hospital

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Gland and Hormone Related Diseases

Rare Diseases

Carcinoma, Non-Small-Cell Lung

Stomach Neoplasms

Lung Neoplasms

Carcinoma, Hepatocellular

Esophageal Neoplasms

Pancreatic Neoplasms

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Adenocarcinoma

Stomach Cancer

Esophageal Cancer

Pancreatic Cancer

Blood draws, urine and tissue asservation, and bone marrow aspiration will be done during surgery

Study sample collection

Jussuf T Kaifi, MD, PhD

Blanche Lasta, RN

Patients with resectable solid primary cancers and even limited number of metastases are potentially curable. However, most patients develop recurrences despite surgery. Circulating and disseminated tumor cell (CTC/DTC) and circulating cell-free (cf) DNA isolation from the blood, urine and bone marrow will increase understanding of cancer spread and advance knowledge to develop individualized therapies.

Background:

Patients with resectable solid primary cancers and even limited number of metastases are potentially curable. However, most patients develop recurrences despite surgery. Circulating and disseminated tumor cell (CTC/DTC) and circulating cell-free (cf) DNA isolation from the blood, urine and bone marrow will increase understanding of cancer spread and advance knowledge to develop individualized therapies.

Hypothesis and Rationale:

CTCs/DTCs and cfDNA isolated from the blood, urine and bone marrow during cancer surgeries undergo pheno- and/or genotype changes. CTCs/DTCs have potential for dissemination and tumor growth in vivo. Investigating the biology of liquid biomarkers in the blood, urine and bone marrow will significantly increase understanding of cancer biology.

Specific Aims:

CTCs/DTCs and cfDNA isolated from cancer patients will be characterized for genetic alterations and expression of key signaling/proliferation biomarkers and grow in vivo in nude mice.

Study Design:

100 patients undergoing solid cancer surgeries will be recruited for perioperative CTC/DTC/cfDNA isolation from the blood, urine and bone marrow with innovative techniques. In addition, 20 patients undergoing similar surgeries for benign disease will also be included as controls. CTCs/DTCs, cfDNA and cancer tissue pheno- and/or genotype analysis will be performed with different innovative techniques. Furthermore, CTCs/DTCs will be enriched, cultured and characterized. Tumor growth potential will be studied in nude mice.

Relevance:

This translational cancer trial addresses fundamental aspects of cancer disease being the cause of death in 1 out of 4 persons in the US. Innovative CTCs/DTCs characterization can shed light on the tumor biology, and identify therapy targets. Results of this study can be fundamentally important to understanding cancer spread and development of personalized therapies.

Tumor Cell and DNA Detection in the Blood, Urine and Bone Marrow of Patients With Solid Cancers

CTC/DTC numbers in the blood, urine and bone marrow will be determined and correlated with survival data (presence of recurrence, death) by univariate analysis (log rank test), multivariate analysis (Cox regression) and t test/ANOVA

A panel of ctDNA mutations detected in the blood will be gathered in a score and correlated with survival data (presence of recurrence, death) by univariate analysis (log rank test), multivariate analysis (Cox regression)

University of Missouri-Columbia

Assistant Professor, Chief, Section for Thoracic Surgery

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Twenty ml of blood will be drawn from each patient : 10 ml of blood will be drawn on CellSave tubes (fixed cells) for CTC detection using the FDA-cleared CellSearch system (gold standard) and 10 ml of blood will be drawn on EDTA tubes (viable cells) for the detection of functional CTCs using the EPIDROP.

Blood sample

Catherine ALIX-PANABIERES, MCU-PH

Stephane DROUPY, MD

The use of liquid biopsy could be the key for precision medicine. Circulating tumor cells (CTCs) are the most studied circulating biomarkers used to assess the metastatic process and they have shown their clinical validity and utility in cancer patients. However, their detection and capture are still a challenge as they are very rare in the bloodstream. In this clinical trial named "EPIDROP", the investigators will use an innovative device called EPIDROP (for EPIspot in a DROP) in metastatic prostate cancer. EPIDROP is a completely new technology answering to biological and clinical questions by proposing a procedure detecting the functional subset of prostatic CTCs at the single cell level. The investigators will stain cells in the sample for EpCAM, PSMA, CD45 before to encapsulate them one by one in microdroplets and measure the PSA secretion by only the viable CTCs. This study aims to demonstrate the non-inferiority of the EPIDROP compared to the CellSearch system.

Methods :

One hundred patients with a metastatic prostate cancer will be recruited plus 50 healthy donors. Twenty ml of blood will be drawn : 10 ml of blood will be drawn on CellSave tubes (fixed cells) for CTC detection using the FDA-cleared CellSearch system (gold standard) and 10 ml of blood will be drawn on EDTA tubes (viable cells) for the detection of functional CTCs using the EPIDROP. Patients will be followed for 18 months.

Samples from fifty control subjects will be provided by the Etablissement Français du Sang.

Detection of Viable CTCs Using the EPIDROP Technology in Metastatic Prostate Cancer (EPIDROP)

Detection of Viable CTCs Using the EPIDROP Technology in Metastatic Prostate Cancer

Proportion of true positive and false negative patients with a confidence interval

Proportion of true negative and false positive healthy controls with a confidence interval

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Detection of Circulating Tumor Cells in Peripheral Blood From Healthy Volunteers and Patients With Cancer	NCT02904161	Circulating Tum...		20 Years -	MiCareo Taiwan Co., Ltd.
Circulating Tumor Cells (CTC) in Cancer	NCT04520672	Cancer	Blood samples Samples from tu...	18 Years -	University Hospital, Basel, Switzerland
WGA in Platinum-refractory HNSCC Underwent Nivolumab	NCT03917537	HNSCC	HNSCC patients ...	20 Years -	Chang Gung Memorial Hospital
Tumor Cell and DNA Detection in the Blood, Urine and Bone Marrow of Patients With Solid Cancers	NCT02838836	Non-small Cell ... Esophageal Canc... Gastric Cancer Pancreatic Canc... Hepatocellular ... Colorectal Canc...	Study sample co...	18 Years -	University of Missouri-Columbia
Detection of Viable CTCs Using the EPIDROP Technology in Metastatic Prostate Cancer (EPIDROP)	NCT04581109	Prostate Cancer	Blood sample	18 Years -	University Hospital, Montpellier
Tumor Cell and DNA Detection in the Blood, Urine and Bone Marrow of Patients With Solid Cancers	NCT02838836	Non-small Cell ... Esophageal Canc... Gastric Cancer Pancreatic Canc... Hepatocellular ... Colorectal Canc...	Study sample co...	18 Years -	University of Missouri-Columbia

Spots Global Cancer Trial Database for circulating tumor cells (ctcs)