Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Pfizer CT.gov Call Center

Ricardo Armisen, MD, PhD

This is a non-interventional multi-center with investigational sites in Chile and Brasil diagnostic study to validate novel diagnostic technologies, such as Next Generation Sequencing (NGS) from both tissue and blood compared to the current gold standard. As a non-interventional study, patients will receive the treatment indicated by their doctor independently of their participation on this study.

Many cancer cells look the same under the microscope. But as these cells are studied at the molecular level, some genetic alterations or defects that are more common to certain types of cancer are identified. In some cases, these defects are what make the cells grow and multiply abnormally.

Biomarkers are the molecular fingerprints of these genetic defects. By testing a sample of your tumor for biomarkers, doctors can learn if your cancer has one of these defects, and that may point to a specific treatment choice.

One of the genetic biomarkers that are believed to cause some cancers to grow is the ALK fusion gene. About 3% to 5% of people with NSCLC may test positive for ALK. ROS1 is a receptor found in 1 to 2% of people with this type of cancer.

The present study is designed to advance the molecular testing methodologies to identify ALK+ and ROS1+ NSCLC patients.

A positive correlation with these new technologies will mean an efficient, more accurate diagnostic test, which could impact a greater number of cancer patients around world.

B. Lung Cancer Non-small cell lung cancer (NSCLC) is a common cause of cancer mortality throughout the world. In 2007, there were 1.5 million new lung cancer cases diagnosed worldwide, including around 733,100 cases in the South American Region.6

Approximately 85% of lung cancer is histologically defined as non small cell and the remaining 14% as small cell. The majority of patients with NSCLC present with inoperable locally advanced (Stage IIIB) or metastatic (Stage IV) disease for which no curative treatment is yet available. In newly diagnosed patients with good performance status, platinum based doublet-combination chemotherapies are associated with a median overall survival (OS) of 7.4 to 9.9 months. 7, 8, 9, 10, 11, 12 Therefore, newer agents with novel mechanisms of action are still desperately needed for this serious life-threatening disease. 15,16

The rapid and efficient identification of key driver genes in non-small-cell lung cancer (NSCLC) is becoming increasingly important.17 Clinical screening efforts have revealed that the most common mutations in lung cancer specimens involve EGFR and KRAS, along with 10 other genes that show a prevalence of mutation in 5% or less of tumors. The ALK gene is rearranged in around 3%-5% of patients with NSCLC and has been the focus of intense basic and clinical research, suggesting that the frequency of the gene rearrangement is similar in Asian and Western patients.

ROS1 is a receptor tyrosine kinase of the insulin receptor family. Chromosomal rearrangements involving the ROS1 gene were originally described in glioblastomas, where ROS1 (chromosome 6q22) is fused to the FIG gene (chromosome 6q22 immediately adjacent to ROS1), 16 and have been shown to be transforming in transgenic mice.17 More recently, ROS1 fusions were identified as potential driver mutations in an NSCLC cell line (HCC78; SLC34A2-ROS1) and an NSCLC patient sample (CD74-ROS1). 18 These fusions led to constitutive kinase activity and were associated with sensitivity in vitro and in vivo to crizotinib. As of December 2013, 16 different variants have been found.16, 17, 18

The present study is designed to advance the molecular testing methodologies to identify ALK+ and ROS1+ NSCLC patients. Advanced next generation sequencing screening methodologies will be used to identify NSCLC patients whose tumors contain a ROS1 gene inversion or translocation or an ALK translocation.

A parallel test for ALK+ by either the Abbott ALK FISH test or the Ventana ALK IHC test is necessary to validate the NGS test in all samples. A parallel test for ROS1+ by either the Kreatech FISH test or the D4D6 ROS1 IHC test may be necessary to validate the NGS test in all samples.

Validation of Molecular Diagnostic Thecnologies for Lung Cancer Patients.

NON INTERVENTIONAL MULTICENTER STUDY, FOR THE VALIDATION OF MOLECULAR DIAGNOSTIC TECHNOLOGIES IN SUBJECTS WITH NON SMALL CELL LUNG CANCER (NSCLC) PROTOCOL N° X9001083

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

ALK status was measured by NGS- Oncomine focus assay (OFA) and Immuno histo chemistry (IHC) Ventana. Ventana -ALK and NGS-OFA were the assay procedures performed for ALK. The corresponding analysis of a specimen had 2 possible test results including ALK positive and ALK negative. True positives (tp) were defined as NGS-OFA and Ventana positive results, whereas false negatives (fn) were defined as NGS-OFA negative results and IHC-Ventana positive results. False positives (fp) were defined as NGS-OFA positive results and IHC-Ventana negative results. True negatives (tn) were defined as NGS-OFA and IHC Ventana negative results.

In this outcome measure, index of concordance with accuracy, sensitivity, specificity, positive predictive value and negative predictive value were measured. Accuracy (Acc): \[tp+tn\]/\[tp+fp+fn+tn\] \*100; Sensitivity (Ss): tp/\[tp+fn\] \*100; Specificity (Sp): tn/\[fp+tn\] \*100; Positive Predictive Value (PPV): tp/\[tp+fp\] \*100; Negative Predictive Value (NPV): tn/\[fn+tn\] \*100.

Participants were categorized on the basis of prospective and retrospective. Prospective participants were those participants whose samples were taken after the informed consent. Retrospective participants were those participants whose samples were taken before the date of signature of the informed consent.

The categories of smoker (tobacco use) were as follows: Never Smoker: No smoking exposure, Current Smoker: Currently uses tobacco in either cigarette, cigar or similar method (tobacco chewers excluded), Former Smoker: Participant at one time smoked but then later quit. Smoking status unknown: Participant whose smoking status is unknown.

Stage was defined at time of initial diagnosis of NSCLC and participants were staged according to the guidelines set by the NCCN version 7.2015. Participant's stage was categorized as: stage 0, stage IA, stage IB, stage IIA, stage IIB, stage IIIA, stage IIIB, and stage IV. Biopsy NSCLC class was categorized as adenocarcinoma, neuroendocrine tumors, other known type of NSCLC and squamous cell carcinoma.

Locations were categorized as lungs, pleura, node mediastinal and others.

In this outcome measure, participants were categorized according to their gender (female/male) and different age ranges (18-30 / 31-40 / 41-60 / 60 and above).

Pfizer

Tissue and blood samples of participants with NSCLC were collected and analyzed to validate new molecular diagnostic technologies (such as NGS) and to compare their performance with the available standard tests. Participants were not treated or affected and only participated in the study for the initial samples and clinical parameters collection.

Non-Small Cell Lung Cancer Participants

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

Full analysis set included all NSCLC participants who satisfied all inclusion and exclusion criteria.

Pfizer ClinicalTrials.gov Call Center

Per protocol analysis set included all participants with valid IHC-Ventana and NGS-OFA results.

Number of Participants With Prevalence of Anaplastic Lymphoma Kinase (ALK) Biomarker

Accuracy

Sensitivity

Specificity

Positive Predictive Value

Negative Predictive Value

Per protocol analysis set included all participants with valid IHC-Ventana and NGS-OFA results. Here, "Number analyzed" signifies the number of participants evaluable at specific rows.

Percentage of Concordance (Agreement) Between Ventana and NGS ALK Result

Per protocol analysis set included all participants with valid IHC-Ventana and NGS-OFA results. Here, "Overall Number of Participants Analyzed" participants evaluable for this outcome measure.

Number of Participants With Prevalence of Anaplastic Lymphoma Kinase (ALK) Biomarker by Type of Participants

Number of Participants With Association of Anaplastic Lymphoma Kinase (ALK) Rearrangement by Smoking (Tobacco Use) History

Biopsy Stage: IA

Biopsy Stage: IB

Biopsy Stage: IIA

Biopsy Stage: IIB

Biopsy Stage: IIIA

Biopsy Stage: IIIB

Biopsy Stage: IV

Biopsy Stage: None

Biopsy NSCLC class: adenocarcinoma

Biopsy NSCLC class: neuroendocrine tumors

Biopsy NSCLC class: other known type of NSCLC

Biopsy NSCLC class: squamous cell carcinoma

Number of Participants With Association of Anaplastic Lymphoma Kinase (ALK) Rearrangement by Stage and Classification of Biopsy

Number of Participants With Association of Anaplastic Lymphoma Kinase (ALK) Rearrangement by Location

Gender: Male

Gender: Female

Age range: 18-30 years

Age range: 31-40 years

Age range: 41-60 years

Age range: Above 61 years

Number of Participants With Association of Anaplastic Lymphoma Kinase (ALK) Rearrangement by Gender and Age

Tissue and blood samples of participants with non-small cell lung cancer (NSCLC) were collected and analyzed to validate new molecular diagnostic technologies (such as Next Generation Sequencing \[NGS\]) and to compare their performance with the available standard tests. Participants were not treated or affected and only participated in the study for the initial samples and clinical parameters collection.

Overall Study

Blood and Lymph Conditions

Symptoms and General Pathology

Hematologic Neoplasms

Disease Susceptibility

Hematologic Diseases

This pediatric oncology study proposing a global approach integrating trio-based whole exome sequencing, somatic DNA and RNA analysis will improve the recognition of genetic predisposition and the characterization of target therapies in children with cancer.

Exome sequencing in pediatrics cancers

Pascal Pujol, PU-PH

Background. Cancer is the leading cause of death by disease in children. Most pediatric tumors differ from adult tumors in terms of biological and clinical characteristics. In children, the part of genetic determinism could be higher since the role of environmental factors may be less pronounced than in adults and that a young age at onset is a main feature of genetic cancer predisposition. Recent studies suggested that a number of genetic predisposition remains to be characterized.

Methods. Trio-Based whole exome sequencing of germline DNA from patients (children and adults diagnosed with cancers between 0 and 17 years) and parents will be performed prospectively in a multicentric study including 40 unselected cases of malignant tumor. Participating hospitals will include the CHU of Montpellier, the CHU de Nice and the AP-HP. Tumor analysis will include whole exome analysis and transcriptome for the identification of therapeutic target and contribute to confirm potential link between constitutive mutations and tumor phenotype (such as loss of expression, loss of heterozygosity).

Perspectives. This pediatric oncology study proposing a global approach integrating trio-based whole exome sequencing, somatic DNA and RNA analysis will improve the recognition of genetic predisposition and the characterization of target therapies in children with cancer.

Analyse of Tumour and Constitutional DNA for the Study of the Determinism in Child Neoplasia

A blood sample will be taken from patients and their parents in order to carry out genetic analyses.

New generation NGS Exome sequencing in trio (patient and 2 healthy parents) on an Illumina HiSeq 2000 platform using the SureSelectXT Human All Exon 50Mb, V5 kit.

Bioinformatics analysis of the data. Confirmation of mutations by Sanger sequencing (gold standard).

In case of identification of mutations in candidate genes confirmed by Sanger sequencing, we will perform functional and clinical-genetic studies.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Validation of Molecular Diagnostic Thecnologies for Lung Cancer Patients.	NCT03220230	Lung Neoplasms		18 Years -	Pfizer
Analyse of Tumour and Constitutional DNA for the Study of the Determinism in Child Neoplasia	NCT04471961	Pediatric Tumor Familial Cancer Solid Tumor, Ch... Hematological T...	Exome sequencin...	-	University Hospital, Montpellier

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