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Next Generation Sequencing of Tumor and Normal Tissues Prospectively in Pediatric Oncology Patients at St. Jude Children's Research Hospital

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ClinicalTrials.gov Identifier: NCT02530658
Recruitment Status : Recruiting
First Posted : August 21, 2015
Last Update Posted : July 11, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:

The development of next generation sequencing (NGS) techniques, including whole genome (WGS), exome (WES) and RNA sequencing has revolutionized the ability of investigators to query the molecular mechanisms underlying tumor formation. Through the Pediatric Cancer Genome Project (PCGP), investigators at St. Jude Children's Research Hospital (SJCRH) have successfully used NGS approaches to evaluate more than 1,000 pediatric cancers ranging from hematologic malignancies to central nervous system (CNS) and non-CNS solid tumors. From these and related studies, it has become clear that genomic approaches can accurately classify tumors into distinct pathologic and prognostic subtypes and detect alterations in cellular pathways that may serve as novel therapeutic targets. Collectively, these studies suggest that by characterizing the genomic make-up of individual tumors, investigators will be able to develop personalized and potentially more effective cancer treatments and/or preventive measures.

Despite recent advances, NGS approaches are not yet routinely used as part of clinical care due to their high cost and technical complexity, as well as the many challenges related to data analysis and translation to the clinical setting. The overarching goal of this protocol is to establish and test processes by which NGS technologies, including WGS, WES and RNA sequencing, can be offered to pediatric oncology patients undergoing treatment at SJCRH.

This is a non-therapeutic study examining the feasibility, acceptance and impact of clinical WGS, WES and RNA sequencing in a pediatric oncology setting. Investigators anticipate a sample size of approximately 400 patients and 400-800 biological parents.


Condition or disease Intervention/treatment
Solid, Liquid, Central Nervous System Tumors Other: Study Introduction Visit Other: Informed Consent Visit Other: Informed Consent Follow-Up Visit Other: Return of Results Conversation Other: Return of Results Follow-Up Visits Procedure: Tissue Sample Procedure: Blood Sample Procedure: Skin Biopsy

Detailed Description:

PRIMARY OBJECTIVES:

  • To perform clinical next generation whole genome (WGS), exome (WES), and RNA sequencing on SJCRH pediatric oncology patients prospectively over a 24-month period.
  • To use WGS, WES and RNA sequence data to identify and characterize somatic genetic variants of pathological significance and germline genetic variants associated with increased cancer risk.

OTHER PRESPECIFIED OBJECTIVES:

  • To generate and analyze data describing the informed consent process and patient/parent perceptions of genomic investigations and research.
  • To generate and analyze data surrounding the return of genomic sequencing results, examine patient/parent understanding of these results and assess the impact of results on patients and families.
  • To determine the feasibility and reliability of performing WES and RNA sequencing on derivatives from formalin-fixed, paraffin-embedded (FFPE) tumor samples alongside the analysis of matched frozen tumor and germline samples.

For participants who give consent, a tumor and/or normal tissue sample will be obtained and used for WGS, WES and RNA sequence analysis. Once the results of these analyses are available, they will be disclosed to physicians, patients and parents. Mixed measures approaches will be used to assess understanding, acceptance and impact of genomic results on patients and parents.

All tumor samples analyzed via the clinical genomics pipeline will undergo routine clinical pathology testing, which will be run in parallel with this study. Genetic variants deemed reportable by the Clinical Genomics Committee will be considered for return to physicians, patients and parents after several validation steps. Genes from the tumor tissue will be analyzed and those with biological and/or clinical relevance will be reported. A defined list of 63 genes will be analyzed for reporting using normal (germline) tissue. During the course of the study, the investigators anticipate the list of genes to be reported using normal tissue to change due to advances in the literature or other evidence linking additional genes to tumor formation and cancer risk, and new lists may be defined.

To assess provider, patient and family understanding and describe the impacts of genomic testing and return of results, this study will also incorporate administration of surveys and semi-structured interviews. Surveys and interviews are optional, but will be offered to all primary SJCRH providers, as well as all eligible participants and parents, regardless of whether or not they consent to pursue the genomic testing.

A sample of blood or a skin biopsy will be obtained as a source of germline DNA. This sample is necessary as it is the comparator against which tumor samples are evaluated. Skin biopsies may be done on patients who have a diagnosis where peripheral blood is likely to be contaminated by tumor cells.


Study Design

Study Type : Observational
Estimated Enrollment : 400 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Genomes for Kids (G4K)
Actual Study Start Date : August 28, 2015
Estimated Primary Completion Date : November 30, 2017
Estimated Study Completion Date : October 31, 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Groups and Cohorts

Group/Cohort Intervention/treatment
Participants

Patients with newly diagnosed, relapsed, or refractory tumors who are prospectively or currently accepted to undergo treatment at SJCRH over a 24-month period following activation of this study, and their biological parents or legally authorized representative.

Interventions: Study Introduction Visit, Informed Consent Visit, Informed Consent Follow-Up Visit, Return of Results Conversation, two Return of Results Follow-Up Visits, Tissue Sample, Blood Sample, Skin Biopsy..

Other: Study Introduction Visit
Within 5±3 weeks following arrival at SJCRH, or at the participant/family's convenience, study introduction materials will be provided. Participants will also complete assessment questionnaires.
Other Names:
  • Study Materials
  • Literacy/Numeracy Assessment
  • Genetic Knowledge Assessment
Other: Informed Consent Visit
Within 1±3 weeks following the Study Introduction Visit, or at the participant/family's convenience, the study team will collect demographic, medical, family and physical examination information. All interviews will be audio-taped for later analysis. Participants will complete assessment questionnaires.
Other Names:
  • History and Physical
  • Questionnaires
Other: Informed Consent Follow-Up Visit
Within 2-4 weeks following the Informed Consent Visit, or at the participant/family's convenience, participants will complete questionnaires. A subset of participants (30-40) will participate in semi-structured interviews.
Other Names:
  • Questionnaires
  • Interviews
Other: Return of Results Conversation
Depending on the availability of genomic results and preference of the participant and parents, audio-taped interviews will be conducted. Participants will complete the assessment questionnaires.
Other Names:
  • Questionnaires
  • Interviews
Other: Return of Results Follow-Up Visits
Return of Results Follow-Up Visits will be conducted twice: the first within 8±4 weeks of the Return of Results Conversation, or at the participant/family's convenience, and the second within 32±8 weeks of the Return of Results Conversation or at the participant/family's convenience. At each visit, participants will complete assessment questionnaires. Semi-structured interviews with parents and adolescents will be conducted.
Other Names:
  • Questionnaires
  • Interviews
Procedure: Tissue Sample
For patients who do not have a tissue sample in the St. Jude Tissue Bank and who give consent, a tumor and/or normal tissue sample will be obtained by biopsy as part of routine diagnostic evaluation for use in WGS, WES and RNA sequence analysis.
Other Name: Tumor Sample
Procedure: Blood Sample
A sample of blood will be obtained as a source of germline DNA.
Other Name: Phlebotomy
Procedure: Skin Biopsy
After consent, for participants with a diagnosis where peripheral blood is likely to be contaminated by tumor cells, skin biopsies may be done as a source of germline DNA.
Other Name: Biopsy


Outcome Measures

Primary Outcome Measures :
  1. Overall success rate [ Time Frame: Approximately 3 months after study enrollment ]

    Success is defined by the combined successes of (1) quality interpretable genomic data are generated from sequencing tumor and germline tissues, and (2) communicating genomic test results to the primary SJCRH oncologist and the patient and his/her parents.

    The Binomial proportion of successful performance will be estimated by the sample proportion and the 99% confidence interval based on the normal approximation. Sample size is 400.


  2. Number and type of somatic genetic variants and germline genetic variants [ Time Frame: Approximately 3-4 months after the germline sample is obtained ]
    WGS, WES and RNA sequence data will be used to identify and characterize somatic genetic variants of pathological significance and germline genetic variants associated with increased cancer risk. Descriptive statistics, such as counts and proportions of variants associated with increased cancer risk will be computed within each patient and in each disease type.


Other Outcome Measures:
  1. Proportion of parents/participants by perception of genomic testing [ Time Frame: At study end (up to 13 months after last participant enrollment) ]
    Parent/participant perceptions of genomic investigations and research will be assessed using audiotaped conversations and surveys. Results will be summarized by descriptive statistics.

  2. Number of participants/parents by level of understanding [ Time Frame: At study end (up to 13 months after last participant enrollment) ]
    Research participant/parent understanding of genomic results and the impact of results on research participants and their families will be assessed by analysis of audiotaped conversations and survey results. Results will be summarized by descriptive statistics

  3. Proportion of successful sequences of formalin-fixed, paraffin-embedded (FFPE) samples [ Time Frame: Approximately 3 months after enrollment ]
    To assess the practicability, proportions of FFPE samples that can be successfully sequenced will be estimated along with a 95% confidence interval.


Biospecimen Retention:   Samples With DNA
Except for patients with retinoblastoma, craniopharyngioma, pontine glioma and optic pathway tumors, tumor and normal tissue will be analyzed. For patients with retinoblastoma, craniopharyngioma, pontine glioma and optic pathway tumors, only blood samples will be collected and studied. Leukemia patients and patients with solid tumors and evidence of bone marrow infiltration may undergo a skin biopsy procedure to obtain the germline specimen.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Participants will be patients at St. Jude Children's Research Hospital (SJCRH) with diagnoses of hematological, solid or central nervous system tumors who agree to participate in this study and their parents or legally authorized representatives who consent to participate.
Criteria

Inclusion Criteria:

  • New St. Jude patients prospectively identified at the time of study activation with:

    • Newly diagnosed solid or liquid tumor (benign or malignant),
    • Relapsed solid or liquid tumor (benign or malignant), or
    • Refractory solid or liquid tumor (benign or malignant)
  • Current St. Jude patients who develop a new mass and undergo a surgical procedure to establish the diagnosis of recurrent disease or a new primary tumor.
  • Current St. Jude patients who, while on therapy, develop refractory disease and undergo a surgical procedure to palliate symptoms.
  • Adequate tissue must be available (e.g. sufficient germline and/or tumor tissue, from which >1 µg DNA and >0.1 µg RNA must be isolated). Patients with retinoblastoma, diffuse intrinsic pontine glioma, craniopharyngioma, or optic pathway tumors who have no tumor tissue available may enroll using only a germline sample.

Exclusion Criteria:

  • Past history of hematopoietic stem cell transplantation (or other condition that would result in hematopoietic cell DNA failing to match host tissue DNA).
  • Tumor or germline tissue not meeting the criteria listed above.
  • Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.
  • Participants who are unable to read, write or converse fluently in English will be excluded from Prespecified Objectives 3 and 4.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02530658


Contacts
Contact: Kim E. Nichols, MD 866-278-5833 referralinfo@stjude.org

Locations
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Kim E. Nichols, MD    866-278-5833    referralinfo@stjude.org   
Principal Investigator: Kim E. Nichols, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
Principal Investigator: Kim E. Nichols, MD St. Jude Children's Research Hospital
More Information

Additional Information:
Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT02530658     History of Changes
Other Study ID Numbers: G4K
First Posted: August 21, 2015    Key Record Dates
Last Update Posted: July 11, 2017
Last Verified: July 2017

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by St. Jude Children's Research Hospital:
Genetic Predisposition
Pediatric
Genomic Analysis
Heritable Disease
Cancer Risk
Genetic Counseling
DNA
Clinical Genomics
Clinical Decision-Making
Treatment Planning

Additional relevant MeSH terms:
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Nervous System Diseases