Surgery in Gastrointestinal Stromal Tumors (GISTs) for Treatment, Tumor Modeling, and Genomic Analysis

Study Overview
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Brief Summary
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Objective: To follow people with GISTs and collect tumor tissue so that it can be studied in the lab. Eligibility: People age 6 and older who have a GIST. Design: Participants will be screened with a review of their medical records and samples. Participants will enroll in 1 other NIH study, and may be asked to enroll in 2 other optional NIH studies. Participants will have a medical history and physical exam. Data about how they function in their daily activities will be obtained. Participants may speak with a genetic counselor. They may have genetic testing. Participants will give blood samples. They may have a cheek swab. For this, small brush will be rubbed against the inside of the cheek. Participants may have a computed tomography (CT) scan of the chest, abdomen, and pelvis. Or they may have a CT scan of the chest and magnetic resonance imaging (MRI) of the abdomen and pelvis. Participants will be monitored every 6-12 months at the NIH Clinical Center, for up to 10 years before having surgery. If they need surgery, it will be performed at the NIH. Then, they will be monitored every 6-12 months, for up to 5 years after surgery. If a participant has surgery, tumor tissue samples will be taken. If a participant does not need surgery, their participation will end after 10 years. If they have surgery, the 5-year monitoring period will restart after each surgery.

Detailed Description
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Background: Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal soft tissue sarcoma, but remain a rare disease entity. Most GISTs are characterized by KIT or PDGFRA mutations, making them susceptible to tyrosine kinase inhibitor (TKI) therapy. Wild-type (WT) GISTs are rarer tumors, usually characterized by SDH mutations and/or lack of KIT or PDGFRA mutations; paragangliomas are frequently associated with WT GISTs. Non-WT GISTs may become refractory to TKI therapy, whereas WT GISTs are generally resistant to TKI therapy. The primary treatment modality for GISTs is surgical resection, which may involve the stomach, liver, and/or peritoneal surfaces; most patients will require multiple operations to remove disease not responsive to systemic agents. Investigational systemic therapies are limited by toxicity and/or lack of efficacy, resulting in an unmet need for novel treatment options. Obtaining fresh tumor tissue is critical to the successful development of GIST models for drug research, as well as for next generation tumor genomic sequencing, and to help identify novel targets and/or agents for the treatment of WT and TKI-resistant non-WT GISTs. Objective: Evaluate and follow patients with GISTs, particularly WT and treatment-refractory non-WT, to support translational research for this rare disease Assess disease-free intervals (DFIs) between surgical resection of disease for at least 5 years Eligibility: Patients with histologically confirmed or clinical presentation suspicious of GIST. Design: Prospective cohort study Patients with histologically confirmed or clinical presentation suspicious of GIST will enroll on study and will have active surveillance every 9-15 months for up to 10 years prior to and up to 5 years after surgical resection and/or cytoreduction. As patients may have multiple resections during the course of the study, 5-year surveillance post-surgery may be initiated multiple times, relative to the last resection performed. All patients enrolled will be evaluated for tumor resection or cytoreduction at the start of study and if appropriate, will be offered surgery, otherwise they will be on active surveillance until surgical resection or cytoreduction is clinically indicated. It is expected that approximately 30-40 patients per year may enroll on this trial; the accrual ceiling will be set at 400 to permit accrual over a 10-year period.

Official Title
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Prospective Study of Surgery in Gastrointestinal Stromal Tumors (GISTs) for Treatment, Tumor Modeling, and Genomic Analysis

Conditions
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Gastric Cancer, Gastric Neoplasm, Gastrointestinal Stromal Sarcoma, Gastrointestinal Stromal Neoplasm, Gastrointestinal Stromal Tumor (GIST)

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Histological confirmation or clinical presentation suspicious of GIST; histological confirmation will be preferably by review of archival tissue if available, fresh biopsy will not be required if inadequate tissue sample. Age >= 6 years ECOG performance status <= 2 (Karnofsky or Lansky >= 60%) Ability of participant or parent/guardian to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: - Non-modifiable medical comorbidities that would preclude cytoreductive surgery.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| 1/ Cohort 1<br>Patients with histologically confirmed or clinical presentation suspicious of GIST | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate and follow patients with GISTs, particularly WT or treatment-refractory non-WT, to support translational research for this rare disease | Patients with non-WT GIST and WT GIST will have the durations of the DFIs described both within each patient as their own control and across patients. Analyses will be done separately for those with WT GIST and those with non-WT GIST as well as for all patients combined. | on-going | 
| Assess disease-free intervals (DFIs) between surgical resection of disease for at least 5 years | Surveillance every 6-12 months and time of surgery, by tumor measurement and imaging studies, to assess disease-free intervals (DFIs) between surgical resection of disease for at least 5 years. | surveillance every 6-12 months and time of surgery, until 5 years after last surgical resection (relative to the last resection performed) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize genomic and clinicopathologic features of GISTs | Characterization of the genomic and clinicopathologic features associated with GISTs. | at clinical visits and follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tyrosine Kinase Inhibitor (TKI) Therapy, Wild-Type GISTs (WT GISTs), PDGFRA Mutation, KIT Mutation, SDH Mutation, Natural History