A Retrospective Pharmacokinetics and Pharmacogenomics Research of Imatinib in Gastrointestinal Stromal Tumor Treatment

Study Overview
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Brief Summary
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For patients of GIST (Gastrointestinal Stromal Tumor), Imatinib has been widely used in GIST with KIT or PDGFRA sensitive mutations. From clinical points of view, individual differences often occur between different patients, leading diverse effect in ADR and drug effect. Meanwhile, the drug effect and adverse drug reaction was significantly influenced by the pharmacokinetic factors and pharmacodynamic and other factors. In this research, we try to establish a more sensitive method to detect sensitive mutations in plasma and discover the correlation between somatic and germline mutations, plasma trough concentration and drug effect, the association between ADME-associated SNP, Target/Receptor/Pathway-associated SNP, trough concentration and TKI adverse effect. Furthermore, in vivo and in vitro research is also crucial for rational explanation for these clinical phenomenon.

Detailed Description
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The plasma concentration of Imatinib were established. The ADME-associated SNPs included are CYP3A4, CYP3A4, CYP1A1, CYP2C9, CYP2C19, ABCB1, ABCG2, ABCC4, SLC22A1, SLCO1B3 and so on. The Target/Receptor/Pathway-associated SNP s included KIT, PDGFRA, PDGFRB, FLT1, FLT3, MAPK1, SHC1, CCL5, CXCL14 and so on. The somatic mutations included are KIT, PDGFRA, BRAF and so on.

Official Title
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Retrospective Study Based on Pharmacokinetics, Somatic Mutations and Genetic Polymorphisms Related to Individual Variations of Drug Effect and Adverse Drug Reaction of Imatinib in Gastrointestinal Stromal Tumor Treatment.

Conditions
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Gastrointestinal Stromal Tumors, Germline Mutation, Somatic Mutation, Plasma Concentration

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The main patient entry criteria included: age≥ 18 years; histologically and cytologically proved GIST; Eastern cooperative oncology group performance status (ECOGPS)≤2; adequate hematological,renal,and hepatic functions. Exclusion Criteria: uncontrolled systemic disease,and other chemotherapy at the time of inclusion. The protocol was approved by the Ethical Committee of Cancer Center of Sun Yat-Sen University (CCSU), and written informed consent was obtained form each patient.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 |
| --- | --- |
| sensitive group; non-sensitive group<br>sensitive patients were defined as patients reached CR or PR after first month administration,SD after first three months administration. non-sensitive patients were defined as patients reached PD after first month administration and first three months administration. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Excluding clinical deterioration without evidence of objective progression according to the Response Evaluation Criteria In Solid Tumors (RECIST), or death from any cause. | The time from the date of randomisation (baseline) to the date of objective tumour progression，and expected average of 36 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with objective response and adverse events | Objective responses (complete response plus partial response) and disease control (objective response plus stable disease≥6 weeks) were established according to RECIST.And adverse events was established according to CTCAE. | one month, three month, 12 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastrointestinal stromal tumor (GIST), Imatinib, Pharmacogenetics, Pharmacokinetics, Precision medicine, Somatic and germ-line mutations