Association of Genetic Polymorphisms With Docetaxel-based Chemotherapy Toxicities in Chinese Solid Tumor Patients

Study Overview
=================
Brief Summary
-----------------
Taxanes are one of the most active agents in the treatment of many kinds of solid tumors, mainly including paclitaxel and docetaxel. However, variability in toxicity and response remains a major problem for patients receiving taxanes. It is general that there are many factors for individual differences of drugs in clinical application, of which genetic factors accounted for more than 20%. Toxicities of docetaxel, such as myelosuppression, neurotoxicity or mucositis, were evaluated for possible relationship with pharmacogenetic polymorphisms in several candidate gene and genome-wide association studies. Due to the levels of evidence of those studies are low and lack of sufficient research data of Chinese, it has the important significance in studying individual differences of docetaxel in toxicities, through the pharmacogenomics research. The aim of this study is to evaluating the association genetic polymorphisms with docetaxel-based chemotherapy toxicities in chinese solid tumor patients. By detecting the gene polymorphism, investigators intend to study the pharmacokinetic/pharmacogenomics (PK-PG) correlation of docetaxel and provide scientific basis for precise medication guide for people to use docetaxel.

Official Title
-----------------
Association of Genetic Polymorphisms With Docetaxel-based Chemotherapy Toxicities in Chinese Solid Tumor Patients

Conditions
-----------------
Solid Tumors, Docetaxel, Drug-Related Side Effects and Adverse Reactions, Pharmacogenetics, Pharmacokinetics

Intervention / Treatment
-----------------
* Genetic: detection of genotype


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Any native Chinese men or women at least 18 years of age; Sign informed consent of the research; Have a histologic or cytologic diagnosis of solid tumor; Will receive docetaxel-based chemotherapy; Or patients who received docetaxel chemotherapy meet the inclusion and exclusion criteria of the research, and their clinical information is complete to obtain; Male and female patients with reproductive potential must use an approved contraceptive method during and for 3 months after discontinuation of study treatment. Women with childbearing potential must have a negative pregnancy test within 7 days prior to study enrollment; Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Have discontinued all previous therapies for cancer for at least 28 days prior to study entry, and have recovered from the acute effects of therapy. Have adequate organ function, including: Bone marrow reserve: ANC≥1.5×109/L PLT≥100×109/L HGB≥10g/dL Hepatic: Bilirubin ≤ 1.5ULN ALT, AST ≤2.5 ULN, ≤5ULN when liver metastases are known Renal: Src ≤1.5mg/dl Electrolytes: Patients may be entered into the study if, in the investigators' opinion, any electrolyte disorders, including K<3.4mEq/L, Ca<8.4mEq/L, or Mg<1.2mEq/L, may be appropriately managed and stabilized by the time of the laboratory evaluation prior to the chemotherapy. If electrolytes have not been stabilized during this time, the patient will be discontinued from the study. Have an estimated life expectancy, in the judgment of the investigator, which will permit the patient to complete the PK phase and at least 2 cycle of the evaluation of the toxicities. Exclusion Criteria; Serious concomitant systemic disorder, including active infection, which is incompatible with the study (at the discretion of the investigator). History of human immunodeficiency virus, hepatitis B, or hepatitis C infections. Cardiac: Have a serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease, as defined by the New York Heart Association Class III or IV. It is recommended that patients with arrhythmias (persistent or paroxysmal ventricular or supraventricular arrhythmias, including atrial fibrillation or bradycardia (heart rate <50 beats per minute))be excluded at the investigator's discretion. Known family history of unexplained sudden death. Personal history of unexplained syncope within the last year. Women who are breast feeding, lactating, or pregnant. Patients with known allergies to docetaxel and its supplementary materials. Drugs and herbal supplements that are known to be potent or moderate inhibitors or inducers of cytochrome P450 (CYP)3A4 are specifically excluded. Foods that are known to be potent or moderate inhibitors of CYP3A4 are also specifically excluded during the study. Patients receiving herbal regimens. Use of drugs with narrow therapeutic windows that are also known substrates of CYP3A4. Failure for any reason to satisfy the investigator for adequate fitness to participated in the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| wild genotype<br>Through next generation sequencing, distinguish wild genotype of docetaxel | Genetic: detection of genotype<br>* detection of genotype by next generation sequencing<br>|
| mutant genotype<br>Through next generation sequencing, distinguish mutant genotype of docetaxel | Genetic: detection of genotype<br>* detection of genotype by next generation sequencing<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of severe hematological toxicity | The toxicity induced by docetaxel-based chemotherapy during observation time will be estimated on the basis of the National Cancer Institute Common Toxicity Criteria Version 4.03. Patients with grade 3-4 adverse events will be considered as having severe toxicity. At the end of each cycle (each cycle is 21 days) the grade will be scored. And the severest grade will be recorded and used for analysis. Hematological toxicity includes neutropenia, leukopenia, anemia and thrombocytopenia. | At 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of other severe toxicities | The other toxicities induced by docetaxel-based chemotherapy during observation time, including gastrointestinal toxicity, neurotoxicity etc., will be estimated on the basis of the National Cancer Institute Common Toxicity Criteria Version 4.03. Toxicities with grade 3-4 will be considered as severe toxicity, except for severe neurotoxicity (grade 2-3). At the end of each cycle (each cycle is 21 days) the grade will be scored. And the severest grade will be recorded and used for analysis. | At 1 year | 
| Genotyping | Collect blood specimen, then detect genotype by next generation sequencing. | Before chemotherapy | 
| The kinds of the metabolites | Determine the metabolic profiles of docetaxel. This outcome is not applicable to patients retrospectively collected. | Pre-dose and 6 hours post-dose in the first cycle | 
| Area under the curve [AUC] | Determine the AUC of docetaxel and its metabolites. This outcome is not applicable to patients retrospectively collected. | Pre-dose and 6 hours post-dose in the first cycle |