Explore the Individual Treatment of Docetaxel and Paclitaxel in NSCLC, NPC and BRC by PK-guided Dosing Strategy

Study Overview
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Brief Summary
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As cytotoxic agents, DTX and PTX have a narrow therapeutic window. BSA dosing leads to great inter-individual PK variability, which is a major contributor for severe toxicity, especially in East-Asian populations. DTX exposures measured by area under plasma concentration-time curve (AUC), PTX exposures measured by the time above a plasma concentration of 0.05 µmol/L (TC>0.05), are the most biologic effects associated PK parameters for DTX and PTX, respectively, which could positively predict related toxicities such as neutropenia, peripheral neuropathy, etc. So, we conducted a randomized clinical trial to compare the effect on related toxicities and efficacy of PK-guided dosing strategy and BSA dosing strategy.

Detailed Description
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3 populations were included: advanced NSCLC patients receive a single-agent docetaxel regimen palliative chemotherapy without restriction of lines; NPC patients receive paclitaxel and carboplatin doublet regimen whether as induction chemotherapy for local advanced patients or palliative chemotherapy for metastatic patients; BRC patients receive a single-agent docetaxel regimen after 4 cycles of adriamycin and cyclophosphamide for adjuvant chemotherapy. Patients are randomly assigned into the BSA-based dosing group and pharmacokinetically-guided dosing group. In the BSA-based dosing group, NPC patients receive paclitaxel (175mg/m2) and carboplatin (AUC=5) treatment, NSCLC and BRC patients receive docetaxel (75mg/m2) treatment, 3-weekly and for up to 6 cycles. BSA group and PK-guided group are with a same starting dose. DTX exposure (AUC) and PTX exposure (TC>0.05) are calculated from a published PK model with an established limited sampling strategy. Dose of subsequent cycles of PK-guided group patients is calculated base on the previous cycle PK results, according to optimal target algorithm. The optimal target for DTX exposure is 2.5 - 3.7 µg•h/mL. Dose reductions were permitted in both arms according to instructions. The study had a power of 80% to detect a 23% reduction of grade >3 neutropenia with PK-guided arm for DTX sub-study in NSCLC. A sample size of 100 NSCLC patients was estimated by using Fisher's exact test to provide a 5% two-sided alpha significance level to observe a decrease in the hematological toxicity with a power of 0.8. This is based on the reported toxicity rates of 85% with dose of 75mg/m2 and 63% with 60mg/m2. Objective response rate is evaluated by imaging examination (CT or MR scan) every 2 cycles. Toxicities are evaluated by patients' diary for toxicity reports and physician's evaluation at day 10 and day 21 at every cycle. Blood samples are collected every cycle. And survival information is collected by clinic and telephone follow-up. Research Hypothesis: 1. The concentrations variability dosed by BSA, and the limitation of BSA- and MTD-based dosing. 2. Verify that paclitaxel TC>0.05 and docetaxel AUC are the most relevant predictor of related toxicities and clinical outcomes. 3. Verify the feasibility of dosing algorithm based on paclitaxel TC>0.05 and docetaxel AUC, quantify its effect on both reducing toxicity and improving Effectiveness. 4. The effect of using dose modification and administration of G-CSF based on toxicity determined by paclitaxel TC>0.05 and docetaxel AUC measurement. 5. Prove the ability of PK-guided dosing strategy in reducing DTX and PTX related hematologic and non-hematologic toxicities, and the effect on treatment efficacy.

Official Title
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An Open-label Randomized Clinical Trial to Compare the Toxicities and Efficacy of Pharmacokinetically-guided and BSA Fixed Dosing Strategy of Docetaxel and Paclitaxel in Chinese Non-small Cell Lung Cancer, Nasopharyngeal Carcinoma, and Breast Cancer Patients.

Conditions
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Non-small Cell Lung Cancer, Breast Cancer, Nasal Cancer

Intervention / Treatment
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* Device: PK guided arm
* Drug: PTX 175mg/m2, DOC 75mg/m2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed by pathology for advanced non small cell lung cancer, suitable for paclitaxel or docetaxel chemotherapy (clinical stage IV according to 2009 IASLC staging or recurrent NSCLC; receiving palliative chemotherapy independent of lines) ECOG PS score: 0 to 2 points Survival is expected to more than 3 month Bone marrow reserve function is good, the function of organs (liver and kidney) is good, can satisfy the conditions of implementation chemotherapy. Sign the informed consent form Compliance is good, can be followed up, willing to comply with the requirements of the study Exclusion Criteria: Physical status score (ECOG) greater than 2 organic disease；Severely active infection；Organ transplantation immune therapy；Can't complete with in four to six cycles of chemotherapy Bone marrow, liver and kidney dysfunction, clinical doctors identify intolerance to chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: body surface area<br>patients receive fixed dose of PTX or DOC based on body surface area every cycle, PTX 175mg/m2, DOC 75mg/m2. Patients should finish up to 6 cycles chemotherapy | Drug: PTX 175mg/m2, DOC 75mg/m2<br>* patients receive PTX or DOC dose based on body surface area every cycle, PTX 175mg/m2, DOC 75mg/m2<br>|
| Active Comparator: Detection Kit<br>PTX 175mg/m2, DOC 75mg/m2 at first cycle. the dose of PTX or DOC will adjust based on the pharmacokinetic results of previous cycle. A optimal target of PTX(TC>0.05) and DOC(AUC) have been set from published PK model with an established limited sampling strategy | Device: PK guided arm<br>* the dose of PTX or DOC will adjust based on the plasma drug concentration of previous cycle<br>* Other names: pharmacokinetic guided dosing stratety;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicities rate | assess the toxicities rate and severity according to CTCAE v4.03, record the toxicities incident and grades from the first cycle to last cycle until the toxicities relieve or stabilize. | 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Object response rate | assess the ORR according to RECIST v1.1, An imaging examination should be performed in 4weeks before treatment initiation, and patients are going to receive (CT or MR scan) every 2 cycles during the treatment, the methods should be identical with baseline. | up to 18 weeks | 
| Survival Effectiveness | after treatment discontinuation, PFS is recorded by imaging examination every 2 cycles (8 weeks) until tumor progression, other anti-cancer treatment start, trial ends or death. OS is recorded by clinic follow-up or telephone follow-up until death. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-small Cell Lung Cancer, Breast cancer, plasma drug concentration, Nasopharygeal carcinoma