Clinical trial NCT02737709: Paclitaxel Detection in NSCLC Treated With TC Regimen
Official title: A Clinical Experience Trial to Detect the Plasma Paclitaxel Drug Concentration in Chinese Non -Small Cell Lung Cancer (NSCLC) Patients Treated With a Paclitaxel Plus Carboplatin (TC) Regimens, and Explore Individualized Treatment Using Pharmacokinetically-guided Dosing Strategy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
First posted: 2016-04-14
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: By detecting the blood concentration of paclitaxel (PTX), Investigator assume this research can identify the individual differences of PTX pharmacokinetics (PK) parameters (TC\>0.05 refers to the duration of paclitaxel plasma concentration above 0.05 µmol/L) in Chinese non-small cell lung cancer (NSCLC) patients, and find the correlation between PK results and PTX toxicities and Effectiveness, acquire the optimization method of PTX, and finally try to explore the individualized PTX pharmacokinetically-guided dosing strategy. Orally administer rosiglitazone, which is a substrate of CYP2C8 the same as paclitaxel, before chemotherapy injection. Detect the blood concentration of rosiglitazone, analyze the correlation of rosiglitazone pharmacokinetic parameter and paclitaxel exposure, and explore the effect of rosiglitazone as an in vivo probe of paclitaxel exposure.

1. The variability of paclitaxel concentrations in the patient population dosed by body surface area (BSA), and the limitation of BSA-based dosing of paclitaxel.
2. Verify that paclitaxel TC\>0.05 is the most relevant predictor of haematological toxicity and clinical outcomes.
3. Define a dosing algorithm based on paclitaxel TC\>0.05 of paclitaxel and 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 measurement.
5. Construct a trial outline with the aim of reducing grade 4 neutropenia toxicity and ensuring the clinical outcome by using individual dose adjustments based on the dosing algorithm.
6. Detect the blood concentration of rosiglitazone after orally administration, explore the effect of rosiglitazone as an in vivo probe of paclitaxel exposure based on CYP2C8 activity. Attempt to establish a model to predict the paclitaxel exposure of patients base on rosiglitazone blood concentration before chemotherapy.

Detailed description: Rosiglitazone probe:

Rosiglitazone: time point - at least 20 hours before the initiation of chemotherapy, orally administrate 2mg rosiglitazone.

Only before the first cycle chemotherapy.

Chemotherapy regimen:

Paclitaxel: 175mg/m2, d1; Intravenous drip injection with 500ml N.S Carboplatin: AUC=5, d1; Intravenous drip injection with 500ml G.S Paclitaxel injection at first, followed with Carboplatin injection. 21 days per cycle; 6 cycles in total.

Blood samples collection design:

1. Rosiglitazone blood sample:

   Only one blood sample before 1st cycle:

   - Sample collected 3 hours after orally administration of rosiglitazone, with EDTA blood tube, at least 4ml;
2. Paclitaxel blood samples:

Two blood samples per cycle:

* Sample collected before PTX, with EDTA blood tube, at least 2ml;
* Sample collected 24 hours after the initiation of PTX, with EDTA blood tube, at least 2ml;

Primary Objective:

Object response rate (ORR): assess the ORR of paclitaxel/carboplatin chemotherapy according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, and analyze the relationship of paclitaxel TC\>0.05 and ORR.

Secondary Objectives:

Pharmacokinetic parameters: detect the blood concentration of paclitaxel 24 hours after the initiation, and the blood concentration of rosiglitazone 3 hours after orally administration of rosiglitazone. Calculate paclitaxel TC\>0.05 and analyze the correlation of rosiglitazone concentration and paclitaxel TC\>0.05.

Toxicities rate: assess the toxicities rate and severity of paclitaxel/carboplatin chemotherapy according to Common Terminology Criteria For Adverse Events (CTCAE) v4.03, and analyze the relationship of paclitaxel TC\>0.05 and toxicities.

Survival Effectiveness: assess the progression free survival (PFS) and overall survival (OS) of paclitaxel/carboplatin chemotherapy, analyze the relationship of paclitaxel TC\>0.05 and survival Effectiveness.

A single arm, phase II, monocentric, clinical experience trial. The eligible patients sign a informed consent form, and receive a 4 - 6 cycles of paclitaxel/carboplatin chemotherapy. 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.

Response follow-up: 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.

Toxicities follow-up: record the toxicities incident and grades from the first cycle to last cycle until the toxicities relieve or stabilize.

Survival follow-up: 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.

Eligibility criteria: Inclusion Criteria:

* Age: 18 \~75 years
* Pathology: Confirmed by pathology (histology or cytology) for advanced non-small cell lung cancer
* Have indications of paclitaxel/carboplatin chemotherapy, suitable for paclitaxel chemotherapy (independent of clinical tumor stage or chemotherapy type or palliative chemotherapy lines)
* At least one measurable tumor lesions (according to RECIST 1.1 criteria)
* ECOG PS score: 0 to 2 points
* Life expectancy: more than 3 months
* Bone marrow reserve function is good, the function of organs (liver and kidney) is good, can satisfy the conditions of implementation chemotherapy. neutrophil count ≥1.5×109/l, platelet ≥75×109/l, hemoglobin \>9g/dl, Total Bilirubin ≤1.5×ULN\*, transaminase \<2.5×ULN\*, creatinine ≤1.5×ULN\*,or creatinine clearance rate ≥45ml/min. ULR: Upper Limit Of Normal.
* Sign the informed consent form; Compliance is good, can be followed up, willing to comply with the requirements of the study

Exclusion Criteria:

* ECOG Performance Scores \> 2 points
* Organic disease (heart, liver, kidney disease etc), Active infection Organ transplantation immunosuppressive therapy, not capable to complete 4 - 6 cycles of paclitaxel / carboplatin chemotherapy.
* Any other tumor history not cured in 3 years before this trial.
* Bone marrow function or organs function not eligible for chemotherapy.
* Diabetic patients currently receiving the standard anti- diabetes treatment.

Primary outcomes:
measure: Change of tumor sizes from baseline
timeFrame: baseline; 6 weeks; 12 weeks; 18 weeks; 24 weeks; 32 weeks; up to 3 years.
Secondary outcomes:
measure: Area under the plasma concentration versus time curve (AUC) of rosiglitazone
timeFrame: 3 hours after rosiglitazone administration
measure: The duration of paclitaxel plasma concentration above 0.05 µmol/L (TC>0.05)
timeFrame: 5min before paclitaxel administration; and 24 hours after.
measure: Toxicities rate
timeFrame: day10, day21, day 31, day 42, day 52, day 63, day 73, day 84, day 94, day 105, day115 and day 126.
measure: progression free survival (months)
timeFrame: From date of consent form until the date of first documented progression, up to 36 months.
measure: Overall survival (months)
timeFrame: From date of consent form until the date of death from any cause, up to 36 months.
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
Study officials:
affiliation: Sun Yat-sen University
name: Li Zhang, M.D.
role: PRINCIPAL_INVESTIGATOR
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