Paclitaxel Detection in NSCLC Treated With TC Regimen

Non-small Cell Lung Cancer Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02737709
• Other study ID #: CA139-703
• Status: Terminated
• Phase: Phase 2
• Start date: March 2016
• Est. completion date: October 25, 2018

Study information

• Verified date: October 2018
• Source: Sun Yat-sen University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 51
• Est. completion date: October 25, 2018
• Est. primary completion date: October 25, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer

Intervention

Drug:
• Paclitaxel and Carboplatin regimen
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.

Locations

Country	Name	City	State
China	Sun Yat-sen University Cancer Center	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-sen University

Country where clinical trial is conducted

China, 

References & Publications (27)

Augusto C, Pietro M, Cinzia M, Sergio C, Sara C, Luca G, Scaioli V. Peripheral neuropathy due to paclitaxel: study of the temporal relationships between the therapeutic schedule and the clinical quantitative score (QST) and comparison with neurophysiological findings. J Neurooncol. 2008 Jan;86(1):89-99. Epub 2007 Jul 5. — View Citation

Baldwin SJ, Clarke SE, Chenery RJ. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol. 1999 Sep;48(3):424-32. — View Citation

Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, Kumar G, McLeod J, Obach SR, Roberts S, Roe A, Shah A, Snikeris F, Sullivan JT, Tweedie D, Vega JM, Walsh J, Wrighton SA; Pharmaceutical Research and Manufacturers of America Drug Metabolism/Clinical Pharmacology Technical Working Groups. The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J Clin Pharmacol. 2003 May;43(5):443-69. Review. — View Citation

Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, Goldstein JA. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics. 2001 Oct;11(7):597-607. — View Citation

Freed MI, Allen A, Jorkasky DK, DiCicco RA. Systemic exposure to rosiglitazone is unaltered by food. Eur J Clin Pharmacol. 1999 Mar;55(1):53-6. — View Citation

Frye RF. Probing the world of cytochrome P450 enzymes. Mol Interv. 2004 Jun;4(3):157-62. Review. — View Citation

Gianni L, Kearns CM, Giani A, Capri G, Viganó L, Lacatelli A, Bonadonna G, Egorin MJ. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol. 1995 Jan;13(1):180-90. — View Citation

Hertz DL, Walko CM, Bridges AS, Hull JH, Herendeen J, Rollins K, Watkins PB, Dees EC. Pilot study of rosiglitazone as an in vivo probe of paclitaxel exposure. Br J Clin Pharmacol. 2012 Jul;74(1):197-200. doi: 10.1111/j.1365-2125.2012.04165.x. — View Citation

Huizing MT, Giaccone G, van Warmerdam LJ, Rosing H, Bakker PJ, Vermorken JB, Postmus PE, van Zandwijk N, Koolen MG, ten Bokkel Huinink WW, van der Vijgh WJ, Bierhorst FJ, Lai A, Dalesio O, Pinedo HM, Veenhof CH, Beijnen JH. Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre. J Clin Oncol. 1997 Jan;15(1):317-29. — View Citation

Huizing MT, Keung AC, Rosing H, van der Kuij V, ten Bokkel Huinink WW, Mandjes IM, Dubbelman AC, Pinedo HM, Beijnen JH. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol. 1993 Nov;11(11):2127-35. — View Citation

Jiko M, Yano I, Sato E, Takahashi K, Motohashi H, Masuda S, Okuda M, Ito N, Nakamura E, Segawa T, Kamoto T, Ogawa O, Inui K. Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers. Int J Clin Oncol. 2007 Aug;12(4):284-90. Epub 2007 Aug 20. — View Citation

Joerger M, Huitema AD, Richel DJ, Dittrich C, Pavlidis N, Briasoulis E, Vermorken JB, Strocchi E, Martoni A, Sorio R, Sleeboom HP, Izquierdo MA, Jodrell DI, Calvert H, Boddy AV, Hollema H, Féty R, Van der Vijgh WJ, Hempel G, Chatelut E, Karlsson M, Wilkins J, Tranchand B, Schrijvers AH, Twelves C, Beijnen JH, Schellens JH. Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group. Clin Cancer Res. 2007 Nov 1;13(21):6410-8. — View Citation

Joerger M, Huitema AD, van den Bongard DH, Schellens JH, Beijnen JH. Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of Paclitaxel in patients with solid tumors. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2150-7. — View Citation

Joerger M, Kraff S, Huitema AD, Feiss G, Moritz B, Schellens JH, Beijnen JH, Jaehde U. Evaluation of a pharmacology-driven dosing algorithm of 3-weekly paclitaxel using therapeutic drug monitoring: a pharmacokinetic-pharmacodynamic simulation study. Clin Pharmacokinet. 2012 Sep 1;51(9):607-17. doi: 10.2165/11634210-000000000-00000. — View Citation

Kobayashi M, Oba K, Sakamoto J, Kondo K, Nagata N, Okabayashi T, Namikawa T, Hanazaki K. Pharmacokinetic study of weekly administration dose of paclitaxel in patients with advanced or recurrent gastric cancer in Japan. Gastric Cancer. 2007;10(1):52-7. Epub 2007 Feb 23. — View Citation

Kumar N. Taxol-induced polymerization of purified tubulin. Mechanism of action. J Biol Chem. 1981 Oct 25;256(20):10435-41. — View Citation

Mielke S, Sparreboom A, Behringer D, Mross K. Paclitaxel pharmacokinetics and response to chemotherapy in patients with advanced cancer treated with a weekly regimen. Anticancer Res. 2005 Nov-Dec;25(6C):4423-7. — View Citation

Mielke S, Sparreboom A, Steinberg SM, Gelderblom H, Unger C, Behringer D, Mross K. Association of Paclitaxel pharmacokinetics with the development of peripheral neuropathy in patients with advanced cancer. Clin Cancer Res. 2005 Jul 1;11(13):4843-50. — View Citation

Miller AA, Rosner GL, Egorin MJ, Hollis D, Lichtman SM, Ratain MJ. Prospective evaluation of body surface area as a determinant of paclitaxel pharmacokinetics and pharmacodynamics in women with solid tumors: Cancer and Leukemia Group B Study 9763. Clin Cancer Res. 2004 Dec 15;10(24):8325-31. — View Citation

Mould DR, Fleming GF, Darcy KM, Spriggs D. Population analysis of a 24-h paclitaxel infusion in advanced endometrial cancer: a gynaecological oncology group study. Br J Clin Pharmacol. 2006 Jul;62(1):56-70. — View Citation

Naik H, Wu JT, Palmer R, McLean L. The effects of febuxostat on the pharmacokinetic parameters of rosiglitazone, a CYP2C8 substrate. Br J Clin Pharmacol. 2012 Aug;74(2):327-35. doi: 10.1111/j.1365-2125.2012.04182.x. — View Citation

Nakajima M, Fujiki Y, Kyo S, Kanaya T, Nakamura M, Maida Y, Tanaka M, Inoue M, Yokoi T. Pharmacokinetics of paclitaxel in ovarian cancer patients and genetic polymorphisms of CYP2C8, CYP3A4, and MDR1. J Clin Pharmacol. 2005 Jun;45(6):674-82. — View Citation

Ohtsu T, Sasaki Y, Tamura T, Miyata Y, Nakanomyo H, Nishiwaki Y, Saijo N. Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion. Clin Cancer Res. 1995 Jun;1(6):599-606. — View Citation

Sahi J, Black CB, Hamilton GA, Zheng X, Jolley S, Rose KA, Gilbert D, LeCluyse EL, Sinz MW. Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metab Dispos. 2003 Apr;31(4):439-46. — View Citation

Sarosy G, Reed E. Taxol dose intensification and its clinical implications. J Natl Med Assoc. 1993 Jun;85(6):427-31. Review. — View Citation

Sparreboom A, Huizing MT, Boesen JJ, Nooijen WJ, van Tellingen O, Beijnen JH. Isolation, purification, and biological activity of mono- and dihydroxylated paclitaxel metabolites from human feces. Cancer Chemother Pharmacol. 1995;36(4):299-304. — View Citation

Spratlin J, Sawyer MB. Pharmacogenetics of paclitaxel metabolism. Crit Rev Oncol Hematol. 2007 Mar;61(3):222-9. Epub 2006 Nov 7. Review. — View Citation

* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change of tumor sizes from baseline	Object response rate (ORR): assess the ORR of paclitaxel/carboplatin chemotherapy according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1	baseline; 6 weeks; 12 weeks; 18 weeks; 24 weeks; 32 weeks; up to 3 years.
Secondary	Area under the plasma concentration versus time curve (AUC) of rosiglitazone	Detect the plasma concentration of rosiglitazone 3 hours after orally administration of rosiglitazone.	3 hours after rosiglitazone administration
Secondary	The duration of paclitaxel plasma concentration above 0.05 µmol/L (TC>0.05)	Detect the blood concentration of paclitaxel 24 hours after the initiation, Calculate paclitaxel TC>0.05	5min before paclitaxel administration; and 24 hours after.
Secondary	Toxicities rate	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.	day10, day21, day 31, day 42, day 52, day 63, day 73, day 84, day 94, day 105, day115 and day 126.
Secondary	progression free survival (months)	Survival Effectiveness: assess the progression free survival (PFS) of paclitaxel/carboplatin chemotherapy	From date of consent form until the date of first documented progression, up to 36 months.
Secondary	Overall survival (months)	Survival Effectiveness: assess the overall survival (OS) of paclitaxel/carboplatin chemotherapy	From date of consent form until the date of death from any cause, up to 36 months.