Paclitaxel Detection in NSCLC Treated With TC Regimen

NCT02737709 | Terminated Phase 2 DMC

• 1 other identifier: CA139-703
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

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. 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. 2.Verify that paclitaxel TC\>0.05 is the most relevant predictor of haematological toxicity and clinical outcomes.
3. 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. 4.The effect of using dose modification and administration of G-CSF based on toxicity determined by paclitaxel TC\>0.05 measurement.
5. 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. 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.

Conditions

Non-small Cell Lung Cancer

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Area under the plasma concentration versus time curve (AUC) of rosiglitazone

  3 hours after rosiglitazone administration

• The duration of paclitaxel plasma concentration above 0.05 µmol/L (TC>0.05)

  5min before paclitaxel administration; and 24 hours after.

• Toxicities rate

  day10, day21, day 31, day 42, day 52, day 63, day 73, day 84, day 94, day 105, day115 and day 126.

• progression free survival (months)

  From date of consent form until the date of first documented progression, up to 36 months.

• Overall survival (months)

  From date of consent form until the date of death from any cause, up to 36 months.

Study Arms (1)

Paclitaxel and Carboplatin regimen

EXPERIMENTAL

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.

Drug: Paclitaxel and Carboplatin regimen

Interventions

Paclitaxel and Carboplatin regimen DRUG

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.

Also known as: treatment group

Paclitaxel and Carboplatin regimen

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sun Yat-sen University: lead

Study Sites (1)

Sun Yat-sen University Cancer Center

Guangzhou, Guangdong, 510060, China

Location

Related Publications (27)

• 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. doi: 10.1200/JCO.1993.11.11.2127.

  PMID: 7901342 BACKGROUND

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

  PMID: 6116707 BACKGROUND

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

  PMID: 8103561 BACKGROUND

• 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. doi: 10.1200/JCO.1997.15.1.317.

  PMID: 8996159 BACKGROUND

• 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, Fety 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. doi: 10.1158/1078-0432.CCR-07-0064.

  PMID: 17975154 BACKGROUND

• 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. doi: 10.1158/1078-0432.CCR-04-1078.

  PMID: 15623609 BACKGROUND

• Gianni L, Kearns CM, Giani A, Capri G, Vigano 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. doi: 10.1200/JCO.1995.13.1.180.

  PMID: 7799018 BACKGROUND

• 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. doi: 10.1177/0091270005276204.

  PMID: 15901749 BACKGROUND

• 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. doi: 10.1111/j.1365-2125.2006.02718.x.

  PMID: 16842379 BACKGROUND

• 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. doi: 10.1007/s10120-006-0411-6. Epub 2007 Feb 23.

  PMID: 17334719 BACKGROUND

• 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. doi: 10.1007/s10147-007-0681-y. Epub 2007 Aug 20.

  PMID: 17701008 BACKGROUND

• 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.

  PMID: 9816021 BACKGROUND

• Spratlin J, Sawyer MB. Pharmacogenetics of paclitaxel metabolism. Crit Rev Oncol Hematol. 2007 Mar;61(3):222-9. doi: 10.1016/j.critrevonc.2006.09.006. Epub 2006 Nov 7.

  PMID: 17092739 BACKGROUND

• 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. doi: 10.1158/1078-0432.CCR-05-0298.

  PMID: 16000582 BACKGROUND

• 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. doi: 10.1007/s11060-007-9438-8. Epub 2007 Jul 5.

  PMID: 17611715 BACKGROUND

• 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. doi: 10.1097/00008571-200110000-00006.

  PMID: 11668219 BACKGROUND

• 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.

  PMID: 16334120 BACKGROUND

• 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. doi: 10.1158/1078-0432.CCR-05-2069.

  PMID: 16609028 BACKGROUND

• 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.

  PMID: 22680343 BACKGROUND

• Frye RF. Probing the world of cytochrome P450 enzymes. Mol Interv. 2004 Jun;4(3):157-62. doi: 10.1124/mi.4.3.5.

  PMID: 15210869 BACKGROUND

• 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. doi: 10.1007/BF00689047.

  PMID: 7628049 BACKGROUND

• 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. doi: 10.1007/s002280050592.

  PMID: 10206085 BACKGROUND

• 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. doi: 10.1046/j.1365-2125.1999.00030.x.

  PMID: 10510156 BACKGROUND

• 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.

  PMID: 22242967 BACKGROUND

• 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.

  PMID: 12751267 BACKGROUND

• 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. doi: 10.1124/dmd.31.4.439.

  PMID: 12642470 BACKGROUND

• 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: 10.1007/BF03261934.

  PMID: 22804749 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Paclitaxel

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Li Zhang, M.D.

  Sun Yat-sen University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 22, 2016
• First Posted: April 14, 2016
• Study Start: March 1, 2016
• Primary Completion: October 25, 2018
• Study Completion: October 25, 2018
• Last Updated: October 29, 2018

Record last verified: 2018-10

Locations

CN (1)