ORIGINAL ARTICLE
Phase I/II study of albumin-bound nab -paclitaxel plus gemcitabine administered to Chinese patients with advanced pancreatic cancer
Dong-sheng Zhang ?De-shen Wang ?Zhi-qiang Wang ?
Feng-hua Wang ?Hui-yan Luo ?Miao-zhen Qiu ?Feng Wang ?Yu-hong Li ?Rui-hua Xu
车刀刃磨Received:7January 2013/Accepted:22January 2013/Published online:13March 2013óSpringer-Verlag Berlin Heidelberg 2013
梁丽芳
Abstract
Purpose The primary objective of this study was to evaluate the dose-limiting toxicities (DLTs)and identify the maximum-tolerated dose (MTD)and recommended dose of nab -paclitaxel plus gemcitabine as a ?rst-line treatment in Chinese patients with advanced panc
reatic ductal adenocarcinoma (PDA).
Methods Patients with previously untreated advanced PDA were treated with nab -paclitaxel followed by gem-citabine (1,000mg/m 2)administered intravenously for 30min on days 1and 8and repeated every 21days.
Results Patients received nab -paclitaxel at the following dose levels:80mg/m 2(n =3),100mg/m 2(n =6),and 120mg/m 2(n =12).The DLTs evaluated were elevated alanine aminotransferase and febrile neutropenia.How-ever,there had no two out of three to six patients experi-enced DLTs,the MTD was not met.A total of 93cycles were administered.The most common grade 3/4toxicities were neutropenia (9.52%),thrombocytopenia (4.76%),and sensory neuropathy (4.76%).For 12patients receiving 120mg/m 2,the overall response rate and disease control
rate were 41.67and 83.33%,respectively,and the median progression-free survival and overall survival were 5.23and 12.17months,respectively.
Conclusions Treatment with albumin-bound nab -paclitaxel (120mg/m 2)plus gemcitabine has a favorable safety pro?le with an encouraging antitumor effect in Chinese patients.Keywords Chemotherapy áGemcitabine ánab -paclitaxel áPancreatic ductal adenocarcinoma áPhase I/II study
Introduction
Pancreatic ductal adenocarcinoma (PDA)is the ?fth most common cancer and the fourth leading cause for cancer-related mortality in Western societies [1],causing approximately 227,000deaths per year [2].More than 80%of patients have local advanced or metastatic disease at the time of initial diagnosis.The patient prognosis remains poor,with a median survival of 5.65months and an 18%1-year survival rate with gemcitabine treatment,the only approved single agent [3].A recent randomized phase III trial compared gemcitabine in metastatic PDA to a combination chemotherapy regimen consisting of oxa-liplatin,irinotecan,?uorouracil,and leucovorin (FOLFIR-INOX).FOLFIRINOX was associated with a survival advantage and was recommended as an option for the treatme
战斗机代数划分nt of patients with metastatic pancreatic cancer and good performance [4].Nonetheless,this survival bene?t is insuf?cient to change the current clinical practice for metastatic PDA.A better understanding of its molecular biological behavior will help to identify new targets for individual treatment [5–7].
Secreted protein acidic and rich in cysteine (SPARC)is an albumin-binding protein that has been found to be
D.Zhang,D.Wang,and Z.Wang contributed equally to this work.D.Zhang áD.Wang áZ.Wang áF.Wang áH.Luo áM.Qiu áF.Wang áY.Li (&)áR.Xu (&)
State Key Laboratory of Oncology in South China,Department of Medical Oncology,Sun Yat-sen University Cancer Center,651Dong Feng Road East,Guangzhou 510060,China e-mail:liyh@www.doczj/doc/7aa910484a7302768e9939a6.html R.Xu
e-mail:xurh@www.doczj/doc/7aa910484a7302768e9939a6.html
Cancer Chemother Pharmacol (2013)71:1065–1072DOI 10.1007/s00280-013-2102-4
大庆油田宽带
overexpressed in the PDA stroma,and it is considered as a potential treatment target[8,9].nab-paclitaxel,a130-nm albumin-bound formulation of paclitaxel particles,has shown antitumor properties in several types of cancer that overexpress SPARC[10–13].Frese et al.[14]found that nab-paclitaxel can reduce the levels of cytidine deaminase protein in cultured PDA cells through reactive oxygen species-mediated degradation,resulting in a marked increase in the intratumoral concentration of gemcitabine. This synergistic effect was con?rmed in another study in mice,which found that the intratumoral concentration of gemcitabine was increased by2.8-fold by nab-paclitaxel plus gemcitabine versus gemcitabine alone[8].This phase I/II trial also demonstrated that nab-paclitaxel plus gem-citabine has substantial antitumor activity with tolerable adverse effects.The maximum-tolerated dose(MTD)was 125mg/m2of nab-paclitaxel plus1,000mg/m2of gem-citabine administered weekly for3weeks and repeated every4weeks.The reported48%response rate, 12.2months median overall survival(OS),and48% 1-year survival rate at the MTD of?rst-line treatment are among the highest reported in patients with PDA,although a phase III study is needed to con?rm the
资本资产定价模型se results[8]. Because its clinical utility was reported in a western country,nab-paclitaxel appears to be an effective therapy for PDA.Moreover,there were some potential pharmaco-genetic differences between western and Chinese patient populations.For example,the degree of obesity was dif-ferent between western and Chinese patients.Some studies suggested that the tumor type,degree of obesity,compli-cations,and choice of chemotherapy regimen should be considered when determining chemotherapy dosage for obese patients[15,16].Furthermore,the tolerability and effects of nab-paclitaxel plus gemcitabine in Chinese patients with PDA are still unknown.
Therefore,the primary objectives of our present study were to evaluate the dose-limiting toxicities(DLTs)and identify the MTD and recommended dose(RD)of gem-citabine plus nab-paclitaxel as a?rst-line treatment in Chinese patients with metastatic PDA.
Patients and methods
Ethics statement
This study was approved by the independent Institute Research Ethics Committee at the Cancer Center of Sun Yat-sen University.Written informed consent was obtained from all patients before enrollment in the study. The study was conducted in accordance with the Decla-ration of Helsinki and the Chinese Good Clinical Practice guidelines.Patient eligibility
The eligibility criteria included an age of18–74years and histologically or cytologically con?rmed metastatic PDA with measurable lesions.Patients had an Eastern Cooper-ative Oncology Group(ECOG)performance status(PS)of 0or1and an expected life expectancy of more than 60days.The eligibility criteria also included adequate hematologic function(whole white blood cell count B12,000/mm3,absolute neutrophil count C2,000/mm3, hemoglobin C9.0g/dl,and platelets C100,000/mm3), hepatic function(aspartate aminotransferase(AST)and alanine aminotransferase(ALT)B100IU/l,serum total bilirubin(TB)B1.5mg/dl,serum albumin C3.0g/dl),and renal function(serum creatinine(Cr)B1.5mg/dl).If patients had received prior adjuvant treatment,the disease-free interval between the previous treatment and the time
of tumor recurrence must have been at least6months. Prior adjuvant chemotherapy with?uorouracil or gemcit-abine or radiation therapy was allowed.Patients must have had no previous antitumor treatment for the metastatic disease.The key exclusion criteria included surgery within 4weeks before enrollment,pre-existing sensory neuropa-thy C grade2,serious pre-existing medical conditions,such as severe heart disease,pulmonary?brosis,uncontrolled infections and psychogenic disorders,human immunode-?ciency virus infection,and active hepatitis B or C virus infection.
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