(2.7)--Napoli-1研究全人群消化系统肿瘤.pdf

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1、A Published online November 22,2015 http:/dx.doi.org/10.1016/S0140-6736(15)00986-1 1Nanoliposomal irinotecan with fl uorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy(NAPOLI-1):a global,randomised,open-label,phase 3 trialAndrea Wang-Gillam*,Chung-Pi

2、n Li,Gyrgy Bodoky,Andrew Dean,Yan-Shen Shan,Gayle Jameson,Teresa Macarulla,Kyung-Hun Lee,David Cunningham,Jean F Blanc,Richard A Hubner,Chang-Fang Chiu,Gilberto Schwartsmann,Jens T Siveke,Fadi Braiteh,Victor Moyo,Bruce Belanger,Navreet Dhindsa,Eliel Bayever,Daniel D Von Hoff*,Li-Tzong Chen*,for the

3、NAPOLI-1 Study GroupSummaryBackground Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies.We assessed the eff ect of nanoliposomal irinotecan alone or combined with fl uorouracil

4、and folinic acid in a phase 3 trial in this population.Methods We did a global,phase 3,randomised,open-label trial at 76 sites in 14 countries.Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned(1:1)using an inte

5、ractive web response system at a central location to receive either nanoliposomal irinotecan monotherapy(120 mg/m every 3 weeks,equivalent to 100 mg/m of irinotecan base)or fl uorouracil and folinic acid.A third arm consisting of nanoliposomal irinotecan(80 mg/m,equivalent to 70 mg/m of irinotecan b

6、ase)with fl uorouracil and folinic acid every 2 weeks was added later(1:1:1),in a protocol amendment.Randomisation was stratifi ed by baseline albumin,Karnofsky performance status,and ethnic origin.Treatment was continued until disease progression or intolerable toxic eff ects.The primary endpoint w

7、as overall survival,assessed in the intention-to-treat population.The primary analysis was planned after 305 events.Safety was assessed in all patients who had received study drug.This trial is registered at ClinicalTrials.gov,number NCT01494506.Findings Between Jan 11,2012,and Sept 11,2013,417 pati

8、ents were randomly assigned either nanoliposomal irinotecan plus fl uorouracil and folinic acid(n=117),nanoliposomal irinotecan monotherapy(n=151),or fl uorouracil and folinic acid(n=149).After 313 events,median overall survival in patients assigned nanoliposomal irinotecan plus fl uorouracil and fo

9、linic acid was 61 months(95%CI 4889)vs 42 months(3353)with fl uorouracil and folinic acid(hazard ratio 067,95%CI 049092;p=0012).Median overall survival did not diff er between patients assigned nanoliposomal irinotecan monotherapy and those allocated fl uorouracil and folinic acid(49 months 4256 vs

10、42 months 3649;099,077128;p=094).The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fl uorouracil and folinic acid were neutropenia(32 27%),diarrhoea(15 13%),vomiting(13 11%),and fatigue(16 14%).Interpretation Nanoliposomal irinot

11、ecan in combination with fl uorouracil and folinic acid extends survival with a manageable safety profi le in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy.This agent represents a new treatment option for this population.Funding Merrimack

12、 Pharmaceuticals.IntroductionPancreatic ductal adenocarcinoma is typically diagnosed late,when curative resection is impossible and prognosis is poor,with only 12%of patients surviving at 5 years.1,2 Gemcitabine-based therapies have been the standard of care for patients with locally advanced or met

13、astatic pancreatic ductal adenocarcinoma for the past two decades.35 However,two combination regimensFOLFIRINOX(a combination of oxaliplatin,folinic acid,irinotecan,and fl uorouracil)and albumin-bound paclitaxel in combination with gemcitabinehave gained acceptance as front-line treatments.6,7 Despi

14、te these advances,progression after front-line therapy is inevitable,leaving patients and clinicians with few options and no universally accepted standard treatmentshowing the unmet need in this population.8Irinotecan has been investigated in several small monotherapy9 and combination therapy1020 st

15、udies.The fi ndings have provided initial evidence of the activity of irinotecan in the second-line setting.1 mg of irinotecan hydrochloride trihydrate salt is equivalent to 086 mg of irinotecan free base.Nanoliposomal irinotecan comprises irinotecan free base encapsulated in liposome nanoparticles.

16、The liposome is designed to keep irinotecan in the circulationsheltered from conversion Published OnlineNovember 22,2015http:/dx.doi.org/10.1016/S0140-6736(15)00986-1*Contributed equallyAdditional investigators listed in the appendix(pp 4,5)Washington University School of Medicine,St Louis,MO,USA(A

17、Wang-Gillam MD);Division of Gastroenterology and Hepatology,Taipei Veterans General Hospital and National Yang-Ming University School of Medicine,Taipei,Taiwan(Prof C-P Li MD);St Lszl Teaching Hospital,Budapest,Hungary(Prof G Bodoky MD);St John of God Hospital,Subiaco,WA,Australia(A Dean MD);Nationa

18、l Institute of Cancer Research,National Health Research Institutes,Tainan,and Kaohsiung Medical University Hospital,Kaohsiung Medical University,Kaohsiung,Taiwan(Prof L-T Chen MD);National Cheng Kung University Hospital,National Cheng Kung University,Tainan,Taiwan(Prof L-T Chen,Prof Y-S Shan MD);TGe

19、n,Phoenix,and HonorHealth,Scottsdale,AZ,USA(G Jameson MSN,Prof D D Von Hoff MD);Vall dHebron University Hospital(HUVH)and Vall dHebron Institute of Oncology(VHIO),Barcelona,Spain(T Macarulla MD);Seoul National University Hospital,Seoul,South Korea(K-H Lee MD);The Royal Marsden Hospital,London,UK(Pro

20、f D Cunningham MD);Hpital Saint-Andr,Bordeaux,France(Prof J F Blanc MD);The Christie NHS Foundation Trust,Manchester,UK(R A Hubner PhD);China Medical University Hospital,Taichung,Taiwan(Prof C-F Chiu MD);Hospital de Clnicas de Porto Alegre,Porto Alegre,BrazilArticles2 Published online November 22,20

21、15 http:/dx.doi.org/10.1016/S0140-6736(15)00986-1(G Schwartsmann MD);Klinikum rechts der Isar der T U Mnchen,Munich,Germany;(Prof J T Siveke MD);Comprehensive Cancer Centers of Nevada,Las Vegas,NV,USA(F Braiteh MD);and Merrimack Pharmaceuticals,Cambridge,MA,USA(V Moyo MBBCh,B Belanger PhD,N Dhindsa

22、DDS,E Bayever MBBCh)Correspondence to:Prof Li-Tzong Chen,National Institute of Cancer Research,National Health Research Institutes,Tainan 704,Taiwanleochennhri.org.twto its active metabolite(SN-38)longer than free(unencapsulated)irinotecan,which would increase and prolong intratumoral levels of both

23、 irinotecan and SN-38 compared with free irinotecan.2123 The roughly 56-fold higher level of SN-38 found in tumours compared with plasma at 72 h suggests local metabolic activation of irinotecan,which was contained in the liposomal nanoparticles,to SN-38.21 In a phase 2 study of 40 patients with met

24、astatic pancreatic ductal adeno carcinoma previously treated with gemcitabine-based therapy,nanoliposomal irinotecan at 120 mg/m every 3 weeks resulted in a median overall survival of 52 months,1-year survival of 25%,and a manageable toxicity profi le.24 The aim of this study(NAPOLI-1)was to assess

25、the eff ect of nanoliposomal irinotecan,alone and in combination with fl uorouracil and folinic acid,compared with a common control(fl uorouracil and folinic acid),for patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy.MethodsStudy design and

26、participantsWe designed a global,multicentre,open-label,phase 3 study conducted at 76 sites in 14 countries(Argentina,Australia,Brazil,Canada,Czech Republic,France,Germany,Hungary,Italy,South Korea,Spain,Taiwan,the UK,and USA).We included patients aged 18 years or older with histologically or cytolo

27、gically confi rmed pancreatic ductal adenocarcinoma and documented measurable or non-measurable distant metastatic disease.The disease must have progressed after previous gemcitabine-based therapy given in a neoadjuvant,adjuvant(only if distant metastases occurred within 6 months of completing adjuv

28、ant therapy),locally advanced,or metastatic setting.Other key inclusion criteria were a Karnofsky performance status score of 70 or more and adequate haematological(including absolute neutrophil count 15 10 cells per L),hepatic(including normal serum total bilirubin,according to local institutional

29、standards,and albumin levels 30 g/L),and renal function.We also enrolled patients who had previously received irinotecan or fl uorouracil,or both.All versions of the protocol and informed consent form were approved by the institutional review board or ethics committees for every site.The study was d

30、one according to the principles of the Declaration of Helsinki,the International Conference on Harmonisation Guidance on Good Clinical Practice,and the requirements of the US Food and Drug Administration and local regulatory authorities regarding the conduct of human clinical trials.All patients pro

31、vided written informed consent.Randomisation and maskingWe initially randomly assigned patients in a 1:1 ratio to receive either nanoliposomal irinotecan monotherapy or a control of fl uorouracil and folinic acid(protocol version 1).Following clinical interest in the combination of nanoliposomal iri

32、notecan with other agents,we amended the protocol to add a third arm(1:1:1 ratio)of nanoliposomal irinotecan plus fl uorouracil and folinic acid(protocol version 2)after safety data on this combination became available from an ongoing study in metastatic colorectal cancer.25 Sites continued to enrol

33、 patients under protocol version 1 until protocol version 2 was approved at that site.We randomised patients according to a prespecifi ed scheme generated by an independent statistician within the funder-designated contract research organisation.On confi rmation of a patients eligibility,investigato

34、rs used a computerised interactive web response system to obtain a patient number,which was associated with a random assignment.We stratifi ed the randomisation by baseline albumin levels(40 g/L vs 40 g/L),Karnofsky performance status(70 and 80 vs 90),and ethnic origin(white vs east Asian vs all oth

35、ers).Research in contextEvidence before this studyThere is no consensus on the standard of care in patients with metastatic pancreatic cancer whose disease progressed after gemcitabine-based therapy despite the availability of more eff ective front-line treatments.At the time this study was designed

36、,guidelines recommended clinical trials in this setting.Nanoliposomal irinotecan has shown activity in phase 2 studies in solid tumours,including metastatic pancreatic cancer,previously treated with gemcitabine-based therapy.Added value of this studyIn patients with metastatic pancreatic cancer prev

37、iously treated with gemcitabine-based therapy,nanoliposomal irinotecan in combination with fl uorouracil and folinic acid increased overall survival,progression-free survival,and time to treatment failure,reduced carbohydrate antigen 19-9(a pancreatic tumour biomarker),and amplifi ed the number of p

38、atients achieving an objective response.In a population with few treatment options,this drug combination was tolerable and did not have a negative eff ect on quality of life,which are important factors for this population.Implications of all the available evidenceNanoliposomal irinotecan in combinat

39、ion with fl uorouracil and folinic acid represents a potential treatment option for patients with metastatic pancreatic cancer that progressed after a gemcitabine-based regimen.Future research will assess its use in front-line therapy.A Published online November 22,2015 http:/dx.doi.org/10.1016/S014

40、0-6736(15)00986-1 3ProceduresAll patients underwent UGT1A1 genotype testing.Patients assigned nanoliposomal irinotecan plus fl uorouracil and folinic acid(combination therapy arm)received an intravenous infusion of nano liposomal irinotecan over 90 min at a dose of 80 mg/m(equivalent to 70 mg/m of i

41、rinotecan free base),followed by folinic acid 400 mg/m over 30 min,then fl uorouracil 2400 mg/m over 46 h,every 2 weeks.For those allocated to the mono therapy arm,nanoliposomal irinotecan was administered at a dose of 120 mg/m(equivalent to 100 mg/m of irinotecan free base),every 3 weeks.24,26 We r

42、educed the initial nanoliposomal irinotecan dose for patients homozygous for the UGT1A1*28 allele by 20 mg/m then increased it to the standard dose after the fi rst cycle in the absence of drug-related toxic eff ects.27 Patients who were assigned fl uorouracil and folinic acid(control arm)received 2

43、00 mg/m of folinic acid as a 30-min infusion followed by an infusion of 2000 mg/m fl uorouracil over 24 h,every week for the fi rst 4 weeks of each 6-week cycle.We based the fl uorouracil and folinic acid schedule of the control arm on that used in the CONKO-003 trial28 and of the combination therap

44、y arm on that used in the PEPCOL study,25 with expected dose intensities of fl uorouracil over a 6-week period of 8000 mg/m in the control arm and 7200 mg/m in the combination therapy arm.Treatment continued until disease progression or intolerable toxic eff ects arose.We did serial imaging studies

45、and measured amounts of carbohydrate antigen 19-9(CA19-9)at baseline and every 6 weeks until either disease progression,a new antineoplastic treatment was started,or withdrawal of consent.We did radiographic tumour response assessment according to Response Evaluation Criteria in Solid Tumors(RECIST)

46、,version 1.1,and we assessed safety by grading adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0.We measured quality of life at baseline and every 6 weeks with the European Organization for Research and Treatment of Cancer Quality-of

47、-Life Core Questionnaire(EORTC-QLQ-C30).We assessed clinical benefi t response as described elsewhere.3 We followed up patients every month after treatment termination for survival until death or study completion.An independent data safety monitoring board assessed cumulative safety and other trial-

48、related data at regular intervals.OutcomesThe primary effi cacy endpoint was overall survival.Secondary endpoints included progression-free survival;time to treatment failure;the proportion of patients achieving an objective response;serum CA19-9 response(ie,50%decrease in amount of CA19-9 from base

49、line at least once during the treatment period);clinical benefi t response(ie,either achievement of pronounced and sustained 4 weeks contiguous improvement in pain intensity,analgesic consumption,or performance status,or a combination of these,without any worsening in any of the other factors,or sta

50、bility in pain intensity,analgesic consumption,and performance status with pronounced and sustained 4 weeks contiguous weight gain);quality of life;and safety.A secondary objective,the pharmaco-kinetics of nanoliposomal irinotecan as a single agent and in combination with fl uorouracil and folinic a