Extract from the Clinical Evaluation Report for imatinib ：從對伊馬替尼的臨床評估報告提取物

1、CER date: July 2012AusPAR Attachment 2Extract from the Clinical Evaluation Report for imatinib (as mesylate)Proprietary Product Name: GlivecSponsor: Novartis Pharmaceuticals Australia Pty LtdAbout the Therapeutic Goods Administration (TGA)The Therapeutic Goods Administration (TGA) is part of the Aus

2、tralian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices.The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards o

3、f quality, safety and efficacy (performance), when necessary.The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices.The TGA relies on the publi

4、c, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action.To report a problem with a medicine or medical device, please see the information on the TGA website .About the Extract

5、from the Clinical Evaluation ReportThis document provides a more detailed evaluation of the clinical findings, extracted from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not include sections from the CER regarding product documentation or post market activities.The wo

6、rds Information redacted, where they appear in this document, indicate that confidential information has been deleted.For the most recent Product Information (PI), please refer to the TGA website .Copyright Commonwealth of Australia 2013This work is copyright. You may reproduce the whole or part of

7、this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of

8、that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific writte

9、n permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to .Contents TOC o 1-3 h z u HYPERLINK l _Toc358205546 List of abbreviations PAG

10、EREF _Toc358205546 h 5 HYPERLINK l _Toc358205547 1.Clinical rationale PAGEREF _Toc358205547 h 9 HYPERLINK l _Toc358205548 2.Contents of the clinical dossier PAGEREF _Toc358205548 h 10 HYPERLINK l _Toc358205549 2.1.Scope of the clinical dossier PAGEREF _Toc358205549 h 10 HYPERLINK l _Toc358205550 2.2

11、.Paediatric data PAGEREF _Toc358205550 h 10 HYPERLINK l _Toc358205551 2.3.Good clinical practice PAGEREF _Toc358205551 h 10 HYPERLINK l _Toc358205552 3.Pharmacokinetics PAGEREF _Toc358205552 h 11 HYPERLINK l _Toc358205553 3.1.Studies providing pharmacokinetic data PAGEREF _Toc358205553 h 11 HYPERLIN

12、K l _Toc358205554 3.2.Summary of pharmacokinetics PAGEREF _Toc358205554 h 11 HYPERLINK l _Toc358205555 3.3.Evaluators overall conclusions on pharmacokinetics PAGEREF _Toc358205555 h 13 HYPERLINK l _Toc358205556 4.Pharmacodynamics PAGEREF _Toc358205556 h 14 HYPERLINK l _Toc358205557 5.Dosage selectio

13、n for the pivotal studies PAGEREF _Toc358205557 h 14 HYPERLINK l _Toc358205558 6.Clinical efficacy PAGEREF _Toc358205558 h 14 HYPERLINK l _Toc358205559 6.1.Pivotal efficacy study: Study CST1571-K2301 PAGEREF _Toc358205559 h 14 HYPERLINK l _Toc358205560 6.2.Other efficacy studies PAGEREF _Toc35820556

14、0 h 29 HYPERLINK l _Toc358205561 6.3.Analyses performed across trials PAGEREF _Toc358205561 h 29 HYPERLINK l _Toc358205562 6.4.Evaluators conclusions on clinical efficacy PAGEREF _Toc358205562 h 30 HYPERLINK l _Toc358205563 7.Clinical safety PAGEREF _Toc358205563 h 31 HYPERLINK l _Toc358205564 7.1.S

15、tudies providing evaluable safety data PAGEREF _Toc358205564 h 31 HYPERLINK l _Toc358205565 7.2.Pivotal studies that assessed safety as a primary outcome PAGEREF _Toc358205565 h 33 HYPERLINK l _Toc358205566 7.3.Patient exposure in the pivotal trial PAGEREF _Toc358205566 h 33 HYPERLINK l _Toc35820556

16、7 7.4.Adverse events PAGEREF _Toc358205567 h 34 HYPERLINK l _Toc358205568 7.5.Laboratory tests PAGEREF _Toc358205568 h 43 HYPERLINK l _Toc358205569 7.6.Post-marketing experience PAGEREF _Toc358205569 h 46 HYPERLINK l _Toc358205570 7.7.Safety issues with the potential for major regulatory impact PAGE

17、REF _Toc358205570 h 47 HYPERLINK l _Toc358205571 7.8.Other safety issues PAGEREF _Toc358205571 h 47 HYPERLINK l _Toc358205572 7.9.Evaluators overall conclusions on clinical safety PAGEREF _Toc358205572 h 48 HYPERLINK l _Toc358205573 8.First round benefit-risk assessment PAGEREF _Toc358205573 h 49 HY

18、PERLINK l _Toc358205574 8.1.First round assessment of benefits PAGEREF _Toc358205574 h 49 HYPERLINK l _Toc358205575 8.2.First round assessment of risks PAGEREF _Toc358205575 h 50 HYPERLINK l _Toc358205576 8.3.First round assessment of benefit-risk balance PAGEREF _Toc358205576 h 50 HYPERLINK l _Toc3

19、58205577 9.First round recommendation regarding authorisation PAGEREF _Toc358205577 h 51 HYPERLINK l _Toc358205578 10.Clinical questions PAGEREF _Toc358205578 h 51 HYPERLINK l _Toc358205579 10.1.Pharmacokinetics PAGEREF _Toc358205579 h 51 HYPERLINK l _Toc358205580 10.2.Pharmacodynamics PAGEREF _Toc3

20、58205580 h 51 HYPERLINK l _Toc358205581 10.3.Efficacy PAGEREF _Toc358205581 h 51 HYPERLINK l _Toc358205582 10.4.Safety PAGEREF _Toc358205582 h 51 HYPERLINK l _Toc358205583 11.Second round evaluation of clinical data submitted in response to questions PAGEREF _Toc358205583 h 51 HYPERLINK l _Toc358205

21、584 12.Second round benefit-risk assessment PAGEREF _Toc358205584 h 52 HYPERLINK l _Toc358205585 13.Second round recommendation regarding authorisation PAGEREF _Toc358205585 h 52 HYPERLINK l _Toc358205586 14.References PAGEREF _Toc358205586 h 52List of abbreviationsAbbreviationMeaningABL1V-abl Abels

22、on murine leukemia viral oncogene homologABL2Abelson-related gene proteinAE(s)adverse event(s)AIOSarcoma Group of the Arbeitsgemeinschaft Internistische OnkologieALLacute lymphatic leukemiaALTalanine aminotransferase/glutamic pyruvic transaminase/ GPT/SGPTANCabsolute neutrophil countARGUSNovartis sa

23、fety databaseASTaspartate aminotransferase/glutamic pyruvic transaminase/ GOT/SGOTATCAnatomical Therapeutic ChemicalAUCarea under the concentration-time curveAUC(0-inf)area under the concentration-time curve from time zero to infinityAUC(0-24h)area under the concentration-time curve from time zero t

24、o 24h, the last sampling time pointBMIbody mass indexCIconfidence intervalCL/Ftotal body oral clearance of drug from the plasmaCLrrenal clearance of drug or metaboliteCmaxmaximum (peak) observed plasma drug concentration after dose administrationCmintrough (24h) plasma drug concentrationCMLchronic m

25、yeloid leukemiaCML-CPchronic myeloid leukemia chronic phaseCRcomplete responseCRFcase report formCROcontract research organizationCSF-1Rcolony stimulating factor 1 receptor/macrophage colony-stimulating factor receptorCS&ENovartis Clinical Safety and EpidemiologyCTcomputerized tomographyCTCCommon To

26、xicology CriteriaCYP450cytochrome P450DDR1, DDR2discoidin domain receptors 1 and 2ECGelectrocardiogramECOGEastern Cooperative Oncology GroupFASFull Analysis SetFrenfraction of dose excreted in the urineGIgastrointestinalGISTgastrointestinal stromal tumorsG-CSFgranulocyte colony stimulating factorGM-

27、CSFgranulocyte macrophage colony stimulating factorHIVhuman immunodeficiency virusHPFhigh power fieldHRhazard ratioIECIndependent Ethics CommitteeIRBInstitutional Review BoardITTintent-to-treatKIT/KITstem cell factor receptor tyrosine kinase gene/gene protein productLC/MS/MSliquid chromatography/tan

28、dem mass spectrometryLDHlactate dehydrogenaseLLOQlower limit of quantificationLVEFleft ventricular ejection fractionMedDRAMedical Dictionary for Regulatory ActivitiesMDRmulti-drug resistanceMRImagnetic resonance imagingmsmillisecondNCI/NIHNational Cancer Institute at the National Institutes of Healt

29、hOSoverall survivalPDGFRplatelet-derived growth factor receptorPDprogression of diseasePFSprogression-free survivalPFS-Metprogression-free survival-metastaticpoper os (oral)Ph+Philadelphia chromosome positivePKpharmacokineticsPRpartial responsePSperformance statusQCquality controlRAPreporting and an

30、alysis planRECISTResponse Evaluation Criteria In Solid TumorsRFSrecurrence-free survivalSAEserious adverse eventSCFstem cell factorSDstable disease SD standard deviationSI UnitsInternational System of UnitsSOCsystem organ classSmPCSummary of Product CharacteristicsSSGScandinavian Sarcoma GroupSULTsu

31、lfotransferaseTKtyrosine kinaseTmaxtime to reach the maximum (peak) plasma drug concentration after dose administrationt1/2elimination half-time associated with the terminal slope (z) of a semi-logarithmic concentration-time curveTMAtumor tissue microarrayTTPtime to progressionTTP-Mettime to progres

32、sion-metastaticUGTUDP-glucuronosyltransferaseULNupper limit of normalVz/Fthe apparent volume of distribution during terminal phase (associated with z)WBCwhite blood cellWHO World Health OrganisationClinical rationaleGastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of th

33、e gastrointestinal (GI) tract and are thought to originate from the interstitial cells of Cajal. GISTs are malignant tumors most commonly resulting from activating mutations in the receptor tyrosine kinase KIT (CD117) or the platelet-derived growth factor receptors (PDGFR).Imatinib was approved in a

34、 number of countries for the treatment of adult patients with KIT(CD117)+ unresectable and/or metastatic GIST, prolonging overall and the progression-free survival and increasing the 5-year survival rate. Subsequent studies showed that imitinab significantly prolonged recurrence-free survival (RFS)

35、when used after apparent complete resection of GISTs at a dose of 400 mg/day for 12 months. The results of the analysis of RFS according to time period indicated that the greatest effect of imatinib was seen while on treatment, up to one year following randomisation. The difference between the group

36、s decreased after study drug was stopped, suggesting that treatment with imatinib should be continued beyond one year. To investigate this hypothesis, a Phase III trial was conducted, comparing the efficacy and safety of 3 years of adjuvant treatment to 1 years treatment.Concerns about acetaminophen

37、 interaction with imatinib: With an overdose of acetaminophen, the sulfation pathway becomes saturated and an increased amount of the drug is oxidized by cytochrome P450-2E1 (CYP2E1) to a highly reactive and hepatotoxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI) (Figure 1). Small amounts of t

38、his imine are detoxified by conjugation with glutathione and further metabolised to acetaminophen mercapturate and cysteinate. Increased production of NAPQI leads to glutathione depletion and eventually to hepatocyte necrosis. Metabolism can shift from one to another pathway after, for example, satu

39、ration of sulfation by an acetaminophen overdose or by inhibition of a particular pathway by co-medications.Figure 1: Metabolism of acetaminophen.Studies conducted in vitro using pooled human microsomes showed that imatinib is a potent inhibitor of acetaminophen-O-glucuronidation but has no effect o

40、n the formation of the intermediate hepatoxic metabolite, NAPQI (Figure 1). However, because the glucuronidation pathway represents 60% of acetaminophen metabolism, the inhibition of acetaminophen glucuronidation by imatinib may result in shunting acetaminophen metabolism to other pathways and more

41、NAPQI may be formed in the body as a consequence of this inhibition. Therefore, the Food and Drug Administration requested the sponsor to conduct a drug-drug interaction study in cancer patients to examine the effect of imatinib on the pharmacokinetics of acetaminophen in order to properly adjust ac

42、etaminophen dose when it is concomitantly administered with imatinib.Comment: The clinical rationale given is acceptable.Contents of the clinical dossierScope of the clinical dossierThe clinical dossier was confined to a pharmacological study of imitanib and paracetamol (Study CST1571-A2107), a comp

43、arative Phase III trial of two different durations of treatment (12 months compared with 36 months) of adjuvant treatment of GIST with Glivec (CST1571-BFI03), and various data supporting changes to the PI, many of which are safety-related.The submission contained the following clinical information:A

44、 clinical pharmacology study (CST1571-A2107) provided pharmacokinetic data on the effects of Glivec on the pharmacokinetics of paracetamol in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP)Population pharmacokinetic analyses were not part of the

45、 submission.The pivotal efficacy/safety study (CST1571-BFI03) primarily compared recurrence-free survival (RFS) in GIST patients who were assessed as being at a high ( 50%) risk of disease recurrence within the first 5 years following surgery, treated with adjuvant imatinib mesylate for either 12 or

46、 36 monthsNo dose-finding studies were included in the submission.The previous study CST1571-BUS89 of the adjuvant treatment of GIST with Glivec for 12 months was supplied for reference only as it had been evaluated previously.A Phase III study, CST1571-K2301, was submitted to support the inclusion

47、of information on hypophosphatemia in the PI. The randomised open-label study of 400 mg versus 800 mg of Glivec (imatinib mesylate) was conducted in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP).An epidemiology report evaluating the frequency

48、of second primary malignancies in Glivec treated patients in Novartis sponsored clinical trials.Paediatric dataThe submission included proposed changes to parts of the paediatric information in the PI with supporting arguments. No new studies in children were presented.Good clinical practiceAll stud

49、ies and any amendments were reviewed by the Independent Ethics Committee or Institutional Review Board for each centre. The studies were conducted according to the ethical principles of the Declaration of Helsinki. Informed consent was obtained from each patient in writing during the screening visit

50、 and prior to his or her enrollment in the studies. The studies were described to the patients by the investigator, who answered any questions; patients were also provided with written information. Samples of the written information and the consent form were provided in the application.Pharmacokinet

51、icsStudies providing pharmacokinetic dataThere was one pharmacokinetic study CST1571-A2107 presented on the interaction of imatinib and paracetamol. This had no deficiencies that excluded the results from consideration, but the conclusions of the evaluator differed from those of the sponsor.Summary

52、of pharmacokineticsThe pharmacokinetics of Glivec are presented in the current Product Information.In this section, only data from the one PK study submitted on the interaction of imatinib and paracetamol are presented.Pharmacokinetic interactions demonstrated in human studiesA summary of the data f

53、rom the PK study of possible acetaminophen/paracetamol and imatinib interaction is shown in Tables 1-3 and Figures 2-3.Table 1: Results for acetaminophen and its glucuronide.Table 2: Statistical analysis of PK results.Figure 2: Arithmetic mean (SD) concentration-time profiles for plasma acetaminophe

54、n: 0-24 hours post-dose (linear view) (pharmacokinetic set).Figure 3: Mean acetaminophen/paracetamol glucuronide (AG) and acetaminophen/ paracetamol sulfate (AS) plasma concentration-time profiles on Day 1 (control; -SD) and Day 8 (treatment with imatinib; +SD) in CML patients (n =12).Table 3: Pharm

55、acokinetic parameters (mean SD) of imatinib and its metabolite obtained for the 400 mg qd dose on Day 8 in CML patients (n=12).Clinical implications of in vitro findingsAs described in the REF _Ref314576965 h * MERGEFORMAT Clinical rationale, the in vitro demonstration that imatinib inhibited glucur

56、onide formation from acetaminophen raised concerns that more of the hepatotoxic metabolite of acetaminophen (NAPQ1) may be formed when imatinib was coadministered. This issue has been addressed by performing the submitted PK study, as requested by the FDA.Evaluators overall conclusions on pharmacoki

57、neticsFrom the PK study of a single dose of acetaminophen/paracetamol coadministered with multiple doses of imatinib at steady-state, a similar ratio of plasma and urinary acetaminophen glucuronide to acetaminophen was observed in the absence and presence of imatinib, and a similar ratio of plasma u

58、rinary acetaminophen sulfate to acetaminophen was also observed in the absence and presence of imatinib. The evaluator concludes that imatinib (400 mg qd) did not significantly affect the pathways of metabolism of acetaminophen to its sulfate and glucuronide in the Korean patients studied. The metho

59、d used was an acceptable surrogate for measuring the hepatotoxic metabolite NAPQ1 itself, which cannot be measured in vivo in humans. From these data, we can conclude that imatinib did not cause significant inhibition of glucuronidation and diversion of acetaminophen towards the toxic metabolite in

60、the population studied.However a number of problems with the study are of concern as follows.Ethnicity of the subjects: In the Evaluators Comments, it is pointed out that significant differences have been reported in the PKs of acetaminophen in some Asian populations compared to some Caucasian popul