Extract from the Clinical Evaluation Report for Pralatrexate：从临床评估报告中针对pralatrexate

1、March 2012AusPAR Attachment 1Extract from the Clinical Evaluation Report for PralatrexateProprietary Product Name: Folotyn Sponsor: Mundipharma Pty LtdAbout the Therapeutic Goods Administration (TGA)The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health

2、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 of quality, safety and efficacy (performa

3、nce), 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 public, healthcare professionals and industry

4、 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 from the Clinical Evaluation ReportThis

5、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 words Information redacted, where they app

6、ear 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 this work in unaltered form for your own

7、 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 that reproduction. Apart from rights to

8、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 written permission from the Commonwealth to do

9、 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 _Toc364764881 List of abbreviations PAGEREF _Toc364764881 h 4 HYPERLINK l _Toc3

10、64764882 1.Clinical rationale PAGEREF _Toc364764882 h 7 HYPERLINK l _Toc364764883 1.1.Peripheral T-cell lymphoma PAGEREF _Toc364764883 h 7 HYPERLINK l _Toc364764884 1.2.Currently available treatment for PTCL PAGEREF _Toc364764884 h 7 HYPERLINK l _Toc364764885 1.3.The rationale for the clinical devel

11、opment of pralatrexate for use in PTCL PAGEREF _Toc364764885 h 7 HYPERLINK l _Toc364764886 1.4.Orphan drug designation PAGEREF _Toc364764886 h 8 HYPERLINK l _Toc364764887 1.5.Guidance PAGEREF _Toc364764887 h 8 HYPERLINK l _Toc364764888 2.Contents of the clinical dossier PAGEREF _Toc364764888 h 8 HYP

12、ERLINK l _Toc364764889 2.1.Scope of the clinical dossier PAGEREF _Toc364764889 h 8 HYPERLINK l _Toc364764890 2.2.Paediatric data PAGEREF _Toc364764890 h 10 HYPERLINK l _Toc364764891 2.3.Good clinical practice PAGEREF _Toc364764891 h 11 HYPERLINK l _Toc364764892 3.Pharmacokinetics PAGEREF _Toc3647648

13、92 h 11 HYPERLINK l _Toc364764893 3.1.Studies providing pharmacokinetic data PAGEREF _Toc364764893 h 11 HYPERLINK l _Toc364764894 3.2.Summary of pharmacokinetics PAGEREF _Toc364764894 h 13 HYPERLINK l _Toc364764895 3.3.Evaluators overall conclusions on pharmacokinetics PAGEREF _Toc364764895 h 23 HYP

14、ERLINK l _Toc364764896 4.Pharmacodynamics PAGEREF _Toc364764896 h 25 HYPERLINK l _Toc364764897 4.1.Studies providing pharmacodynamic data PAGEREF _Toc364764897 h 25 HYPERLINK l _Toc364764898 4.2.Summary of pharmacodynamics PAGEREF _Toc364764898 h 25 HYPERLINK l _Toc364764899 4.2.2.Pharmacodynamic ef

15、fects PAGEREF _Toc364764899 h 26 HYPERLINK l _Toc364764900 4.3.Evaluators overall conclusions on pharmacodynamics PAGEREF _Toc364764900 h 30 HYPERLINK l _Toc364764901 5.Dosage selection for the pivotal studies PAGEREF _Toc364764901 h 31 HYPERLINK l _Toc364764902 6.Clinical efficacy PAGEREF _Toc36476

16、4902 h 32 HYPERLINK l _Toc364764903 6.1.Peripheral T-cell lymphoma in adults PAGEREF _Toc364764903 h 32 HYPERLINK l _Toc364764904 6.2.Evaluators conclusions on clinical efficacy for PTCL PAGEREF _Toc364764904 h 55 HYPERLINK l _Toc364764905 7.Clinical safety PAGEREF _Toc364764905 h 58 HYPERLINK l _To

17、c364764906 7.1.Studies providing evaluable safety data PAGEREF _Toc364764906 h 58 HYPERLINK l _Toc364764907 7.2.Pivotal studies that assessed safety as a primary outcome PAGEREF _Toc364764907 h 61 HYPERLINK l _Toc364764908 7.3.Patient exposure PAGEREF _Toc364764908 h 61 HYPERLINK l _Toc364764909 7.4

18、.Adverse events PAGEREF _Toc364764909 h 65 HYPERLINK l _Toc364764910 7.5.Laboratory tests PAGEREF _Toc364764910 h 75 HYPERLINK l _Toc364764911 7.6.Post-marketing experience PAGEREF _Toc364764911 h 82 HYPERLINK l _Toc364764912 7.7.Safety issues with the potential for major regulatory impact PAGEREF _

19、Toc364764912 h 82 HYPERLINK l _Toc364764913 7.8.Other safety issues PAGEREF _Toc364764913 h 85 HYPERLINK l _Toc364764914 7.9.Evaluators overall conclusions on clinical safety PAGEREF _Toc364764914 h 88 HYPERLINK l _Toc364764915 8.First round benefit-risk assessment PAGEREF _Toc364764915 h 90 HYPERLI

20、NK l _Toc364764916 8.1.First round assessment of benefits PAGEREF _Toc364764916 h 90 HYPERLINK l _Toc364764917 8.2.First round assessment of risks PAGEREF _Toc364764917 h 90 HYPERLINK l _Toc364764918 8.3.First round assessment of benefit-risk balance PAGEREF _Toc364764918 h 91 HYPERLINK l _Toc364764

21、919 9.First round recommendation regarding authorisation PAGEREF _Toc364764919 h 91 HYPERLINK l _Toc364764920 10.Clinical questions PAGEREF _Toc364764920 h 91 HYPERLINK l _Toc364764921 10.1.Efficacy PAGEREF _Toc364764921 h 91 HYPERLINK l _Toc364764922 11.References PAGEREF _Toc364764922 h 92List of

22、abbreviationsAbbreviationMeaningALCL anaplastic large cell lymphomaALKanaplastic lymphoma kinaseALTalanine transaminase ANCabsolute neutrophil countASTaspartate transaminaseBCRPbreast cancer resistance proteinBSAbody surface areaCHOPcyclophosphamide, doxorubicin, vincristine, and prednisoneCERclinic

23、al evaluation reportCRcomplete responseCRucomplete response unconfirmedCYPcytochrome P450DLBCL diffuse large B-cell lymphomaDHAPdexamethasone, cisplatin and cytarabineDHFdihydrofolateDHFRdihydrofolate reductaseECOGEastern Cooperative Oncology GroupEMAEuropean Medicines AgencyEPOCHinfusional etoposid

24、e, doxorubicin, vincristine plus bolus cyclophosphamide and prednisoneEUEuropean UnionFPGSfolylpolyglutamyl synthetaseGARFTglycinamide ribonucleotide formyltransferaseGCPgood clinical practicehERG human ether-a-go-go-related geneHcyhomocysteineIC50the concentration of an inhibitor causing 50% inhibi

25、tionICEifosfamide, carboplatin and etoposideINDinvestigational new drug (USA)LC/MS/MSliquid chromatographytandem mass spectrometryLLOQlower limit of quantificationMMAmethylmalonic acidMRPmultidrug resistance-associated proteinMTDmaximum tolerated doseNSCLCnon small cell lung cancerNHLnon-Hodgkins ly

26、mphomaOATorganic anion transporterOCTorganic cation transporterOSoverall survivalpB-LBL precursor B-cell lymphoblastic lymphomaPDXpralatrexatePETPositron-emission tomographyPFSprogression-free survivalP-gpP-glycoproteinsPIPpaediatric investigation planPPFpre-submission planning form (TGA)PTCLperiphe

27、ral T-cell lymphomaPRpartial responsePR interval time from the beginning of the P wave to the QRS complex of an ECGQT interval time between the beginning of the Q wave and the end of the T wave of an ECGQTcF Fridericias rate-corrected QT intervalQTcB Bazetts rate-corrected QT intervalRR interval tim

28、e duration between two consecutive R waves of an ECGRFC-1reduced folate carrier 1RT-PCRreverse transcription combined with polymerase chain reactionSCTstem cell transplantTCCtransitional cell carcinomaTGATherapeutic Goods AdministrationT-LBLT-cell lymphoblastic lymphomaTHFtetrahydrofolateTSthymidyla

29、te synthaseWHOWorld Health OrganizationClinical rationaleThe sponsor provided a detailed and well argued clinical rationale for the development of pralatrexate as a treatment for peripheral T-cell lymphoma (PTCL). Key elements of the sponsors rationale are presented below.Peripheral T-cell lymphomaP

30、TCL is a rare, heterogeneous group of aggressive non-Hodgkins lymphomas (NHLs) with a generally poorer prognosis than their B-cell counterparts. The natural history and outcome of PTCL varies widely with various histological subtypes. Patients with anaplastic large cell lymphoma (particularly the su

31、btype positive for anaplastic lymphoma kinase ALK+) have better survival that those with other subtypes, with 5-year survival being reported as high as 70% (Vose et al., 2008). However, for other subtypes in patients characterised as high risk by the International Prognostic Index (IPI) (Shipp, 1994

32、), 5-year survival has been reported to be as low as 6% (Sonnen et al., 2005). Several clinical studies have reported a median survival of less than 2 years for patients with T-cell neoplasms and 5-year survival rates of less than 30% (Armitage & Weisenburger, 1998; Lopez-Guillermo et al., 1998; Rud

33、iger et al., 2002).Currently available treatment for PTCLCurrently there are no therapies specifically approved for the treatment of PTCL. Given the aggressive clinical course and generally poor outcomes with PTCL, treatment typically involves combination chemotherapy regimens. However, the regimens

34、 used have been based largely on their utility and benefit in B-cell diseases. The majority of patients are initially treated with standard regimens of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy (Savage, 2007). A variety of other anthracycline-based combination the

35、rapies have also been utilised as first-line treatments (Fisher et al., 1993). The first-line response rates for CHOP chemotherapy in patients with PTCL have been reported to range between 50% and 70%. However, patients often relapse soon after responding to first-line treatments (Vose et al., 2008)

36、. Also, there have been relatively few studies of potential therapeutic agents for use in relapsed or refractory PTCL - gemcitabine (Sallah et al., 2001), denileukin diftitox (Dang et al., 2007), deoxycoformycin (Dang et al., 2003; Dearden et al., 1991; Mercieca et al., 1994) and lenalidomide (Dueck

37、 et al., 2009). However, these studies have commonly included indolent tumour types, such as non-transformed mycosis fungoides, and none included more than 30 patients with the more aggressive PTCL subtypes. The rationale for the clinical development of pralatrexate for use in PTCLPralatrexate is a

38、10-deazaaminopterin analogue of the widely used antifolate/antimetabolite, methotrexate that inhibits the enzyme dihydrofolate reductase (DHFR). Antifolates are well established as effective anticancer agents in the treatment of malignancies such as acute lymphoblastic leukaemia, lymphomas, and brea

39、st and lung cancer (Walling, 2006). During the preclinical development program a range of in vitro and in vivo pharmacodynamic studies of pralatrexate were performed using model systems of a variety of solid tumour types and haematological malignancies. The sponsor reported these studies demonstrate

40、d pralatrexate has a broad and potent cytotoxic activity as a single agent as well as in combination with a variety of currently used chemotherapeutic agents. Of note, in vitro studies in CCRF-CEM human leukaemia cells demonstrated that pralatrexate is 14 times more efficiently transported into the

41、cells and 10 times more efficiently polyglutamated than methotrexate (Sirotnak et al., 1998). These results were reflected in a 30-fold improvement in cytotoxic activity of pralatrexate compared with methotrexate in these cells. Also, after 5 days of continuous in vitro exposure, pralatrexate demons

42、trated an 8- to 20-fold greater potency than methotrexate in 5 lymphoma cell lines. It was also reported by the sponsor that this greater efficacy was confirmed by in vivo animal studies that used human lymphoma xenografts. A clinical development program was then initiated to determine potential eff

43、icacy in patients with refractory Hodgkins and non-Hodgkins lymphomas, and solid tumours (including non small cell lung cancer, malignant pleural mesothelioma, metastatic breast cancer and transitional cell carcinoma of the urinary bladder). An early clinical study in which a variety of refractory l

44、ymphoma patients were treated with pralatrexate (PDX-02-078) found that PTCL patients responded particularly well. Consequently, in view of the strong clinical need for more effective treatments, a specific clinical development program for PTCL commenced. Orphan drug designationPralatrexate was gran

45、ted orphan drug status in Australia for the “treatment of adult patients with relapsed or refractory peripheral T-cell lymphoma (nodal, extranodal and leukaemic/disseminated)” in September 2011. Although the wording of the proposed indication is slightly different to the wording of the orphan drug d

46、esignation, the meaning is the same. It has been estimated that the prevalence of PTCL in Australia in 2010 was approximately 840 patients.GuidanceThe TGA-adopted EU guidelines applicable to this submission are:Guideline on the Evaluation of Anticancer Medicinal Products in Man (CPMP/EWP/205/95/Rev.

47、3/Corr), effective June 2006; andAppendix 2 to the Guideline on the Evaluation of Anticancer Medicinal Products in Man (CPMP/EWP/205/95/Rev. 3) on Confirmatory studies in Haematological Malignancies, effective 17 December 2010;Guideline on Clinical Trials in Small Populations (CHMP/EWP/83561/2005),

48、effective December 2006; andPoints to Consider on Validity and Interpretation of Meta-analyses, and One Pivotal Study (CPMP/EWP/2330/99), effective 27 March 2002.Contents of the clinical dossierScope of the clinical dossierThe submission contained the following clinical information:Clinical pharmaco

49、logy:Pharmacodynamic (PD) data from a Phase I/II trial in lymphoma patients (PDX-02-078);One study examining effects of pralatrexate on QT interval (PDX-007 QTc);One mass balance study in advanced cancer patients (PDX-016);One integrated analysis of pharmacokinetic (PK) data derived from three Phase

50、 I/II clinical studies (PDX-008, PDX-007 and PDX-99-083);One full population PK (POPPK) analysis;Protocol for an ongoing open-label, Phase I study to evaluate the safety and PKs of pralatrexate in cancer patients with mild, moderate and severe renal impairment (PDX-019) that is in the earliest stage

51、s of enrolment with no data generated as yet.Efficacy/safety studies:One ongoing pivotal Phase II study involving 115 patients with relapsed or refractory PTCL, of whom 111 were treated with pralatrexate (PDX-008, also known as PROPEL). Enrolment was completed and a full clinical study report (CSR)

52、was submitted;One Phase I/II study involving 72 adult patients with relapsed or refractory non- Hodgkins lymphoma (NHL) or Hodgkins lymphoma, of whom 36 (50%) had T/natural killer (NK)-cell lymphoma (PDX-02-078 also listed under clinical pharmacology studies above). This study was completed and a fu

53、ll CSR was submitted;Twelve Phase I/II studies (1 controlled; 11 uncontrolled) in varied stages of completion, conducted in other cancer indications and using treatment regimens other than that proposed, and which have been evaluated only from a safety point of view in this CER:pralatrexate combined

54、 with gemcitabine for treatment of relapsed of refractory lymphoproliferative malignancies (PDX-009 - enrolment ongoing, interim CSR submitted); relapsed or refractory cutaneous T-cell lymphoma (PDX-010 study ongoing, interim CSR submitted);advanced solid tumours (PDX-97-006, PDX-01-014 - both studi

55、es completed, abbreviated CSRs submitted);stage IIIB or IV non small cell lung cancer (PDX 99-053 - study completed, abbreviated CSR submitted; PDX-007 - study completed, full CSR submitted; PDX-012 comparative ongoing study of PDX versus erlotinib interim CSR submitted);pralatrexate combined with a

56、 taxane (paclitaxel or docetaxel) for treatment of “advanced cancer” (PDX 99-083 - study completed, abbreviated CSR submitted); unresectable malignant pleural mesothelioma (PDX-01-076- study completed, abbreviated CSR submitted);advanced or metastatic relapsed transitional cell carcinoma of the urin

57、ary bladder (PDX-011 enrolment ongoing, interim CSR submitted);advanced or metastatic breast cancer (PDX-014 enrolment ongoing, synopsis of interim CSR submitted); andrelapsed or refractory B-cell NHL (PDX-015 enrolment ongoing, synopsis of interim CSR submitted).Details (but no data) were also subm

58、itted for two confirmatory Phase III, controlled clinical studies pertinent to the proposed indication of PTCL:PDX-017 (Protocol submitted) a randomised, study of sequential pralatrexate versus observation in patients with previously undiagnosed PTCL who achieved a response after completing at least

59、 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based treatment. The study is open to enrolment in the US, UK and Australia with a target of 549 patients randomised 2:1 to pralatrexate or observation, with follow-up through 7 years post-randomisation. PDX-3501 (Protoco

60、l synopsis submitted) a randomised, comparative, open-label, study of pralatrexate versus treatment of physicians choice in patients who have progressed after at least one prior therapy for PTCL. This study is currently in the planning and initiation stages. It is planned that 148 adult patients wil