Normal = Times New Roman 12pt

(1)

エボルトラ点滴静注 20mg

第 2 部 CTD の概要（サマリー）

2.1. CTD の目次（第 2 部から第 5 部）

(2)

エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 1

2.1 CTD の目次

第 2 部（モジュール 2）の目次 巻／巻数 2 第 2 部（モジュール 2） CTD の概要 1 ／ 1 2.1 CTD の目次（第 2 部から第 5 部） 1 ／ 1 2.2 緒言 1 ／ 1 2.3 品質に関する概要 1 ／ 1 緒言 1 ／ 1 2.3.S. 原薬 1 ／ 1 2.3.S.1 一般情報 1 ／ 1 2.3.S.2 製造 1 ／ 1 2.3.S.3 特性 1 ／ 1 2.3.S.4 原薬の管理 1 ／ 1 2.3.S.5 標準品または標準物質 1 ／ 1 2.3.S.6 容器及び施栓系 1 ／ 1 2.3.S.7 安定性 1 ／ 1 2.3.P 製剤 1 ／ 1 2.3.P.1 製剤の処方 1 ／ 1 2.3.P.2 製剤開発の経緯 1 ／ 1 2.3.P.3 製造 1 ／ 1 2.3.P.4 添加剤の管理 1 ／ 1 2.3.P.5 製剤の管理 1 ／ 1 2.3.P.6 標準品または標準物質 1 ／ 1 2.3.P.7 容器及び施栓系 1 ／ 1 2.3.P.8 安定性 1 ／ 1 2.3.A その他 1 ／ 1 2.3.A.1 製造施設及び設備 1 ／ 1 2.3.A.2 外来性感染性物質の安全性評価 1 ／ 1 2.3.A.3 添加剤 1 ／ 1 2.3.R 各極の要求資料 2.4 非臨床試験の概括評価 1 ／ 1 2.4.1 非臨床試験計画概略 1 ／ 1 2.4.2 薬理試験 1 ／ 1 2.4.3 薬物動態試験 1 ／ 1

(3)

エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 2 巻／巻数 2.4.4 毒性試験 1 ／ 1 2.4.5 総括及び結論 1 ／ 1 2.4.6 参考文献 1 ／ 1 2.5 臨床に関する概括評価 1 ／ 1 2.5.1 製品開発の根拠 1 ／ 1 2.5.2 生物薬剤学に関する概括評価 1 ／ 1 2.5.3 臨床薬理に関する概括評価 1 ／ 1 2.5.4 有効性に関する概括評価 1 ／ 1 2.5.5 安全性に関する概括評価 1 ／ 1 2.5.6 リスクとベネフィットに関する結論 1 ／ 1 2.6 非臨床試験の概要文及び概要表 1 ／ 1 2.6.1 緒言 1 ／ 1 2.6.2 薬理試験の概要文 1 ／ 1 2.6.3 薬理試験の概要表 1 ／ 1 2.6.4 薬物動態試験の概要文 1 ／ 1 2.6.5 薬物動態試験の概要表 1 ／ 1 2.6.6 毒性試験の概要文 1 ／ 1 2.6.7 毒性試験の概要表 1 ／ 1 2.7 臨床概要 1 ／ 1 2.7.1 生物薬剤学及び関連する分析法の概略 1 ／ 1 2.7.1.1 背景及び概観 1 ／ 1 2.7.1.2 個々の試験結果の要約 1 ／ 1 2.7.1.3 全試験を通しての結果の比較と解析 1 ／ 1 2.7.1.4 付録 1 ／ 1 2.7.2 臨床薬理の概要 1 ／ 1 2.7.2.1 背景及び概観 1 ／ 1 2.7.2.2 個々の試験結果の要約 1 ／ 1 2.7.2.3 全試験を通しての結果の比較と解析 1 ／ 1 2.7.2.4 特別な試験 1 ／ 1 2.7.2.5 付録 1 ／ 1 2.7.3 臨床的有効性の概要 1 ／ 1 2.7.3.1 背景及び概観 1 ／ 1 2.7.3.2 個々の試験結果の要約 1 ／ 1 2.7.3.3 全試験を通しての結果の比較と解析 1 ／ 1 2.7.3.4 推奨用量・用法に関する臨床情報の解析 1 ／ 1

(4)

エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 3 巻／巻数 2.7.3.5 効果の持続、耐薬性 1 ／ 1 2.7.3.6 付録 1 ／ 1 2.7.4 臨床的安全性の概要 1 ／ 1 2.7.4.1 医薬品への暴露 1 ／ 1 2.7.4.2 有害事象 1 ／ 1 2.7.4.3 臨床検査値の評価 1 ／ 1 2.7.4.4 バイタルサイン、身体的所見及び安全性に関連する他の観察項目 1 ／ 1 2.7.4.5 特別な患者集団及び状況下における安全性 1 ／ 1 2.7.4.6 市販後データ 1 ／ 1 2.7.4.7 付録 1 ／ 1 2.7.5 参考文献 1 ／ 1 2.7.6 個々の試験のまとめ 1 ／ 1

(5)

エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 4 第 3 部（モジュール 3）の目次 巻／巻数 3 第 3 部（モジュール 3）品質に関する文書 1- 4 ／ 4 3.1 目次 1 ／ 4 3.2 データ又は試験報告書 1- 4 ／ 4 3.2.S. 原薬（Clofarabine、XXXXXXXXXXXXXXXXXX） 1- 2 ／ 4 3.2.S.1 一般情報 1 ／ 4 3.2.S.1.1 名称 1 ／ 4 3.2.S.1.2 構造 1 ／ 4 3.2.S.1.3 一般特性 1 ／ 4 3.2.S.2 製造 1 ／ 4 3.2.S.2.1 製造業者 1 ／ 4 3.2.S.2.2 製造方法及びプロセス・コントロール 1 ／ 4

Method Development & Validation Report: MDV-C-146.4 1 ／ 4

Method Development Report: MDV-C-146.28 1 ／ 4

SOP: XXXXXXXX, Title: HPLC Method for Analysis of XXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

1 ／ 4

SOP: XXXXXXXX, Title: Purity Determination of XXXXXXX Clofarabine (XXXX) by HPLC

1 ／ 4

3.2.S.2.2 _{製造方法及びプロセス・コントロール（Ash）}

1 ／ 4

3.2.S.2.3 原材料の管理 _{1 ／ 4}

Method Development & Validation Report: MDV-C-146.9 Amendment 1 1 ／ 4

SOP: XXXXXXXX, Title: IR SPECTROSCOPY 1 ／ 4

SOP: XXXXXXXX, Title: Calibration and Operation of the Mettler Toledo Thermosystem -FP90/FP81HT Melting Point System

1 ／ 4

SOP: XXXXXXXX, Title: pH DETERMINATION 1 ／ 4

SOP: XXXXXXXX, Title: Physical Examination 1 ／ 4

SOP: XXXXXXXX, Title: REFRACTIVE INDEX 1 ／ 4

SOP: XXXXXXXX, Title: OPERATION AND CALIBRATION OF RUDOLPH RESEARCH AUTOPOL V AUTOMATIC POLARIMETER

1 ／ 4

(6)

エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部）

2.1 - 5

巻／巻数 SOP: XXXXXXXX, Title: PURITY DETERMINATION OF XXXX OR

XXXXXX BY HPLC

1 ／ 4

SOP: XXXXXXXX, Title: Purity Determination of XXXXXXXXXXXXXX XXXXXXX by HPLC

1 ／ 4

SOP: XXXXXXXX, Title: GC-FID DETERMINATION OF PURITY FOR SOLVENTS

1 ／ 4

SOP: XXXXXXXX, Title: GC-FID DETERMINATION OF PURITY FOR XXXXXXXXXXXXXXXX

1 ／ 4

3.2.S.2.4 重要工程の開発の経緯 1 ／ 4

3.2.S.2.4 重要工程の開発の経緯（XXXX） 1 ／ 4

Technical Report: Validation of XXXXXXXX Clofarabine Assay by HPLC: 0027AD9101

1 ／ 4

3.2.S.2.5 プロセス・バリデーション／プロセス評価 1 ／ 4

Summary Report For The Process Validation For XXXX (Clofarabine) Referencing Protocol: 4.134-0033

1 ／ 4

3.2.S.2.5 プロセス・バリデーション／プロセス評価（XXXX） _{1 ／ 4}

PROCESS VALIDATION PROTOCOL (ASI # XXXXXX) XXXXXXXX CLOFARABINE (XXXXXXXX) DRUG SUBSTANCE INTERMEDIATE PRODUCTION

1 ／ 4 PROCESS VALIDATION REPORT (ASI # XXXXXXXX)

CLOFARABINE (XXXXXXXX) ACTIVE

PHARMACEUTICAL INGREDIENT PRODUCTION

1 ／ 4

3.2.S.2.6 製造工程の開発の経緯 _{1 ／ 4}

Clofarabine Process Development Report _{1 ／ 4}

CERTIFICATE OF ANALYSIS by XXXXXXXXXXXXXXX . Lot No:

XXXXXXXX 1 ／ 4

CERTIFICATE OF ANALYSIS by XXXXXXXXXXXXXXX . Lot No:

XXXXXXXX 1 ／ 4 3.2.S.2.6 製造工程の開発の経緯（XXXX） 1 ／ 4 CERTIFICATE OF ANALYSIS by XXXXXXXX XXXXXXXX . Lot No: XXXXXXXX 1 ／ 4 CERTIFICATE OF ANALYSIS by XXXXXXXX XXXXXXXX . Lot No: XXXXXXXX 1 ／ 4 3.2.S.3 特性 1 ／ 4 3.2.S.3.1 構造その他の特性の解明 _{1 ／ 4}

Research Report, Polymorph Screen of Clofarabine: Report No. R2012001.01

1 ／ 4

(7)

エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 6 巻／巻数 3.2.S.4 原薬の管理 1 ／ 4 3.2.S.4.1 規格及び試験方法 1 ／ 4 3.2.S.4/3.2.S.4.1 原薬の管理（XXX）/ 規格及び試験方法（XXX） 1 ／ 4 3.2.S.4.2 試験方法 1 ／ 4

SOP: XXXXXXXX , Title: Endotoxin Testing 1 ／ 4

SOP: XXXXXXXX , Title: Residue on Ignition 1 ／ 4

SOP: XXXXXXXX , Title: Headspace GC Determination of XXXXXXXX XXin Clofarabine

1 ／ 4

SOP: XXXXXXXX , Title: Determination of Residual Solvents in Clofarabine (XXXXX) by Headspace GC

1 ／ 4

Analytical Test Procedure for Clofarabine Drug API (Revision 4): XXXXXX 1 ／ 4 Analytical Test Procedure for Clofarabine Drug API (Revision 4): XXXXXX 1 ／ 4

3.2.S.4.2 試験方法（XXXX） 1 ／ 4

Analytical Test Procedure for Clofarabine Drug API (Revision 4): XXXXXXX

1 ／ 4

Test Method pH Determination: XXXXXXX 1 ／ 4

Test Method Karl Fischer Moisture Analysis: XXXXXXX 1 ／ 4 Test Method Microbial Limits Testing: XXXXXXXX 1 ／ 4 Test Method Residual Solvent Analysis of XXXX or XXXX

by Headspace GC: XXXXXXXX

1 ／ 4

Test Method Percent Weight Based Assay of Clofarabine (XXXX) or Clofarabine (XXXX) by HPLC: XXXXXXX

1 ／ 4

3.2.S.4.3 試験方法のバリデーション 2 ／ 4

Protocol: Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid Chromatography-Revision 4: 07TRSA144

2 ／ 4

Protocol Amendment: Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid Chromatography-Revision 4: 07TRSA144

2 ／ 4

Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid Chromatography-Revision 4: 07TRSA144

2 ／ 4

Protocol : Determination of the XXXXXXXX XXXXXXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level using High Performance Liquid Chromatography

Project No. 6074-5124 XXXXXXXX

(8)

2.1 - 7

巻／巻数 Protocol Amendment: Determination of the XXXXXXXX XXXXXXXX

for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level using High Performance Liquid Chromatography

2 ／ 4

Determination of XXXXXXXX XXXXXXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level Using High Performance Liquid Chromatography: 07TRSA103

2 ／ 4

Addendum to Determination of the XXXXXXXX XXXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level Using High Performance Liquid Chromatography: 07TRSA103 (Addendum 01)

2 ／ 4

Validation Protocol of Clofarabine Process Impurities for Test Methods XXXXXXX and XXXXXXX: 08TRSA010

2 ／ 4

Method Validation of Clofarabine Process Impurities for Test Methods XXXXXXX and XXXXXXX: 08TRSA010

2 ／ 4

エボルトラの純度試験 HPLC 法のシステム適合性（検出の確認）の検討： IDCAD-12-025 試験報告書/試験計画書

2 ／ 4

3.2.S.4.3 試験方法のバリデーション（XXX） 2 ／ 4

Protocol: Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid Chromatography-Revision4: 07TRSA144

2 ／ 4

Protocol Amendment: Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid Chromatography-Revision4: 07TRSA144

2 ／ 4

Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid

Chromatography-Revision4: 07TRSA144

2 ／ 4

Protocol : Determination of the XXXXXXXX XXXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level using High Performance

(9)

エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 8 巻／巻数 Liquid Chromatography Project No. 6074-5124 XXXXXXXX XXXX

Protocol Amendment: Determination of the XXXXXXX X XX XXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level using High Performance Liquid Chromatography: Project No. 6074-5124 XXXXXXXX XXXX

2 ／ 4

Determination of XXXXXXXX XXXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level Using High Performance Liquid Chromatography: 07TRSA103

2 ／ 4

Addendum to Determination of the XXXXXXXX XXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level Using High Performance Liquid Chromatography: 07TRSA103 (Addendum 01)

2 ／ 4

Addendum to Determination of the XXXXXXX XXXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level Using High Performance Liquid Chromatography: 07TRSA103 (Addendum 02)

2 ／ 4

Validation of Headspace GC Method for Assay of Residual Solvents in Clofarabine Drug Substance: Report-0142 Revision: 00

2 ／ 4

Amendment to the Validation of Headspace GC Method for Residual Solvents in Clofarabine Drug Substance:

0027CM5008

2 ／ 4

Validation of a Head space GC Method for the Assay of Residual Solvents in Clofarabine Drug Substance: 0027CM5009

2 ／ 4

3.2.S.4.4 ロット分析 2 ／ 4

CERTIFICATE OF ANALYSIS Clofarabine XXXX Lot No: XXXXXXX 2 ／ 4

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2.1 - 9

巻／巻数

CERTIFICATE OF ANALYSIS Clofarabine XXXX Lot No: XXXXXXX 2 ／ 4

3.2.S.4.4 ロット分析（Ash） 2 ／ 4

Certificate of Analysis Lot No: XXXXXXX 2 ／ 4

3.2.S.4.5 規格及び試験方法の妥当性 2 ／ 4

Evoltra (clofarabine) EMEA/H/C/000613; Responses to Follow Up Measures (Quality) FUM029, XXXXXXX

2 ／ 4

3.2.S.4.5 規格及び試験方法の妥当性（XXXX） 2 ／ 4

3.2.S.5 標準品または標準物質 2 ／ 4

Certificate of Analysis Clofarabine Impurity Solution: XXXXXXX XXXX 2 ／ 4 Certificate of Analysis Clofarabine Impurity Solution: XXXXXXX XXXX 2 ／ 4 Certificate of Analysis Clofarabine Impurity Solution: XXXXXXX XXXX 2 ／ 4 Certificate of Analysis Clofarabine Impurity Solution: XXXXXXX XXXX 2 ／ 4 Certificate of Analysis Clofarabine Impurity Solution: XXXXXXX XXXX 2 ／ 4 Certificate of Analysis Primary Reference Standard Qualification: 2 ／ 4

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2.1 - 10

巻／巻数 Lot No: XXXXXXX

PREPARATION OF CLOFARABINE REFERENCE STANDARD: Batch No.: Lot No: XXXXXXX

2 ／ 4

3.2.S.6 容器及び施栓系 2 ／ 4

Container Closure System: XXXXXXX XXXXXXX 2 ／ 4

3.2.S.6 容器及び施栓系（XXXX） 2 ／ 4

RAW MATERIAL SPECIFICATIONS & TEST RECORD FORM: XXXXX

2 ／ 4

RAW MATERIAL SPECIFICATIONS & TEST RECORD FORM: XXXXX

2 ／ 4

RAW MATERIAL SPECIFICATIONS & TEST RECORD FORM: XXXXX 2 ／ 4 3.2.S.7 安定性 2 ／ 4 3.2.S.7.1 安定性のまとめ及び結論 2 ／ 4 3.2.S.7/3.2.S.7.1 安定性 (XXX), 安定性のまとめ及び結論（XXX） 2 ／ 4 3.2.S.7.2 承認後の安定性試験計画の作成及び実施 2 ／ 4 3.2.S.7.2 承認後の安定性試験計画の作成及び実施（XXX） 2 ／ 4 3.2.S.7.3 安定性データ 2 ／ 4 3.2.S.7.3 安定性データ（XXX） 2 ／ 4 3.2.P 製剤（XXXXXXX XXXXXXX XXXXXXX XXXXXXX） 3 - 4 ／ 4 3.2.P.1 製剤の処方 3 ／ 4 3.2.P.2 製剤開発の経緯 3 ／ 4 3.2.P.2.1 製剤成分 3 ／ 4 3.2.P.2.1.1 原薬 3 ／ 4 3.2.P.2.1.2 添加剤 3 ／ 4 3.2.P.2.2 製剤 3 ／ 4

Solubility of Clofarabine in Saline Solution 3 ／ 4

3.2.P.2.2.1 製剤設計 3 ／ 4 3.2.P.2.2.2 過量仕込み 3 ／ 4 3.2.P.2.2.3 物理学的及び生物学的性質 3 ／ 4 3.2.P.2.3 製造工程の開発の経緯 3 ／ 4 3.2.P.2.4 容器及び施栓系 3 ／ 4 XXXXXXX XXXXXXXXXXXXXX XXXXXXX 3 ／ 4

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2.1 - 11

巻／巻数

3.2.P.2.5 微生物学的観点からみた特徴 3 ／ 4

Method Development of a Container Integrity Test by the Microbial Ingress Method for Media Filled Vials: 1203-AXJ24-ILEX-RE 1

3 ／ 4

PROTOCOL FOR CONTAINER/CLOSURE INTEGRITY TESTING OF MEDIA-FILLED VIALS: Protocol No. ILEX103003

3 ／ 4

3.2.P.2.6 溶解液や使用時の容器／用具との適合性 3 ／ 4

Clofarabine IV Bag Solution Stability Study: 0027AD8001 3 ／ 4

Analytical Report: Compatibility study between Clofarabine injection and 0.9% saline solution over a XXXX dosing period

3 ／ 4 3.2.P.3 製造 3 ／ 4 3.2.P.3.1 製造者 3 ／ 4 3.2.P.3.2 製造処方 3 ／ 4 3.2.P.3.2 製造処方（XXXXX） 3 ／ 4 3.2.P.3.3 製造工程及びプロセス・コントロール 3 ／ 4

Hot Water System P& ID 3 ／ 4

3.2.P.3.4 重要工程及び重要中間体の管理 3 ／ 4

3.2.P.3.4 重要工程及び重要中間体の管理（XXXXX） 3 ／ 3

3.2.P.3.5 プロセス・バリデーション／プロセス評価 3 ／ 4

Validation summary of Bl study in XXXXXX steam autoclave: Protocol No: 1309.8.62

3 ／ 4

FINAL REPORT Amended

D(121)-Value Determination of XXXXXXXXXXXXXXXXXXXXXXXX

Suspension (XXXXXXXXXXXX. Lot No. XXXXXX) in Clofarabine 1mg/mL (Batch No. XXXXXX)

3 ／ 4

Liquid qualification summary of-The XXXXXX steam autoclave: Protocol No: 1309.8.61

3 ／ 4

3.2.P.3.5 プロセス・バリデーション／プロセス評価（XXXX） 3 ／ 4

Filtration Sterilization Validation, Clofarabine Injection Solution, Doc. # 0027CM9004

3 ／ 4

D-Value Determination For

XXXXXXXXXXXXXXXXXX in 1 mg/mL Clofarabine Injection, Microbiology Report #. M200202

3 ／ 4

D(121)-Value Determination of XXXXXXXXXXXXXXXX

Suspension (XXXXXXXXXXXX. Lot No. XXXXXX) in Clofarabine 1mg/mL (Batch No. XXXXXX)

(13)

エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 12 巻／巻数 3.2.P.4 添加剤の管理 3 ／ 4 3.2.P.4.1 規格及び試験方法 3 ／ 4 3.2.P.4.2 試験方法 3 ／ 4 3.2.P.4.3 試験方法のバリデーション 3 ／ 4 3.2.P.4.4 規格及び試験方法の妥当性 3 ／ 4 3.2.P.4.5 ヒト又は動物起源の添加剤 3 ／ 4 3.2.P.4.6 新規添加剤 3 ／ 4 3.2.P.5 製剤の管理 3 ／ 4 3.2.P.5.1 規格及び試験方法 3 ／ 4 3.2.P.5/3.2.P.5.1 製剤の管理（XXX） / 規格及び試験方法（XXX） 3 ／ 4 3.2.P.5.2 試験方法 3 ／ 4

Analytical Procedure Quality Control No: XXXXXXXX 3 ／ 4

Analytical Test Procedure for Clofarabine Drug Product (1mg/mL) (Revision4): XXXXXXXX

3 ／ 4

3.2.P.5.2 試験方法（XXX） 3 ／ 4

Analytical Test Procedure for Clofarabine Drug Product (1mg/mL (Revision 4): XXXXXXXX

3 ／ 4

UV ID Test for Clofarabine Drug Product Release Testing: XXXXXXXX

3 ／ 4

UV-Visible Spectrophotometric Identification of Clofarabine Injection,

3 ／ 4

Assay and Impurities for Clofarabine Drug Product (1mg/mL) for GENZYME Corporation: TP:66061

3 ／ 4

3.2.P.5.3 試験方法のバリデーション 3 ／ 4

Protocol: Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid Chromatography-Revision 4: 07TRSA144

3 ／ 4

Protocol Amendment: Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid Chromatography-Revision 4: 07TRSA144

3 ／ 4

Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid Chromatography-Revision 4: 07TRSA144

3 ／ 4

Protocol : Determination of the XXXXXXXX XXXXXXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level using High Performance Liquid Chromatography

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2.1 - 13

巻／巻数 Project No. 6074-5124 XXXXXXXX

Protocol Amendment: Determination of the XXXXXXXX XXXXXXXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level using High Performance Liquid Chromatography

3 ／ 4

Determination of XXXXXXXX XXXXXXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level Using High Performance Liquid Chromatography: 07TRSA103

3 ／ 4

Qualification of the Analytical Method XXXXXXX for UV-Visible Spectrophotometric Identification of Clofarabine Injection 1mg/mL BIEN5000A1 3 ／ 4 エボルトラの純度試験 HPLC 法のシステム適合性（検出の確認）の検討： IDCAD-12-025 試験報告書/試験計画書 3 ／ 4 3.2.P.5.3 試験方法のバリデーション（XXXX） 3 ／ 4

Protocol: Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid Chromatography-Revision4: 07TRSA144

3 ／ 4

Protocol Amendment: Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid Chromatography-Revision4: 07TRSA144

3 ／ 4

Method Validation of Clofarabine API and Clofarabine Drug Product by High Performance Liquid

Chromatography-Revision4: 07TRSA144

3 ／ 4

Protocol : Determination of the XXXXXXXX XXXX for Clofarabine Degradation Impurities at the Limit of

(15)

2.1 - 14

巻／巻数 Quantification (LOQ) Level using High Performance

Liquid Chromatography

Project No. 6074-5124 XXXXXXXX XXXX

Protocol Amendment: Determination of the XXXXXXX X XX XXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level using High Performance Liquid Chromatography: Project No. 6074-5124 XXXXXXXX XXXX

3 ／ 4

Determination of XXXXXXXX XXXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level Using High Performance Liquid Chromatography: 07TRSA103

3 ／ 4

Addendum to Determination of the XXXXXXXX XXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level Using High Performance Liquid Chromatography: 07TRSA103 (Addendum 01)

3 ／ 4

Addendum to Determination of the XXXXXXX XXXX for Clofarabine Degradation Impurities at the Limit of Quantification (LOQ) Level Using High Performance Liquid Chromatography: 07TRSA103 (Addendum 02)

3 ／ 4

Qualification of the Analytical Method XXXXXXX for UV-Visible Spectrophotometric Identification of Clofarabine Injection 1mg/mL BIEN5000A1

3 ／ 4

METHOD DEVELOPMENT AND VALIDATION OF STERILITY TEST: ILEX3003A

3 ／ 4

Method Development and Validation of USP Bacterial Endotoxins (LAL) Test for Clofarabine Injection: 2524-AMF72-ILEX

3 ／ 4

METHOD DEVELOPMENT AND VALIDATION OF BIOBURDEN TEST: ILEX3002D

3 ／ 4

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2.1 - 15

巻／巻数 Assay of Clofarabine in Clofarabine Injection (1mg/mL):

ILEX3006

3.2.P.5.4 ロット分析 4 ／ 4

CERTIFICATE OF ANALYSIS Batch/lot number: XXXXXXX 4 ／ 4

CERTIFICATE OF ANALYSIS LOT #: XXXXXXX 4 ／ 4

CERTIFICATE OF ANALYSIS Batch ID: XXXXXXX 4 ／ 4

CERTIFICATE OF ANALYSIS LOT#: XXXXXXX 4 ／ 4

3.2.P.5.4 ロット分析（XXXX） 4 ／ 4

Certificate of Analysis Lot#: XXXXXXX 4 ／ 4

Certificate of Analysis Batch/lot#: XXXXXXX 4 ／ 4

3.2.P.5.5 不純物の特性 4 ／ 4

3.2.P.5.5 不純物の特性（XXXX） 4 ／ 4

3.2.P.5.6 規格及び試験方法の妥当性 4 ／ 4

3.2.P.5.6 規格及び試験方法の妥当性（XXXX） 4 ／ 4

Analytical Test Procedure for Clofarabine Drug Product (1 mg/mL) TM19.031

4 ／ 4

3.2.P.6 標準品または標準物質 4 ／ 4

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2.1 - 16

巻／巻数

ANALYTICAL PROCEDURE QUALITY CONTROL SNAP CAPS 4 ／ 4

XXXX FLIP OFF SEAL XXXX XXXXX DRAWING: NO. XXXX XXXX 4 ／ 4

Flip Off Seal XXXXXXXXX 4 ／ 4

XXXXXXXX STOPPER DRAWING: NO. XXXX X 4 ／ 4

XXXXXXXXXXXXXXXXXXXXXXXXXXXX 4 ／ 4

STANDARD OPERATING PROCEDURE – INSTRUCTION: Rubber Stoppers

4 ／ 4

Injection vial XXXX Drawing number XXXXXXXX 4 ／ 4

STANDARD OPERATING PROCEDURE – INSTRUCTION: Injection vials, type XXXXXXXX

4 ／ 4

CERTIFICATE 4 ／ 4

XXXXXXXX clear, Technical Data 4 ／ 4

Certificate of Conformity 4 ／ 4

3.2.P.7 容器及び施栓系（XXXX） 4 ／ 4

XXXX FLIP OFF SEAL XXXX XXXXX DRAWING: NO. XXXXXXXX

4 ／ 4

XXXX PURFORM VIAL SERUM / LYOPHILIZATION XXXX XXXX

4 ／ 4

Packaging Component Specification Vial:20mL, XXXX Type 1 Glass (XXXX Product #6800321): PC-3196-03

4 ／ 4

Packaging Component Specification XXXX Flip-Off XXXXXXXXXXXX Seal: PC-3201-01

4 ／ 4

Packaging Component Specification XXXXXXXX NP Stopper, XXXX XXXX (Product ID #10144257): PC-3274-00

4 ／ 4

Packaging Component Specification Label: Vial for ClolarTM Clofarabin (1mg/mL) 20cc- Genzyme Oncology: PC-3554-01

4 ／ 4

Packaging Component Specification Stopper: XXXXXXX XXXXXXXX XXXX XXXX (Item # XXXX XXXX): XXXXXXXX

4 ／ 4

XXXXXXXX STOPPER DRAWING: NO. XXXX XXXX 4 ／ 4

CERTIFICATE OF ANALYSIS Master Lot # XXXX XXX 4 ／ 4 Additional Information About USP Type I Glass 4 ／ 4

(18)

エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 17 巻／巻数 3.2.P.8 安定性 4 ／ 4 3.2.P.8.1 安定性のまとめ及び結論 4 ／ 4

Technical Report: Clofarabine Drug Product (1 mg/ml) Photostability Study Report Number: 0027AD5005

4 ／ 4 3.2.P.8/3.2.P.8.1 安定性（XXXX）/ 安定性のまとめ及び結論（XXXX） 4 ／ 4 3.2.P.8.2 承認後の安定性試験計画の作成及び実施 4 ／ 4 3.2.P.8.2 承認後の安定性試験計画の作成及び実施 (XXXX) 4 ／ 4 3.2.P.8.3 安定性データ 4 ／ 4

Stability Report to Evaluate the Light Sensitivity of Clofarabine Injection, XXmg/mL, Lot No. B100713: Technical Report No.: XXXXXXXX

4 ／ 4 3.2.P.8.3 安定性データ（XXXX） 4 ／ 4 3.2.A その他 4 ／ 4 3.2.A.1 製造施設及び設備 4 ／ 4 3.2.A.2 外来性感染性物質の安全性評価 4 ／ 4 3.2.A.3 添加剤 4 ／ 4 3.2.R 各極の要求資料 3.3 参考文献 4 ／ 4

3.3.1 Andrzejewska M, Dzierzgowska-Szmidt A, Kazimierczuk Z. Alkaline hydrolysis of cladribine. Pharmazie 58: 122-124 (2003)

4 ／ 4

3.3.2 Fresenius W, Huber JFK, Pungor E, Rechnitz GA, et al. Tables of Spectral Data for Structure Determination of Organic Compounds

13C-NMR, 1H-NMR, IR, MS, & UV/VIS. 2nd edition Springer-Verlag, NY 1989; page C212

4 ／ 4

3.3.3 _{Montgomery JA, Shortnacy-Fowler AT, Clayton SD, et al. Synthesis and} Biologic Activity of 2´-fluoro-2-halo Derivatives of 9-

β-D-Arabinofuranosyladenine. J Med Chem 1992; 35:397-401.

4 ／ 4

3.3.4 _{Saenger W. Principles of Nucleic Acid Structure, Springer-Verlag, NY,} 1983: Chapter 4 - Structures and Conformational Properties of Bases, Furanose Sugars, and Phosphate Groups.

4 ／ 4

3.3.5 Saenger W, Principles of Nucleic Acid Structure, Springer-Verlag, New York, 1984: Chapter 5- Physical Properties of Nucleotides: Charge Densities, pK values, Spectra, and Tautomerism

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(20)

エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 19 第 4 部（モジュール 4）の目次 巻／巻数 4 第 4 部（モジュール 4）非臨床試験報告書 1 - 7／ 7 4.1 目次 1 ／ 7 4.2 試験報告書 1 - 6 ／ 7 4.2.1 薬理試験 1 ／ 7 4.2.1.1 効力を裏付ける試験 1 ／ 7 4.2.1.1.1 Genz0503-01 1 ／ 7

Antiproliferation, cytokine secretion, hydrogen peroxide generation, and phagocytosis in MOLT-4 tumor, U937 cells and normal peripheral leukocytes

4.2.1.1.2 0303RX34-1 1 ／ 7

National Cancer Institute Developmental Therapeutics program In-Vitro Testing Results

4.2.1.1.3 ILEX 14 1 ／ 7

RESPONSE OF SC CCRF-CEM LEUKEMIA TO TREATMENT WITH ARA-C AND CLOFARABINE

4.2.1.1.4 ILEX 12 1 ／ 7

RESPONSE OF SC CCRF-CEM LEUKEMIA TO TREATMENT WITH CLOFARABINE AND ARA-C

4.2.1.1.5 GZ-14 1 ／ 7

RESPONSE TO SUBCUTANEOUSLY IMPLANTED RL HUMAN

LYMPHOMA TO COMBINATION TREATMENT WITH CLOFARABINE AND RITUXAN

4.2.1.1.6 ILEX 16 1 ／ 7

RESPONSE OF SC NCI-H460 LUNG TUMOR TO TREATMENT WITH CLOFARABINE

4.2.1.1.7 ILEX 27 1 ／ 7

RESPONSE OF SC HT29 COLON TUMOR TO TREATMENT WITH CLOFARABINE OR CPT-11

4.2.1.1.8 DE111802 02 1 ／ 7

CLOFARABINE DOSED PO OR IP AGINST HT29 HUMAN COLORECTAL CARCINOMA XENOGERAFT MODEL

4.2.1.1.9 ILEX 11 1 ／ 7

RESPONSE OF SC HT29 COLON TUMOR TO TREATMENT WITH CLOFARABINE

(21)

2.1 - 20

巻／巻数

4.2.1.1.10 ILEX 24 1 ／ 7

RESPONSE OF SC HT29 COLON TUMOR TO COMBINATION TREATMENT WITH OXALIPLATINE AND CLOFARABINE

4.2.1.1.11 ILEX 8 1 ／ 7

RESPONSE OF SC HT29 COLON TUMOR TO COMBINATION TREATMENT WITH CLOFARABINE AND 5-FU

4.2.1.1.12 ILEX 4 1 ／ 7

RESPONSE OF SC HT29 COLON TUMOR TO COMBINATION TREATMENT WITH CLOFARABINE AND IRINOTECAN

4.2.1.1.13 ILEX 19 1 ／ 7

RESPONSE OF SC HT29 COLON TUMOR TO COMBINATION TREATMENT WITH CLOFARABINE AND IRINOTECAN

4.2.1.1.14 ILEX 25 1 ／ 7

RESPONSE OF SC HT29 COLON TUMOR TO COMBINATION TREATMENT WITH CLOFARABINE AND CAMPTOSAR

4.2.1.1.15 5260-7#138 1 ／ 7

RESPONSE OF SC PC-3 PROSTATE TUMOR TO TREATMENT WITH 2-CL-2’-F-ARA-A (MSC 606869) AND 2-F-ARA-AMP (MSC 312887)

4.2.1.1.16 ILEX 9 1 ／ 7

RESPONSE OF SC PC-3 PROSTATE TUMOR TO COMBINATION TREATMENT WITH CLOFARABINE AND TAXOTERE

4.2.1.2 副次的薬理試験 1 ／ 7

4.2.1.2.1 Cerep Study 7417 1 ／ 7

In Vitro Pharmacology

Study of compounds 144-116-10 CLO and 144-127-28-CMP

4.2.1.3 安全性薬理試験 1 ／ 7

4.2.1.3.1 05.059/2 1 ／ 7

EVALUATION OF CLOFARABINE IN THE IRWIN TEST IN THE RAT (I.V. ADMINISTRATION SLOW BOLUS)

4.2.1.3.2 05.060/3 1 ／ 7

SAFETY PHARMACOLOGY STUDY ON RESPIRATORY FUNCTION FOR CLOFARABINE IN THE RAT (WHOLE BODY

PLETHYSMOGRAPHY)

4.2.1.3.3 05.061/2 1 ／ 7

EVALUATION OF CLOFARABINE ON DIURESIS AND URINARY ELECTROLYTE EXCRETION AFTER INTRAVENOUS

(22)

2.1 - 21

巻／巻数 ADMINISTRATION (SLOW BOLUS) IN THE RAT

4.2.1.3.4 MBU00028-04-1071 1 ／ 7

A STUDY TO ASSESS THE CARDIOVASCULAR EFFECTS OF CLOFARABINE FOLLOWING REPEAT INTRAVENOUS ADMINISTRATION IN TELEMETERD FISCHER 344 RATS

4.2.1.3.5 05.062/3 1 ／ 7

IN-VITRO EFFECT OF CLOFARABINE ON hERG CURRENT (IKr)

EXPRESSED IN HUMAN EMBRYONIC KIDNEY (HEK) CELLS

4.2.1.4 薬力学的薬物相互作用試験

4.2.2 薬物動態試験 2 ／ 7

4.2.2.1 分析法及びバリデーション報告書 2 ／ 7

4.2.2.1.1 BIOV111_003a.Bioenvision 3 2 ／ 7

Method for the quantitation of clofartabine in dosing solutions

4.2.2.1.2 AU211 2 ／ 7

THE VALIDATION OF AN HPLC/MS ASSAY TO MEASURE CLOFARABINE IN RAT PLASMA

4.2.2.1.3 AU214 2 ／ 7

The application of an HPLC/MS assay to measure clofarabine in rat plasma Study: 05.060.3

4.2.2.1.4 MC02113 2 ／ 7

Validation of a Method for the Determination of Clofarabine in Rat Plasma using High Performance Liquid Chromatography with Mass Spectrometric (MS/MS) Detection

4.2.2.1.5 MC02114 2 ／ 7

Validation of a Method for the Determination of Clofarabine in Dog Plasma using High Performance Liquid Chromatography with Mass Spectrometric (MS/MS) Detection

4.2.2.2 吸収 2 ／ 7

4.2.2.2.1 MC02410 2 ／ 7

Intravenous and Oral Pharmacokinetic Study of Clofarabine in Male CD-1 Mice

4.2.2.3 分布 2 ／ 7

4.2.2.3.1 QKAN-2002-0783-ADM 2 ／ 7

(23)

2.1 - 22

巻／巻数 Intravenous Dose Regimen of 14C-Clofarabine

4.2.2.3.2 DMPK12-R056 2 ／ 7

Determination of Red Blood Cell Partitioning of Clofarabine in Human Whole Blood

4.2.2.3.3 DMPK12-R055 2 ／ 7

Protein Binding of Clofarabine in Human Plasma Using Rapid Equilibrium Dialysis

4.2.2.4 代謝 2 ／ 7

4.2.2.4.1 QKAN-2002-0642-BIO 2 ／ 7

In Vivo Metabolism of Clofarabine in Rat Myocardium, Liver, Urine, Feces and Plasma Samples Collected from Protocol (PK-917)

4.2.2.4.2 QKAN-2002-0542-BIO 2 ／ 7

In Vitro Metabolism of Clofarabine in Rat, Dog and Human Cryopreserved

Hepatocytes

4.2.2.4.3 13558-103 2 ／ 7

Clofarabine: in Vitro Metabolic Stability in Liver Microsomes

4.2.2.4.4 DMPK12-R009 2 ／ 7

In Vitro Metabolism of Clofarabine by Recombinant Human Adenosine

Deaminase

4.2.2.4.5 DMPK12-R022 2 ／ 7

In Vitro Metabolism of Clofarabine in Recombinant Human Monoamine

Oxidase A and Monoamine Oxidase B Enzymes

4.2.2.5 排泄 2 ／ 7

4.2.2.5.1 QKAN-2002-0705-ADM 2 ／ 7

Radiokinetic and 14C Excretion/Mass Balance Study of 14C-Clofarabine in Fischer 344 Rats.

4.2.2.5.2 Traft/15Aug07 2 ／ 7

Clofarabine Excretion in the Perfused Rat Kidney

4.2.2.6 薬物動態学的薬物相互作用（非臨床） 2 ／ 7

4.2.2.6.1 13558-109 2 ／ 7

Inhibition Study of Human Cytochrome P450 Isozyme catalytic activities by Clofarabine Using Human Liver Microsomes.

4.2.2.6.2 14060-033 2 ／ 7

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エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 23 巻／巻数 Substrates. 4.2.2.6.3 5GENZP2 2 ／ 7

CYP INDUCTION ASSESSMENT - In vitro study to assess the potential inducing effect of clofarabine on the activity of CYP1A2 and CYP3A4 in human hepatocytes.

4.2.2.7 その他の薬物動態試験

4.2.3 毒性試験 2-6 ／ 7

4.2.3.1 単回投与毒性試験 2 ／ 7

4.2.3.1.1 MDACC1 2 ／ 7

Clofarabine Mouse Studies

4.2.3.2 反復投与毒性試験 2-4 ／ 7

4.2.3.2.1 0106-01 2 ／ 7

Five-Day Intravenous GLP Toxicity Study of Clofarabine in Male Fischer 344 Rats

4.2.3.2.2 0110-02 2 ／ 7

Five-Day Intravenous Infusion GLP Toxicity Study of Clofarabine in Male Fischer 344 Rats

4.2.3.2.3 0204-03、MC02116（トキシコキネティクス） 3 ／ 7

CLOFARABINE: A MULTI-CYCLE (FIVE DAYS’ DOSING PLUS 23 DAYS’ RECOVERY PER CYCLE) INTRAVENOUS TOXICITY AND TOXICOKINETICS STUDY IN FISCHER 344 RATS

4.2.3.2.4 0204-05 3 ／ 7

THREE WEEKLY ORAL AND INTRAVENOUS DOSE BRIDGING TOXICITY STUDY OF CLOFARABINE IN FISCHER 344 RATS

4.2.3.2.5 0203-01、MC02111 及び MC02111-A1（トキシコキネティクス） 4 ／ 7

CLOFARABINE: A MULTI-CYCLE (FIVE DAYS’ DOSING PLUS 23 DAYS’ RECOVERY PER CYCLE) INTRAVENOUS TOXICITY AND TOXICOKINETICS STUDY IN BEAGLE DOGS

4.2.3.2.6 MDACC2 4 ／ 7

Clofarabine Dog Studies

4.2.3.2.7 0111-01 4 ／ 7

Five-Day Intravenous Infusion Range-Finding Study of Clofarabine in Beagle Dogs

(25)

エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 24 巻／巻数 4.2.3.3.1 In vitro 試験 5 ／ 7 4.2.3.3.1.1 CLO.00.07.02 5 ／ 7

Bacterial Reverse Mutation Assay

4.2.3.3.1.2 CLO.00.07.03 5 ／ 7

IN VITRO MAMMALIAN CHROMOSOME ABERRATION TEST

4.2.3.3.2 In vivo 試験 5 ／ 7

4.2.3.3.2.1 CLO.00.48 5 ／ 7

MAMMALIAN ERYTHYROCYTE MICRONUCLEUS TEST

4.2.3.4 がん原性試験

4.2.3.5 生殖発生毒性試験 5 ／ 7

4.2.3.5.1 受胎能及び着床までの初期胚発生に関する試験

4.2.3.5.2 胚・胎児発生に関する試験 5 ／ 7

4.2.3.5.2.1 0202-01 5 ／ 7

INTRAVENOUS DOSE-RANGE DEVELOPMENT TOXICITY STUDY OF CLOFARABINE IN RATS

4.2.3.5.2.2 0204-01 5 ／ 7

INTRAVENOUS DEVELOPMENT TOXICITY STUDY OF CLOFARABINE IN RATS

4.2.3.5.2.3 0202-02 5 ／ 7

INTRAVENOUS DOSE-RANGE DEVELOPMENT TOXICITY STUDY OF CLOFARABINE IN RABBITS

4.2.3.5.2.4 0204-02 5 ／ 7

INTRAVENOUS DEVELOPMENT TOXICITY STUDY OF CLOFARABINE IN RABBITS

4.2.3.5.3 出生前及び出生後の発生並びに母体の機能に関する試験

4.2.3.5.4 新生児を用いた試験

4.2.3.6 局所刺激性試験 5 ／ 7

4.2.3.6.1 MBU00008 5 ／ 7

A PRIMARY EYE IRRITATION STUDY IN RABBITS WITH CLOFARABINE (RAW POWDER)

4.2.3.6.2 MBU00010 5 ／ 7

A PRIMARY EYE IRRITATION STUDY IN RABBITS WITH CLOFARABINE (CLINICAL FORMULATION)

4.2.3.6.3 MBU00009 5 ／ 7

(26)

2.1 - 25

巻／巻数 CLOFARABINE (RAW POWDER)

4.2.3.6.4 MBU00011 5 ／ 7

A PRIMARY SKIN IRRITATION STUDY IN RABBITS WITH CLOFARABINE (CLINICAL FORMULATION)

4.2.3.7 その他の毒性試験 6 ／ 7

4.2.3.7.1 抗原性試験

4.2.3.7.2 免疫毒性試験

4.2.3.7.3 毒性発現の機序に関する試験 6 ／ 7

4.2.3.7.3.1 0204-04 6 ／ 7

Five-Day Intravenous GLP Cardiac Biomarker Study of Clofarabine in Male Fischer 344 Rats

4.2.3.7.4 依存性試験

4.2.3.7.5 代謝物の毒性試験

4.2.3.7.6 不純物の毒性試験 6 ／ 7

4.2.3.7.6.1 3569.4 6 ／ 7

A 5-DAY INTRAVENOUS TOXICITY STUDY IN FEMALE FISCHER 344 RATS COMPARING TWO LOTS OF CLOFARABINE

4.2.3.7.6.2 GT-237-TX-1 6 ／ 7

A 5-DAY INTRAVENOUS TOXICITY STUDY IN FEMALE FISCHER 344 RATS COMPARING TWO LOTS OF CLOFARABINE

4.2.3.7.6.3 GT-237-TX-2 6 ／ 7

A 5-Day Toxicity Study Comparing Clofarabine to Two Lots of Clofarabine Containing Degradants 9 and 12 Administered Intravenously to Fischer 344 Rats

4.2.3.7.7 その他の試験 6 ／ 7

4.2.3.7.7.1 0658-07156 6 ／ 7

A FIVE DAY INTRAVENOUS, A FIVE DAY ORAL, AND A 21-DAY ORAL COMPARATIVE HEMATOLOGICAL TOXICITY STUDY OF CLOFARABINE IN MALE FISCHER 344 RATS

4.3 参考文献 7 ／ 7

4.3.1 Ajvon AD, Bonate PL, Taft DR. Renal excretion of clofarabine: Assessment of dose-linearity and role of renal transport systems on drug excretion. Eur J Pharm Sci. 2010; 40: 209-16.

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2.1 - 26

巻／巻数 4.3.2 Albertioni F, Hassan M, Silberring J, Liliemark J. Kinetics and metabolism

of 2-chloro-2’-deoxyadenosine and 2-chloro-2’ arabino-fluoro-2’-deoxyadenosine in the isolated perfused rat liver. Eur J Drug Metab Pharmacokinetics. 1995; 20: 225-32.

7 ／ 7

4.3.3 Arner ESJ, Eriksson S. Mammalian deoxyribonucleoside kinases. Pharmac Ther 1995;67:155-86.

7 ／ 7

4.3.4 Bacon W. Cyclophosphamide-induced temporomandibular synostosis. Am J Orthod. 1983; 83: 504-12.

7 ／ 7

4.3.5 Baldwin SA, Mackey JR, Cass CE, Young JD. Nucleoside transporters: molecular biology and implications for therapeutic development. Molecular Medicine Today 1999; 5: 216-24.

7 ／ 7

4.3.6 Beesley AH, Palmer ML, Ford J, Weller RE, Cummings AJ, Freitas JR, et al.

In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric

acute lymphoblastic leukaemia. Br J Haematol. 2007; 137: 109-116.

7 ／ 7

4.3.7 Beesley AH, Palmer ML, Ford J, Weller RE, Cummings AJ, Freitas JR, et al. Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines. Br J Cancer. 2006; 95: 1537-44.

7 ／ 7

4.3.8 Beutner G, Rück A, Riede B, Brdiczka D. Complexes between porin, hexokinase, mitochondrial creatin kinase and adenylate translocator display properties of the permeability transition pore. Implication for regulation of permeability transition by the kinases. Biochim Biophy Acta. 1998; 1368: 7-18.

7 ／ 7

4.3.9 Brock N, Kreybig T. Experimentller beitrag zur prüfung teratogener wirkungen von arzneimitteln an der laboratoriumsratte. Naunyn-Schmiedebergs Arch Exp Pathol Pharmakol 1964; 249: 117-45.

7 ／ 7

4.3.10 Carson DA, Wasson DB, Esparza LM, Carrera CJ, Kipps TJ, Cottam HB. Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2’-arabino-fluoro-2’-deoxyadenosine. Proc Natl Acad Sci USA. 1992; 89:2970-4.

7 ／ 7

4.3.11 Chaube S, Kury G, Murphy ML. Teratogenic effects of cyclophosphamide (NSC-26271) in the rat. Cancer Chemother Peports. 1967; 51: 363-76.

7 ／ 7

4.3.12 Conrad DM, Robichaud MR, Mader JS, Boudreau RT, Richardson AM, Giacomantonio CA, et al. 2-chloro-2’-deoxyadenosine-induced apoptosis in T leukemia cells is mediated via a caspase-3-dependent mitochondrial feedback amplification loop. Int J Oncol. 2008;32:1325-33.

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2.1 - 27

巻／巻数 4.3.13 Cooper T, Ayres M, Nowak B, Gandhi V. Biochemical modulation of

cytarabine triphosphate by clofarabine. Cancer Chemothr Pharmacol 2005; 55: 361-8.

7 ／ 7

4.3.14 Eaton GJ et al Dystrophic cardiac calcinosis in mice. Am J Phathol 1978; 90: 173-86.

7 ／ 7

4.3.15 Eriksson S, Arner E, Spasokoukotskaja T, Wang L, Karlsson A, Brosjo O, et al. Properties and levels of deoxynucleoside kinases in normal and tumor cells; implications for chemotherapy. Advan Enzyme Regul 1994; 34: 13-25.

7 ／ 7

4.3.16 Eudaly JA, Tizzano JP, Higdon GL, Todd GC. Developmental toxicity of gemcitabine, an antimetabolite oncolytic, administered during gestation to CD-1 mice. Teratology 1993; 48: 365-81.

7 ／ 7

4.3.17 Faustman EM, Ponce RA, Seeley MR, Whittaker SG. Experimental approaches to evaluate mechanisms of developmental toxicity. Handbook of Developmental Toxicology. 1997; pp13-41.

7 ／ 7

4.3.18 Fosslien E. Review: Mitochondrial medicine- Molecular pathology of defective oxidative phophorylation. Annal Clin Lab Science 2001; 31(1): 25-67.

7 ／ 7

4.3.19 Gati WP, Paterson ARP, Belch AR, Chlumecky V, Larratt LM, Mant MJ et al. Es nucleoside transporter content of acute leukemia cells: role in cell sensitivity to cytarabine (araC). Leuk Lymphoma 1998;32:45-54.

7 ／ 7

4.3.20 Genini D, Adachi S, Chao Q, Rose DW, Carrera CJ, Cottam HB, et al. Deoxyadenosine analogs induce programmed cell death in chronic

lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood 2000; 96: 3537-43.

7 ／ 7

4.3.21 Hijiya N, Gaynon P, Barry E Silverman L, Thomson B, Chu R, et al. A multi-center phase 1 study of clofarabine, etoposide and cyclophosphamide in combination in pediatric patients with refractory or relapsed acute leukemia. Leukemia. 2009; 23: 2259-64.

7 ／ 7

4.3.22 Janion C. On the ability of Salmonella typhimurium cells to form deoxycytidine nucleotides. Mol Gen Genet 1977: 153(2): 179-83.

7 ／ 7

4.3.23 Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004; 103: 784-9.

7 ／ 7

4.3.24 Kang YJ. New understanding in cardiotoxicity. Current Opinion Drug Dis Development. 2003; 6(1): 110-6.

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巻／巻数 4.3.25 King KM, Vickers MF, Damaraju V, Mowles DA, Lang T, Young JD et al.

Nucleoside transporter proteins are determinants of cytotoxicity of clofarabine (Clofarex™) in cultured leukemic cell lines. Blood 2002;100. Abstract 1247.

7 ／ 7

4.3.26 King KM, Damaraju VL, Vickers MF, Yao SY, Lang T, Tackaberry TE et al. A comparison of the transportability, and its role in cytotoxicity, of

clofarabine, cladribine, and fludarabine by recombinant human nucleoside transporters produced in three model expression systems. Mol Pharmacol 2006;69:346-53.

7 ／ 7

4.3.27 Kline JP and Larson RA. Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review. Expert Opin Pharmacother. 2005; 6: 2711-8.

7 ／ 7

4.3.28 Korff S et al. Calcification of myocardial necrosis is common in mice. Virchows Arch 2006; 448; 630-638.

7 ／ 7

4.3.29 Lau C, Narotsky MG, Lui D, Best D, Setzer RW, Mann PC, et al. Exposure-disease continuum for 2-chloro-2’-deoxyadenosine (2-CdA), a prototype teratogen: induction of lumbar hernia in the rat and species comparison for teratogenic responses. Teratology 2002; 66(1): 6-18.

7 ／ 7

4.3.30 Lindemalm S, Liliemark J, Larsson BS, Albertioni F. Distribution of 2-chloro-2’-deoxyadenosine, 2-chloro-2’-arabino-fluoro-2’-deoxyadenosinde, fludarabine, and cytarabine in mice: a whole-body autoradiography study. Med Oncol 1999; 16: 239-44.

7 ／ 7

4.3.31 Lindemalm S, Liliemark J, Gruber A, Eriksson S, Karlsson MO, et al. Comparison of cytotoxicity of 2-chloro-2’-arabino-fluoro-2’deoxyadenosine (clofarabine) with cladribine in mononuclear cells from patients with acute myeloid and chronic lymphocytic leukemia. J Hematol 2003; 88: 324-32

7 ／ 7

4.3.32 Locatelli F, Testi AM, Bemardo ME, Rizzari C, Bertaina A, Merli P, et al. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009; 147: 371-8.

7 ／ 7

4.3.33 Lotfi K, Mansson E, Spasokoukotskaja T, Petterson B, Liliemark J, Peterson C et al. Biochemical pharmacology and resistance to 2-chloro-2‘-arabino-fluoro-2‘-deoxyadenosine, a novel analogue of cladribine in human leukemic cells. Clin Cancer Res 1999; 5: 2438-44.

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巻／巻数 4.3.34 Månsson E, Flordal E, Liliemark J, Spasokoukotskaja T, Elford H,

Lagercrantz S, et al. Down-regulation of deoxycytidine kinase in human leukemic cell lines resistant to cladribine and clofarabine and increased ribonucleotide reductase activity contributes to fludarabine resistance. Bioche Pharmacol. 2003; 65: 237-47.

7 ／ 7

4.3.35 Montgomery JA, Shortnacy-Fowler AT, Clayton SD, Riordan JM, Secrist JA III. Synthesis and biologic activity of 2-fluoro-2-halo derivatives of 9- β-D-arabinofuranosyladenine. J Med Chem 1992; 35: 397-401.

7 ／ 7

4.3.36 Nagai S, Takenaka K, Nachagari D, Rose C, Domoney K, Sun D, et al. Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity. Cancer Res. 2011;71:1781-91.

7 ／ 7

4.3.37 Okamoto M, Hiratani N, Arai K, Ohkuma S. Properties of H+-ATPase from rat liver lysosomes as revealed by reconstitution into proteoliposomes. J Biochem. 1996; 120:608-15.

7 ／ 7

4.3.38 Parker WB, Shaddix SC, Chang CH, White EL, Rose LM, Brockman RW et al. Effects of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5‘-triphosphate. Cancer Res 1991; 51: 2386-94.

7 ／ 7

4.3.39 Parker WB, Shaddix SC, Rose LM, Shewach DS, Hertel LW, Secrist JA III et al. Comparison of the mechanism of cytotoxicity of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine, 2-chloro-9-(2-deoxy-2-fluoro-β-D-ribofuranosyl) adenine, and 2-chloro-9-(2-deoxy-2,2-difluoro-

β-D-ribofuranosyl) adenine in CEM cells. Molecular Pharmacol 1999; 55: 515-20.

7 ／ 7

4.3.40 Pession A, Masetti R, Kleinschmidt K and Martoni A. Use of clofarabine for acute childhood leukemia. Biologics. 2010; 24: 111-8.

7 ／ 7

4.3.41 Qian M, Wang X, Shanmuganathan K, Chu CK, Gallo JM. Pharmacokinetics of the anticancer agent 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine in rats. Cancer Chemother Pharmacol 1994; 33: 484-8.

7 ／ 7

4.3.42 Reichelova V, Liliemark J, Albertioni F. Liquid chromatographic study of acid stability of arabino-fluoro-2‘-deoxyadenosine, 2-chloro-2‘-deoxyadenosine and related analogues. J Pharm Biomed Anal 1995b; 13: 711-14.

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巻／巻数 4.3.43 Rosen MB, Chernoff N. 5-aza-2’-deoxycytidine-induced cytotoxicity and

limb reduction defects in the mouse. Teratology 2002; 65: 180-90.

7 ／ 7

4.3.44 Saven A, Piro LD. The newer purine analogs. Significant therapeutic advance in the management of lymphoid malignancies. Cancer 1993; 72: 3470-83.

7 ／ 7

4.3.45 Sjöberg AH, Wang L, Eriksson S. Substrate specificity of human recombinant mitochondrial deoxyguanosine kinase with cytostatic and antiviral purine and pyrimidine analogs. Mol Pharmacol. 1998; 53: 270-3.

7 ／ 7

4.3.46 Spasokoukotskaja T, Sasvari-Szekely M, Keszler G, Albertioni F, Eriksson S, Staub M. Treatment of normal and malignant cells with nucleoside analogues and etoposide enhances deoxycytidine kinase activity. Eur J Cancer 1999; 35: 1862-7.

7 ／ 7

4.3.47 Styczynski J, Gil L, Derwich K, Wachowiak J, Balwierz W, Badowska W, Krawczuk-Rybak M, et al. Comparison of clofarabine cytotoxic activity in childhood and adult acute leukemia. Anticancer Res. 2009; 29: 1643-1650.

7 ／ 7

4.3.48 Takahashi T, Kanazawa J, Akinaga S, Tamaoki T, Okabe M. Antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine, a novel deoxyadenosine analog, against human colon tumor xenografts by oral administration. Cancer Chemother Pharmacol 1999; 43: 233-40.

7 ／ 7

4.3.49 Veuger MJ, Honders MW, Willemze R and Barge RM. Deoxycytidine kinase expression and activity in patients with resistant versus sensitive acute myeloid leukemia. Eur J Haematol. 2002; 69: 171-8.

7 ／ 7

4.3.50 Wang J, Neuhard J, Eriksson S. An Escherichia coli system expressing human deoxyribonucleoside salvage enzymes for evaluation of potential antiproliferative nucleoside analogs. Antimicrob Agents Chemother 1998: 42: 2620-5.

7 ／ 7

4.3.51 Waud WR, Schmid SM, Montgomery JA, Secrist JA III. Preclinical antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine (Cl-F-ara-A). Nucleosides, Nucleotides and Nucleic Acids 2000; 19(1-2): 447-60.

7 ／ 7

4.3.52 Woodfield K, Rück A, Brdiczka D, Halestrap P. Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem J. 1998; 336: 287-90.

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巻／巻数 4.3.53 Xie C, Plunkett W. Metabolism and actions of

2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-adenine in human lymphoblastoid cells. Cancer Res 1995; 55: 2847-52.

7 ／ 7

4.3.54 Xie KC, Plunkett W. Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-9-(2-deoxy-2-fluoro- β-D-arabinofuranosyl) adenine. Cancer Res 1996; 56: 3030-7.

7 ／ 7

4.3.55 Yamauchi T, Nowak BJ, Keating MJ, Plunkett W. DNA repair initiated in chronic lymphocytic leukemia lymphocytes by

4-hydroperoxycyclophosphamide is inhibited by fludarabine and clofarabine. Clin Cancer Res. 2001; 7: 3580-9.

7 ／ 7

4.3.56 Zhu C, Johansson M, Permert J, Karlsson A. Enhanced cytotoxicity of nucleoside analogs by overexpression of mitochondrial deoxyguanosine kinase in cancer cell lines. J Biol Chem 1998; 273(24): 14707-11.

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エボルトラ点滴静注 20mg モジュール 2.1 CTD の目次（第 2 部から第 5 部） 2.1 - 32 第 5 部（モジュール 5）の目次 巻／巻数 5 第 5 部（モジュール 5）臨床試験報告書 1 - 25 ／ 25 5.1 目次 1 ／ 25 5.2 臨床試験一覧表 1 ／ 25 5.3 試験報告書及び関連情報 1 - 24 ／ 25 5.3.1 生物薬剤学試験報告書 1 ／ 25 5.3.1.1 バイオアベイラビリティ（BA）試験報告書 5.3.1.2 比較 BA 試験及び生物学的同等性試験（BE）試験報告書 5.3.1.3 In Vitro-In Vivo の関連を検討した試験報告書 5.3.1.4 生物学的及び理化学的分析法検討報告書 1 ／ 25 5.3.1.4.1 MC06123

Method Validation Report

Validation of a Method for the Determination of Clofarabine and 6-Ketoclofarabine in Human Plasma using High-Performance Liquid Chromatography with Mass Spectrometric (MS/MS) Detection

1 ／ 25

5.3.1.4.2 MC02298

Validation of a Method for the Determination of Clofarabine in Human Urine using High-Performance Liquid Chromatography with Mass Spectrometric (MS/MS) Detection

1 ／ 25

5.3.1.4.3 MC02293

Qualification Report

Qualification of Minor Modifications to the Method for the Determination of Clofarabine in Human Plasma using High-Performance Liquid

Chromatography with Mass Spectrometric (MS/MS) Detection

1 ／ 25

5.3.1.4.4 MC02017

Validation of a Method for the Determination of Clofarabine in Human Plasma using High-Performance Liquid Chromatography with Mass Spectrometric (MS/MS) Detection

1 ／ 25

5.3.1.4.5 MC03065

Qualification Report

Qualification of Minor Modifications to the Method for the Determination of Clofarabine in Human Plasma using High-Performance Liquid

Chromatography with Mass Spectrometric (MS/MS) Detection

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2.1 - 33

巻／巻数 5.3.1.4.6 MC05432

Validation of a Method for the Determination of Clofarabine and 6-Ketoclofarabine in Human Plasma using High-Performance Liquid Chromatography with Mass Spectrometric (MS/MS) Detection

1 ／ 25

5.3.1.4.7 MC03171 Stability Report

Evaluation of the Frozen Stability of Clofarabine in Human Plasma using High-Performance Liquid Chromatography with Mass Spectrometric (MS/MS) Detection

1 ／ 25

5.3.1.4.8 MC03105 Stability Report

Evaluation of the Frozen Stability of Clofarabine in Human Urine using High-Performance Liquid Chromatography with Mass Spectrometric (MS/MS) Detection

1 ／ 25

5.3.2 ヒト生体試料を用いた薬物動態関連の試験報告書

5.3.3 臨床薬物動態（PK）試験報告書 1 -2 ／ 25

5.3.3.2 患者における PK 及び初期忍容性試験報告書 1 -2 ／ 25

5.3.3.2.1 Population Pharmacokinetic Analysis of Clofarabine in Adult Patients with Advanced Solid Tumors Enrolled in Study CLO-151

1 ／ 25

5.3.3.2.2 Pharmacokinetic Analysis Report – CLO-152 and CLO-151 (Interim) Pharmacokinetic Analysis of Patients Enrolled in Study CLO-152 (A Phase I, Dose Escalation and Pharmacokinetic Study of Oral Clofarabine Administered Daily for 5 Days in Adult Patients with Refractory Solid Tumors) And

Interim Pharmacokinetic Analysis of Patients Enrolled in Study CLO-151 (A Phase I and Pharmacokinetic Study of Clofarabine in Adult Patients with Advanced Solid Tumors)

1 ／ 25

5.3.3.5 ポピュレーション PK 試験報告書 1 -2 ／ 25

5.3.3.5.1 FINAL Pharmacokinetic Report

Population Pharmacokinetics and Pharmacodynamics of Plasma

Clofarabine and Intracellular Clofarabine Triphosphate in Pediatric Patients with Refractory or Relapsed Acute Lymphoblastic Leukemia or Acute Myelogenous Leukemia

1 ／ 25

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2.1 - 34

巻／巻数 Erratum #1: Pooled Population Pharmacokinetic Model of Clofarabine

5.3.4 臨床薬力学（PD）試験報告書

5.3.5 有効性及び安全性試験報告書 2 ／ 25

5.3.5.1 申請する適応症に関する比較対照試験報告書

5.3.5.2 非対照試験報告書 2 – 10 ／ 25

5.3.5.2.1 CLO05908 2 ／ 25

PHASE 1 FINAL CLINICAL STUDY REPORT Clofarabine

A Phase 1, Open-label, Multi-center Study of Clofarabine in Japanese Pediatric Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia

5.3.5.2.2 ID99-383 2／ 25

Clinical Report – Protocol ID99-383

Phase I Study of CL-F-Ara-A (Clofarabine) in Pediatric Patients with Hematologic Malignancies

5.3.5.2.3 CLO-212 3 ／ 25

Final Clinical Study Report – Protocol CLO-212

A Phase II, Open-Label Study of Clofarabine in Pediatric Patients with Refractory or Relapsed Acute Lymphoblastic Leukemia

Erratum #1: Final Clinical Study Report – Protocol CLO-212

Erratum #1: Final Clinical Study Report and Addendum –Protocol CLO-212

Addendum to CLO-212 Clinical Study Report Final Clinical Study Report – Protocol CLO-212

5.3.5.2.4 CLO-222 3 ／ 25

A Phase II, Open-Label Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Myelogenous Leukemia

Erratum #1: Final Clinical Study Report – Protocol CLO-222 Erratum #1: Final Clinical Study Report – Protocol CLO-222 Addendum to CLO-222 Clinical Study Report

5.3.5.2.5 BIOV-111 4 ／ 25

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2.1 - 35

巻／巻数 A phase II, open-label study of clofarabine in paediatric patients with

refractory / relapsed acute lymphoblastic leukaemia

Erratum #1: Final Clinical Study Report – Protocol BIOV-111 Erratum #2: Final Clinical Study Report – Protocol BIOV-111 Erratum #3: Final Clinical Study Report – Protocol BIOV-111

5.3.5.2.6 CLOAML10508 5 ／ 25

PHASE 1 FINAL CLINICAL STUDY REPORT Clofarabine (Evoltra®)

A Phase 1, Open-label, Multi-center Study of Clofarabine in Japanese Patients with Acute Myeloid Leukemia (AML)

5.3.5.2.7 DM93-036 5 ／ 25

Clinical Report – Protocol DM93-036

Phase I Study of 2-chloro-2′-fluoro-Deoxy-9-β-d –

rabinofuranosyladenine (Cl-F-Ara-A; clofarabine) in Solid and Hematologic Malignancies

5.3.5.2.8 CLO-221 6 ／ 25

Clinical Report – Protocol CLO-221

A Phase II, Open-Label Study of Clofarabine in Adult Patients with Refractory or Relapsed Acute Myelogenous Leukemia

5.3.5.2.9 CLO24300606 6 – 8 ／ 25

Final Clinical Study Report – CLO24300606

A Phase II Study of Single Agent Clofarabine in Previously Untreated Older Adult Patients with Acute Myelogenous Leukemia (AML) for Whom Standard Induction Chemotherapy is Unlikely to be of Benefit

5.3.5.2.10 BIOV-121 9 ／ 25

A Phase II Trial of Clofarabine In Older Patients With Acute Myeloid Leukaemia For Whom Intensive Chemotherapy Is Not Considered Suitable BIOV-121

CLINICAL STUDY REPORT

ADDENDUM OF CLINICAL STUDY REPORT

ADDEMDUM TO BIOV -121 CLINICAL STUDY REPORT Final Clinical Study Report – Protocol BIOV – 121

5.3.5.2.11 CLO-151 10 ／ 25

Final Abbreviated Clinical Study Report – CLO-151

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2.1 - 36

巻／巻数 Advanced Solid Tumor

5.3.5.2.12 CLO-152 10 ／ 25

PHASE I DOSE-ESCALATION AND PHARMACOKINETIC STUDY A Phase I, Dose-Escalation and Pharmacokinetic Study of Oral Clofarabine Administered Daily for 5 Days in Adult Patients with Refractory Solid Tumors

5.3.5.3 複数の試験成績を合わせて解析した報告書

5.3.5.4 その他の臨床試験報告書 11 -18 ／ 25

5.3.5.4.1 CLO34100405 11 -18 ／ 25

Final Clinical Study Report – CLO34100405

A Phase III Randomized, Double-Blind, Controlled Study Comparing Clofarabine and Cytarabine vs Cytarabine Alone in Adult Patients 55 Years and Older with Acute Myelogenous Leukemia (AML) who have Relapsed or are Refractory after Receiving up to Two Prior Induction Regimens

5.3.6 市販後の使用経験に関する報告書 19 -21 ／ 25

5.3.6.1 PSUR 1 19 ／ 25

Evoltra® PERIODIC SAFETY UPDATE REPORT

5.3.6.2 PSUR 2 19 ／ 25

Evoltra® (clofarabine) PERIODIC SAFETY UPDATE REPORT

5.3.6.3 PSUR 3 19 ／ 25

Evoltra@ (Clofarabine) EU/1/06/334/001-004 Periodic Safety Update Report 3

5.3.6.4 PSUR 4 19 ／ 25

PSUR 4: PERIODIC SAFETY UPDATE REPORT for ACTIVE SUBSTANCE(S): Clofarabine

5.3.6.5 PSUR 5 19 ／ 25

Evoltra@, 1mg/m1 concentrate for solution for infusion EU/1/06/334/001-004

Periodic Safety Report 5

5.3.6.6 PSUR 6 20 ／ 25

6th PERIODIC SAFETY UPDATE REPORT for Evoltra® / Clolar® (clofarabine) 1 mg/ml concentrate for solution for infusion

5.3.6.7 PSUR 7 20 ／ 25

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2.1 - 37

巻／巻数 (clofarabine) 1 mg/ml concentrate for solution for infusion

5.3.6.8 PSUR 8 21 ／ 25

8th PERIODIC SAFETY UPDATE REPORT for Evoltra® / Clolar® (clofarabine) 1 mg/ml concentrate for solutioli for infusion

5.3.7 患者データ一覧表及び症例記録 22 -24 ／ 25

5.3.7.1 用量設定の根拠となった主要な試験及び主要な有効性の検証試験の

症例一覧

22 ／ 25

5.3.7.1.1 ID99-383 22 ／ 25

Listing of Individual Patient Data Summary – ID99-383

5.3.7.1.2 CLO-212 22 ／ 25

Listing of Individual Patient Data Summary – CLO-212

5.3.7.1.3 CLO-222 22 ／ 25

Listing of Individual Patient Data Summary – CLO-222

5.3.7.1.4 BIOV-111 22 ／ 25

Listing of Individual Patient Data Summary – BIOV-111

5.3.7.1.5 CLO05908 22 ／ 25

Listing of Individual Patient Data Summary – CLO05908

5.3.7.1.6 CLOAML10508 22 ／ 25

Listing of Individual Patient Data Summary – CLOAML10508

5.3.7.2 実施された臨床試験において副作用が観察された症例の一覧表 22 ／ 25

5.3.7.2.1 ID99-383 22 ／ 25

Listing of Adverse Reactions – ID99-383

5.3.7.2.2 CLO-212 22 ／ 25

Listing of Adverse Reactions – CLO-212

5.3.7.2.3 CLO-222 22 ／ 25

Listing of Adverse Reactions – CLO-222

5.3.7.2.4 BIOV-111 22 ／ 25

Listing of Adverse Reactions – BIOV-111

5.3.7.2.5 CLO05908 22 ／ 25

Listing of Adverse Reactions – CLO05908

5.3.7.2.6 CLOAML10508 22 ／ 25

Listing of Adverse Reactions – CLOAML10508

5.3.7.3 実施された臨床試験において重篤な有害事象が観察された症例の一

覧表

22 ／ 25

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2.1 - 38

巻／巻数 Listing of Serious Adverse Events – ID99-383

5.3.7.3.2 CLO-212 22 ／ 25

Listing of Serious Adverse Events - CLO-212

5.3.7.3.3 CLO-222 22 ／ 25

Listing of Serious Adverse Events – CLO-222

5.3.7.3.4 BIOV-111 22 ／ 25

Listing of Serious Adverse Events – BIOV-111

5.3.7.3.5 CLO05908 22 ／ 25

Listing of Serious Adverse Events – CLO05908

5.3.7.3.6 CLOAML10508 22 ／ 25

Listing of Serious Adverse Events – CLOAML10508

5.3.7.4 実施された臨床試験において臨床検査異常変動が観察された症例の

一覧表

22 - 24 ／ 25

5.3.7.4.1 ID99-383 22 ／ 25

Listing of Clinical Laboratory Abnormalities – ID99-383

5.3.7.4.2 CLO-212 23 ／ 25

Listing of Clinical Laboratory Abnormalities - CLO-212

5.3.7.4.3 CLO-222 24 ／ 25

Listing of Clinical Laboratory Abnormalities – CLO-222

5.3.7.4.4 BIOV-111 24 ／ 25

Listing of Clinical Laboratory Abnormalities – BIOV-111

5.3.7.4.5 CLO05908 24 ／ 25

Listing of Clinical Laboratory Abnormalities – CLO05908

5.3.7.4.6 CLOAML10508 24 ／ 25

Listing of Clinical Laboratory Abnormalities – CLOAML10508

5.4 参考文献

5.4.1 Xie KC, Plunkett W. Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine. Cancer Res. 1996; 56 (13):3030-7.

25 ／ 25 5.4.2 松尾恵太郎、新しい診断と治療の ABC 急性白血病、第 1 章概念・分類と疫学、疫学．大野竜三編．最新医学社． 2006:20-2. 25 ／ 25 5.4.3 木崎昌弘、カラーテキスト血液病学、第 9 章造血器腫瘍と関連疾患 B. 急性白血病．押味和男編著中央医学社．2007:312-329. 25 ／ 25