第2 部 CTD の概要（サマリー）

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）

ジェンザイム・ジャパン株式会社

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


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



2.7.2.4 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



2.7.3.4 推奨用量・用法に関する臨床情報の解析 1 ／ 1


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


2.1 - 4


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

SOP: XXXXXXXX, Title: WATER DETERMINATION 1 ／ 4


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

3.2.S.3.2 不純物 1 ／ 4


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

2 ／ 4


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


High Performance Liquid Chromatography: 07TRSA103 (Addendum 01)

2 ／ 4




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


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


2 ／ 4

Protocol : Determination of the XXXXXXXX XXXX

for Clofarabine Degradation Impurities at the Limit of

Quantification (LOQ) Level using High Performance

2 ／ 4


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


Quantification (LOQ) Level Using High Performance

Liquid Chromatography: 07TRSA103 (Addendum 01)

2 ／ 4

Addendum to Determination of the XXXXXXX XXXX




2 ／ 4

Validation Protocol of Clofarabine Process Impurities for

Test Methods XXXXXXX and XXXXXXX: 08TRSA010

2 ／ 4

Method Validation of Clofarabine Process Impurities for


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



2.1 - 9

巻／巻数







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 Primary Reference Standard Qualification: 2 ／ 4


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

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


FORM: XXXXX

2 ／ 4


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


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)

3 ／ 4


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

3 ／ 4


2.1 - 13

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


3 ／ 4

Determination of XXXXXXXX XXXXXXX for Clofarabine


High Performance Liquid Chromatography: 07TRSA103

3 ／ 4




3 ／ 4




3 ／ 4

Validation Protocol of Clofarabine Process Impurities for Test Methods


3 ／ 4

Method Validation of Clofarabine Process Impurities for Test Methods


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


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


3 ／ 4

Protocol : Determination of the XXXXXXXX XXXX


3 ／ 4


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




3 ／ 4

Addendum to Determination of the XXXXXXX XXXX




3 ／ 4

Validation Protocol of Clofarabine Process Impurities for


3 ／ 4

Method Validation of Clofarabine Process Impurities for


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

Qualification of the Analytical Method XXXXXXX for UV 3 ／ 4


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

3.2.P.7 容器及び施栓系 4 ／ 4


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

XXXX XXX clear 4 ／ 4


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

4 ／ 4


2.1 - 18


2.1 - 19


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


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


TREATMENT WITH CLOFARABINE AND 5-FU

4.2.1.1.12 ILEX 4 1 ／ 7


TREATMENT WITH CLOFARABINE AND IRINOTECAN

4.2.1.1.13 ILEX 19 1 ／ 7


TREATMENT WITH CLOFARABINE AND IRINOTECAN

4.2.1.1.14 ILEX 25 1 ／ 7


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


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

Tissue Distribution in Male Fischer 344 Rats Following a Five Day


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

In Vitro Cytochrome P450 Profile for Clofarabine Using Fluorescent Probe


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

4.2.3.3 遺伝毒性試験 5 ／ 7


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

A PRIMARY SKIN IRRITATION STUDY IN RABBITS WITH


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.

7 ／ 7


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.

7 ／ 7


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.

7 ／ 7


2.1 - 28

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.

7 ／ 7


2.1 - 29

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 2-chloro-2‘-arabino-fluoro-2‘-deoxyadenosine, 2-chloro-2‘-

deoxyadenosine and related analogues. J Pharm Biomed Anal 1995b; 13:

711-14.

7 ／ 7


2.1 - 30

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.

7 ／ 7


2.1 - 31

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.

7 ／ 7


2.1 - 32


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


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


1 ／ 25


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


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

5.3.3.5.2 Pooled Population Pharmacokinetic Model of Clofarabine 2 ／ 25


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


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



Addendum to CLO-222 Clinical Study Report


5.3.5.2.5 BIOV-111 4 ／ 25

CLINICAL STUDY REPORT


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



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

A Phase I and Pharmacokinetic Study of Clofarabine in Adult Patients with


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



2.1 - 37

巻／巻数

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

5.3.6.8 PSUR 8 21 ／ 25


(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

5.3.7.3.1 ID99-383 22 ／ 25


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


2.1 - 39

巻／巻数

5.4.4 厚生労働省平成 20年度患者調査、閲覧第 4表、推計患者数、性 ×

傷病小分類別［白血病のみ］、政府統計の総合窓口

25 ／ 25

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第2 部 CTD の概要（サマリー）

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