DAIICHI-SANKYO Briefing Information, QUIZARTINIB Tablets, for the May
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Quizartinib NDA 212166 FDA Advisory Committee Briefing Document Daiichi Sankyo April 9, 2019 TABLE OF CONTENTS 1 EXECUTIVE SUMMARY ...................................................................................................11 1.1 Indication ........................................................................................................................11 1.2 Disease State, Current Treatment Options, and Unmet Medical Need ..........................11 1.3 Clinical Pharmacology of Quizartinib ............................................................................13 1.4 Quizartinib Clinical Development Program in AML .....................................................14 1.4.1 Companion Diagnostic for FLT3-ITD Mutation Testing and FLT3-ITD Allelic Ratio ....................................................................................................................14 1.4.2 Response Criteria Definitions .............................................................................15 1.5 QuANTUM-R Pivotal Phase 3 Study .............................................................................15 1.5.1 Design .................................................................................................................15 1.5.2 Study Endpoints ..................................................................................................17 1.5.3 Efficacy ...............................................................................................................17 1.5.3.1 Primary Endpoint ..............................................................................17 1.5.3.2 Prespecified Sensitivity Analyses .....................................................18 1.5.3.3 Post Hoc Sensitivity Analyses ..........................................................19 1.5.3.4 Event-Free Survival ..........................................................................20 1.5.3.5 Additional Efficacy Endpoints ..........................................................21 1.5.4 Efficacy Conclusions ..........................................................................................22 1.5.5 Safety in QuANTUM-R......................................................................................23 1.5.5.1 Safety Experience in Cycle 1: Days 1 to 28 ......................................24 1.5.5.2 Safety Experience Over Two Cycles of Quzartinib or Salvage Chemotherapy ...................................................................................24 1.5.5.3 Overall Safety Experience ................................................................24 1.5.5.4 QT Prolongation ................................................................................25 1.5.5.5 Infection, Bleeding, and Hepatic Events in QuANTUM-R ..............27 1.6 Integrated Safety Summary ............................................................................................27 1.6.1 Safety Conclusions .............................................................................................28 1.7 Proposed Risk Mitigation Strategy .................................................................................28 1.8 Benefit/Risk Conclusions ...............................................................................................28 2 BACKGROUND AND SCIENTIFIC RATIONALE .........................................................30 2.1 Background of Acute Myeloid Leukemia ......................................................................30 2.2 Role of FLT3 in AML ....................................................................................................30 2.3 Treatment of FLT3-ITD AML ........................................................................................31 2.4 FLT3 Inhibitors ...............................................................................................................32 3 PRODUCT OVERVIEW ......................................................................................................34 3.1 Structural Formula ..........................................................................................................34 3.2 Mechanism of Action......................................................................................................34 3.3 Proposed Indication ........................................................................................................38 3.4 Dosage and Administration ............................................................................................38 4 NONCLINICAL OVERVIEW .............................................................................................39 5 CLINICAL PHARMACOLOGY .........................................................................................42 5.1 Completed Studies ..........................................................................................................42 5.2 Summary of Clinical Pharmacology ...............................................................................42 5.2.1 Absorption, Distribution, Metabolism, and Elimination ....................................42 5.2.1.1 Absorption .........................................................................................42 Page 2 of 130 Quizartinib NDA 212166 FDA Advisory Committee Briefing Document Daiichi Sankyo April 9, 2019 5.2.1.2 Distribution .......................................................................................43 5.2.1.3 Metabolism........................................................................................43 5.2.1.4 Elimination ........................................................................................43 5.2.2 Intrinsic Factors ..................................................................................................43 5.2.3 Effect of Concomitant Medications on the Pharmacokinetics of Quizartinib ....44 5.2.3.1 Inhibition of Cytochrome P450 3A (CYP3A) ..................................44 5.2.3.2 Coadministration With Inducers of CYP3A .....................................45 5.2.4 Exposure Response .............................................................................................45 5.2.4.1 Exposure-QTc Analysis ....................................................................45 5.2.4.2 Exposure Response ...........................................................................46 5.2.4.3 Exploratory E-R Analyses of Additional Pharmacodynamic Endpoints ..........................................................................................47 6 CLINICAL DEVELOPMENT PROGRAM .......................................................................48 6.1 Overview of the Quizartinib Clinical Development Program ........................................48 6.2 Development of Quizartinib in Relapsed or Refractory AML .......................................48 6.3 Companion Diagnostic for FLT3-ITD Mutation Testing ...............................................49 6.4 FLT3-ITD Allelic Ratio ..................................................................................................49 7 SUMMARY OF PHASE 1 CLINICAL EXPERIENCE ....................................................50 7.1 Study CP0001: Open-Label, Sequential Dose Escalation, First-in-Human Phase 1 Study50 7.1.1 Design, Objectives, and Study Treatment ..........................................................50 7.1.2 Patient Baseline Characteristics ..........................................................................50 7.1.3 Efficacy ...............................................................................................................50 7.1.4 Safety ..................................................................................................................51 8 SUMMARY OF PHASE 2 CLINICAL EXPERIENCE ....................................................52 8.1 Study AC220-002: Monotherapy Efficacy Study in Patients With AML With and Without FLT3-ITD .........................................................................................................52 8.1.1 Study Design and Objectives ..............................................................................52 8.1.2 Efficacy ...............................................................................................................54 8.1.3 Safety ..................................................................................................................54 8.1.3.1 QTcF Based on Central Laboratory Reading of ECGs .....................55 8.1.3.2 Cardiac Treatment-Emergent Adverse Events ..................................56 8.2 Study 2689-CL-2004: Randomized, Open-Label Study of the Safety and Efficacy of 2 Doses of Quizartinib in Patients With FLT3-ITD-Positive Relapsed or Refractory AML57 8.2.1 Design and Objectives ........................................................................................57 8.2.2 Patient Characteristics.........................................................................................57 8.2.3 Efficacy ...............................................................................................................58 8.2.4 Safety ..................................................................................................................58 8.2.4.1 QTcF Based on Central Laboratory Reading of ECGs .....................59 8.2.4.2 Cardiac Treatment-Emergent Adverse Events ..................................60 8.2.4.3 Exposure Response for Safety (QTc) ................................................60 8.3 Conclusions .....................................................................................................................60